Pharmacology Book

Ministry of Healthcare of Ukraine
National Pirogov Memorial Medical University
Germanyuk T.A., Bobruk V.P., Lysogora V.V.
GENERAL
PHARMACOLOGY
and
PHARMACOLOGY
of the drugs affecting
mediatory processes,
vegetative and central
nervous systems
TUTORIAL
2016
UDC 615.2
LBC 52.81
G 39
Recommended by: State Institution "Central methodical cabinet of higher medical
education Ministry of Healthcare of Ukraine" as tutorial for English-speaking
students of pharmaceutical faculties of higher educational institutions of the
Ministry of Healthcare of Ukraine. Approved, Protocol of Comission meeting from
16.12.2016 №4)
Reviewers:
Voloshchuk N.I. – doctor of medical sciences, Professor of pharmacology
department of National Pirogov Memorial Medical University, Vinnytsya
Shtrugol S.Y. – doctor of medical sciences, Professor of pharmacology and
toxicology department of National University of Pharmacy
Piniazhko O.R. – doctor of medical sciences, Professor of pharmacology
department of Lviv National Medical University
Kryvoviaz О.V. – PhD, associate Professor, head of Pharmacy department of
National Pirogov Memorial Medical University, Vinnytsya
Dudikova L.V. – PhD, associate Professor, head of department of Foreign
languages of National Pirogov Memorial Medical University, Vinnytsya
G 39 General Pharmacology and Pharmacology of the drugs affecting

mediatory processes, vegetative and central nervous systems tutorial /
Germanyuk T.A., Bobruk V.P., Lysogora V.V. – Vinnytsya: Nilan-LTD,
2016 – 334P.
ISBN 978-966-924-096-5
The tutorial contains data concerning general conception of
pharmacokinetics, pharmacodynamics, data about drugs affecting mediatory
processes, vegetative nervous system, central nervous system, their
classifications, lists of the drugs (International Nonproprietary Name,
Proprietary commercial / brand / trade / generic names), medicinal forms, routs
of administration and dose of the drugs, mechanisms of their action,
pharmacological effects, including adverse effects and the ways to reduce them,
indications, contraindications, the principles of rational combined use of the
drugs, pharmacological drug safety and custody.
The tutorial is designed for students in higher pharmaceutical education
institutions of III-IV level of accreditation of the specialty “Pharmacy” and
“Clinical pharmacy”.
UDC 615.2
LBC 52.81
ISBN 978-966-924-096-5 © Germanyuk T.A., Bobruk V.P.,
Lysogora V.V., 2016
Contents Contents 3
Foreword 4
List of abbreviations 6
Introduction 9
UNIT 1: General pharmacology 13-36
Chapter 1. Pharmacokinetics 13
Chapter 2. Pharmacodynamics 25
UNIT 2: Drugs affecting mediatory processes 37-90
Chapter 3. Intermediants: 37
adenosinergic 37
dopaminergic 43
serotoninergic 53
histaminergic 65
eicosanoids: prostaglandins, leucotriens, thromboxans 71
UNIT 3: Drugs affecting the Autonomic Nervous System 91-157
Chapter 4. Cholinergic agonists 91
Chapter 5. Cholinergic antagonists 99
Chapter 6. Adrenergic agonists 109
Chapter 7. Adrenergic antagonists 128
UNIT 4: Drugs affecting the Afferent innervation 158-199
Chapter 8. Local anesthetics 158
Chapter 9. Sorbents, covering drugs, astringents 171
Chapter 10 Irritants 186
UNIT 5: Drugs affecting the Central Nervous System 200-316
Chapter 11. General anesthetics 200
Chapter 12. Opioid analgesics 213
Chapter 13. Non-opioid analgesics 226
Chapter 14. Antipsychotics (Neuroleptics) 245
Chapter 15. Anxiolytics (Tranquilizers) 259
Chapter 16. Hypnotics 265
Chapter 17. Antiepileptic and Antiparkinsonian drugs 274
Chapter 18. Sedative drugs 287
Chapter 19. Antidepressants 289
Chapter 20. Psychomotor stimulants 300
Chapter 21. Analeptics 304
Chapter 22. Nootropics (Cognitive Enhancers) 308
Chapter 23. Adaptogens, Actoprotectors 313
REFERENCES 317
4 | Foreword
Foreword
The tutorial "Pharmacology of the drugs affecting vegetative and central

nervous system" includes the foundations of modern knowledge of the
pharmacology of drugs that act on the peripheral and central nervous system
(CNS) and is intended for students of a pharmacy department in specialty
"Pharmacy" and "Clinical pharmacy".
Necessity to write a tutorial is caused by the need to provide the main
aspects of current knowledge in pharmacology of drugs acting on the autonomic
and central nervous system in accordance with the requirements of the credit-
module system. According to the authors, the tutorial will be useful, given the fact
of the necessity to intensify the efforts towards the students' independent work for
the obtaining of knowledge in pharmacology.
The tutorial presents the key components of the pharmacokinetics and
pharmacodynamics of the drugs with examples for better learning. In accordance
with the tasks of pharmacology in this tutorial there are classifications of the drugs
that affect the autonomic and central nervous system, according to the chemical
structure, mechanisms of action, pharmacological effects; list of drugs (their INN
and trade names, medicinal forms and routes of administration); mechanisms of
action, pharmacological effects, including adverse effects, ways of reducing of the
possible negative impact of a drug on the organism, indications and
contraindications for use of the drugs, application features, pharmacological safety
and pharmacological custody of the drugs, use of antidotes and symptomatic drugs
in case of both, an overdose of drugs and the emergence of dangerous toxic effects.
The presented chapters of a tutorial show a close relationship of
pharmacology with biology, normal and abnormal physiology, physics, normal and
abnormal anatomy, biological chemistry, physical chemistry, pharmaceutical
chemistry, etc. That is what allows correlating pharmacology with related medical
sciences, to rethink the actions and uses of the drugs, to emphasize the applications
of pharmacokinetics and pharmacodynamics to therapeutics to create the book that
will be useful for the students of pharmacology, for the teachers of pharmacology
and for the physicians.
The tutorial has a list of references, which were used by the authors and may
be used by the students, teachers and physicians for improving personal knowledge
in pharmacology.
The tutorial is written in accordance with the Program of pharmacology for
the students of pharmaceutical faculty of higher educational institutions of III-IV
accreditation levels for specialties 7.12020101 – "Pharmacy" and 7.12020102 –
"Clinical Pharmacy" according to the educational qualification characteristics and
educational and professional training program approved by the order of the
Ministry of Healthcare of Ukraine dated 07.12.09 № 931 (period of study in this
field – 5 years).
In today's pharmaceutical market there are so many drugs, which require a
high level of knowledge of pharmacists and clinical pharmacists. The volume of
Foreword | 5
information about the mechanisms of drug action, their pharmacological effects,

and the possibility of clinical use is growing rapidly. The position mentioned above
leads to the necessity of teaching pharmacology to a much greater extent than it is
provided in curriculum. Thence, the tutorial has been prepared based on the State
Formulary of Ukraine, and the the British National Formulary of drugs, the
Russian Register of medicines, Compendium and the current literature on
pharmacology and pharmacotherapy.
The authors of the tutorial are the teachers of the pharmacy department of
Vinnitsa National Pirogov Memorial Medical University, Faculty of Pharmacy,
with experience of teaching of pharmacology both in terms of previous training
programs, and in terms of credit-modular system.
The authors are grateful to the reviewers who have put great efforts to
improve the tutorial and gratefully accept all comments and suggestions from
readers for further improvement of the tutorial.
6 | List of abbreviations
List of abbreviations
AA - arachidonic acid
AANAT - arylalkylamine N-acetyltransferase
ACE - angiotensin-converted-enzyme
ACEI - angiotensin-converted-enzyme
inhibitor Ach - acetylcholine
AchE - acetylcholine esterase
ACTH - adreno-cortico-tropic hormone
ADME - absorption, distribution, metabolism, excretion of the
drugs ARs - adrenergic receptors
API - active pharmaceutical ingredient
ADP - adenosine diphosphate
ALX receptor(s) - lipoxin eceptor(s)
AT receptor - angiotensin receptor
ATP - adenosine triphosphate
AV - block - atrio-ventricular blockage
AV- node - atrio-ventricular node
AVP - additional vasodilating propertie(s)
AUC - area under curve
Ахе - acethylcholinesterase
BAS - biologically active substance(s)
BBB - blood brain barrier
BCSFB - blood-cerebrospinal fluid barrier
Ca+2 - calcium ion(s)
Cel. - constant of elimination
cAMP - cyclic adenosine monophosphate
cGMP - cyclic guanosinemonophosphate
Cl - total clearance
CNS - central nervous system
CO - carbon monoxide
COMT - catecol-orto-methyl-transferase
COX - cyclooxygenase
CysLT receptor(s) - cysteinyl leukotriene receptor(s)
D - dopamine
DAG - diacylglycerol
DNA - deoxyribonucleic acid
DDC - decarboxylase
DGLA - dihomo-γ-linolenic acid
EET - Epoxy-eicosa-trienoic acid
e.g. - for example
Ep - epinephrine
EPA - icosapentaenoic acid
E2 (PGE2) - prostaglandin Е2
List of abbreviations | 7
F2α (PGF2α) - prostaglandin F2α

FDA - Food and Drug
Administration FFA - free fatty acid
fMLP - Formyl-Methionyl-Leucyl-Phenylalanine
GIT - gastrointestinal tract
GPCR - G-protein-coupled receptor(s)
H2S - hydrogen sulphide
h/chl. - hydrochloride
h/tr. - hydrotartrat
I2 (PGI2) - prostacyclin
i.e. - that is
IHD - ischemic heart disease
i/m - intramuscularly
INN - international nonproprietary name
IP3 - inositol 1,4,5-trisphosphate
ISA - intrinsic sympathomimetic
activity i/v - intravenous
Кel. - constant of elimination
LTs - leucotriens
LXA4- lipoxin A4
MAO - monoaminoxydase
MAOI - MAO inhibitor
MIC - minimum inhibitory concentration
MF - medicinal form
MP - medicinal preparation
NE - norepinephrine
NO - nitric oxide
OTC - over-the-counter
Р receptor(s) - purine receptor(s)
PAE - “postantibiotic” effect
PAF - platelet-activating factor
PB - placental barrier
PGs - prostaglandins
PI - phosphatidylinositol
PLA2 - phospholipase А2
PLC - phospholipase C
RNA - ribonucleic acid
s/c - subcutaneously
Se - serotonine
SNRI(s) - serotonine-norepinephrine reuptake inhibitor(s)
SSRI(s) - selective serotonine reuptake inhibitor(s)
SVT - supraventricular tachycardia
TCA(s) - tricyclic antidepressant(s)
TG - triglyceride(s)
8 | List of abbreviations
TI - therapeutic index
TPH - tryptophan hydroxylase
Tx - thromboxane
TxA2 - thromboxane A2
T1/2 - half-life
V - volume distribution
USAN - United States Adopted Name(s)
WHO - World Health Organization
WPW syndrome - Wolff-Parkinson-White syndrome
5-HIAA - 5-hydroxyindoleacetic acid
5-HT - 5-hydroxytryptamine
5-LOX - 5-lipoxygenase
Introduction | 9
Introduction
Pharmacology is the study of the interactions that occur between medical
devices, biologically active substances with a living organism. Pharmacology is
concerned with the study of medical devices, which are used for treatment,
prevention and diagnostics of diseases and pathological conditions. From Greek
“pharmacon” – there is drug and “logos” – there is a science. Pharmacology is
the branch of medicine which is connected with other disciplines such as biology,
chemistry, normal and pathological anatomy, normal and pathological physiology,
histology and pharmaceutical sciences such as pharmaceutical chemistry and toxic
chemistry, pharmacognosy and drug technology.
To the sciences about drugs belongs not only pharmacology but also
pharmacy. And if pharmacology is a science that deals with the effect and usage of
medicines, so pharmacy is a science that deals with the preparation and dispensing
of drugs.
An active pharmaceutical ingredient (medical substance (MS) or active
substance) (API) – is any substance or mix of substances that is used in
manufacture of drugs and during its usage exerts pharmacological activity. Such
substances have pharmacological or other direct effect on the human body; in the
composition of the prepared forms of drugs which are used for cure, diagnosis and
prevention of diseases, for the change of condition, structures or physiological
functions of the organism, for care, treatment and facilitation of symptoms. (The
order of The Ministry of Health of Ukraine № 723, completed in accordance with
The Ministry of Health of Ukraine № 427 (z0923-13) dated 24.05.2013).
Pharmaceutical drug – is any substance or combination of substances (one
or more API and excipients) that has properties and is intended for use in the
treatment or prevention of diseases or it’s any substance or combination of
substances (one or more API and excipients) that can be prescribed for the
pregnancy prevention, restoration, correction or change of physiological functions
in humans by providing pharmacological, immunological or metabolic actions, or
for diagnosis.
Medicinal Form (MF) – is a combination of the form in which a drug is
submitted by the manufacturer (release form), and also the forms in which a drug is
prescribed for usage including physical form (the form of usage).
Medicinal preparation (MP) – is a drug that is made in the appropriate
dosage (medicinal) form. Medical preparations can be simple which are made from
medical raw material (usually from plants, but also can be of mineral and animal
origin) using a simple processing (drying or grinding), complex or galenicals,
which are made by using more complex processing of plant raw materials with
extraction (by alcohol, ether, water) of biologically active components and their
partial exemption from impurities (ballast substances). These are tinctures and
extracts. However galenicals contain many impurities (proteins, coloring
substances, mucuses, etc.) which reduce the effect of the preparation, may cause a
pharmacological effect which differs from that of the purified substance (e.g., there
10 | Introduction
is no equality between the pharmacological effect of opium galenic preparations

and morphine, between the extract of uterine horn and ergometrine, between the
ascorbic acid and rosehip extract, etc.) and do not allow its parenteral use.
Neogalenicals are made by the pharmaceutical industry. They are more purified of
ballast substances, have a longer expiration date, less of side effects and are
suitable for parenteral use. (e.g., atropine, platyphylline, morphine, ephedrine,
digoxin, strophanthin etc.). Each MP is registered in the state register of the
pharmaceutical drugs of the country.
Some drugs are in an inactive form and in order to convert them into an
active form, they should be metabolized in the human body and should form
metabolites that have pharmacological activity. These drugs are called prodrugs.
Substances with medicinal properties can be synthesized within the human
body (e.g., hormones) or may be xenogenic to the human body, the so-called
xenobiotics (Greek xenos – “alien “).
Some drugs are administered as racemic mixtures of stereoisomers. The
stereoisomers can exhibit different pharmacodynamic as well as pharmacokinetic
properties. More than half of the drugs exist as enantiomeric pairs: R (+)
enantiomeric, S (-) enantiomeric and the racemic mixture RS (+ / -).
Drugs have three main names:
the chemical name, which reflects the chemical structure of drugs and is rarely
used in medical practice, but often – in the annotations to the drugs and in the
reference books. For example, 2-acetoxy-benzoic acid (acid acetylsalicylic).
international nonproprietary name (INN) of drugs. This name of drugs is
offered by the WHO (World Health Organization) and is adapted for use
worldwide in the academic and scientific literature for easier identification by
experts and for prevention of errors in determining generic / trade names of drugs.
For example, acid acetylsalicylic (2-acetoxy-benzoic acid).
commercial / trade name (brand names ) is given by pharmaceutical companies /
manufacturers of drugs and is a commercial property, protected by patents and
indicated by a pictogram – an English letter "R" inside a circle. For example,
Aspirin ® (2 -acetoxy-benzoic acid, acid acetylsalicylic). Trade name is used by
the company that produces these drugs for marketing purposes, to advance it in the
market and to compete with other similar drugs. After the expiration of the patent
the manufacturer can sell the right to produce drugs under the INN. Such drugs are
called generics (branded equivalent). Generics are usually cheaper than original
drugs because their price does not include money spent on development,
preclinical and clinical drug testing. For example, Trombo ASS (2-acetoxy-
benzoic acid, acid acetylsalicylic, Aspirin).
Equal drug substances may contain the same doses of a chemical substance
in one dosage form and have different trade names (synonyms). Thus, the
pharmacist can make a so-called generic substitution of drugs, focusing on its INN,
in the absence of drugs recommended by your doctor or the drugs required by the
patient in the drugstore. For example, (2-acetoxy-benzoic acid, acid acetylsalicylic,
Aspirin, Trombo ASS).
Introduction | 11
Peculiarities of marking of ready dosage forms

The symbol «®» (from English "Registered trademark" – the registered
mark) is a marking which is written down on the package near a certain brand
name and means the registration of the mark as a trademark for goods. In the
registration certificate and other registration documents the symbol «®» is written
down next to the trade name of medicinal preparation.
Tablets with a modified release are covered or uncovered tablets which
contain special excipients or substances received by a special technology that allow
to program the speed or location of the release of the medical substance (the
modified-release tablets – MR). The name is used to mark the tablets with a
controlled release, sustained-release (SR) tablets, and tablets with a gradual
release, prolonged/extended release (ER). The name is not used to name the tablets
that are indicated as the depot tablets, tablets that are implanted, retard-tablets,
rapid-retard tablets.
There are Drug Delivery Systems: Osmotic Release Oral System (OROS) –
there is the system based on the principle of osmotic pump, with which there is a
constant controlled release of a drug in a unit time; Transdermal System (TS) of
drug delivery in the form of patches; Gastrointestinal Therapeutic System (GITS),
which provide release of drug substances from the medicinal forms in a neutral,
acidic or alkaline environment of gastrointestinal tract GIT; Orally disintegrating
tablet (ODT), dry powder inhalers (DPI), metered-dose inhalers (MDI), etc. The
main merit of therapeutic systems is improvement in bioavailability as well as
reduced adverse effects and limitation of high initial drug concentrations in plasma
and opportunity to change the mode of taking drugs, dosing regimen on a
convenient for the patients.
Retard tablets are tablets with a prolonged (periodic) release of medical
substance from the stock. Usually they are in the shape of microgranules from a
medical substance, surrounded by a biopolymer matrix (base), a base or
microgranules are dissolve in layers releasing another portion of medical
substance.
Rapid tablets contain a mixture of microgranules with an immediate release
of medical substance.
Rapid retard tablets are tablets with a biphasic release that contain a
mixture of microgranules with a rapid and prolonged release of the medical
substance.
Tablets UNO – a recommended average dose for adults and children over
12 years is 1 tablet every 24 hours.
The tablets durules provide a gradual release of the active ingredient (iron
ions) during a long time. The plastic matrix of the tablets Sorbifer Durules is
completely inert in the digestive juice, but is completely dissolved under the
influence of the intestinal peristalsis, when the active ingredient is completely
released.
12 | Introduction
There are international standards (International rules-standards), which

determine the process of production of drugs: GMP – good manufactory practice;
GLP – good laboratory practice – appropriate preclinical drug testing: on animals,
test-systems (ex vivo), on cells, etc.; GCP – good clinical practice – appropriate
clinical drug testing: on healthy volunteers, on patients; GDP – good distribution
practice – appropriate practice of distribution of drugs; GPP – good pharmacy
practice.
Despite the complexity of the creation and production of new drugs and their
generics, new dosage forms, the study and specification of the action mechanisms
in accordance with new knowledge in related sciences, the discovery of new
pharmacological effects of the known drugs, determination of pharmacological
safety, pharmacological custody and the combined use of medicine, pharmacology
and pharmacy are very fast-developing sciences that require a constant monitoring
and addition in teaching in the learning process.
Pharmacology includes Pharmacokinetics and Pharmacodynamics.
In order to understand and control drug action in the human body, one needs
to know how a drug reaches the site(s) of drug action and when this will happen.
Besides, understanding biochemical and physiological effects of the drugs and
their mechanisms of action can provide the basic for the rational therapeutic use of
the drugs and development of new and better therapeutic agents. More over, the
adverse effects of the drugs and their toxicity can be expected by understanding a
drug’s mechanism(s) of action, its pharmacokinetics, and its interactions with other
drugs. Thereby, both the pharmacodynamic properties of a drug and its
pharmacokinetics promote the safe and successful therapy. It is necessary to
remember that the effects of many drugs, both curative and maleficent, may differ
widely from patient to patient due to genetic differences that alter pharmacokinetic
and pharmacodynamic of a given drug.
Chapter 1. Pharmacokinetics | 13
UNIT 1. GENERAL PHARMACOLOGY

Chapter 1. Pharmacokinetics
Pharmacokinetics studies the routes of administration, the processes of

absorption, distribution and metabolism (biotransformation), routes of excretion of
drugs (often referred to collectively as ADME). Pharmacokinetics studies what the
body does to the drugs. Realizing and applying pharmacokinetic principles can
increase the probability of therapeutic success and reduce the emergence of
adverse effects of the drug.
There are enteral and parenteral routes of drug administration. There
are several reasons for different routes of administration of the drugs: convenience,
good absorption, to avoid destruction by some enzymes, reaching of possibility to
increase the drug concentration in the site of action and to decrease the drug
concentration in the other places, prolongation of therapeutic effects, minimization
of adverse effects, etc. But, one of reasons is to avoid the first-pass effect (in case
of sublingual, transdermal, rectal routs of drug administration). Although the drugs
that were administrated by inhalation bypass the hepatic first-pass effect, they may
metabolize or excrete in the lung (the lung first-pass effect). More over the lung
first-pass effect may be important for parenteral routes of drug administration.
The parenteral routes (by-passing gastrointestinal tract) of drug
administration include: transdermal, intradermal, subcutaneous, intramuscular,
intravenous, intra-arterial, intracardiac, intraperitoneal, intrapleural, intratracheal,
in the joints, intrasternal, under the brain membranes (intrathecal), intranasal,
inhalation, instillation, and vaginal routes.
The enteral routes (through gastrointestinal tract) of drug administration
include: sublingual, transbuccal, per oral, per rectum, intraduodenal.
The route of drug administration is determined first of all by the properties
of the drugs (medicinal form, mechanism of action, water or lipid solubility,
ionization, features of metabolism, stability in acidic or alkaline environment, the
type of absorption; the rate of absorption of the drug from the mucous membranes
and skin) and by the therapeutic objectives (the diagnosis; the desirability of a
rapid onset of action or need for long-term action; restriction to a local site or need
for general action; the presence of concomitant diseases, especially liver, kidney,
heart insufficiency, blood diseases, GIT diseases; vomiting; violation of
swallowing; loss of consciousness; psychical diseases; the general condition of the
patient; age of the patient; target organ for the drug.
The parenteral routes (by-passing GIT) of the drug administration
introduce drugs directly across biological body’s barrier defenses into the systemic
circulation or other vascular tissue. Parenteral administration is used for the drugs
14 | Unit 1. General Pharmacology
that are poorly absorbed from GIT, and for substances that are unstable in GIT, and
for substances that irritate mucosa of GIT, and for substances that have not enteral
MFs, or in patients that can’t take the drugs through GIT. Parenteral administration
is also used for treatment under circumstances that require a rapid onset of action.
Parenteral routes have the highest bioavailability and aren’t subject to first-pass
metabolism (rapid metabolism in the liver) or harsh GIT environment
(hydrochloric acid and digestive enzymes). Parenteral administration provides the
highest possible control over the actual dose of drug delivered to the body.
However, these routes are irreversible and may cause pain, fear and infections. The
different parenteral routes of drug administration have advantages and limitations.
Transdermal route of drug administration is appropriated to drugs that are
well absorbed through intact skin. They are used in the form of ointments, plasters.
For better penetration of such drugs they may be used in combination with drugs
that increase their absorption. Part of the drugs can be absorbed and enter the
bloodstream, and may cause unwanted effects on the entire body.
Intradermal route of drug administration is used rarely, only in case of
diagnostic tests for allergy etc.
Subcutaneous route of drug administration is like intramuscular injection,
but is somewhat slower than intramuscular route.
Intramuscular route of drug administration provides the drug entrance to
the systemic circulation in 10-15 minutes. The oil solutions and suspensions can be
introduced intramuscularly. Substances that can cause tissue necrosis are not
injected intramuscularly, subcutaneously or intradermally.
Intravenous route of drug administration is the most common parenteral
route. This route is used for the drugs that aren’t absorbed orally and under
circumstances that require a rapid onset of action, or in the patients’ conditions that
can’t allow introducing the drugs orally. Intravenous route of administration may
cause thrombosis, thrombophlebitis and thromboembolism.
Sometimes the intra-arterial route of drug administration is used to the
artery that supplies the target organ. This route can be used not only for the
treatment but also for the X-ray diagnostics.
The intracardiac route of drug administration is used very rarely.
In the cavity of the body (intraperitoneal, intrapleural, intratracheal, in the
joints routes of drug administration) the drugs are injected in case of treatment the
diseases, only at special indications.
Intrasternal route of drug administration is sometimes applied to children
and old people when a quick help is required and it is technically impossible to
enter the drug intravenously.
Under the brain membranes – intratecal route of drug administration is
used in case of the infection diseases and for local anesthesia.
Inhalation provides the rapid delivery of the drugs across the large surface
area of the mucous membranes of the respiratory tract and pulmonary epithelium,
producing effects almost as rapidly as intravenous injection. This route is used for
the drugs such as gases or aerosols and is effective and convenient for the patients
with respiratory complaints (asthma, chronic obstructive pulmonary disease,

bronchospasm). In this route the drugs is delivered directly to the site of action and
systemic side effects are minimized.
Instillation is the route of the drug administration by putting the drops into
eyes, nose and ears.
Intranasal route of drug administration is used for the treatment of nasal
mucous diseases (local action), but sometimes for the systemic action.
Vaginal route of drug administration is used for treatment of female genital
organ diseases and for diagnostics – introduction of contrast agents.
Sublingual / transbuccal route of drug administration allows a drug to
diffuse into the capillary network and to enter the systemic circulation directly.
This route of administration has several advantages including rapid absorption,
convenience of administration, low incidence of infection, avoidance of harsh GIT
environment, avoidance of the first-pass metabolism.
Oral route of drug administration provides many advantages to the patient:
the ease of self-administration and the limit number of systemic infections,
toxicities and overdose may be overcome with antidotes such as activated charcoal.
At the same time, the pathways involved in drug absorption are the most
complicated, and the drug is exposed to harsh GIT environment that may limit its
absorption. The drugs absorbed from the stomach or from the other site of GIT
enter the portal circulation and encounter the liver before they are distributed into
the general blood circulation. These drugs undergo first-pass metabolism in the
liver, where they may be extensively metabolized before entering the systemic
blood circulation. The first-pass metabolism in the intestine or in the liver limits
efficacy of the drugs when taking orally. The dose of the drugs taking orally should
be enough to reach the target organ and to provide the therapeutic or prophylactic
effects. About 75% of the drugs taking orally are absorbed in 1-3 hours. In
addition, ingestion of drugs with food, combination with other drugs can influence
absorption. In other side, the drugs may irritate GIT mucous, hydrochloric acid and
digestive enzymes may destroy drugs, but medicinal forms of the drugs may
prevent gastric irritation, may protect active remedies against destruction and may
prolong the period of drugs elimination providing the prolonged effect. Thus, the
oral route of administration can not be applied to newborns, infants or mental
patients, to patients with loss of consciousness, to patients with nausea, vomiting,
to patients with impaired swallowing, insufficiency of heart (edema), to patients
with violation of the absorption in GIT, or if rapid effect is required. We must
remember that some of the drugs are digested in GIT (protein and polypeptide
substances), some of the drugs are destroyed by hydrochloric acid and digestive
enzymes and shouldn’t be taken orally too. For rapid absorption the drugs should
be taken on an empty stomach. Absorption of the fat-soluble vitamins may be only
in the presence of bile and fatty acids. And the administration of several drugs
simultaneously should be carefully monitored and the possibility of their
interaction should be taken into account.
Rectal route of drug administration provides drug absorption in lower and

middle hemorrhoidal veins. In this way the drugs enter the bloodstream bypassing
the liver. 50% of the drainage of the rectal region bypasses the portal circulation;
thus the biotransformation of the drugs by the liver is minimized. Like the
sublingual/transbuccal route of administration, the rectal route of administration
has additional advantage of preventing the destruction of the drugs by intestinal
enzymes or by hydrochloric acid in the stomach. The effect of the drugs introduced
rectally develops rapidly as well as at intramuscular introduction. The rectal route
of drug administration is useful for newborns, infants, for patients with nausea,
vomiting, for patients with loss of consciousness. On the other hand, rectal
absorption is often erratic and incomplete, and many drugs irritate the rectal
mucosa.
Intraduodenal route of drug administration allows to enter the drugs in a
specific area – duodenum. Duodenum is major site of entry to systemic circulation
because of its large absorptive surface.
Absorption of the drugs is the transfer of the drugs from its site of
administration to the bloodstream. The rate and efficiency of absorption depends
on the route of administration. The total absorption means that the total dose of a
drug reaches the systemic circulation. Only the direct administration of the drug in
blood provides a full dose of a drug into the bloodstream (total absorption). Drug
delivery by other routes may result in only partial absorption, and thus, to lower
the bioavailability.
Drugs may be absorbed by passive diffusion, facilitated diffusion (with
carrier proteins), filtration, active transport, pinocytosis (endocytosis or
exocytosis).
The driving force for passive diffusion of a drug is the concentration
gradient across a membrane separating two body compartments: the drug moves
from region of high concentration to one of lower concentration without a carrier,
isn’t saturable, and shows a low structural specificity. The vast majority of drugs
gain access to the body by this mechanism. Lipid-soluble drugs readily move
across most biologic membranes due to their solubility in the membrane bilayers.
Water-soluble drugs penetrate the cell membranes through aqueous channels or
pores (filtration). The capillaries of some vascular beds (e.g. in the kidney) have
large pores, which permit the passage of molecules as large as proteins. Other
drugs can enter the cell through specialized transmembrane carrier proteins that
facilitate the passage of large molecules (facilitated diffusion). These carrier
proteins undergo conformational changes allowing the passage of drugs or
endogenous molecules into the interior of cells, moving them from an area of high
concentration to an area of lower concentration. This type of diffusion does not
require energy, can be saturated, and may be inhibited. Active transport also
involves specific carrier proteins that span the membrane. Active transport is
energy-dependent and is driven by the hydrolysis or adenosine triphosphate
(ATPh). These drugs are capable of moving against a concentration gradient – that
is, from a region of the lower drug concentration to one of higher drug
concentration.
Pinocytosis (endocytosis or exocytosis) –is the type of delivery that
transports drugs of exceptionally large size across the cell membrane. Endocytosis
involves engulfment of a drug molecule by the cell membrane and transports into
the cell by pinching off the drug-filled vesicle. Exocytosis is the opposite to
endocytosis and is used by cells to secrete many substances by a similar vesicle
formation process.
The passive diffusion is typical for lipid-soluble substances, electrolytes
(potassium and sodium), weak organic acids (e.g., benzoic acid), and ethyl alcohol.
Facilitated diffusion is inherent in transport of glucose, glycerol, amino acids and
vitamins. The substances insoluble in lipids (e.g., water, ions of potassium and
sodium) and small hydrophilic molecules (e.g., urea) are absorbed by filtration.
The low molecular cations (potassium and sodium), amino acids, cardiac
glycosides, vitamins of B group, corticoids are absorbed with the help of active
transport The macromolecules of proteins and nucleic acids, fat acids, fat-soluble
vitamins and also liposomes with drugs use pinocytosis for the absorption.
There are many factors that can influence the process of absorption: pH
of environment, physiological properties of membranes, bioavailability of drugs,
peculiarities of drug metabolism in the organism, including the processes of
presystemic drug elimination, drug ability to dissolve in water and in lipids, drug
aptitude and power to bind with plasma proteins, chemical stability in human body,
features of chemical structure of drugs (molecular size, their forms, presence of a
specific coating, supplemental substances, etc.), availability of specific enzymes
for drug metabolism.
pH effect of drugs on drug absorption. Most of drugs are weak acids or
weak bases. Acidic drugs release an H+ causing a charged anion (A-). Weak bases
can also release an H+. However, the protonated form of basic drugs is usually
charged, and the loss of a proton produces the uncharged base. The uncharged
drugs more readily pass through membranes than the charged drugs. Therefore, the
effective concentration of the permeable form of each drug at its absorption site is
determined by the relative concentrations of the charged and uncharged forms. The
ratio between the two forms is, in turn, determined by the pH at the site of
absorption and by the strength of the weak acid or base. Distribution equilibrium is
achieved when the permeable form of a drug achieves an equal concentration in all
body water spaces.
Physical factors affecting the absorption. Absorption from the intestine is
favored over than from stomach because the blood flow to the intestine is much
greater than the flow to the stomach.
Absorption of the drugs across the intestine is more efficient because the
intestine has a surface rich in microvilli, it has a surface area about 1000-fold that
of the stomach.
If a drug moves through the GIT very quickly, it isn’t well absorbed.
Conversely, anything that delays the transport of the drug (the presence of food,
other drugs) from the stomach to the intestine delays the rate of absorption of the
drug.
In the blood medication is usually bound to plasma proteins: the stronger
such a connection, the slower developing therapeutic effect and vice versa;
hypoproteinemia may lead to the increase of the drug activity and drug toxicity;
drugs compete for binding to plasma proteins as a result can displace each other
from the bound fraction.
Bioavailability is the fraction of administrated drug that reaches the systemic
circulation in a chemically unchanged form. When the drug is given orally, only
part of the administrated dose appears in the plasma. In case of intravenous
administration a full dose of the drug reaches the systemic circulation and
bioavailability is 100%. But not only the administrated dose of the drug and route
of drug administration influence on the amount of the drug that reaches the
systemic circulation, and also the fraction of the dose that is absorbed and escapes
any first-pass elimination. This fraction is the drug’s bioavailability.
By plotting plasma concentration of the drug versus time, one can measure
the area under the curve (AUC). This curve reflects the extent of absorption of the
drug. Bioavailability is AUC oral/AUC injected x 100.
Bioavailability is the main parameter of pharmacokinetics and is used to
determine the dosing regimen for different routes of administration of the drugs.
Bioavailability denoted by the letter F and is expressed in %. There are: absolute
and relative bioavailability. Absolute bioavailability is the ratio of area under the
kinetic curve "concentration - time" (AUC) of the active medicinal substance in the
systemic circulation after administration of the drug by other than intravenous
route (peroral, rectal, subskin, under the skin, etc.) to bioavailability of the same
medicinal substance, but in case of intravenous route of administration (F = 1). If
the drug was introduced by other route than intravenous its bioavailability will be
less than 1 (F < 1). Relative bioavailability – is AUC the certain drug that was
compared with another medicinal form that has been accepted as a standard, or was
introduced into the body by other route of administration. If a standard is the drug
that was introduced by intravenous – there is absolute bioavailability.
Factors that influence bioavailability: first-pass hepatic metabolism,
solubility of the drug, chemical instability, nature of the drug formulation, physical
properties of the drug, MF of the drug, systems of delivery of the drug, dosage
regime of the drug, stomach emptying rate, the presence of other drugs in the body,
that can be inductors or inhibitors, interaction with certain food, transported
proteins, substrate for transported proteins, condition of GIT, etc.
First-pass hepatic metabolism. When the drug is absorbed across GIT,
before entering the systemic blood circulation the drug enters the portal circulation.
If the drug is rapidly metabolized in the liver, the amount of unchanged drug that
gains access to the systemic blood circulation is decreased (presystemic
elimination). Many drugs undergo significant biotransformation during a single
passage through the liver.
Solubility of the drug. Very hydrophilic drugs are poorly absorbed because
of their inability to cross the lipid-rich cell membranes. However, the hydrophobic
drugs are also poorly absorbed because of they are totally insoluble in aqueous
body fluids and, therefore, can’t gain access to the surface of cells. For the drugs to
be readily absorbed, it must be largely hydrophobic, yet have some solubility in
aqueous solutions. This is one reason why many drugs are weak acids or weak
bases. The highly lipid-soluble drugs are transported in aqueous solutions of the
body on carrier proteins.
Chemical instability. Some drugs are instable in the pH of the gastric
contents. Others are destroyed in the GIT by degradative enzymes.
Nature of the drug formulation. Drug absorption may be altered by factors
unrelated to the chemistry of the drug, such as particle size, salt form, crystal
polymorphism, enteric coating, the presence of excipients, like binders and
dispersing agents, can influence the ease of dissolution and, therefore, alter the rate
of absorption.
Bioequivalence. Bioequivalence matters in comparing several medications.
Two relative drugs are bioequivalent if they show comparable bioavailability and
similar times to achieve peak blood concentration. Two relative drugs with
significant difference in bioavailability are said to be bioinequivalent. Two similar
drugs are therapeutically equivalent if they have comparable efficacy and safety.
At the same time, two drugs are bioequivalent may not be therapeutically
equivalent. Thus, there are the pharmacokinetic bioequivalence, pharmaceutical
bioequivalence, therapeutical bioequivalence. Pharmacokinetic bioequivalence –
is a degree of similarity of pharmaceutically equivalent drug to the reference
product (usually – the generic to original patented drug). Pharmacokinetic
bioequivalence is determined experimentally, in vivo. The basic criteria of
bioequivalence are: degree and rate of absorption of a drug, time of achievement
the maximum concentration in the blood and its value, distribution pattern in
tissues, type and rate of drug elimination. Pharmaceutical bioequivalence – is a
complete reproduction by generic drug the composition and medicinal form of the
original drug. Therapeutical bioequivalence according to FDA assumes
equivalence of generic drug to the original drug by pharmaceutical,
pharmacokinetic and pharmacodynamic properties.
The causes of incomplete bioequivalence can be: variations in the
composition and structure of the drug substances for manufacturing (impurities,
isomers, crystalline form, etc.); differences in the composition of excipients that
were used for the production of generic; differences in production technologies of
MFs.
Drug distribution is the process by which a drug reversibly leaves the
bloodstream and enters the interstitium (extracellular fluid) and/or the cells of the
tissues. The delivery of a drug from the plasma to the interstitium primarily
depends on blood flow, capillary permeability, the degree of binding of the drug to
plasma and tissue proteins, and relative hydrophobicity of the drug.
Thus, the high blood flow of the tissues permits drugs to rapidly move into
the tissues, and poor blood flow of the tissues provides slow drug distribution.
Capillary permeability is determined by capillary structure and by the
chemical nature of the drug.
The degree of binding of the drug to plasma and tissue proteins determines
the degree of possibility of absorption of the drug from the vascular bed of the
tissue. Both forms of the drug (free and bound to plasma proteins) are in a state of
dynamic equilibrium. Major drug-binding proteins may act as a drug reservoir. The
free drugs render the biological effects; bound drugs remain in the vascular bed.
Macromolecular compounds which are tightly bound to plasma proteins do not
penetrate through the vascular endothelium and stay in the vascular bed. Low
molecular compounds can pass through the pores in the walls of capillaries into the
intercellular space. In case of decreasing of plasma protein quantity the quantity of
free forms of the drugs is rising and the toxic effects of the drugs may develop.
Drugs may compete for the relationship to plasma proteins and replace each other
from the binding, thereby increasing the free fraction of the displaced drug. High
degree of connection a drug with plasma proteins contributes to the duration of
drug action. Depot in fat tissue provides a gradual release of the drug and its long-
term effect. The selective distribution of the drugs to specific organs and tissues
determines its pharmacodynamics.
Hydrophobic drugs (fat-soluble drugs) pass all biological barriers: blood-
brain, placental, walls of vessels, walls of intestine, membranes of cells,
intracellular membranes, blood-cerebrospinal fluid, blood-testis, blood-glomerular,
blood-retinal, blood-thymus and blood-lung, etc.
Drug distribution is dependent on the ability to penetrate biological barriers,
bioavailability of a drug, supply of organs and tissues with blood, accumulation:
extra- and intracellular depots.
Concentration of the drugs (Cd) – is quantity of the drug in a certain
volume of blood, in a specific time after the introduction of a drug into the human
body, and it is expressed in mg / l, mcg / l, mmole / l, %.
The apparent volume distribution (V) – is the ratio of the total amount of
the drug in human body to its quantity in the blood plasma. This coefficient is very
important in case of overdoses of the drug, when must remove the drug by
hemodialysis. The removing of a drug by hemodialysis is effective if most of it is
in the plasma.
The structural features of blood-brain and placental barriers. Blood-
brain barrier (BBB) is the physiology barrier between blood and brain cells to
protect the nervous tissue of xenobiotics and to maintain homeostasis of the brain.
The main structural element of the BBB is endothelial cell. The peculiarity of the
cerebral vessels is the presence of tight junctions between endothelial cells, and
intercellular spaces between endothelial cells, pericytes and astrocytes, smaller
than the spaces between cells in other tissues. Difficulties in passing of the drugs
through blood-brain barrier connected with peculiarities of structure of brain
capillaries: they haven’t pores, can’t carry out pinocytosis and they have an
additional lipid membrane. In addition, on the surface of the cell membranes of

BBB endothelial cells are a series of enzymes, and in much greater quantities than
in the membranes of other cells in the parenchyma. Due to the high concentration
of enzymes in the endothelial cells of the BBB, many substances are metabolized
during transport through the cytoplasm of these cells. Besides, BBB has a
significant electrical resistance. In connection with the above, through the blood-
brain barrier can be the diffusion of small polarized molecules on the concentration
gradient without energy consumption. Further, BBB permeability depends on the
lipophilicity of each particular substance, the molar mass of the substance.
Diffusion of the substances through BBB can occur through specific channels of
the cell membranes. In the cells of the brain is also the diffusion of substances by
transport systems without energy consumption and active transport with energy
consumption. With the help of a receptor-mediated transcytosis the large molecules
are transferred into the cells of the brain through BBB. There is the cationic
transport for negatively charged molecules.
Damage to the BBB in humans occurs in a wide range of diseases:
Syndrome of deficiency of protein GLUT-1, which is responsible for
the BBB permeability for glucose and ascorbic acid. This is an autosomal
dominant inherited disease that causes the development of microcephaly,
psychomotor disturbances, ataxia, and a host of other neurological disorders:
Hereditary of folic acid malabsorption
Diabetes mellitus
Multiple sclerosis
Ischemic stroke
Bacterial infection of the central nervous system (CNS)
Viral infection of the central nervous system
Brain tumors
Table 1. BBB permeability to antibacterial drugs*
Penetrate well Penetrate well in Poorly penetrate even Not penetrate

inflammation in inflammation
Isoniazidum Aztreonam Gentamycin Clindamycin
Pefloxacinum Amikacin Carbenicillinum Lincomycin
Rifampicinum Amoxicillin Macrolides
Chloramphenicol Ampicillin Norfloxacin
Co-Trimoxazole Vancomycin Streptomycin
Meropenem Lomefloxacin
Ofloxacin
Cephalosporins of III—
IV generations
Ciprofloxacin
Levofloxacin
* adapted from: AV Kuznetsov, O. Dreval Posttraumatic meningitis and meningoencephalitis / /
Clinical guidelines in traumatic brain injury / edited by AN Konovalov, LB Likhterman, AA
Potapov - M: "Antidor", 2002. - T. 3. - P. 420. - 632 p.
Placental barrier (PB) - is the physiology barrier between maternal blood

and fetal blood. Placental barrier shall perform such functions as: prevents mixing
of blood between mother and fetus; carries gas exchange - the diffusion of oxygen
from maternal blood to fetal blood and carbon dioxide in the opposite direction;
provides entry into the blood of the fetus vitamins, water, electrolytes, nutrients
and minerals, as well as removal of metabolic products (urea, creatine, creatinine)
by means of active and passive transport; absorbs some of the substances
circulating in maternal blood, and prevents them from entering the bloodstream of
the fetus. Unfortunately, however, the large number of medicines, nicotine,
alcohol, drugs, pesticides and other toxic chemicals, as well as a series of
infectious agents that have adverse effects on the fetus, penetrate into the
bloodstream of the fetus. In addition, under the influence of pathogenic factors
placental barrier function is disturbed to a greater extent. PB starts at 12 weeks of
age of the fetus.
The blood-cerebrospinal fluid barrier (BCSFB) limits the central nervous
system from the bloodstream and supports homeostasis of the brain. The blood-
cerebrospinal fluid barrier is formed by epithelial cells with tight contacts that line
the choroid plexus of brain ventricles. From the blood into surrounding brain
cerebrospinal fluid received vitamins, nucleotides, and glucose through the blood-
cerebrospinal fluid barrier. The overall contribution of the BCSFB in the exchange
processes between the brain and the blood is low. In addition to the blood-brain,
blood-cerebrospinal fluid barrier, placental barrier in humans, there are the blood-
testis, blood-glomerular, blood-retinal, blood-thymus, blood-lung barriers, etc.
Drug metabolism (biotransformation). Biotransformation of drugs may take
the form of metabolic transformation and conjugation. The drugs may undergo
biotransformation in the liver, kidneys, intestines. Metabolic transformation includes
oxidation, reduction, and hydrolysis. Metabolism is the main process of detoxification
and elimination of drugs and other chemicals. Lipid-soluble drugs must be
metabolized in the liver in two sets of reactions, called Phase I and Phase II.
In the Phase I lipophilic drugs convert into more polar metabolites by
introducing or unmasking a polar functional group (-OH, -NH2, -SH). Phase I may
alter or unalter pharmacologic activity of the drugs.
Many of the enzymes that metabolize drugs, are located on lipophilic
membranes of the endoplasmic reticulum of the liver, GIT and other tissues. When
these membranes are isolated by homogenization and fractionation, they transform
to vesicles named as microsomes. Microsomes contain enzymes that play an
important role in oxidation and reduction processes. The process of microsomal
oxidation of the drugs requires the participation of cytochrome P450, cytochrome
P450-reductase, NADP.
The cytochrome P450 system is involved in the PhaseI biotransformation:
drug bind with cytochrome P450 system which is important for metabolism of
endogenous compounds and exogenous substances (xenobiotics). Some drugs
induce microsomal enzymes and other drugs inhibit microsomal enzymes are very
important for pharmacokinetic drug interactions and reintroduction of drugs.
If the substances or metabolites from PhaseI biotransformation is sufficiently polar,

they can be excreted by the kidney. Nevertheless, many Phase I metabolites are too
lipophilic to be retained in the kidney tubules. The substances or metabolites from
Phase I biotransformation are subjected to conjugation with endogenous substrates,
such as glucuronic acid, sulfuric acid, acetic acid, or amino acid. This is PhaseII
biotransformation. The conjugates are too polar molecules that readily excrete and
very often haven’t pharmacologic activity. Since, the endogenous substrates may
contain in foodstuffs, nutrition plays an important role in regulation of the drug
conjugation process. Conjugation is the final event of drug inactivation and reaction
of “true detoxification”, although some these reactions of conjugation may lead to
form of active conjugates, possessing hepatotoxic effect. Moreover, neonates are
deficient in this conjugating system, making them vulnerable to some drugs. Drugs
already possessing an -OH, -NH2, or -COOH group may enter Phase I directly and
become conjugated without Phase I metabolism. The highly polar drug conjugates
may then be excreted by kidney or bile. In reality, metabolism of the drugs and/or
xenobiotics is not always harmless. The toxicity of the metabolites may be higher than
initially introduced substance. This phenomenon is named lethal synthesis. An
example of the formation of toxic metabolites during biotransformation may be a
metabolite of acetaminophen (paracetamol) – N-acetyl-benzoquinoneimine (NAPQI),
formed under conditions of glutathione depletion in the liver, which is required for
conjugation of NAPQI. The accumulation of the active toxic metabolite of
acetaminophen leading to liver necrosis. Toxic effects of phenacetin, namely
nephrotoxic, methemoglobinemia and hemolysis, carcinogenic (formation of tumors
of the urinary tract) also occur due to the formation of toxic metabolites. Lethal
synthesis is inherent to codeine, which by a biotransformation process turns into more
toxic morphine; to ethyl alcohol which is transformed into a toxic acetaldehyde and
methanol is converted into formaldehyde and formic acid, isoniazid, which is
biotransformed into monoatsetilgidrazin etc. However, the toxic reactions may not be
apparent if alternative detoxification mechanisms aren’t overloaded or exhausted and
the availability of endogenous detoxifying co-substrates (glutathione, glucuronic acid,
sulfate) isn’t limited.
The metabolism of drugs has peculiar properties which are determined by
age, gender, genetic characteristics, functions of all organs and systems of the
body, environmental factors and nutrition, etc. The metabolism of the drugs is also
affected by the interaction of drugs with their combined application and the
interaction with endogenous compounds, as well as by the presence of diseases.
Drug elimination. The main routs of drugs elimination are through kidney
and liver. There are other routs of drugs elimination: through intestine, lung, milk
in nursing mother, skin, exocrine glands (lachrymal glands, salivary glands, sweat
glands, sebaceous glands, stomach glands, intestinal glands, bronchial).
Filtration, channel (tubular) secretion and channel (tubular) reabsorption
play the main role in the process of excretion of the drugs with urine. If the drugs have
less than 90 MW and don’t bind with plasma proteins they filtrate through kidney
glomeruli – glomerular filtration. The drugs with 90-300 MW may excrete as with
urine as with bile. Process of filtration is disturbed in case of shock, collapse,

decreased blood circulation, decreased hydrostatic pressure of the plasma in
glomerular capillaries.
Some of drugs excrete by the way of tubular secretion with help of specific
enzymes and with energy consumption. This process may be broken in case of
hypoxia, infection, intoxication in kidney.
The tubular reabsorption affects the degree of drug elimination: the fat-
soluble substances passively reabsorbed, ionized drugs that are weak acids or
alkalis actively reabsorbed. The degree of the reabsorption can be regulated. The
acid urine improves degree of the drugs ionization that lead to decreasing of their
reabsorption and increasing of their excretion. And vice versa: alkalization of urine
leads to increasing of degree of the drugs ionization and accelerates excretion of
drugs (weak acids) with urine.
The drugs and their metabolites with more than 300 MW are excreted with gall.
Some of them form gastrointestinal-hepatic/intestinal-hepatic recirculation. In this
case the drug excreted with gall to intestine, where is reabsorbed, reaches the liver and
again is excreted with gall. Due to this phenomenon the drugs may cumulate and
remain in the body. Intestinal-hepatic recirculation of the drugs can lead to toxic
effects of these drugs (e.g., cardiac glycosides, tetracycline, morphine, etc). Due to
intestinal-hepatic recirculation the toxic doses of drugs are created in human body.
The gases and volatile substances are excreted through lung. Some
substances that were directed through GIT and were not absorbed are excreted
through intestine. Some substances can be excreted through exocrine glands and
damage the mucous, skin and with mother’s milk get into the body of the child.
There are indicators of drug elimination process such as a constant of elimination
(Cel.), half-life (T1/2), a clearance (Cl) for the quantitative evaluation of the process of
removing drugs. Constant of elimination (Cel.) – is the percentage (%) of reducing of the
concentration of a drug in blood per unit time. Constant of elimination
is determined by the formula: Cel. = 0.693/ T1/2.. Half-life (T1/2) – is the time required to
reduce the drug concentration (Cd) in the blood in twice: from Cd to 1/2Cd.
Clearance (Cl) – is the factor that predicts the rate of elimination in relation to the
drug concentration, and is expressed as the volume of plasma from which all drug
appears to be removed in given time (ml/min): Cl = Rate of elimination/Cd. There
are: renal, liver, other and systemic clearance (the last is sum of clearances from
the various drug-metabolizing and drug-eliminating organs). “Other” tissues of
elimination could include the lung, blood, muscles and other additional sites of
metabolism.
Drug accumulation. Whenever doses of the drug are repeated, it can
accumulated in the body. If the interval between an administration of the drug is
shorter than its 4T1/2, the accumulation can occur. The accumulation of
biologically active substances (drugs, poisons) is named a material accumulation.
The accumulation of the effects caused by it is named a functional accumulation.
Chapter 2. Pharmacodynamics | 25
Chapter 2. Pharmacodynamics
Pharmacodynamics studies localization and mechanism of action,
pharmacological effects of the drugs, dose-effect relationship, factors modifying
drug effects and dosage, and drugs’ toxicity. Pharmacodynamics studies what the
drugs do to the body. The effects of most drugs result from their interaction with
macromolecular components of the organism. These interactions remodel the
function of the appropriate component and lay the foundation of the biochemical
and physiological changes that are characteristic of the response to the drug.
Mechanism of action – is the interaction of drugs with the organism on the
biomolecular level. Mechanism of drug action – is a way to achieve its
pharmacological effect. The main types of mechanism action of the drugs:
connection with receptors
influence on ion channels
influence on the transport systems
influence on the enzymes
influence on the neurotransmitters
antimetabolic action
action in the genes level: deoxyribonucleic acid (DNA), ribonucleic acid (RNA)
chemical and physical interaction with the body fluids and mucous.
Receptors – are specialized target macromolecules that are localized on the
cell surface or intracellularly. The majority of medicines exert their effects by
interaction with receptors. Drugs may bind with receptors and alter biochemical
and/or biophysical activity of cells. Drugs may bind with enzymes and indirectly to
affect the receptors: anticholinesterase (AchE) drugs, monoaminoxydase (MAO)
inhibitors (MAOIs), inhibitor of catechol-orto-methyl-transferase (COMT), etc.
Drugs can exert on the neurotransmitters and change their action on the receptors:
sympathomimetics, sympatholytics, etc. Most receptors are named to indicate the
type of drug/chemical that interacts best with it: the receptors for serotonin are
called serotonin receptors, the receptors for angiotensin are called angiotensin (AT)
receptors, etc. In each case, the formation of drug-receptor complex leads to
biological response. The cells have a lot of receptors.
Remedies that bind with receptors are named ligands. There are the internal
(natural opioid peptides, certain amino acids, etc.) and external (drugs and other
xenobiotics) ligands. Interaction of receptors with their ligands follows the
principle: lock-and-key. This interaction demonstrates the high degree of
specificity of receptors with respect to the ligands. The size, shape, charge of the
ligand molecules determines myriad binding sites of the receptors in the cells and
tissues of human body. Nevertheless, in the presence of ligands the receptors can
undergo a conformational change to bind with ligands. Thereby, the receptors are
flexible, not rigid as implied by the lock-and-key model.
The richest sources of pharmacological receptors are proteins that are
responsible for transducing extracellular signals into intercellular responses. These
receptors are divided into four families: 1) ligand-gated ion channels; 2) G protein-
coupled receptors; 3) enzyme-linked receptors; 4) intracellular receptors.
Hydrophilic ligands interact with receptors on the cell surface (families 1, 2, 3). As
opposed, lipophilic ligands interact with receptors inside cells, because of they can
enter cell through the lipid bilayers of the cell membrane.
Ligand-gated ion channels are responsible for regulation of the flow of ions
across cell membranes. The concentration of second messengers is changed due to
G protein-coupled receptors. In turn, second messengers are responsible for
actions within the cell, and stimulation of these receptors results in responses that
last several second to minutes.
Second messengers are essential in conducting and amplifying signals from
G protein-coupled receptors. Second messengers are molecules that relay signals
from receptors on the cell surface to target molecules inside the cell, in the
cytoplasm or nucleus. The types of second messengers: cAMP (cyclic adenosine
monophosphate), cGMP (cyclic guanosine monophosphate), IP3 (inositol 1,4,5-
trisphosphate), Ca+2 ions – they are located in cytosol; DAG (diacylglycerol),
phosphatidylinositol, AA (arachidonic acid) – they are membrane-associated and
diffuse from the plasma membrane into the intermembrane space where they can
reach and regulate membrane-associated effector proteins; NO (nitric oxide), CO
(carbon monoxide), H2S (hydrogen sulphide) – gases which can diffuse both
through cytosol and across cellular membranes.
An effector is a molecule that binds to a protein and thereby alters the
activity of that protein. A modulator molecule binds to a regulatory site during
allosteric modulation and allosterically modulates the shape of the proteins. An
effector can also be a protein that is secreted from a pathogen, which alters the host
organism to enable infection, e.g. by suppressing the host's immune system
capabilities.
Enzyme-linked receptors have cytosolic enzyme activity as an integral
component of their structure or function. Binding of a ligand to an extracellular
domain activates or inhibits this cytosolic enzyme activity. Duration of responses
is on the order of minutes to hours.
Intracellular receptors significantly differ from described above receptors.
Intracellular receptors are completely intracellular and resulting in the ligands must
diffuse into the cell to interact with intracellular receptors. In this case the ligands
must be lipid-soluble to move across cell membranes and they are transported in
the body with help of the specific transport systems – plasma proteins, such as
albumin. The time of activation of the intracellular receptors and time of response
is much longer than other described above.
Spare receptors are present in many tissues. To achieve the maximum effect
is not necessarily binding of the agonist with all its receptors. After reaching the
maximal response remained free receptors, which are called spare receptors. The
presence of receptor reserve ensures adequate pharmacological effects at relatively
low concentrations of drugs or neurotransmitters. Pharmacological effect is not in a
linear dependence on the fraction of occupied receptors.
Desensitization of receptors is reduced agonist effect when prolonged or

repeated exposure. Type of acute desensitization can be explained by the
conversion of the activated drug-receptor complexes in the non-activated,
desensitized forms, although the receptor retains its ability to bind to the agonist,
then the binding effect does not occur. Chronic desensitization usually develops
slowly and is not easily reversible. It can be caused by loss or sequestration of
receptors from the surface of effector cells by endocytosis (internalization), and
their irreversible conformational changes or destruction. Long-term increase in the
concentration of hormone or neurotransmitter can cause a decrease in the number
and density of the receptors (down-regulation), and their destruction. Thus, the loss
of receptors may occur if the effector cells are exposed to excessive concentrations
of agonist. Some receptors, especially voltage-gated channels, require a rest period
before can be activated again. These receptors are called “refractory” or
“unresponsive”.
The drugs that bind with receptors and activate them are named
agonists/mimetics (e.g., cholinergic agonists or cholinergic mimetics). There are
the endogenous agonists (e.g., hormones, neurotransmitters, etc.) and exogenous
agonists (e.g., cholinomimetics, adrenomimetics, etc.). There are the full agonists
that in case of interaction with receptors induce the effect similar to this, which
cause the endogenous agonists ( e.g., isoprenaline – agonist of β -adrenergic
receptors) and partial agonists that cause less effects as compared with full agonist
(e.g., aripiprazole – atypical antipsychotic, partial agonist of dopamine receptors).
If receptor activation requires interaction with several different molecules, they are
called co-agonists (e.g., NMDA-receptors that are activated by binding both
glutamate and glycine). There are the competitive agonists (e.g., caffeine and
adenosine that bind with adenosine receptors). The drugs that bind with receptors
and block them are named antagonists/blockers (antagonists of adrenergic
receptors, cholinergic receptors, etc.). If drugs bind to the same receptors as
endogenous ligands, they are named competitive antagonists (e.g., naloxone –
competitive antagonist of opioid receptors, losartan – competitive antagonist of
adenosine), and if drugs bind to receptors of other sites, they are named
noncompetitive antagonists (e.g., valsartan - noncompetitive antagonist of AT1
receptors). It is important for clinical use of the drugs that action of competitive
antagonist can be overcome by administration of high dose of full agonist, but
action of noncompetitive antagonist cannot be overcome by this way. If drugs can
activate a one subtype of receptor and block the other subtype of receptor, they are
named agonists-antagonists (e.g., pentazocine and nalbuphine- agonists of δ and κ
opioid receptors). If drugs exert on a one type of receptors they manifest a
selective action, and if drugs exert on several types of receptors they manifest a
nonselective action (e.g., prazosin – selective α1-adrenoblocker, propranolol –
nonselective β1-, β2-adrenoblocker, etc.).
Drugs can bind not only with receptors but also with other macromolecules
(plasma proteins, cell proteins, enzymes) that are named dumb (secondary)
receptors.
With regard to ion channels drugs may also manifest selective and
nonselective action, and the drugs may act as activators and blockers of ion channels
(e.g., amiodarone – nonselective blocker of K+ channels, verapamil – selective
blocker of Ca2+ channels, etc.).
Drugs may be inductors or inhibitors of enzymes (e.g., phenobarbital,
carbamazepine, rifampicin – inductors of microsomal enzymes of the liver, and
cimetidine, peroral contraceptives, paracetamol, сhloramphenicol, chlorpromazine,
isoniazid, etc. – inhibitors of microsomal enzymes of the liver). These properties of
drugs are important in their combined use: they will influence on pharmacokinetics
and pharmacodynamics of the drugs that are metabolized by microsomal enzymes of
the liver. At the same time the drugs can be interacted with specific enzymes (e.g.,
anticholinesterase drugs with anticholinesterase in cholinergic synapse, cardiac
glycosides with К+,Na+,АТphase, MAOIs with MAO, ACEIs with ACE, etc.).
Some drugs due to its structure can be integrated into the metabolic
processes of the organism like structure of natural metabolites (e.g., metabolites
and antimetabolites, hormones and antihormohes, sulfonamides, etc.).
Some drugs influence on DNA, RNA in human body or in microbial cells,
viruses, funguses, protozoa (e.g., antibiotics, antiviral drugs, antifungal drugs,
antiprotozoal drugs).
In the base of mechanism of action of some drugs may be nonspecific changes
caused by their physical and/or chemical properties (e.g., diuretic effect of osmotic
diuretics connects with their ability to increase osmotic pressure in kidney channels;
antacids interact with the hydrochloric acid of the stomach and neutralize it, heparin
directly interacts with its antagonist – protamine sulfate, etc.).
Nevertheless progress of pharmacology, chemistry, physiology, and other
fundamental sciences, mechanism of action of majority drugs unknown and
requires further investigation.
Pharmacological effect – is the clinical manifestation of the body's reaction to
the drug action. Pharmacological effect – is the manifestation of mechanism of action
resulting in the change of organ functions and organisms’ systems. In the base of the
same pharmacological effects may be different mechanisms of action and different
pharmacological effects can be provided by the similar mechanisms of action.
The principles of pharmacokinetics and pharmacodynamics form the base for
understanding the time course of drug effect. In practical terms the effect isn’t usually
linearly proportional to the concentration of this drug in the blood because of
relationship between drug concentration and its effect is not linear. Often the changes
in drug effects are delayed to changes in drug concentration in the blood. The reasons
of this delay may be time that required for drug to reach the site of action (delays of a
few minutes, or a few hours), or slow turnover of physiologic substances that are
involved in the expression of the drug effect (delays of many hours, or even days).
Some of the drug effects are related to the accumulation. Very often there are
negative, adverse effects of the drugs, but the positive effects may be based on the
accumulation (for example, anticancer drugs that bind with DNA of cancer cells).
Thus, there are immediate effects, delayed effects and cumulative effects of the
drugs.
An effect (action) of drugs on the body may be local, reflexive, systemic
(resorptive), selective, nonselective, the main, side/adverse (both positive and
negative), reversible, irreversible.
Local action is manifested in the ways of drug introduction: skin, mucosa,
vascular endothelium, muscles etc. Local action can be astringent, enveloping
(covering), absorbent, irritating, local anesthetic.
Reflexive action is often due to irritants. In this way the irritating substance
excites the ends of the sensory nerves and reflex and changes the function of
internal organs.
Resorptive (systemic) action develops after absorption or direct introduction
of the drug in the blood. There are direct (primary) action and indirect (secondary)
action.
Selective action is seen in drugs that affect receptors, ion channels, cells,
determined organ or tissues. The higher the selectivity of the drug, the fewer side
effects. Some drugs are characterized by nonspecific (nonselective) action.
The main action the doctor tries to get by the introduction of drugs into the
patient’s body.
Side/adverse action/effect is usually negative (harmful), but may be positive
(beneficial) in some causes.
The effects of most drugs are reversible – they disappear after elimination of
drugs, but some drugs have irreversible effects – they remains after elimination of
drugs from the body. There are predictable side effects of drugs that are a
consequence of the known pharmacological effects of these drugs, but there are
unexpected side effects of drugs that may have an unknown mechanism of the
development, remain unrecognized in clinical trials and are identified only when
the drugs enter the broad consumer market.
Some of antibacterial drugs have so-called “postantibiotic” effect (PAE) of
which is defined as persistent suppression of bacterial growth after a brief exposure (1
or 2 h) of bacteria to an antibiotic even in the absence of host defense mechanisms.
Factors that affect the duration of the postantibiotic effect include duration of
antibiotic exposure, bacterial species, culture medium and class of antibiotic. It has
been suggested that an alteration of DNA function is possibly responsible for post
antibiotic effect following the observation that most inhibitors of protein and nucleic
acid synthesis (e.g., aminoglycosides, fluoroquinolones, tetracyclines, clindamycin,
certain newer macrolides/ketolides, and rifampicin and rifabutin) induce long-term
PAE against susceptible bacteria. Theoretically, the ability of an antibiotic to induce a
PAE is an attractive property of an antibiotic since antibiotic concentrations could fall
below the minimum inhibitory concentration (MIC) for the bacterium yet retain their
effectiveness in their ability to suppress the growth.
The long-term adverse outcomes of drugs – there are embryotoxic,
teratogenic, fetotoxic, mutagenic, cancerogenic effects.
The embryotoxic effect is developed in first days and weeks after

fertilization (before 12 weeks of pregnancy). This is the toxic effect of the drugs on
embryo. As a result, the evolution of embryo, processes of its implantation in
uterus wall, placentation are disturbed. In this case, the pregnancy does not
progress or there is an abortion in the early stages of embryo development (e.g.,use
of estrogens, progestins, anabolic steroids, Aspirin, Biseptol, tetracycline,
isoniazid, nicotine, caffeine, ethyl alcohol, barbiturates, etc.).
The teratogenic effect – is the ability of the drugs to interfere in the
development of the embryo and cause fetal malformations. This toxic effect is
observed under the influence of drugs during the period from 3 weeks to 4 months of
intrauterine development of the embryo, where the most intense is the differentiation
of its tissues. Sometimes, abnormalities are developed due to violations of feto-
placental blood flow, placental structure, or hormonal, fluid and electrolyte, vitamin
imbalance. Teratogenic effect is typical for antiepileptic drugs, antituberculosis
drugs, oral hypoglycemic drugs, high doses of vitamins A, D, ethyl alcohol, etc.
The fetotoxic effect is developed as a result of drug actions on the fetus (after
12 weeks of pregnancy). The use of Acetylsalycilic acid and other non-opioid
analgesics in late pregnancy can lead to premature imperforation of the ductus
arteriosus; the use of reserpine in this period can cause fetal respiratory depression,
impaired sucking reflex in this newborn; captopril in this case can induce newborn
kidney violation; sulfonamides that are used in third trimester of pregnancy can
provoke fetus kernicterus. In addition to morphological changes in organs and tissues
can occur so-called “behavioral teratogenesis”, namely, behavioral disorders, memory
and learning ability in the postnatal period. It is based on a violation of the neuro-
mediator processes, development and the formation of neurons, the distortion of
biochemical processes in the fetus. The reason of “behavioral teratogenesis” may be
ethyl alcohol, other psychoactive drugs, components of tobacco smoke.
The mutagenic effect is the result of the influence of drugs on germ cells
before fertilization and during embryo development. These disorders in organs and
tissues are inherited (e.g., use of cytostatics).
The cancerogenic effect is the ability of the drugs to cause the growth of
tumors. But all the drugs are tested for the absence of such effect before receiving
permission to use them.
Specific adverse effects of drugs are tolerance, tachyphylaxis, euphoria,
psychological and physical drug dependence, drug addiction, withdrawal
syndrome, abstinence, idiosyncrasy, allergic reaction, cross allergic reaction,
inhibition of immunity, chemoresistance, dysbiosis, superinfection.
In case of repeated use of the drugs its pharmacological effect may decrease or
disappear. This phenomenon is named tolerance. Mechanisms of development of
tolerance may be: changes of speed of biotransformation of the drugs, restriction of
drug absorption, consolidation of body biological barriers, acceleration of drug
elimination, desensitization of receptors, internalization of receptors (dawn-regulation,
reducing the number of the receptors), etc. At the same time an increasing of the drug
dose may restore the pharmacologic effect, but not always. It depends on the
formation mechanism of tolerance. The rapid development of tolerance is called

tachyphylaxis (e.g., naphazoline. ephedrine, etc.)
Euphoria is a state of complete physical and mental well-being. If, after the
discontinuation of drug use the patient has an uncontrollable craving for this drug,
a violation of psychological functions, this phenomenon is called psychological
dependence. And, if in this case the patient has an uncontrollable craving for this
drug, severe disfunction of internal organs, this phenomenon is called physical
dependence. Abstinence means a significant deterioration of health by reducing
the number of received drug or a complete cessation of its use. The most
widespread is the drug that has this specific adverse effect such as ethyl alcohol,
tobacco, opioid analgesics.
Thereby, the euphoria, psychological and physical dependence, abstinence
are typical for opioid analgesics, caffeine, ethyl alcohol, nicotine, etc.
Withdrawal syndrome is a complex of changes that may occur after the
sudden discontinuation of the drug that the patient took a long time. This complex
includes manifestation of symptoms of disease which was treated (e.g., most of
hypotensive drugs, antianginal drugs, hormones, etc.).
Drug idiosyncrasy is the distortion of sensitivity to drug. The basis of this
side effect is genetic disorders and connections with insufficiency of certain chains
of metabolism in condition of internal or external load (e.g., use of sulfonamides,
analgesics, antipyretics, primaquine, mepacrine in people with insufficiency of
glucose-6-phosphat-dehydrogenase cause hemolytic anemia; the intensified
barbiturate induction of synthetase of aminolevulinic acid induces attack of
hepatic porphyria; malignant hyperthermia in case of use of opioid analgesics;
deficiency of methemoglobin reductase in case of treatment by nitrates lead to
development of methemoglobinemia; deficiency of hypoxanthine-guanine-
phosphoriboxil-transferase in the treatment of gout by allopurinol evinces by
intensive renal excretion of purine, sometimes with formation of stones (lithiasis);
in children of early age (infants) in the treatment by chloramphenicol the Grey
syndrome (flatulence, diarrea, vomiting, cyanosis, circulatory disorders) may be
developed that is connected with deficiency of glucuronyl transferase, disorder of
chloramphenicol elimination and as a result – intoxication and death.
Allergic reactions as a response to the use of the drugs can be developed
within a few days after the start of medication, or immediately after the first dose.
With respect to drugs with similar chemical structure may develop cross-allergy
(e.g., sulfonamides, procaine, sulfonylurea derivatives of oral hypoglycemic drugs,
β-lactam antibiotics, tetracycline, oleandomycin, promethazine, chlorpromazine
etc.). Inhibition of immunity is elicited by immunosuppressants, cytostatics,
corticosteroids. In these patients the bacterial, viral, fungal, and other infection can
acquire a generalized character.
Chemoresistance of microorganisms is the general biological reaction of
adaptation to the changed conditions of existence. There are different mechanisms of
development of this condition: synthesis of specific enzymes that can destroy
antibiotics (e.g., β-lactamases, esterases), cell membrane sealing of microorganisms,
decrease of affinity of microorganism’s structure to antibiotics, genetic mutations

of microorganisms, efflux, etc.
Dysbiosis is a condition that is accompanied by a violation of the natural
microflora of the skin, mucous membranes. It develops as a result of broad-
spectrum antibiotics use, and often accompanied by a superinfection, which is
characterized by a population of skin and mucous membranes by resistant
microorganisms to the antibiotic which is used. These microorganisms may be
fungi, Pseudomonas aeruginosa, methicillin-resistant staphylococci, and others.
Types of drug doses – there are such therapeutic doses as minimal therapeutic
dose, average therapeutic dose, maximal therapeutic dose, saturating dose (e.g., for
cardiac glycosides) and loading dose (e.g., for sulfonamides), maintenance dose (e.g.,
for hypotensive drugs), toxic dose, and lethal dose. Therapeutic dose is the quantity of
a drug which is used with therapeutic reason. Minimal therapeutic dose cases the
minimal pharmacologic effect. Average therapeutic dose causes the average
pharmacologic effect. Maximal therapeutic dose causes the maximal pharmacologic
effect. Maintenance dose allows maintaining in human body a therapeutic dose (a
target concentration) of the drug in view of its elimination. If it is necessary to reach a
target concentration of a drug very quickly, it is desirable to introduce its loading
dose. Toxic dose is the quantity of a drug which causes the toxic effects after use.
Lethal dose is the quantity of a drug which causes death after use. Latitude of
therapeutic action – is the diapason of doses between minimal therapeutic dose and
minimal toxic dose. If the latitude of therapeutic action of drugs is large, the drug is
safer than a drug with small latitude of therapeutic action. Therapeutic index (TI) – is
the indicator which quantifies the relative safety of a drug, and it is the ratio of median
lethal dose LD50 to median effective dose ED50 (ratio risk/ benefit). TI =
LD50/ED50. The LD50 of a compound is determined experimentally, usually by
administration of the chemical to mice or rate (orally or intraperitoneally) at a several
doses in the lethal range. LD50 is the concentration of a drug at which 50% of the
population will have death. ED50 is the concentration of a drug at which 50% of the
population will have the desired response. Drugs with low therapeutic indexes are not
safe, but the drugs with high therapeutic indexes are relatively safe.
In addition, there is a single dose, daily dose, a course dose. Single dose is a
quantity of drug that was introduced at a time. Daily dose is a quantity of drug that
was introduced during the day. Course dose is a quantity of drug that was
introduced during the course of treatment.
Largely the effect of drug is determined by its dose, but the dose-effect
relationship is not direct. The relationship of dose-effect of the drug also depends
on the exposure time, ways of direction, bioavailability of the drug, etc.
Factors that affect action of the drugs (factors modifying drug effects and
dosage). It is well known that all patients are different and have different reactions at
the same drugs. There are endogenous and exogenous factors influencing drug effects.
The endogenous factors: sex, age, physiologic condition (biologic rhythms of
hormones and enzymes releasing, pregnancy, menstruation, climax), presence of other
diseases or pathologic conditions, genetic peculiarities, ethnic and race differences in
drug effects. The exogenous factors: chemical structure and chemical and physical
properties of drugs, drug medicinal forms, routs of drug administration, drug doses,
regimes of feeding, diets (foods may be inductors or inhibitors of microsomal and
other enzymes, they may contain substances that have chemical or physical action on
the drugs), factors of environment such as weather, time of day, seasons, climate, etc.
Drug-Drug Interaction. Patients are commontly treated with more than one
drug, have individual dietary choices, and may also be using over-the-counter
(OTC) medications, vitamins, and other “natural” supplements. Drug-drug
interaction requires the consideration because of it may cause the changes in
pharmacokinetics and in pharmacodynamics such as after overdose, may lead to
altered rates of absorption, altered protein binding, or different rates of
biotransformation or excretion of one or both or several interacting substances.
There are the mechanisms of chemical interaction*:
Pharmacokinetic mechanism:
biotransformation
distribution
absorption
excretion
Pharmacodynamic mechanism
non-receptor
receptor
Classification of chemical interactions*:

additive
synergistic
potentiation
antagonism
a) functional
b) chemical
c) dispositional
d) receptor
* - adopted from Goodman & Gilman’s The Pharmacological Bases of THERAPEUTICS. 12
edition. Medical. 2011. – 2084 P.
There are pharmaceutical, pharmacokinetic and pharmacodynamic

interactions of the drugs. The base of pharmaceutical interaction of the drugs is the
physical and chemical interactions of the substances that are in the medicinal form of
the drug or in case of combine use of them. Consequences of it interaction are
negative as rule (e.g., acids can not be combined with alkalis, cardiac glycosides can
not be soluble in hypertonic solution of glucose or in alkaline solution due to their
inactivation in these solutios; vitamin B1 can not be introduced in the syringe
together with nicotinic acid by reason of destruction of vitamin B1; vitamin B1 can
not be introduced in the syringe together with penicillin because of disintegration of
penicillin). Pharmacokinetic interaction of the drugs is manifested on the stage of
drug absorption, transportation, dissemination, deport, biotransformation and

excretion (e.g., malabsorption of fluoroquinolones and tetracyclines in their joint
application with antacides, calcium, iron preparations, bismuth preparations;
diphenine hampers absorption of folic acid; fat-soluble vitamins are better absorbed
in the presence of bile; sulfonamides reduce the connection of indirect anticoagulants
with plasma proteins; disintegration of suxamethonium iodide in action of butyril-
cholin-esterase of blood is impeded in concomitant use with anticholinesterase drugs;
disulfiram slows metabolism of ethyl alcohol at the stage of acetaldehyde; if
salicylates or barbiturates are administrated together this lead to acceleration of their
elimination; amiodarone inhibits digoxine elimination through kidney; etc.).
Pharmacodynamic interaction of the drugs is appeared in case of the combine use
of the drugs that have similar or opposite effects or mechanism of action. In this
way the pharmacologic effects of the drugs may be increased (synergism of the
drugs) or may be decreased (antagonism of the drugs). If the general effect of the
drugs is higher than each effect of every drug this phenomenon is named
potentiating (e.g., concomitant use of antipsychotics, opioid analgesics and drugs
for general anesthesia). If the drugs have similar mechanism of action and improve
effect each of other this synergism of the drugs is named direct (e.g., epinephrine
and norepinephrine). If the drugs have different mechanism of action but improve
the effect of each other, this synergism of the drugs is named indirect (salbutamol
and atropine). Antagonism of the drugs may be physical (e.g., absorption of toxic
substances by activated charcoal), chemical, or inactivation (e.g., interaction
between acids and alkalis), physiological, or functional (e.g., hypotensive drugs
and hypertensive drugs), direct (e.g., adrenomimetics and adrenoblockers),
indirect (e.g., bronchspasm is caused by use of β-adrenoblockers can be obviate by
use of cholinoblockers) and competitive (e.g., sulfonamides and para-amino-
benzoic acid), one-sided (e.g., atropine removes the effects of cholinomimetics, but
not conversely) and two-sided (e.g., strychnine and chloralhydrate, sulfonamides
and oral hypoglycemic drugs of sulfonylurea derivatives – they eliminate effects of
some other). Dispositional antagonism is the alteration of the disposition of a
substance (its absorption, biotransformation, distribution, or excretion) so that less
of the agent reaches the target organ or its persistence in the target organ is
reduced. Receptor antagonism entails the blockage of the effect of a drug with
another drug that competes at the receptor site. If in case of combine use of the
drugs, one effect of them is increased and other effect of them is decreased, this
phenomenon is named synergo-antagonism (on the background action of α-
adrenoblockers the stimulating effect of epinephrine on the α-adrenergic receptors
of the vessels is decreased and the stimulating effect of epinephrine on the β-
adrenergic receptors of the vessels becomes more pronounced). As a result of
concomitant administration of the drugs may be distortion of their effects (e.g.,
introduction of phentolamine leads to distortion of pressor effect of epinephrine).
If drugs-antagonists are used for treatment poisonings, they are named
antidotes. Antidotal therapy involves antagonism or chemical inactivation of an
absorbed poison. The pharmacodinamics of morphine overdose may be varied by
competition at a receptor, as in the antagonism provided by naloxon therapy; overdose

of propranolol may be overcomed by physiological antidote glucagon with help a
different cellular mechanism, as in stimulation an alternative to the blocked β-
adrenergic receptors and increase cellular cyclic AMP; venoms and chelating agents
bind and directly inactivate poisons; biotransformation of a drug can also be changed
by an antidote: fomepizole will inhibit alcohol dehydrogenase and cease the formation
of toxic acid metabolites from ethylene glycol and methanol. There are nonspecific
functional antidotes that are used in supportive care of a poisoned patient (e.g.,
anticonvulsants, vasoconstricting agents, drugs supporting cardiac function,
respiratory center activity, etc.). The basis of antipoisoning therapy is a support of
airway, breathing, circulation, and vital metabolic processes of the poisoned patient
until the poison is eliminated from the body.
Table 2. Some common antidotes and their indications*
Antidote Poisoning indication(s)

Acetylcysteine Acetaminophen
Alloximum Organophosporus and carbamate pesticides
Amyl nitrite Cyanides (hydrogen cyanide, or prussic acid, or
hydrocyanic acid and its salts)
Anticholinesterase drugs Anticholinergic syndrome
(physostigmine salicylate,
neostigmine methylsufate)
Atropine sulfate Organophosporus and carbamate pesticides
Bemegride Barbiturates, Drug for general anesthesia
Benztropine Drug-induced dystonia
Bicarbonate sodium Na+ channel blocking drugs,
(Hydrocarbonate sodium) Acetylsalicilic acid, acids, ethyl alcohol, tricyclic
antidepressants, quinidine, etc.
Bromocriptine Neuroleptic malignant syndrome
Calcium folinate Methotrexate
Calcium gluconate Ca+2 channel blocking drugs,
or chloride Fluoride
Carbo activatus Alkaloids, glycosides, salts of heavy metals except
cyanides, iron, lithium, alcohols
Carbolongum Alkaloids, glycosides, salts of heavy metals
Chloride sodium Silver nitrate
Crotalidae polyvalent North American crotaline snake envenomation
immune Fab
Cytochrom C Hypnotics, carbon monoxide
Dantrolene Malignant hyperthermia
Diaethyximum Organophosporus and carbamate pesticides
Deferoxamine Iron
36 | Unit 1.
General Pharmacology
Digoxin immunew Fab Cardiac glycosides
Dimercaprol Lead, mercury, arsenic, gold in the presence of
encephalopathy
Dipyroximum Organophosporus and carbamate pesticides
(Trimedoxime bromide)
Diphenhydramine Drug-induced dystonia
EDTA, CaNa2 (Sodium Lead, mercury, cobalt, nickel, etc., cardiac
calcium edetate) glycosides
Ethanol Methanol, ethylene glycol
Ferrocin (Potassium-ferric Radioisotopes of cesium and rubidium, the decay
hexacyanoferrit) products of uranium
Flumazenil Benzodiazepines
Fomepizole Methanol, ethylene glycol
Glucagon hydrochloride Β-adrenergic antagonists
Hydroxocobalamin Cyanide
hydrochloride
Insulin (high dose) Ca+2 channel blockers
Leucovorin calcium Methotrexate
Menadione sodium Indirect anticoagulants (phenindione, ethyl
bisulfite (Vicasol) biscoumacetate, etc.)
Methylene blue Methemoglobinemia
Naloxone hydrochloride Opioids
Naltrexone Opioids
Octreotide acetate Sulfonylurea-unduced hypoglycemia
Oxygen, hyperbaric Carbon monoxide, hydrocyanic acid, chrome,
phosgene, etc.
Penicillamine Lead, mercury, copper, arsenic, gold
Pralidoxime chloride Organophosporus pesticides
Protamine sulfate Heparin
Pyridoxine hydrochloride Isoniazid seizures
Succimer (DMSA) Lead, mercury, arsenic
Thiosulfate sodium Cyanide, mercury, arsenic, lead, iodine
Trimephacinum Uranium, beryllium, radionuclides
Unitiolum Arsenic, mercury, bismuth, and other heavy metals,
cardiac glycosides, propranolol, amitriptyline, etc.
Vitamin K1 Coumarin, indanedione
Vitamin A, C, B group Vitamin D
* adapted from Goodman & Gilman’s The Pharmacological Bases of THERAPEUTICS. 12
edition. Medical. 2011. – 2084 P.; M.P.Skakun, K.A.Posochova Pharmacology. Ternopil.
Ukrmedkniga. 2003. – 740P.
Chapter 3. Intermediants | 37
UNIT 2: DRUGS AFFECTING MEDIATORY PROCESSES

Chapter 3. Intermediants: adenosinergic, dopaminergic,
serotoninergic, histaminergic, eicosanoids: prostaglandins,
leucotriens, thromboxans
Substances that specifically interact with certain systems of
neurotransmitters / modulators are called substances of intermediated type.
These are mainly agonists or antagonists of the receptors. The action of
others are mediated by endogenous ligands due to altering their metabolism,
release, capture and deposit.
Adenosine is a purine nucleoside comprising a molecule of adenine attached
to ribofuranose via β-N9-glycosidic bond. Adenosine plays an important role in
biochemical processes, such as energy transfer (adenosine triphosphate – ATP and
adenosine diphosphate – ADP), signal transduction (cyclic adenosine
monophosphate – cAMP). Adenosine is also an inhibitory neurotransmitter,
believed to play a role in promoting sleep and suppressing arousal, because its
concentration is increased in the body during the sleep.
Metabolism of adenosine: Adenosine used as a second messenger can be
the result of de novo purine biosynthesis via adenosine monophosphate; though the
existence of other pathways is possible.. When adenosine enters the circulation, it
is broken down by adenosine deaminase, which is present in red blood cells
(erythrocytes) and the vessel wall. So, inhibitors of adenosine deaminase, allow
adenosine to accumulate in the blood stream. This causes an increase in coronary
vasodilatation. Adenosine deaminase deficiency is a known cause of
immunodeficiency.
Adenosine is an endogenous purine nucleoside that modulates many
physiological processes. Cellular signaling by adenosine occurs through four
known adenosine receptor subtypes (A1, A2A, A2B, and A3). The adenosine
receptors (or P receptors) are a class of purinergic receptors, G-protein-coupled
receptors with adenosine as endogenous ligand. In regard to stress or injury, the
function of adenosine is primarily that of cytoprotection preventing tissue damage
during instances of hypoxia, ischemia, and seizure activity. Activation of A2A
receptors produces a constellation of responses that in general can be classified as
anti-inflammatory. Different adenosine receptor subtypes (A1, A2A, A2B, and A3)
are all seven transmembrane spanning G-protein-coupled receptors. These four
receptor subtypes are further classified on the basis of their ability to either
stimulate or inhibit adenylate cyclase activity. The A2A and A2B receptors
mediate the stimulation of adenylate cyclase, while the A1 and A3 adenosine
receptors inhibit adenylate cyclase activity. Additionally, A1 receptors have been
38 | Unit 2. Drugs affecting mediatory processes
reported to mediate adenosine inhibition of Ca2+ conductance, whereas A2B and

A3 receptors stimulate phospholipase activity. Both A1 receptors and A2A play
roles in the heart, regulating myocardial oxygen consumption and coronary blood
flow, while the A2A receptor also has broader anti-inflammatory effects
throughout the body. These two receptors also have an important role in the brain,
regulating the release of other neurotransmitters such as dopamine and glutamine,
while the A2B and A3 receptors are located mainly peripherally and are involved
in processes such as inflammation and immune responses.
Most older compounds acting on adenosine receptors are nonselective, with
the endogenous agonist adenosine being used in hospitals as treatment for severe
tachycardia, and acting directly to slow the heart through action on all four
adenosine receptors in heart tissue, as well as producing a sedative effect through
action on A1 and A2A receptors in the brain.
Xantines derivatives such as caffeine and theophylline act as non-selective
antagonists at A1 and A2A receptors in both heart and brain and so have the
opposite effect to adenosine, producing a stimulant effect and rapid heart rate.
These compounds also act as phosphodiesterase inhibitors, which produces
additional anti-inflammatory effects, and makes them medically useful for the
treatment of conditions such as asthma, but less suitable for use in scientific
research.
By nature of caffeine's purine structure it binds to some of the same
receptors as adenosine. Caffeine's principal mode of action is as an antagonist of
adenosine receptors in the brain.
With the proviso that theophylline and theobromine cross the blood brain
barrier very poorly (thus a low CNS effects on the heart), the pharmacological
effects of adenosine may therefore be blunted in individuals who are taking large
quantities of methylxanthines (e.g., caffeine, found in coffee, or theophylline in
tea, or theobromine, as found in chocolate). Generalized, adenosine has an
inhibitory effect in the CNS. Caffeine's stimulatory effects, on the other hand, are
primarily (although not entirely) credited to its inhibition of adenosine by binding
to the same receptors, and therefore effectively blocking adenosine receptors in the
CNS. This reduction in adenosine activity leads to increased activity of the
neurotransmitters dopamine and glutamate.
Adenosine antagonists are widely used in neonatal medicine, because a
reduction in A1 expression appears to prevent hypoxia-induced ventriculomegaly
and loss of white matter and therefore raise the possibility that pharmacological
blockade of A1 may have clinical utility. Theophylline and caffeine are
nonselective adenosine antagonists that are used to stimulate respiration in
premature infants.
Newer adenosine receptor agonists and antagonists are much more potent
and subtype-selective, and have allowed extensive research into the effects of
blocking or stimulating the individual adenosine receptor subtypes, which is now
resulting in a new generation of more selective drugs with many potential medical
uses. Some of these compounds are still derived from adenosine or from the
xanthine family, but researchers in this area have also discovered many selective
adenosine receptor ligands that are entirely structurally distinct, giving a wide
range of possible directions for future research.
Adenosine is believed to be an anti-inflamatory agent at the A2A receptor.
Topical treatment of adenosine to foot wounds in diabetes mellitus has been shown
in lab animals to drastically increase tissue repair and reconstruction. Topical
administration of adenosine for use in wound healing deficiencies and diabetes
mellitus in humans is currently under clinical investigation. Methotrexate's anti-
inflammatory effect may be due to its stimulation of adenosine release.
When administered intravenously, adenosine causes transient heart block in
the atrioventricular (AV) node. This is mediated via the A1 receptor, inhibiting
adenylyl cyclase, reducing cAMP and so causing cell hyperpolarization by
increasing outward K+ flux. It also causes endothelial dependent relaxation of
smooth muscle as it is found inside the artery walls. This causes dilation of the
"normal" segments of arteries; i.e. where the endotelium is not separated from the
tunica media by atherosclerotic plaque. This feature allows physicians to use
adenosine to test for blockages in the coronary arteries, by exaggerating the
difference between the normal and abnormal segments. In individuals suspected of
suffering from a supraventricular tachycardia, adenosine is used to help identify
the rhythm. Certain supraventricular tachycardias (SVTs) can be successfully
terminated with adenosine. This includes any re-entrant arrhythmias that require
the AV node for the re-entry, e.g., AV re-entrant tachycardia, AV nodal re-entrant
tachycardia. In addition, atrial tachycardia can sometimes be terminated with
adenosine. Adenosine has an indirect effect on atrial tissue causing a shortening of
the refractory period. When administered via a central lumen catheter, adenosine
has been shown to initiate atrial fibrillation because of its effect on atrial tissue. In
individuals with accessory pathways, the onset of atrial fibrillation can lead to a
life-threatening ventricular febrilation. Fast rhythms of the heart that are confined
to the atria (e.g., atrial fibrillation, atrial flutter) or ventricles (e.g., monomorphic
ventricular tachycardia) and do not involve the AV node as part of the re-entrant
circuit is not typically converted by adenosine. However, the ventricular response
rate is temporarily slowed with adenosine in such cases. Because of the effects of
adenosine on AV node-dependent supraventricular tachycardias, adenosine is
considered as a class IV antiarrhythmic agent. When adenosine is used to
cardiovert an abnormal rhythm, it is normal for the heart to enter ventricular
asystole for a few seconds. This can be disconcerting to a normally conscious
patient, and is associated with angina-like sensations in the chest. Thereby, there
are:
Parmacologic effects of adenosine are:
antiarrhythmic
vasodilatation
improvement of microcirculation
decreasing of platelet aggregation
| Unit 2. Drugs affecting mediatory processes
improvement of methabolic and reparative processes in eye lens and for

deceleration of its degeneration
antiphlogistic
negative inotropic, negative chronotropic, negative dromotropic associated
with inhibition of transport of calcium ions into the cell
Indications for adenosine use:
supraventricular tachyarrhythmias
arrhythmia re-entry
Wolff-Parkinson-White (WPW) syndrome (adenosine can be administered
only when available equipment for cardioversion)
in ophthalmology - for improvement of methabolic and reparative processes
in eye lens and for deceleration of its degeneration
inflammatory eye diseases
cataracta
Side effects of adenosine:
facial flushing
rash on the chest
bradycardia
arterial hypotension
lightheadedness
diaphoresis
nausea after administration of adenosine due to its vasodilatory effects
Contraindications for adenosine use:
sick sinus syndrome (without a pacemaker)
2nd and 3rd degree of heart block (without a pacemaker)
long QT syndrome
severe arterial hypotension
decompensated heart failure
asthma (in nowadays the selective adenosine antagonists are being
investigated for the use in the treatment of asthma)
poisoning-induced tachycardia
in WPW syndrome, adenosine may be administered if equipment for
cardioversion is immediately available as a backup.
These symptoms are transitory, usually lasting less than one minute. This
lasts a few seconds after administration of a bolus dose, during transient asystole
induced by intravenous administration. In some cases adenosine can make patients'
limbs feel numb for about 2–5 minutes after administration intravenously
depending on the dosage (usually above 12 mg).
Caution! The recommended dose may be increased in patients on
theophylline since methylxanthines prevent binding of adenosine at receptor sites.
The dose is often decreased in patients on dipyridamole (Persantine) and diazepam
(Valium) because adenosine potentiates the effects of these drugs. The
recommended dose is also reduced by half in patients who are presenting
congestive heart failure, myocardial infarction, shock, hypoxia, and/or hepatic or
renal insufficiency, and in elderly patients. Dopamine may precipitate toxicity in

the patient. Carbamazepine may increase heart block. Theophylline and caffeine
(methylxanthines) competitively antagonize adenosine's effects; an increased dose
of adenosine may be required. Dipyridamole potentiates the action of adenosine,
requiring the use of lower doses.
The adenosine analog, NITD008 has been reported to directly inhibit the
recombinant an RNA-dependent RNA polymerase of the dengue virus by
terminating its RNA chain synthesis. This suppresses peak viremia, rise in
cytokines and prevented infected animal from death raising the possibility of a new
treatment for this flavivirus. The 7-deaza-adenosine analog has been shown to
inhibit the replication of the hepatic C virus. Such adenosine analogs are
potentially clinically useful since they can be taken orally.
Table 3. Places of location, mechanism and effects of activation of adenosine

receptors in human body
Receptor Mechanism Places of location Effects of
activation*
This receptor has an Ubiquitous negative chronotropic;
A1 inhibitory function on throughout the antinociception; role in
most of the tissues in entire body: spermatozoa
which it is expressed. In brain > heart, capacitation;
the brain, it slows kidney, lung; chemotaxis in
metabolic activity by a spermatozoa; immature
combination of actions. adipocytes; plasmacytoid dendritic
Presynaptically, it brain (cerebral cells
reduces synaptic vesicle cortex,
release while post hippocampus),
synaptically it has been spinal cord and
found to stabilize the trigeminal ganglia
magnesium on the N-
methyl-D-aspartate
receptor.
The activity of A2A It is abundant in coronary artery
A2A adenosine receptor, a G- basal ganglia, vasodilatation;
protein coupled receptor vasculature and increases blood flow to
family member, is platelets and it is a the myocardium;
mediated by G proteins major target of causes arterial
that activate adenylyl caffeine. hypotension; decreases
cyclase. Jejunum, ileum, in neurotransmission
colon; activity such as
Heart, lung > norepinephrine,
kidney, brain; dopamine and
Thymus gland > acetylcholine;
heart, lung > inhibition of platelet
spleen, leukocytes aggregation;
42 |Unit 2. Drugs affecting mediatory processes
down-regulation of
chemokine receptor
function, that is very
important in case of
infectious diseases and
inflammatory
processes;
regulation of cytokine
production
This integral membrane Jejunum, ileum, bronchospasm;
A2B protein stimulates colon; inhibition of cell
adenylate cyclase activity Brain, heart, kidney proliferation;
in the presence of and lung; vasodilation of small
adenosine. It stimulate Bronchial smooth coronary arteries;
release calcium → muscle cells; vasoconstriction of
activate calmodulin → Large intestine, chorionic vessels
activate myosin light cecum, urinary
chain kinase → bladder
phosphrylate myosin light
chain → myosin light
chain plus actin →
bronchoconstriction.
This protein also interacts
with netrin-1, which is
involved in axon
elongation.
Stimulation of
Phospholipase С activity.
It has been shown in Liver, lung > brain, cardioprotective in
A3 studies to inhibit some aorta; cardiac ischemia;
specific signal pathways CNS: corpus inhibition of neutrophil
of adenosine. It allows for callosum, degranulation
the inhibition of growth substantia nigra,
in human melanoma cells. thalamus,
subthalamic
nucleus, spinal
cord; hippocampus;
adrenal cortex,
adrenal medulla >
spleen, small
intestine;
jejunum, ileum,
colon; kidney,
heart; placenta
* - there are pharmacologic effects of adenosine agonists.
Table 4*. Agonists and antagonists of adenosine receptors

Receptor Agonists Antagonists
A1 adenosine; cyclopentyladenosine; theophylline; caffeine; flavanone;
2-chloroadenosine galangin; sakuranetin; morin
A2A adenosine; cyclopentyladenosine; theophylline; caffeine; flavone;
2-chloroadenosine; galangin; sakuranetin; morin; visnagin
N(6)-cyclohexyladenosine; metrifudil
A2B adenosine; cyclopentyladenosine; alloxazine; theophylline
2-chloroadenosine
A3 adenosine; (R)-niguldipine; galangin; nicardipine;
cyclopentyladenosine sakuranetin; flavanone; flavone;
visnagin; theophylline
* - adopted from IUPHR Database. International Union of Pharmacology. 2012.
http://www.iuphar-db.org/DATABASE
An adenosine reuptake inhibitor is a type of drug which acts as a reuptake

inhibitor for the purine nucleoside and neurotransmitter adenosine by blocking the
action of one or more of the equilibrative nucleoside transporters. This in turn
leads to increased extracellular concentrations of adenosine and therefore an
increase in adenosinergic neurotransmission.
List of the adenosine reuptake inhibitors:
Acadesine, Acetate, Barbiturates, Benzodiazepines, Calcium Channel Blockers,
Carbamazepine, Carisoprodol, Cilostazol, Cyclobenzaprine, Dilazep,
Dipyridamole, Estradiol, Ethanol (Alcohol), Flumazenil, Hexobendine,
Hydroxyzine, Indomethacin, Inosine, Meprobamate, Nitrobenzylthioguanosine,
Nitrobenzylthioinosine, Papaverine, Pentoxifylline, Phenothiazines, Phenytoin,
Progesterone, Propentofylline, Propofol, Puromycin, Soluflazine, Toyocamycin,
Tracazolate, Tricyclic antidepressants.
Dopamine a simple organic chemical in the catecholamine family is a
monoamine neurotransmitter which plays a number of important physiological
roles in the bodies of animals. In addition to being a catecholamine and a
monoamine, dopamine may be classified as a substituted phenethylamine. Its name
derives from its chemical structure, which consists of an amine group (NH 2) linked
to a catechol structure called dihydroxyphenethylamine, the decarboxylated form
of dihydroxyphenylalanine (acronym DOPA). In the brain, dopamine functions as
a neurotransmitter – a chemical agent released by nerve cells to send signals to
other nerve cells. The human brain uses five known types of dopamine receptors,
labeled D1, D2, D3, D4, and D5. Dopamine is produced in several areas of the
brain, including the substancia nigra and the ventral tegmental area.
Dopamine is a neurotransmitter produced in the brains of humans and animals.
Also, it is a hormone produced by the adrenal medulla and other tissues (eg kidneys).
Dopamine is a biochemical precursor of norepinephrine (and epinephrine). Dopamine
has synthetic analogs and stimulatirs of its release in the brain. In particular,
amphetamine stimulates dopamine release directly by influence of its transport,
cocaine and psychostimulators block the dopamine reuptake and increase of its
concentration in synaptic and that allows people who use them, get a sense of fun
artificially. Morphine and nicotine mimic the action of natural neuromediators, but
alcohol blocks action of dopamine antagonists. A long-term drug stimulation of
dopamine release lead to decline of natural dopamine production and reduction of
quantity of dopamine receptors in the brain that encourages addicts to increase the
dose to get the same effect.
Currently some dopamine agonists are used for treatment of Parkinson’s
disease, and some antidepressants have dopaminergic activity. Simultaneously,
reserpine blocks the presynaptic dopamine pumping into vesicles. Drugs that
reduce dopamine level cause inability to experience pleasure.
Biosynthesis (scheme 1). Dopamine is synthesized in the body from within
cells (mainly by neurons and cells in the medulla of the adrenal glands) and can be
created from any one of the following three amino acids:
L-Phenylalanine (PHE)
L-Tyrosine (L-4-hydroxyphenylalanine; TYR)
L-DOPA (L-3,4-dihydroxyphenylalanine; DOPA)
These amino acids are provided from natural sources such as the ingestion of
various kinds of food, with L-tyrosine being the most common of the three.
Although dopamine itself is also commonly found in many types of food, unlike
the amino acids that form it, it is incapable of crossing the protective blood-brain-
barrier (BBB), which severely restricts its functionality upon consumption. It must
be formed from within the walls of the BBB to properly perform its cognitive
duties, though not its peripheral actions. Dopamine itself is also used in the
synthesis of the following related catecholamine neurotransmitters:
Norepinephrine (β,3,4-trihydroxyphenethylamine; Noradrenaline; NE, NA)
Epinephrine (β,3-dihydroxy-N-methylphenethylamine; Adrenaline;
EPI, ADR)
This is the complete metabolic pathway:
 L-Phenylalanine → L-Tyrosine → L-DOPA → Dopamine
→ Norepinephrine → Epinephrine
L-Phenylalanine is converted into L-tyrosine by the enzyme phenylalanine
hydroxylase (PAH) with molecular oxygen (O2) and tetrahydrobiopterin (THB) as
cofactors. L-Tyrosine is converted into L-DOPA by the enzyme tyrosine
hydroxylase (TH) with tetrahydrofolic acid (THFA), O2, and ferrous iron (Fe2+) as
cofactors. L-DOPA is converted into dopamine by the enzyme aromatic L-amino
acid decarboxylase (AAAD; also known as DOPA decarboxylase – DDC) with
pyridoxal phosphate (PLP) as the cofactor. The reactions are illustrated as follows:
PAH: L-Phenylalanine + THB + O2 → L-Tyrosine + DHB + H2O
TH: L-Tyrosine + THFA + O2 + Fe2+ → L-DOPA + DHFA + H2O + Fe2+
AAAD: L-DOPA + PLP → Dopamine + PLP + CO2
Dopamine is converted into norepinephrine by the enzyme dopamine β-
hydroxylase (DBH) with O2 and L-ascorbic acid as cofactors. Finally,
norepinephrine is converted into epinephrine by the enzyme phenylethanolamine
Scheme 1. Catecholamine biosynthesis (adopted from http://en.wikipedia.org).

N-methyltransferase (PNMT) with S-adenosyl-L-methionine (SAMe) as the

cofactor. The reactions are illustrated as follows:
 DBH: Dopamine + Ascorbic Acid + O2 → Norepinephrine + DHA + H2O
PNMT: Norepinephrine + SAMe → Epinephrine + Homocysteine
It should be noted that some of the cofactors also require their own synthesis.
Guanine → Guanosine → Guanosine Monophosphate (GMP) →
Guanosine Diphosphate (GDP) → Guanosine Triphosphate (GTP)
GTP Cyclohydrolase I (GTPCH, GCH): GTP → 7,8-
 Dihydroneopterin Triphosphate (DHNTP)
6-Pyruvoyltetrahydropterin Synthase (PTS, PTPS): DHNTP →
 6-Pyruvoyltetrahydropterin (Dyspropterin)
Sepiapterin Reductase (SPR): Dyspropterin → Tetrahydrobiopterin (THB)
Folic Acid → DHFA → THFA
Pyridoxine → Pyridoxamine → Pyridoxal → PLP (requires Zn 2+ as
a cofactor)
Niacin → Nicotinamide → NMN → NAD+ → NADH / NADP+ →
NADPH
Deficiency in any required amino acid or cofactor will result in subsequent
dopamine, norepinephrine, and epinephrine biosynthesis impairment and
deficiency as well. Conversely, supplementation with L-phenylalanine, L-tyrosine,
L-DOPA, or any of the cofactors will increase their respective concentrations.
Storage, release, and reuptake. Upon synthesis, dopamine is transported
from the cell cytosol into synaptic vesicles by the vesicular monoamine transporter
2 (VMAT2). Dopamine is stored in and remains in these vesicles until an action
potential occurs and forces them to merge with the cell membrane via a process
known as exocytosis, thereby dumping dopamine into synapses.
Once in the synapse, dopamine binds to and activates postsynaptic dopamine
receptors, resulting in the signal of the presynaptic cell being propagated to the
postsynaptic neuron. Dopamine also binds to presynaptic dopamine receptors,
which can either excite the presynaptic cell or inhibit it depending on their
electrical potential. Presynaptic receptors with an inhibitory potential are called
autoreceptors and inhibit neurotransmitter synthesis and release. They serve to
keep dopamine levels normalized in certain pathways when release is acutely
disrupted and becomes too high or too low.
After dopamine has performed its synaptic duties, it is taken up via reuptake
back into the presynaptic cell by either the high-affinity dopamine transporter
(DAT) or the low-affinity plasma membrane monoamine transporter (PMAT).
Once back in the cytosol, it is subsequently repackaged into vesicles by VMAT2.
Degradation (scheme 2). Dopamine is directly broken down into inactive
metabolites by two enzymes, monoamine oxidase (MAO), and catechol-O-methyl
transferase (COMT). It is equally metabolized by the two respective isoforms of
MAO, MAO-A and MAO-B. Dopamine is metabolized by MAO into 3,4-
dihydroxyphenylacetaldehyde (DOPAL). DOPAL is further metabolized into 3,4-
dihydroxyphenylacetic acid (DOPAC) by the enzyme aldehyde dehydrogenase
(ALDH). DOPAL can also be reduced to 3,4-dihydroxyphenylethanol (DOPET;

also known as hydroxytyrosol) by aldose reductase (AR) to a lesser extent. Finally,
COMT reduces DOPAC and DOPET to homovanillic acid (HVA) and 3-methoxy-
4-hydroxyphenylethanol (MOPET), respectively, which are then excreted in the
urine. COMT can also directly metabolize dopamine into 3-methoxytyramine (3-
MT), which is then subsequently metabolized to HVA by MAO and is excreted in
the urine as well. The reactions are illustrated and summarized here:
Dopamine → DOPAL → DOPAC → HVA
Dopamine → DOPAL → DOPET → MOPET
Dopamine → 3-MT → HVA
Scheme 2. Dopamine degradation (adopted from http://en.wikipedia.org/).
In most areas of the brain, including the striatum and basal ganglia,
dopamine is inactivated by reuptake via the DAT, then enzymatic breakdown by
MAO into DOPAC. In the prefrontal cortex, however, there are very few DAT
proteins, and dopamine is inactivated instead by reuptake via the norepinephrine
transporter (NET), presumably on neighboring norepinephrine neurons, then
enzymatic breakdown by COMT into 3-MT. The DAT pathway is roughly an order
of agnitude faster than the NET pathway. Dopamine that is not broken down by
enzymes is repackaged into vesicles for reuse by VMAT2.
Dopamine receptors. Dopamine binds and activates a group of called the
dopamine receptors to cause its physiological effects in the body. The dopamine
receptors are a series of five G protein-coupled receptors (GPCRs), which consist
of the D1, D2, D3, D4, and D5 receptors. As GPCRs, they work by modulating the
cyclic adenosine monophosphate (cAMP) second messenger system to produce a
cellular response. The five receptors are individually categorized into two
distinctive groups based on their varying properties and effects, the D1-like and
D2-like subfamilies. The D1 and D5 receptors belong to the D1-like subfamily.
They are coupled to Gs and increase the cellular concentrations of cAMP by the
activation of the enzyme adenylate cyclase. The D2, D3, and D4 receptors belong
to the D2-like subfamily. They are coupled to Gi/Go and decrease the cellular
concentrations of cAMP by inhibition of adenylate cyclase. Ultimately, the cAMP
second messenger system, through several downstream mechanisms, works by
facilitating the opening of plasmalemmal ion channels which allow extracellular
positively charged ions such as Na+ and K+ to enter the cytoplasm of the cell in
excess quantities, thereby generating an action potential. The D1-like receptors
enhance the activity of the system and are therefore excitatory, while the D2-like
receptors in contrast do the opposite and are therefore inhibitory. The D1 receptor
is the most widespread dopamine receptor in the central nervous system. The D3,
D4, and D5 receptors are present in significantly lower levels than are the D1 and
D2 receptors. In fact, the D1 receptors are approximately 100x more common than
the D5 receptors. However, dopamine binds to the D3, D4, and D5 receptors with
nanomolar or submicromolar affinity constants, while its corresponding constants
for D1 and D2 receptors are in the micromolar ranges. As an example, dopamine
has 20-fold higher binding affinity for the D3 receptor in comparison to the D2
receptor, and 10-fold higher binding affinity for the D5 receptor over the D1
receptor. Hence, overall activation of the system seems to be more or less well-
balanced.
Table 5*. Dopamine receptors: family, gene, type, mechanism and potential in
human body
Family Receptor Gene Type Mechanism Potential

D1 DRD1 Increasing intracellular levels of
D1-like D5 DRD5 Gs-coupled. cAMP by activating adenylate Excitatory
cyclase.
D2 DRD2 Decreasing intracellular levels of
D2-like D3 DRD3 Gi/Go- cAMP by inhibiting adenylate Inhibitory
D4 DRD4 coupled. cyclase.
Table 6. Places of location, mechanism and effects of activation of dopamine

Receptor Mechanism Places of location Effects of
activation**
D1 Adenylate Adrenal cortex, heart, Contribution to
cyclase kidney; pathophysiology and/or
stimulation; Leukocytes*; maintenance of
Calcium channel Immune cells in the increased blood
spleen, bone marrow, and pressure in essential
blood circulation hypertension;
D1 receptors are
responsible for the
cognitive-enhancing
effects of dopamine;
Analgesic
D2 Adenylate Adrenal cortex; Stimulation of
cyclase Leukocytes*; accumulation of cAMP
inhibition; Immune cells in the in membrane particles
Potassium spleen, bone marrow, and of the kidney medulla;
channel blood circulation Control of renal blood
flow;
D2 receptors are more
specific for motor
actions;
Low D2 receptor-
binding is found in
people with social
anxiety;
Analgesic
D3 Adenylate Ventral striatum/nucleus
cyclase accumbens > neostriatum,
inhibition; cerebral cortex, cerebellar
Potassium cortex;
channel Brain: nucleus accumbens
and islands of Calleja;
Leukocytes*;
Immune cells in the
spleen, bone marrow, and
blood circulation
D4 Adenylate Brain: Pre-frontal cortex, Modulation of von
cyclase inhibition temporal neocortex > Willebrand factor
occipital cortex; secretion in endothelial
Pulmonary artery; cells;
Aortic endothelium, D4 receptors are
umbilical vein responsible for the
endothelium; cognitive-enhancing
50 | Unit 2.
Drugs affecting mediatory processes
Brain: Occipital lobe, effects of dopamine
cerebellum, hippocampus,
middle frontal gyrus of
temporal lobe, cingulate
gyrus of frontal lobe,
amygdala > superior
temporal gyrus of temporal
lobe, superior frontal gyrus
of frontal lobe, thalamus,
septal nuclei,
hypothalamus > substantia
nigra, caudate nucleus,
globus pallidus, superior
parietal lobe;
Leukocytes*;
Immune cells in the
blood circulation
D5 Adenylate Pulmonary artery;
cyclase Brain: striatum,
stimulation hippocampus, dentate
gyrus, subiculum, frontal
cortex, limbic cortex,
occipital cortex,
cerebellum;
Leukocytes*;
Immune cells in the
blood circulation
* - there is low expression of receptors on T lymphocytes and monocytes, moderate expression
on neutrophils and eosinophils, and high expression on B cells and natural killer cells.
** - there are pharmacologic effects of dopamine agonists.
Biological role. Dopamine has many functions in the brain, including

important roles in behavior (inhibits the tendency to make unwanted actions) and
cognition, voluntary movement, motivation, punishment and reward, inhibition of
prolactin production (involved in lactation and sexual gratification), sleep, mood,
attention, working memory, and learning. Sociability is also closely tied to
dopamine neurotransmission. Dopaminergic neurons (i.e., neurons whose primary
neurotransmitter is dopamine) are present chiefly in the ventral tegmental area
(VTA) of the midbrain, the substantia nigra pars compacta, and the arcuate nucleus
of the hypothalamus. Dopaminergic neurons of the midbrain are the main source of
dopamine in the brain.
Dopamine is commonly associated with the reward system of the brain,
providing feelings of enjoyment and reinforcement to motivate a person to perform
certain activities. Dopamine is released (particularly in areas such as the nucleus
accumbens and prefrontal cortex) by rewarding experiences such as food, sex,
drugs, and neutral stimuli that become associated with them. Recent studies
indicate that aggression may also stimulate the release of dopamine in this way.
Dopamine may also have a role in the salience of potentially important stimuli,
such as sources of reward or of danger, and dopamine assists decision-making,
increases the creative drive of idea generation.
Other pathological states have also been associated with dopamine
dysfunction, such as schizophrenia, psychosis, autism, and attention deficit,
hyperactivity disorder, as well as drug abuse, whereas hyperdopaminergic state is
related with hypersociality, hypersexuality. Libido can be increased by drugs that
affect dopamine, but not by drugs that affect opioid peptides or other
neurotransmitters. Insufficient dopamine biosynthesis in the dopaminergic neurons
can cause Parkinson's disease, a condition in which one loses the ability to execute
smooth, controlled movements. Decreased levels of dopamine have been associated
with painful symptoms that frequently occur in Parkinson's disease: painful clinical
conditions, including burning mouth syndrome, fibromyalgia, and restless legs
syndrome.
Dopamine is the primary neuroendocrine inhibitor of the secretion of
prolactin from the anterior pituitary gland. Thus, in the context of regulating
prolactin secretion, dopamine is occasionally called prolactin-inhibiting factor
(PIF), prolactin-inhibiting hormone (PIH), or prolactostatin.
In the frontal lobes, dopamine controls the flow of information from other
areas of the brain.
The analgesic capacity of dopamine occurs as a result of dopamine D2 and
D3 receptor activation.
Dopamine is one of the neurotransmitters implicated in the control of nausea
and vomiting via interactions in the chemoreceptor trigger zone.
Dopamine acts upon receptors present on immune cells, with all subtypes of
dopamine receptors found on leukocytes: T lymphocytes, monocytes, neutrophils,
eosinophils, B cells and natural killer cells.The sympathetic innervation of
lymphoid tissues is dopaminergic, and increases during stress. Dopamine can also
affect immune cells in the spleen, bone marrow, and blood circulation. In addition,
dopamine can be synthesized and released by the immune cells themselves. The
effects of dopamine on immune cells depend upon their physiological state. While
dopamine activates resting T cells, it inhibits them when they are activated.
Disorders such as schizophrenia and Parkinson's disease, in which there are
changes in brain dopamine receptors and dopamine signaling pathways, are also
associated with altered immune functioning.
Dopamine as a hormone has some physiological properties: increases the
peripheral vascular resistance, systolic blood pressure, increases the force of heart
contractions, cardiac output, heart rate, increases myocardial oxygen demand and
myocardial oxygen delivery by increased coronary blood flow, reduces renal
vascular resistance, increases blood flow in them, and kidney filtration, increases
natriuresis, extends the mesenteric vessels, in contrast to other catecholamines,
inhibits the synthesis of aldosterone in the adrenal cortex, decreases the secretion
of renin by the kidneys, increases the secretion of prostaglandins by kidney tissue,

inhibits the motility of the stomach and intestines, causes relaxation of the lower
esophageal sphincter and strengthens gastro-esophageal and duodeno-gastric
reflux, in the CNS dopamine stimulates chemoreceptors trigger zone and vomiting
center and thus participates in the act of vomiting.
Should be noted that increased levels of dopamine in the blood plasma has
little effect on the central nervous system functions because it was a bad passes
through the blood-brain barrier, except on the outside of the blood-brain barrier
sites, such as the trigger zone.
Increased levels of dopamine in the blood plasma is in shock, trauma, burns,
blood loss, stress states, with different pain syndromes, anxiety, fear. Thereby,
dopamine plays a role in adaptation of the organism to stressful situations, trauma,
blood loss, etc.
Also, dopamine levels in the blood are increased with deterioration of renal
blood flow or increased content of sodium ions, as well as angiotensin or
aldosterone in plasma. Apparently, this is due to increased synthesis of dopamine
from DOPA in kidney tissue in case of renal ischemia, or when they are under the
influence of angiotensin and aldosterone. Perhaps this is a physiological
mechanism for the correction of renal ischemia, and to counteract
hyperaldosteronemia and hypernatremia. According to researches, aging process
manifests a decrease in the number and density of dopamine D2-receptor striatum,
reduced concentration of dopamine in the subcortical brain.
Clinical symptoms of these changes are impoverishment facial expressions,
some general slowness, stooped, old man's posture, a shortening of stride length,
changes are also noted in the cognitive sphere: decreased with age, speed of
reaction, it becomes harder to acquire and implement a new program of action,
reduced the level of attention and the volume of memory.
As a drug dopamine cannot cross the BBB and it does not directly affect
CNS, but its precursors cross the BBB relatively easily. Pharmacologic effects of
dopamine are dependent from dose (Chapter 6., p. 121).
Table 7**. Agonists and antagonists of dopamine receptors

D1 dopamine, norepinephrine, lisuride, flupentixol, fluphenazine, haloperidol,
cabergoline, bromocriptine, pergolide, butaclamol, flupentixol,
quinogolide, apomorphine, rotigotine chlorpromazine, thioridazine,
clozapine, ketanserin, spiperone
D2* dopamine, aripiprazole, lisuride, domperidone, nemonapride, N-
cabergoline, terguride, roxindole, N- methylspiperone, raclopride,
porphynorapomorphine, eticlopride, spiperone, terguride,
bromocriptine, apomorphine, nafadotride, roxindole, nafadotride,
pergolide, bromocriptine, piribedil, haloperidol, raclopride, amisulpiride,
apomorphine, quinpirole, flupentixol, pimozide, amisulpiride,
pramipexole, quinelorane, quinpirole raclopride, chlorpromazine, sulpiride,
clozapine, flupenthixol
Chapter 3. | 53
Intermediants
D3 dopamine, lisuride, cabergoline, nemonapride, spiperone, eticlopride,
terguride, roxindole, N- nafadotride, flupentixol, raclopride,
porphynorapomorphine, pramipexole, pimozide, haloperidol, raclopride,
pergolide, apomorphine, amisulpiride, butaclamol,
bromocriptine, quinpirole, chlorpromazine, domperidone,
quinelorane, quinpirole, apomorphine, haloperidol, risperidone, sulpiride,
piribedil clozapine
D4 dopamine, apomorphine, lisuride, nemonapride, N-methylspiperone,
roxindole, quinpirole, cabergoline, spiperone, haloperidol, terguride,
pergolide chlorpromazine, clozapine,
aripiprazole, eticlopride, piribedil,
bromocriptine, nafadotride, butaclamol,
raclopride, sulpiride
D5 dopamine, lisuride, cabergoline, flupentixol, fluphenazine, butaclamol,
apomorphine, beta-ergocriptine, chlorpromazine, clozapine, haloperidol,
norepinephrine, pergolide, ketanserin, thioridazine, spiperone
bromocriptine, rotigotine
* - terguride is a partial agonist at the D2S receptor and an antagonist at the D2L receptor;
roxindole is a partial agonist at the D2S receptor and an antagonist at the D2L receptor.
** - adopted from IUPHR Database. International Union of Pharmacology. 2012.
Serotonin or 5-hydroxytryptamine (5-HT) is a monoamine

neurotransmitter, derived from tryptophan. Approximately 90% of human’s
serotonin is located in the enterochromaffin cells in the GIT. The remainder is
synthesized in serotonergic neurons of the CNS and regulates mood, appetite,
sleep, cognitive functions, including memory and learning.
Biosynthesis (scheme 3). Serotonin is synthesized from the amino acid L-
tryptophan by a short metabolic pathway consisting of two enzymes: tryptophan
hydroxylase (TPH) and amino acid decarboxylase (DDC). The TPH-mediated
reaction is the rate-limiting step in the pathway. TPH has been shown to exist in
two forms: TPH1, found in several tissues, and TPH2, which is a brain-specific
isoform. Tryptophan hydroxylase is synthesized only in the soma of serotonergic
neurons, hydroxylation occurs in the presence of iron ions and the cofactor of
pteridine.
A prerequisite for the synthesis of serotonin is the presence of sunlight. In
the dark hormone melatonin is synthesized from serotonin in the pineal gland.
Methabolism of Serotonin. Under the action of the enzyme monoamine
oxidase (MAO), serotonin is converted to 5-hydroxyindolaldehyd which, in turn,
can be reversibly transformed into a 5-hydroxytriptophol under the influence of
alcohol dehydrogenase. 5 hydroxyindolaldehyd irreversibly under the influence of
acetat dehydrogenase converted into 5-hydroxyindoleacetic acid, which is then
excreted in the urine and feces.
Serotonin is a precursor of melatonin, which is formed by the pineal gland’s
enzyme arylalkylamine N-acetyltransferase (AANAT) in the pineal gland.
Also, turning with a MAO into 5-hydroxyindol-3-acetaldehyde, serotonin
can be under the influence of aldehydreductase become tryptophol, and under the
influence of acetaldehydrogenase-2 – into 5-hydroxyindoleacetic acid (5-HIAA)

chiefly by the liver.
Serotonin may be involved in the formation of endogenous opiates, reacts
with acetaldehyde to form a harmalol. Norepinephrine inhibits serotonin release.
Scheme 3. The pathway for the synthesis of serotonin from tryptophan (adopted from
http://en.wikipedia.org/).
Circulation of serotonin. Serotonin which was synthesized by neuron is

pumped into vesicles. This process is a proton-conjugate transport. In the vesicle
ions H+ are pumped with the proton-dependent ATPase. On leaving the protons the
molecules of serotonin enter the vesicle on a gradient. Further, in response to
depolarization of terminals, serotonin output in the synaptic cleft.
Part of it is involved in the transmission of nerve impulses, acting on the
postsynaptic membrane of cell receptors, and the other part returns to the
presynaptic neuron with reuptake. Autoregulation of serotonin release is achieved
by activation of presynaptic 5-HT receptors, triggering a cascade of reactions that
regulate the entry of calcium ions into presynaptic terminals. Calcium ions, in turn,
activate the phosphorylation of the enzyme 5-tryptophan hydroxylase, which
provides the conversion of tryptophan into serotonin, which leads to increased
synthesis of serotonin.
Reuptake of serotonin is produced by the transporter which is the specific
protein, which produces sodium-potassium-coupled transport. Returning in the cell
mediator splits with MAO to 5-HIAA.
The chemistry of serotonin transport systems is also similar to those of
norepinephrine.
Biological role. The physiological functions of serotonin are extremely
diverse. Reduction of the serotonin level leads to increase of sensitivity of pain in
the human organism.
Serotonin secreted from the enterochromaffin cells and releases eventually
into the blood. There, it is actively taken up by blood platelets, which store it.
When the platelets bind to a clot, they disgorge serotonin, where it serves as a
vasoconstrictor and helps to regulate hemostasis and blood clotting. Serotonin also
is a growth factor for some types of cells, which may give it a role in wound
healing.
One type of tumor, called carcinoid, sometimes secretes large amounts of
serotonin into the blood, which causes various forms of the carcinoid syndrome of
flushing, diarrhea, and heart problems. Because of serotonin's growth-promoting
effect on cardiac myocytes, persons with serotonin-secreting carcinoid may suffer
a right heart (tricuspid) valve disease syndrome, caused by proliferation of
myocytes onto the valve.
Serotonin is also found in fungi and plants. Serotonin's presence in insect
venoms and plant spines serves to cause pain, which is a side effect of serotonin
injection. Serotonin is produced by pathogenic amoebas, and its effect on the gut
causes diarrhea. Its widespread presence in many seeds and fruits may serve to
stimulate the digestive tract into expelling the seeds.
Serotonin functions as a neurotransmitter in the nervous systems of human
organism. Serotonergic neurons are grouped in the brain stem (truncus encephali)
where are descending projections in spinal marrow and ascending projections in
cerebellum, limbic system, basal ganglia and cortex. At the same time neurons are
distinguished morphologically, electrophysiologically, target innervation and
sensitivity to certain neurotoxic agents.
Ultimately, the functions of serotonin are: to facilitate motor activity; to play
an important role in the mechanisms of hypothalamic regulation of hormonal
pituitary function; to cause an increase in the secretion of prolactin and other

hormones of the anterior pituitary. These effects are opposite to the effects of
stimulation of dopaminergic pathways.
Serotonin as a hormone. Serotonin plays an important role in blood
clotting. Blood platelets contain significant amounts of serotonin and have the
ability to capture and accumulate serotonin from blood plasma. Serotonin increases
the functional activity of platelets and their tendency to aggregation and thrombus
formation. Besides, serotonin causes an increase of synthesis of clotting factors by
the liver. Serotonin excretion from damaged tissue is one of the mechanisms of
blood clotting at the place of injury, the more so that serotonin causes
vasoconstriction.
Serotonin is involved in the processes of allergy and inflammation. It
increases vascular permeability, enhances chemotaxis and migration of leukocytes
to inflammatory, increases levels of eosinophils in the blood, enhances mast cell
degranulation and release of other mediators of allergy and inflammation.
Local (eg, intramuscular) administration of exogenous serotonin causes

intense pain at the injection site. Presumably serotonin along with histamine and
prostaglandins, stimulating receptors in the tissues, plays a role in the occurrence
of pain impulses from the site of injury or inflammation.
Large amount of serotonin is produced in the intestine. Serotonin enhances
motility and secretory activity of GIT, more over, it increases bacterial metabolism
in the colon. Colon bacteria themselves have the ability to decarboxylate
tryptophan and thereby increase the secretion of serotonin by intestine. In
dysbiosis and several other diseases of the colon intestinal serotonin production is
greatly reduced.
The massive release of serotonin from the dying cells of the stomach and
intestine mucous when exposed to cytotoxic chemotherapy is one of the causes of
ausea and vomiting, diarrhea during chemotherapy of malignant tumors. A similar
condition is in some malignant tumors, ectopically producing serotonin.
A high quantity of serotonin is also observed in the uterus. Serotonin plays a
role in paracrine regulation of contractility of the uterus and fallopian tubes, and to
coordinate delivery. Production of serotonin in the myometrium increases in a few
hours or days before birth and increases even more directly in the process of
childbirth.
Also, serotonin is involved in the process of ovulation - the serotonin
concentration (and other biologically active substances) in the follicular fluid is
increased just before the rupture of the follicle, which apparently leads to an
increase pressure within the follicle. Serotonin has a significant influence on the
processes of excitation and inhibition in the sexual organs. Thus, the increase in
the concentration of serotonin in males delays the onset of ejaculation.
In humans, though insulin regulates blood sugar and insulin-like growth
factors (IGF) regulates growth, serotonin controls the release of both hormones, so
serotonin suppresses insulin release from the beta cells in the pancreas, and
exposure to selective serotonin re-uptake inhibitors reduces fetal growth. Human

serotonin can also act as a growth factor directly. Liver damage increases cellular
expression of 5-HT2A and 5-HT2B receptors. Serotonin present in the blood then
stimulates cellular growth to repair liver damage. 5HT2B receptors also activate
osteocytes, which build up bone. However, serotonin also inhibits osteoblasts,
through 5-HT1B receptors.
In summary, we can say that serotonin has the main
Biologic/Pharmacologic effects:
increases tone of smooth muscles
causes vasoconctrictin except the vessels of skeleton muscles and heart
increases blood pressure
activates platelet aggregation and clot formation
enhances tone and motility of GIT and myometrium
stimulates pain
stimulates nausea and vomiting
stimulates cellular growth to repair liver damage
suppresses insulin release from the beta cells in the pancreas
regulates the bone formation
causes fibrosis anywhere in the body, especially retroperitoneal fibrosis,
cardiac fibrosis.
Pathologies associated with serotonin. Reduced level of serotonin in the
brain is one of the factors in the formation of depressions and severe migraines.
Hyperactivation of serotonin receptors may lead to hallucinations. Elevated levels
of activity may be associated with schizophrenia.
Several classes of drugs target the 5-HT system, including some
antidepressants, antipsychotics, anxiolytics, antiemetics, and antimigraine drugs, as
well as the psychedelic drugs and empathogens. Some serotonergic agonist drugs
also cause fibrosis anywhere in the body, particularly the syndrome of
retroperitoneal fibrosis, as well as cardiac valve fibrosis. In the past, three groups
of serotonergic drugs have been epidemiologically linked with these syndromes.
They are the serotonergic vasoconstrictive antimigraine drugs (ergotamine and
methysergide), the serotonergic appetite suppressant drugs (fenfluramine,
chlorphentermine, and aminorex), and certain anti-Parkinsonian dopaminergic
agonists, which also stimulate serotonergic 5-HT2B receptors. These include
pergolide and cabergoline, but not the more dopamine-specific lisuride.
Some 5-HT3 antagonists, such as ondansetron, granisetron, and tropisetron,

are important antiemetic agents. They are particularly important in treating the
nausea and vomiting that occur during anticancer chemotherapy using cytotoxic
drugs. Another application is in the treatment of postoperative nausea and
vomiting.
In humans defective signaling of serotonin in the brain may be the root
cause of sudden infant death syndrome. Researchers now believe that low levels
of serotonin in the animals' brainstem, which control heartbeat and breathing, may
have caused sudden death.
Serotonin syndrome. Extremely high levels of serotonin can cause a
condition known as serotonin syndrome, with toxic and potentially fatal effects.
This is a rare but potentially deadly reaction to taking drugs (psychostimulators,
antidepressants, opiates, tranquilisers and the like) or drugs that increase
serotonergic transmission including the recreational use of them. The clinical
symptoms include disorientation, confusion, agitation, hypomania, restlessness,
fever, chills, tremors, sweating, diarrhea, nausea, vomiting, ataxia, hyperreflexia,
myoclonia (sudden brief jerks of the muscles), abdominal cramping pain,
hyperpyrexia (fever above 41,1° C), hypertension, tachycardia, etc., ranging from
barely noticeable to the deadly. The intensity of the symptoms of serotonin
syndrome varies over a wide spectrum, and the milder forms are seen even at
nontoxic levels.
At the initial stage of the serotonin syndrome manifested primarily by the
gastrointestinal and nervous system disorders characterized by dyspeptic
symptoms (wildness, abdominal cramps, bloating, diarrhea, nausea, and rarely
vomiting, etc.), extrapyramidal disorder (tremor, dysarthria, restlessness, muscle
hypertonicity), hyperreflexia, myoclonic twitches, usually beginning in the feet
and spreading throughout the body. At its last stages, with extremely rarely
observed in the malignant form of flow, serotonin syndrome similar to neuroleptic
malignant syndrome clinic: sudden onset of fever, profuse sweating, mask ike face,
greasiness of the face, acute cardiovascular disorders leading to death.
Serotonin is found in mushrooms, fruits and vegetables, in nuts of the

walnut (Juglans) and hickory (Carya) genera, in plantains, pineapples, bananas,
kiwifruit, plums, and tomatoes. Foods with a high content of tryptophan (an amino
acid from which serotonin is produced): dates, bananas, plums, figs, tomatoes,
milk, soybeans, dark chocolate, contribute to the biosynthesis of serotonin and
often improves mood. They can cause acute toxic effects (serotonin syndrome), if
they used in large quantities during treatment with certain groups of
antidepressants. Unlike its precursors, 5- HTP and tryptophan, serotonin does not
cross the BBB, which means ingesting serotonin in the diet has no effect on brain
serotonin levels.
Wasps and deathstalker scorpions have serotonin in their venom that allow
to increase the pain of their stings on large animals, and also to cause lethal
vasoconstriction in smaller prey. Serotonin is one compound of the poison
contained in stinging nettles (Urtica dioica), where it causes pain on injection in
the same manner as its presence in insect venoms. Several plants contain serotonin;
examples are plants from the Anadenanthera genus that are used in the
hallucinogenic yopo snuff.
Table 8. Places of location, mechanism and effects of activation of serotonin

Receptor Mechanism Places of location Effects of activation*

5-HT1A Adenylate Benign and malignant Stimulation of cell
cyclase prostate tissue; proliferation
inhibition; Poorly expressed in
Stimulates cAMP coronary arteries, atrium,
accumulation ventricle and epicardium;
Spinal cord: dorsal horn >
ventral horn;
CNS: dentate gyrus,
hippocampus, subiculum,
parahippocampal gyrus
and neocortical regions
(superficial and middle
laminae), raphe of the
brainstem;
Kidney: medullary and
cortical thick ascending
limbs, distal convoluted
tubules, connecting tubule
cells, principal cells of the
initial collecting tubule
5-HT1B Adenylate Cortical cerebral arteries Vasoconstriction
cyclase inhibition (smooth muscle cell layer
> endothelial cell layer);
Coronary artery > atrium >
ventricle, epicardium;
Benign and malignant
prostate tissue;
Brain: substantia nigra,
globus pallidus > striatum
> amygdala, hippocampus,
septa region,
hypothalamus;
Trigeminal ganglion;
Brain: substantia nigra,
globus pallidus > caudate
nucleus, putamen, nucleus
accumbens, central gray,
hippocampal formation >
various cortical regions;
Brain: striatum, cortex,
lateral geniculate nucleus,
raphe nucleus
60 | Unit 2.
5-HT1D Adenylate Benign and malignant Growth hormone
cyclase inhibition prostate tissue; release
Globus pallidus > frontal
cortex > putamen;
Spinal cord: dorsal horn >
ventral horn;
Poorly expressed in
coronary arteries, atrium,
ventricle and epicardium;
Trigeminal ganglion
5-ht1e Adenylate Putamen > frontal cortex,
cyclase inhibition globus pallidus;
Cortical areas, caudate
nucleus, putamen,
amygdala
5-HT1F Adenylate Brain, uterus
cyclase inhibition (endometrium and
myometrium), mesentery;
Ventricle wall > atrium,
epicardium, coronary
artery;
Brain: lamina V of the
frontal cortex in large
pyramidal cells,
hippocampal pyramidal
cells, thalamic nuclei and
dorsal raphe
5-HT2A Phospholipase C Atrium, coronary artery > Contraction of
stimulation ventricle wall, epicardium; coronary arteries;
CNS: parahippocampal Enhancement of
gyrus and neocortical platelet activation
regions (superficial and induced by ADP
middle laminae) > dentate
(adenosine-
gyrus, hippocampus (all
diphosphate) and
fields), subiculum;
Spinal cord: dorsal horn thrombin
5-HT2B Uterus, trachea, small

intestine > liver, heart,
ovary, skeletal muscle,
brain, kidney, testis,
placenta, prostate,
pancreas
5-HT2C Phospholipase C Resting lymphocytes
stimulation;
Adenylate
cyclase inhibition
Chapter 3.
Intermediants | 61
5-HT4 Adenylate Brain: caudate nucleus > Potentiation of
cyclase lenticular nucleus, neurally-mediated
stimulation substantia nigra, contraction of the
Calcium channel; hippocampus, frontal detrusor muscle;
Following cAMP cortex; Stimulation of
production Heart: atria, ventricles;
activation of Ca2+ Brain: striato-nigral aldosterone secretion
channels and system > hippocampus, from the adrenal
inhibition of K+ neocortex and colliculus; cortex;
channels have Brain: basal ganglia Stimulation of gastric
been described in (caudate nucleus, putamen, emptying;
atrial myocytes nucleus accumbens), Relaxation of colon;
and neurons hippocampal formation Stimulation of
respectively (CA1, CA2, CA3 fields, peristaltic reflex
subiculum, dentate gyrus, (ascending contraction
entorhinal cortex); and descending
Brain: basal ganglia relaxation);
(caudate nucleus, putamen, Atrial arrhythmic
nucleus accumbens, globus contractions
pallidus, substantia nigra)
> amygdala, hippocampal
formation, cortex;
Smooth muscle of the
rectum;
Myenteric plexus and
smooth muscle of the
colon;
Myenteric plexus of the
stomach;
Esophagus, atrium,
sinoatrial node, adrenal
gland, frontal cortex;
Brain: Frontal cortex,
hippocampus > caudate,
putamen > globus palidus,
substantia nigra
5-ht5a Adenylate Resting lymphocytes;
cyclase Brain: amygdala, caudate
inhibition; nucleus, cerebellum,
Phospholipase C hypothalamus, substantia
stimulation; nigra, thalamus;
It should be noted Expression not seen in any
that as well as peripheral tissues;
reports showing Brain: neocortical regions
that the receptor (mainly layers II-III and
couples to many V-VI), hippocampus
different (dentate gyrus and
62 | Unit 2.
signalling pyramidal cell layer of
pathways, there CA1 and CA3 fields),
are also reports cerebellum (Purkinje cells,
showing that the dentate nucleus and
receptor has granule cells)
difficulty
coupling to any
intracellular
pathways
5-ht5b
5-HT6 Adenylate A truncated, nonfunctional
cyclase 5-HT6 receptor with a 289
stimulation; bp deletion of the region
Phospholipase C coding for transmembrane
stimulation IV and third intracellular
loop has been identified in
the caudate and substantia
nigra of the human brain
5-HT7 Adenylate Heart: ventricle wall >
cyclase epicardium > atrium,
stimulation coronary artery;
Coronary artery > brain >
descending colon, ileum;
Amygdala, aorta, cerebral
cortex, hippocampus,
thalamus, small intestine >
spleen, pancreas, stomach,
kidney;
CNS: trigeminal ganglia;
CNS: suprachiasmatic
nucleus
* - there are pharmacologic effects of serotonin agonists.
Table 9**. Agonists and antagonists of serotonin receptors

5-HT1A lisuride, roxindole, flesinoxan, repinotan, tiospirone, tertatolol,
spiroxatrine, ipsapirone, pergolide, pindolol, methiothepin, spiperone,
terguride, ziprasidone, aripiprazole, propranolol, flurocarazolol, pizotifen,
tandospirone, zalospirone, yohimbine, fluspirilene, thioridazine,
naphthylpiperazine, ocaperidone, iloperidone, pimozide, flurocarazolol,
bromocriptine, buspirone, sertindole, zotepine, risperidone,
cabergoline, donitriptan, eletriptan, butaclamol, cyamemazine,
naratriptan, nafadotride, xanomeline, chlorpromazine, haloperidol,
apomorphine, clozapine, fluparoxan, pipamperone, raclopride, ketanserin,
zolmitriptan, quetiapine, piribedil, ritanserin
rizatriptan, sumatriptan, quinpirole,
olanzapine, urapidil
Chapter 3. | 63
Intermediants
5-HT1B alniditan, eletriptan, sumatriptan, ketanserin, mianserin, spiperone,
donitriptan, oxymetazoline, yohimbine, cyanopindolol, pindolol,
donitriptan, alniditan, 7-methoxy-1- methiothepin, metergoline, zotepine,
naphthylpiperazine, methysergide, sertindole, rauwolscine,
dihydroergotamine, ziprasidone, 5- risperidone, flurocarazolol,
(nonyloxy)-tryptamine, lysergol, pipamperone, ocaperidone, ritanserin
naratriptan, eletriptan, 1-
naphthylpiperazine, lisuride,
zolmitriptan, sumatriptan,
xanomeline, rizatriptan, pergolide,
terguride, bromocriptine, cabergoline,
olanzapine, tryptamine, clozapine,
aripiprazole, roxindole
5-HT1D eletriptan, alniditan, sumatriptan, zotepine, metergoline, ocaperidone,
donitriptan, dihydroergotamine, methysergide, risperidone, bufotenine,
oxymetazoline, donitriptan, 7- rauwolscine, methiothepin, ritanserin,
methoxy-1-naphthylpiperazine, ketanserin, yohimbine, sertindole,
lysergol, alniditan, lisuride, cyanopindolol, pipamperone,
ziprasidone, eletriptan, lysergic acid, haloperidol, fluspirilene, spiperone
zolmitriptan, naratriptan, sumatriptan,
xanomeline, 1-naphthylpiperazine,
cabergoline, bromocriptine, pergolide,
rizatriptan, terguride, aripiprazole,
dimethyltryptamine, tryptamine,
roxindole, clozapine, olanzapine,
quetiapine,
5-ht1e naratriptan, zolmitriptan, lysergol, methylergonovine, 1-
ergonovine, eletriptan, rizatriptan, naphthylpiperazine, methiothepin,
clozapine, ziprasidone, 5- methysergide, zotepine, sertindole,
fluorotryptamine, ergotamine, risperidone, yohimbine, metergoline,
tryptamine, donitriptan, quetiapine, fluspirilene, rauwolscine
olanzapine, sumatriptan,
dihydroergotamine, xanomeline
5-HT1F naratriptan, eletriptan, sumatriptan, methysergide, methylergonovine, 1-
zolmitriptan, clozapine, naphthylpiperazine, yohimbine,
dihydroergotamine, ergotamine, metergoline, sertindole, methiothepin,
rizatriptan, olanzapine, xanomeline, risperidone, metergoline
quetiapine, tryptamine, donitriptan,
ergotamine, sumatriptan,
5-HT2A methylergonovine, ergotamine, altanserin, ketanserin, methylspiperone,
lisuride, ergonovine, terguride, risperidone, ritanserin, sertindole,
cabergoline, pergolide, aripiprazole, ziprasidone, spiperone, amoxapine,
methysergide, tryptamine, methysergide, clozapine,
bromocriptine, quetiapine, quipazine, cyamemazine, chlorpromazine,
lorcaserin, donitriptan, quinpirole, mianserin, olanzapine,
pindolol butaclamol,mesulergine, metergoline,
zotepine, amesergide, methiothepin,
risperidone, sarpogrelate, amitriptyline,
methysergide, sergolexole, clozapine,
pipamperone, ritanserin, perphenazine,
roxindole, loxapine, fluspirilene,
64 | Unit 2.
trazodone, trifluoperazine, thioridazine,
fluphenazine, haloperidol, trazodone,
pimozide, thiothixene, mesulergine,
apomorphine, xanomeline, bufotenine,
quetiapine, fluoxetine, molindone,
duloxetine, norfluoxetine, agomelatine,
pindolol
5-HT2B* methylergonovine, cabergoline, rauwolscine, methiothepin, ritanserin,
ergotamine, methysergide, pergolide, lisuride, metergoline, 1-
norfenfluramine, quipazine, naphthylpiperazine, mesulergine,
tryptamine, quipazine, lorcaserin, clozapine, tegaserod, mianserin,
quinpirole, pindolol, lorcaserin terguride, amesergide, xanomeline,
yohimbine, roxindole, bromocriptine,
mianserin, trazodone, apomorphine,
agomelatine, piboserod, sarpogrelate,
spiroxatrine, ketanserin, piboserod,
spiperone, haloperidol, piribedil,
pindolol, fluoxetine, norfluoxetine,
melatonin
5-HT2C ergotamine, methysergide, methysergide, mesulergine, mianserin,
methylergonovine, lisuride, sertindole, ritanserin, metergoline,
lorcaserin, aripiprazole, quipazine, amoxapine, zotepine, amitriptyline,
oxymetazoline, pergolide, tryptamine, methiothepin, tiospirone, olanzapine,
cabergoline, bromocriptine, ziprasidone, clozapine, cyamemazine,
quinpirole loxapine, chlorpromazine, risperidone,
sarpogrelate, xanomeline, fluoxetine,
terguride, thioridazine, ketanserin,
apomorphine, perphenazine, trazodone,
norfluoxetine, roxindole,
trifluoperazine, agomelatine,
duloxetine, spiperone
5-HT4 tegaserod, prucalopride, cisapride, piboserod, tropisetron,
renzapride, zacopride, mosapride,
metoclopramide
5-ht5a donitriptan, lysergic acid, sumatriptan methiothepin, ergotamine, ritanserin,
methysergide, clozapine, metergoline,
bufotenine, yohimbine, clozapine,
propranolol, ketanserin
5-ht5b
5-HT6 ergotamine, lisuride, bromocriptine, zotepine, methiothepin,
pergolide, lergotrile, chlorpromazine, thioridazine,
dimethyltryptamine, 1- dihydroergotamine, olanzapine,
naphthylpiperazine, 5- amoxapine, clozapine, fluperlapine,
benzyloxytryptamine, aripiprazole, perphenazine, bufotenine, loxapine,
tryptamine, xanomeline, donitriptan fluperlapine, iloperidone, fluphenazine,
α-ergocryptine, dihydroergocristine,
pimozide, ritanserin, thioridazine,
mianserin, perphenazine, tiospirone,
amitriptyline, metergoline,
cyproheptadine, methysergide,
duloxetine, risperidone, tiospirone,
Chapter 3. | 65
Intermediants
fluoxetine, spiperone, risperidone,
sumatriptan, mesulergine
5-HT7 lisuride, pergolide, aripiprazole, risperidone, pimozide, methiothepin,
bromocriptine, tryptamine, 1- tiospirone, zotepine, metergoline,
naphthylpiperazine, bufotenine, ziprasidone, pirenperone, fluperlapine,
xanomeline, tryptamine, buspirone, fluphenazine, dihydroergotamine,
cisapride mesulergine, methysergide, spiperone,
ritanserin, clozapine, iloperidone,
chlorpromazine, perphenazine,
butaclamol, mianserin, amoxapine,
cyproheptadine, ergotamine,
cyamemazine, thioridazine, loxapine,
ritanserin, dihydroergocryptine,
amitriptyline, olanzapine, ketanserin,
haloperidol, buspirone, sumatriptan,
yohimbine
* - methysergide is a low intrinsic efficacy partial agonist, although in some functional assays it
may behave as an antagonist.
**- adopted from IUPHR Database. International Union of Pharmacology. 2012.
At present, the physiological significance of serotonin has been

insufficiently studied. In clinical practice, serotonin and its synthetic analogues,
substances similar to it in chemical structure, agonists and antagonists of serotonin
receptors are not used widely. Among them were used in the clinic, highly anti-
emetics (ondansetron, tropisetron, granisetron), drugs stimulating GIT motility
(metoclopramide), haemostatic drugs (serotonin adipinate), antialergic drugs
(cyproheptadine, fenspiride, etc.), antihypertensives (ketanserin, urapidil,
indoramin) and as the drugs for treatment and prophylactic of migraine
(dihydroergotamine, ergotamine, sumatriptan, naratriptan, pizotifen, etc.) as an
adaptogen (mexaminum, melatonin, etc.) to improve sleep (mexaminum,
melatonin, etc.) as antipsychotics (olanzapine, clozapine, chlorpromazine,
perphenazine, fluphenazine, etc.). For more details, these drugs will be discussed
in the relevant chapters.
Histamine is an organic nitrogen compound involved in local immune
responses as well as regulating physiological function in the GIT and acting as a
neurotransmitter.
Synthesis and methabolism (scheme 4). Histamine is derived from the
decarboxylation of the amino acid histidine, a reaction catalyzed by the enzyme L-
histidine decarboxylase. It is a hydrophilic vasoactive amine. Once formed,
histamine is either stored or rapidly inactivated by its primary degradative
enzymes, histamine-N-methyltransferase or diamine oxidase. In the central
nervous system, histamine released into the synapses is primarily broken down by
histamine-N-methyltransferase, while in other tissues both enzymes may play a
role. Several enzymes, including MAO-B and aldehyde dehydrogenase 2 family
(mitochondrial) (ALDH2), further process the immediate metabolites of histamine
for excretion or recycling.
Bacteria also are capable of producing histamine using histidine

decarboxylase enzymes unrelated to those found in animals. A non-infectious form
of foodborne disease, scombroid poisoning (is a foodborne illness that results from
eating spoiled/decayed fish), is due to histamine production by bacteria in spoiled
food, particularly fish. Fermented foods and beverages naturally contain small
quantities of histamine due to a similar conversion performed by fermenting
bacteria or yeasts. Sake contains histamine in the 20– 40 mg/L range; wines
contain it in the 2–10 mg/L range.
Scheme 4. Conversion of histidine to histamine by histidine decarboxylase (adopted

from http://en.wikipedia.org/).
Storage and release. Histamine is a ubiquitous chemical messenger that can

be released from a variety of cells (e.g. mast cells, enterochromaffin-like cells,
neurons) to act on one of four histamine receptors: H1, H2, H3 and H4.
Most histamine in the body is generated in granules in mast cells or in white
blood cells called basophils. Mast cells are especially numerous at sites of potential
injury - the nose, mouth, and feet, internal body surfaces, and blood vessels. Non-
mast cell histamine is found in several tissues, including the brain, where it
functions as a neurotransmitter. Another important site of histamine storage and
release is the enterochromaffin-like (ECL) cell of the stomach.
The most important pathophysiologic mechanism of mast cell and basophil
histamine release is immunologic. These cells, if sensitized by IgE antibodies
attached to their membranes, degranulate when exposed to the appropriate antigen.
Certain amines and alkaloids, including such drugs as morphine, and curare
alkaloids, can displace histamine in granules and cause its release. Antibiotics like
polymyxin are also found to stimulate histamine release.
Histamine release occurs when allergens bind to mast-cell-bound IgE

antibodies. Reduction of IgE overproduction may lower the likelihood of allergens
finding sufficient free IgE to trigger a mast-cell-release of histamine.
Mechanism of action. Histamine exerts its actions by combining with
specific cellular histamine receptors. The four histamine receptors that have been
discovered in humans are designated H1 through H4, and are all G protein-coupled
receptors (GPCR).
Table 10. Places of location, mechanism and effects of activation of histamine

Receptor Mechanism Places of location Effects of activation*

H1 Adenylate Smooth muscle; Bronchoconstriction,
cyclase Myometrium; Endothelium; bronchial smooth muscle
stimulation; Cranial arteries; contraction; Vasodilation;
Phospholipase C Central nervous system; Separation of endothelial
stimulation; GIT; cells (responsible for hives);
Ca2+ Myocardium (ventricle > Pain and itching due to
mobilisation atrium) insect stings;
The primary receptors
involved in allergic rhinitis
symptoms and motion
sickness;
Sleep/wake regulation;
Mediation of
hypersensitivity reactions
and allergic response
(release of proinflammatory
mediators, interleukins,
cytokines, cell adhesion,
chemotaxis, and others);
Regulation of food intake
and cognitive functions in
the CNS
H2 Phospholipase C GIT, parietal cells; Relaxation of smooth
stimulation; Mast cells; muscle;
Adenylate Vascular smooth muscle Primarily involved in
cyclase cells; vasodilation; Stimulate
stimulation Brain (cerebrum, caudate gastric acid secretion;
leading to the and putamen nuclei, Inhibition of neutrophil
formation of external layers of cerebral activation; Inhibition of
cAMP cortex > hippocampal neutrophil chemotaxis and
formation > dentate nucleus T-lymphocyte proliferation
of cerebellum);
Myocardium (atrium and
ventricle)
H3 Adenylate Central nervous system - Decreased neurotransmitter
cyclase inhibition brain: thalamus, caudate release: histamine,
nucleus, putamen, acetylcholine,
cerebellum, amygdala, norepinephrine, serotonin;
substantia nigra, Vasoconstriction; Activation
hippocampus, of spinal H3 receptors
hypothalamus, cerebral inhibits mechanical
cortex; to a lesser extent nociception
peripheral nervous system Regulation of activity of
68 | Unit 2.
tissue; histamine and other
Presynaptic receptors are neurotransmitters in CNS;
located in adrenergic and Regulation of sleep/wake;
cholinergic nerve endings cognitive functions in CNS;
Inhibition of nociception;
H4 Phospholipase C Basophils; Plays a role in chemotaxis,
stimulation; Monocytes; eosinophil shape change;
Inhibition of Eosinophils and dendritic Upregulation of cell surface
adenylyl cyclase; cells; adhesion molecules;
Mobilisation of Mast cells; Activation of chemotaxic,
calcium from Leukocytes, spleen, lung, acummulation of eosinophils
intracellular liver > heart, skeletal in place of inflammation
stores; muscle;
Stimulation of Brain: cerebellum,
mitogen-activated hippocampus, bone
protein (MAP) marrow; thymus, small
kinase in both intestine, spleen, colon
heterologous
expression
systems and
native immune
cells
* - there are pharmacologic effects of histamine agonists.
Physiologic functions. Histamine is one of the endogenous factors

(mediators) involved in the regulation of vital body functions and plays an
important role in the pathogenesis of several disease states. Under normal
circumstances, histamine is in the body mostly in the bound, inactive state. In
various pathological processes (anaphylactic shock, burns, frostbite, hay fever,
urticaria and allergic diseases), as well as when certain chemicals are increased in
the body, the amount of free histamine is enhanced. Liberatores of histamine are d-
tubocurarine, morphine, iodine-containing radiocontrast agents, macromolecular
compounds (dextran, etc.) and other drugs.
Free histamine has high activity: it causes spasm of smooth muscles
(including muscles of the bronchi), the expansion of the capillaries and a decrease
in blood pressure, blood stasis in the capillaries and increased permeability of their
walls, causes swelling of surrounding tissue and blood clots.
Histamine causes increased secretion of gastric juice. In CNS histamine
plays the role of mediator, regulates sleep, and controls the mechanisms of
memories and learning. It also affects erection and sexual functions. While
histamine has stimulatory effects upon neurons, it also has suppressive ones that
protect against the susceptibility to convulsion, drug sensitization, denervation
supersensitivity, ischemic lesions and stress. Metabolites of histamine are
increased in the cerebrospinal fluid of people with schizophrenia, while the
efficiency of H1 receptor binding sites is decreased.
Histamine plays a role in angiogenesis. As an integral part of the immune

system, histamine may be involved in immune system disorders and allergies.
Effects on nasal mucous membrane: Increased vascular permeability causes
fluid to escape from capillaries into the tissues, which leads to the classic symptoms
of an allergic reaction: a runny nose and watery eyes. Allergens can bind to IgE-
loaded mast cells in the nasal cavity's mucous membranes. This can lead to three
clinical responses: sneezing due to histamine-associated sensory neural stimulation;
hyper-secretion from glandular tissue; nasal congestion due to vascular engorgement
associated with vasodilation and increased capillary permeability.
Table 11*. Agonists and antagonists of histamine receptors

H1 dimethylhistaprodifen, histamine, 2- cyproheptadine, doxepin, clozapine,
pyridylethylamine zotepine, olanzapine, pyrilamine,
triprolidine, thiothixene, quetiapine,
cetirizine, chlorpromazine,
chlorpheniramine, loxapine,
perphenazine, diphenhydramine,
fluspirilene, fluphenazine, risperidone,
thioridazine, ziprasidone, aripiprazole,
trifluoperazine, sertindole, cetirizine,
chlorpheniramine, arpromidine,
pimozide, haloperidol, molindone,
clobenpropit, pipamperone,
impromidine
H2 impromidine, arpromidine, histamine, aminopotentidine,
burimamide iodoaminopotentidine, tiotidine,
ranitidine, cimetidine, metiamide,
burimamide, clobenpropit
H3 methylhistamine, histamine, iodoproxyfan, clobenpropit,
iodoproxyfan, immepip, perceptin, ciproxifan, iodophenpropit,
imetit, imbutamine, proxyfan, clobenpropit, thioperamide, proxyfan,
impentamine, impromidine, dimaprit impentamine, burimamide, clozapine
H4 histamine, methylhistamine, imetit, pyrilamine, clobenpropit,
immepip, impromidine, iodophenpropit, thioperamide,
ethylhistamine, dimethylhistamine, burimamide, clozapine, ciproxifan
dimaprit, methimepip, improgan
http://www.iuphar-db.org/DATABASE .
The use of histamine, its analogs and histamine receptors activators is

restricted by their advers effects and specific biological and pharmaceutical
activities. Of all the known histamine receptor blockers in clinical practice
primarily the blockers H1 and H2 histamine receptors are used, mostly, as the drugs
that reduce gastric mucosa secretion, and as the antiallergic drugs.
Classification of H1 histamine blockers

 I generation:
o diphenhydramine (Alledryl, Allergan, Allergin, Allergival, Amidryl, Benadryl,
Benzhydraminum, Diabenyl, Dimedrolum, Dimedryl, Dimidril, Restamin, etc.). o
clemastine (Alagyl, Anhistan, Fenistil, Fumartin, Lecasol, Meclastin,
Mecloprodine fumarate, Rekonin, Rivtagil, Tavegil, Tavist, etc.).
o promethazine (Allergan, Antiallersin, Atosil, Diprazinum, Fargan, Phenergan,
Pipolphen, etc.).
o sequifenadine (Sequifenadine hydrochloride, Bicarphenum, Histafen).
o chloropyramine (Allergan S, Chlorneoantergan, Chloropyribenzamine h/cl.,
Chlortripelenamine h/cl., Halopyramine, Sinopen, Suprastin, Synopen).
 II generation:
o astemizole (Alermizol, Asmoval, Astelong, Astemisan, Hismanal, Histalong,
Histamanal, Ifirab, Lembil, Mibiron, Stelert, Stemiz, Vagran).
o azelastine (Allergodil). o
acrivastatine (Semprex). o
dimetindene (Fenistil).
o loratadine (Claritin, Clarotadinum, Klarisens, Lomilan, Loratin, Loridin).
o mebhydrolin (Dialin, Diazolinum, Incidal, Mebhydrolini Napadisylas, Omeril).
o qiufenadine (Phencarolum).
o terfenadine (Bronal, Caradonel, Daylert, Histadine, Rapidal, Riter, Seldane,
Tamagon, Teridine, Termenadin, Thelladadan, Triludan, Tofrin, Toldan, Teridine,
Termenadin, Thelldan, Triludan, Tofrin, Toldan, Trexyl, etc.)
o cyproheptadine (Adekin, Apetigen, Astonin, Cipractin, Cyprodin, Istabin,
Pariactin, Peritol, Supersan, Vieldrin, Vinorex, etc.).
o ebastine (Kestine). o
fenspiride (Eurespal)
 III generation:
o desloratadine (NeoClarityn, Claramax, Clarinex, Larinex, Aerius, Dazit,
Azomyr, Deselex and Delot.).
o levocetirizine (Allear, Alcet , Seasonix, Teczine, T-Day Syrup, Vozet, Zyxem,
Zilola, Xaltec, Xozal, Xusal, Xuzal, Xyzal).
o fexofenadine (Allegra, Telfast).
o cetirizine (Alerza, Allertec, Cetirinax, Cetrine, Letizen, Parlazin, Reactine,
Zetrinal, Zodac, Zyncet, Zyrtec, etc.).
H1 histamine blockers for local use:
o levocabastyine (Gistimet)
o bamipine (Soventol)
Classification of H2 histamine blockers
 I generation: cimetidine (Altramet, Belomet, Benomet, Cigamet, Cimesan,
Histodyl, Primamet, Tagamet, Ulcometine, Ulcuzal, Zagastrol, etc.) – it is deleted
preparation (deregistered), not manufactured and is not used nowadays because of
the many side effects.
II generation: ranitidine (Acidex, Aciloc-E, Anistal, Gertocalm, Histac,

Raniberl, Ranigast, Ranisan, Ranital, Ranitin, Rantac, Renx, Zantac, Zantin, Zoran,
Ulcodin, Ulcosan, Ulran, etc.).
III generation: famotidine (Acipep, Amifatidine, Antodine, Blokacid,
Famocid, Famodar, Femocin, Fudon, Fluxid, Gaster, Gasterogen, Lecedil,
Novafam, Pepcidine, Pepcid, Pepdul, Quamatel, Topcid, Ulceran, Ulfamid, etc.).
IV generation: nizatidine (Axid)
V generation: roxatidine (Roxane).
Miscellaneous H2 blockers
lafutidine (Stogar, Protecadin)
ebrotidine (Ebrocit)
Eicosanoids. Prostaglandines and others arachidonate metabolites, such as
prostacyclin (PGI2), thromboxane A2 (TxA2), leukotroenes (LTs), lipoxins,
hepoxilins belong to the class of eicosanoids. Membrane lipids supply the substrate
for the synthesis of eicosanoids and platelet-activating factor (PAF). Eicosanoids
are not stored but are produced by most cells. PGs, PGI2, TxA2 are known as
prostanoids. The eicosanoids act through activation of specific cell surface
receptors that couple to intracellular second-messenger systems to modulate
cellular activity.
This table (tabl. 12) lists the major classes of eicosanoid receptors and their
signaling characteristics. Splice variants for EP3, TP, and FP are indicated. Major
phenotypes in knockout mouse models are listed. Ca2+i – cytosolic Ca2+; cAMP –
cyclic AMP; PLC - phospholipase C (activation leads to increased cellular inositol
phosphate and diacylglycerol generation and increased Ca2+i); IsoPs – isoprostanes;
Table 12*. Eicosanoid receptors
Receptor Primary ligand Secondary Primary Major phenotype in

ligand coupling knockout mice**
DP1 PGD2 cAMP (Gs) ↓Allergic asthma
DP2/CHRT2 PGD2 15d-PGJ2 ↓cAMP, Ca2+ or ↓Allergic airway
(Gi) inflammation
EP1 PGE2 PGI2 Ca2+ i (Gq) ↓Response of colon
carcinogens
EP2 PGE2 cAMP (Gs) Impaired ovulation
and fertilization
Salt-sensitive
hypertension
EP3 I-VI, e,f PGE2 ↓cAMP, Ca2+ i Resistance to pyrogens
(Gi); ↓Acute cutaneous
cAMP (Gs); inflammation
PLC, Ca2+ i (Gq)
EP4 PGE2 cAMP (Gs) Patent ductus
arteriosus
↓Bone mass/density in
aged mice
Bowel inflammatory
response
↓Colon
carcinogenesis
FPA,B PGF2α IsoPs PLC, Ca2+ i (Gq) Failure of parturition
IP PGI2 PGE2 cAMP (Gs) Thrombotic response
↓Response to vascular
injury
Atherosclerosis
Cardiac fibrosis
Salt-sensitive
hypertension
↓Joint inflammation
TPα, β TxA2 IsoPs PLC, Ca2+ i (Gq, Bleeding time
Gi, G12/13, G16); ↓Response to vascular
Rho, ERK injury
activation (Gq,
↓Atherosclerosis
G12/13, G16) Survival after cardiac
allograft
BLT1 LTB4 Ca2+I, ↓cAMP Some suppression of
(G16, Gi) inflammatory response
BLT2 LTB4 12(S)-HETE Ca2+I (Gq-like, Gi- ?
like, Gz-like)
CysLT1 LTD4 LTC4/LTE4 PLC, Ca2+i (Gq) ↓Innate and adaptive
immune vascular
permeability response
Pulmonary
inflammatory and
fibrotic response
2+
CysLT2 LTC4/ LTD4 LTE4 PLC, Ca i (Gq) ↓Pulmonary
inflammatory and
fibrotic response
- adopted from Goodman & Gilman’s The Pharmacological Basis of Therapeutics. 12th
Edition, 2011.
** - A knockout mouse is a genetically engineered mouse in which researchers have inactivated,
or "knocked out," an existing gene by replacing it or disrupting it with an artificial piece of
DNA. The loss of gene activity often causes changes in a mouse's phenotype, which includes
appearance, behavior and other observable physical and biochemical characteristics. Knockout
mice are important animal models for studying the role of genes which have been sequenced but
whose functions have not been determined. By causing a specific gene to be inactive in the
mouse, and observing any differences from normal behaviour or physiology, researchers can
infer its probable function. Mice are currently the most closely related laboratory animal species
to humans for which the knockout technique can easily be applied. They are widely used in
knockout experiments, especially those investigating genetic questions that relate to human
physiology. Gene knockout in rats is much harder and has only been possible since 2003. The
first recorded knockout mouse was created by Mario R. Capecchi, Martin Evans and Oliver
Smithies in 1989, for which they were awarded the Nobel Prize for Medicine in 2007 (adopted
from http://en.wikipedia.org/wiki/Knockout_mouse).
ERK – extracellular signal regulated protein kinase; Rho – a family of small

signaling G proteins; 15d-PGJ2 – 15-deoxy-∆12, 14- PGJ2; DP2 – is a member of the
fMLP-receptor superfamily; fMLP – formyl-methionyl-leucyl-phenylalanine;
CysLT – Cysteinyl leukotriene receptor; HETE – hydroxyeicosatetraenoic acid.
A prostaglandin (PG) is any member of a group of lipid compounds that
are derived enzymatically from fatty acids and have important functions in the
animal body. Every prostaglandin contains 20 carbon atoms, including a 5-carbon
ring.
They are mediators and have a variety of strong physiological effects, such
as regulating the contraction and relaxation of smooth muscle tissue.
Prostaglandins are not endocrine hormones, but autocrine or paracrine, which are
locally acting messenger molecules. They differ from hormones in that they are not
produced at a discrete site but in many places throughout the human body. Also,
their target cells are present in the immediate vicinity of the site of their secretion
(of which there are many).
Biosynthesis (scheme 5). PGs are synthesized in almost all nucleated cells
except erythrocytes and lymphocytes. They are autocrine and paracrine lipid
mediators that act upon platelets, endothelium, uterine and mast cells. They are
synthesized in the cell from the essential fatty acids. An intermediate arachidonic
acid (AA) is created from diacylglycerol via phospholipase-A2 (PLA2), and then
brought to either the cyclooxygenase pathway or the lipoxygenase pathway to form
either prostaglandin and thromboxane (Tx) or leukotriene (LT), respectively. The
cyclooxygenase pathway produces thromboxane, prostacyclin and prostaglandin D,
E and F. Alternatively, the lipoxygenase enzyme pathway is active in leukocytes
and in macrophages and synthesizes leukotrienes. Tx defines the formation of
blood clot. Prostacyclin prevents blood coagulation and it is a potent stimulator of
myometrial contractility, and it is derived at first from COX-2. The prostacyclin
formation and release is regulated by vasoconstrictor and vasodilator autacoids. It
became apparent that the oppression of Tx and stimulation of prostacyclin provides
a good therapeutic effect in cardiovascular diseases.Thereby, eicosanoids affect
platelet function.
It is known that the eicosanoids have short T1/2 and do not circulate and are
considered not to impact on systemic vascular tone directly. However, they may
modulate vascular tone locally or through renal or other indirect effects.
Inhibitors of Eicosanoid biosynthesis. There are the drugs that reduce the
availability of Ca2+, because PLA2 is activated by Ca2+ and calmodulin, and
inhibition of PLA2 decreases the release of the precursor fatty acid and thus the
synthesis of all its metabolites; glucocorticoids that also inhibit PLA 2 and
glucocorticoids also downregulate induced expression of COX-2, but not COX-1;
traditional non-steroid anti-inflammatory drugs (tNSAIDs) that inhibit the COX.
Release from the cells. Prostaglandins were originally believed to leave the
cells via passive diffusion because of their high lipophilicity. The discovery of the
prostaglandin transporter, which mediates the cellular uptake of prostaglandin,
Scheme 5. Biosynthesis of eicosanoids (adopted from http://en.wikipedia.org/).
demonstrated that diffusion alone cannot explain the penetration of prostaglandin

through the cellular membrane. The release of prostaglandin has now also been
shown to be mediated by a specific transporter, namely the multidrug resistance
protein 4 (MRP4, ABCC4), a member of the ATP-binding cassette transporter
superfamily. Whether MRP4 is the only transporter releasing prostaglandins from
the cells is still unclear.
Cyclooxygenases (COX). Prostaglandins are produced following the
sequential oxidation of arachidonic acid (AA), dihomo-γ-linolenic acid (DGLA) or
eicosapentaenoic acid (EPA) by cyclooxygenases (COX-1 and COX-2) and
terminal prostaglandin synthases. The classic dogma is as follows: COX-1 is
responsible for the baseline levels of prostaglandins; COX-2 produces
prostaglandins through stimulation. COX-2 is the predominant COX at the sites of
inflammation, whereas COX-1 is the major sourse of cytoprotective PGs in the
gastrointestinal tract (GIT). However, while COX-1 and COX-2 are both located in
the blood vessels, stomach and the kidneys, prostaglandin levels are increased by
COX-2 in scenarios of inflammation.
Endogenous PGs, TXs, LTs function in physiological and pathological
processes. PGs activate membrane receptors locally near their sites of formation.
There are currently ten known prostaglandin receptors on various cell types.
Prostaglandins ligate a sub-family of cell surface seven-transmembrane receptors,
G-protein-coupled receptors. These receptors are termed DP1-2, EP1-4, FP, IP1-2,
and TP, corresponding to the receptor that ligates the corresponding prostaglandin
(e.g., DP1-2 receptors bind to PGD2). The diversity of receptors means that
prostaglandins act on an array of cells and have a wide variety of effects such as:
cause constriction or dilation in vascular smooth muscle cells; cause aggregation or
disaggregation of platelets; sensitize spinal neurons to pain; induce labor (PGF 2α
and TxA2 are important in final stage of delivery); may play a role in the
maintenance of placenral blood flow; decrease intraocular pressure; regulate
inflammatory mediation; regulate calcium movement; control hormone regulation;
control cell growth; act on thermoregulatory center of hypothalamus to produce
fever; act on mesangial cells in the glomerulus of the kidney to increase glomerular
filtration rate; regulation of blood pressure in response to high-salt diet; support the
renal blood flow and salt excretion; act on parietal cells in the stomach wall to
inhibit acid secretion. Furthermore polymorphisms in the genes for PGD 2 synthase
and TP receptor have been associated in asthma in humans.
Considering the role of both COX-1 and COX-2 in the syntesis of PGs and
role of COX-2 in protection against oxidative injury in cardiac tissue, it can be
assumed connection between inhibitors of COX-2 and myocardial
isсhemia/reperfusion injury, violation of cardiac function. Moreover, COX-2
derivated TxA2 facilitated to oxidant stress, isoprostane generation, and activation
of TP and feasibly the FP to increase cardiomyocite apoptosis and fibrosis.
Selective reduction of COX-2 in cardiomyocites leads to mild heart failure and
tendency to arrhythmogenesis.
Pharmacological inhibition or genetic removal of COX-2 hampers tumor
formation, such as colon, breast, lung and other cancers. Large human
epidemiological investigations demonstrated link between use of NSAIDs and
considerable descension in relative risks for cancer development, whereas
polymorphism in COX-2 have been associated with heightened risk of colon and
other cancers. Whereas aspirin use is associated with reduced risk of a breast
cancer in women. Besides, the pro- and anti-oncogenic roles of both COX, not
only COX-2, and LT inhibitors and LT receptors are studied. Moreover, an
increased interest is the use of LT antagonists/ihibitors for prevention/therapy of
various types of cancer. Thereby the pro- and anti-oncogenic roles of prostanoids
not yet fully explored and are under research.
Prostaglandins are potent but have a short half-life before being inactivated
and excreted. Therefore, they send only paracrine (locally active) or autocrine
(acting on the same cell from which it is synthesized) signals. LTs are potent
mediatios of inflammation.
The following (tabl. 13) is a comparison of different types of prostaglandin,

prostacyclin I2 (PGI2), prostaglandin E2 (PGE2), and prostaglandin F2α (PGF2α).
Table 13*. Prostaglandine receptors: type and functions
Type Receptor Functions

 vasodilation
PGI2 IP  inhibit platelet aggregation
 bronchodilatation
 bronchoconstriction
EP1
 GI tract smooth muscle contraction
 bronchodilatation
EP2  GI tract smooth muscle relaxation
 vasodilatation
 decrease gastric acid secretion
 increase gastric mucus secretion
PGE2  uterus contraction (when pregnant)
 GI tract smooth muscle contraction
EP3  lipolysis inhibition
 increase autonomic neurotransmitters
 increase platelet response to their agonists and increase
atherothrombosis in vivo
 hyperalgesia
Unspecified
 pyrogenic
 uterus contraction
PGF2α FP
 bronchoconstriction
* - adopted from http://en.wikipedia.org/
Fatty acid cyclo-oxygenase (COX) converts arachidonic acid to

prostaglandin H2 (PGH2), from which further prostanoids, PGD2, PGE2, PGF2α,
PGI2 (prostacyclin) and TxA2 (thromboxane A2), may be derived. Eicosanoid
receptors interact with Gs, Gi, Gq to modulate the activities of adenyl cyclase and
phospholipase C.
Five prostanoid receptors were recognized and correspondingly named DP, EP,
FP, IP and TP receptors. Additionally, EP receptors have been subdivided into four
groups, termed EP1, EP 2, EP3 and EP4; the DP receptor also has two subtypes
– DP1 and DP2; TP receptor has isoforms α and β; FP receptor has isoforms A, B.
DP1 receptors are coupled to adenylate cyclase via a Gs protein. Activation
of DP1 receptors leads to inhibition of platelet activation and vasodilatation. DP 1
receptors are expressed in the brain, where they may be involved in the regulation
of sleep.
The DP2 receptor is structurally distinct from all of the other known
prostanoid receptors. Indeed this receptor was originally termed CRTH2 to indicate
both its activity and the cell type in which it was initially identified. Unlike the
DP1 receptor, it is activated by prostanoids with an unnatural configuration at C-15
and also by 15-oxo analogues (potential products of 15-hydroxy prostaglandin
dehydrogenase). Furthermore, the COX inhibitor indomethacin is an agonist at the
DP2 receptor. Activation of DP2 receptors leads to eosinophil, basophil and Th2 (T
helper) cell activation, while DP1 receptor activation may oppose these events.
Ramatroban, originally developed as a TP antagonist, also blocks DP2 receptors.
DP2 receptor is an exception and is unrelated to the other prostanoid receptors;
rather, it is a member of the formyl-methionyl-leucyl-phenylalanine (fMLP)
receptor superfamily.
As a broad generalization, EP1 and EP3 receptors mediate excitatory effects,
while EP2 and EP4 receptors mediate inhibitory effects. EP1 receptors are believed
to be coupled via regulatory G proteins to (PLC-independent) influx of
extracellular Ca2+; phosphatidylinositol hydrolysis ensues as a consequence of this
influx. EP3 receptors are subject to splice variance at the C-terminus and, to date,
ten isoforms have been identified across species, six of these being expressed in
man . These isoforms differ in their G-protein coupling thereby contributing to the
wide spectrum of EP3 actions: contraction of smooth muscle, enhancement of
platelet aggregation, inhibition of autonomic neurotransmitter release, inhibition of
gastric acid secretion, and inhibition of fat cell lipolysis. EP2 and EP4 receptors are
believed to be coupled through a Gs protein to stimulation of adenylate cyclase.
Both EP subtypes may be present on smooth muscle cells with the latter usually
showing considerably higher sensitivity to PGE2. Selective agonists exist for all
four EP subtypes. Selective antagonists for EP1 receptors have been known for
some time and several have progressed into clinical trials as analgesic/anti-
inflammatory agents. EP1 and EP2 receptors have limited distribution compared
with the distribution of EP3 and EP4 receptors.
FP receptors are believed to be coupled via a regulatory G protein to
stimulation of PI (phosphatidylinositol) hydrolysis. FP receptors are expressed in
kidney, heart, lung, stomach, and eye; they are abundant in the corpus luteum,
where their expression pattern varies during the estrus cycle. They are found in
smooth muscle, being particularly widely distributed in cats and dogs, where they
mediate contraction. Fluprostenol is a highly selective FP agonist. FP receptors
present in the corpus luteum of many species mediate luteolysis, and PGF 2α
analogues (fluprostenol, cloprostenol) have been used in animal husbandry to
synchronize oestrus and induce parturition. FP receptor-stimulation also
profoundly lowers intraocular pressure in laboratory animal species and man and
FP agonists applied topically as C1-ester pro-drugs (latanoprost, travoprost) are
increasingly used as anti-glaucoma drugs. FP receptor antagonists have been slow
to emerge; the PGF2α analogue appears to be a partial agonist at the FP receptor.
IP receptors are coupled via a Gs protein to stimulation of adenylate cyclase.
IP receptors are expressed in many tissues and cells, including human kidney, lung,
spine, liver, vasculature, and heart. IP receptors relax vascular smooth muscle and
inhibit platelet aggregation. They appear to contribute to cardiovascular health
by counteracting vasoconstriction and platelet activation mediated via TP

receptors. Prostacyclin and a few of its stable analogues are used to treat
pulmonary hypertension, with careful attention to dosage to avoid excessive
lowering of arterial blood pressure. Cicaprost is the most selective IP agonist; other
commonly used agonists (carbacyclin, iloprost) have sufficient EP 1 and/or EP3
agonism to oppose their IP-receptor-mediated actions. A large range of non-
prostanoid prostacyclin mimetics exists; while some of these agents appear to be IP
partial agonists, analysis is hampered by the their ability to inhibit PLC-driven
events via a non-prostanoid mechanism. Selective IP receptor antagonists that
competitively block the vasodilator platelet-inhibitory actions of IP agonists have
recently been described. These agents suppress hyperalgesia and oedema in animal
models of inflammation, indicating that PGI2 may not always have beneficial
actions in the body.
TP receptors are expressed in platelets, vasculature, lung, kidney, heart,
thymus, and spleen. TP receptors are present in nearly all mammalian blood
vessels, airways and blood platelets, where they mediate smooth muscle
contraction and platelet aggregation. Signal transduction occurs via regulatory G
proteins linking to stimulation of PI hydrolysis. Both PGH 2 and TxA2 are potent
agonists for the TP receptor, but are rarely used in characterization studies owing
to the instability of their bicyclic ring systems. A number of highly potent TP
agonists have been synthesized, but their utility is compromised by their slow onset
/ slow offset on isolated tissue preparations. There are many TP receptor
antagonists, some of which are obviously analogues of PGH2 / TxA2, while others
bear little structural resemblance to prostanoids. Heterogeneity in the affinities of
TP antagonists has stimulated much debate about the existence of subtypes of TP
receptor; however, species differences may account for much of the variation. On
the other hand, there is now evidence for splice variance within TP receptors, and a
resulting C-terminus extended form of the TP receptor has been shown to be
particularly highly expressed in vascular endothelial cells. Simple TP receptor
antagonists have found little use in cardiovascular disease; preventative treatment
with low-dosage aspirin is sufficient to tip the balance away from thromboxane.
Agents combining TP antagonism and Tx synthase inhibition (ridogrel) have
shown more promise.
There is interest in the isoprostanes, a class of prostanoids that are not
products of the enzyme cyclo-oxygenase, but are rather formed by direct oxidation
of membrane phospholipids. The isoprostanes exhibit a wide range of biological
actions, and most evidence suggests that they act at the same receptors as the
'classical' prostanoids. There is evidence, however, that 8-epi PGF2α may act at a
receptor that, although similar to a TP receptor, is not identical.
It has been proposed that C1-ethanolamides of PGE2 and PGF2&alpha and
their analogues (e.g. bimatoprost) can activate prostamide receptors, which are
distinct from the known prostanoid receptors.
Leucotriene (LT) and Lipoxin (ALX) receptors. Two receptors exist for both
LTB4 (BLT1 and BLT2) and the cysteinyl leukotrienes (CysLT1 and CysLT2). A
receptor that binds lipoxin, ALX, is identical to the fMLP-1 receptor; the
nomenclature now reflects LXA4, as a natural and potent ligand. The BLT1 is
expressed predominantly in leukocytes, thymus, and spleen, whereas BLT 2 (the
low-affinity receptor for LTB4) is found in spleen, leukocytes, ovary, liver, and
intestine.
CysLT1 is expressed in lung and intestinal smooth muscle, spleen, and
peripheral blood leukocytes, wheares CysLT2 is found in heart, spleen, peripheral
blood leukocytes, adrenal medulla, and brain.
The CysLTs apparently prevail during allergic constriction of the airway. 5-
LOX (lipoxygenase) influence on the level of eosinophils in airway and bronchial
smooth muscle tone. From this it follows that the CysLTs receptors antagonists and
inhibitors of 5-LOX are effective in the treatment in human asthma. As a rule,
prostanoids promote acute inflammation notwithstanding the exceptions, such as
PGE2 which is an inhibitor of mast cells activation.
The ALX receptors are expressed in lung, peripheral blood leukocytes, and
spleen. Responses to ALX receptor activation vary with cell type. AA release is
stimulated in human neutrophils, whilst Ca2+ mobilization is blocked; in
monocytes, LXA4 stimulates Ca2+ mobilization.
Pharmacological effects. Prostanoids may modulate local vascular smoth
muscle tone at the site of their formation and influence the systemic blood pressure
through their renal function and tone of efferent arteriole. Reduction of the
systemic blood pressure may cause reflex tachycardia. So, PGE2, PGI1, PGD2
cause vasodilatation and reduce systemic blood pressure, whereas PGE 2 can elicit
vasoconstriction via activation of EP1 and EP2. PGF2α is a powerful constrictor of
both pulmonary arteries and veins in humans.
TxA2 is a powerful constrictor also. Infusion of PGs of E and F series
increases cardiac output.
LTs can constrict or relax vascular smooth muscle tone, particularly in renal
autoregulation, decrease the vascular volume and decrease cardiac contractility,
reduce the coronary blood flow. At higher concentrations LTs can constrict
arterioles and reduce exudation of plasma, and may promote the vascular smooth
muscle proliferation. Epoxyeicosatrienoic acids (EET) elicit vasodilatation,
especially in coronary circulation. Isoprostanes may constrict or dilate the vessels.
PGs also act on smooth muscles in human internal organs outside the
vasculature. They can contract or relax the smooth muscles. LTs contract majority
of smooth muscle and act predominantly on smooth muscles in the airways and are
a thousand times more potent that histamine. LTs also stimulate bronchial mucus
secretion and elicit mucosal edema. TxA2, PGF2α, PGD2 contract bronchial and
tracheal muscles, in contrary, PGE2, PGI2 relax them. Approximately 10% of
people have bronchospasm as a result of treatment with aspirin or others NSAIDs,
but only non-selective inhibitors of COX and never - with selective inhibitors of
COX-2, which indicates the involvement of COX-1 in this pathological process.
Action of PGs, prostacyclins on the uterus muscles depends on physiological
conditions of women, so that phases of menstrual cycle, pregnancy and its absence,
and duration of gestation. So, the response of uterus muscles on PGs action
increases with pregnancy progresses; sensitivity to the contractile response is the
most apparent before menstruation, while relaxation - at the midcycle.
Longitudinal muscles of GIT are contracted by PGEs and PGFs. They also
stimulate the movement of water and electrolytes into the intestinal lumen, that is
the basis of watery diarrhea in case of their use, as well as oral and parenteral. As
opposed PGI2 does not cause this effect, moreover prevents that provoked by other
PGEs. PG endoperoxides, TxA2, PGI2 have the same action, but less potent.
Circular muscles of GIT are relaxed by PGE2 and are contracted by PGF2α. LTs
contract muscles of GIT. PGEs decrease transit time in the small intestine and
colon. PGs induce diarrhea, cramps, reflux of bile, nausea and vomiting in oral
introduction.
PGE2 and PGI 2 manifest the cytoprotective effect in the stomach: reduce
acid secretion and pepsin content, enchance mucus secretion, inhibit gastric
damage and promote healing of duodenal and gastric ulcers.
The impact of PGE2 on the platelet aggregation depends on its
concentration: low concentration of PGE2 increases platelet aggregation, and vice
versa - high concentration of PGE2 decreases platelet aggregation. Both PGI2 and
PGD2 reduce platelet aggregation. Mature platelets express only COX-1, but
immature platelet forms also express COX-2, although its role in platelet
development and function has yet to be clarified. TxA2 is a major product of COX-
1 in platelets, it induces platelet shape change and aggregation, but TxA2 action is
restricted by its short T1/2 and by endogenuos inhibitors of platalet function, such
as NO, PGI2 and others.
On the whole eicosanoids are involved in the inflammatory and immune
responses in humans, as reflected by clinical use of the NSAIDs. Besides, LTs
induce inflammation, lipoxins have anti-inflammatory effect, and prostanoids can
cause both kind of activity. So, PGE2 and PGI2 are the prevalent pro-inflammatory
prostanoids; TxA2 can enhance platelet-leukocyte interaction; PGD2 also promotes
inflammation; PGE2 and TxA2 regulate apoptosis of immature thymocytes.
The renal prostanoids such as PGE2, PGI2, PGF2α, TxA2 are synthesized
largely in renal medulla, but in cortex layer too. PGE2 and PGI2 (COX-2-
derivatives) increase medullary blood flow, renal blood flow, glomerular filtration
due to their local vasodilatative effects, and inhibit sodium reabsorption. COX-1
derivatives promote salt excretion in the collecting ducts. On the other hand, the
action of PGE2 and PGI2 lead to increased renin release, and, as a result, to sodium
retention and increased blood pressure.
PGF2α contracts the iris sphincter muscle and reduces intraocular pressure
by increasing the aqueous humor outflow of the eye through the uveoscleral and
trabecular meshwork pathway.
PGE2 can cross BBB and act on thermosensitivity neurons in CNS. PGE2
obviously is a mediator for endogenous and exogenous pyrogens into separate
brain areas. Exogenous PGF2α and PGI2 promote fever but do not facilitate the
pyretic response. PGD2 and TxA2 do not induce fever, besides PGD2 also appears
to mediate an increase in extracellular adenosine that, in turn, facilitates induction

of sleep. There is evidence that COX-2-derivative prostanoids are involved in
several CNS degenerative disorders, however therapeutic effect of blocking their
synthesis or action has to be studied.
PGs and LTs increase the sensitivity of nociceptors and potentiate pain
receptors. PGE2 and PGI2 reduce the threshold to stimulation of nociceptors,
causing so called “peripheral sensitization”. Centrally, in the response to peripheral
pain, COX-1 and COX-2 are expressed in the spinal cord and release PGs. PGs and
LTs induce hyperalgesia and allodynia via increasing in pain transmission neuronal
pathway in the spinal cord.
PGs also act on endocrine tissues. So, PGE2 elevates the concentration of
ACTH, GH, prolactin, gonadotropins, stimulates steroid production, insulin
release, thyrotropin-like effects on the thyroid. PGE2 induces oocyte maturation
required for fertilization during and after ovulation.
PGs are powerful modulators of bone metabolism. The COX-1 is expressed
in normal bone, whereas the COX-2 is expressed in inflammation and mechanical
stress. PGE2 induces bone formation due to increasing osteoblastogenesis, and
PGE2 activates bone resorption via activation of osteoclasts.
Eicosanoids, their inhibitors, agonists and antagonists of eicosanoid
receptors have broad therapeutic applications. Inhibitors of eicosanoid
biosynthesis and COX inhibitors are widely used as anti-inflammatory drugs. Low-
dose aspirin is used for cardioprotection, LT antagonists are employed for
treatment of asthma and aspirin-induced asthma, FP agonists are used in treatment
of open-angle glaucoma, EP agonists are used to stimulate delivery and alleviate
gastric irritation owing to application of tNSAIDs. In general, the therapeutic use
of eicosanoids and their derivatives is limited because of the frequent and
significant adverse effects and their short T1/2. Notwithstanding these limitations,
prostanoids are used in following conditions: therapeutic abortion (PGEs and
PGFs: dinoprostone, carboprost tromethamine), for gastric cytoprotection
(misoprostol), impotence (alprostadil), maintenance of patent ductus arteriosus
(alprostadil), pulmonary hypertension (prostacyclin, epoprostenol, iloprost,
treprostinil), glaucoma (latanoprost, bimatoprost, travoprost).
Table 14. Medicinal forms of the drugs of intermediated type
INN Trade names Medicinal forms

Adenosine, Adenocor Parenteral solution for 0.006 g in 2 ml;
i/m, i/v injections in
flacons;
in ampoules 1% -1 ml; 2 ml;
2% - 1 ml
Adenosine Phosphaden solution Powder-substance;
phosphate, for injections Tablets; 0.5; 0.25
Phosphaden
Phosphaden tablets
Cytochrome C + Oftan Catachrom Eye drops in flacons; 0.675 mg + 1 mg +
82 | Unit 2.
Sodium succinate + 2 mg + 20 mg +
Adenosine + 40 mg - 10 ml
Nicotinamide +
Benzalkonium
chloride,
Calcium chloride + Vita-Iodunol Eye drops in flacons- 20 mg + 30 mg +
Magnesium chloride droppers 3 mg + 10 mg -
+ Nicotinic acid + 10 ml
Adenosine
Caffeine Guaranin, Theinum Powder;
Parenteral solution for 200 mg/1 ml;
s/c injections in
ampoules;
Parenteral solution for 100 mg/1 ml
subconjunctival
injection;
Coffein-benzoate Tablets; 0.1; 0.2;
sodium
Сaffeine + Coffetaminum, Tablets; 0.1 + 0.001
ergotamine tartrat Cofergot, Ergofein,
Ergoffin
Theobromine Theostene, Thesal Powder;
Tablets 0.25
Theophylline Afonylum, Aqualin, Powder;
Asmafil, Diffumal, Suppositories 0.2
Durofilin, Uniler,
Euphylong,
Lanophyllin,
Neotheopecum,
Optiphyllin,
Oralphyllin, Retafil,
Slow-bid, Slow-
Phylline, Ventax,
Spophylline retard,
Teo, Teodil, Teolix,
Theobiolongum,
Theocin, Theofin,
Theopecum,
Theophylline,
Theostat, Theotard,
Uni-dur, etc.
Dopamine Допамін, Допмін, Parenteral solution for 0.5%, 1% - 2 ml;
Aprical, Cardiosteril, i/v injections in 2% - 10 ml;
Dopamex, Dopastat, ampoules 4% - 5 ml
Dophan, Dopmin,
Dynatra, Giludop,
Hydroxytyra-
Min, Inovan,
Intropan, Intropin,
Revivan, Rivimine,
Dynatra
Chapter 3. | 83
Intermediants
Ibopamine Escandin Tablets 0.05; 0.1
Bromocriptine Aberginum, Tablets; 0.0025; 0.004; 0.01;
Bromergon, Capsules 0.005; 0.01
Bromocriptinum
mesilat, Lactodel,
Parlodel, Pravidel,
Serocriptine
Cabergolin Dostinex Tablets 0.0005
Quinagolide Norprolac Tablets 0.025 mg;
0.05 mg;
0.075 mg; 0.15 mg
Apomorphine Apokyn, Ixense, Parenteral solution for 1% - 1 ml;
Spontane, Uprima s/c injections in
ampoules;
Gelatin capsules 0.01; 0.02; 0.03;
0.04; 0.06
Levodopa Avodopa, Bendopa, Tablets; 0.25; 0.5
Bio-dopa, Brocadopa, Capsules
Caldopa, Madopan,
Cicandopa, Dalutrin,
Deadopa, Dopacin,
Dopaflex, Dopal,
Doparkin, Dopastral,
Doprin, Eldopar,
Eurodopa, Larodopa,
L-Dopa, Levopa, Le-
vopar, Medidopa,
Oridopa, Pardopa,
Parkidopa, Parmidin,
Veldopa Speciadopa,
Tonodopa, etc.
Pergolide Permax Tablets 0.00005; 0.000025;
0.001
Ropinirole Requip Modutab Tablets 0.25 mg; 1 mg;
2 mg; 5 mg
Domperidone Cilroton, Euciton, Tablets; 0.01;
Motilak, Motilium, Suspension for per 0.1% - 200 ml
Nauseline, Nauzelin, oral use in flacons
Passagix, Peridal, etc.
Pimozide Орап, Antalon, Tablets 0.001; 0.004
Norofen, Opiran,
Oralep, Orap, Pimotid,
Pirium
Metoclopramide Apo-Metoclop, Tablets; 0.005; 0.01;
Cerucal, Cerulan, Peroral solution in 0.1% - 30ml, 100ml,
Clometol, Clopan, flacons; 200 ml;
Comportan, Dibertil, Aerosol for intranasal 20% - 2 ml;
Emetisan, Gastrobids, administration in vials; 40% - 4 ml;
Gastrosil, Imperal, Parenteral solution for 0.5% - 2 ml
Klometol, Legir, i/m, i/v injections in
Maxeran, Maxolon, ampoules
84 | Unit 2.
Metoclol, Moriperan,
Nausifar, Paspertin,
Peraprin, Perinorm,
Plastil, Pramin,
Primperan, Primperil,
Reglan, Regastrol,
Rimetin, Reliverin,
Terperan, Viscal, etc.
Thiethylperazine Thiethylperazini Dragee; 6.5 mg;
maleas, Rectal suppositories; 6.5 mg;
Thiethylperazine Parenteral solution for 6.5 mg/1 ml - 0,65%
maleate, Torecan, i/m injections in - 1 ml
Toresten, Tresten ampoules
Haloperidol Haldol, Aloperidin, Tablets; 0.0005; 0.001;
Apo-Haloperidol, 0.0015; 0.002;
Halidol, Haloper, 0.005; 0.01;
Halophen, Halopidol, Tablets-forte; 0.005;
Senorm, Seranase, Peroral solution; 0.2% - 10 ml;
Serenace, Trancodol, Parenteral solution for 0.5% - 1 ml;
etc. i/m, i/v injections in
ampoules;
Parenteral oil solution
for i/m injections in 5% - 1 ml
ampoules
Perphenazine Chlorpiprazin, Tablets 0.004; 0.006; 0.01
Chlorpiprozine,
Decentan, Fentazin,
Neuropax, Trilifan,
Perphenan, Trilafon,
etc.
Fluphenazine Fluphenazine Tablets; 0.001; 0.0025;
decanoate: Modecate, 0.005; 0.00025;
Prolixin Decanoate, 0.001;
Dapotum D, Dragee; 0.0025; 0.005;
Anatensol, Fludecate, Parenteral solution for 0.25% - 1 ml
Sinqualone i/m injections in
Deconoate; ampoules
Fluphenazine
enanthate: Dapotum
Injektion, Flunanthate,
Moditen Enanthate
Injection, Sinqualone
Enanthate;
Fluphenazine
hydrochloride:
Prolixin, Permitil,
Dapotum, Lyogen,
Moditen, Omca,
Sediten, Selecten,
Sevinol, Sinqualone,
Trancin flucate
Chapter 3. | 85
Intermediants
Chlorpromazine Thorazine, Coated tablets for 0.01;
Ларгактил, children;
Ampliactil, Amplictil, Dragee; 0.025; 0.05;
Chlorazin,
Chlorpromanyl, Parenteral solution for 2.5% - 1.0 ml,
Chlorpromazine, i/m, i/v injections in 2.0 ml, 5.0 ml, 10ml
Contomin, Fenactil, ampoules
Hibanil, Hibernal,
Kloproman, Largactil,
Megaphen, Promactil,
Plegomazin,
Propaphenin, etc.
Clozapine Clazaril, Iprox, Tablets; 0.025; 0.1;
Lapenax, Lepotex, Granules for peroral 0.5; 1.0
Fazaclo solution preparation
in packages (for
children);
Leponex, Parenteral solution for 2.5% - 2 ml
i/m, i/v injections in
ampoules;
Alemoxan Tablets 0.05
Aripiprazole Abilify, Amdoal, Tablets 0.005; 0.01; 0.015;
Zylaksera 0.02; 0.03
Serotonin Serotonin adipinate Powder-substance;
Parenteral solution for 1% - 1 ml;
i/m, i/v injections in 0.5% - 10 ml
ampoules
Mexaminum Mexaminum Tablets 0.05
Melatonin Eucalin, Melapur, Tablets; 0.003
Melatonum, Melaton, Capsules;
Melaxen, etc. Powder-substance
Sumatriptan Sumatriptan succinate Powder-substance
Amigrenin, Imigran, Tablets 0.05; 0.1;
Imitrex Solution for i/m, i/v 1.2% - 0.5 ml;
injections in syringes
Aerosol for intranasal 10 mg, 20 mg/1 dose
introduction
Dihydroergotamine Agit, Angionorm, Peroral solution in 0,2% (2 mg in 1 ml
Clavigrenin, flacons; - 20 drops) -
Cornhidral; DH- 10 ml, 30 ml;
Ergotamin, Diergotan, Peroral solution in 0,1% (1 mg) - 1 ml;
Dihydergot, flacons;
Dihydroergotamine Tablets; 0.0025;
mesilate, Dihytamin,
Ditamin, Migretil, Aerosol for intranasal 0.4%; 1%
Ergomimet, Ikaran, introduction
Ergovasan, Vasogin,
Migrifen, Tonopress,
Verteblan, etc.
Dihydroergotoxinum Alkergot, Circanol, Tablets; 0.0015;
Clavor, DH- Peroral solution in 0.1% - 50 ml
86 | Unit 2.
Ergotoxin, Erginemin, flacons; (50 mg);
Ergocomb, Ergodibat, Parenteral solution for 0.03% - 1ml
Ergohydrin, Ergoloid i/m, i/v injections in (0.3 mg)
mesylat, Ergomed, ampoules
Ergoxyl, Hyderan,
Hydergin, Optamine,
Trigot, Redergin,
Redergot, Secamin,
Secatoxin,
Vasolax,etc.
Tropisetron Navoban Capsules; 0.005;
Parenteral solution for 1 mg/1 ml - 5 ml
i/v injections in
ampoules
Naratriptan Naramig Tablets 0.0025
Pizotifen Litec, Pizotylin, Tablets; Dragee 0.0005
Sandolitec,
Sandomigran,
Sandomigrin,
Sanmigran,
Sanomigran
Ketanserin Perketal, Serefrex, Tablets; 20 mg, 40 mg;
Sufrexal, Sufroxal, Parenteral solution for 0.5 % - 2 ml, 10 ml
Taseron i/m, i/v injections in
ampoules
Urapidil Ebrantil, Eupressyl Capsules; 30 mg, 60 mg,
90 mg;
Parenteral solution for 0,5% - 5 ml, 10 ml
i/v injections in
ampoules
Indoramin Baratol, Doralese Tablets 20 mg, 25 mg
Histamine Eramin, Ergamine, Powder-substance;
Histalgine, Histamyl, Parenteral solution for 0.1% - 1 ml
Histapon, Imadyl, s/c injections in
Imido, Istal, Peremin, ampoules
etc.
Diphenhydramine Alledryl, Allergan, Tablets; 0.02; 0.025; 0.03;
Allergin, Allergival, 0.05; 0.1;
Amidryl, Benadryl, Parenteral solution for 1% - 1 ml;
Benzhydraminum, i/m, i/v injections in
Diabenyl, ampoules;
Dimedrolum, Rectal suppositories; 0.01
Dimedryl, Dimidril, Eye drops; 0.5%;
Restamin, etc. Intranasal solution; 3%-10%
Ointment
Clemastine Alagyl, Anhistan, Tablets; 1 mg;
Fenistil, Fumartin, Parenteral solution for 1 mg/1 ml - 2 ml;
Lecasol, Meclastin, i/m, i/v injections in
Mecloprodine ampoules;
fumarate, Rekonin, Syrup in flacons 0.67 mg/1 ml - 5 ml
Rivtagil, Tavegil,
Tavist, etc.
Promethazine Allergan, Antiallersin, Parenteral solution for 2.5% - 2 ml;
Atosil, Diprazinum, i/m, i/v injections in
Fargan, Phenergan, ampoules;
Pipolphen, etc. Dragee; Tablets; 0.025; 0.05;
Powder for injections 0.005; 0.01
in ampoules; 0.05;
Paracetamol/ Coldrex Nite Syrup 1.0 + 20 mg +
promethazine/ 15 mg - 20ml;
dextromethorphan;
Pethidine/ Capsules;
promethazine; Parenteral solution for 1 ml;
i/m injections in
ampoules;
Guaifenesin + Prothiazine Syrup 5 mg + 45 mg +
Ipecacuanha + Expectorant 10 mg - 5 ml
promethazine
Sequifenadine Sequifenadine Tablets 0.05
hydrochloride,
Bicarphen, Histafen
Chloropyramine Allergan S, Tablets; 0.025;
Chlorneoantergan, Parenteral solution for 2% - 1ml
Chloropyribenzamine i/m, i/v injections in
h/cl., ampoules
Chlortripelenamine
h/cl., Halopyramine,
Sinopen, Suprastin,
Synopen
Astemizole Alermizol, Asmoval, Tablets; 0.01; 0.005;
Astelong, Astemisan, Peroral suspension in 0.001/1 ml - 50 ml,
Hismanal, Histalong, flacons 100 ml
Histamanal, Ifirab,
Lembil, Mibiron,
Stelert, Stemiz,
Vagran
Acrivastatine Semprex Capsules 0.008
Dimetindene Fenistil Tablets retard; 0.0025, 0.004;
Peroral solution in 0.1% - 10 ml, 20 ml;
flacons;
Gel in tubes 0.1% - 20.0, 30.0
Loratadine Claritin, Tablets; 0.01;
Clarotadinum, Syrup in flacons; 0.001/1 ml -100 ml,
Klarisens, Lomilan, 120 ml;
Loratin, Loridin Peroral suspension in 0.1% - 30 ml, 100ml
flacons
Mebhydrolin Dialin, Diazolinum, Tablets; 0.1;
Incidal, Dragee 0.05, 0.1
Mebhydrolinum
Napadisylas, Omeril
Azelastine Allergodil Tablets; 0.002;
Intranasal spray in 0.14 mg/1 dose -
88 | Unit 2.
flacons 10 ml;
Eye drops in flacons 0.05% - 6 ml, 10 ml
Qiufenadine Phencarolum Tablets 0.025
Terfenadine Bronal, Caradonel, Tablets; 0.06, 0.12;
Daylert, Histadine, Peroral suspension in 0.6% - 30 mg/5 ml
Rapidal, Riter, flacons
Seldane, Tamagon,
Teridine, Termenadin,
Thelladadan, Triludan,
Tofrin, Toldan,
Teridine, Termenadin,
Thelldan, Triludan,
Tofrin, Toldan,
Trexyl, etc.
Cyproheptadine Adekin, Apetigen, Tablets; 0.004;
Astonin, Cipractin, Syrup in flacons 0.04% - 0.4 mg/1 ml
Cyprodin, Istabin, – 100 ml
Pariactin, Peritol,
Supersan, Vieldrin,
Vinorex, etc.
Fenspiride Eurespal Tablets; 0.08;
Syrup in flacons 0.2% - 150 ml
Ebastine Kestine Tablets 0.01
Cetirizine Alerza, Allertec, Tablets; 0.01;
Cetirinax, Cetrine, Peroral solution in 1% - 10 ml, 20 ml
Letizen, Parlazin, flacons
Reactine, Zetrinal,
Zodac, Zyncet, Zyrtec,
etc.
Desloratadine NeoClarityn, Powder-substance;
Claramax, Clarinex, Tablets; 0.005, 0.0025;
Larinex, Aerius, Syrup 0.5 mg/1 ml - 60 ml,
Dazit, Azomyr, 120 ml;
Deselex, Delot
Levocetirizine Allear, Alcet , Cezera, Tablets; 0.005;
Glencet, Seasonix, Peroral solution in 5 mg/1 ml – 10 ml,
Suprastinex, Teczine, flacons; 20 ml;
T-Day Syrup, Vozet, Syrup 2.5 mg/5 ml
Zyxem, Zilola, Xaltec,
Xozal, Xusal, Xyzal
Fexofenadine Allegra, Allerfex, Tablets; 0.03, 0.06, 0.12,
Beksist-sanovel, 0.18;
Gifast, Dinox, Capsules 0.12, 0.18;
Fexadin, Fexofast,
Rapido, Telfast
Bamipine Soventol Gel in tubes 2% - 20.0
Cimetidine Altramet, Belomet, Tablets; 0.2, 0.3, 0.4;
Benomet, Cigamet, Tablets retard; 0.35;
Cimesan, Histodyl, Capsules; 0.2, 0.3;
Primamet, Tagamet, Syrup; 4% - 5 ml;
Ulcometine, Ulcuzal, Parenteral solution for 10% - 2 ml
Chapter 3.
Intermediants | 89
Zagastrol, etc. i/m, i/v injections in
ampoules
Ranitidine Acidex, Aciloc-E, Tablets; 0.075, 0.15, 0.2, 0.3;
Anistal, Gertocalm, 1% - 5 ml, 10% -
Histac, Raniberl, Parenteral solution for 2 ml
Ranigast, Ranisan, i/m, i/v injections in
Ranital, Ranitin, ampoules
Rantac, Renx, Zantac,
Zantin, Zoran,
Ulcodin, Ulcosan,
Ulran, etc.
Famotidine Acipep, Amifatidine, Tablets; 0.02, 0.04;
Antodine, Blokacid, Powder for i/v 0.02
Famocid, Famodar, injections in ampoules
Femocin, Fudon,
Fluxid, Gaster,
Gasterogen, Lecedil,
Novafam, Pepcidine,
Pepcid, Pepdul,
Quamatel, Topcid,
Ulceran, Ulfamid, etc.
Nizatidine Axid Capsules; 0.15, 0.3;
Parenteral solution for 2.5% - 4ml
i/v injections in
ampoules
Roxatidine Roxane Tablets retard; 0.075;
Tablets forte 0.15
Lafutidine Stogar, Protecadin Tablets 0.005
Ebrotidine Ebrocit, Ebrodin, Tablets 0.4
Ulsanic
Dinoprost Amoglandin, Parenteral solution in 0.5% - 1ml, 5 ml,
Enzaprost F, ampoules for i/v, 8 ml
Minprostin F2α, intraamnial,
Panacelan F, extraamnial,
Prostaglan, intravaginal injections
Prostarmon,
Prostarmon F, Prostin
F2α
Dinoprostone Cerviprost, Enzaprost Parenteral solution for 0.1%, 0.5% - 1ml
E, Medullin, Predinil, i/v injections in
Prepidil, Prostarmon ampoules
E, Prostin E2 Vaginal gel 0.017%, 0.034%,
0.07% - 3ml
Powder for injections 0.0005
in syringe
Carboprost Hemabate, Tham Parenteral solution in 250 mcg - 1 ml
tromethamine ampoules for i/m,
intraamnial injections
Misoprostol Cytotec Tablets 0.2 mg
Misoprostol + Artrotec Tablets 0.2 mg + 200 mg
diclophenac sodium
90 | Unit 2.
Alprostadil Alprostane, Caverject, Powder for injections 0.01 mg, 0.02 mg
Edex, Mews, in ampoules (i/m, i/v)
Minprog, Prostadin, Powder for injections 0.01 mg, 0.02 mg
Prostavasin, Prostin in flacons (i/m, i/v)
VR, Vazaprostan Concentrate in 0.05% - 0.2 ml
ampoules (i/m, i/v)
Urethral suppositories 0.125 mg, 0.25 mg,
0.5 mg, 1mg
Epoprostenol Flolan Powder for injection in 500 mcg; 1.5 mg
flacons (i/v)
Iloprost Ventavis By inhalation of 10 mcg/1 ml (initial
nebulised solution dose 2.5 mcg)
Treprostinil Remodulin, Parenteral solution in 1.0 mg/1 ml -20 ml;
flacons for s/c, i/v 2.5 mg/1 ml - 20 ml;
5 mg/1 ml - 20 ml;
10 mg/1 ml - 20 ml;
Tyvaso Solution for 2.9 ml (0.6 mg/1ml)
inhalations in - initial dose - 3
ampoules breaths of Tyvaso
(18 mcg of
treprostinil)
Latanoprost Xalatan Eye drops in flacons 0.005% - 2.5ml
Bimatoprost Lumigan, Allergan, Eye drops in flacons 100 mcg/1ml - 3ml;
Ganfort Eye drops in flacons bimatoprost

300 mcg/1mL +
timolol (as maleate)
5 mg/1ml
Travoprost Travatan, Alcon Eye drops in flacons 40mcg/1ml;
DuoTrav Eye drops in flacons travoprost 40 mcg +
timolol (as maleate)
5 mg/1 ml
Montelucast Singular Chewable tablets 5 mg
Zafirlucast Accolate Tablets 20 mg
Zileuton Syflo Tablets 0.3; 0.6
Ozagrel Domenan Tablets 0.1; 0.2
Chapter 4. Сholinergic agonists | 91
UNIT 3: DRUGS AFFECTING the AUTONOMIC

NERVOUS SYSTEM
Chapter 4. Cholinergic agonists
Drugs that act on the cholinergic receptors are named cholinergic drugs.
Mediator (neurotransmitter) of cholinergic nervous system is Acetylcholine (Ach).
Synapse – is the place of primary pharmacological reaction (“butt”) of synapse
tropic drugs. Cholinergic synapse is constructed of presynaptic and postsynaptic
structures between which is a synaptic cleft.There are cholinergic receptors on the
postsynaptic membrane that are specific proteins with the spatial construction.
Form of this complex complies with the principle of structural complementarity.
The first step of neurotransmission process in cholinergic neurons is
synthesis of acetylcholine: choline acetyltransferase catalyzes the reaction of
choline with acetyl coenzyme A (CoA) to form Ach. The second step of
neurotransmission process in cholinergic neurons is storage of Ach in vesicles:
Ach is contained in presynaptic vesicles together with adenosine triphosphate
(ATP) and proteoglycan. The third step is release of Ach into the synaptic space.
The fourth step is binding of Ach (after its diffusion across the synaptic space) to
the postsynaptic receptors on the target cells or presynaptic receptors in the
membrane of the neuron. This process leads to a biologic response within the cells
like initiation of nerve impulse in a postganglionic fiber, activation of specific
enzymes in effector cells as mediated by second-messenger molecules. The fifth
step of neurotransmission process in cholinergic neurons is degradation of Ach:
acetylcholinesterase (AchE) destroys Ach to choline and acetate in synaptic gap.
The sixth step is recycling of choline: in the neuron choline is acetylated into Ach
and is stored until released by a subsequent action potential.
There are postsynaptic Muscarinic (M-cholinoreceptors) and Nicotinic (N-
cholinoreceptors) cholinergic receptors on the surface of the effector organs.
According to mechanism of action all agonists of cholinergic receptors (also
called cholinomimetics) are divided into several groups: M-N-cholinomimetics,
M-cholinomimetics, N-cholinomimetics, Anticholinesterases (reversible and
irreversible).
Table 15. Places of location and effects* of activation of M-cholinoreceptors
Places of location Effects of activation

CNS excitement
Vegetative ganglions improvement of nervous impulses transmission
Eye -miosis,
-reduction of intraocular pressure,
92 | Unit 3. Drugs affecting the Autonomic Nervous System
-spasm of accommodation (the vision is established on
proximate visibility)
Bronchi increase of bronchial muscle tonus and bronchial
glands secretion that lead to bronchospasm
Heart cardiodepressive effect: reduction of heart contractility
(negative inotropic effect);
reduction of heart conductivity (negative dromotropic
effect);
bradycardia (negative chronotropic effect)
GIT increase of smooth muscle tonus of walls and reducing
of sphincter tonus that lead to diarrhea, abdominal
pain
Gall bladder increase of smooth muscle tonus of walls and reducing
of sphincter tonus
Urinary bladder increase of smooth muscle tonus of walls and reducing
of sphincter tonus that lead to frequent uresis/urinary
incontinence
Uterus increase of smooth muscle tonus
Smooth muscle of vessels reducing of smooth muscle tonus of vessels that lead
to vasodilatation
Exocrine glands: increase of glands secretion
salivary, gastric, intestinal,
lachrymal, sweat,
bronchial
* - effects of activation of M-cholinoreceptors there are pharmacologic effects of M-cholinergic
agonists, both direct and indirect action.
Table 16. Places of location and effects* of activation of N-cholinoreceptors
Places of location Effects of activation

Posterior lobe of pituitary increase of secretion of antidiuretic hormone (ADH)
that lead to edema (anasarca)
Vegetative ganglions improvement of nervous impulses transmission
Carotid sinus stimulation of chemoreceptors and in this way
stimulation of respiratory center and vasomotor
center that lead to intensification of breathing and
blood circulation
Cerebral layer of adrenal increase of epinephrine secretion, as a result
gland increase of the blood pressure and acceleration of
the heart rate
Skeletal muscles improvement of neuromuscular transmission
* - effects of activation ofN-cholinoreceptors are pharmacologic effects of N-
cholinergic agonists.
Classification of Cholinergic agonists: Cholinomimetics,

Anticholinesterases and
Reactivators of cholinesterase
M-, N- cholinomimetics
Acetylcholine
Carbachol
M- cholinomimetics
Pilocarpine
Aceclidine
Cisapride
N- cholinomimetics
Lobeline
Cytisin
Anticholinesterases
reversible:
tertiary amines:
Physostigmine
Galanthamine
quaternary amines:
Neostigmine methylsulfate
Pyridostigmine bromide
Ambenonіum chloride
Distigmine bromide
- irreversible:
Arminum
• Reactivators of Cholinesterase
Trimedoxime bromide
Alloximum
Izonitrozinum
Diaethyximum
Mechanism of action of direct cholinergic agonists (also called

cholinomimetics). Cholinergic agonists mimic the effects of Ach by binding
directly to cholinergic receptors. The direct-action cholinergic drugs have longer
duration of action than acetylcholine.
Mechanism of action of indirect cholinergic agonists (reversible
anticholinesterases). Indirect cholinergic agonists (reversible anticholinesterases)
are inhibitors of AchE that prolong lifetime of Ach, improve the accumulation of
Ach in the synaptic space and cause cholinomimetic effects in the body. As a result
these drugs provoke stimulation of both muscarinic and nicotinic receptors in the
effector organs. In accordance with the chemical structure there are tertiary amines
and quaternary amines. The tertiary amines overcome the BBB and they are
effective in patients with patology of CNS. The quaternary amines can not get over
the BBB and are used in case of violations of peripheral cholinergic innervation.
Mechanism of action of indirect cholinergic agonists (irreversible
anticholinesterases). The indirect cholinergic agonists (irreversible
anticholinesterases) are the organophosphate compounds. It can bind covalently to
AchE that lead to long-term increase in Ach in cholinergic synapses. Many of
these remedies are extremely toxic and are used as nerve agents in military
purposes or as insecticides.
Mechanism of action of reactivators of acetylcholinesterase. These drugs
can reactivate inhibited AchE and use as antidotes for irreversible
anticholinesterases.
Pharmacologic characteristic of Cholinergic agonists
Indications for M-cholinomimetics use:

Pilocarpine:
Glaucoma
Trombosis of central vien of retina, acute retinal artery occlusion, optic
atrophy to improve the eye trophic
Xerostomia (dry oral mucosa)
Systemic effect of the drug is not used because of its high toxycity. The most
dangerous manifestation of pilocarpine poisoning is pulmonary edema.
Aceclidine:
Glaucoma
Atonia of intestine, gall bladder, urinary bladder, uterus
Uterus blood bleeding after delivery
To accelerate the peristalsis in the digestive tract in case of X-ray
examination
Cisapride:
Reflux-ezophagit
Atony of GIT, gall bladder, urinary bladder, uterus
To accelerate the peristalsis in the digestive tract in case of X-ray
examination
Adverse effects of M-cholinomimetics:
Miosis
Spasm of accommodation
Bradycardia, blockage of heart, arterial hypotension
Bronchospasm
• Intestine spasm abdominal pain, diarrhea/fecal incontinence/encopresis
Hypersalivation, sweating
Frequent uresis/ urinary incontinence
Convulsion (cramps)
Contraindications for M-cholinomimetics use:
• Bronchial asthma, obstructive bronchinis
Angina pectoris (IHD)

Atherosclerosis
Organic heart lesions, conduction disturbances in the myocardium
Malfunction of liver and kidney
Epilepsy
Hyperkinesias, Parkinson disease
Pregnancy
Inflammatory process in abdominal cavity
Acute poisoning with drugs with M-cholinomimetic effect may occur when
they overdose or when using fungi of the genus Inocybe, fly agaric (Amanita) –
they contain a toxic substance muscarine. Diarrhea, abdominal pain, constriction of
the pupils, salivation, bronchospasm, confusion, convulsions, and coma are
developed in the patient. Medical care in such poisoning is gastric lavage and
administration of physiological antagonists: drugs with M-cholinolytic action –
atropine sulfate, and – symptomatic treatment.
Indications for N-cholinomimetics use:

In current clinical practice, they are used very rarely, more often – in
experimental pharmacology.
Depress of respiratory center – respiratory arrest of reflex origin, namely due to
the inhalation of irritating substances in injuries, electric shock, surgical
operation, morphine poisoning, carbon monoxide poisoning (cytitone –
0.15% solution of cytisine, or 1% solution of lobeline)
Shock, collapse, impairment of blood circulation and respiration in patients
with infection diseases (cytitone as a drug that can increase BP through
reflex excitation of vasomotor center, stimulation of sympathetic ganglia and
adrenal medulla
Smoking (tablets “Tabex” and “Lobesilum”): in recent years, N-
cholinomimetics are used as aids to relieve withdrawal symptoms in case of
failure of tobacco
Adverse effects of N-cholinomimetics:
in case of quick injection:
Respiratory standstill
Disturbances in heart muscle conductivity
Arterial hypotension
in case of orally administration:
Weakness
Dizziness
Nausea
Headache
Contraindications for N-cholinomimetics use:
in case of orally administration:
Blood circulation insufficiency
Arterial hypertension
Bleeding, intensification of ulcerative disease

in case of intravenous administration:
Bleeding
Pulmonary edema
Pneumothorax
Rib’s ruptures
Fibrocavernous tuberculosis
Lesions of cardiovascular system
Foreign bodies in trachea and bronchi
Full depression of respiratory center
Indications for Anticholinesterases use:

Glaucoma (except for Galanthamine that can cause edema of conjunctiva
Intestine and urine bladder atony after surgical operation (appropriate to appoint
quaternary amines: Neostigmine methylsulfate, Pyridostigmine bromide,
Ambenonіum chloride, Distigmine bromide; they can not overcome BBB)
Myasthenia
Paresis, paralysis, polyneuritis
Muscle paralysis associated with dysfunction of the brain and spinal cord
(appropriate to appoint tertiary amines: Physostigmine, Galanthamine; they
overcome BBB)
For the activation of mental (cognitive) function in Alzheimer's disease (tertiary
amines: Physostigmine, Galanthamine)
Antidotes in case of overdoses by Nondepolarizing Myorelaxants and M-
cholinoblockers (the most frequently Neostigmine methylsulfate is used as a
drug of peripheral and short action)
Xerostomia (in dental practice)
Adverse effects of Anticholinesterases:
Miosis
Spasm of accommodation
in case of system action:
Bradycardia, heart blockages, arterial hypotension
Bronchospasm
Spasm of intestine, abdominal pain, diarrhea/ fecal incontinence/encopresis
Hypersalivation, sweating
Frequent uresis/ urinary incontinence
Convulsion (cramps)
Contraindications for Anticholinesterases use:
Epilepsy
Hyperkinesias
Bronchial asthma, obstructive bronchinis
Angina pectoris (IHD)
Bradycardia
Foreword | 97
Reactivators of cholinesterase are used in case of poisoning by irreversible

anticholinesterases.
Table 17. Medicinal forms of Cholinergic agonists, Anticholinesterases,

Reactivators of cholinesterase

Acetylcholine Acetylcholine chloride Powder in ampoules 0.1; 0.2
Carbachol Carbacholine, Isopto Eye drops; 0.5%; 1%; - 5 ml
carbachol, Oftan Eye drops (Carbacel, 0.75 %; 1.5 %;
carbachol, Secretin, Isopto carbachol); 2.25 %, 3 % - 5 ml
Carbachol,
Carbaminoylcholine Powder/tablets 0,001
Carbamiotin, Carcholin, Parenteral solution (i/v, 0.01%; 0.025% -
Doryl, Duracholine, i/m, sub skin) in ampoules 1 ml
Enterotonin, Glaucomil,
Jestril, Lentin, Moryl,
Tonocholin, etc.
Pilocarpine Isopto-carpine, Eye drops: 1%; 2%; 4% -
Pilocarpinum in containers, flacons, 0.5 ml; 10 ml
hydrochloridum, Oftan 1% - 1.5 ml
Pilocarpine, Pilocar, in tube-droppers, 1%; 6% - 5 ml
Pilogel, Pilocarpine in flacons;
optifilm, Pilocarpine- Eye ointment in tubes 1%; 2%; 4% - 5.0
long, Humacaprine, Eye ointment in 1%; 2%; 4% - 5 ml
Salagen containers;
Water solution in flacons; 1% - 5 ml
Eye films;
Eye gel (Pilogel) in tubes; 0.0027
Tablets (Salagen) 4% - 5.0
0,005
Aceclidine Aceclidine, Glaudin, Parenteral solution 0.2% 1ml
Glaunorm, (subskin) in ampoules
Eye ointment; 3%; 5% - 20.0
Powder for eye drops:
Glaucostat Eye drops (extemporal 2%; 3%; 5%
solutions)
Cisapride Coordinax, Peristil, Tablets; 0.005; 0.01
Cisapro, Cisap, Suspension per oral in 0.1% - 60ml; 100ml
Cisapid, Prepulsid flacons;
Parenteral solution in 0.2%; 0.5% - 2 ml
ampoules
Lobeline Lobeline hydrochloride, Parenteral solution (i/v, 1% -1 ml
Lobesil, i/m) in tube-syringes, in
Antisol, Atmulatin, ampoules
Bantron, Lobatox, Tablets 0.002
Lobeton, Lobidan, etc.
Cytisin Cytitone Water solution in 0.15% - 1ml

ampoules (i/v, i/m);
Tabex, Tablets; 0.0015
Cypercuten TTS, Transdermal therapeutic 125 mg/30 sq. cm
systems (TTS);
Cytisin films Films bonded to the gum 0.0015
Physostigmine Physostigmine Powder
salicylate, Eserine
salicylas,
Physostigminum
salicylicum
Galanthamine Galanthamine Powder
hydrobromide, Nivalin,
Parenteral solution 0.1%, 0.25%, 0.5%,
(sub skin) 1% - 1 ml
Reminyl Peroral solution 0.4% - 100 ml
Tablets 0.004; 0.008; 0.012
Neostigmine Proserinum Powder
methylsulfate Parenteral solution in 0.05% - 1ml
ampoules (s/c, i/v, i/m)
Proserin granules for
children 60.0
Tablets
0.015
Pyridostigmine Kalymin 60 N, Kalimin Tablets 0.06
bromide forte, Parenteral solution in 0.5% - 1ml
ampoules (s/c, i/v, i/m)
Mestinon Tablets 0.01;
Dragee 0.06
Ambenonlum Oxazylum Powder
chloride Tablets 0.001; 0.005; 0.01
Distigmine Hexamarium bromide, Tablets; 0.005;
bromide Ubretid, Ubritil Parenteral solution in 0.1% - 1 ml
ampoules (i/m)
Arminum Arminum Eye drops 0.005%; 0,01% -
10 ml
Trimedoxine Dipyroximum Powder
bromide Parenteral solution in 15% - 1 ml
ampoules (i/v)
Alloximum Alloximum Powder for injections in 0.075
ampoules (i/m)
Izonitrozinum Izonitrozinum Parenteral solution in 40% - 3 ml
ampoules (i/v, i/m)
Diaethyximum Diaethyximum Parenteral solution in 10% - 5 ml
ampoules (i/m)
Chapter 5. Сholinergic antagonists | 99
Chapter 5. Cholinergic antagonists

Cholinergic antagonists (also called cholinergic blockers,
anticholinergic drugs, parasympatholytics) bind to cholinergic receptors and
block transmission of nerve impulse in parasympathetic autonomic nervous
system. One group of these drugs blocks M-cholinoreceptors. A second group of
these drugs blocks N-cholinoreceptors. There are Ganglioblockers and
Myorelaxants (neuromuscular blocking drugs).
Mechanism of action of Ganglionic blockers. Ganglionic blockers
specifically act on the nicotinic receptors of both parasympathetic and sympathetic
autonomic ganglia.
Mechanism of action of Myorelaxants (Depolarizing drugs,
Nondepolarizing drugs and drugs of mixed action). Depolarizing
(leptocurare) drugs connect with N-cholinoreceptors and act similar as Ach, but
unlike Ach Depolarizing drugs cause stable depolarization of N-cholinoreceptors
because of they aren’t instantly destroyed by AchE like Ach. As a result,
Depolarizing drugs persist at high concentrations in the synaptic gap, remain
bound with N-cholinoreceptors for a relatively longer time and provide a constant
stimulation of N-cholinoreceptors. This renders the receptor incapable to transmit
further nerves impulse. Thus the nerves impulse transmission in skeleton muscles
is stopped. The duration of action of Depolarizing agent depend on diffusion to
plasma and hydrolysis by plasma cholinesterase. Clearly that Depolarizing drugs
haven’t antidotes.
Nondepolarizing (pahycurare) drugs interact with N-cholinoreceptors to
prevent the binding of acetylcholine, in this way decrease the sensitivity of N-
cholinoreceptors to Ach that lead to prevent depolarization of muscle cell
membranes and inhibit muscular contraction. As Nondepolarizing drugs compete
with Ach at the receptors and don’t activate them, they are named competitive
blockers. Their effects can be overcome by increasing concentration of Ach in the
synaptic gap. It follows that, antidotes of Nondepolarizing drugs are reversible
anticholinesterases - inhibitors of cholinesterase in the synaptic gap.
Myorelaxants of mixed action in the first phase cause depolarization of N-

cholinoreceptors and in the second phase act as Nondepolarizing drugs. In case of
overdose can use reversible anticholinesterases.
Muscle relaxation under the influence of Myorelaxants is as follows:
fingers, toes, eyes, extremities, head, neck, trunk, intercostal muscles, diaphragm,
and as a result – respiratory arrest. Restoration of muscle tone is in reverse.
Table 18. Places of location and effects* of blockage of M-cholinoceptors
Places of location Effects of blockage

CNS depression
Vegetative ganglions deceleration of nervous impulses transmission
Eye -mydriasis,
-increasing of intraocular pressure,
-paralysis of accommodation (the vision is established on
distal visibility)
Bronchi reducing of bronchial muscle tonus and bronchial glands
secretion that lead to bronchodilatation
Heart Cardiopositive effects: increase of heart contractility
(positive inotropic efferct);
increase of heart conductivity (positive dromotropic
efferct);
tachycardia (positive chronotropic effect);
increase of heart excitability (positive batmotropic efferct)
GIT reducing of smooth muscle tonus of walls and increase of
sphincter tonus that lead to atonia of GIT and
constipation
Gall bladder reducing of smooth muscle tonus of walls and increase of
sphincter tonus that lead to retention of gall
Urinary bladder reducing of smooth muscle tonus of walls and increase of
sphincter tonus that lead to urine retention/ischuria
Uterus reducing of smooth muscle tonus
Exocrine glands: oppression of glands secretion that lead to dryness of
bronchial, salivary, gastric, mucous (xerosis)
intestinal, lachrymal,
sweat
* - effects of blockage of M-cholinoceptors are the pharmacologic effects of M-cholinergic
antagonists.
Table 19. Places of location and effects* of blockage of N-cholinoreceptors
Places of location Effects of blockage

Posterior lobe of pituitary reducing of secretion of antidiuretic hormone (ADH)
Vegetative ganglions deceleration of nervous impulses transmission in
parasympathetic and sympathetic ganglions
Carotid sinus reducing of activity of respiratory center and vasomotor
center that lead to respiratory center paralysis (stop of
breath), dilatation of the vessels and hypotension
Cerebral layer of adrenal reducing of secretion of epinephrine reducing of
gland the blood pressure (hypotension) and deceleration of the
heart rate (bradycardia)
Skeletal muscles deceleration of neuromuscular transmission
- effects of blockage of N-cholinoceptors there are the pharmacologic effects of N-cholinergic
antagonists.
Classification of antagonists of cholinergic receptors
M-, N- cholinoblockers (central blocking agents)

Trihexyphenidyl
Benactyzine
tertiary amines: Adiphenine
Aprophene
Arpenalum
M-cholinoblockers
plant origin:
Atropine
Platyphylline
Scopolamine
Homatropine hydrobromide
Atropa Belladonna medications: Extract/Tincture Belladonnae; Besalolum;
Bepasalum; Bethiolum; Anusolum; Bellaspon; Bellastesin; Belalginum
synthetics:
- quarterly amines (peripheral action): Metocinium iodide
Нyoscine butylbromide
Ipratropium bromide
Pirenzepine
Tropicamide
Tiotropium bromide
Troventolum
• N-cholinoblockers:
Ganglioblockers:
tertiary amines (central action): Pempidine
Pachycarpine hydroiodide
quarterly amines (peripheral action): Hexamethonii benzosulfonas
Azamethonium bromide
Trepirium iodide
Dimecolinum
• N- cholinoblockers:
Myorelaxants (neuromuscular blocking drugs):
1) Depolarizing (leptocurare)
Suxametonium chloride, Succinylcholine
2) Nondepolarizing (pahycurare)
Tubocurarine chloride
Pancuronium bromide
Pipecuronium bromide
Mellictinum
Atracurium besilate
Vecuronium bromide
| Unit 3. Drugs affecting the Autonomic Nervous System
3) Mixed
Dioxonium
Myorelaxants (neuromuscular blocking drugs):
Shot action (duration is 5-7 minutes): Suxametonium chloride
Middle action (duration is up to 40 minutes): Atracurium besilate
Vecuronium bromide
• Long action (duration is more than 40 minutes): Tubocurarine chloride
Pancuronium bromide
Pipecuronium bromide
Pharmacologic characteristic of Cholinergic antagonists
Indications for M-,N-cholinoblockers use:

Parkinson disease/syndrome
Biliary colic, intestinal colic, stomach/duodenum ulcer disease, renal colic, liver
colic (abdominal pain)
Endarteritis
Neuritis
Premedication in patients with spasm of the smooth muscles
Examination of eyeground (eye bottom/ocular fundus)
Dry cough (oppresses the cough reflex)
Adverse effects of M-,N-cholinoblockers:

Depression of CNS
Mydriasis
Increasing of intra-ocular pressure
Paralysis of accommodation (the vision is established on distal visibility) –
cycloplegia
Tachycardia, extrasystoles
Constipation
Dysfunction of the gall bladder
Urinary retention
Contraindications for M-, N-cholinoblockers use:
Glaucoma
Organic heart diseases with tachycardia, extrasystoles
Atherosclerosis
Acute kidney and liver insufficiency
Hypertrophy of prostate
Indications for M-cholinoblockers use:

Eye bottom (fundus of the eye, eyeground) examination
Glasses selection
Acute infections in iris of the eye, cornea and tissues in the eye for medicinal
immobilization
Trauma of the eye (for medicinal immobilization of the eye)

Spasm of smooth muscles of the internal organs (biliary colic, intestinal colic,
stomach/duodenum ulcer disease, renal colic, liver colic – abdominal pain)
Hemorrhoids
Anal fissures
Cystitis
Nocturnal enuresis (incontinence of urine, nocturia, nocturnal urinary
incontinence)
Bronchospasm
Spasm of the vessels in patients with arterial hypertension or IHD
(platyphylline)
Spasm of the brain vessels
Migraine
Atrioventricular block in the heart
Premedication
Vestibular disorders
Adverse effects of M-cholinoblockers:
Mydriasis
Cycloplegia – paralysis of accommodation (the vision is established on distal
visibility)
Depression of exocrine gland secretion (xerosis) – xerophtalmus, xeroderma,
xeromycteria, xerostomia, decreasing of viscosity of sputum, hoarseness (of
voice), fever
Ischuria (retention of urine)
Peripheral vessels dilatation
Oppression/Excitement of CNS
Paralysis of breath
Increasing of intra-ocular pressure
Constipation
Contraindications for M-cholinoblockers use:
Glaucoma
Organic heart diseases with tachycardia, extrasystoles
Atherosclerosis
Acute kidney and liver insufficiency
Hypertrophy of prostate
Intestine atony
Indications for Ganglioblockers use:

Control of arterial hypotension during surgical operation
Enforcement of contractile ability of myometrium (pachycarpine hydroiodide)
Spasm of peripheral vessels
Hypertensive crisis
Pulmonary edema
Brain edema
Ganglionitis
Ulcerative diseases of stomach and/or duodenum
Adverse effects of Ganglioblokcers:
Orthostatic (postural) hypotension
Tachycardia
Constipation
Meteorism (distension)
Xerophthalmus
Cycloplegia (paralysis of eye accommodation)
Mental disorders
Tremor
Increase of intra-ocular pressure
Contraindications for Ganglioblockers use:
Glaucoma
Atherosclerosis
Myocardial infarction/IHD
Cerebral insult
Pheochromocytoma
Renal and liver insufficiency
In the 50 - 60 years of the last century ganglionic blockers were the first
effective drugs for the treatment of hypertension. But according to the role of
ganglionic parasympathetic and sympathetic nervous transmission and support
regarding the hypotensive effect of ganglionic numerous negative side effects in
clinical practice greatly limited their use.
Indications for Myorelaxants use:

For relax of skeleton muscles during different surgical operations
Reposition of broke bones
Set a bone
Tetanus
In anesthesiological practice Nondepolarizing (pahycurare) muscle relaxants
are used for prolonged muscular relaxation, while Depolarizing (leptocurare)
muscle relaxants – are used for short-term muscular relaxation.
Adverse effects of Myorelaxants:
Weakening of a diaphragm
Arterial hypotension, collapse
Micro trauma and pain in muscles after surgical operation
Hypertermia (inherent in patients with congenital structural myopathy – a
disease of the central rod)
Long apnea
Hyperkalemia
Anaphylaxis (rarely)
The peculiarity of the pharmacological effects of muscle relaxants is their
ability to increase histamine release, which causes side effects such as prolonged
apnea, anaphylaxis, cardio-vascular collapse. In addition, there are conditions that
contribute to the emergence of side effects of muscle relaxants: a change in body
temperature; electrolyte imbalance, particularly with respect to potassium content,
as well as muscle relaxants may displace potassium from the cells
(succinylcholine-induced hyperkalemia can be life-threatening); low level of
butyrylcholinesterase (genetic defect, prior appointment anticholinesterase drugs,
delivery with food organophosphorus compounds, pregnancy, liver disease),
leading to a decrease in the rate of biotransformation of succinylcholine (lengthens
the duration of its action and, consequently, the intercostal muscle relaxation and
apnea duration), presence of patients with latent myasthenia gravis or malignant
disease, such as small cell lung carcinoma with myasthenic syndrome of Eaton-
Lambert; decrease in blood flow to skeletal muscles, which results in slower
elimination of muscle relaxants, besides a violation of hepatic function (for
vecuronium), renal function (for pancuronium) leads to slower elimination of
muscle relaxants also.
Contraindications for Myorelaxants use:
Allergy
Myasthenia
Respiratory failure
Heart failure
Renal and/or liver failure
Disturbances of electrolyte balance (especially hyperkalemia)
Table 20. Medicinal forms of Cholinergic antagonists: M-N-cholinoblockers, M-
cholinoblockers, Ganglioblockers and Myorelaxants

Trihexyphenidyl Cyclodolum, anti-Spas, Tablets 0.001; 0.002; 0.005
Antitrem, Aparkan,
Atrane, Apo-Trihex,
Parkopan, Peragit,
Pipanol, Tremin, Trixyl,
Trifen, etc.
Benactyzine Actozine, Amitakon, Powder for eye drops 1%; 2%
Amizylum, Benactina, (extemporal solution);
Benactyzinum, Cafron, Tablets 0.001; 0.002
Cevanol, Lucidil,
Nervatil, Neurobenzile,
Parasan, Phobex,
Procalm, Suavitil,
Tranquilline, etc.
106 | Unit 3.
Drugs affecting the Autonomic Nervous System
Adiphenine Spasmolytin, Trasentin, Powder
Vagospasmyl,
Vegavthin
Aprofene Aprofene, Aprophenum Tablets; 0.025
Parenteral solution in 1% - 1ml
ampoules (s/c, i/m)
Arpenalum Arpenalum Tablets 0.05
Atropine Atropinum, Atropine Powder;
sulfate, Atromed Parenteral solution in 0.05%; 0.1% - 1 ml
ampoules (s/c, i/v,
i/m);
Parenteral solution in 0.1% - 1 ml
tube-syringes;
Peroral solution in 0.1% - 10 ml
flacons;
Tablets; 0.0005
Eye drops in flacon- 1% - 5 ml; 10 ml;
droppers; 15 ml; 20 ml; 30 ml
Eye ointment; 1%
Eye films 0.0016
Tropicamide Mydriacyl, Mydrum, Eye drops in flacon- 0.5% - 10 ml;
Midriatikum-Stulln PU droppers;
Eye drops in flacon 0.5%, 1% - 10 ml
Platyphylline Platyphylline-Ferein, Powder;
Platyphylline-Darnitsa, Tablets; 0.005
Platyphylline Parenteral solution in 0.2% - 1 ml
hydrotartrate, ampoules;
Platyphylline Peroral solution 0.5%
hydrotartrate 0.2% (extemporal);
Leciva-Geo, Solutio for 0.5%; 1%
Platyphylline microclysters
hydrotartrate solution (extemporal);
for injections 0.2%,
Platyphylline Rectal suppositories; 0.01
hydrotartrate tablets
0.005 g
Thepaphyllinum,
Platyphyllinum Tablets (Platyphylline
hydrotartrate 0.003;
Phenabarbital 0.03;
Papaverine
hydrochloride 0.03)
Tablets (Platyphylline
hydrotartrate 0.005;
Phenabarbital 0.02,
Palufinum Papaverine
hydrochloride 0.02)
Scopolamine Hyoscini Powder;
hydrobromidum,
Scopolaminum Parenteral solution in 0.05% - 1 ml
hydrobromicum ampoules (s/c);
Chapter 5. | 107
Сholinergic antagonists
Eye drops; 0.25%
Eye ointment; 0.25%
Transdermal
therapeutic systems
(TTS);
Scopolaminum Solution in flacons; 0.25% -5 ml; 10 ml
hydrobromicum cum
methylcelluloso
Aeronum
Tablets scopolamine
camphoric acid
0.0001 cum
hyoscyamine
camphoric acid
0.0004
Homatropine Homatropinum Powder;
hydrobromide hydrobromidum Eye drops in flacons 0.25% - 5 ml
Extract of Extractum Belladonnae Extract 0.015
Belladonnae siccum siccum
Tincture of Tinctura Belladonnae Tincture 10 ml
Belladonnae
Extract of Besalolum Tablets Extractum
Belladonnae + Belladonnae 0.01 +
Phenyl salicylate Phenyl salicylate 0.3
Phenyl salicylate + Bepasalum Tablets Phenyl salicylate
Papaverinum h/cl. + (salol) 0.3 +
Extractum Papaverinum h/cl.
Belladonnae 0.03 + Extractum
Belladonnae 0.012
Extract of Bethiolum Rectal suppositories Extractum
Ichthyol Ichthyol 0.2
Extract of Anusolum Rectal suppositories Extractum
Xeroformium + Xeroformium 0.1 +
Zinc sulfate + Zinc sulfate 0.05 +
Glycerol Glycerol 0.12
Phenobarbital + Bellaspon Tablets Phenobarbital 0.02 +
Ergotamine tartrate Ergotamine tartrate
+ Belladonnae 0.0003 +
alkaloids Belladonnae alkaloids
0.0001
Belladonnae extract Bellastesinum Tablets Belladonnae extract
+ Benzocaine 0.015 + Benzocaine
0.3
Metamizole sodium Bellalginum Tablets Metamizole sodium
+ Benzocaine + 0.25 + Benzocaine
Belladonna extract + 0.25 + Belladonna
Sodium extract 0.015+Sodium
hydrocarbonate hydrocarbonate 0.1
108 | Unit 3.
M etocinium
Methacinum Tablets; 0.002
iodide Parenteral solution 0.1% - 1 ml
(s/c, i/m, i/v)
Нyoscine Butylscopolamini Dragee; 0.01
butylbromide, bromidum, Buscolysin, Rectal suppositories; 0.01
Butylscopolamine Buscopin, Buscopan, Parenteral solution 2% 1 ml
Buscoridin, Hyoscine- (s/c, i/m, i/v)
N-butylbromide, Spanil,
Spasmalexin, Tirantil,
Toscopan
Ipratropium Atrovent, Arutropid, Aerosol in balloon; 15 ml
bromide Itrop, Normosecretol, Solution for 0.025% - 20 ml
Vagos inhalation in flacons;
Powder for inhalation 0.005
in capsules;
Parenteral solution in 0.0005 mg/1 ml
ampoules (i/v)
Tiotropium bromide Spiriva, Tiova Capsules with specific 18 mg

HandiHaler inhaler
Pirenzepine Abrinac, Bisvanil, Tablets; 0.025; 0.05
Duogestral, Gastril, Parenteral solution 0.5% - 2 ml
Gastrol, Gastrozepin, (i/m, i/v) in ampoules
Gastromen, Gastropin,
Gastropiren, Gastrozem,
Leblon, Pirehexal,
Piren, Pirigast, Ulcepin,
Ulcin, etc
Pempidine Pirilenum Powder;
Tablets 0.005
Pachycarpine Pachycarpine Powder;
hydroiodide hydroiodide Tablets; 0,1
Parenteral solution in 3% - 2 ml
ampoules (s/c, i/m)
Hexamethonii Benzohexonium, Tablets; 0,1
benzosulfonas Hexonium, Parenteral solution in 2,5% - 1ml
Bistrium, Gangliostat, ampoules (s/c, i/v,
Hexameton, Hexanium, i/m)
Hexathide, Hiohex,
Methobromin,
Methonium, Vegolysen,
etc.
Azamethonium Pendiomid, Parenteral solution in 5% - 1 ml; 2 ml

bromide Pentamethazene, ampoules (i/v, i/m)
Pentaminum
Dimecolinum Dimecolonium iodide Tablets 0.025; 0.05
Trepirium iodide Hygronium Powder for injection 0,1
in flacons (i/v)
Chapter 6. Adrenergic agonists | 109
Suxametonium Dithyllinum, Parenteral solution in 2% - 5 ml; 10 ml

chloride, Anectine, Quelicin ampoules (i/v, i/m)
Succinylcholine
Tubocurarine Amelizol, Parenteral solution in 1% - 1ml
chloride Tubadil,Curadetensin, ampoules (i/v)
Curarin, Delacurarine,
Myostatine, Myricin,
Tubaril, Tubarine,
Tubocuran, etc.
Pancuronium Pavulon Parenteral solution in 0.2% - 2 ml
bromide ampoules (i/v)
Pipecuronium Arduan, Pipecurium Powder for injection 0.004
bromide bromide in ampoules (i/v)
Mellictinum Tablets 0.02
Atracurium besilate Tracrium Parenteral solution in 1% - 2.5; 5 ml
ampoules (i/v)
Atracurium chloride Alloferin Parenteral solution in 0.5% - 2 ml
ampoules (i/v)
Vecuronium Muscuron, Norcuron Powder for injection 0.004
bromide in flacons (i/v)
Dioxonium Dioxonium Parenteral solution in 0.1% - 5 ml
ampoules (i/v)
Chapter 6. Adrenergic agonists

Drugs that act on the adrenergic receptors are named adrenergic drugs. The
main mediator (neurotransmitter) of adrenergic nerves system is Norepinephrine
(NE).
The process of neurotransmission in adrenergic neurons includes five
steps. The first step is synthesis of NE. Tyrosine is transported to adrenergic
neurons, where is hydroxylated to dihydroxyphenylalanine (DOPA) by tyrosine
hydroxylase. This is the rate-limited step in catecholamine transmitter synthesis.
DOPA is decarboxylated by dopa-decarboxylase to dopamine (D) in cytoplasm of
presynaptic neurons. Dopamine is hydroxylated by dopamine-β-hydroxylase to
NE. The second step is storage of NE in vesicles. Dopamine, norepinephrine,
ATPh, β-hydroxylase are in synaptic vesicles. In adrenal medulla and certain areas
of the brain NE is transformed into epinephrine (Ep) by methylation. The adrenal
gland releases 80% of Ep and 20% of NE directly into bloodstream. The third step
is release of NE from synaptic vesicles, and NE diffuses to synaptic gap. After
release from synaptic vesicles NE may be metabolized by monoamine oxidase
(MAO) in presynaptic structure, may be metabolized by catecol-orto-
methyltransferase (COMT) in synaptic gap, may be recaptured by an uptake
system that returns NE into the neuron (this is the primary mechanism for
termination of NE’s effects and are called neuronal recapture), NE may diffuse out
of synaptic space and enter the general circulation. After neuronal recapture NE
may be taken up into adrenergic vesicles or may persist in a protected pool or can
be oxidized by MAO. The fourth step is receptor binding of NE: as presynaptic

receptors on the nerve endings and postsynaptic receptors on the effector organs.
The fifth step is removal of NE from the synaptic gap. There are inactive products
of NE metabolism: vanillylmandelic acid, metanephrine, normetanephrine.
There are several classes of adrenergic receptors (adrenoceptors): α, β and
dopaminergic receptors (D). There are the several subtypes of them: α1, α2, β1, β2,
β3, and there are dophaminergic receptors: D1, D2, etc.
Adrenergic agonists (also called adrenomimetics) increase activity of
adrenergic nerve system. In accordance with the mechanism of action some
adrenergic drugs act directly on the adrenergic receptors, stimulate them and are
named direct-action adrenergic agonists (mimetics); other adrenergic agonists act
on neurotransmitters of adrenergic nerves system (norepinephrine and/or its
predecessor – dopamine), increase the amount of neurotransmitters in adrenergic
synapses and are named indirect-action adrenergic agonists or sympathomimetics.
They not only release stored NE from nerve endings but also inhibit neuronal
uptake of NE by presynaptic structure in the adrenergic synapse and directly
stimulate both α and β receptors. Adrenergic neurons are located in CNS, as well
sympathetic (adrenergic) nervous system and release neurotransmitter
norepinephrine that is the final product of catecholamine synthesis in most
sympathetic postganglionic neurons. Catecholamine transmitters are stored in
membrane-bound vesicles. Adrenergic neurons are a bridge between the ganglia
and effector organs. There are presynaptic and postsynaptic adrenergic neurons and
receptors on the effector organs. Long-term use of β-agonists leads to
internalization, or sequestration, or down-regulation of the β -adrenergic receptors.
This means that β -adrenergic receptors go into a state of low affinity and
disappear from the surface of the membrane. This phenomenon explains tolerance
to β-agonists.
Table 21. Places of location and effects* of activation of adrenergic receptors
Receptors Places of location Effects of activation

Vessels of skin, mucous, mesentery, constriction of the vessels,
α1 abdominal cavity, heart, lung, kidney increase of BP
Eye mydriasis, reducing of
intraocular pressure
Sphincters of GIT increase of tonus
Sphincters of Urinary bladder increase of tonus
Uterus increase of tonus
Exocrine glands: bronchial, salivary, increase of gland secretion
gastric, intestinal, lachrymal, sweat
CNS excitement
α2 CNS (vasomotor center) depression,
reducing of BP
Vessels dilatation
GIT reducing of tonus
Thrombocytes increase of aggregation
Heart cardiopositive effects:
β1 positive inotropic effect;
positive dromotropic effect;
tachycardia (positive
chromotropic effect);
positive batmotropic effect
Vessels of skeleton muscles reducing of tonus
(relaxation)
Kidney increase of renin secretion
Lipid tissues lipolysis
Bronchi reducing of tonus
β2 (bronchodilatation)
Peripheral vessels reducing of tonus
(dilatation)
GIT reducing of tonus (atony)
Uterus reducing of tonus (tocolytic
effect)
Thrombocytes reducing of aggregation
Urinary bladder reducing of smooth muscle
tonus (urinary retention)
Hepar glycogenolysis,
glycogenoneogenesis
Pancreas insulin and glucagon
secretion
Skeletal muscles increase of contractility,
glycogenolysis,
capture of K+
Lipid tissues increase of lipolysis,
β3 increase of FFA level in
the blood
increase of glycogenolysis,
increase of glucose level in
the blood
Heart cardiopositive effects:
D1 positive inotropic effect;
weak positive chronotropic
effect
Peripheral vessels reducing of tonus,
improvement of peripheral
blood circulation
Sphincters of GIT reducing of tonus
3.
112 | Unit Drugs affecting the Autonomic Nervous System
Sphincters of Urinary bladder reducing of tonus
CNS stimulation of motor
activity
CNS reducing of synthesis and
D2 secretion of NE, Ach, D, Ep
Peripheral n.s. deceleration of nervous
impulse transmission
Kidney reducing of rennin
secretion
* - effects of activation of adrenergic receptors/dopamine receptors there are pharmacologic
effects of adrenergic/dopaminergic agonists.
Classification of Adrenergic agonists
 Adrenomimetics of direct action:

Nonselective α-, β- adrenomimetics (Drugs that stimulate α- and β-ARs):
α1, α2, β1: Norepinephrine h/tr.
β1 β2 α1, α2: Epinephrine h/chl., h/tr., Dipivefrine
Drugs that stimulate α-ARs:
α1: Phenylephrine
Oxymetazoline
Tetryzoline
α1, peripheral α2: Xylometazoline
Naphazoline
central α2: Clonidine
Guanfacine
Methyldopha
c) Drugs that stimulate β-ARs:
β1 β2: Isoprenaline
Orciprenaline sulfas
β1: Dobutamine
β2: shot action (3-8h.) Fenoterol
Salbutamol
Terbutalin
Hexoprenaline
long action (10-12h.)
Salmeterol
Formaterol
 Adrenomimetics of indirect action (Sympathomimetics):

Ephedrine, Pseudoephedrine

Dopaminomimetics:
D, α1, α2, β1: Dopamine (Dophamine), Ibopamine
D2: Bromocriptine, Cabergolin, Quinagolide
Pharmacologic characteristic of Adrenergic agonists
Peculiarities of the several Adrenomimetics
Epinephrine h/chl, h/tr. (β1 β2 α1, α2,)

The main feature of epinephrine is the fact that its impact on the
corresponding receptors depends on the dose. Thus, in small doses it stimulates β-
adrenergic receptors alone and in medium and large doses – as β-, and α-adrenergic
receptors. Under the influence of epinephrine on the heart there are two opposing
mechanisms of action: direct β1-adrenoreceptor stimulating and inhibitory reflex
via the vagus nerve.
Pharmacological effects of epinephrine
Cardiopositive (cardiostimulator) – by stimulation of β1-adrenergic receptors,
but increasing stroke volume leads to a reflex bradycardia due to the
exposure of the vagus nerve
Bronchodilatation (bronchodilatator) – by stimulation of β2-adrenergic
receptors (subcutaneous injection of drug is sufficient)
Functional antagonist of insulin (epinephrine increases the glucose level in the
blood due to stimulation of glycogenolysis in the liver – stimulatory effect of
epinephrine on β2-adrenergic receptors)
Increase of the functional ability of skeleton muscles, increase of blood flow to
the skeletal muscles
Stimulation of the glycogen degradation to lactic acid, increase of lactate level
in blood (β-stimulating effect on the skeleton muscles)
Constriction of arterioles in the skin, mucous membranes, and viscera (α-
stimulating effects), and dilatation of vessels going to the liver and skeletal
muscles (β2-stimulating effects). Renal blood flow is decreased
Inibition of the release of biology active remedies (BAR) from mast cells
Reduction of the intraocular pressure through vasoconstriction, and decrease in
production of intraocular fluid
Mydriasis by means of stimulation of α1 adrenergic receptors of musculus
dilatator pupilla
After introduction of epinephrine first the blood pressure increases, but in the
future – decreases. The cumulative effect of epinephrine is an increase in
systolic BP, coupled with a slight decrease in diastolic BP
Increase of BP in case of i/v bolus administration of epinephrine due to
stimulation of α-adrenergic receptors of skin, mucous membrane, mesentery,
abdominal organs (α1-adrenergic receptors) and increased cardiac activity
(β1-adrenergic receptors)
Indications for epinephrine use:
Cardiac arrest (i/v, intratracheal administration of epinephrine)
Anaphylactic shock
Angioneurotic edema of larynx

Bronchospasm
Hypoglycemic coma (in case of insulin overdoses) – useful in this case
where is a stimulation by epinephrine of α2-adrenoceptor of pancreas, which
leads to inhibition of insulin secretion
Insufficiency of peripheral blood circulation (during the operation, local
anesthesia)
Open-angle glaucoma
Examination of eye bottom
Local anesthesia (together with local anesthetics for it prolonged action)
Advers effects of epinephrine:
Cardiac arrhythmia, especially in condition of hypoxia: Epinephrine
increases the requirement in oxygen of heart muscle
Hypotonia after short hypertension
Atonia of GIT
Mydriasis and light disturbance of accommodation
Bronchospasm that connect with a loss of sensitivity of β2-adrenergic
receptors epinephrine and a saving of sensitivity of α-adrenergic receptors to
epinephrine (with repeated administration of epinephrine as manifestations
of tachyphylaxis)
Hypokalemia
Tremor
Constriction of the vessels of the mucous, of the skin, of the abdominal
cavity
In high doses Epinephrine penetrates BBB and causes excitement of CNS:
headache, nervousness, sleeplessness (insomnia), vomiting
Contraindications for epinephrine use:
Together with other adrenomimetics (threat of heart arrhythmia)
Together with general anesthetics: Cyclopropane, Phthorothanum, Isoflurane
(threat of heart arrhythmia)
Together with diuretics and cardiac glycosides (threat of heart arrhythmia)
In patient with bronchial asthma and IHD, hypertension, atherosclerosis and
other organic diseases of myocardium
In patient with diabetes mellitus
Dipivefrine (eye drops – antiglaucoma drug) – prodrug, it easily penetrates

into the anterior chamber, where exposed to enzymatic hydrolysis with the
formation of epinephrine. Epinephrine is distributed in the ciliary muscle and
trabecular tissue of the eye; it reduces the production of intraocular fluid and
increases its outflow.
Norepinephrine h/tr.(α1, α2,β1)
The peculiarity of the mechanism of norepinephrine action is the fact of
preferred and overriding stimulation of α-adrenergic receptors, to a lesser extent –
β1-adrenergic receptors.
Pharmacological effects of norepinephrine:

Constriction of the vessels
Cardiopositive (cardiostimulating)
Hypertensive
Indications for norepinephrine use:
Acute arterial hypotonia (during the surgical operation, shock, collapse,
poisoning, after removing of pheochromocytoma)
Local anesthesia (together with local anesthetics for it prolonged action), e.g.,
Xylestesin-F (forte) (lidocaine+norepinephrine), Trimecaine with
norepinephrine for injections (trimecaine+norepinephrine)
Adverse effects of norepinephrine:
Deterioration of the peripheral blood circulation
In cardiogenic and hemorrhagic shock with severe arterial hypotension
norepinephrine may impair blood flow to internal organs
Bradycardia as a reflex response to an increase in stroke volume that leads to
immutability of minute volume or even to reduce of minute volume
Cardiac arrhythmia
Vasoconstriction and as a result of gangrene (necrosis of the tissues) in case of
introduction to tissues
ONLY INTRAVENOUS INTRODUCTION!!!
Tremor
In high doses norepinephrine penetrates BBB and causes excitement of CNS:
headache, nervousness, sleeplessness (insomnia), vomiting
Contraindications for norepinephrine use:
Together with other adrenomimetics (threat of heart arrhythmia)
Together with general anesthetics: Cyclopropane, Phthorothanum, Isoflurane
(threat of heart arrhythmia)
Heamorrhagic and cardiogenic shocks
Atherosclerosis
Pregnancy
AV-blocks
Introduction of norepinephrine to the tissues of the body (at accidental
norepinephrine delivery under the skin, in the muscles should be immediately
drugged around the site of solution norepinephrine injection by α-adrenoblockers
such as phentolamine).
Phenilephrine (α1)
It is a synthetic α1-adrenomimetic.
Pharmacological effects of phenilephrine:
Vasoconstrictive
Mydriasis
Decongestive
Indications for phenilephrine use:
Collaps, arterial hypotonia
Prophylaxis of BP reduction in case of infection diseases and poisoning
Rhinitis
Conjunctivitis, iridocyclitis
Examination of eye bottom
Local anesthesia (together with local anesthetics for it prolonged and safe
action)
It may be used in case of arterial hypotonia during halothane and isoflurane
general anesthesia
Adverse effects of phenilephrine:
Bradycardia
Deterioration of the peripheral blood circulation
Xerosis (dryness of mucous)
Contraindications for phenilephrine use:
Heart blockages
Atherosclerosis
Tendency to angiospasm
Heart insufficiency
Oxymetazoline (α1), Tetryzoline (α1), Xylometazoline (α1, peripheral α2),

Naphazoline (α1, peripheral α2)
Pharmacological effects of them:
Vasoconstriction
Indications for their use:
Acute and allergic rhinitis, conjunctivitis, iridocyclitis, sinusitis, eustachitis,
hay fever
Adverse effects of them:
Xeromycteria, mucous atrophy
Excitement of CNS: headache, nervousness, sleeplessness (insomnia), nausea,
vomiting
Tachycardia
Mydriasis
Tahyphylaxia
Contraindications for their use:
Cardiac arrhythmia
Clonidine (central α2), Guanfacine (central α2),

Methyldopha (central α2)
Reduction of the intraocular pressure
Glaucoma (for clonidine)
Alcohol abstinence
clonidine, guanfacine:
Sedative
Analgesive
Withdraval (abolition) syndrome
Ortostatic hypotension
methyldopha:
Bradicardia
Addiction
Atherosclerosis
IHD
Together with other drugs that depress CNS
Heart arrhythmia, heart blockages
Isoprenaline (β1 β2), Orciprenaline sulfas (β1 β2)

Cardiopositive
Bronchodilatative
Vasodilatative due to reduction of peripheral vascular resistance of kidney,
mesentery, sckeleton muscles that leads to decline of diastolic and systemic BP
improvement of blood circulation to the internal organs
They hamper the release of BAR (biology active remedies) from mast cells
Bronchospasm
Bronchial asthma
Heart blockages
Prophylaxis of Gerbezius-Morgagni-Adams-Stokes syndrome
Adverse (side) effects of them:
Tachycardia
Cardiac arrhythmia
Tremor
Excitement of CNS
Hyperglycemia
Arterial hypotonia
Headache
Tocolitic tffect
Atherosclerosis
Heart arrhythmia
Arterial hypotonia
Diabetes mellitus
Organic diseases of CNS
Dobutamine (β1)
Pharmacological effects of dobutamine:
Strong positive inotropic
Improvement of the kidney blood circulation
Indications for dobutamine use:
Cardiogenic shock
Acute heart insufficiency
Chronic heart insufficiency (sometimes)
Adverse (side) effects of dobutamine:
Tachycardia
Cardiac arrhythmia
Heart pain
Bronchospasm
Excitement of CNS
Tolerance in case of uninterrupted introduction within 3-4 days
Contraindications for dobutamine use:
Organic heart diseases with disorder of heart rhythm
Atherosclerosis
Fenoterol, Salbutamol, Terbutalin, Salmeterol, Hexoprenaline, Formoterol

(β2)
Bronchodilatation
Tokolitic effect
Bronchospasm
Bronchial asthma
Premature (untimely) delivery
Hypertonus of uterus
Swift delivery
Adverse (side) effects of them:
Tachycardia (mainly occurs in patients with concomitant cardiovascular disease
and rarely without it, as well as the combined use of MAO-inhibitors or
other sympathomimetics)
Cardiac arrhythmia (mainly occurs in patients with concomitant cardiovascular
disease and rarely without it, as well as the combined use of MAO-inhibitors
or other sympathomimetics)
Arterial hypotonia
Excitement of CNS: anxiety, trouble
Tachyphylaxis
Allergic reaction
Urinary retention, especially in old people
Tremor that can be avoided or reduced by the use of β2 adrenergic agonists

beginning with small doses with a gradual increase of them. In case of
parenteral use these drugs can increase concentration of glucose, lactate, free
fatty acids (FFAs) in blood plasma and reduce concentration of K+ ions
Hyperglycemia in the patients with diabetes mellitus that requires correction of
hypoglycemic drug doses
All adverse effects of β2 adrenergic agonists are diminished in inhalation
therapy in comparison with peroral or parenteral administration.
Organic heart diseases with disorder of heart rhythm
Old age
Uterine inertia
Ephedrine, Pseudoephedrine
According to the mechanism of action they are similar to epinephrine, but
less powerful. Besides, they aren’t catecols and are poor substrates for COMT and
MAO, as a result these drugs have long action, good oral absorption and
penetration into the CNS. Ephedrine, Pseudoephedrine are α-, β-adrenergic
agonists, they stimulate release of norepinephrene from sympathetic neurons,
thereby, they activate adrenergic receptors. These drugs are the drugs of mixed
sympatomimetic action.
Ephedrine increases the heart rate, cardiac output, peripheral vascular
resistance, BP, stimulates CNS, causes addiction, euphoria and tahyphylaxia.
Stimulation of α-adrenergic receptors of smooth muscles of sphincters of urinary
bladder elicits urinary retention. Activation of β-adrenergic receptors of smooth
muscles of bronchi leads to bronchodilatation.
Ephedrine, Pseudoephedrine have limited clinical applications in nowadays
through their adverse effects.
Dopamine (Dophamine), Ibopamine (D1, α1, β1)

Dopamine is the immediate metabolic precursor of NE and it is the
neurotransmitter in the CNS in the basal ganglia. Dopamine activates α and β
adrenergic receptors. Dopamine is a dose-dependent drug: in low doses dopamine
stimulates D1 receptors that lead to vasodilatation of peripheral mesenteric vessels,
renal vessels and vessels of the heart and the brain, increasing blood flow to renal,
mesenteric, coronary arteries, and brain arteries, increasing overall renal perfusion,
induces natriuresis (sodium loss) in the kidneys, and has a diuretic effect; in
moderate doses dopamine stimulates β1 adrenoceptors and causes an increase in
cardiac output and stroke volume, it has a positive inotropic and chronotropic
effect; in high doses dopamine activates α1 adrenoceptors and causes
vasoconstriction of the kidney vessels to the point that urine output is reduced,
increases systemic vascular resistance, blood pressure, causes heart arrhythmia,
nausea, vomiting. Thereby, the low doses of dopamine are considered the "renal
doses", the moderate doses of dopamine are known as the "cardiac doses", the
high doses of dopamine are the "pressor doses" . Ibopamine on structure and
pharmacological properties similar to dopamine, but it is effective after oral
administration.
Pharmacological effects of dopamine, ibopamine:

Positive inotropic
Positive chronotropic
Vasodilatative
Increase of cardiac output
Increase of BP
Indications for dopamine use:
Heamorrhagic and cardiogenic shocks
The emergency clinical treatment of severe hypotension
Bradycardia
Cardiac arrest for the purpose of cardiopulmonary resuscitation
Adverse (side) effects of dopamine:
May be a tissue necrosis (ONLY INTRAVENOUS INTRODUCTION!!!)
Cardiac arrhythmia, tachycardia
Indications for ibopamine use:
Chronic heart insufficiency
Adverse (side) effects of ibopamine:
Cardiac arrhythmia, tachycardia
Dyspepsy
Hyperglycemia (in high doses)
Bromocriptine
(powerful agonist of D2 receptors and lesser extent of D1 receptors)
Pharmacological effects of bromocriptine:
Stimulates dopamine receptors of hypothalamus that lead to decreasing of
secretion (not synthesis) of hormones of anterior lobe of hypothalamus,
especially of prolactin and in a less degree – of somatotropin (growth
hormone)
Emetic
Hypothermic
Hypotensive
Reduces the smooth muscle tonus in the vessels
Inhibits the uterus contractions that were caused by methylergometrine
Reduces the blood level of catecolamines
Strong sedative effect
Indications for bromocriptine use:
For suppression of postpartum lactation
For normalization of the menstrual cycle in women with hyperprolactin
amenorrhea
Sterility
Acromegaly
Icenko-Cushing disease/syndrome
Benign tumors of the mammary glands
Prolactinoma
Parkinson disease/syndrome (in high therapeutic doses)
Adverse (side) effects of bromocriptine
Nausea, sometimes vomiting
Constipations
Headache
Dizziness
Sleepiness
Postural hypotension
Disorder of peripheral blood circulation
Contraindications for bromocriptine use:
Toxemia of pregnancy
Lactation
Recent myocardial infarction
Cardiac arrhythmia
GIT diseases
Psychical diseases
Pergolide
(partial agonist of D1 receptors and powerful agonist of D2 receptors)
Pergolide in modern terms is almost never used because of the high risk of
valvular heart disease. In addition, there can be hypotension (especially in the first
days of therapy), arrhythmia, dizziness, insomnia, dyskinesia, and peripheral
edema.
Cabergolin (agonist of D2 receptors)
Cabergolin has the similar effects as bromocriptine, but cabergolin is a long-term
action drug.
Quinagolide (agonist of D2 receptors)
Quinagolide inhibits the prolactin secretion.
Table 22. Medicinal forms of Adrenomimetics, Sympatomimetics

Norepinephrine Noradrenaline Solution for 0.2% - 1ml
hydrotartrate, injections in
Arterenol, Levarterenol, ampoules (i/v)
Levophed, Norartrinal,
Norexadrine, etc.
Epinephrine Adrenaline, Adnephrine, Solution for 0.18% - 1ml;
Adrenamine, Adrenine, injections in 0.1% - 1ml;
122 | Unit 3.
Epirenan, Epirinamine, ampoules (s/c,
Eppy, Hypernephrine i/m, i/v);
Levorenine, Nephridine, Solution for 0.1% - 10ml;
Paranephrine, external use in 0.18% - 10ml;
Renostypticin, Styptirenal, flacons;
Suprarenalin, Suprarenin, auto-injector; 150mcg,
Tonogen, etc.; 300mcg,
Dipivalat, Diopine, 500mcg,
Oftan Dipivefrine, Propin, 0.15 mcg,
Thilodrin, Vistapin, 300mcg,
Epifrin, Epiglaucon, 150 mcg,
Epinal, Glaucon, 300mcg;
Glauconin, Glaukosan, etc.
Adrenaline auto-injector
devices for anaphylaxis:
Anapen, Epipen,
Dipivefrine Jext Eye drops in 0.1% - 5ml
flacons-
droppers
Phenylephrine Irifrin, Vistosan Eye drops 2.5% - 5ml;
in flacons; 10% - 5 ml;
Mesaton, Adrianol, Parenteral 1% - 1 ml
Almefrin, Derizene, solution for
Idrianol, Isophrin, injections in
Neophryn, Neo- ampoules (s/c,
Synephrine, m-Sympatol, i/m, i/v)
Visadron, etc.
Oxymetazoline Fazin, Fervex, Nasivin, Nasal spray in 0.05% - 5 ml,
Nazol, flacons, 20 ml, 30 ml;
4-Way, Alka-Seltzer plus in flacon- 0.05% - 10 ml;
nosespray Afrin, inhalator;
Bartell Drugs 12 Hour Nasal drops in 0.01% - 5 ml;
Decongestant Nasal, flacon- 0.025% -10ml;
Wick Sinex, Lekonyl, dropper; 0.05% -10 ml;
Oxymetazoline, Vistoxyn, Eye drops in 0.025% -10ml,
etc. flacons 20ml
Tetryzoline Berberill N, Eye drops in 0.05% - 10 ml;

flacons; 0.05% - 0.5ml;
Visine, Nasal drops in 0.05% - 15 ml;
Octilia, flacons; 0.05% - 8 ml;
Tyzine, Nasal solution; 0.1% - 10 ml;
Burnil, Ophthalmic 0.05% - 10 ml;
Visine, etc. solution 0.05%, 0.1%
0.05% - 15 ml
Xylometazoline Brizoline, Nasal drops in 0.05%, 0.1% -
flacons 10ml;
Galazolin Nasal gel in 0.05%, 0.1% -
Grippostad Rhino, Dlianos, tubes 5.0 ml;
Xilen, Nasal drops 0.1%, 0.05% -
Xylobene, and Nasal 10ml;
Chapter 6. | 123
Adrenergic agonists
Xylometazoline-Rusphar, spray in 0.1%, 0.05% -
Xylometazoline, flacons 10ml;
Xylometazoline Nasal drops 5mg, 10mg -
hydrochloride, 10ml;
Xymelin, Nasal spray in 0.05%, 0.1% -
flacons 10ml;
Doctor Theiss, Nasal drops in 0.05%, 0.1% -
Olynth, flacons 15ml, 20ml,
Otrivin, Nasal drops in 25ml, 30ml;
flacons
Rhinostop, Nasal spray in 0.5, 1.0 mg/ml
NasenSpray ratiopharm, flacons - 10ml, 15ml
Pharmazolin, Nasal spray in 0.1% - 10ml;
flacons
Galazolin, Nasal spray in 0.05%, 0.1% -
etc. flacons 10ml;
Nasal drops in 0.05%, 0.1% -
flacons 10ml;
flacons 10ml, 15ml,
20ml, 5mg -
10ml;
Nasal spray in 0.05%, 0.1% -
flacons 10ml
Nasal drops in
flacons
Aerosol and 0.05%, 0.1% -
Nasal drops in 10ml
flacons
Naphazoline Nafazol-Hemofarm, Nasal drops in 0.05%, 0.1% -

Naphazoline-Ferein, flacons 10ml;
Naphazoline, Solution in 0.05%, 0.1% -
flacons 5ml, 10ml;
Solution in 0.05%, 0.1% -
Naphthyzin-Rusfur, flacons and 10ml, 20ml;
Naphthyzin-UBF,
Naphthyzin, flacons 10ml;
Nasal drops in 0.1% - 5ml,
flacons 10ml, 15ml,
Sanorin, etc. 20ml;
0.05%, 0.1% -
10ml;
Nasal drops in 0.1% - 10ml;
flacons and
Nasal spray in
flacons and
Nasal 0.05%, 0.1% -
emulsion 10ml
124 | Unit 3.
Clonidine Hemiton, Tablets 0.075mg,
Clophelin-Darnitsa, 0.3mg, 0.15mg
Clophelin,
Clonidine hydrochloride,
Clophelin-M, Clophelin Parenteral 0.01% - 1ml
solution for
injections in
ampoules (s/c,
i/m, i/v)
Chlophasolin, Eye drops:
Hyposyn, Normopresan, solution in
Prescatan, tube-droppers - 0.125%,
etc. 0.25%, 0.5% -
1.5ml
Guanfacine Estulic, Hipertensal, Tenex Tablets 1mg
Methyldopha Dopegyt, Aldomet, Tablets 0.25, 0.5
Alfadopha, Dopanol,
Equibar, Hypotonal,
Levomet, Modepres,
Normopres, Presinol,
Presolisin, etc.
Isoprenaline Isadrin, Novodrin, Euspiran Tablets 0.005
Novodrin, Euspiran, Solution for 0.5%, 1% -
Aleudrin, Aludrin, inhalations in 25ml, 100ml
Antasthmin, flacons
Bronchodilatin, Iludrin, Aerosol 25ml (350
Isodrenal, Isonorin, single doses -
Isoprenalini 0.075mg/dose)
hydrochloridum,
Isoprenaline hydrochloride,
Isopropylarterenol,
Isoproterenol, Isorenin,
Isuprel, Neodrenal,
Neoepinephrine,
Norisodrin, etc.
Orciprenaline Astmopent, Aerosol; 20ml-400doses
Alupent, Alotec, Astor, - 0.75mg/dose
Dosalupent, Tablets; 0.02;
Metaproterenolsulfat, Parenteral 0.05% - 1ml;
Novasmasol solution for
injections in
ampoules (s/c,
i/m, i/v)
Dobutamine Dobutamine-Grindeks, Parenteral 0.5% -50ml;
Dobutamine Hexal, solution for 1.25% - 20ml
Dobutamine Lachema, injections in
Dobutamin Solvay, ampoules (i/v)
Dobutrex, Dobuject, Powder for 0.25, 0.53
Dobutamin Giulini, injections in
Dobutamin Nycomed, flacons
Inotrex
Chapter 6. | 125
Adrenergic agonists
Fenoterol Berotec, Solution for 1.25mg - 2ml;
inhalations in 0.1% - 20ml,
flacons; 40ml, 100ml;
Aruterol, Aerosol for 10ml, 15ml, 20
inhalations; ml (100, 200
single doses -
0.1, 0.2
mg/dose)
Partusisten, Tablets; 0.005;
Parenteral 0.5mg - 10ml;
solution for i/v
injections in
ampoules;
Fenoterol, Tablets; 0.005;
Ftagirol, Aerosol for 300 single
Airum, Dosberotec, inhalations; doses - 0.2
Segamol, etc. mg/dose),
Ipratropium Berodual, Berodual N, 15 ml (300
bromide+Fenoterol single doses -
0.02, 0.5
mg/dose);
Solution for 10ml 10ml
inhalations in (200 single
flacons; doses);
Fenoterol+Cromoglicic acid Ditec Aerosol for 10ml (200
inhalations single doses)
Salbutamol Saltos, Asthalin, Ventolin, Tablets; 0.002, 0.004;
Salamol, Ventolin, Tablets-retard; 0.006, 0.007;
Nebules, Salben, 0.004, 0.008;
Salgim, Syrup; 0.04% - 100ml
Sterineb Salamol, Aerosol for 0.025 і 0,1mg
Cybutol cyclocaps, inhalations; /dose; 120,
Airomir, Asthalin, 200, 400 doses
Bronchovaleas Gen- Solution for 0.1% - 2.5ml;
Salbutamol, Salamol easi- inhalations in
breathe, Salmo, ampoules, in 2.5; 5; 10,
Aloprol, Albuterol, flacons; 50ml;
Asmadil, Salbuvent, Powder for 0.1; 0.2 і 0.4
Ventodisk, inhalations; mg/dose;
Volmax, Solution for 0.1% - 5 ml;
Salbuvent, injections (s/c,
Salbupart, i/m, i/v);
Spreor, Capsules for 0.002, 0.004;
Ecovent, inhalations;
Budesonide+Salbutamol Biasten, Aerosol for 0.1; 0.2, 0.4
Ipratropium Combivent, etc. inhalations; mg/dose - 100,
bromide+Salbutamol 200 dose;
Powder for 0,02 mg/0,12
inhalations in mg – 1dose
capsules; /200 doses/ -
10 ml;
126 | Unit 3.
Solution for 2,5 ml
inhalations in
flacons
Terbutaline Aironyl Sedico, Bricanyl, Tablets; 2.5mg
Arubendol, Bricanyl Aerosol for 400 single
inchaler inhalations; doses -
Bricanyl, 0.25mg/dose;
Solution for 0.05% - 1ml;
injections in
ampoules (s/c,
i/v);
Bricanyl turbuhaler Powder for 200 single
inhalations doses -
Asthmasian, Betasmac, 0.5mg/dose
Bricalin, Dracanyl,
Spiranyl, Terbasmin,
Terbutol, Tergil, etc.
Salmeterol Salmeter, Serevent Aerosol for 60, 120 single
inhalations; doses -
25 microgram/
dose
Powder for 4 single doses
inhalations -50microgram/
dose
Hexoprenaline Gynipral, Ipradol Tablets; 0.5mg
Solution for 0.00025% -
injections in 2ml, 0.0005%
ampoules (i/v); - 2ml, 5ml
Powder for for
injections in
ampoules 25 microgram
Formoterol Oxis Тurbuhaler, Powder for 60 doses - 4.5
inhalations; mcg/dose
Powder for 9 microgram/
Foradil, inhalations in dose
capsules; 12 microgram
/dose
Budesonide+Formoterol Simbicort Turbuhaler Aerosol for 120, 60 doses -
inhalations; 160 microgram
Powder for - 4.5
inhalations microgram
/dose, 80
microgram -
4.5 microgram/
dose
Ephedrine Ephedrine hydrochloride Nasal drops in 2%, 3% -
flacons; 10ml;
Solution for 5% - 1ml;
injections in
tube-syringes,
in ampoules
Chapter 6. | 127
Adrenergic agonists
(s/c, i/m, i/v);
Tablets 0.002, 0.003,
0.01, 0.025
Pseudoephedrine: Nurofen Stopcold Tablets;
Pseudoephedrine+ Sudafed
Ibuprofen,
Pseudoephedrine+ Solvin plus, Solvin Syrup in 100ml;
Guaifenesin, expectorant flacons;
Pseudoephedrine+ Clarinase Tablets; 0.008/0.06;
Bromhexine,
Dynafed plus Peroral 60ml, 100ml
solution 120ml;
Pseudoephedrine+ TeraFlu, AntiFlu, Our
Lorataidine, choice - drug against Tablets 0.005/0.12;
Pseudoephedrine+ grippus and cold, Fervex
Paracetamol, rhinitis
Pseudoephedrine+Paraceta- Children's Tylenol cold, Tablets
mol+Chlorphenamine, Mulsynex
Pyranol plus Tablets,
Metered-dose
powders
Pseudoephedrine + Rinasek Syrup in 60ml, 120ml;
Paracetamol + flacons
Dextromethorphan + Benicol Tablets
Chlorphenamine, Powder for
peroral
solution
Tablets, 60mg/2.5mg;
Pseudoephedrine Syrup in 100ml
+Triprolidine, flacons
Pseudoephedrine+Dextromet
horphan + Chlorphenamine
Dopamine Aprical, Cardiosteril, Parenteral 0.5%, 1%-2ml;
Dopamex, Dopastat, solution in 2% - 10ml; 4%
Dophan, Dopmin, Dynatra, ampoules (i/v) - 5ml
Giludop, Hydroxytyra-
Min, Inovan, Intropan,
Intropin, Revivan,
Rivimine, Dynatra
Ibopamine Escandin Tablets 0.05, 0.1
Bromocriptine Aberginum, Bromergon, Tablets; 0.0025, 0.004,
Bromocriptinum mesilat, 0.01;
Lactodel, Parlodel, Capsules 0.005, 0.01
Pravidel, Serocriptine
Pergolide Permax Tablets 0.05 mg,
0.25 mg, 1 mg
Cabergolin Dostinex Tablets 0.0005
Quinagolide Norprolac Tablets 0.025mg,
0.05mg,
0.075mg,
0.15mg
Chapter 7. Adrenergic antagonists

Adrenergic antagonists (also called adrenoblockers, direct adrenergic
antagonists) bind to adrenergic receptors and prevent its action by endogenous
catecholamines. Adrenergic antagonists are classified according to their relative
affinities for α or β receptors.
Sympatholytics (also called indirect adrenergic antagonists) don’t bind to
adrenergic receptors directly. Instead, they regulate the quantity of
neurotransmitter in adrenergic neurons. There are the two types (two subgroups) of
sympatholytics according to the mechanism of their actions: the first subgroup
(reserpine, Rauwolfia alkaloids) block the Mg+2/ATP-dependent transport of
biogenic amines, norepinephrine, dopamine, serotonin from cytoplasm into storage
vesicles in adrenergic nerves that induces the ultimate depletion of biogenic
amines. The result of this process is the reducing of the norepinephrine release and
an impairment of sympathetic function. The drugs have a slow onset, a long
duration of action and cause Parkinson syndrome. The second subgroup
(guanethidine, bretylium tosilate) displace norepinephrine from storage vesicles
that cause a transient increase in BP. Thereafter the part of norepinephrine quantity
is destroyed by MAO, and thus it leads to gradual depletion of norepinephrine in
nerve endings except for those in the CNS. In this way, the drugs commonly cause
orthostatic (postural) hypotension and interfere with male sexual function. In the
patient with pheochromocytoma they induce hypertensive crisis due to
supersensitivity to norepinephrine.
Classification of adrenoblockers
■ α-adrenoblockers
- Nonselective α1-, α2- adrenoblockers:
Ergot alkaloids: Dihydroergotamine (dehydrated derivative of ergot alkaloid
ergotamine)
Dihydroergotoxine (dehydrated derivative of total alkaloids of
ergotoxinum that is similar in structure
and pharmacological properties of
Dihydroergotamine).
Analogs of Ergot alkaloids: Nicergoline
Synthetic drugs: Phentolamine
Tropodifene
Proroxan
Phenoxybenzamine
Ketanserin
Urapidil
Indoramin
- Selective α1-adrenoblockers:
Prazosin
Chapter 7. Adrenergic atagonists | 129
Doxazosin
Tamsulosin
Terazosin
- Selective α2- adrenoblockers:
alkaloid from the bark of a tree Corynanthe Yohimbe: Yohimbine
■ β-adrenoblockers:
- Nonselective (β1, β2):
Propranolol
Sotalol
Timolol
Nadolol
with internal sympathomimetic activity: Pindolol
Oxprenolol
with additional vasodilating properties: Dilevalol
Bucindolol
Carteolol
- Selective (β1):
Atenolol
Metoprolol
Betaxolol
Bisoprolol
Talinolol
with internal sympathomimetic activity:
Acebutolol with additional vasodilating
properties: Celiprolol Nebivolol
Nonselective (β1, β2, α1):
Labetalol
Carvedilol
■ Sympatholitics:
- Drugs that are the pharmacologic competitor of NE in adrenergic
synapses:
Guanethidine
Bretylium tosilate
- Drugs that decrease the store (supply) of NE in adrenergic synapses:
Reserpine
Rauwolfia alkaloids
Pharmacologic characteristic of α-adrenergic antagonists
In general, α-adrenoblockers affect BP due to reducing of sympathetic tone

of the vessels, decreasing of peripheral vascular resistance, diminishment of
vessel’s smooth muscle tone, that lead to vasodilation. Lowering of BP induces a

reflex tachycardia.
Pharmacodynamics of α-adrenoblockers:
Vessels: relaxation, as a result – hypotension, improving of peripheral blood
circulation; Heart: reflex tachycardia; GIT: increase of motor activity, relaxation
of sphincters, increase of secretion of exocrine glands; Eye: miosis; Exocrine
glands: sweating, nasal congestion; Urogenital system: sphincter relaxation,
improving erection.
All α-adrenoblockers have opposite α-agonist (epinephrine) activity. So,
vasoconstrictive effect of epinephrine caused by stimulation of α-adrenergic
receptors under the influence of α-blockers is interrupted, while vasodilatation
mediated by β2-adrenoreceptor stimulation is not blocked. Іt becomes apparent that
the α-adrenoblockers prevent the peripheral vasoconstrictive effects of epinephrine,
leaving the vasodilating (β2-stimulation) unopposed. These results in a marked
decrease in diastolic pressure coupled with a slight increase in systolic pressure
due to increased cardiac output. This phenomenon is named “epinephrine
reversal”, and it is characteristic of the effect of α-adrenoblockers on the
cardiovascular effects of epinephrine. The action of norepinephrine aren’t
reversed, but are decreased because of norepinephrine lacks significant β-agonist
action on the vessels.
Peculiarities of the several α-adrenoblockers
Nonselective α1-, α2- adrenoblockers

Ergot alkaloids: Dihydroergotamine, Dihydroergotoxine
Dihydroergotamine blocks α1, α2- adrenergic receptors and stimulates 5-
HT2A и 5-HT1D serotonine receptors that are located on intracranial blood vessels
of the brain and the dura mater.
Pharmacological effects of dihydroergotamine:
Reduction of arterial tonus
Increase of vein tonus
Selective narrowing (vasoconstriction) of the external and internal carotid
arteries
Reduction of phonophobia and photophobia (in case of migraine)
Indications for dihydroergotamine use:
For relief of migraine attacks
Varicose veins of lower extremities
Intestinal atony
Autonomic regulation disorders with a predominance of adrenergic system
tonus
Adverse effects of dihydroergotamine:
• Arterial hypotension
Vomit, nausea
Sickness
Sleepiness
Diarrhea (seldom)
Paresthesia
Nasal congestion
Collapse
Allergic reactions
Contraindications for dihydroergotamine use:
Atherosclerosis
Organic heart diseases
Renal and hepatic insufficiency
Pregnancy
Lactation
Overdose symptoms or poisoning is named ergotism: chest pain, dyspnea,
depression of the respiratory center until his paralysis, dilated pupils, drowsiness,
confusion, delirium, dizziness, disorientation, delusions, disorders of speech and
movement, cooling and paresthesia of fingers and toes, prolonged vasospasm,
which can lead to gangrene of the extremities, pallor, hypothermia, cruel blood
pressure reduction is possible orthostatic collapse, tachycardia, abdominal pain,
difficulty in urinating, abortion in pregnant, uterine bleeding, nausea, vomiting, not
related to migraines, myasthenia gravis, twitching of individual muscle groups,
convulsions, coma.
In case of overdose or poisoning: Gastric lavage, activated charcoal, saline
laxatives, forced diuresis. In the case of vascular spasm – i/v sodium nitroprusside,
phentolamine or dihydralazine, local application of heat. In the case of coronary
spasm – nitroglycerine. In the case of convulsions – diazepam. Further –
symptomatic therapy.
There may be persistent neurological disorders, trophic ulcers of limbs,
endarteritis after recovery.
Interactions with other drugs: dihydroergotamine increases the toxicity of
reserpine. Macrolide antibiotics (oleandomitsin, erythromycin, josamycin),
doxycycline, tetracycline, dopamine, nitroglycerin, vasodilators, α-blockers, β-
agonists enhance the effects of dihydroergotamine. The α-agonists, clonidine,
vasopressin impair the effects of dihydroergotamine. Vasoconstrictor drugs
(ergotamine, sumatriptan, nicotine) increase the likelihood of vasospasm.
Dihydroergotoxine blocks α1, α2-adrenergic receptors and D receptors

Pharmacological effects of dihydroergotoxine:
Vasodilation
Bradycardia
Improves NE synthesis and its release
Positive inotropic
Overcomes the histohematogenous barriers

Reduces the intensity of anaerobic metabolism and stimulates oxygen
consumption by the brain cells
Activates the intracellular metabolism of functionally damaged neurons
Acts on the neurochemical processes in aging brain tissue
Indications for dihydroergotoxine use:
Migraine
Disorder of brain blood circulation
Diabetic angiopathy
Thrombophlebitis
Consequences of traumatic brain injury
Transient arterial hypertension
Meniere's syndrome
Poor blood circulation in the retina
Adverse effects of dihydroergotoxine:

Anorexia
Dispepsy
Vision disorders
Nasal congestion
Orthostatic collapse
Skin rash
Contraindications for dihydroergotoxine use:
Kidney insufficiency
IHD
Senile age
Organic heart disease
Arterial hypotonia
Idiosyncrasy
Nicergoline
Nicergoline is analog of Ergot alkaloids, blocks α1, α2-adrenergic receptors.
Nicergoline contains in its structure ergoline nucleus and bromosubstituted
nicotinic acid remainder.
Pharmacological effects of nicergoline:
Vasodilation (brain and peripheral vessels)
Improves microcirculation
Increases vascular permeability to glucose
Increases cerebral, pulmonary and renal blood flow
Lowers the tone of the central vessels
Increases arterial blood circulation
Increases oxygen and glucose delivery to the tissues
Indications for nicergoline use:
Cerebral blood circulation disorders
Vascular dementia
Migraine
Peripheral blood circulation disorders
Diabetic retinopathy
Combination therapy of hypertensive crisis
Ischemia of visual nervous
Dystrophy of cornea
Adverse effects of nicergoline:
Dizziness
Dyspepsia
Insomnia
Redness of skin and upper half of the body
Allergic reactions
Hyperuricemia
Contraindications for nicergoline use:
IHD, stenocardia
Atherosclerosis
Hypersensitivity
Bradycardia
Caution: hyperuricemia, gout, pregnancy, lactation.
During the period of the treatment one must be careful when driving and
during occupation of other potentially hazardous activities that require high
concentration and quickness of psychomotor reactions.
Phentolamine
Phentolamine is imidazoline derivator, blocks α1, α2- adrenergic receptors.
Pharmacological effects of phentolamine:
Vasodilation of arteries and vein, especially the arterioles and precapillaries
Improving blood supply to the muscles, skin, mucous membranes
Reduces the total peripheral vascular resistance and pulmonary vascular tone
Reduces left ventricular filling pressure
Positive inotropic
Positive chronotropic – tachycardia is mediated by the baroreceptor reflex and
by blockade of the α2-adrenoreceptors of the cardiac sympathetic nerves
Increases NE release, as a response to blockade of presynaptic α-adrenoceptors
Stimulates the insulin hyposecretion in patient with chronic heart insufficiency
and thus has beneficial effects on myocardial metabolism
In patients with pheochromocytoma distorts the effect of epinephrine (also
endogenous), which reinforces its hypotensive effect in this pathology
Indications for phentolamine use:
• Arterial hypertension in patients with pheochromocytoma
Disorders of peripheral blood circulation

Trophic ulcers of limbs, frostbites, bedsores
Acute heart insufficiency
Phentolamine can be combined with propranolol in the treatment of patients
with the withdrawal syndrome of clonidine
For short-term BP management in the patients with pheochromocytoma
Rarely phentolamine is used for treatment of impotence (intracavernosally
injections to produce vasodilation of penile arteries)
Locally phentolamine is used for prevention of tissue necrosis in case of
accidental administration of α-adrenergic agonists under the skin or into
muscles
For stopping or reducing of actions of combined forms (together with
adrenomimetics) of local anestetics
Adverse effects of phentolamine:
Arterial hypotension, ortostatic collapse
Arrhythmia, tachycardia
IHD, angina pectoris (stenocardia), anginal pain
Sickness
Hypoglycemia (due to increasing of insulin secretion)
Edema of mucous membranes
Diarrhea
Increase the stomach acidity
Contraindications for phentolamine use:
IHD, stenocardia
Stomach ulcer with high acidity
Diabetes mellitus (use with caution)
Hypersensitivity
Heart insufficiency
Interaction with other drugs: antipsychotic drugs and anxiolytics enhance
the hypotensive effect of phentolamine.
During the period of the treatment one must be careful when driving and
during the occupation of other potentially hazardous activities that require high
concentration and quickness of psychomotor reactions. During treatment you
should avoid drinking alcohol.
Caution: the presence of sulfite in ampoules with phentolamine, especially
in patients suffering from bronchial asthma, may cause in some cases, allergic
reactions, which are manifested in the form of asthma attacks, shock and loss of
consciousness.
Tropodifene
Tropodifene blocks α1, α2 adrenergic receptors and has weak
cholinoblocking activity.
Pharmacological effects of tropodifene:
Vasodilative
Hypotensive
Improves blood supply, relieves pain, improves the functional state of the
limbs
Indications for tropodifene use:
Peripheral blood circulation disorders
Trophic ulcers of limbs
Slowly healing wounds
Hypertensive crisis
Arterial hypertension that is associated with increased levels of catecholamines
in the blood during general anesthesia and surgical operations
For diagnosis of pheochromocytoma, pheochromoblastoma
Adverse effects of tropodifene:
Tachycardia
Contraindications for tropodifene use:
Organic heart and vessel diseases
Hypersensitivity
Cerebral atherosclerosis
Heart insufficiency
Proroxan
Proroxan blocks α1, α2- adrenoceptors.
Pharmacological effects of proroxan:
Central and peripheral α-adrenoblocking effects
Vasodilation, especially the arterioles and precapillaries
Inhibits the excitability of diencephalic structures of the brain and regulates the
tone of the sympathoadrenal system
Reduces mental stress, anxiety in case of sympathetic hypertone
Antipruritic effect
Indications for proroxan use:
Diseases that are associated with increased sympathetic tone, including
diencephalic and hypertonic crises
Overexcitation of the vestibular apparatus (the best use in combination therapy
with cholinolytics and antihistamines)
To relieve symptoms of morphine and alcohol abstinence
Anxious-depressive syndrome
Allergic dermatosis
Adverse effects of proroxan:
• Increasing pain in the heart in patients with IHD
Bradycardia
Contraindications for proroxan use:
Expressed atherosclerosis
IHD with stenocardia
Disorders of cerebral circulation
Expressed heart insufficiency
Interaction with other drugs: the effects of proroxan are enhanced by
neuroleptics.
Phenoxybenzamine
Phenoxybenzamine blocks α1, α2 adrenergic receptors. This blockade is
reversible and noncompetitive. New adrenergic receptors for overcoming the
blockade are synthesized in the body which requires a day or more. The blockade
of α1, α2 adrenergic receptors by phenoxybenzamine is developed during few
hours because molecule of phenoxybenzamine must convert to the active form.
Phenoxybenzamine will also affect the postsynaptic α1, α2 adrenergic
receptors in the nervous system, and so reduces sympathetic activity. This results
in further vasodilation, pupil constriction, an increase in GIT motility and
secretions, and also glycogen synthesis.
Besides, phenoxybenzamine has partial agonist/antagonist properties at the
serotonin 5-HT2A receptors. Due to 5-HT2A receptor antagonism of
phenoxybenzamine, it is useful in the treatment of carcinogenic tumor, a neoplasm
that secretes large amounts of serotonin and causes diarrhea, bronchoconstriction,
and flushing.
Pharmacological effects of phenoxybenzamine:
Prevents vasoconstriction of peripheral blood vessels by endogenous
catecholamines
Decreases the vessel’s peripheral resistance
Provokes a reflex tachycardia
Contributes to an increased cardiac output through the stimulation of β-
adrenoreceptors of the heart as a result of more NE release mediated by α-
adrenoblockade
Indications for phenoxybenzamine use:
Pheochromocytoma
Raynaud’s disease/syndrome
Autonomic hyperreflexia, which causes paraplegics as a result of stroke
Adverse effects of phenoxybenzamine
Nasal stuffiness (nasal congestion)
Nausea
Vomiting
Inhibition of ejaculation
Reflex tachycardia mediated by baroreceptor reflex
Contraindications for phenoxybenzamine use:
• In patients with decreased coronary reperfusion
Nonselective α1, α2 adrenergic blockers are not represented in today's

pharmaceutical market of Ukraine and are not used in clinical practice. However,
phentolamine and phenoxybenzamine play an important role in establishing the
importance of α -adrenergic receptors in the regulation of cardiovascular and other
body systems. Most researchers attribute these drugs to "classical" α-
adrenoblockers as opposed to newer, such as prazosin. Phentolamine and
phenoxybenzamine effects on the cardiovascular system are the same: reduction of
peripheral vascular tone (resistance), vessel’s expansion due to blockade of α-
adrenergic receptors of the vessels and cardiac output increase is partly as a result
of reflex stimulation of the sympathetic nervous system. Moreover, cardiac
stimulation is enhanced by increased release of NE in cardiac sympathetic nerves
through the antagonism with presynaptic α2-adrenoceptors of nonselective α1, α2-
adrenergic blockers. Postural hypotension is a characteristic feature of these drugs
and is accompanied by reflex tachycardia, a possible arrhythmia, which greatly
limits the use of nonselective α1, α2-adrenoceptor antagonists for the treatment of
essential hypertension.
Ketanserin, Urapidil, Indoramin

They block α1, α2 adrenergic receptors, but not only them and not only
block: ketanserin besides α adrenergic receptor blockade also blocks 5-НТ2A, 5-
HT2C, 5-HT6 serotonin receptors and H1 histamine receptors; urapidil is a weak β-
adrenoblocker, also blocks the 5-HT1A serotonin receptors of vasomotor center (to
prevent a reflex increase in sympathetic nervous system); indoramin in addition to
blockade of α adrenergic receptors also it is a competitive antagonist of 5-HT
serotonin and H1 histamine receptors.
Ketanserin
Pharmacologic effects of ketanserin:
Vasodilation
Hypotensive
Bronchodilation
Platelet aggregation inhibitor
Indications for ketanserin use:
Hypertension crisis
Thrombosis, hemorrhoidal thrombosis
Thrombophlebitis
Ketanserin can be used together with β-adrenoblockers and diuretics to
enhance the hypotensive effect.
Adverse effects of ketanserin:
• Platelet aggregation inhibitor (microhematuria)
Drowsiness
Reduction in concentration of attention
Headache
Indigestion
Increase in body weight (with prolonged use)
Contraindications for ketanserin use:
Hypersensitivity
Bradycardia
AV-blocks
Ventricular tachycardia
Ventricular fibrillation in the history
Prolongation of QT interval
Hypokalemia
Pregnancy
Lactation
Urapidil
Pharmacologic effects of urapidil:
Vasodilation
Reduction in peripheral vascular resistance
Hypotensive, it reduces both systolic and diastolic blood pressure
Increase of low cardiac output and reduced minute volume of heart
Reduction in preload and afterload on the heart
Blockade of the vasoconstrictive action of catecholamines (endogenous and
exogenous)
with prolonged use it lowers triglycerides and total cholesterol
does not cause reflex tachycardia induced vasodilation
it does not lead to arrhythmias
it has no effect on carbohydrate metabolism, metabolism of uric acid, and it
does not hold fluid in the human body
Interaction with other drugs: antihypertensive drugs and alcohol increase the
antihypertensive effect urapidil can be combined with diuretics, β-blockers,
calcium antagonists.
Indications for urapidil use:
Hypertension crises that are resistant to other antihypertensive drugs
Adverse effects of urapidil:
Headache
Dizziness
Weakness
Rarely – palpitations, bradicardia, arrhythmia
Gastrointestinal disturbances
Dry mouth
Sometimes there are allergic skin reactions
Thrombocytopenia
Collapse with the rapid intravenous injection
Priapism (it is a potentially painful medical condition in which the erect penis does not
return to its flaccid state, despite the absence of both physical and psychological
stimulation, within four hours. Priapism is considered a medical emergency, which
should receive proper treatment by a qualified medical practitioner)
Contraindications for urapidil use:
Aortic stenosis
Patent ductus arteriosus
Pregnancy
Lactation
Childhood and adolescence to 18 years
Patients who require rapid mental or physical reactions
It is not recommended to combine with ACE inhibitors
Idiosyncrasy
Indoramin
Pharmacologic effects of indoramin:
• Hypotensive
Indications for indoramin use:
Raynaud’s disease/syndrome
Adverse effects of indoramin:
Drowsiness
Nasal congestion
Dry mouth
Ejaculation disorder
Contraindications for indoramin use:
Pregnancy
Lactation
Selective α1-adrenoblockers
Prazosin, Terazosin, Doxazosin, Tamsulosin
They are selective competitive blockers of α1 adrenergic receptors. The use
of α1-adrenoblockers in case of arterial hypertension is more preferably in patients
with benign prostate hypertrophy, erectile disorders, diabetes mellitus,
dyslipoproteinemia, chronic obstructive pulmonary disease and obliterating
atherosclerosis of the lower extremities. All selective α1-adrenoblockers decrease
peripheral vascular resistance and arterial BP due to relaxation of both, arterial and
venous smooth muscles. The first dose of these drugs should be adjusted because it
may cause syncope as a result of exaggerated orthostatic hypotension. The first
dose of these drugs must be one-third or one-fourth of the therapeutic dose and to
be given at bedtime. The risk of development of congestive heart failure is high if
selective α1-adrenoblockers use in arterial hypertension as monotherapy. The most
common side effects of selective α1-adrenoblockers are orthostatic hypotension,

tachycardia, vertigo and sexual dysfunction.
Prazosin
The peculiarity of prazosin is its selective blockage of vessel postsynaptic α1
adrenergic receptors, this leads to interruption of vasospastic action of mediator –
NE and vasodilatation. Besides, prazosin blocks the α1 adrenergic receptors of
urethra and neck of the urinary bladder that leads to dilatation of them and
improves uresis. Prazosin is short action drug.
Pharmacologic effects of prazosin:
Vasodilative (both, arteries and veins)
Hypotensive
Decreases the peripheral vessel resistance
Diminishes the pre- and afterload on the myocardium
Favorably influences on the lipid composition of blood
Moderate cholinolitic activity
Dilatation of urethra and neck of the urinary bladder
Indications for prazosin use:
Benign prostatic hypertrophy
Adverse effects of prazosin:
Phenomenon of the “first dose” – postural hypotension, collapse
Dizziness
Headache
Weakness
Fatigue
Insomnia
Nausea
Diarrhea
Constipation
Dry mouth
Frequent urination
Peripheral edema
Rarely – tachycardia
Contraindications for prazosin use:
Pregnancy
Lactation
With caution – to patients with kidney diseases
Terazosin
The chemical structure of terazosin is closed to prazosin, but terazosin is
long term action drug. Terazosin blocks postsynaptic α1 adrenergic receptors of the
vessels, prostate and the urinary bladder.
Pharmacologic effects of terazosin, indications, side effects,

contraindications for its use are similar to those for prazosin.
Doxazosin
The chemical structure of doxazosin and pharmacological characteristics are
closed to prazosin, but doxazosin is long term action drug.
Pharmacologic effects of doxazosin, Indications, Side effects and
Contraindications for doxazosin use are the same as for prazosin. Also, has been
described the cases of visual impairment, cholestasis, jaundice, impotence.
Tamsulosin
Tamsulosin is high selective α1A adrenoblocker of the receptors of prostate,
neck of urine bladder and prostatic part of urethra and doesn’t influences on α1
receptors of the vasculature. Tamsulosin is long term action drug. Unlike the first
three drugs tamsulosin is excreted preferably by the kidneys.
Pharmacologic effects of tamsulosin:

Diminishes the hypertrophy of prostate
Lowers the tone of smooth muscles of the prostate, neck of urine bladder,
prostatic part of urethra
Improves uresis
Reduces the symptoms of obstruction and irritation of the urinary tract in
benign prostatic hyperplasia
Indications for tamsulosin use:
• Benign prostatic hypertrophy
Side effects and contraindications for tamsulosin use are the same as for
prazosin, doxazosin, terazosin.
Selective α2- adrenoblockers

Yohimbine
Yohimbine is an alkaloid of indolealkylamine that is found in bark of a tree
Pausinystalia yohimbe and Rauwolfia roots; its structure is similar to the structure
of reserpine. Yohimbine is a selective competitive antagonist of α2-adrenergic
receptor, easily overcomes the BBB, enters in the CNS, increases the activity of
the sympathetic nervous system, potentiates release of norepinephrine from nerve
endings, which leads to activation of α1 adrenergic receptors and β1 adrenergic
receptors in the heart and peripheral blood vessels, increases BP and heart rate, and
locomotor activity and causes tremors.
Pharmacologic effects of yohimbine:
Activates the adrenergic processes in CNS
Enhances the flow of sympathetic impulses from the CNS and release of
norepinephrine from nerve endings
Improves the motor activity
Improves the spine reflexes
Relieves vasoconstriction associated with Raynaud’s disease

Indications for yohimbine use:
Erectile dysfunction
Incontinence
Atony of urine bladder
Menopause in women
Raynaud’s disease
Adverse effects of yohimbine:
Tachycardia
Hand tremor
Headache
Hypererethism
Priapism
Ortostatic hypotension*
- orthostatic hypotension as a side effect of yohimbine may be due to the fact that the drugs
affects both the central and the peripheral α2-adrenergic receptors of vessels that can lead to
dilatation of peripheral vessels and thus may reduce BP [Goodman & Gilman's The
Pharmacological Bases of THERAPEUTICS. 12 edition. Medical. , 2011. - 2084 P.].
Contraindications for yohimbine use:
IHD
High sensitivity to yohimbine
Kidney and/or liver insufficiency
Table 23*. Comparative characteristics of some α-adrenoblockers
Drugs Term of Maximal effect Therapeu Multiplicity

action in after direction tic doses in of drug
hours in hours mg/day introductio
n in day
Dihydroergotamine when i/m when i/m 4-6 2-3 times
administ- administration
ration – – from 30
3-4 minutes to few
hours
Dihydroergotoxinum its pharmacokinetic 0.3-0.6 1-3 times
parameters correlate poorly
with pharmacological effects
due to containing in drugs 4
derivatives of Ergot alkaloids,
namely dihydroergokornin,
dihydroergocrystine, dihydro-
α-ergocryptine, dihydro-β-
ergocryptine, each of which
has its own pharmacokinetic
parameters
Nicergoline up to 17 2-4 8-60 2-3 times
Phentolamine from 10-15 from 2 75-500 3-5 times
minutes (i/v) minutes (i/v)
up to 4 hours to 20 minutes
(i/m) (i/m)
Tropodifene few 20-60 1-3 times
Proroxan its pharmacokinetic 180 2-3 times
parameters are not defined
Phenoxybenzamine > 48 few 10 1 time
Prazosin 4-6 0,5 1-20 2-3 times
Doxazosin 18-36 5-6 1-20 1 time
Terazosin > 18 1-1.7 1-20 1-2 times
Tamsulosin 9-22 4-7 0.4 1 time
Indoramin >6 2 50-150 2-3 times
Ketanserin > 12 1-2 20-40 1-2 times
Urapidil 6-8 3-5 15-120 1-2 times
*- adapted from Kaplan N.M. Clinical hypertension 7th edition. Baltimore, 1998 with
amendments of authors
Table 24. Medicinal forms of α-adrenoblockers

Dihydroergotamine Agit, Angionorm, Peroral solution in 0.2% - 10 ml,
Clavigrenin, Cornhidral; flacones; 30 ml;
DH-Ergotamin, Parenteral solution 0.1% - 1 ml
Diergotan, Dihydergot, in ampoules (i/m);
Dihydroergotamine Tablets; 0.0025;
mesilate, Dihytamin, Aerosol for 1%
Ditamin, Ergomimet, intranasal
Ergovasan, Ikaran, introduction
Migretil, Migrifen,
Tonopress, Vasogin,
Verteblan, etc.
144 | Unit 3.
Dihydroergotoxinum Alkergot, Circanol, Tablets; 0.0015;
Clavor, DH-Ergotoxin, Peroral solution in 0.1% - 50ml;
Erginemin, Ergocomb, flacones;
Ergodibat, Ergohydrin,
Ergoloid mesylat, Parenteral solution 0.03% - 1ml
Ergomed, Ergoxyl, in ampoules (i/a, i/v,
Hyderan, Hydergin, i/m, s/c)
Optamine, Redergin,
Redergot, Secamin,
Secatoxin, Trigot,
Vasolax, etc.
Nicergoline Sermionum, Dasovas, Tablets; 0.005, 0.01;

Dospan, Ergotop, Fisilax, Powder for 0.004
Nargoline, Nicotergoline, injections in
Nimergoline, Sinscleron, ampoules (i/v, i/m)
Varsan, etc.
Phentolamine Dibasin, Phentolamine, Tablets; 0.025;
Regitine, Rogitine Powder for 0.005;
injections in
ampoules (i/m, i/v);
Parenteral solution 1% - 1ml, 5ml
in ampoules (i/m,
i/v)
Tropodifene Tropaphenum Powder lyophilized 0.02
for injections in
ampoules to prepare
ex tempore 1%, 2%
solution (i/m, i/v,
s/c)
Proroxan Pyrroxanum Parenteral solution 1% - 1ml;
in ampoules (i/m,
s/c);
Tablets 0.015
Phenoxybenzamine Dibenyline Tablets 0.01
Ketanserin Perketal, Serefrex, Tablets; 20mg, 40mg;
Sufrexal, Sufroxal, Parenteral solution 0,5 % - 2ml,
Taseron in ampoules (i/m, 10ml
i/v)
Urapidil Ebrantil, Eupressyl Capsules; 30mg, 60mg,

90mg;
Parenteral solution 0.5% - 5 ml,
in ampoules (i/v) 10 ml
Indoramin Baratol, Doralese Tablets 20 mg, 25mg
Prazosin Adversuten, Decliten, Tablets 0.0005, 0.001,
Deprazolin, Duramipress, 0.002, 0.005
Eurex, Furazosin-
hydrochloride,
Hypovase, Minipress,
Chapter 7.
Adrenergic atagonists | 145
Orbisan, Patsolin,
Peripress, Prastiol,
Prazac, Prazopress,
Prazosin, Sinetens;
Vasoflex, etc.
Terazosin Tablets 0.001, 0.002,
0.005, 0.01
Doxazosin Cardura, Tonocardin Tablets 0.001, 0.002,
0.004, 0.008
Tamsulosin Omnic Capsules 0.4 mg
Yohimbine Iohimbina, Quebrachin, Tablets 0.005
Yohimvenol
Pharmacologic characteristic of β-adrenergic antagonists
All β-adrenoblockers are competitive antagonists. Non-selective β-

adrenoblockers act on β1 and β2 adrenergic receptors, but selective β-
adrenoblockers act on β1 adrenergic receptors. β-adrenoblockers also differ in
intrinsic sympathomimetic activity (ISA) mediated by stimulation of β2
adrenoceptors of smooth muscles of the vessels and bronchi; in additional
vasodilating properties (AVP) due to blockage of α2 adrenoceptors of the vessels;
in CNS effects resulting the lipophilic properties and ability to overcome BBB, and
in pharmacokinetics. All β-adrenoblockers decrease BP, inhibit renin secretion and
reduce renin-angiotensin system activity, but don’t induce postural hypotension
because α-adrenoceptors remain functional. β-adrenoblockers also are used as
drugs for treatment IHD (reduce the need of the heart muscle in oxygen and
diminish of heart rate), cardiac arrhythmias (they have negative chronotropic and
negative batmotropic effects), congestive heart failure (although β-adrenoblockers
themselves can cause heart failure due to negative inotropic effect),
hyperthyroidism, glaucoma (lowering intraocular pressure), and they are used for
prophylaxis of migraine. β-adrenoblockers belong to antiarrhythmic drugs of the
second class. β-adrenoblockers, especially nonselective, deteriorate peripheral
blood circulation because result in a narrowing of vessels due to blockade of β-
adrenoceptors of the vessels. The names of all β-adrenoblockers end in “-olol”
except for labetalol and carvedilol.
Pharmacodynamics of nonselective β-adrenoblockers:

Vessels: constriction that leads to disoders of peripheral blood circulation;
Heart: negative inotropic effect, negative chronotropic effect, negative
dromotropic effect, negative batmotropic effect; decrease oxygen demand and the
influence of β-adrenoblockers on the heart leads to hypotensive, antiarrhithmic,
antiischemic effects; Bronchi: bronchospasm; Metabolism: atherogenic effect,
hypoglycemic effect, stimulation of the prostaglandin production, inhibition of
platelet aggregation.
Peculiarities of the several β-adrenoblockers

Nonselective β-adrenoblockers:
Propranolol, Sotalol, Timolol, Nadolol
They have all pharmacologic effects which are prescribed in tables 23, 24,
27.
Pharmacologic effects of them:
Negative inotropic, diminish cardiac output, and cardiac work
Negative chronotropic
Negative batmotropic, depress sinoatrial and atrioventricular activity
Decrease the cardiac oxygen consumption
Inhibit the rennin release from the kidney
Decrease the sympathetic stimulation from CNS
Hypotensive
Antarrhythmic
Antiischemic
Decrease the glycogenolysis, decrease the glucagon secretion that may cause
expressed hypoglycemia in patient with diabetes mellitus who are receiving
insulin or oral hypoglycemic drugs
Debilitate the normal physiological response to hypoglycemia
Diminish the intraocular pressure in glaucoma by decreasing the secretion of
aqueous humor by the ciliary body (β-adrenoblockers neither affect the
ability of the eye to focus for near vision nor change pupil size, as
cholinergic drugs)
Prophylactic of IHD and insult
Chronic IHD (β-adrenoblockers not useful for acute IHD)
Increase tolerance to moderate exercises in patients with IHD (but not to
strenuous exercises)
Prophylactic of sudden death in patients with cardiovascular disorders
Chronic heart insufficiency
Aortic aneurysm (aortic dilation) – prophylactic of aortic exfoliation
Cardiomiopaty
Organic heart defects
Chronic glaucoma (β-adrenoblockers aren’t drugs of choice in an acute attack
of glaucoma)
Migraine (β-adrenoblockers reduce migraine episodes and severity of the
attacks if are used prophylactically because they block catecholamine-
induced vasodilatation in the brain vasculature)
Hyperthyroidism (β-adrenoblockers attenuate the sympathetic stimulation
that occurs in hyperthyroidism and prevent serious cardiac arrhythmias)
Peripheral vasoconstriction, insufficiency of peripheral blood circulation
Bradycardia
Heart blocks
Bronchoconstriction
Decrease the renal perfusion, resulting in an increase in Na + retention and
plasma volume, and in some cases elevate the BP (the combination with
diuretics is needed)
Disturbances of lipid metabolism (atherogenesis)
Disturbances of carbohydrate metabolism (hypoglycemia)
CNS dysfunction, sleep disorders, weakness, hallucinations
Withdrawal syndrome (treatment with β-adrenoblockers must never be stopped
quickly because of the risk of cardiac arrhythmias, hypertensive crisis, but
this treatment must be stopped gradually for 1 week)
Up-regulation of the β-adrenergic receptors as a result the stoppage of therapy
and may lead to worsen angina or arterial hypertension
Sexual impairment in men: the mechanism of this side effect isn’t clear,
because the sexual function in male occurs through α-adrenergic regulation
Obstructive pulmonary diseases
Asthma
Impairments of peripheral blood circulation
Diabetes mellitus
Expressed atherosclerosis
Pregnancy (β-adrenoblockers reduce the placental blood circulation)
Lactation
During the period of treatment one should refrain from driving motor vehicles
and classes of potentially hazardous activities that require high
concentration and quickness of psychomotor reactions
Timolol and nadolol are more potent than propranolol. Timolol reduces the
production of aqueous humor in the eye and is used topically in treatment of
chronic open-angle glaucoma. Nadolol is a long-term action drug. Nadolol reduces
the formation of cAMP from ATP which is stimulated by catecholamines, as a
result nadolol reduces intracellular calcium ion current. The features of sotalol are:
ability to block potassium current, increase the action potential and the absolute
refractory period in all the areas of cardiac conduction system which gives grounds
to consider it as an antiarrhythmic drug of the third and second class (a mixed
mechanism of action).
Table 25*. Metabolic adverse effects of nonselective β-adrenoblockers that are

connected with blockade of β2-adrenergic receptors
Adverse effects Mechanism

Impairment of glucose tolerance Reduction of insulin secretion and increasing in
(diabetogenic effect) insulin resistance by 25-30%
Dyslipidemia (hypertriglyceridemia, Reduced activity of lipoprotein lipase, splitting
reduced HDL cholesterol) triglycerides to free fatty acids
Violation of detection of Reducing emissions of catecholamines that

hypoglycemia (in patients with mediate the symptoms of hypoglycemia
diabetes mellitus receiving glucose- (tachycardia, tremor, etc.)
lowering therapy)
Difficult exit from the hypoglycemic Braking mechanisms for the release of glucose
state (risk of hypoglycemic coma) into the blood (glycogenolysis in liver and
muscle and gluconeogenesis in the liver),
suppression of glucagon secretion
Worsening of peripheral angiopathy Arterial vasoconstriction
*- adapted from Shestakova M.V. Beta-blockers in diabetes mellitus: view of endocrinologist. /
Diseases of heart and vessels. V 2.- №2. 2006.
Selective β1-adrenoblockers:
Atenolol, Metoprolol, Betaxolol, Bisoprolol, Talinolol
Compared with the nonselective β-adrenoblockers selective β-
adrenoblockers are less likely cause bronchoconstriction, they are less likely
worsen the peripheral blood circulation, they are less likely cause hypoglycemia,
they are less manifest atherogenic effect, they rarely cause withdrawal syndrome.
A common side effect of therapy by selective β1-adrenoblockers is less frequent
compared to that of nonselective β-adrenoblockers. The cardioselectivity is most
pronounced at low doses and is lost at high doses. Thereby, the treatment with
selective β1-adrenoblackers of the patients with hypertension or/and angina and
concomitant diseases such as asthma, obstructive bronchitis, diabetes mellitus must
be carefully monitored to make that respiratory activity, level of glucose in the
blood, peripheral blood circulation aren’t compromised.
Nonselective β1-, β2-adrenoblockers with intrinsic sympathomimetic activity:

pindolol, oxprenolol, and
Selective β1-adrenoblockers with intrinsic sympathomimetic activity:
acebutolol
β-adrenoblockers with ISA (pindolol, oxprenolol, acebutolol) stimulate β2-
adrenergic receptors and yet they inhibit stimulation by more potent endogenous
catecolamines, epinephrine and norepinephrine. That's why they have less effect
on cardiac rate, cardiac output, do not impair the peripheral blood circulation,
minimize the bronchoconstriction, disturbances of lipid and carbohydrate
methabolism compared to that of β-blockers without ISA. β-adrenoblockers with
ISA are effective in patients with angina and hypertensive patients with moderate
bradycardia, diabetes mellitus, asthma, obstructive bronchitis, but aren’t used as
antiarrhythmic drugs.
Nonselective β1-, β2-adrenoblockers with additional vasodilating

properties: (dilevalol, bucindolol, carteolol, and
Selective β1-adrenoblockers with additional vasodilating properties:
celiprolol, nebivolol
β-adrenoblockers with AVP (dilevalol, bucindolol, carteolol, celiprolol,

nebivolol) block α1-adrenergic receptors of the vessels and don’t cause peripheral
vasoconstriction. Nebivolol also stimulates synthesis of endogenous NO (nitric
oxide) which is an additional factor of vasodilating. Dilevalol is the R,R-
stereoisomer of labetalol, it is β2 agonist, and a weak blocker of α1-adrenergic
receptors, reduces hypertrophy of the left ventricle, has positive action on plasma
lipid profile. The use of dilevalol is restricted by its hepatotoxic activity.
Nonselective β1-, β2-, α1-adrenoblockers:

Labetalol, Carvedilol
Labetalol and carvedilol are simultaneous β1-, β2-, α1-adrenoblockers that
induce peripheral vasodilating effect and reduce BP. They are effective in patients
with increased peripheral vascular resistance and don’t change lipid and glucose
blood levels. Carvedilol also decreases lipid peroxidation, thickening of the
vessel’s walls that are very important in the patients with heart insufficiency.
Labetalol may be used as an alternative to methyldopa in the treatment of
pregnancy-induced hypertension and as intravenous injections it is also used to
treat hypertensive crisis.
Sympatholitics: Guanethidine, Bretylium

tosilate, Reserpine, Raunatinum
They are indirect adrenergic blockers that act on endogenous norepinephrine
and don’t act on adrenergic receptors directly.
Guanethidine (Octadin, Isobarin) is the pharmacologic competitor of NE in
vesicles of adrenergic synapse. Practically Guanethidine is not applied currently
because of serious side effects and contraindications.
Pharmacologic effects of guanethidine:
Hypotensive
Antarrhythmic
Indications for guanethidine use: in nowadays іts use is restricted by its adverse
effects.
Adverse effects of guanethidine:
Bradycardia, tachycardia
Contraindications for guanethidine use:
IHD
Impairment of brain blood circulation
Impairment of coronary blood circulation
Pheochromocytoma
Bretylium tosilate (Ornid) blocks NE release from presynaptic endings that
leads to the reduction of its influence on adrenergic receptors. Besides, Bretylium
tosilate has direct action on cell’s membranes of the heart, blocks potassium
channels in the membrane cells of the heart, as the antiarrhythmic drug of the third
class. At the first phase of Bretylium tosilate action is NE release from depots that
causes tachycardia and hypertension. At the second phase of Bretylium tosilate

action is sympathetic blockage adrenergic neurons that leads to decreasing of BP
and heart rate and it may cause postural hypotension. Bretylium tosilate doesn’t
affect the function of postganglionic adrenergic receptors.
Pharmacologic effects of bretylium tosilate:
Hypotensive
Antarrhythmic
Indications for bretylium tosilate use:
Ventricular fibrillation
Ventricular tachycardia refractory to other antiarrhythmic drugs, especially in
the patients with acute myocardial infarction
Ventricular arrhythmia
Arrhythmia torsade de pointes
Adverse effects of bretylium tosilate:
Bradycardia, tachycardia
Chest pain, increased frequency of angina attacks
Dizziness, mental confusion
Psychosis, drowsiness, increased tactile and pain sensitivity
Hyperthermia
Dyspnoea
Nausea, vomiting
Diarrhea
Nasal congestion
Contraindications for bretylium tosilate use:
Aortic stenosis
Severe pulmonary hypertonia
Uncontrolled heart insufficiency
Acute impairment of brain blood circulation
Severe kidney insufficiency
Drugs that decrease the reserves of NE in adrenergic synapses: reserpine,

Rauwolfia alkaloids (Raunatinum is a combined drug).
Pharmacologic effects of reserpine:
Hypotensive effect is developed gradually in few weeks after enteral
introduction and in 2-4 hours after parenteral introduction
Neuroleptic
Indications for reserpine use only as part of combination drugs:
Arterial hypertension (its use is restricted through development of Parkinson
syndrome and need a long time for the manifestation of hypotensive effect)
Severe psychosis, shizophrenia (in combined therapy)
Thyrotoxicosis (in combined therapy)
Alcoholic psychosis
The late toxemia of pregnancy

Adverse effects of reserpine:
Drowsiness
Dizziness
Depression
Stupor
Extrapyramidal syndrome
Increased frequency of epileptic seizures
Nightmares
Diarrhea
Nasal congestion
Peptic ulcers of stomach
Liquid retention and edema that doesn’t connect with heart insufficiency
Weight gain
Bradycardia, arrhythmia
Decreased libido
Hyperemia of the mucous membranes of the eyes
Rash
Syndrome of disseminated lupus erythematosus
Contraindications for reserpine use:
Severe heart insufficiency
Bradycardia
Nephrosclerosis
Severe cerebral atherosclerosis
Stomach and duodenum ulcer disease
Epilepsy
Parkinson disease
Depression
Pharmacologic effects of Raunatinum:

• Hypotensive effect is developed gradually in 10-14 days
Indications for Raunatinum use, side effects, and contraindications are the
same as in reserpine, but Raunatinum has peculiarities: it has antiarrhythmic effect,
calming effect on the CNS, hypotensive effect, neuroleptic effect and side effects
are less pronounced than in reserpine.
Table 26. Medicinal forms of β-adrenoblockers, Sympatolitics

Propranolol Alindol, Anaprilin, Tablets; 0.01, 0.04, 0.08,
Angilol, Antarol, 0.16;
Avlocardyl, Bedranol, Capsules; 0.04, 0.08;
Betadren, Bricoran, Parenteral 0.25% - 1 ml;
Cardinol, Caridorol, solution in
Dederal, Deralin, ampoules (i/v);
152 | Unit 3.
Dociton, Elanol, Eye drops in 1% - 1.5 ml;
Eliblok, Inderex, tube-droppers
Indicardin, Naprilin, and in flacons 1% - 5 ml
Noloten, Obsidan,
Opranol, Prolol,
Propanur, Propral,
Propranobene,
Pylapron, Sloprolol,
Stobetin, Tenomal,
Tiperal, etc.
Betakep TR,
Inderal, Obsidan
Sotalol Berdex, Betapace, Tablets; 0.08; 0.16;

Darob, Gilucor, Parenteral 1% - 4 ml
Loritmic, Sotahexa, solution in
Sotalex, Tachytalol ampoules (i/v)
Timolol Blocadren, Blocanol, Tablets; 0.005, 0.01, 0.02;
Temserin, Timacar, Eye drops in 0.1%, 0.25% -5ml;
Timacor, Arutimol, flacons and in 0.1%, 0.25% -
Glaumol, Glymol, tube-droppers 2.5 ml, 10 ml
Glucomol, Cusimolol,
Nyolol, Ocumed,
Ocumol, Ocupres-E,
Ocuryl, Ocutim,
Optimol, Oftan
Timolol, Oftensin,
Timohexal, etc.
Pylocarpine +Timolol Fotil, Timpilo 0.5%+2% - 5 ml;
0.5%+4% - 5 ml
Nadolol Anabet, Betadol, Tablets; 0.04, 0.08;
Corgard, Nadic, Solgol
Corzid
Nadolol + Tablets 0.04/0.08 + 0.005
Bendroflumethiazide
Pindolol Betadren, Blocklin, Tablets; 0.005;
Carvisken, Durapindol,
Pectobloc, Pinadol,
Pinbetol, Pindomex,
Pinloc, Prindolol,
Viscen, etc.
Pindolol + Clopamid Viskaldix Tablets 0.01 + 0.005
Oxprenolol Captol, Cordexol, Tablets 0.02, 0.08, 0.16
Coretal, Laracor,
Oxanol, Oxprenololi
hydrochloridum,
Tracosal, Trasacor,
Trasicor, Slow-trasicor,
etc.
Dilevalol Tablets; 0.2;
Parenteral 50 mg
Chapter 7. | 153
Adrenergic atagonists
solution in
ampoules (i/v)
Carteolol Tablets; 2.5 mg;
Teoptic Eye drops 1% - 5 ml
Atenolol Apo-Atenolol, Atcardil, Tablets; 0.025, 0.05, 0.1;
Atenobene, Atenol,
Atenova, Betacard,
Betadur, Blokium,
Catenol, Catenolol,
Highpoten, Hipres,
Myocord, Normiten,
Ormidol, Prenormine,
Prinorm, Sinarom,
Telvodin, Tenobloc,
Tenolol, Tenormin,
Tensicor, Uniloc,
Velorin, Vericordin,
etc.
Atehexal compositum,
Tenoret, Tenoretic
Atenolol+Chlortalidone Tablets 50 mg + 12.5 mg,
100 mg + 25 mg
Metoprolol Beloc, Betaloc, Tablets; 0.025, 0.05, 0.1;
Blocksan, Egiloc, Tablets-retard; 0.05, 0.1, 0.2;
Korvitol, Lopressor, Parenteral 0.1% - 5 ml
Metocard, Metohexal, solution in
Metolol, Metazok, ampoules (i/v);
Neobloc, Opresol,
Selopral, Specior,
Presolol, Vasocardin,
Veobloc, etc.
Metoprolol + Felodipine Logimax Tablets 47,5/90 mg +
5/10 mg
Betaxolol Betac, Locren, Tablets; 0.01, 0.02;
Betoptic, Betoptima, Eye suspension 0.25% - 5 ml,
Betoxolol, Kerione in flacons; 10 ml;
Eye drops in
flacons- 0.5% - 5 ml
droppers
Bisoprolol Bisogamma, Concor, Tablets 0.005, 0.01,
Concor Cor 0.0025
Talinolol Cordanum, Dragee; 0.05;
Tablets;
Parenteral 0.2% - 5 ml;
solution in
ampoules (i/v);
Prolonged 0.1
Codanum-100 tablets, dragee
Acebutolol Sectral Tablets 0.2, 0.4
Celiprolol Cellipres, Celiprol Tablets 0.1, 0.2
Nebivolol Nebilet Tablets 0.005
154 | Unit 3.
Labetalol Tablets; 0.1, 0.2;
Parenteral (i/v) 1% - 5 ml
solution in
ampoules
Carvedilol Credex, Dilatrend Tablets 0.00625, 0.0125,
0.025
Guanethidine Abupressin, Antipres, Tablets 0.025
Azetidin, Declidin,
Eutensol, Guanexil,
Guanisol, Ipoctal,
Ipoguanin, Iporal,
Ismelin, Isobarin,
Octadin, Octatenzine,
Oftalmotonil,
Oktatensin, Pressedin,
Sanotensin, Visutensil,
etc.
Bretylium tosilate Bretylan, Bretylat, Parenteral 5% - 1 ml
Bretylin, Bretylol, solution in
Darenthin, Ornid, etc. ampoules (i/v,
i/m)
Rauwolfia alkaloids Raunatinum, Tablets 0.002
Rauwasan, etc.
Reserpine Serpasil, Rausedyl, etc. Tablets; 0.0001, 0.00025;
Parenteral 0.1% - 1 ml;
solution in 0.25% - 1 ml
ampoules (i/v,
Adelphan i/m);
Reserpine+Dihydralazine Adelphane-Esidrex, Tablets; 10 mg + 100 mg
Reserpine+Dihydralazine+H Antihypertonin, Tablets; 0.1 mg +10 mg +
ydrochlorothiazide Barophane Zidrex, 10 mg
Relsidrex-G,
Phensidrex-H,
Alsidrex-H,
Trirezid, Triniton
Trirezid K
Reserpine+Dihydralazine+H Tablets; 0.1 mg + 10 mg +
ydrochlorothiazide+ 10 mg + 30 mg
Potassium chloride Brinerdin, Crystepin,
Reserpine+ Normatens, Acenosin Tablets, 0.1 mg + 0.5 mg +
Dihydroergocristine+ Neocristipin Dragee; 5 mg
Clopamide
Reserpine+ Sinepres Dragee; 1 mg + 0.58 mg +

Dihydroergocristine+ 25 mg
Chlortalidone
Reserpine+ Tablets, Dragee 0.1 mg + 0.6 mg +
Dihydroergotoxine+ 10 mg
Hydrochlorothiazide
Table 27*. Pharmacological characteristics of Adrenergic Antagonists
Pharmacolo Pharmacological Principal Untoward Comments

gical group actions therapeutic effects
aplications
α-blockers:
non-selective Reduction of Treatment of Postural Cardiac stimulation
α1,α2 peripheral vascular catecholamine hypotension, due to initiation of
(phenoxybenz resistance and BP, excess (e.g., Failure of reflexes and to
amine, Venodilation pheochromocyto ejaculation enchanced release
phentolamine ma) of NE via α2
, tolazoline) receptor blockade;
phenoxybenzamine
produces long-
lasting α receptor
blockade, can block
neuronal and
extraneuronal
uptake of amines
α1-selective Reduction of Primary Postural prazosin and related

(prazosin, peripheral vascular hypertension, hypotension quinazolines are
terazosin, resistance and BP, Increase urine when therapy selective for α1
doxazosin, Relax smooth flow in benign instituted receptors
tamsulosin, muscles in neck of prostatic tamsulosin exhibits
trimazosin, urinary bladder hypertrophy some selectivity for
alfuzosin, and in prostate α1А receptors
silodosin)
β-blockers:
non-selective Reduction of heart IHD, angina Bradycardia, Effects depend on
(first rate, pectoris, Negative sympathoadrenal
generation): Reduction of Hypertension, inotropy, tone,
nadolol, contractility, Cardiac Diminution of Bronchoconstriction
penbutolol, Diminution of arrhythmias, cardiac output, (of concern in
pindolol, cardiac output, Congestive heart Bradyarrhythm asthmatics and
propronolol, Slow conduction failure, ias, chronic obstructive
oxprenolol, atria and AV node, Pheochromocyto Slow AV pulmonary disease),
timolol Elongation of ma, conduction, Hypoglycemia (of
refractory period, Glaucoma, Bronchoconstr concern in
AV node, Hypertropic iction, hypoglycemics and
Bronchoconstrictio obstructive Fatigue, diabetics),
n, cardiomyopathy, Sleep Membrane
Prolonged Hyperthyroidism, disturbances stabilizing effect

hypoglycemia, Migraine (insomnia, (propranolol);
Reduction of prophylaxis, nightmares), intrinsic
plasma level of Acute panic Prolongation sympathomimetic
FFA, symptoms, of activity (strong for
Reduction of HDL Substance abuse hypoglycemia, pindolol,
cholesterol level, withdrawal, Sexual oxprenolol, weak
Increase of LDL Variceal bleeding dysfunction in for penbutolol –
cholesterol level in portal men, long action drug)
and TG, hypertension Drug
Hypokalemia, interactions
Reduction of
intraocular
pressure
β1-selective Membrane
(second stabilizing effect
generation): and intrinsic
acebutolol, sympathomimetic
atenolol, activity (weak)
bisoprolol, (betaxolol)
betaxolol,
esmolol,
metoprolol
non-selective Membrane Vasodilation seen in
(third stabilizing effect 3rd generation drugs;
generation) (carteolol, multiple
vasodilators: carvedilol), mechanisms (table
carteolol, Intrinsic 24)
carvedilol, sympathomimetic
bucindolol, activity
labetalol (bucindolol),
Vasodilation
(labetalol)
β1-selective
(third
generation)
vasodilators:
celiprolol,
nebivolol
edition. Medical. 2011. – 2084 P. with amendments of authors
Table 28. Third generation β receptor antagonists with putative additional

mechanisms of vasodilatation*
Nitric oxide Β2 receptor α1 receptor Ca2+ entry K+ Antioxydan

production agonism antagonism blockade channel t activity
opening
celiprolol**, celiprolol**, carvedilol, carvedilol, tilisolol* carvedilol
nebivolol, carteolol, bucindolol, betaxolol, *
carteolol, bopindolol* bevantolol* bevantolol*
bopindolol** * * *
, nipradilol**
nipradilol** ,
labetalol
** - not currently available in the U.S., where most are under investigation for use
158 | Unit 4. Drugs affecting the Afferent innervation
UNIT 4. DRUGS AFFECTING the AFFERENT

INNERVATION
The drugs affecting the Sensory nerve endings are devided in two groups:
Drugs reducing sensitivity of afferent nerve endings, or defending
them from irritant effects of various substances: local anestetics,
adsorbents, enveloping substances, astringents
Drugs stimulating afferent nerve endings: irritants, bitterness,
emetics, laxatives, expectorants.
Chapter 8. Local anesthetics
Local anesthetics (LAs) are the plant origin drugs that induce reversible
loss of algesthesia (pain sensitivity) and other types of sensitivity due to direct
contact with membrane of nerve cells while maintaining the consciousness.
Mechanism of action. Las are the drugs that reversibly connect with certain
receptor site within the pores of Na+ channels in nerves and block ion movement
via the pores. LAs decrease permeability of cell membranes for Na + ions, block
Na+ ions channels. LAs stabilise cell membranes in phase of polarization.
Therefore, LAs block the generation and the conduction of nerve impulses. LAs
can bind to other membrane proteins, in particular, they can block K+ channels, but
this requires its higher concentrations.
Different sensitivity of nerve fibers to LAs has great individual variation.
Herewith LAs are the dose-dependent drugs, and can act on any part of the nervous
system and on every type of nerve fiber, reversibly blocking the transmission of
nerve impulse. LAs firstly block pain sensitivity, followed – temperature
sensitivity, and further LAs block tactile sensitivity (touch and deep pressure), and
finally – motor function. Thereby, the LAs cause the reversible loss of different
types of sensitivity: pain, temperature, tactile when applied locally to nerve tissue.
Moreover, LAs act on vegetative nerves, namely on autonomic nervous system in
case of systemic action. Currently the exact mechanisms responsible for the special
action of LAs on the different nerve fibers are not known.
The requirements for local anesthetics:
selective action
short latent period
large latitude of therapeutic action, which ensures the safety of Las use
long-term and strong effect
high effectiveness in all types of anesthesia
they must cause vasoconstriction
they shouln’t irritate tissues in the place of administration
Chapter 8. Local anesthetics | 159
- they should withstand the sterilization

Unfortunately, all known LAs, except cocaine, bupivacaine, ropivacaine
cause vasodilatation, which leads to a shortening of the duration of the action and
to the manifestation of negative side effects, as a result of their systemic action. So,
the modern LAs are applied, as combined forms with vasoconstrictors such as
epinephrine, norepinephrine, and phenylephrine to prevent absorption in vascular
bed.
Classification of LAs
(concerning the origin, the chemical structure and ability to dissolve in water)
Native drugs
cocaine (methylbenzoylecgonine)
II. Syntetic drugs
esters
water-soluble: procaine
tetracaine
benzofuracaine
chloroprocaine
partly water-soluble: benzocaine
amides: lidocaine
articaine
trimecaine
bupivacaine
ropivacaine
mepivacaine
bumecaine
prilocaine
III. Combined drugs:
Pavesthesinum
Bellasthesinum
Anesthesiolum
Anaesthesol
Menovasin
Almagel
Palnmagel A
Remagel A
Heparin ointment
Ultracaine D-C
Emla
Pliaglis
Synera
Ligenten
Dietrin
Xylestesin-F "Forte"
Dentinox
Mydocalm-Richter
Xylodont
Lidocaton
Xylocain adrenaline
Octocaine 50
Oflocaine-Darnitsa
Instillagel
Cathejell with lidocaine
Lidochlor
Supertendin 2000 N
Consol
Alphacaine N
Alphacaine SP
Brilocaine - adrenaline
Septanest with adrenaline
Ubistesine
Citocartin
Primacaine
Septonest with adrenalin
Marcaine Adrenaline
Trimecaine with noradrenaline for injections
Dioxysol
Galagran
Catacel A
Levosin
Mepidont, etc.
There are 3 types of local anesthesia:

terminal (superficial, topical – anesthesia of the mucous membranes and skin)
regional, field block (conductive – via the nerve fibers)
infiltrative (is the injection of LAs directly into tissue, layer by layer, not
considering the course of cutaneous nerves).
The advantages of amide LAs before ester LAs:
amide LAs are stable in human tissues in place of administration,
consequently they have a long-term action, inasmuch amide LAs are
destroyed in the liver by microsomal enzymes after absorption of LAs in
vascular beds. Whereas, the ester LAs are rapidly destroyed in place of
administration by specific tissue esterases and plasma esterase after
absorption into the circulation, and as a result have a short-term action
amide LAs are more potent in comparison with ester LAs because they are
stable in acid environment (environment of inflammation), while ester LAs
are not stable in these conditions
amide LAs less likely to cause allergic reactions than ester LAs.
Clinical uses of LAs. Cocaine does not apply in the clinic because of the toxic
effects. Of all known LAs only cocaine reduces the reuptake of catecholamines, specifically NE,
in both the central and peripheral nervous systems that provides its high toxicity:
vasoconstriction, euphoria. In some contries cocaine is used as 1%, 4%, 10% solution for topical
application for topical anesthesia of the upper respiratory tract. Maximal safe dose of cocaine for
topical anesthesia in a healthy 70-kg adult are 150mg. Peak of anesthetic effect of cocaine occurs
within 2-5 minutes and lasts for 30-45 minutes.
Lidocaine is the standard for all LAs and is used for all types of local
anesthesia, namely topical, ophthalmic, mucosal, transdermal, injection.
Additionally lidocaine is used in combined preparations such as Lidoderm
(transdermal path for relief of pain associated with postherpetic neuralgia),
Dentipath (oral patch for application to superficial dental procedures), Emla (for
venipunctura, skin graft harvesting, infiltration anesthesia into genitalia), Pliaglis
(for superficial dermatological procedures such as a filler injections and laser-
based treatment), Synera (for skin excision, electrodesiсcation, shave biopsy of
skin lesions). Lidocain is absorbed rapidly after parenteral, enteral administration
and from respiratory tracts. Co-administration lidocaine with any vasoconstrictors
allow decreasing the rate of its absorption, toxicity, and prolongs its activity.
Moreover, lidocaine is also used as antiarrhythmic drug, as well as trimecaine.
Lidocaine has side effects, especially in high doses. There are drowsiness, tinnitus,
dysgeusia, dizziness, twitching, and even seizures, coma, respiratory depression
and arrest and cardiovascular depression.Maximal safe dose of lidocaine for topical
anesthesia in a healthy 70-kg adult are 300mg. Peak of anesthetic effect of
lidocaine occurs within 2-5 minutes and lasts for 30-45 minutes.
Bupivacaine is a popular drug for prolonged analgesia during labor or the
postoperative period and in case of indwelling catheters and continuous infusions.
But bupivacaine is cardiotoxic and may cause ventricular arrhythmias, myocardial
depression after inadvertent intravascular administration. This cardiac toxicity is
enhanced by coexisting acidosis, hypercarbia, and hypoxemia.
Articaine is used for dental and periodontal anesthesia. This drug has a rapid
(analgesia occurs within 1-2 minutes after administration) and prolonged (1-3
hours) action. Articaine has low toxicity, can not overcome BBB, it binds weakly
to plasma proteins, and it is the drug of choice for pregnant women and nursing
mothers.
Mepivacaine, Prilocaine are the intermediate-acting amide Las and they
have pharmacological effects similar to lidocaine. Mepivacaine is more toxic in the
neonate, and thus it is not used in obstetrical anesthesia. Prilocaine has a small
vasodilatory effect and may be used without a co-administered vasoconstrictor, it
has small CNS toxicity, but its use is limited by methemoglobinemia, which may
be treated by the intravenous administration of methylene blue.
The other local anesthetic benzocaine which is poorly soluble in the water
and is used for terminal anesthesia, it can also elicit methemoglobinemia.
Ropivacaine is less potent and less cardiotoxic than bupivacaine, and more
motor-sparing than bupivacaine. The S-enantiomer is less toxicy than R-isomer.
Rupivacaine is suitable for both epidural and regional anesthesia.
Procaine was the first synthetic LA, and it is an ester. In nowadays procaine
is bounded to infiltration anesthesia and sometimes for diagnostic nerve block,
because procaine has low potency, slow onset, short duration of activity and often
causes allergic reactions including cross-allergic reaction with antimicrobial drugs
such as sulphonamides and peroral hypoglycemic drugs such as sulfonylureas.
Chloroprocaine is a new ester, chlorinated derivative of procaine. It has
rapid onset, short duration of action, fast metabolism, reduced acute toxicity, and it
is used for epidural and subarachnoid anesthesia.
Benzofuracaine is a local anesthetic and has central analgesic activity. It may
be used in stomatology for infiltration anesthesia, and as an analgesic in patients
with pancreatitis, peritonitis, kidney and liver colics, acute pleuritis, and diseases
and trauma of peripheral nervous system.
Tetracaine is an ester and it is more potent, has longer duration, more slowly
metabolized and has higher toxicity than procaine. Currently tetracaine is widely
used in spinal anesthesia in case of need for long duration anesthesia, and as a part
of several topical anesthetic preparations. Maximal safe dose of tetracaine for
topical anesthesia in a healthy 70-kg adult are 50mg. Peak of anesthetic effect of
tetracaine occurs within 3-8 minutes and lasts for 30-60 minutes.
LAs are used primarily for mucous membranes and skin anesthesia.
There are benzocaine, tetracaine, trimecaine, bumecaine, etc. Proparacaine and
tetracaine are used frequently in ophthalmology. It should be stressed that long-
term use of the topical anesthesia to the eye has been associated with retarded
healing, pitting, sloughing of the corneal epithelium, and predisposition of the eye
to inadvertent injury. Thus, self-treatment with these drugs is dangerous.
For the local anesthesia of mucous membranes of the nose, ear, mouth,
throat, tracheobronchial tree, esophagus, genitourinary tract the water solution of
many LAs or suspensions of the poorly soluble LAs can be applied. There are
tetracaine, lidocaine, and cocaine. The shrinking of mucous membranes (one of
the effects of LAs) reduces the operative bleeding that is very important during the
operation. Epinephrine, topically, as additional vasoconstrictor, as a part of any
LAs, has no considerable local effects and can not prolong the term of LAs action
applied to mucous membranes due to poor penetration.
In general, topical anesthesia always has the risk of systemic toxic effects in
consequence of properties of LAs are absorbed rapidly into the circulation. LAs rate
of absorption into circulation depends on the place of application. So, the highest rate
of absorption of the LAs occurs from alveolar mucosa, and the smallest - from the
laryngeal mucosa, that can be represented as following order: larynx < trachea <
bronchi < alveoli. In addition, LAs absorption into the circulation occurs from uretra
very quickly, and from the mucosa of the urinary bladder – slowly.
Infiltrative anesthesia. For this type of local anesthesia the epinephrine can
be used as vasoconstrictor. But, its application should be avoided in those for
whom adrenergic stimulation is undesirable, and into tissues supplied by end
arteries, videlicet fingers, toes, ears, the nose, the penis because narrowing of blood
vessels can lead to gangrene. Lidocaine, procaine, bupivacaine are used most
frequently for infiltration anesthesia. The main advantage of this type of anesthesia
is an absence of disordes of normal body functions. The main disadvantage of this
type of anesthesia is the feasibility to use LAs on relatively small areas in minor
surgery, and the inability to use LAs on the large areas in major surgery because of
possible systemic toxic effects. Infiltrative anesthesia may be applied at one of
several levels: subcutaneously, at major nerves, or the spinal roots.
Field block (regional) anesthesia is performed by subcutaneous injection of
solution of LAs in order to anesthetize the region distal to the injection. This type
of anesthesia can be viewed as a special case of infiltrative anesthesia.
Nerve block anesthesia is the injection of solution of LAs into or around
individual peripheral nerves or nerve plexuses that provides the anesthesia of
actually the large areas. Lidocaine, mepivacaine, bupivacaine are used for this type
of anesthesia. The choice of LAs for nerve block anestesia is determined firstly by
LAs properties, secondly by purposes of local anesthesia.
Intravenous regional anesthesia is based on using the vasculature to
deliver the LAs to the nerve trunks and endings. For intravenous regional
anesthesia local anesthetic solution such as lidocaine, prilocaine are used without
vasoconstrictor. Intravenous regional anesthesia is applied most often for surgery
of the forearm and hand, but can be adapted for the feet and legs.
Spinal anesthesia is the most popular forms of anesthesia, and is performed
by injection of LAs, such as lidocaine, bupivacaine, ropivacaine, into the
cerebrospinal fluid in the lumbar space. Spinal anesthesia is a safe and effective
technique, especially during surgery involving the lower abdomen, the lower
extremities, and perineum.
Epidural anesthesia is administered by injection of LAs into epidural space
- the space bounded by the ligamentum flavum posteriorly, the spinal periosteum
laterally and the dura anteriorly. Epidural anesthesia can be performed in the sacral
hiatus, or in the lumbar, thoracic, or cervical regions of the spine. The primary site
of action of this form of anesthesia is on the spinal nerve roots, also on the spinal
cord and on the paravertebral nerves. For epidural anesthesia bupivacaine,
lidocaine, chloroprocaine may be used.
Table 29. The main clinical use of Local anesthetics
Drug Types of anesthesia Additional properties

Terminal Infiltrative Conductive Spinal
Procaine + + + Procaine is used for
blokades in case of different
diseases of internal organs,
eczema, atopic dermatitis;
Also it can be used in
patients with vessel
spasms, ulcer disease in
GIT, atherosclerosis, arterial
hypertension, arthronosos
(joint disease), late toxicosis
of regnancy with arterial
hypertension;
Procaine potentiates action
of drugs for general
anesthesia, it has antishock
action, spasmolitic action;
Procaine is used in patients
with atrial fibrillation as
antiarrhythmic drug;
Procaine is used as solvent
for antibiotics
Tetracaine + It has limited use because of
the high toxicity
Benzocaine + It is used for anesthesia of
the mucous membrane of
the esophagus and stomach
in the form of tablets and
powders;
as well as a combined
preparations in the form of
ointments, powders,
aerosols, oil solutions for
external use, it can be use
for local anesthesia for relief
pain in case of hemorrhoids,
anal fissures, burns of Ist and
IInd degree, etc.
Lidocaine + + + + Lidocaine is used not only
as LA, but also it is used as
antiarrhythmic drug;
It is a solvent for
antibiotics; It has significant
side effects
Articaine + + + It is drug of choice
for pregnant women and
nursing mothers
Trimecaine + + + + It is used as a LA and
as an antiarrhythmic drug
Bupivacaine + + + This is one of the most
active and long-acting (up to
Chapter 8. | 165
Local anesthetics
7 hours) LA;
It has a high cardiotoxicity
in getting into general
circulation;
It can be used for labor pain
relief, as it does not
overcome the placenta and
other biological barriers in
the body;
It is contraindicated for use
in children under 12 years
Ropivacaine + + + Ropivacaine is used in those
with cesarean section;
It is contraindicated for use
in children under 12 years
Mepivacaine + + + Mepivacaine is not
recommended for
subarachnoid
administration;
It should be used with
caution in elderly people
Bumecaine + It is used as a LA and
as antiarrhythmic drug
Prilocaine + + The risk of
methemoglobinemia is
higher in case of the use of
prilocaine than other LAs;
It should be used
carefully in children and the
elderly people
Chloropro- + + It has a rapid onset of action,
caine rapid metabolism, low acute
toxicity
Benzofuro- + Benzofurocaine has a central
caine analgesic properties;
As analgesic agent, it is used
in patients with pancreatitis,
peritonitis, hepatic and renal
colic, acute pleuritis,
diseases and injuries of the
peripheral nervous system;
This drug is prone to
accumulation
Undesired effects of LAs. LAs have significant effects on the CNS, the
autonomic ganglia, the neuromuscular junction and all muscles . Herewith, the
danger of adverse reactions is proportional to the concentration of LAs in the
bloodstream, and their chiral centers: the S-enantiomer is less toxic than the R-
enantiomer.
Following absorption, LAs may provoke stimulation of CNS, and cause
tremor and clonic convulsions. With it the more potent LAs cause more easily
convulsions. Central stimulation is accompanied by depression and death has
occurred as a result of respiratory failure.
In case of systemic absorption the LAs act on cardiovascular system, namely,
they reduce electrical excitability of myocardium, its conduction and force of
contraction. Most LAs dilate blood vessels. But the negative effects of LAs on
cardiovascular system can manifest only in high concentration of LAs in vascular bed,
and may be in its low doses a very rare. Ventricular tachycardia and fibrillation are the
rare consequences of LAs use except for bupivacaine. At the same time, such LAs as
lidocaine and procainamide are used as antiarrhythmic drugs.
LAs relax vascular and bronchial smooth muscles, notwithstanding the low
concentration of LAs and spinal and epidural anesthesia, instillation of LAs into
peritoneal cavity can result in increased tone of GI musculature.
LAs, for example, procaine can block the response of sceletal muscles to
action of acetylcholine. Besides, high concentation of LAs can block N-
cholinoreceptors at autonomic ganglia.
Allergic reactions may appear as an allergic dermatitis or a typical asthmatic
attack. It is very important to differentiate allergic reactions from toxic side effects
of LAs and the effects of co-administered vasoconstrictors and preservatives such
as methylparaben and an antioxidant such as sulfite which added to amide type of
LAs with catecholamine/vasoconstrictor.
The use of amide type of LAs in patient with liver diseases requires caution taking
into account their metabolism. The features of metabolism explain a negative side
effect of prilocaine such as methemoglobinemia. The amide LAs are extensively
bound to plasma proteins therefore change their level entails a change in the
metabolism of LAs and thus affect their toxicity. Age-related changes in the levels
of plasma proteins are essential too. Uptake by lung also is important for
distribution of amide LAs in the body.
Table 30. Medicinal forms of Local anesthetics

Cocaine h/cl. Solution for 1%, 4%, 10%
external use in
flacons
Procaine Aethocain, Allocaine, Poweder;
Ambocain, Parenteral 0.25%, 0.5% - 1 ml,
Aminocaine, solution in 2 ml, 5 ml, 10 ml,
Anesthocaine, ampoules, 20 ml;
Atoxicain, Cerocain, and in flacons; 200 ml, 400 ml;
Chemocain, Citocain, Parenteral 1%, 2% - 1 ml, 2 ml,
Ethocaine, Genocaine, solution in 5 ml, 10 ml;
Herocaine, Isocain, ampoules;
Chapter 8. | 167
Local anesthetics
Jenacain, Marecaine, Ointment; 5%, 10%;
Minocain, Naucain, Rectal 0.1
Neocaine, Pancain, suppositories
Paracaine, Planocaine,
Polocainum,
Protocaine, Sevicaine,
Syncaine, Syntocain,
Topocaine, etc.
Tetracaine Dicain Powder;
Eye drops in 0.3% -5ml, 10ml
flacons
Benzocaine Aethylis Tablets; 0.3;
aminobenzoas, Ointment; 5%, 10%;
Anaesthalgin, Solution for 5%;
Anaesthesinum, external use in
Anaesthicin, Anaesthin, flacons;
Bartel drugs anesthetic,
Dentispray, Ethoforme,
Norcaine, Parathesine,
Rhaetocain,
Topanalgin, etc.
Benzocaine + Nigepanum, Rectal 0.05+0.083;
Heparin suppositories
Anaesthesinum + menthol+ Amprovisolum Aerosol 50.0, 80.0, 170.0
ergocalciferol+
glycerol+propolis+ ethyl
alcohol
Lidocaine Acetoxyline, Alocaine, Parenteral 1%, 2% - 5ml, 10ml;
Anestacon, solution in 2% - 2 ml;
Anestecain, Astracaine, ampoules, 4% - 5 ml, 10 ml;
Dolicaine, Dulcicaine, 10% - 2 ml;
Esracaine, Fastocaine,
Leostesin, Lidestin, and in flacons; 1%, 2% - 50 ml,
Lidocard, Lidocaton, 100 ml;
Lignocain, Lignom, Parenteral 2% - 1.8 ml;
Luan, Maricain, solution in
Nulicaine, Octocaine, syringe pen, 2%, 4% - 5 ml;
Remicaine, Solcain, capsules-
Stericaine, Xycain, ampoules; 2%, 4% - 1.5 ml;
Xylesin, Xylocain, Eye drops in
Xylocard, Xylocitin, flacons, 10% - 38.0;
Xylodont, Xylorolland, in tubes-
Xyloton, Xylotox, etc. droppers;
Spray for 10% - 50.0;
topical use in 1%, 5% - 30.0, 50.0;
balloons and
in flacons;
Gel for external 2.5% - 15.0
use
Lidocaine Lidoderm Transdermal 5%
patch
168 | Unit 4.
Drugs affecting the Afferent innervation
Lidocaine Dentipatch Transoral 46.1 mg
Delivery
System (TDS)
Articaine Articaine h/cl., Parenteral 1%, 2% - 5 ml,
Ultracaine solution in 20 ml
ampoules
Trimecaine Mesdicain, Mesocain Parenteral 0.25% - 10 ml;
solution in 0.5% - 2.5 ml, 10ml;
ampoules 1%, 2% - 1 ml, 2 ml,
5 ml, 10 ml;
5% - 1 ml, 2 ml
Bupivacaine Anekain, Carbostesin, Parenteral 0.25%, 0.5% - 20ml;

Duracain, Marcain, solution in
Narcain, Sensorcain, flacons;
Svedosan Parenteral 0.5% - 4 ml
solution in
ampoules
Ropivacaine Naropin Parenteral 0.2%, 0.75%, 1% -
solution in 10 ml, 20 ml;
ampoules, in 0.2% - 100 ml,
flacons 200 ml
Mepivacaine Carbocaine, Isocaine, Parenteral 1%, 1.5%, 2%, 3% -
Mepicatone, Mepidont, solution in 1.7 ml, 1.8 ml
Mepivastesine, cartridges
Polocaine, Scandonest
Bumecaine Pyromecaine; Parenteral 0.5% - 1 ml, 3 ml,
solution in 5 ml;
Pyromecaine solution; ampoules;
Parenteral 1% - 5 ml, 10 ml;
Pyromecaine solution solution in
for injections 1% with ampoules;
glucose;
Pyromecaine ointment Ointment 5% - 30.0
Prilocaine Citanest, Xylonest Parenteral 0.5%, 2.0%, 2.5%,
solution in 3% - 10 ml, 20 ml
ampoules
Chloroprocaine Nesacaine Parenteral 1%, 2%, 3% - 30 ml,
solution in 20 ml
flacons
Benzofurocaine Parenteral 1% - 2 ml, 5 ml,
solution in 10 ml
ampoules
Benzocaine + papaverine h/cl. Pavesthesinum Tablets 0.3 + 0.05
Benzocaine + Extract Bellasthesinum Tablets 0.3 + 0.015
Belladonnae
Metamizole sodium + Bellalgin Tablets 0.25 + 0.25 + 0.015
benzocaine + Belladonna + 0.1
extract + sodium
hydrocarbonate
Chapter 8. | 169
Local anesthetics
Phenylpropanolamine + Dietrin Capsules 75 mg + 9 mg
benzocaine
Benzocaine + Dermatolum + Anesthesiolum Rectal 0.1 + 0.04 + 0.004 +
menthol + zincum oxydum suppositories 0.02
Bensocaine + bismuth Anaesthesol Rectal 0.1 + 0.04 + 0.02 +
subgallate + Z suppositories 0.004
zincum oxide + menthol
Menthol + procaine + Menovasin Solution for 2.5 + 1.0 + 1.0 -
benzocaine external use in 40 ml, 50 ml
flacons
Algeldrate + magnesium Almagel Peroral 0.3 + 0.1 + 0.1 -
hydroxide + benzocaine suspension 170 ml, 200 ml
Algeldrate + magnesium Palnmagel A Peroral gel 3.0 + 1.35 + 2.0 -
hydroxide + benzocaine 150ml, 180ml,
200ml, 250ml
Algeldrate + magnesium Remagel A Peroral 0.3 + 0.1 + 0.1 - 5ml
hydroxide + benzocaine suspension
Heparin sodium + benzocaine Heparin ointment Ointment in 100 ME + 0.04 +
+ benzonicotinic acid tubes 0.08mg - 15.0, 25.0,
30.0
Lidocaine + prilocaine Emla Emulsion; 5% (25mg/1.0 +
25mg/1.0) - 5.0,
30.0;
Cream for 25 mg + 25 mg -
topical use in 5.0, 30.0
tubes;
Transdermal
patch
Lidocaine + tetracaine Pliaglis Cream for 7% (2.1+2.1) - 15.0,
topical 30.0
anesthesia in
tubes
Lidocaine + tetracaine Synera Topical patch 70 mg + 70 mg
Gentamicin + lidocaine + Ligenten Gel for 6.25 mg + 180 mg +
ethonium intravaginal and 1.25 mg - 10.0
intrauretral
administration
Lidocaine + norepinephrine Xylestesin-F "Forte", Parenteral 30 mg + 0.048 mg -
Xylorolland solution in 1.8 ml
cartridges
Lidocaine + polidocanol + Dentinox Gel for topical 3.4 mg + 3.2 mg +
Chamomillae floridis extract use in tubes; 150 mg - 10.0
Solution for
external use in 3.4 mg + 3.2 mg +
flacons 0.15 - 1 ml
Lidocaine + tolperisone Mydocalm-Richter Parenteral 2.5 mg + 0.1 - 1 ml
solution in
ampoules
Lidocaine + epinephrine Xylodont, Lidocaton, Parenteral 5 mg + 5 mcg/ml,
Xylocain adrenaline, solution in 10 mg + 5 mcg/ml,
Octocaine 50 calsules- 20 mg + 5 mcg/ml;
170 | Unit 4.
ampoules, in 20 mg/12.5 mcg;
cartridges 2% - 1.8 ml
Ofloxacin + lidocaine Oflocaine-Darnitsa Ointment 15.0, 20.0, 30.0,
100.0, 1000.0
Neomycin + polymyxin B + Anauran Ear drops in 0.5 + 1000000 IU +
lidocaine flacons 4.0
Chlorhexidine + lidocaine Instillagel, Cathejell Gel for topical 0.05 + 2.0 - 6 ml,
with lidocaine, use 11 ml; 10.0; 12.0
Lidochlor
Dexamethasone + lidocaine Supertendin 2000 N Parenteral 4 mg + 40 mg
solution in
ampoules
Dextran + inosine + potassium Consol Parenteral 400 ml
gluconate + potassium solution in
chloride + lidocaine flacons
hydrochloride + magnesium
sulfate + sodium
hydrocarbonate + sodium
chloride
Articaine + epinephrine Ultracaine D-C Parenteral 40 mg + 6 mcg –
solution in 1.7 ml
cartridges
Articaine + epinephrine Alphacaine N; Parenteral 40 mg + 1:200000 -
solution in 1.8 ml;
cartridges;
Alphacaine SP Parenteral 40 mg + 1:100000 -
solution in 1.8 ml
cartridges
Articaine + epinephrine Brilocaine - adrenaline Parenteral 40 mg + 1:200000 -
solution 1.8 ml, 1.7 ml
Articaine + epinephrine Septanest with Parenteral 40 mg + 1:200000/
adrenalin solution in 1:100000 - 1.8 ml
cartridges
Articaine + epinephrine Ubistesine Parenteral 40 mg + 6 mcg/1 ml
solution in - 1.7 ml
cartridges
Articaine + epinephrine Citocartin Parenteral 40 mg + 1:200000/1:
solution in 100000 - 1.7 ml
cartridges
Articaine + epinephrine Primacaine Parenteral 40 mg + 1:200000/1:
solution in 100000 - 1.7 ml
cartridges
Bupivacaine + epinephrine Marcaine Adrenaline Parenteral 2.5 mg/ml +
solution in 5 mcg/ml,
flacons 5 mg/ml +
5 mcg/ml – 20 ml
Trimecaine + norepinephrine Trimecaine with Parenteral 1 ml, 2 ml
noradrenaline for solution in
injections ampoules
Hydroxymethylhinoxilindioxi Dioxysol Aerosol; 30 ml, 60 ml;
de + trimecaine Solution for 50 ml, 100 ml,
Chapter 8. | 171
external
Local anesthetics
use in 1000 ml
flacons
Hydroxymethylhinoxilindioxi Galagran; Powder for 2.5, 5.0, 10.0;
de + trimecaine + topical use;
methyluracil Dioxycol Ointment in 30.0, 100.0, 1000
banks
Benzalkonium chloride + Catacel A Pasta for 20.0 - 100.0, 500;
trimecaine external use in 30.0 - 300.0
banks, in tubes
Chloramphenicol + Levosin Ointment in 50.0, 100.0, 1000.0
methyluracil + banks
sulfadimethoxine + trimecaine
Mepivacaine + epinephrine Mepidont Parenteral 2% - 1.8 ml
solution in (epinephrine -
cartridges 1:100000)
Chloroprocaine + epinephrine Parenteral 1%, 2%, 3% - 20 ml,
solution in 30 ml + (epinephrine
ampoules -1:100000)
Chapter 9. Sorbents, covering drugs, astringents
Absorbents are the drugs with high surface activity that capable of
absorbing of different chemical substances and thus prevent irritation of nerve
endings.
Mechanism of action: Effect of absorption is provided by fixation of
molecules of different chemical substances on the sorbent surface.
Classification of Sorbents
Neutral absorbents:
Carbo activatus
Charcoal medicinae
Enterosgel
Silicon dioxide
Diosmectite
Special absorbents:
Ion exchange resins
Various substances with absorption properties:
Spherical carbonite
Coke charcoal Spherical
carbon sorbent
Activated carbon fibers
Clinical use of Sorbents
Neutral absorbents are administrated in GIT and use for enterosorption, in

other words they are used for extraction of toxic substances (as xenobiotics and
endogenous toxins) from GIT.
Special absorbents are used for extraction of toxic substances from blood
(hemosorption), from plasma (plasmasorption), from lymph (lymphosorption) and
from other liquids of the body.
Pharmacological characteristic of Sorbents
Carbo activatus (activated charcoal) adsorbs toxic substances, prevents

their absorption, reduces activity of other drugs in case of their simultaneous
administered, and weakens stomach acidity.
Indications for Carbo activatus use:
Poisonings by chemical substances including organophosporus and
 chlorophosporus substances, psychoactive drugs
Dyspepsia, diarrhea, flatulence
Stomach hyperacidity
Alkaloid poisoning
Glycoside poisoning
Poisoning by heavy metal salts
Food poisoning, dysentery, salmonellosis
Burn disease in the stage of toxemia and septicotoxemia
Kidney insufficiency
Chronic hepatitis, acute viral hepatitis
Cirrhosis of liver
Atopic dermatitis
Bronchial asthma
Chronic cholecystitis, pancreatitis
Allergy
Metabolism disorders
Alcohol withdrawal syndrome
Intoxication in the patient on the background of radiotherapy and chemical
 therapy
Preparation for X-ray and endoscopy
Adverse effects of Carbo activatus:
Dyspepsia, diarrhea, constipation
Hypovitaminosis, reduction of absorption of lipidsproteins, hormones in GIT
 with prolonged use of this sorbent
Thromboembolism, hemorrhages, hypoglycemia, hypocalcemia, hypotermia,
arterial hypotension when hemoperfusion through activated charcoal
Staining of stool in black color
Chapter 9. Sorbents, covering drugs, astringents, irritans | 173
Contraindications for Carbo activatus use:

Hypersensitivity
Stomach and duodenum ulcer
GIT blood bleeding
Simultaneous administered Carbo activatus and antitoxic drugs the effect of
which develops after their absorption
Charcoal medicinae (Sorbex) is a plant origin carbo activatus with

developed active surface, it is able to adsorb gases and liquid toxic compounds that
are formed and accumulated in excess amount in acute and chronic diseases, or
these toxic substances come from outside the body. Sorbex is nontoxic inert
substance. In the body it is not metabolized, it is not absorbed from the intestinal
lumen, it is not entered abroad GIT, it is not defined in any biological fluids of the
body and it was eliminated from the body through the intestines.
Indications for Sorbex use:
In case of poisoning by household and industrial toxins (alkaloids, heavy metal
salts, other substabces), foodstuffs, drugs, alcohol for diminution of their
 absorption and acceleration of their excretion
Habitation in unfavorable ecological conditions or the action of harmful factors,
changing the usual way of nutrition during the holidays, trips, travel
As additional therapy in case of:
GIT disturbances: dyspepsia, flatulence, intestine infections, acute and
chronic hepatitis
diseases with syndrome of endogenous intoxication, acute and chronic liver
and kidney damage, allergy, autoimmune and cancer, high cholesterol level
in blood
Adverse effects of Sorbex:
Simultaneous administration of this drug and food reduces its absorption,
thereby Sorbex should be taken before meals (1-1.5 hours), or after meals
(1-1.5 hours)
Long-term use (more than 15 days) of Sorbex may cause disorders of
absorption of vitamins, hormones, lipids, proteins, that require medical or
 alimentary correction
Staining of stool in black color
Nausea, vomiting
Long-term use of Sorbex may evoke disturbance of intestine function (diarrhea,
constipation) that is easily eliminated by discontinuation of drug receiving
 and symptomatic therapy
Sorbex is capable to reduce effects of the drugs in case of simultaneous
administration due to its absorption properties
Contraindications of Sorbex use:
 Individual hypersensitivity
GIT ulcers in acute stage
 GIT bleeding
Iliac passion (intestinal obstruction)
Enterosgel – is the hydrogel of methylcilicic acid, enterosorbent that

removes toxic substances (midle molecules, products of incomplete metabolism,
incorporated radionuclides) from GIT and blood. Enterosgel eliminates
manifestations of toxemia, dysbiosis, normalizes methabolic processes and
intestinal microflora, protects the mucosa of GIT from toxic effects, improves
immunity, prevents the development of purulent processes, and owns mediated
antimicrobial, hepatoprotective regenerative activity. Enterosge is not absorbed in
GIT.
Indications for Enterosgel use:
 Acute poisoning including ethanol, alkaloids, heavy metal salts
Detoxication on occasion kidney diseases, toxicoinfections, liver diseases,
enterocolitis
Diarrhea
Alcohol intoxication
Drud intoxication
Burn disease
Radiation disease
Pyo-septic processes
Dysbiosis
Adverse effects of Enterosgel:
 Constipation
Nausea
Reduced absorption of other drugs during their simultaneous administration
Contraindications for Enterosgel use:
Intestine atony
Acute Iliac passion (ileus)
Simultaneous administration with other drugs
Silicon dioxide has adsorbing action due to formation of specific complexes,

connection with proteins, enzymes, microbial toxins, bilirubin, bile acids, and
microorganisms. Silicon dioxide is not absorbed in GIT and can not be
accumulated.
Indications for Silicon dioxide use:
 Endogenous and exogenous intoxications
Food allergy
Allergic dermatitis
Psorias
Eczemas
Purulent inflammation of soft tissues of the body
Acute intestinal diseases
Diarrhea as a result of salmonellosis, dysentery, food toxic infections
Adverse effects of Silicon dioxide:
Constipation
Dyspepsia
In case of local use – formation of crusts, which impede the wound surface
aeration
Reduction of drug effectiveness on occasion simultaneous administration
with them
Contraindications for Silicon dioxide use:
Ulcer disease of stomach and duodenum in acute stage
Esophagitis
Ileus
Children under 1 year
Local application in case of clean granulating and aseptic wounds
Simultaneous administration with other drugs
Diosmectite is a plant origin drug, an active sorbent and it is capable to

excrete viruses, pathogenic bacteria, toxins, intestinal gases, and salt of bile acids
from the body. This drug has a high enveloping activity in respect of
gastrointestinal mucosa, prevents water-electrolyte losses. Diosmectite interacts
with mucus glycoproteins, enhances barrier function of gastrointestinal mucosa,
and protects it from negative influence of hydrochloric acid, bile acids, intestinal
microbes, their toxins, and other irritants. In therapeutic doses Diosmectite does
not affect intestinal motility. It is not absorbed in GIT and is excreted from the
body in unchanged form.
Indications for Diosmectite use:
Symptomatic treatment of acute and chronic diarrhea in children and adults
As an auxiliary medicine in event of inflammatory diseases of GIT
Adverse effects of Diosmectite:
Rarely – constipation, which is disappeared after reduction of the drug dose
Reduction of drug effectiveness on occasion simultaneous administration
with them
Contraindications for Diosmectite use:
Individual hypersensitivity
Ileus
Ion exchange resins – are the solid sorbents that capable to ion exchange.
There are cation-exchange resins (cationites) and anion-exchange resins
(anionites); amphoteric ion exchange resins that include complex forming groups;
the redox resins that contains functional groups capable of altering the ion charges.
Besides ion exchange resins can comprise the groups of different classes and they
are named polyfunctional resins. According to the structure ion exchange resins are
divided into gel (microporous) and macroporous. This diversity of ion exchange
resins determines a wide range of their application in modern terms. In the
pharmaceutical industry ion exchange resins used for purification of antibiotics,
vitamins, hormones, sugar syrup, water, separation of proteins, and in modern
medicine – for selective purification of blood plasma.
Table 31. Medicinal forms of Sorbents

Activated charcoal, Carbactinum, Powder; 0.25, 0,5;
activated carbon, activated Carbolenum, Tablets;
coal Carbolongum,
Enterosorbentum,
Microsorbum-Р, Capsules 0.2;
Ultra-adsorb 110 mg
Charcoal medicinae Sorbex Capsules; 0.25;
Powder in packages; 5.0;
Tablets 0.32, 0.25
Enterosgel Gel for preparing peroral 45.0, 225.0;
suspension in packages;
Pasta 70%
Silicium dioxide Silics, Atoxil Powder in packages for 1.0, 2.0, 10.0,
preparing peroral 12.0
suspension and
suspension for external
use
Diosmectite Smecta Powder in packages for 3.0
preparing peroral
suspension
Covering drugs are indifferent substances with high molecular mass that
form colloid solution with water (mucus), cover a surface of skin or GIT mucosa
by thin layer and mechanically protect nerve endings from irritation.
Mechanism of action is connected with the formation of a thin layer of the
colloid solution and thus the corresponding reflex response is reduced, intestinal
motility is inhibited, GIT absorption is decelerated including drugs and toxins
absorption. Covering drugs possess adsorbing, anti-inflammatory, analgesic action,
detoxifying properties (slowing absorption of toxic substances); reduce reflex
dysphagia, nausea, vomiting, heartburn, and diarrhea.
As covering substances mucus of starch (mucilago Amyli) of wheat
(Amylum Tritici), of corn (Amylum Maydis), of rice (Amylum Oryzae), of potatoes
(Amylum Solani) are used,they are prepared with boiling water. Mucus is applied
topically, inside, and in enemas. Mucus of starch is added to the mixtures, enemas
if they contain substances with a local irritant effect. Mucus is used to slow the
absorption of poisons, which came in the GIT, to protect the mucosa in case of
poisoning by cauterizing substances (acids, alkalis). Tubers of Orchis (tuber
Salep), gum acacia (Gummi arabicum), Marshmallow root (radix Althaeae),
Psyllium seeds (semen Plantaginis majoris) and Flax seeds (semen Lini) are used
for preparing mucus. Many plants contain enveloping substances. There are: Geum
river (Geum rivale), Oat (Avéna satíva), Plantain leaves (folia Plantaginis
majoris), Licorice root (radices Glycyrrhizae), Potentilla erecta (synonyms:
Tormentilla erecta, Potentilla laeta, Potentilla tormentilla) rhizomes (rhizomata
Tormentillae), Bistorta officinalis rhizomes (rhizomata Bistortae), Sanguisorba
officinalis (great burnet) rhizomes with roots and grass (rhizomata cum radicibus
Sanguisobrae, herbae Sanguisobrae) etc.
Pharmacological characteristics of Covering drugs
Marshmallow root (radix Althaeae) is used in powder, tincture, extract,

syrup forms as an expectorant, anti-inflammatory and enveloping drug.
Flax seeds (semen Lini) are used as a decoction (1:30), mucus from Flax
seeds (mucilago seminis Lini) is used externally and inside as enveloping agent and
emollient.
Tubers of Orchids (tuber Salep) are used for treatment diarrhea, dysentery,
stomach and duodenal ulcers, hyperacidic gastritis, enterocolitis and colitis,
cystitis, food poisoning, and other poisonings, when the treatment of inflammation
of the digestive tract needs enveloping mucus.
Oat (Avéna satíva). Oat groats and flour have a large number of easily
digestible, rich in essential amino acids of proteins, carbohydrates, fats and vitamin
of B group, so they are widely used in dietary and baby food. They are prepared
porridges, soups and mucous broths that are enveloping and dietary agents in acute
inflammatory diseases of the GIT (gastritis, enterocolitis), intestinal atony, viral
hepatitis, and fatigue, diseases of the nervous system, cardiac arrhythmias and iron
deficiency anemia caused by violation of the synthesis of porphyrins. Green grass
of oats for the healing properties is not inferior to grains. Its extract has
diaphoretic, diuretic and antipyretic effects. Oats have enveloping properties by
which is used in acute inflammatory diseases of the GIT and as antiflatulent, and as
a laxative.
Plantain leaves (folia Plantaginis majoris) have a lot of mucus and the
drugs containing them possess enveloping and anti-inflammatory properties and
are used for treatment inflamatory diseases of GIT.
Geum River (Geum rivale) has enveloping, astringent, analgesic, antiseptic,
wound healing, anthelmintic, antacid effects and is used for treatment of diarrhea,
tonsillitis, rheumatism and hemorrhoids. In dental practice, this plant is used for
treatment of periodontal disease, ulcerative necrotic stomatitis and laryngitis. It is
not advisable to apply the Geum River in thrombophlebitis and thrombosis.
Licorice roots, the roots of Glycyrrhiza glabra (radices Glycyrrhizae) is
used as an expectorant (especially in children with bronchial asthma), diuretic,
enveloping, laxative for constipation, hemorrhoids, stomach ulcer. Licorice can be
used as an antidote for treatment of poisoning by mushrooms. Furthermore, given
that the glycoside glycyrrhizin (found in liquorice) is a source of glucuronic acid,
which neutralizes in the human body various toxins (including tetanus toxins),
Licorice is used in case of gallstones and liver diseases. Licorice extract soothes
pain, but we must remember that glycyrrhizin may violate electrolytic-water
balance (water retention, decrease urinary sodium excretion and increase
potassium excretion) and cause edema, lower content of vitamin C in the adrenal
glands.
Potentilla erecta rhizomes (rhizomata Tormentillae) are used in event of

GIT diseases (gastritis, dyspepsia, enteritis, enterocolitis), externally – in case of
inflammatory diseases of oral cavity and throat.
Bistorta officinalis rhizomes (rhizomata Bistortae) are known as a strong
astringent and are used in diarrhea (per oral use), and for external use in treatment
of wounds, blood bleeding, abscesses, urinary bladder diseases.
Sanguisorba officinalis (great burnet) rhizomes with roots and grass
(rhizomata cum radicibus Sanguisorbae, herbae Sanguisorbae) due to the high
content of tannins are used as drugs to stop the stomach, uterine and intestinal
bleedings, for strengthen the gums in periodontal disease, hemorrhoids, in
lambliasis cholecystitis, diarrhea. This plant is a good anti-inflammatory,
astringent and diaphoretic agent. Sanguisorba officinalis has strong antibacterial
properties and is used for treatment of inflammation of the mouth and throat for
lubrication of gums in case of gingivitis, stomatitis, in gynecology on occasion of
trichomonas disease. An external application of decoction of Sanguisorba
officinalis rhizomes with roots and grass makes quick therapeutic effect in acute
purulent conjunctivitis.
Covering effects are also aluminum products (Almagel, Maalox, Gastal,
Fosfalugel, Sucralfate, Gastrogel, Carbaldrate, etc.) bismuth preparations (Vicair,
De-Nol). These drugs are used in inflammatory diseases of GIT, in case of stomach
hypersecretion, stomach ulcer and duodenal ulcer. In the application they prevent
the absorption of vitamins, cause constipation, violate digestive. Due to ability of
these drugs to reduce gastric acidity, they are called antacids. Antacids are not
recommended to be used together with any drugs through the obstacle of their
absorption.
In dentistry the starch and white clay, which have expressed adsorbent
properties are used as enveloping agents.
Table 32. Medicinal forms of Covering (enveloping) drugs

Tuber Salep Powder in the 45.0
containers
Radices Althaeae Powder in bottles; 19.6
Powder in the packets 1.47
Folia Plantaginis mayoris Shredded raw in 50.0

packs,
in filter packets 1.5
Semen Lini Raw in packs 1000
Geum rivale Shredded raw in packs 100.0
Avéna satíva Raw in packs 100.0
Radices Glycyrrhizae Powder in banks 600.0, 800.0
Rrhizomata Tormentillae Shredded raw in packs 50.0
Rhizomata Bistortae Shredded raw in packs 50.0
Rhizomata cum radicibus Shredded raw in packs 100.0
Sanguisorbae
Chapter 9. | 179
Sorbents, covering drugs, astringents, irritans
Herbae Sanguisorbae Raw in carton packs 100.l0
Aluminum preparations:
Аluminum Almagel Oral suspension in 170 ml, 200 ml:
hydroxide+mаgnesium flacons each 5 ml of drug
oxide+D-sorbitol contains
0.3 Аluminum
hydroxide,
0.1 Magnesium
hydroxide with the
addition of
D-sorbitol
Algedrate*+Magnesium Maalox Oral suspension in 250 ml
hydroxide flacons;
Chewable tablets
Аluminum hydroxide+ Gastal Tablets 0.45+0.45+0.3
magnesium hydroxide+
magnesium carbonate
Aluminium phosphate Fosfalugel, Alfogel, Gel for taking inside 8%, 55% - 16.0
(алюмінію фосфат+ Gefal, Phosphalugel in plastic bags
гель пектину+
гель агар-агару)
Sucralfate Alsucral, Ancrusal, Tablets 0.5, 1.0;
Andapsin, Keal, Granules in sachets; 0.5, 1.0;
Sucrabest, Sucrafil, Gel for oral 20% -5 ml;
Sucras, Sucrat, administration in
Ulcon, Venter etc. sachets;
Oral suspension in 10 ml,
sachets and flacons 250 ml
Original Silicea Gastrogel Gel for oral 2.8%-500 ml
administration in
plastic flacons
Carbaldrate Oral suspension in 250 ml
vials;
Lozenges (lingual 355 mg
tablets, dispersible
tablets)
Bismuth preparations:
Bismuth subnitrate + Vicair Tablets 0.35+0.4+0.2+
Magnesium carbonate + 0.025+0.025
Sodium hydrocarbonate +
Frangulae cortex +
Rhizomata Саlami
Bismuthate tripotassium De-Nol, Tablets 0.12

dicitrate Biskolcitrate, Bisnol,
De-Noltal, Duosol,
Pylocide, Trimo,
Tripotassium
dicitrabismutate,
Trybimol, Ulceron,
Ventrisol
Astringents protect sensitivity nerve endings of mucous and skin from

negative influence of irritant agents.
Classificstion of Astringents
I. Drugs of plant origin:

Tanninum
Oak bark (cortex Quercus)
Alder cones (fructus Alni)
St John's wort (herba Hyperici)
Vaccinium myrtillus/ European blueberry (fructus Myrtilli)
Bidens tripartita / Three-lobe Beggarticks / Three-part Beggarticks
(herba Bidentis)
Salvia leaves (folia Salviae officinalis)
Matricaria Chamomilla / Chamomile flowers (flores
Chamomillae) Rotocanum
II. Drags of nonorganic origin (salts of metals):
Bismuthi subnitras
III. Combined drugs:
Vicalinum
Vicair
Alcidum
Mechanism of action of astringents is associated with precipitation of tissue

proteins in their contact with the mucous membranes or damaged skin to form a
dense film of circulating albuminates, which protects the sensitive nerve endings in
tissues from the influence of irritating agents. It reduces or stops pain sensitivity.
Founded membrane is shrinked, it takes less surface and mechanically compresses
blood vessels, resulting in capillary walls are compacted, their lumen is narrowed,
exudation is reduced, bleeding is stopped, enzyme activity in the tissues are
reduced, the formation of inflammatory mediators is slowed, and thus anti-
inflammatory action of astringents is implemented. Antimicrobial action of them
due to the fact that the dense protein membrane protects the tissue against the
penetration of microorganisms and denaturation of protein structures of microbes
leads to the violation of metabolism of microbial cells and bacteriostatic effect.
Pharmacological characteristics of Astringents
Tannin (Taninum) is used as an astringent and local anti-inflammatory

drugs in inflammatory processes of the mouth, nose, throat as a rinse and as a
lubricating in burns, ulcers, fractures, bedsores. It is forbidden to use of tannin
inside (as oral and rectal) through its interaction with proteins of the mucous
membrane of the digestive tract, indigestion, of thrombosis in the cracks of the
rectum. Tannin forms stable insoluble compounds with salts of alkaloids, heavy
metals, but with some alkaloids (morphine, cocaine, atropine, nicotine,

physostigmine) tannin forms unstable compounds. Thus, tannin (0.5% aqueous
solution) is used for gastric lavage in poisonings be substances listed above.
Oak bark (cortex Quercus) in the form of decoctions has astringent and
tannic characteristics; it has the ability to denature proteins, providing anti-
inflammatory effect in the external and internal use. An oral decoction of Oak bark
enhances motility of the stomach and reduces its secretion, reduces the enzymatic
activity and gastric acidity, slows absorption of the mucous membrane with respect
stomach contents. All parts of this plant have a disinfecting effect. Gallic acid and
its derivatives have effect, similar to the effect of bioflavonoids: compact vascular
tissue membranes, increase their strength and reduce permeability, also have
antiradiation property and antihemorrhagic property. Antimicrobial and
antiprotozoal actions are associated with both gallic acid derivatives, and to the
presence of oak bark catechins. Oak bark reduces sweating, binds cations.
Indications: stomatitis, gingivitis, tonsillitis, halitosis, burns, frostbite, infected
wounds, sores, blisters, sweating feet, hemorrhoids. In folk medicine, a decoction
of oak bark is used to treat diarrhea, dysentery, gastric ulcer and duodenal ulcer,
bleeding from the digestive tract, hemorrhoids, polymenorrhea, mushroom
poisoning, copper salts poisoning. Contraindications: hypersensitivity.
Alder cones (fructus Alni) have astringent, disinfectant, anti-inflammatory,
desensitizing and hemostatic properties. Indications: acute and chronic enteritis,
enterocolitis, colitis, dyspepsia. Contraindications: idiosyncrasy. Not
recommended for use for children under 5 years.
St John's wort (herba Hyperici) has astringent, anti-inflammatory and mild
antibacterial activity, it accelerates tissue regeneration, stimulates the secretion of
bile and gastric juice. Indications: externally prescribed for the prevention and
treatment of oral inflammation (gingivitis, stomatitis), and internally in the liver
diseases and bile ducts diseases (biliary dyskinesia, chronic hepatitis, cholecystitis)
and in diseases of the GIT, accompanied by diarrhea and flatulence (acute and
chronic colitis, gastritis with secretory insufficiency). Contraindications:
idiosyncrasy.
Vaccinium myrtillus/ European blueberry (fructus Myrtilli) have
astringent, antiseptic, anti-inflammatory (in diarrhea, enterocolitis), hypoglycemic,
haemostatic, restorative, detoxification, multivitamin, anti-anemic actions.
Indications: diarrhea, gout, rheumatism, diabetes mellitus, weak twilight vision,
hemorrhoidal bleeding. In folk medicine, a decoction of the fruit is used in pyelitis,
cystitis, urethritis, kidney stones and gallstones, atony of the bladder, stomach
ulcers, intestinal colic and hemorrhoids (astringent, diuretic, uroseptyc actions),
also in case of rheumatism, gout, psoriasis, mouthwashes for treatment of
stomatitis, pharyngitis, tonsillitis; it is used externally for treatment of eczema,
dermatitis, burns. Blueberry Shoots have hypoglycemic properties and are used in
milder forms of diabetes mellitus. Contraindications: hypersensitivity.
Bidens tripartita / Three-lobe Beggarticks / Three-part Beggarticks
(herba Bidentis) has astringent, enveloping and antacid properties, it reveals a
diuretic, diaphoretic, anti-inflammatory, anti-allergic, antibacterial and choleretic

effect, improves digestion, normalizes impaired metabolism, lowers BP.
Indications: internally it is used in diseases of the urinary system, catarrhal
diseases (acute respiratory infections, flu, etc..); externally it is used in pediatric
patients with diathesis, allergic skin diseases, pyoderma, psoriasis, eczema, atopic
dermatitis and other skin diseases. Contraindications: individual intolerance to
substances contained in the medicinal product. Allergic reactions are possible
(rash, itching, redness and swelling of the skin).
Salvia leaves (folia Salviae officinalis) possess astringent, enveloping and
antacid properties. Indications: Salvia leaves are used for treatment of stomatitis,
gingivitis, tonsillitis, ulcerative processes of the mouth, inflammation of the upper
respiratory tract and skin, light burns and frostbite, as well as gastritis and gastric
ulcer and duodenal ulcer with secretory insufficiency and low acidity of gastric
juice. Side effects: at high individual sensitivity to local Salvia may develop
allergic reactions (redness, itching and swelling of the skin). In lactating women
Salvia can inhibit lactation. Contraindications: Salviae is contraindicated in
hypersensitive to biologically active substances (BAS) contained in it. Internal use
of Salvia drugs are contraindicated in inflammatory kidney diseases and in patients
with a strong cough and in young children and in women during lactation. Children
aged from 1 to 12 years and women who are breastfeeding, Salvia is prescribed
only for external use.
Matricaria Chamomilla / Chamomile flowers (flores Chamomillae) have
astringent, antispasmodic, anti-inflammatory, aseptic, sedative and some analgesic
activity. Infusion of Chamomile when taking increases the secretion of digestive
glands, has a choleretic effect, inhibits fermentation, and relieves spasms of the
intestine. Mechanism of spasmolytic action is explained by M-cholinolytic
properties of plant glycosides. Chamomile essential oil strengthens and deepens
breathing, accelerates heart rate, dilates blood vessels of the brain, and has
disinfectant and anti-inflammatory properties due to the presence of a
chamazulene. Preparations of Chamomile accelerate the regeneration of the
epithelium in experimental ulcers and delay the development of experimental
inflammation.
Rotocanum has a local astringent, anti-inflammatory, antiseptic action,
promotes regeneration of damaged mucosa, and has haemostatic properties. Apply
in dental practice in adults with inflammatory diseases of the mouth mucous
membrane (aphthous stomatitis, periodontal disease, ulcerous-necrotic gingivitis
and stomatitis) and in gastroenterology. Possible side effects – there are allergic
reactions. Contraindications: hypersensitivity to the components of Rotocanum.
Bismuthi subnitras has astringent, and skin-protective, antimicrobial,
absorbent, antacid, anti-inflammatory properties. Bismuthi subnitras coagulates the
proteins to form dense albuminate membranes on the surface of the mucous
membrane of the digestive tract, has vasoconstrictor effect, reduces local
inflammation, and inhibits the growth and development of Helicobacter pylori.
Intensity of antacid action is low. Drugs are used in inflammatory diseases of the
skin and mucous membranes (dermatitis, ulcers, erosions, eczema), for the
treatment of gastro-duodenitis, gastric ulcer and duodenum ulcer, reflux
esophagitis, enteritis, colitis. Side effects: headache, swelling of the eyelids and
gums, vesicles and pigmentation on the tongue, nausea, vomiting,
methemoglobinemia. Interaction: Bismuthi subnitras is compatible with
cholinolytic, antispasmodic agents – often used for stomach ulcers and duodenal
ulcers. It is not compatible with tetracyclines through the formation of complexes
that are not absorbed. Limitations for use are hypersensitivity and renal failure.
Vicalinum has astringent, antacid, laxative and antispasmodic action.
Magnesium carbonate and sodium bicarbonate reduce gastric acidity and pepsin
activity. Bismuth subnitrat forms a protective membrane on the mucosa of the
stomach, and has anti-inflammatory, antibacterial, restorative effects. Acorus
calamus and Khellin which are contained in the Vicalinum, have antispasmodic
action, and Frangulae – laxative action. Indications: peptic ulcer and duodenal
ulcer, hyperacidic gastritis. Side effects: may be diarrhea, allergic reactions.
Contraindications: hypersensitivity to the components of Vicalinum, hypoacidic
gastritis, renal failure.
Vicair has astringent, antacid, laxative and antispasmodic action.
Magnesium carbonate reduces gastric acidity and pepsin activity. Bismuth
subnitrat forms a protective membrane on the mucosa of the stomach, reveals anti-
inflammatory, antibacterial, restorative effects. Acorus calamus and Frangulae are
contained in Vicair; commit at first – antispasmodic action, and at second –
laxative action, thus contributing to the improvement of the intestinal passage.
Indications: gastric ulcer and duodenal ulcer, hyperacidic gastritis with a tendency
to constipation. Side effects: diarrhea, allergic reactions. Contraindications:
hypersensitivity, hypoacidic gastritis, chronic renal failure, infancy. Interaction
with other drugs: in patients receiving M-cholinoblockers or H2 histamine
receptors blockers the need to use Vicair is reduced; it reduces absorption of
tetracyclines; in combination with other drugs that keep bismuth, Vicair increases
the concentration of bismuth in blood.
Alcidum has antiulcer effect due to Glycyrrhizae spissum and Chamomile
blossoms; antacid action – through alkaline magnesium carbonate, aluminum
hydroxide, sodium bicarbonate; subnitrat bismuth as a part of this drug has
astringent, antiseptic and absorbent effects; aluminum hydroxide has antacid effect
and it has absorbent and astringent properties, at the same time forming a
protective layer on the gastric mucosa, resulting in reduced acidity and peptic
activity of gastric juice; alkaline magnesium carbonate and Buckthorn bark
provides a laxative effect for constipation that can occur under the influence of
bismuth subnitrat and aluminum hydroxide. Alcidum is used for the treatment of
gastric ulcer and duodenal ulcer in the acute stage, acute and chronic gastritis. Side
effects: painting stool in gray-black. Contraindications: severe renal impairment;
the control of plasma electrolytes is needed; it is not compatible with antibiotics
through a decrease in their absorption.
Table 33. Medicinal forms of Astringents

Tannin Tanninum Powder;
Alcohol solution for 4% - 25 ml
topical use
Cortex Quercus Shredded raw material 100.0
in packages;
Broth; Powder;
Gathering
Fructus Alni Shredded raw material 40.0, 50.0, 100.0

in packages
Herba Hyperici Raw material in boxes; 30.0, 100.0;
In briquettes;
Tincture in flacons 75.0;
25-100 ml
Fructus Myrtilli Raw material in 100.0
cardboard boxes
Herba Bidentis Shredded raw material 50.0, 75.0, 100.0;
in packages;
In briquettes;
In filter-packages 75.0;
2.0
Folia Salviae officinalis Shredded raw material 1.0, 5,0;
in filter- packages;
Alcohol solution in
flacons for external use; 1%-10 ml;
Shredded raw material
in filter- packages
50.0
Flores Chamomillae, Shredded raw material 0.5;
in
filter- packages,
packages; 50.0, 100.0, 150.0,
200,0;
Azulan; The liquid extract in
flacons; 25 ml;
flores Chamomillae + Babynos The liquid extract in 30 ml
semen flacons
Foeniculum vulgare +
semen Coriandrum
sativum (0,6:1:1)
Calendulae officinalis Rotocanum The liquid extract in 25 ml, 50 ml,
floridis extract + bottles 110 ml
Chamomillae recutitae
floridis extract + Achillea
millefolii herbae extract
(2:1:1)
Chapter 9. | 185
Sorbents, covering drugs, astringents
Bismuthi subnitras Substance powder; 25 kg;
Ointment 10%-25.0
Bismuth subnitrate + Vicalinum Tablets
Magnesium carbonate +
Sodium hydrocarbonate
+ Calami rhizomata +
Frangulae cortex +
Rutoside + Khellin
Bismuth subnitrate + Vicairum, Tablets
Magnesium carbonate + Vicair
Sodium hydrocarbonate +
Calami rhizomata +
Frangulae cortex
Extractum Glycyrrhizae Alcidum Tablets
spissum + Extractum
Chamomilla recutita +
Alkaline magnesium
carbonate + Aluminum
hydroxide + Sodium
bicarbonate + Bismuth
subnitrate + Frangulae
cortex + fructus Coriandri
+ fructus Foeniculi
Irritants contain substances that are readily soluble in fats, easily penetrate
the skin, mucous membranes and irritate nerve endings. This is followed by the
arrival of nerve impulses in different parts of the central nervous system and the
emergence of relevant reflex reactions, changing the function of various parts of
the nervous system, including the vital centers (respiratory and vasomotor) of
medulla oblongata, hypothalamus, where the formation of enkephalins, which
reduce the intensity of pain. Local reactions arise in place of irritation of skin or
mucosal. There are: redness as a result of the expansion of arterioles and
capillaries; swelling as a result of penetration of plasma through the capillary walls
into the surrounding tissue; tingling, burning, heat from the impact of Irritants and
tissue BAS on sensitive nerve endings. In other words, the occurrence of local
reactions is explained by reflex reactions, including axon-reflexes, i.e. reflexes that
are closed within the peripheral sensory nerve fibers. These reflexes begin in
cutaneous receptors; they are distributed via sensory nerve fibers and in fibers that
innervate arterioles, and causing their extension. The products of decomposition
(BAS: histamine, serotonin etc.) that are released from the tissue during application
of Irritants to the skin or mucosa, leading to chemical and mechanical tissue
damage. Thereby, the local reaction is explained by neural and humoral factors and
is used in the treatment of subacute and chronic joint disease, myositis, neuralgia,
and neuritis of peripheral nerves, because vasodilation and increased blood
delivery of nutrients lead to activation of metabolic processes in inflammatory
tissues, acceleration of washout of products of inflammation, i.e. to the anti-
inflammatory effect.
Chapter 10. Irritants
Classification of Irritants
I. Drugs of plant origin:
Drugs that contain essential oils:
Folia Menthae piperitae
Menthol
Menthol solution in menthyl isovalerate (Validolum)
Folia Eucalypti viminalis
Semen Sinapis
Fructus Capsici
Extract Salviae sclareae (Salmus)
Oleum Terebinthinae rectificatum
Spiritus Acidi formici
Bitterness:
Tinctura amara
Herba Centaurii
Herba et folia Artemisiae absinthii
Succus Plantaginis
Radices Taraxaci
Folia Menyanthidis trifoliatae
Rhizomata Calami
II. Synthetic drugs:
Chloroform
Finalgon
Solutio Ammonii caustici 10%
III. Drugs that contain venoms of bees and snakes:
Apiphor
Apisartron
Ungapiven (Bees venom)
Vipraxin pro injectionibus
Najaxin
Viprosal
Nizhvisal
Thus, Irritants have folloving Pharmacological effects:

Local irritanting effect due to release of BAS, vasodillatation, exudation, and
 improvement of microcirculation
Analgesic effect is explained by the fact that:
the interference of pain impulses from the affected organ and the site of
application of irritating substance in segments of the spinal cord, that
eliminates the dominant focus of the pathological process, hyperalgesia, and
muscle tension;
washout of BAS from the area of skin irritation, rising flow of afferent
impulses that affect the brain, alter the metabolism of neurotransmitters,
Chapter 10. Irritants | 187
promote the release of antinociceptive factors (β-endorphins, enkephalins,

and others);
reduction of liberation of pain mediators (substance P, somatostatin,
cholecystokinin);
increase of the secretion of hypothalamic releasing hormone, ACTH,
thyroid-stimulating hormone, increased secretion of glucocorticoids;
inhibition of inflammatory response;
pain impulses from the area of skin irritation entering the rear horn
segments of the spinal cord, they switch on the side horn segments of the
spinal cord, excite cores of preganglionic sympathetic nerve fibers;
sympathetic impulses improves blood flow to the lungs, skeletal muscles,
reduces inflammation
Stimulatory effect on the vital centers (respiratory and vasomotor) of
 medulla oblongata that leads to deepening of respiration and increase BP
Expectorant effect through glands of the bronchial mucosa
Antiviral and immunostimulatory effects as a result of increase of
 interferone synthesis
Trophic effects as a result of application of Irritants on the skin i.e. the
change of metabolism in the defined tissues. For spinal cord segmental
structure and innervation is characterized: one segment innervates internal
organs and the corresponding area of the skin. Projection areas of the
internal organs on the skin surface are called zones of Zakharyin-Head and
irritating effect of Irritants the relevant areas of the skin causes cutano-
visceral reflexes leading to vasodilatation in the corresponding internal
organ, improves its blood circulation, promotes washout of degradation
products and toxins that is manifested in anti-inflammatory effect. This
mechanism underlies the treatment of inflammatory diseases of the
respiratory tract via chafing and the use of mustard plasters
A distracting effect: the flow of impulses in the CNS from arteficial fire (due
to action of irritants) reduces the flow of impulses from the pathological
focus and thus anesthesia comes. Perhaps that BAS from pathological focus
reflexively influence on the hypothalamus and stimulate the synthesis of
enkephalins, which reduce the intensity of pain. This effect of irritating
drugs is used in the treatment of angina pectoris (stenocardia), arthritis and
 other diseases associated with pain syndrome
Reflectory redistribution of blood, restoration of normal blood delivery of
organs and tissues of the body. Thus, application of mustard plasters on the
foot contributes to reduction of cerebral blood delivery in case of
hypertensive crisis, as a result it diminishes risk of stroke, on occasion of
catarrhal diseases it promotes vasodilatation in respiratory tract and
improves their trophy, that allow to use Irritants for treatment of bronchitis
and pneumonia.
Pharmacological characteristics of Irritants
Folia Menthae piperitae (Peppermint leaves) contain essential oil,

flavonoids, ursolic acid and oleanolic acid, betaine, carotene, hesperidine, tannins,
organic acids, trace elements (microelements). This complex of BAS has
choleretic, sedative and weak hypotensive effects. Drugs with peppermint leaves
enhance the secretion of digestive glands, stimulate the appetite, inhibit the
processes of decay and fermentation in GIT, reduce smooth muscle tone of the
intestine, bile duct and urinary tract, increase the secretion of bile. Indications: in
the treatment of GIT diseases (nausea of various origins, intestinal colic,
flatulence, gastrointestinal spasms); liver diseases (cholecystitis, hepatitis,
cholangitis, cholelithiasis); as a light sedative agent. Side effects: inefficient use of
peppermint leaves can cause pain in the heart; in some cases may manifest allergic
reactions (urticaria, pruritus, contact dermatitis). Contraindications:
hypersensitivity to BAS, which are included in the drugs; spasmophilia, croup,
asthma; children under 3 years.
Menthol is obtained from mint oil; it stimulates receptors in the mucous
membranes, skin and subcutaneous tissue. Inunction it into the skin and application
to the mucous membranes causes irritation of nerve endings, which is accompanied
by a feeling of cold, mild burning and tingling. Menthol has a local analgesic
effect, weak antiseptic properties. Indications: externally it is prescribed as an
analgesic (distracting) remedy for treatment of neuralgia, myalgia, arthralgia, in
case of itching dermatoses, as well as it is used in migraine, inflammatory diseases
of the upper respiratory tract (rhinitis, pharyngitis, laryngitis, tracheitis etc.).
Menthol is prescribed inside as a sedative agent, often in combination with tincture
of Valerian, Belladonna; sometimes – in mild forms of angina pectoris due to the
possibility of Menthol reflexively cause expansion of coronary vessels through
stimulation of the receptors of oral mucosa. Side effects: possible reflex apnea on
occasion of nasal lubrication by Menthol in small children. Contraindications:
small children.
Menthol solution in menthyl isovalerate (Validolum) stimulates receptors
of mucous membranes, has a calming effect on the CNS, has a moderate reflex
vasodilating properties. Validolum is used to relieve mild attacks of stenocardia, in
case of neuroses, hysteria, also as antiemetic in sea and air sickness. Adverse
reactions: rarely occurs slight nausea, watery eyes, dizziness, that disappear on
their own.
Folia Eucalypti viminalis (Eucalyptus leaves) exhibit antibacterial,
antiviral, antifungal, antiprotozoal and anti-inflammatory effects. The degree of
manifestation of these effects depends on the content of essential oil. At oral
administration of eucalyptus leaves cause expectorant, mucolytic, broncholytic
effects, when it is applied to the skin – astringent, antiexudative, antipruritic,
anesthetic effects, and in high concentrations – local irritating action. Infusion of
the Eucalyptus leaves due to the presence of essential oil and a small amount of
bitterness in the structure stimulates the secretion of digestive glands, improves
digestion. Oral infusion of Eucalyptus leaves has sedative effect due to aldehyde of
isovaleric acid. Chlorophyllipt that is contained in the leaves of Eucalyptus, has
antimicrobial, especially antistaphylococcal activity, stimulates regenerative
processes. Components of essential oil with organic acids, tannins and trace
elements as manganese, zinc, selenium, increases the resistance of body tissue to
hypoxia of different origin. Indications: in combined therapy for acute and chronic
infectious and inflammatory processes of different localization: rhinitis, stomatitis,
gingivitis, laryngitis, bronchitis, pneumonia, hypersecretion of stomach glands,
enterocolitis, goiter, cholecystitis, pielonephritis, vaginitis, colpitis, cervical
erosion, burns, dermatitis, sciatica (radiculitis), neuritis, myositis, trophic ulcers,
nervous disorders, mild form of insomnia, low back pain. Side effects: possible
allergic reactions; in high doses – nausea, vomiting, diarrhea, muscle cramps; in
case of frequent inhalation use – dry mucous membranes of the respiratory system.
Contraindications: hypersensitivity to the components of Eucalyptus, atrophy of
the mucous membranes of the respiratory tract. Warning: it is not desirable to use
Eucalyptus at elevated secretion of digestive glands, to avoid the the contact of the
drug with eyes, before applying to check sensitivity to Eucalyptus by its smell.
Semen Sinapis (Mustard seeds) are rich in fatty oils (oleic, erucic, stearic
and linolenic acids), steroids (brassicasterol, campesterol, sitosterol, cholesterol,
metylenholesterol) thioglycoside sinalbin, saponins, and glycoside sinigrin.
Traditional medicine recommends the use of Mustard seeds to enhance the
functions of GIT, for the treatment of arterial hypertension, atherosclerosis,
diseases of liver and gall bladder, digestive disorders, neuralgia, rheumatism,
pneumonia, bronchitis, gout, hemorrhoids. Mustard seeds are also used as a
laxative and to reduce fever. The Official medicine uses mustard plasters which are
made of mustard powder, they are well warmed, facilitate breathing, promote
blood flow in space applications. For this purpose they are used in pneumonia,
bronchitis, rheumatism, angina pectoris, hypertensive crisis, the risk of stroke.
Contraindications: tuberculosis, kidney diseases. Caution should be exercised to
use large doses of mustard, which can lead to shortness of breath, bradycardia and
even loss of consciousness. It is undesirable to use high doses of mustard in
patients with hyperacidic gastritis, stomach and duodenal ulcers, acute
enterocolitis. Given the fact that Mustard is a poisonous plant, you need to consider
its dosage carefully.
Fructus Capsici (fruits of Cayenne pepper) have a distracting and irritant
effect. Apply externally for rubbing in case of neuralgia, radiculitis, myositis,
lumbago, rheumatic pains in the joints, to treat frostbite. Alcohol tincture of fruits
of Cayenne pepper is used to excite the appetite, has antibacterial properties so it is
useful in acute disorders of GIT. There is evidence of antiviral activity of fruits of
Cayenne pepper. In addition, fruits of Cayenne pepper are multivitamin
concentrate and they particularly rich in rutin and ascorbic acid, thus positively
affect metabolism, and make it easier during of radiation sickness. Side effects: for
external use, itching and flaking of the skin are possible. Warning: cannot be
applied to damaged skin, mucous membranes. Contraindications: hypersensitivity,

gastric and duodenal ulcers, acute and chronic gastritis, colitis, enteritis, hepatitis,
cholecystitis.
Extract Salvia sclarea (extract of Clary sage, Salmus) has a local anti-
inflammatory, antiseptic and local irritanting action, improves tissue trophic, has
analgesic effects on receptors of sensory nerves, and reduces sweating.
Indications: it is used as bathes, as reflex distracting agent for treatment of the
peripheral nervous system diseases (mononeuritis, polyneuritis, sciatica, lumbago,
in case of recovery period after injury), for treatment of CNS diseases
(neurasthenia, fatigue); diseases of the muscular and skeletal systems (rheumatoid
arthritis, primary deforming osteoarthritis, spondylosis, bursitis, restricted
movement of joints). Side effects: balneology reactions (asthenia, palpitations,
dizziness, headache, tachypnea, tachycardia, increased BP), allergic reactions.
Contraindications: hypersensitivity; asthma; diabetes mellitus (severe course);
tuberculosis; expressed heart failure; vascular crises; expressed atherosclerosis of
the vessels of a brain, heart, kidneys; coronary artery disease; skin diseases (acute
phase); cancer; rheumatoid arthritis (active phase).
Oleum Terebinthinae rectificatum (oil of turpentine, Turpentine) is
applied externally as distracting and irritating agent. When applied to wounds and
ulcers in weak concentrations it contributes to their healing, activating of
granulation, improving blood circulation, acting as antiseptic; Turpentine promotes
blood clotting; if it was introduced subcutaneously Turpentine oil causes aseptic
abscess, which is used for exacerbation of chronic processes; in case of resorptive
action Turpentine oil moderately stimulates the CNS, stimulates respiration,
improves reflex excitability. Indications: for aggravation of chronic diseases; as an
expectorant, antiseptic, anti-inflammatory agent, as well as laxative and anti-
fermentative agent. Side effects: in patients with hypersensitivity to Turpentine
may occur local allergic reactions (itching, swelling, and redness, burning, rash); in
some cases may occur generalized allergic reactions (dyspnea, palpitations,
decreased BP, dizziness, seizures, loss of consciousness). Contraindications:
severe kidney and liver diseases and skin diseases of various origins. Caution: do
not allow to enter Turpentine ointment on mucous membranes and eyes. If the
ointment accidentally gets in the eyes, you should rinse thoroughly them with
plenty of running water. Not recommended for use in children. It is not known
whether Turpentine penetrates into breast milk or pass through the placenta during
pregnancy because Turpentine for pregnant and lactating women is not
recommended.
Spiritus Acidi formici (1.4% formic acid in 70% or 96% ethyl alcohol) has
bactericidal, local irritanting, anti-inflammatory, analgesic actions, it dilates blood
vessels, improves blood circulation in the tissues. Indications: arthritis, arthralgia,
myalgia, neuralgia, to treat acne. Side effects: local allergic reaction.
Contraindications: oral administration, applying to the mucous membranes and
damaged skin.
Tincture amara (bitter tincture) has properties inherent in its components.

Tincture amara is used to stimulate appetite, improve digestion.
Herba Centaurii (grass of Centaury) increases appetite, secretion of gastric
juice, accelerates GIT motility, has a mild laxative effect and has anthelmintic
properties. Indications: decreased appetite, indigestion (burping, nausea, vomiting,
flatulence), atonic constipation, hepatitis, cholecystitis, the recovery period after
severe infections, helminthiasis (infestation by whipworm). Side effects: possible
allergic reaction. Contraindications: gastric and duodenal ulcers, hypersensitivity
to Herba Centaurii. Grass of Centaury is part of the combined herbal preparations
Canephron and Bittner Balsam.
Herba et folia Artemisiae absinthii (grass and leaves absinthe Wormwood)
stimulate the function of the GIT glands, increase the secretion of gastric juice,
bile, exhibit anti-inflammatory, antiseptic properties. Indications: it is used as a
bitter for stimulation of appetite and improve digestion, increase of secretory
activity in patients with decreased secretion of the stomach. Side effects are not
established. Contraindications: cholelithiasis; are not recommended for children
under 12 years and for women during pregnancy and lactation.
Succus Plantaginis (Plantain juice) has anti-inflammatory, analgesic,
wound healing, haemostatic, ants-allergic effects; it stimulates secretion and
regulates digestion, increases appetite. Indications: anorexia, gastritis with
decreased secretion, functional dyspepsia which occurs on a background of low
gastric acid secretion. Side effects: allergic reactions. Contraindications:
hypersensitivity to the components of Plantain juice, children under 12 years,
increased acidity of gastric juice, stomach and duodenal ulcers. Disclaimer: it is
used only in cases of low or normal stomach acidity; pregnant and lactating women
can use the drug with Plantain juice only if the benefits of the use outweigh the
potential risk. The interaction of Plantain juice with antacids and H2-blockers
reduce the effectiveness of the drug last.
Radices Taraxaci (Dandelion roots) in folk medicine is used as drugs to
increase appetite and stimulate digestion, reducing putrefactive and fermentative
processes in the digestive tract. Bitterness that is contained in Dandelion root,
irritates taste buds and stimulates the reflex secretion of gastric juice. Dandelion
root tincture is useful for cholelithiasis, hypoacidic gastritis and chronic
constipation, also as an expectorant for treatment of respiratory diseases, as
sedative and hypnotic – in disorders of CNS, for treatment of kidney diseases,
spleen, gall bladder (as cholagogue) diseases, and hemorrhoids. As part of the
mixed teas Dandelion root is used to treat early stages of diabetes mellitus
(moderately reduces blood glucose levels), it improves metabolism, and it has anti-
atherosclerotic properties. External infusion of Dandelion root is rubbed in the skin
for treatment of acne, boils (furuncles), medicamental dermatitis. Powder
Dandelion root improves wound healing, burns, ulcers. Studies revealed
antituberculosis, antiviral, fungicidal, antihelmintic, anti-cancer activities of
Dandelion. Caution: not recommended the use of drugs with Dandelion root for
acute conditions with occlusion of the biliary tract; carefully – in hyperacidic
gastritis, stomach and duodenal ulcers. Side effects: in large doses Dandelion root
can cause vomiting and diarrhea. Contraindications: individual intolerance.
Folia Menyanthidis trifoliata (leaves of Menyanthes trifoliata, Bog-bean,
Buckbean) contain bitter that irritates taste receptors of the mucous membranes of
the mouth and tongue, reflexes an increase of the secretion of gastric glands,
improves appetite, and digestion. Leaves of Bog-bean have also antiseptic and
antipyretic effects. It is applied at hypoacidic gastritis, constipation, flatulence, for
the treatment of headaches, trigeminal neuralgia, rheumatism, diseases of the liver
and gall bladder, dysentery, pulmonary tuberculosis, scurvy, fever, malaria,
dyspepsia, migraine, helminthiasis; in dentistry – for treatment of periodontitis,
stomatitis, gingivitis, toothache; external leaves of Bog-bean are used as an
antiseptic for the wash of venous (trophic) ulcers, wounds that heal poorly,
diseases of the skin and mucous membranes.
Rhizomata Calami (Calamus rhizome, rhizome of Acorus calamus, rhizome
of Sweet Flag, Calamus, rhizome of Beewort) in official medicine is used for
gastritis with low acidity, to improve appetite and digestion, in case of
cholecystitis, colic, diseases of kidney and urinary bladder; also it is used as an
expectorant, disinfectant and antiflatulent; Calamus rhizome is used for treatment
of diseases of the male and female reproductive organs, thyroid disease, diabetes
mellitus, acute respiratory diseases, besides as a sedative agent in patients with
mental illness; in dentistry – to treat periodontal diseases, stomatitis, pharyngitis,
and tonsillitis;. Calamus rhizome in the form of baths is also used in children with
rickets and eczema and in adults with violation of the peripheral circulation.
Contraindications: pregnancy, increased acidity of the stomach, and acute
exacerbation of chronic gastric ulcers, nasal bleeding, acute inflammation of the
kidney diseases, and arterial hypertension. In large doses it can cause vomiting.
Chloroform in modern medicine is used externally due to the presence
irritating activity on the skin for rubbing in patients with neuralgia, myositis
(usually mixed with methyl salicylate, turpentine and other irritating agents). Very
rarely chloroform in mixture with tincture of Valerian may be appointed in case of
vomiting, hiccups, and as antismoke mixture (solution of ammonia and ethanol) in
patients with lesions of the respiratory tract by irritant arsines (organic arsenic
compounds).
Finalgon contains in its composition Nonivamide and Nicoboxil.
Nonivamide is a synthetic analogue of Capsaicin; it has analgesic effect by
stimulating peripheral nociceptive nerve fibers when applied to the skin. Nicoboxil
reveals a direct vasodilatative action, accelerates enzymatic reactions, activates
metabolism; vasodilation leads to hyperemia, improves blood circulation in the
tissues, thus achieving a warming effect. Indications: arthritis, myalgia, arthralgia,
sports injuries, bruises and injuries of ligaments, lumbago, neuritis, bursitis,
tenosynovitis, violations of peripheral blood circulation (in the complex therapy).
Side effects: allergic reactions, excessive redness and burning of the skin, irritation
at the site of application of the drug. Contraindications: hypersensitivity,
dermatitis, open wounds, the skin with impaired permeability, causing the skin in
the neck, abdomen and inside thighs, drawing on the mucous membranes;
pregnancy and lactation.
Solutio Ammonii (solution of Ammonia caustic) 10% operates in the field
of sensory (afferent) nerve endings, inhalation of it reflex stimulates the respiratory
center due to the effects on receptors of the upper airway (endings of trigeminal
nerve); when it is taken inside has emetic effect. Indications: solution of Ammonia
caustic is used for excitation breath in patients with loss of consciousness, for call
vomiting; externally – in the form of lotions it is used in patients with insect bites;
in surgical practice – it is used for hand washing. Side effects: in large doses
solution of Ammonia caustic causes reflex stop of breathing. Caution: when it is
taken inside can only be used in diluted form because of the high risk of burns of
the esophagus and stomach. When using ammonia solution should be wary of
getting vomit into the respiratory tract.
Apiphor – tablets for making solution for external use, or rectal
suppositories and ointment containing lyophilized bee venom. Apiphor is used for
electrophoresis in the treatment of arthritis, myositis, deforming spondylarthrosis,
sciatica, peripheral vascular diseases (endarteritis, thrombosis without purulent
process), keloid scars after burns and operations; and rectal suppositories of
Apiphor is used for treatment of metabolic disorders, diabetes mellitus, conditions
after stroke and myocardial infarction, arrhythmias, angina, coronary artery
disease, atherosclerosis, arterial hypertension, furunculosis, radiculitis,
hemorrhoids, to improve the condition of rectal mucosa, in diseases of the genital
and urinary systems, pathological menopause, infertility, for regulation of
menstrual cycle. Side effects: may be hives, runny nose, severe itching, sneezing,
chills, headache, nausea, vomiting, flushing, edema, pyrexia, pain, itching at the
site of application. Contraindications: individual intolerance, decompensated liver
and/or kidney failure, pancreatitis, blood diseases, mental illness, adrenal
insufficiency, chronic heart failure of I-II degrees, diabetes mellitus, cancer,
cachexia, sepsis, acute purulent diseases, tuberculosis and other infectious diseases
in the acute stage, and pregnancy. Caution: during treatment by this drug the status
of skin and kidney function drug should be monitored; it must be used with caution
during menstruation, in childhood or old age; after rubbing wash the hands
thoroughly.
Apisartron – ointment containing bee venom, methyl salicylate, allyl
isothiocyanate, emulsifiers, Vaseline and water; it has a local irritating effect due
to stimulation of peripheral nerve endings, reveals a direct vasodilating effect,
which leads to improvement of blood supply to the tissues, accelerates the decay of
products of metabolism that cause pain; and methyl salicylate, allyl isothiocyanate
cause flushing of the skin, providing soothing and warming effects. Apisatron
helps to enhance metabolism, to increase the elasticity of the connective tissue and
muscles, reducing muscle tone. This drug is used for rubbing in rheumatism,
myalgia, neuritis, neuralgia, disturbance of peripheral circulation, pain syndrome in
injuries of muscles, tendons, ligaments, in bruises and sprains, to warm up the
muscles before and during exercise. Side effects: possible allergic reactions.
Contraindications: individual intolerance, chronic renal failure, liver disease, skin

tumors, inhibition of hematopoiesis, mental illness, acute arthritis, children under
12 years. Disclaimer: Apisatron should not be applied to damaged skin, avoid
contact of the drug with the eyes, mucous membranes and open wounds.
Ungapiven (Bees venom) – ointment with bee venom, which has anti-
inflammatory, local irritating, analgesic effects and stimulates the endocrine and
immune systems, and is used as an analgesic and anti-inflammatory drug for
treatment of arthritis, arthrosis, osteochondrosis, radiculitis, myalgia, myositis,
lumbago, peripheral vascular disease, keloid scars after burns and operations. Side
effects: possible allergic reactions, chills, headache, nausea, vomiting, redness,
swelling, pain at the site of application. Contraindications: individual intolerance,
decompensated liver and/or renal failure, chronic heart failure of I-II degrees,
diabetes mellitus, cancer, cachexia, sepsis, acute purulent diseases, tuberculosis
and other infectious diseases in the acute stage, and pregnancy. Disclaimer: this
drug must be used with caution during menstruation, in childhood or in elderly, it
can not be applied to damaged skin, avoid contact with eyes, mucous membranes
and open wounds; after rubbing the hands should be thoroughly washed; during the
application one should monitor the renal function and skin condition.
Vipraxin pro injectionibus contains poison of adder (Vipera berus L.) and
is used as an analgesic and anti-inflammatory agent in case of neuralgia, arthralgia,
myalgia, chronic non-specific mono- and polyarthritis, myositis. Side effects: may
occur allergic reactions, pain at the injection site. Contraindications: individual
intolerance, tuberculosis, fever, cachexia, cerebral insufficiency and/or coronary
circulation insufficiency, heart diseases, predisposition to angiospasm, organic
liver and kidney diseases, pregnancy, lactation. Disclaimer: given the fact that this
drug is thermolabile the syringe must be cooled to prevent loss of drug activity.
Najaxin is clear, colorless liquid that contains poison of central asian cobra,
procaine and sodium chloride and is used for the relief of pain in the case of
sciatica, neuralgia, neuritis of various origins. Najaxin increases the effects of
opioid analgesics and local anesthetics. Side effects: possible allergic reactions.
Contraindications: individual intolerance, tuberculosis, fever, cachexia, cerebral
insufficiency and/or insufficiency of coronary circulation, heart diseases,
predisposition to angiospasm, organic liver and kidneys, pregnancy, lactation.
Viprosal is ointment with poison of adder, with the addition of camphor,
salicylic acid, Turpentine oil, Vaseline, glycerine, emulsifier and water. Viprosal
has local irritating and analgesic effects, causing irritation of sensory receptors of
the skin and subcutaneous tissue, dilates blood vessels, and improves tissue
trophism. Assign externally for rheumatic pain, neuralgia, radiculitis, lumbago,
myositis, arthritis. Side effects: possible allergic reactions. Contraindications:
individual intolerance, pustular disease and skin damage at the site of application,
pregnancy, lactation, fever, cachexia, severe lack of cerebral and coronary
circulation, a tendency to angiospasm, severe renal and/or liver dysfunction.
Warning: to avoid the application of Viprosal to open wounds and mucous
membranes; in case of appearance of side effects you should stop using the drug;
the need of its use for children is determined individually.
Nizhvisal is ointment containing venom viper, salicylic acid, camphor,
spruce oil or Turpentine and has analgesic, absorbing, anti-inflammatory effects.
Neurotropic component of viper venom has analgesic effect, and its enzymatic
component with hyaluronidase activity accelerates the healing process. It is used
for pain relief and anti-inflammatory effect when injuries, lumbago, radiculitis,
rheumatic pain, myalgia, sciatica. Side effects: possible allergic reactions, burning
at the site of application. Contraindications: hypersensitivity, pustular skin
diseases, violation of the integrity of the skin at the site of application of the drug.
Caution: avoid getting the drug on the mucous membranes, and in the case of a hit
should be abundantly rinse with water.
Table 34. Medicinal forms of Irritants

Folia Menthae piperitae Infusum foliorum Infusion; 5.0 : 200 ml;
Menthae piperitae,
Briketum foliorum Briquettes; 8.0;
Menthae piperitae,
Oleum Menthae Oil;
piperitae,
Menthae piperitae Tincture in 15 ml, 25 ml;
Aqua Menthae flacons;
piperitae
Tooth drops in 10 ml;
flacons-droppers;
Shredded raw in 50.0
packs
Menthol Mentholum Powder;
Alcohol oral 5% у 70% alcohol;
solution for 1%, 2% - 10 ml;
sublingual
administration in
flacons;
Oil solution in 1%, 2% - 10 ml;
flacons for
intranasal
administration;
Menthol pencil in
a plastic pencil
case;
Menthol oil in 1%, 2% - 10 ml;
flacons;
Oinment in jars 5.0, 25.0, 50.0,
and tubes; 30.0, 50.0;
0.5 part of Menthol : 5
parts of boric acid : 94.5 Peroral solution 40 ml;
parts of Vaselinum; in flacons;
0,15 Menthol + Eucatolum;

20 ml tincture of
Eucalyptus + 90% Ethyl Liquid for 40 ml;
alcohol up to 40 ml; external use in
2,5 Menthol + 1,0 Menovasinum; flacons;
procaine + 1,0 Anaesthin
+ 70% Ethyl alcoho up to Ointment in glass 15.0, 25.0, 40.0;
100 ml; jars;
18.0 Menthol racemic (or Geucamenum;
22.5 Peppermint oil) +
10.0 Camphor + 10.0
Eucalyptus oil + 1.0 Clove
oil + Paraffin and Vaseline Aerosol in 35 ml, 45 ml;
up to 100.0; balloons;
0.06 (or 0.09) Menthol + Camphomenum;
0.61 (or 0.915) Camphor
oil (or Castor oil) + 0.002
(or 0.003) Furacilinum +
10.0 (or 15.0) Olive oil +
2 ml (or 3 ml) Ethyl Mixture for 40 ml;
alcohol; inhalations in
0.71 Menthol + 35.7 ml Mixtio pro flacons;
tincture of Eucalyptus + inhalationibus;
357 ml Glycerin + 96% Pocket inhaler;
Ethyl alcohol up to 100ml;
0.3 Camphor + 0.17 Inhacamfum;
Menthol + 0.08 Methyl
salicylate + 0.1 Eucalyptus
oil; Ointment in 10.0, 25.0;
tubes;
10.0 Camphor + 3.0 Clove Efcamonum;
oil + 3.0 Mustard oil + 7.0
Eucalyptus oil + 14.0
Menthol + 8.0 Methyl
salicylate + 4.0 tincture of
Capsicum + 3.0 Thymol +
3.0 Chloral hydrate +1.0
Cinnamon alcohol + 4.4
Paraffin + Spermaceti and Peroral solution 15 ml, 20 ml,
Vaseline up to 100.0; in flacons; 25 ml, 30 ml,
Tincture Convallariae drops of Zelenin; 40 ml;
100 ml and tincture
Valerianae 100 ml +
tincture Belladonnae 5 ml Peroral solution 25 ml, 50 ml;
+ Menthol 0.2 ; in flacons;
Tincture Convallariae drops of Votchal;
10 ml and tincture
Valerianae 10 ml + 1 ml
1% solution of
Nitroglycerin + 2 ml Аеrosol 30.0, 45.0
Validolum;
Chapter 10. | 197
Irritants
Camphore + Menthol + Cametonum
Chlorbuthanol +
Eucalyptus oleum
Menthol solution in Validolum Tablets; 0.06;
menthyl isovalerate Capsules; 0.05, 0.1;
Peroral solution 5 ml, 15 ml
in flacons-
droppers
Folia Eucalypti viminalis Shredded raw in 50.0, 100.0, 500.0;
packs;
INSTI; Granules for
making oral
solution;
Mixture for 25 ml, 30 ml,
inhalations in 40 ml, 50 ml;
flacons;
Tincture in 40 ml;
flacons;
Eucaliminum Solution for 1% - 25 ml, 50 ml
topical
application and
inhalation
Semen Sinapis Powder, Patch
Fructus Capsici alcohol tincture 1:10 - 50 ml,
(90%) in flacons; 100 ml;
Unguеntum соntrа Ointment in 30.0, 60.0;
соngеlаtiоnem; flacons;
Сарsitrinum; Liquid in glass 100 ml;
vials;
Linimentum Сарsici Liniment in vials; 40 ml;
ammoniatum,
Linimentum Сарsici Liniment in vials; 80 ml;
саmphoratum,
Еmplastrum Сарsici, Patch; 12 х 18 sm;
10 х 18 sm;
6 х 10 sm;
"Еспол" (Unguentum Ointment in
"Еspolum"), tubes; 30.0;
Niсоflех -crème Crème in tubes 50.0
Extract Selviae sclarea Salmus Concentrate 10 kg
Oleum Terebinthinae Carmolis; Gel for external 72.0, 145.0;
rectificatum in tubes;
Liniment; 20% - 25.0,
Ointment; 20% - 30.0;
Doctor Mom, Ointment, 20.0;
Salvisar, Alvipsal, Ointment, 15.0, 25.0;
Мuv,
Nigvisal Ointment; 30.0, 50.0;
Parenteral 5 ml, 10 ml
solution in
ampoules (s/c)
198 | Unit 4.
Spiritus Acidi formici Solution for 1.4%
external use in
flacons
Herbae Centaurii 60.0, Tincture amara Tincture in 25 ml
Folium Menyanthidis flacons
60.0, Rhizomata Calami
30.0, Herba Artemisiae
absinthii 30.0, fruits of
Coriander 15.0 and 40%
Ethyl alcohol pu to 1 l
Herba Centaurii Shredded raw in 100.0;
packs;
Original Grosser Balsam for oral
Bittner Balsam, administration in
vials; 50 ml, 100 ml,
250 ml;
Herbae Centaurii 18mg, Canephron Peroral solution 50 ml, 100 ml;
Radicis Levistici 18mg, in flacons;
Foliorum Rosmarini 18mg Dragee
Herba et folia Artemisiae Shredded raw in 50.0
absinthii packs
Succus Plantaginis Liquid for oral 100 ml;
administration in
vials;
Plantaglucidum Granules in vials 50.0;
and packages 2.0
Radices Taraxaci Shredded raw in 100.0
packs; Powder
Folia Menyanthidis Shredded raw in 100.0
trifoliata packs
Rhizomata Calami Shredded raw in 100.0
packs
Chloroform Fluid for external 100 ml;
use in glasses;
Complex 25 ml
liniment in vials
Nonivamide+Nicoboxil Finalgon, Betalgon Ointment in tubes 20.0
Solutio Ammonii caustici Solution in vials 10ml, 40ml,
10% with ground 100ml;
stoppers and
ampoules 1 ml
Bees venom Apiphor, Tablets for 0.001
making solution
for external use;
Ointment;
Apiphor -1, Suppositories
Apiphor -2
Bees venom 3 mg + Apisartron Ointment in tubes 20.0, 30.0, 50.0,
methyl salicylate 10.0 + 100,0
allyl isothiocyanate 1.0
Chapter 10. | 199
Irritants
Bees venom Ungapiven, Bees Ointment in tubes 30.0
venom
Vipraxin pro Parenteral 1 ml
injectionibus, Viper solution in
venom ampoules (i/s, s/c,
i/m)
Viper venom 1mg + Najaxin Parenteral 1 ml
procaine 4 mg solution in
ampoules (s/c,
i/m)
Viper venom 1IU + Viprosal Ointment in tubes 25.0, 50.0
salicylic acid 10 mg +
Сamphora 30 mg +
Therpentine 30 mg/100.0
Venenum vipirae 16 IU + Nizhvisal Ointment in tubes 25.0, 50.0
Camphor 3.0 + salicylic
acid 1.0 + Therpentin
oleum 8.0/100.0
200 | Unit 5. Drugs affecting the Central Nervous System
UNIT 5. DRUGS AFFECTING the CENTRAL NERVOUS

SYSTEM
Chapter 11. General anesthetics
General anesthetics (GAs) depress the CNS to permit the surgery

operations and unpleasant procedures. General anesthesia is a reversible depression
of CNS function with the loss of response and perception of all external stimuli.
The features of the use of General anesthetics are:
Decrease in systemic arterial blood pressure due to vasodilatation,
myocardial depression, blunting of baroreceptor control, reduction in
central sympathetic tone
Reduction or elimination ventilatory drive and reflexes that maintain
 airway patency
Loss of passive and active regurgitation due to the loss of gag reflex and
 cough reflex, and decrease of lower esophageal sphincter tone
During surgery the hypothermiais is developed in patients as a result of
low environment temperature, exposed body cavities, cold intravenous
fluids, altered termoregulatory control, reduced metabolic rate
Peripheral vasoconstriction is activated to defend against heat loss
Total body oxygen consumption is decreased by 30%
Nausea and vomiting in the post-operative period are caused by an action
of general anesthetics on chemoreceptor trigger zone and brainstem
vomiting center, which are modulated by serotonin, histamine,
acetylcholine, and dopamine.
Pharmacological effects of GAs:
 Amnesia
Immobility in response to harmful stimulation
Abatement of autonomic responses to harmful stimulation
Analgesia
Unconsciousness
Mechanism
 of anesthesia.
At the cellular level GAs generates two main physiologic effects. First, the
inhalational anesthetics cause hyperpolarization of neurons that may be important
in synaptic connection, whereas diminished excitability in postsynaptic neurons
may reduce probability of initiation of an action potential in response to
neurotransmitter release. Second, both inhalational anesthetics and intravenous
anesthetics in anesthetizing concentrations have significant effects on synaptic
transmition and far less effects on action potential formation or distribution.
Chapter 11. General anesthetics | 201
At the molecular level GAs modulate ligand-gated ion channels, receptors,

and signal transduction proteins: K+ channels, Cl- channels, GABA (gamma-
aminobutyric acid) receptors, NMDA (N-methyl-D-aspartate) receptors, Glycine
receptors, N-cholinoreceptors, GABA-receptors proteins.
So, inhibition of NMDA receptors leads to anesthetic effect and produces
unconsciousness; the increase of sensitivity of GABA receptors to GABA
enhances inhibitory neurotransmission and depressing nervous system activity; the
ability of some GAs to inhibit noxious stimuli and to elicite sedative effects is
mediated by their actions on GABA receptors; Glycine receptors mediate the
inhibition of responses to noxious stimuli by GAs; GAs increase the capacity of
glycine to activate Glycine receptors that leads to inhibition of neurotransmission
in the spinal cord and brainstem; N-cholinoreceptors could mediate analgesia or
amnesia; the molecular interactions inhalation GAs with specific protein complex
involved in synaptic neurotransmitter release explain the ability of inhalation GAs
to cause presynaptic inhibition in the hippocampus and promote to the amnesic
effect of them; inhalation anesthetics activate K+ channels that are located in both
pre-synaptic and post-synaptic sites, and in first case they cause hyperpolarization
of the pre-synaptic terminal, thereby reducing neurotransmitter release, and in the
second case they induce resting membrane potential.
In summary, it should be noted that modern data support the view that
intravenous GAs act predominantly through GABA receptors and possibly through
the interactions with other ligand-gated ion channels – NMDA receptors, two-pore
K+ channels. The halogenated inhalational GAs have a variety of molecular
targets. Nitrous oxide, ketamine, xenon inhibite NMDA receptors and/or activate
the two-pore-domain K+ channels.
Classification of General anesthetics
Non-inhalational (intravenous, parenteral) anesthetics:

drugs of short action (less than 10-15 min.): ketamine, propanidid, propofol,
methohexital, etomidate;
drugs of average duration of action (20-30 min): thiopental sodium,
hexobarbital;
drugs of long action (60 min and more): sodium oxybate.
II. Inhalational anesthetics:
liquid volatile substances: еther for anesthesia, halothane, isoflurane, enflurane,
desflurane, sevoflurane;
gas-like substances: nitrous oxide, xenon.
Pharmacological characteristics of Non-inhalational
(intravenous, parenteral) anesthetics
Through lipophilic properties of general anesthetics they easily overcome
BBB and penetrate into the brain and spinal cord providing general anesthesia.
These drugs accumulate in fatty tissue, prolonging recovery if multiple doses are
given. The sensitivity of the patients to GAs depends on the physiological and/or
pathological condition of the patients such as age, body mass, comorbidities,
cardiac output, serum protein levels, liver and/or kidney insufficiency, the
combination with other drugs, etc. Each general anesthetic has its own unique
properties, adverse effects, advantages and application features.
Ketamine is an arylcyclohexylamine. Ketamine is typically administrated
intravenously but may be introduced intramuscularly, oraly and rectaly. It is
metabolized in the liver and is excreted with the bile and urine. In case of
intravenous introduction of ketamine the onset of anesthesia after single bolus is
20-60 seconds and the duration of anesthesia is 5-10 minutes.
Ketamine after single bolus induces the general anesthesia, although it does
not produce the classic anesthetic state, but it causes profound analgesia, slight
hypnotic effect and partial loss of consciousness with mild amnesia. Muscle
relaxation is poorly expressed. Swallowing, laryngeal, cough reflexes are
expressed and even are increased. Ketamine slightly increases general blood
pressure, causes tachycardia, salivation, increased intraocular and intracranial
pressure. Besides, ketamine has psychomimetic effects.
Mechanism of analgesic action of ketamine is based on activation of μ-
opioid receptors of talamus and activation of κ-opioid receptors of spinal cord, and
activation of serotonine receptors of middle brain, talamus and cortex. Mechanism
of hypnotic action of ketamine is based on the blockage of cholinergic receptors,
and N-methyl-D-aspartat (NMDA) receptors, and activation of GABA. Mechanism
of cardiac effects is provided by sympathomimetic action of ketamine mediated by
inhibition of central and peripheral catecholamine reuptake. Furthermore, ketamine
has direct negative inotropic and vasodilating activities that are overpowered by its
sympathomimetic action. Mechanism of psychomimetic effects of ketamine is a
capacity to activate dopaminergic systems of the brain and to stimulate σ-opioid
receptors, serotonine receptors of the brain.
Side effects of ketamine: it increases blood pressure, heart rate, and cardiac
output, myocardial oxygen consumption; induces cataleptic state, is accompanied
by nystagmus, pupillary dilatation, salivation, lacrimation, spontaneous limb
movements with increased general muscle tone; it increases cerebral blood flow,
intracranial pressure, intraocular pressure; during the introduction in the anesthesia
and during the removal from the anesthesia can occur delirium, characterized by
hallucinations, vivid dreams, delusions; ketamine as NMDA receptor agonist may
cause neurotoxicity is known as Olney's lesions.
Prevention of ketamine-induced delirium may be by benzodiazepines;
spontaneous limb movements with increased general muscle tone, hallucinations,
vivid dreams, delusions may be prevented by tranquilizers or neuroleptics;
increased salivation can be prevented by cholinoblockers; anticholinergics,
benzodiazepines, barbiturates and central α2 adrenergic agonists such as clonidine
suppress neurotoxicity of ketamine, conversely, coadministration of NMDA-
antagonists with α2 adrenergic antagonists, like yohimbine could theoretically

potentiate neurotoxicity.
The advantages of ketamine over other parenteral GAs: it induces profound
analgesia, increases blood pressure, heart rate, cardiac output, ketamine produces
less severe respiratory depression than other GAs, is a potent bronchodilatator due
to its sympathomimetic activity.
Thus, ketamine is the parenteral anesthetic which is the best suited for the
patients with the risk of development significant hypotension during anesthesia, for
the patients with high risk of bronchospasm during anesthesia; for children
undergoing short painfull procedures considering that delirium symptoms occur
less frequently in children.
But, ketamine is not good anesthetic for the patients with risk of miocardial
ischemia, for the patients with intracranial pathology or cerebral ischemia, for the
patients with open eye injuries.
Propanidid is a propyl ester of phenylacetic acid. In case of its intravenous
single bolus onset of anesthesia arises in 20-40 seconds without stage of
excitement and lasts 4-10 minutes. In human body Propanidid rapidly is
hydrolyzed by plasma cholinesterase. Propanidid is excreted by kidney and is not
accumulated.
Side effects of Propanidid: spontaneous limb movements, tremor; slight
decrease in general blood pressure, tachycardia; laryngeal spasm; transient
tachypnea, followed by a brief apnea; nausea, vomiting, headache, salivation,
phlebitis, thrombophlebitis, and anaphylactic shock due to its ability to increase
histamine release.
Propanidid is suited the best for the short painful procedures, examinations,
reposition of bone fragments, and removal of stitches.
Contraindications for Propanidid use: kidney and liver insufficiency, shock.
Propofol is the most frequently used parenteral anesthetic in USA. Propofol
is 2,6 disopropylphenol, insoluble in aqueous solutions. Propofol as lipid emulsion
causes pain on injection, hyperlipidemia and risk of patient infection due to
possible contamination of open containers with this anesthetic. Untapped propofol
emulsion must be discarded. Presently there is water-soluble analog of propofol –
Fospropofol. It is a prodrug form which is converted to propofol in vivo.
Fospropofol does not induce adverse effects that inherent to propofol lipid
emulsion. Propofol is metabolized in the liver and is excreted by kidney. Propofol
is highly protein bound.
The mechanism of sedative and hypnotic action of propofol is mediated by
its activation of GABA receptors that lead to increase chloride conduction and
hyperpolarization of neurons. Propofol produces cardionegative effects:
bradycardia, dose-dependent arterial hypotension due to both vasodilatation and
mild depression of myocardial contractility, suppression of cerebral blood flow,
cerebral oxygen consumption, intracranial and intraocular pressure. There is
evidence of anticonvulsant activity of propofol and the possibility of its use for the
treatment of epileptic status in humans.
Side effects of Propofol: transient choreiform movements, opisthotonus,

respiratory depression, airway obstruction, apnea, bradycardia, moderate arterial
hypotension. Propofol causes pain on injection, but have considerable anti-emetic
effect. It may elicit allergic reaction rarely. Propofol transiently depresses activity
in newborns. Propofol rarely can produce “profocol infusion syndrome” which was
described in prolonged, higher-dose infusions. Profocol infusion syndrome
includes the metabolic acidosis, hyperlipidemia, rhabdomyolysis, and enlarged
liver.
Side effects of Fospropofol are similar to that of Propofol, but they are less
expressed, and it has not “profocol infusion syndrome”. Fospropofol has slower
onset of sedation due to the need for hydrolysis of the prodrug.
Propofol is the best suited for the patients with cerebral ischemia, but no
evidences about its neuroprotective effect.
Propofol should be used with caution in patients with hypotension or
unstable pressure, in patients with hypovolemia, in astmatics, in pregnant women
by reason of pass through the placental barrier. Patients given propofol should be
monitored to adequate oxygenation and ventilation. Taking into account propofol
painful injection it should be administered with lidocaine and into a large vein to
prevent phlebitis and/or thrombosis.
Both Propofol and Fospropofol can be used in patients with adequate airway
and cardiorespiratory function.
Three derivatives of barbituric acid are used for general anesthesia the
most widely. There are sodium thiopental, thiamylal, and methohexital.
Barbiturates are precipitated as the free acid if they are used with other drugs in
acid solutions during anesthetic induction, therefore the administration of other
drugs should be delayed until the barbiturates has cleared the intravenous tubing.
Veno-irritant effect of barbiturates can be reduced by injection into larger veins
and by prior intravenous injection of lidocaine. In pediatric practice barbiturates
can be given per rectum. After single dose barbiturates are redistributed from the
brain to other tissues that limit anesthetic duration. But after multiple doses
anesthetic duration of barbiturates becomes longer and they may accumulate. All
three anesthetic barbiturates are eliminated by hepatic metabolism and renal
excretion of inactive metabolites; a small fraction of sodium thiopental is
transformed to the longer-acting hypnotic pentobarbital. In patients with cirrhosis
can result in prolongation of the action of barbiturates. Three derivatives of
barbituric acid that are used for general anesthesia are highly protein bound. In
patients with the diseases that lead to low levels of serum protein concentration the
initial free concentration and hypnotic effect of an induction dose of the
barbiturates will be increased.
Sodium thiopental is most frequently used for inducing anesthesia and does
not elicit pain on injection, but has anti-analgesics effect and reduces the pain
threshold. Thiopental has been used as a protectant against cerebral ischemia, but
for this purpose the large doses are required that elicits prolonged sedation and
limits such use. Thiopental is effective in case of status epilepticus. Besides, this
general anesthetic supports ratio of myocardial oxygen supply to demand in

patients with ischemic heart disease. Sodium thiopental in single induction may
elicit mild transient depression of newborn activity. Thiopental does induce
precipitation of neuromuscular blockers or other drugs during anesthetic induction.
Thiamylal is used only in veterinary medicine. Prolonged infusions or large doses
of sodium thiopental and thiamylal can cause unconsciousness continuing a few
days due to their slow excretion and large volumes of distribution. Methohexital is
used for inducing anesthesia during short surgical, diagnostic and therapeutic
procedures with minimal pain. It causes mild pain on injection to a greater degree
than thiopental. Methohexital has much more rapid clearance, and it accumulates
less during prolonged infusions than other barbiturates. Methohexital can increase
ictal activity and seizures.
Side effects of the barbiturates: suppression of electroencephalogram (EEG),
reduction of cerebral metabolic rate and cerebral oxygen consumption in dose-
dependent manner, decrease of cerebral blood flow and intracranial pressure,
anticonvulsant effect; dose-dependent decrease of general blood pressure, as a
result of vasodilation, especially in patients with hypovolemia, cardiomyopathy,
valvular heart disease, ischemic heart disease, cardiac tamponade, β adrenergic
blockade, direct decrease in cardiac contractility, and as a compensatory response -
increase of heart rate, though barbiturates abate the baroreceptor reflex; depression
of respiratory center, diminution the minute ventilation and tidal volume, and
reduce sensitivity of respiratory center to carbon dioxide; increase of histamine
release from mast cells during induction anesthesia; barbiturates can induce fatal
attacks of porphyria in patients with porphyria that are manifested by severe
abdominal pain, nausea, vomiting, psychiatric disoders, neurologic anomalies;
inadvertent intra-arterial injection of thiobarbiturates can induce a severe
inflammatory and necrotic reaction that threaten limb survival; barbiturates
particularly Methohexital can produce cough, hiccup, muscle tremors, twitching,
hypertonus.
Etomidate is a carboxylated imidazole derivative that has anesthetic and
amnestic properties, but that has no analgesic and myorelaxants properties.
Etomidate is poorly soluble in water and is formulated as a solution in propylene
glycol. Etomidate is used as parenteral solution and may be given rectally.
Etomidate does not induce precipitation of neuromuscular blockers or other drugs
during anesthetic induction.
In the main Etomidate is used for anesthetic induction of patients with
hypotension. Induction doses of Etomidate have a rapid onset and short duration of
action and are accompanied by pain on injection and myoclonic movements.
Therefore it is injected with lidocaine to reduce pain and with premedication by
benzodiazepines or opiates for relieving myoclonic movements. Etomidate is the
best general anesthetic for patients with ischemic heart disease, cardiomyopathy,
cerebral vascular disease, hypovolemia.
Methabolism of Etomidate takes place in liver and elimination of it is both
renal and biliary. Etomidate has a high binding with plasma proteins.
Side effects of Etomidate: Etomidate produces hypnosis and hasn’t analgesic

effect; decreases a cerebral blood flow and intracranial pressure, reduces a cerebral
metabolism, this general anesthetic increases the EEG activity and may cause
seizures; it has a small effects on heart work: small increase in heart rate, little or
no decrease in blood pressure and cardiac output, little effect on coronary perfusion
pressure; to a lesser degree depresses the respiratory center; induces hiccups,
nausea, vomiting; it does not stimulate histamine release; single induction of
Etomidate may reduce cortisol levels, but can not cause adrenocortical
suppression.
Sodium oxybate (Sodium oxybutyrate) is a synthetic analog of natural
metabolite which is in the brain, it is sodium salt of γ-hydroxybutyric acid
(GOBA). As a general anesthetic Sodium oxybutyrate has low activity and it
requires high doses to achieve anesthetic effect, it has hypotoxicity, easily
overcomes the BBB, decreases a blood pressure level and may cause hypokalemia.
Sodium oxybutirate has hypotermic effect, anticonvulsive effect; it increases the
resistance to radiation, brain tissues hypoxia, and starvation. Sodium oxybutyrate
has a sedative, anxiolytic, antihypoxic, myorelaxant effect, and mild analgesic
effect. Sodium oxybutyrate is excreted basically by the lungs as carbon dioxide.
Sodium oxybutyrate can be used intravenously and peroral for general anesthesia.
The basic place of its action is tissue metabolism, first of all – the carbohydrate
metabolism.Synaptic component of mechanism of its action is an increase of
acetylcholine and a dopamine level, decrease of serotonin level, and it does not
influence the level of epinephrine, norepinephrine, opioid peptides, GABA,
glutamate in brain tissues. This general anesthetic blockes N-cholinoreceptors,
GABA, postsynaptic adrenergic receptors, dopamine receptors, M-
cholinoreceptors, and activates inhibitory α-adrenergic receptors, and GABA
receptors. Overdose may depress respiratory center. Sodium oxybutirate can be
used for the induction and basic anesthesia in case of delivery, brain hypoxia and
shock.
Pharmacological characteristics of Inhalational

anesthetics (gases and volative liquids)
One of the disadvantages of inhalational anesthetics is a low degree of

safety. They are dangerous in clinical use. Each of them has a unique side-effect
profile. The choice of inhalational anesthetic in clinic use is difficult. Advantages
of inhalational anesthetics are rapid removal from the body and out of the
anesthesia. The recovery from anesthesia for the inhalational anesthetics with low
blood and tissue solubility reflects the anesthetic introduction despite duration of
anesthetic administration. The recovery from anesthesia is the function of duration
of anesthetic administration for the inhalational anesthetics with high blood and
tissue solubility. The ability of the inhalational anesthetic to be accumulated in
fatty tissue prevents blood and alveolar partial pressures from a rapid fall.
Ether for anesthesia is the volatile highly flammable liquid, dangerously

explosive. Advantages of Ether for anesthesia are: the large latitude of therapeutic
action, rapid recovery from anesthesia, and simple control of the depth of
anesthesia. The main place of its distribution is the brain. The ether for anesthesia
is mainly eliminated by the lungs in an unchanged form and the remains of it are
eliminated by kidney, skin and GIT. The ether for anesthesia has analgesic effect,
which is saved in after recovery from anesthesia; depresses of the cortex activity; it
does not influences blood pressure, increases the heart rate; causes myocardial
depression, but produces epinephrine and norepinephrine release, it does not
change sensitivity of myocardium to catecholamines; the ether for anesthesia does
not damage internal organs; it has myorelaxant effect, impoves the action of
neuromuscular blockers. The disadvantages of ether for anesthesia are long-term
introduction of anesthesia with a severest phase of excitation due to induction of
subcortical activity and depression of cortex activity; irritation of the mucous
membranes that cause inflammatory process in respiratory ways, vomiting; it
depresses the renal function and may provoke proteinurua; ether for anesthesia
may elicit acidosis, ketonemia. Premedication by atropine in case of ether for
anesthesia use prevents bradycardia, cardiac arrest, and apnoe.
Halothane is the volatile liquid at the room temperature and it must be
stored in a sealed container. Halothane and its mixtures with air or oxygen are
neither flammable nor explosive. Halothane is soluble in fat and other body tissues,
it has high blood; gas partition coefficient and high fat; blood partition coefficient,
is accumulated during prolonged administration. About 80% of halothane is
eliminated by lungs in unchanged form in the first 24 hours, and remainder of it is
biotransformed by hepatic enzymes. In the rare cases halothane may cause
fulminant halothane-induced hepatic necrosis as a result of modification of several
proteins in the liver. Halothane does not irritate the respiratory tract; it diminishes
bronchial secretion and causes bronchodilatation, inhibits both laryngeal and
swallowing reflexes, reduces salivation, relaxes masticatory muscles, and
accelerates the rate of breathing. Halothane potentiates the effects of non-
depolarizing neuromuscular blocking agents. However the analgesic effect of
halothane is weak.
Halothane is used for maintance of anesthesia and is well tolerated for
inhalation induction, especially in children, in whom preoperative administration
of intravenous catheter can be difficult. Side effects of halothane appear to be
diminished in children, and low cost of it allows using halothane widely in
developing contries. Bronchodilatory properties of halothane are allowed to use it
in patients with status asthmaticus as a last resort. Due to uterine smooth muscle
relaxation effect of halothane, it is used for manipulation of the fetus (version) in
the prenatal period and for delivery of retained placenta postnatally.
Side effects of halothane. From the cardio-vascular system halothane causes
dose-dependent reduction in general blood pressure, as a result of direct
myocardial depression, decreased cardiac output, and on the molecular level these
side effects of halothane are explained by depression of depolarization-induced
intracellular calcium transients. Hypotension is accompanied by bradycardia or

may be normal heart rate because of damped baroreceptor reflex function
diminishes chronotropic and inotropic responses to a decrease in general blood
pressure. But the cardio-vascular adverse effects vanish after several hours of
halothane administration due to progressive sympathetic stimulation. Halothane
increases cerebral blood circulation and skin perfusion as a result of alteration of
specific vascular beds, redistribution of blood flow; it increases perfusion to poorly
ventilated regions of the lung and elevares alveolar oxygen gradient; halothane
inhibits kidney and visceral perfusion, nevertheless coronary blood flow is largely
preserved during haloten anesthesia. Necessary to consider the possibility of
halothane to increase sensitivity of myocardium to arrhythmogenic effects of
epinephrine, as endogenous adrenal production and exogenous administration. On
the side of respiratory system halothane has bronchodilatory effect; it causes
frequent and shallow breathing, decrease of alveolar ventilation, and inhibition of
ventilatory response to carbon dioxide due to halothane depression of central
chemoreceptor mechanisms, inhibition of peripheral chemoreceptor response to
arterial hypoxemia. From CNS halothane may increase intracranial pressure and
may suppresses cerebral metabolism. Halothane relaxes skeletal muscles by central
depressant effects, potentiates the effects of non-depolarizing muscle relaxants, can
provoke specific fatal syndrome with malignant hyperthermia, severe muscle
contraction, and increase in metabolic rate in genetically sensitive patients.
Halothane inhibits uterine contractions during parturition, prolonging labor and
increasing blood loss. Halothane elicits reversible reduction of renal blood flow
and glomerular filtration, hepatic and visceral blood flow on account of reduced
general blood pressure. Halothane-induced hepatic necrosis as a result of immune
response to hepatic proteins that become trifluoroacetylated as a consequence of
halothane metabolism (see above) is rare: 1 in 10,000 patients receiving halothane.
Isoflurane is halogenated inhalation anesthetic similar to halothane for most
of the pharmacokinetic and pharmacodynamic parameters. But isoflurane has a
blood/gas partition coefficient lower than halothane or enflurane; therefore
induction with isoflurane and recovery from isoflurane are faster than with
halothane, and changes in anesthetic depth can be achieved more rapidly with
isoflurane than halothane or enflurane. About 99% of inhaled isoflurane is
eliminated by the lungs in unchanged form; the remainder of it is metabolized in
liver. Isoflurane is typically used for maintenance of anesthesiaafter induction of
other agents. Isoflurane is safe anesthetic for the patients with ischemic heart
disease. If it is used together with opioids or nitrous oxide isoflurane concentration
may be reduced.
Side effects of isoflurane: decrease in general blood pressure due to the
decreased systemic vascular resistance, vasodilatation without reduction of cardiac
output; isoflurane improves cardiac blood flow and decreases myocardial oxygen
consumption; it causes tachycardia in response to reduced blood pressure, although
isoflurane as well as halothane attenuates baroreceptor function; rapid changes in
isoflurane concentration may cause tachycardia and hypertension as a result of
isoflurane-induced sympathetic stimulation; isoflurane suppresses ventilation, tidal

volume, it elicits bronchodilatation, irritates an airway, stimulates an airway reflex
during induction anesthesia, producing coughing and laryngospasm; isoflurane
increases cerebral blood flow, but lower than halothane or enflurane; isoflurane has
moderate risk of an increase in intracranial pressure; it reduces cerebral metabolic
rate and cerebral metabolic oxygen consumption in a dose-dependent manner;
isoflurane relaxes the skeletal muscles, uteine smooth muscles and enchances the
effects of both non-depolarizing and depolarizing muscle relaxants; isoflurane
reversibly reduces renal blood flow and glomerular filtration; splanchnic and
hepatic blood flow is reduced according elevated doses of isoflurane as systemic
arterial pressure decreases. Isoflurane is not recommended for analgesia or
anesthesia for labor and vaginal delivery.
Enflurane like other inhalation anesthetic is volatile, nonflammable and
non-explosive in mixtures of air or oxygen. Enflurane has high blood/gas
coefficient, induction of anesthesia and recovery from it are relatively slow. A
small part of enflurane is metabolized in the liver, and most of it is excreted
through lungs with expired air. As with isoflurane, enflurane is used for rather than
induction of anesthesia. Opioids and nitrous oxide reduce required concentration of
enflurane for anesthesia. Enflurane is rarely used for anesthesia in developed
countries.
Side effects of enflurane: concentration-dependent decrease in arterial blood
pressure, depression of myocardial contractility, peripheral vasodilatation, minimal
effects on heart rate; rapid shallow breathing, decrease in minute ventilation, more
significant depression of ventilatory responses to hypoxia and hypercarbia than do
either halothane or isoflurane, bronchodilatation; improving of cerebral blood
circulation due to cerebral vasodilatation, increase of intracranial pressure,
reduction of cerebral metabolic oxygen consumption; seizures may occur in case of
high concentration of enflurane and in hypocapnia during anesthesia; skeletal
muscle relaxation and enhancement of non-depolarizing muscle relaxant effects;
relaxation of uterine smooth muscle; reduction of renal blood flow, glomerular
filtration rate, and urinary output; reduction of splanchnic and hepatic blood flow
in proportion to reduced arterial blood pressure.
Enflurane does not use in the patients with seizure disorders, and for
obstetric anesthesia.
Desflurane is a highly volatile liquid at room temperature. It has a very low
blood/gas partition coefficient and also is not very soluble in fat or other peripheral
tissues. More than 99% on desflurane is eliminated unchanged through the lungs.
A small amount of absorbed desflurane is metabolized by liver enzymes.
Desflurane provides a very rapid induction of anesthesia and the time of
awakening. Therefore desflurane is a widely used anesthetic for outpatient surgery
for maintance of anesthesia. Lower concentrations of desflurane are used in case of
co-administration with nitrous oxide or opioids.
Side effects of desflurane: irritation of tracheobronchial tree can provoke
coughing, salivation, bronchospasm, although desflurane like other inhalational
agents is bronchodilatator; a concentration-dependent acceleration in respiratory

rate, and a diminution in tidal volume, may become apneic, a concentration-
dependent decrease in arterial blood pressure, moderate negative inotropic effect,
systemic vasodilatation, transient tachycardia results from desflurane-induced
stimulation of the sympathetic nervous system; a decrease in cerebral vascular
resistance and cerebral metabolic oxygen consumption, an increase in cerebral
blood flow, a raise in intracranial pressure under condition of normocapnia and
normotension, but under condition of hypocapnia deflurane causes a
vasoconstriction; skeletal muscle relaxation and it improves the effects of non-
depolarizing and depolarizing neuromuscular blocking agents.
Desflurane is not used for inductive of anesthesia due to its irritant
properties.
Sevoflurane can undergo an exothermic reaction with desiccated Carbon
dioxide absorbent to produce airway burns or spontaneous ignition, explosion, and
fire. Thereby, sevoflurane is not used with an anesthesia machine in which the
Carbon dioxide absorbent has been dried by prolonged gas flow through the
absorbent. Sevoflurane has a low solubility in blood and other tissues. That ensures
the rapid induction of anesthesia, rapid changes in anesthetic depth, and rapid
output from anesthesia. Sevoflurane is a widely used anesthetic for outpatient,
especially for children, due to the rapid recovery profile and due to the absence
irritant effect on the airways. Sevoflurane is a preferable agent in patients who are
inclined to myocardial ischemia because it does not provoke tachycardia.The
greater part of absorbed sevoflurane is excreted in unchanged form and
insignificant part of it is metabolized in the liver.
Side effects of sevoflurane: a concentration-dependent decrease in arterial
blood pressure, systemic vasodilatation, a concentration-dependent decrease in
cardiac output; a concentration-dependent reduction in tidal volume and increase in
respiratory rate, and an increase in partial pressure of carbon dioxide in the blood,
sevoflurane like other inhalational agents is bronchodilatator; its cerebral
vasodilatation is less than of isoflurane and desflurane, an increase in intracranial
pressure, delirium in children; skeletal muscle relaxation; and it improves the
effects of non-depolarizing and depolarizing neuromuscular blocking agents like
other inhalational anesthetics; transient renal injury.
Nitrous oxide is very insoluble in blood and other tissues; as a result it
provides rapid equilibration between delivered and alveolar anesthetic
concentration, rapid induction of anesthesia and rapid anesthesia recovery. Nitrous
oxide is eliminated in unchanged form by the lungs and with minimal diffusion
through the skin. Nitrous oxide can oxidize cobalt form of vitamin B12 to cobalt,
thereby inhibiting methionine synthetase and synthesis of methionine, DNA, RNA,
myelin, and it can produce vitamin B12 deficiency, megaloblastic anemia, and
peripheral neuropathy. That's why nitrous oxide is not used in patients with vitamin
B12 deficiency, anemia, chronic alhocolism, malnutrition, and it is not used as
chronic analgesic although nitrous oxide has a significant analgesic effect or as a
sedative agent. Analgesic effect of nitrous oxide is a function of the
activation of opioidergic and adrenergic neurons in CNS. Nitrous oxide is used as

an adjunct to other inhalational or intravenous anesthetic to reduce their doses.
Side effects of nitrous oxide: stimulatory effects on sympathetic nervous
system; the cardiovascular effects of nitrous oxide are dependent on concomitant
administration with other anesthetic agents, an increase in venous tone of both the
peripheral and pulmonary vasculature; an increase in respiratory rate and a
decrease in tidal volume, depression in ventilatory response to hypoxia; an increase
in cerebral blood flow and intracranial pressure.
If nitrous oxide is co-administered with halogenated inhalational anesthetic,
it elicits an increase in heart rate, arterial blood pressure, cardiac output, and if
nitrous oxide is co-administered with opioids, it causes a decrease in arterial blood
pressure and cardiac output. Nitrous oxide is not used in patients with pulmonary
hypertension.
Nitrous oxide has two major problems. Firstly: on discontinuation of nitrous
oxide administration, nitrous oxide gas can diffuse from blood to the alveoli, diluting
oxygen in the lungs and provoke an effect called diffusional hypoxia. In order to
prevent diffusional hypoxia, 100% oxygen rather than air should be administered after
the cessation of supply of nitrous oxide for 4-5 minutes. Secondly: nitrous oxide can
exchange with nitrogen in any air-containing cavity in the human body. Furthermore,
nitrous oxide can enter the cavity faster than nitrogen escapes, and therefore
increasing the volume and pressure in this cavity. Thereby, nitrous oxide can expande
a Pneumothorax, an obstructed middle ear, an aire embolus, an obstructed loop of
bowel, an intraocular air bubble, a pulmonary bulla, and intracranial air. As a result,
nitrous oxide cannot be used in these clinical setting.
Xenon is an inert gas. It has minimal cardiorespiratory side effects, has
analgesic and anesthetic effects due to influences on receptors and potassium
channels in the CNS. At the same time, xenon is a rare gas and must be extracted
from air and cannot be manufactured. This renders xenon very expensive. Its use is
limited. Xenon is extremely insoluble in blood and other tissues, provides rapid
induction of anesthesia and rapid anesthesia recovery. Xenon is well tolerated in
the patients of advanced age. Side effects of xenon: a slight decrease in respiratory
rate, an increase in tidal volume, minimal respiratory depression; reduction in
cerebral metabolism and cerebral blood flow.
Table 35. Medicinal forms of General anesthetics

Ketamine Kalipsol, Ketaject, Ketalar, Parenteral solution 1% - 5 ml;
Ketanest, Ketaset, Ketolar, for i/v, i/m injections 5% -2 ml, 10 ml
Velonarcon, Vetalar, etc. in ampoules,
in flacons 1% -20 ml;
5% - 5 ml, 10 ml;
10% - 10 ml
Propanidid Epontol, Fabantol, Fabantal, Parenteral solution 5% - 10 ml
Sombrevin, etc. for i/v injections in
ampoules
212 | Unit 5.
Drugs affecting the Central Nervous System
Propofol Diprivan, Pofol, Recofol Isotonic water 1% - 20 ml;
emulsion in
ampoules;
Isotonic water
emulsion in flacons; 1% - 20 ml, 50 ml,
Isotonic water 100 ml;
emulsion in syringes
1% - 50 ml
Methohexital Brietal Powder in flacons 0.5
for i/v injections
Etomidate Amidate, Hypnomidate, Parenteral solution 0.2% - 10ml
Radenarcon, etc. for i/v injections in
flacons
Hydroxydione Hydroxydione Sodium Powder in flacons 0.5
sodium succinate succinate, Pregnocin- and ampouls for i/v
natrium, Presuren, Viadril injections
Thiopental sodium Farmotal, Nesdonal, Powder in flacons 0.5, 1.0
Penthiobarbital, Pentothal for i/v injections
sodium, Thiopenten,
Thiopentobarbital,
Thiopentone, Thiotal,
Trapanal, etc.
Hexobarbital Cyclobarbitalum soluble, Powder in flacons 1.0
Evipan sodium, for i/v injections
Hexobarbitone soluble,
Noctivane, Novopan, etc.
Sodium oxybate Natrium oxybutyricum Parenteral solution 20% - 5 ml, 10 ml;
for i/v, i/m
injections in
ampoules;
concentrate for 66,7% - 37,5 ml;
peroral solution in
flacons;
Syrup in flacons 5% - 400 ml
Ether for anesthesia Anesthetic Ether, Ether Liquid in a tightly 140 ml, 150 ml
Anaesthesicus sealed flacons
Halothane Narcotan, Fluothane, etc. Liquid in a tightly 50 ml, 250 ml
sealed flacons
Isoflurane Forane Liquid in vials 100 ml, 250 ml

Enflurane Ethrane Liquid in flacons 125 ml, 250 ml
Desflurane Liquid in flacons 125 ml, 250 ml
Sevoflurane Liquid in flacons 125 ml, 250 ml
Nitrous oxide Nitrogenium oxydulatum, Gas in tanks 10 l
Oxydum nitrosum,
Protoxyde d’Azote,
Stickoxydal
Xenon Gas in tanks 10 l
Chapter 12. Opioid analgetics | 213
Chapter 12. Opioid analgesics

Opioid analgesics – are the drugs that stop pain and cause euphoria, abuse,
and addiction.
Pain is the primary clinical imperative and a component of all clinical
pathology.
Nociceptive system – there is the system which provides the sensation of
pain in humans.
Nociceptors –are the peripheral sensory (touch) neurons that are activated
by damaging stimuli. Nociceptors are activated by mechanic or temperature
stimuli, by action of chemical substances (algogenic substances – producing pain).
Nociceptors have various sensitivity to different types of stimuli. There are the
specific “silent” nociceptors that are responded on the stimuli only after their
damage or in case of inflammation of nearby organs. Peripheral nerves endings of
nociceptors are located in the skin, subdermal fat layer, periosteum, joints,
muscles, internal organs.
The higher echelon of perception of nociceptive information is the cortex
of the brain. Somatosensory areas and regions of the cortex of the brain evaluate
the painful signals; they form feeling of the pain. Association areas of the brain
cortex take part in formation of complex emotional and affective symptoms of pain
and associated mental experiences.
Antinociceptive system (ANS) is a hierarchical set of neural structures on
different levels of CNS with their own neurochemical mechanisms, which can stop
the activity of nociceptive system. The opiatergic regulation acts in ANS, and it is
based on the interaction of ligands-opioids with opioid receptors. Ligands are the
agents that are connected with biological acceptors, for example, receptors, ion
channels, etc. In this case there are opioids both endogenous and exogenous.
Structures of ANS:
ANS structures of middle brain, medula oblangate, spinal cord
They inhibit nociceptive upstream excitation.
There is the system of downstream abscopal control of pain.
The transmitters of ANS are opioids and serotonin.
ANS structures of hypotalamus
They have various actions on nociceptive system:
downstream abscopal control for the nociceptors of spinal cord neurons
upstream abscopal control for the pituitary nociceptive neurons
activating influence on the system downstream abscopal control
3. ANS structures of the brain cortex

These areas activate ANS of the first and second levels. ANS release biological
active endogenous opioid substances are the “internal opioids” – internal
ligands. They are named endorphins, enkephalins, dynorphins, nociceptins or
orphanins, endomorphins. They are aminoacids, and are
named neuropeptides, or opioid peptides. At the same time endorphins,

endomorphins exercise maximum affinity for the type μ, enkephalins – type δ,
dynorphin – type κ.
Endogenous opioid peptides are produced in the body and exercise their
opioid effects. Discovery of opioid receptors led to the discovery of their
endogenous ligands.
Exogenous opioids enter the body from the outside and bind to opioid
receptors. The first discovered opioid was morphine, an alkaloid of opium poppy.
Currently we know a large number of exogenous opioids, which are ligands to
opioid receptors. By origin we distinguish natural, synthetic and semi-synthetic
opioids. Many of them are used in medicine as analgesics and anti-cough drugs.
In human body opioids connect with specific receptors and block

nociceptive system activity in neurons. This leads to stop the pain. But in human
body there are non-opioid peptides, such as neurotensin, seritonin,
catecholamines.
Interaction of nociceptive and antinociceptive systems:
Hyperalgesy – high pain sensitivity in case of:
increase of excitement of nociceptive system;
reduction of excitement of antinociceptive system.
Hypoalgesy – low pain sensitivity in case of:
reduction of excitement of nociceptive system;
increase of excitement of antinociceptive system.
Pain tolerance – depends on interaction of both: nociceptive system and
antinociceptive system.
Both of this systems form general system of pain.
There are 4 main types of opioid receptors: μ, δ, κ, NOP. σ-receptors (sigma)
previously attributed to opioid, because it is considered that the antitussive effect
of many opioid is realized through action on these receptors, as well as the first
selective σ-opioid agonists were derivatives of opioids. However, it was found that
σ-receptors are not activated by endogenous opioid peptides, and very different
from other opioid receptors both in function and in genetic structure. It has been
suggested the existence of ε-opioid (epsilon) receptors. Currently there are several
selective agonists and antagonists of the alleged ε-receptors, but attempts to detect
the gene of these receptors have been unsuccessful.
Opioid receptors were named using the first letter of the first ligand that
was found to bind to them: for μ-receptor – morphine; for κ-receptor –
ketocyclazocine; δ-receptor was named after the mouse vas deferens tissue in
which the receptor was first characterised; the nociceptin receptor or OLR (opiate-
like receptor)1 was later identified and cloned based on homology with the cDNA.
Table 36*. Types of opioid receptors and their Locations, Functions and Presumed
Endogenous ligands
Presumed
Receptor Subtypes Location Function Endogenous
ligands
 analgesia enkephalins,
 antidepressant β-endorphin
 brain effects
o pontine nuclei  convulsant
o amygdala effects
delta (δ)
o olfactory bulbs  physical
DOP δ1, δ2
o deep cortex dependence
 peripheral sensory perhaps of mu-opioid

neurons receptor-mediated
respiratory
depression
 brain dynorphin A,
o hypothala dynorphin B,
mus α-neo-
 analgesia
o periaqued endorphin
 sedation
uctal gray
kappa (κ)  miosis
o claustrum
KOP κ1, κ2, κ3  inhibition of
 spinal cord
o substantia
ADH release
gelatinosa  dysphoria
 peripheral
sensory neurons
 brain μ1: β-endorphin,
o cortex  analgesia enkephalins,
(laminae  physical endomorphin-1,
III and dependence endomorphin-2
IV)
o thalamus μ2:
mu (μ)
o striosome
MOP μ1, μ2, μ3 s  respiratory
o periaqued depression
uctal gray  miosis
o rostral  euphoria
ventrome  reduced GIT
dial motility
medulla  physical
 spinal cord dependence

o substantia
gelatinosa μ3:
 peripheral
sensory neurons  possible
vasodilation
 intestinal tract
 brain nociceptin/
o cortex orphanine FQ
o amygdala
 anxiety
o hippocam
 depression
Nocicepti pus
n receptor o septal  appetite
NOP ORL1 nuclei  development
o habenula of tolerance to
o hypothala
μ agonists
mus
 spinal cord
* - adopted from Corbett AD, Henderson G, McKnight AT, Paterson SJ (2006). «75 years of
opioid research: the exciting but vain quest for the Holy Grail». Br. J. Pharmacol. 147 Suppl 1:
S153–62 with autor’s changes and additions.
Opioid receptors are expressed in the brain and spinal cord. Besides, opioid
receptors also are expressed widely in peripheral tissues, including vascular,
cardiac, airways, lungs, GIT, immune/inflammatory cells.
Table 37*. Actions and selectivities of some opioids at: μ, δ, κ receptors.
Opioid ligands Receptor types

μ δ κ
Agonists
Morphine +++ +
Fentanyl +++
Sufentanil +++ + +
Trimeperidine ++
Codeine ±
Methadone +++
Buprenorphine ± ––
Butorphanol ± +++
Nalbuphine –– ++
Nalorphine –– ++
Pentazocine ± +
Tramadol ++ ++ ++
Antagonists
Nalmefene +
Naloxone ––– – ––
Naltrexone ––– – –––
Endogenous peptides
Met-enkephaline ++ +++
Leu-enkephaline ++ +++
β-endorphin +++ +++
Dynorphin A ++ +++
Dynorphin B + + +++
α-neoendorphin + + +++
Endomorphin-1 +++
Nociceptin/ – – –
orphanine FQ
+ agonist; – antagonist; ± partial agonist.
* - adopted from Goodman & Gilman’s The Pharmacological Bases of THERAPEUTICS. 12th
edition. Medical. 2011. – 2084 P. with autor’s changes and additions.
Classification of Opioids according mechanism of action
1. Agonists:
Morphine
Fentanyl
Sufentanil
Omnoponum (Papaveretum) – is the mixture of hydrochloride salts of
opium alkaloids
Trimeperidine
(Promedolum) Codeine
Dimenoxadol
Methadone
2. Agonists-antagonists and Partial agonists:
Buprenorphine
Butorphanol
Nalbuphine
Nalorphine
Pentazocine
Antagonists:
Nalmefene
Naloxone
Naltrexone
Others (opioid analgesic with opioid and non-opioid mechanism of action)
Tramadol
Mechanism of action of opioid analgesics is based on intracellular events,

including:
 inhibition of adenylyl cyclase activity
 reduced opening of voltage-gated Ca2+ channels
stimulation of K+ current through channels including G protein-activated
 inwardly rectifying K+ channels
activation of Protein kinase C and Phosphoinositide-specific
phospholipase C.
Mechanism of opioid-induced analgesia. After systemic delivery opioid
analgesics act in the brain, spinal cord and in the periphery. Opioid analgesics act
on opioid receptors in CNS and block the nociceptive responces, alter nociceptive
transmission. Direct introduction of opiates to a peripheral nerve can produce a
local anesthetic-like action at high concentrations. But, analgesic effects are
limited if opiates do not readily penetrate the brain. And yet the local injection of
opiates into peripheral sites under condition of inflammation where there is
exaggerated pain response (e.g. hyperalgesia) can cause a normalizing effect upon
exaggerated threshold.
In general opioids have good absorption from GIT and rectal mucosa, nasal
mucosa, transdermally. Opioids are metabolized in the liver by the microsomal
enzymes and are eliminated through kidney and liver.
Pharmacological effects of Opioid analgesics depend of opiate receptor
preferences.
Pharmacological effects of Opioid agonists:
Analgesia
Euphoria
Sedative
Oppression of breath
Oppression of cough reflex
Miosis, increase accommodative powder and lower intraocular pressur
Increasing of muscle tone
Nausea & vomiting (stimulation of the trigger zones of medula oblangata)
Stimulation of the vagus nerve and elicit bradicardia
Increasing of intracranial pressure
Decreasing of motility of GIT and increasing of the tone of sphincters of GIT
(constipation), gallbladder, urinary bladder
Constipation
Urine retention
Decreasing of stomach acidity
Spasms of intestine, gall bladder, sphincter Oddi, urine bladder (colic)
Decreasing of kidney function, kidney blood circulation
Increasing of plasma prolactin, ADH (antidiuretic hormone), STH
(somatotropic hormone) secretion
Block release of gonadotropin-releasing hormone (GnRH) and corticotrophin-

releasing hormone (CRH) that leads to reduce release of LH (luteinizing
hormone), FSH (folicule stimulating hormone), ACTH and β-endorphin.
In males - decreasing of plasma cortisol, gonadotropins, testosterone,
adrenal androgens
• In females - decreasing of LH secretion and FSH
In both males and females - cause endocrinopathies, including
hypogonadotrophic hypogonadism: decrease libido, in males reduce
secondary sex characteristics; in females lead to menstrual cycle
irregularities. These changes are reversible with removal of the opiates.
Decreasing of uterus tone, decreasing of strength, duration, frequency of uterine
contractions
Increasing of histamine secretion: vasodilatation, bronchoconstriction,
erythema, sweating, feeling of warmth
Immunomodulative effect
Adverse effects of Opioid analgesics:
Withdrawal (abstinence) syndrome as a result of tolerance
Cross tolerance
Physical and psychical dependence
Restlessness, tremor, hyperactivity
Oppression of breath
Nausea & vomiting
Increasing of intracranial pressure
Constipation
Urine retention
Itching of the nose wings, urticaria
Dysphoria
Cerebral and spinal ischemia
In case of short-time or long-time use opioids may exert some adverse
effects: desensitization, internalization of opioid receptors (down-regulation)
tolerance (loss of drug effect), dependence, addiction.
The clinical use of opioid analgesics is determined by their ability to
activate or block different types of opioid receptors (tabl. 29, 30). So, selective
agonists of MOP produce analgesia, affect mood and rewarding behavior, and alter
respiratory, cardiovascular, GIT, and neuroendocrine function. KOP agonists, with
rare exceptions, can not be used for long-term therapy because they produce
dysphoric and psycotomimitic effects. DOP agonists have not yet been used in the
clinic. NOP agonists have not analgesic effects. The selectivity of opiates is
disappeared in case of their use in high doses. The doses of opiates should increase
to overcome tolerance. The agonists-antagonists of opioid receptors frequently
interact with more than one receptor and can activate one
type of opioid receptors and block other type of opioid receptors. These agents
have less addictive potential, less respiratory depression than opioid agonists.
Indeed, in practice, for the same degree of analgesia, the same intensity of adverse
effects occurs.
Indications for opioid analgesics use:
Analgesia in cases of tissue injury, nerve injury in some pathological conditions
and diseases, that lead to pain
Diarrhea
Cough
Acute pulmonary edema
Anesthesia & premedication
Contraindications for opioid analgesics use*:
Pregnance, lactation
Children (up to 2 years) and old age
Breath insufficiency, bronchial asthma, lung insufficiency
Hepatic and renal insufficiency
Traumatic brain injury, hemorrhagic stroke, convulsive state, psychostimulant
poisoning, drug
Idiosyncrasy to morphine
Cachexia, fever, myxedema
The syndrome of "acute abdomen."
* - The contraindications for opioid analgesics use are relative, not absolute.
Caution!
Do not use with antipsychotics, sedatives, hypnotics (depression of CNS and
depression of breath center) & MAO inhibitors (hyperpyrexia, hypertension)
Do not use in patients with hepar insufficiency and insufficiency of breath.
Indications for opioid agonists-antagonists and antagonists use

Drug addiction
Drug overdose
Side effects of opioid agonists.
Peculiarities of opioid analgesics use. Given many adverse effects,

morphine currently is rarely used, mainly during prolonged severe pain. Omnopon
rarely causes the severe adverse effects in comporison with morphine. Codein is
used mainly for relief of cough. In the application of pentazocine one should
consider its ability to increase blood pressure. One should take into account, that
medicinal form of nalbuphine contains sodium disulfide which can induce an
attack of breathlessness in patients with
bronchial asthma. Buprenorphine produces euphoria and addiction to a lesser

degree. Butorphanol does not have a marked influence on GIT sphincter tone and
GIT motility and tone of other smooth muscles. It increses pressure in lung artery,
general BP, and intracranial pressure, besides, has positive intropic effect.
Trimeperidine has moderate spasmolitic effect on smooth muscles of bronhi and
renal ducts, and in less degree increases the tone of intestine and bile ducts. At the
same time trimeperidine increases the tone of myometrium, badly passes through
the placental barrier in usually therapeutic doses, and can be used for analgesia
during labor. Fentanyl due to its short action is used for neuroleptanalgesia
together with neuroleptics (droperidol or haloperidol).
Dimenoxadol has analgesic and antitussive activity, moderate spasmolitic

effect on GIT and bronhi, and is used also for pain relief in parturition. The opioid
antagonists basically are used in case of acute intoxication by opiates, and in case
of abstinent syndrome in newborns whose mothers used drugs during pregnancy.
Tramadol is the drug with mixed mechanism of action: opioid and non-opioid. It is
an agonist of μ, δ, κ receptors, and it inhibits neuronal recapture of serotonin and
norepinephrine. In fact tramadol is a racemic mixture of RS(+/-) enantiomers. In
addition it has an analgesic effect and weak antitussive effect and sedative effect.
Methadone is used for control opiates abuse, of opioid dependence. It has cross-
tolerance with other opioids including heroin and morphine, offering very similar
effects and a longer duration of effect. Oral doses of methadone can stabilise
patients by mitigating opioid withdrawal syndrome. Higher doses of methadone
can block the euphoric effects of heroin, morphine, and similar drugs. As a result,
properly dosed methadone by patients can reduce or stop altogether their use of
these substances. Methadone is approved for different indications in different
countries. Common is approval as an analgesic and approval for the treatment of
opioid dependence. It is not intended to reduce the use of non-opioid drugs such as
methamphetamine, or alcohol. The principal effects of methadone maintenance are
to relieve narcotic craving, suppress the abstinence syndrome, and block the
euphoric effects associated with opiates.
In summary, it can be noted that opioid analgesics provide symptomatic

relief of pain, but underlying disease remains. The decision to control pain by
repeated introductions of opioid analgesics must be made cautiously. In cases of
pain is due to chronic nonmalignant diseases, conservative treatment of pain
should begin with use of non-opioid analgesics, local nerve blocks,
antidepressants, electrical stimulation, acupuncture, hypnosis, and behavioral
modification.
Table 38*. Pain management with opioids, and Equivalent doses of opioid
analgesics
This is only an approximate guide (doses may not correspond with those
given in clinical practice); patients should be carefully monitored after any
change in medication and dose titration may be required
Analgesic Route Dose
Codeine PO 100 mg
Diamorphine IM, IV, SC 3 mg
Dihydrocodeine PO 100 mg
Hydromorphone PO 2 mg
Morphine PO 10 mg
Morphine IM, IV, SC 5 mg
Oxycodone PO 6.6 mg
Tramadol PO 100 mg
PO = by mouth; IM = intramuscular, IV = intravenous, SC= subcutaneous

* - adopted from British National Formular 2013, www.bnf.org
Table 39. Buprenorphine patches are approximately equivalent to the following 24-
hour doses of oral morphine
morphine salt 12 mg daily ≡ BuTrans® ‘5’ patch
morphine salt 24 mg daily ≡ BuTrans® ‘10’ patch 7-day patches
morphine salt 48 mg daily ≡ BuTrans® ‘20’ patch
morphine salt 84 mg daily ≡ Transtec® ‘35’ patch
morphine salt 126 mg daily ≡ Transtec® ‘52.5’ patch 4-day patches
morphine salt 168 mg daily ≡ Transtec® ‘70’ patch
Note: Conversion ratios vary and these figures are a guide only. Morphine
equivalences for transdermal opioid preparations have been approximated
to allow comparison with available preparations of oral morphine
Table 40. 72-hour Fentanyl patches are approximately equivalent to the

following 24-hour doses of oral morphine
morphine salt 30 mg daily ≡ fentanyl ‘12’ patch
Note: Conversion ratios vary and these figures are a guide only. Morphine
equivalences for transdermal opioid preparations have been approximated to allow
comparison with available preparations of oral morphine
Table 41*. Summary of Drug Target and Site of Action of Common Drug Classes
and Relative Efficacy by Pain State
Drug cases Drug action Site of actiona Relative efficacy
(representative agents in pain strategyb
in parentheses)
NSAIDs (ibuprofen, Nonspecific COX Peripheral and Tissue injury >>
aspirin, inhibitors spinal acute stimuli =
acetominophen) nerve injury = 0
COX 2 inhibitors COX 2 selective Peripheral and Tissue injury >>
(celecoxib) inhibitors spinal acute stimuli =
nerve injury = 0
Opioids (morphine) µ receptor agonist Supraspinal and Tissue injury =
spinal acute stimuli ≥
nerve injury > 0
Anticonvulsants Na+ channel block, Supraspinal and Nerve injury >
2+
(gabapentin) α2δ subunit of Ca spinal tissue injury =
channel acute stimuli = 0
Tricyclic Inhibit uptake of 5- Supraspinal and Nerve injury ≥
antidepressants HT/NE spinal tissue injury >>
(amitryptiline) acute stimuli = 0
* adopted from Goodman & Gilman’s The Pharmacological Bases of THERAPEUTICS. 12tth
a - Studies based on local delivery in preclinical models, e.g., intracranial microinjection or
intraventriculal injections, lumbar intrathecal delivery or topical/sq application at injury site.
b - Pain state are defined by principal models: acute: hot plate/tailflick/acute mechanical
compression; tissue injury: intraplantarinjection of irritants, focal thermal injury; nerve injury:
compression/ligation of sciatic nerve or its branches or of nerve roots; systemic delivery of
chemotherapeutics.
Table 42. Medicinal forms of Opioid analgesics

Morphine MS Contin, Doltard, Powder in flacons; 0.3;
MSIR, Avinza, Kadian, Tablets;
Oramorph, Roxanol, Parenteral solution 0.01;
Kapanol (s/c, i/m, i/v) in 1% - 1 ml
ampoules
Fentanyl Fentonest, Leptonal, Parenteral solution 0.005% - 1 ml,
Sublimaze, Actiq, (i/m, i/v) in ampoules 2 ml, 10 ml
Durogesic, Sentonil,
Duragesic, Fentora,
Matrifen, Haldid,
Onsolis, Instanyl,
Abstral, Lazanda, etc.
Morphine hydrochloride + Papaveretum; Parenteral solution 1%, 2% - 1ml
Papaverine hydrochloride + (s/c) in ampoules;
Codeine; Tablets
Morphine+Narcotine + Omnopon
Papaverine hydrochloride
+ Codeine + Tebaine
Trimeperidine Promedolum Tablets; 0.025;

Parenteral solution 1%, 2% - 1 ml
(s/c, i/m, i/v) in
ampoules and in
ampins
Codeine Tussamag with codeine Powder;
Tablets; 0.015;
Syrup; 0.1% - 5 ml;
Peroral solution; 2%
Parcocet, Perdolan; Tablets;
Caffeine+Codeine+Acetylsa
licylic acid+Paracetamol; Tablets;
Caffeine+Codeine+Paraceta Caffetin;
mol+Propyphenazone; Tablets;
Caffeine+Codeine+Paraceta Plivalgin;
mol+Propyphenazone+Phen
obarbital; Tablets;
Caffeine+Codeine+Paraceta Pentalgin-N;
mol+Metamizole
sodium+Phenobarbital; Tablets;
Caffeine+Codeine+Naproxe Pentalgin-N, Pyralgin
n+Metamizole
sodium+Phenobarbital;
Codeine+Ipecacuanha Neo-Codion;
syrup; Syrup;
Paracodamol; 0.1% - 125 ml,
Panadein; Co-codamol; Tablets; 140 ml,180 ml
Cought control tablets;
Codeine+Sodium Tablets;
hydrocarbonate + Neo-Codion;
Glycyrrhizae radix + Tablets
Thermopsidis herba; HC Continus
Codeine+Sulfogaiacol+Grin
delia extract; Tablets
Dihydrocodeine
Dimenoxadol Dimenoxadoll Powder;
hydrochloridum, Tablets; 5, 15, 30, 60 mg
Dimenoxadol Parenteral solution 2% - 2 ml
hydrochloride, Estocin, (s/c, i/m) in ampoules
Lokarin, Propalgyl
Methadone; Phenadone, Amidone, Tablets 40 mg

Anadon, Dolophine,
Physeptone, Symoron,
Methadose Heptadone,
Levo-Polamidone,
Polamidone,
L-Methadone
Buprenorphine Bupranal, Bupremen, Tablets; 0.0002;
Buprenex, Bupresic, Parenteral solution 0.03% - 1 ml, 2 ml
Buprex, Lepetan, (s/c, i/m, i/v) in
Nopan, Norfin, ampoules
Norphine, Sangesic,
Temgesic
Butorphanol Stadol, Beforal, Parenteral solution 0.2%- 1 ml, 2 ml;

Moradol, Torate, (i/m, i/v) in ampoules,
Torbugesic, Torbutrol, in ampin;
Torgesic, Verstadol Aerosol for intranasal
introduction
1%
Nalorphine Lethidrone, Nalline, N- Parenteral solution for adults - 0.5% -
allyl-normorphine, (s/c, i/m, i/v) in 1ml;
Norfin, ampoules; for newborns - 0.05%
- 0.5 ml in the
umbilical vienna;
Sublingual tablets; 0.2 mg;
Tidigesic, Parenteral solution
(s/c, i/m, i/v, in the 0.03% -1 ml
umbilical vienna) in
ampoules
etc.
Nalbuphine Nubain Parenteral solution 1%, 2% - 1 ml;
(s/c, i/m, i/v) in
ampoules and in
flacons
1%, 2% - 10 ml
226 | Unit 5.
Pentazocine
Dolapent, Fortal, Tablets; 0.05;
Fortalgesic, Fortral, Parenteral 3% - 1 ml
Fortvin, Lexit, solution (s/c, i/m)
Magadolin, Pentagin, in ampoules
Sosegon, Sosenyl,
Sosigon, Talvin, etc.
Nalmefene Revex Parenteral 0.01% - 1 ml, 2 ml
solution (s/c, i/m,
i/v) in ampoules;
Tablets
25mg
Naloxone Narcan, Nalone, Parenteral 0.04% - 1ml;
Narcanti, Intrenon, solution (i/m, i/v)
in ampoules
Narcan neonatal 0.002% - 2 ml
Naltrexone Revia, Depade, Capsules; 0.05
Vivitrol,
Nalorex, Tablets 0.05
Tramadol Conzip, Ryzolt, Tablets; Capsules; 0.05;
Ultracet, Ultram, Tablets retard; 0.05;
Ralivia, Zytram XL, Peroral solution in 0.1, 0.15, 0.2;
Tramal flacons; 10ml, 20ml, 30ml, 50
Rectal ml, 100 ml;
suppositories; 0.1;
Parenteral
solution (s/c, i/m, 5% - 1ml, 2ml;
i/v) in ampoules 10% - 1ml
Chapter 13. Non-opioid analgesics (nonsteroid anti-

inflammatory drugs – NSAIDs)
Traditional NSAIDs (tNSAIDs) act by inhibition the prostaglandines G/H
synthase enzymes that known as the COX (see the Chapter 3). This inhibition of
COX 2 is a facilitator of antipyretic, analgesic, and anti-inflammatory action of
tNSAIDs. Simultaneously, inhibition of COX 1 leads to adverse effects in GIT.
All of known NSAIDs have anti-inflammatory, analgesic, and antipyretic
effects. The inflammatory response is characterized by transient local
vasodilatation, increased capillary permeability, infiltration of leukocytes and
phagocytes cells, tissue degeneration, and fibrosis and is accompanied by pain and
often - fewer. In these conditions prostanoid biosynthesis is greatly increased in
inflamed tissues. Inhibitors of COX that depress prostanoid formation are effective
and widely used anti-inflammatory drugs.
Inflammatory mediators increase the sensitivity of nociceptors and potentiate
pain perception. The main components of this inflammatory “mixture” are
bradykinin, H+, neurotransmitters such as serotonin and ATP, neutrophins (nerve
growth factor), LTs, and PGs, cytokines, some of neuropeptides, are involved in
eliciting pain. PGE2 and PGI2 decrease the threshold to stimulation of nociceptors,
exerting peripheral sensitization. The basic of peripheral component
Chapter 13. Non-opioid analgetics | 227
of analgesic activity of NSAIDs is reversal of peripheral sensitization. Besides,

NSAIDs have central component of reducing pain. These drugs have central action
in spinal cord and brain, the more so because both COX 1 and COX 2 are
expressed in the spinal cord. and release PGs in response to peripheral pain stimuli.
Centrally active PGE2, also PGD2, PGI2, and PGF2α facilitate to central
sensitization, an increase in excitability of spinal dorsal horn neurons that lead to
hyperalgesia and allodynia. Necessary to consider that chronic inflammatory
diseases may evoke persistent modification of the architecture of the nociceptive
system, and long-lasting changes in its responsiveness. This mechanism promotes
chronic pain.
In human body hypotalamus regulates body temperature. The temperature is
lelvated in response to an infection, tissue damage, inflammation, graft rejection,
or malignancy. All these conditions increase formation of cytokines that act as
endogenous pyrogens. The initial phase of the thermoregulatory response is
mediated by ceramide release in neurons in the anterior hypothalamus. The late
response is mediated by coordinate induction of COX 2 and microsomal PGE
synthase-1 in the blood vessel edndotelium in hypothalamus to form PGE2 which
can cross BBB and act on EP3 and EP1 receptors on termosensitive neurons. This
motivates hypothalamus to raise body temperature by increasing in heat generation
and decreasing in heat lost. NSAIDs suppress this process by inhibition PGE2
synthesis.
Mechanism of action of NSAIDs are the inhibition of PG production and
thereby inhibition of first enzyme in the PG synthesis – COX, also known as PG
G/H synthase. This enzyme converts AA to the unstable intermediates PGG2 and
PGH2, and causes release of the prostanoids, TxA2, and series of PGs. COX 1 is
expressed in most cells, is a dominant (but not exclusive) source of prostanoids for
maintance functions, such as gastric epitelial cytoprotection and hemostasis. COX
2, induced by cytokines, is more important source of prostanoid formation in
inflammation and possibly in cancer. So, both enzymes COX 1 and COX 2
promote to formation of autoregulatory and homeostatic prostanoids, and can
facilitate to prostanoid formation in human inflammation and pain (see above).
NSAIDs do not inhibit lipoxygenase (LOX) pathway of AA methabolism
and consequently do not suppress LT formation.
Indications for NSAIDs use:
Pain of mild and moderate intensity
Fever
Inflammation in some tissues
Musculoskeletal disoders, such as rheumatoid arthritis, and osteoarthritis,
ankylosing spondylitis
Gout
Mild arthropaties
To close inappropriately patent ductus
As an antiplatelet drugs in patients with cardiovascular diseases and
atherosclerosis
| Unit 5. Drugs affecting the Central Nervous System
Systemic mastocytosis
Bartter syndrome (hypokalemic, hypochloremic, metabolic alkalosis with
normal BP and hyperplasia of the juxtaglomerular apparatus) – in complex
therapy
Cancer chemoprevention
Alzheimer’s disease
Adverse effects of NSAIDs use:
GI system: abdominal pain, nausea, diarrhea, anorexia, gastric erosions/ulcers*,
GI hemorrhage**, perforation/obstruction*
Platelets: inhibited platelet activation*, propensity for bruising*, increased risk
of hemorrhage*
Renal: salt and water retention, edema, worsening of renal function in
renal/cardiac and cirrhotic patients, decreased effectiveness of
antihypertensive medications, decreased effectiveness of diuretics, decreased
urate excretion (especially with aspirine), hyperkalemia
Cardiovascular: closure of ductus arteriosus, myocardial infarction**,
stroke**, thrombosis**
CNS: headache, vertigo, dizziness, confusion, hyperventilation (salicylates);
Uterus: prolongation of gestation, inhibition of labor
Hypersensitivity: vasomotor rhinitis, angioneurotic edema, asthma,urticaria,
flushing, hypotension, shock
Aspirin resistance: the precise mechanism of this phenomenon is not clear;
Bronchospasm***
Reye’s syndrome (salicylates): is a severe and often fatal disease, is
characterized by acute encephalopathy, liver dysfunction, and fatty
infiltration of the liver and other viscera. The etiology and pathophysiology
of it are not clear, but relationship between aspirin and Reye’s syndrome
exists
Cardiac insufficiency, arrhythmogenesis****
* - side effects decreased with COX 2-selective NSAIDs
- with the exception of low-dose aspirin
- there is no this side effect in case of COX 2-selective NSAIDs
- side effects increased with COX 2-selective NSAIDs
Contraindications for NSAIDs use:
Children and adults under 20 years (high risk of Reye’s syndrome)
cautiously apply in old patients, in patients with cardiovascular diseases, GI
diseases, Helicobacter pylori infection, heavy alcohol consumption, or other
risk factors for mucosal injury, including glucocorticoid use
Hypersensitivity
Pregnancy
Lactation
Bronchial asthma, obstructive bronchitis
Drug interactions. Angiotensine-converting enzyme (ACE) inhibitors act
by partly prevention of breakdown of kinins that stimulate PG production. So,
NSAIDs reduce the effectiveness of ACE inhibitors. By virtue of hyperkalemia
(the side effect of both NSAIDs and ACE inhibitors) may arise bradycardia,
syncope. Corticosteroids and selective serotonin reuptake inhibitors (SSRIs) in
case of combined use with NSAIDs may increase the frequency or severity of GI
disorders. Anticoagulants may enhance the risk of hemorrhages when are used
together. NSAIDs are highly bound to plasma proteins and may displace other
drugs (warfarin, sulfonylurea hypoglycemic drugs, methotrexate, etc.) from their
binding sites that require the regulation of the drug dosage to prevent toxicity.
Table 43*. Classification and some features of NSAIDs
Class/Drug Pharmaco Comments Compared to

kinetics Aspirin
Salicylates
Aspirin (acetyl Peak Cpa 1hour Permanent platelet COX1
ester) Protein binding 80- inhibition in dose less
90% than 300mg/day
Metabolitesb - (acetylation).
salicyluric acid Main side effects: GI,
T1/2c, therapeutic increasing bleeding time,
dose - 2-3 hours hypersensitivity.
T1/2, toxic dose - Avoid in children with
15-30 hours acute febrile illness.
Antidote for Aspirin is
Sodium bicarbonate
(sodium hydrogen
carbonate), carbo
activates
Diflunisal Peak Cp 2-3 hours Not metabolized to Analgesic and
(defluorophenyl) Protein binding salicylic acid. anti-
99% Competitive COX inflammatory
Metabolites - inhibitor. effects
glucuronide Excreted into breast milk. 4-5 times more
T1/2 8-12 hours potent.
Antipyretic
effect weaker.
Fewer platelet
and GI side
effects.
Para-amonophenol derivative
Acetaminophen Peak Cp 30-60 min Weak nonspecific Analgesic and
Protein binding 20- inhibitor at common antipyretic
50% doses. effects
Metabolites - Potency may be equivalent.
glucuronide modulated by peroxides. Anti-
conjugates (60%); Overdose leads to inflammatory,
sulfuric acid production of toxic GI and platelet
conjugates (35%) metabolite and liver effects less than
230 | Unit 5.
1/2
T 2 hours necrosis. aspirin at 1000

The risk of liver necrosis mg/day
is elevated with hereditary
deficiency of glucose-6-
phosphate dehydrogenase.
It does not form the toxic
metabolites in children to
12 years old due to
immaturity of cytochrome
P450 enzyme system.
Antidote for
acetaminophen is
acetylcysteine, carbo
activatus.
Acetic acid derivatives
Indomethacin Peak Cp 1-2 hours Side effects (3-50% of 10-40 x more
Protein binding patients): frontal potent.
90% headache, neutropenia, Intolerance
Metabolites - O- thrombocytopenia; limits dose
demethylation 20% discontinue therapy
(50%);
Unchanged (20%)
T1/2 2.5 hours
Sulindac Peak Cp 1-2 hours; 20% suffer GI side Efficacy
(sulfoxide 8 hours for sulfide effects; 10% get CNS side comparable
prodrug) metabolite; effects
extensive
enterohepatic
circulation
Metabolites -
sulfone and
conjugates (25%)
T1/2 7 hours; 18
hours for metabolite
Etodolac Peak Cp 1 hours Some COX 2 selectivity 100mg etodolac
(pyranocarbolic Protein binding in vitro has similar
acid) 99% efficacy to 650
Metabolites - mg of aspirin,
hepatic metabolites but may be
T1/2 7 hours better tolerated
Tolmetin Peak Cp 20-60 min Food delays decreases Efficacy
(heteroaryl Protein binding peak absorption. similar.
acetate 99% May persist longer in 25-40%
derivative) Metabolites - synovial fluid to give a develop side
oxidized to biological efficacy longer effects.
carboxylic than its plasma T1/2 5-10%
acid/other discontinue
Chapter 13. | 231
Non-opioid analgetics
derivatives, then drug
conjugated
T1/2 5 hours
Ketorolac Peak Cp 30-60 min Commonly given Potent
(pyrrolizine Protein binding parenterally (60mg i/m analgesic, poor
carboxylate) 99% followed by 30mg every 6 anti-
Metabolites - hours, or 30mg i/v every 6 inflammatory
glucuronide hours).
conjugate (90%) Available as ocular
T1/2 4-6 hours preparation (0.25%); 1
drop every 6 hours
Diclofenac Peak Cp 2-3 hours Available as topical gel, More potent.
(phenyllacetate Protein binding ophthalmic solution, and 20% develop
derivatives) 99% oral tablets combined with side effects.
Metabolites - misoprostol. 2% discontinue
glucuronide and First-pass effect; oral use.
sulfide (renal 65%, biovailability, 50%. 15% develop
bile 35%) High doses and prolonged elevated liver
T1/2 1-2 hours use of the drug increases enzymes
the risk of stroke
Fenamates (N-phenyl-anthranilates)
Mefenamic acid Peak Cp 2-4 hours Isolated cases of Efficacy
Protein binding - homolytic anemia. similar.
High May have some central GI side effects
Metabolites - action (25%)
conjugates of 3-
hydroxy and 3-
carboxyl
metabolites (20%
recovered in feces)
T1/2 3-4 hours
Meclofenamate Peak Cp 0.5-2 hours Efficacy
Protein binding - similar.
99% GI side effects
Metabolites - (25%)
hepatic metabolism;
fecal and renal
excretion
T1/2 2-3 hours
Flufenamic acid Not evailable in
U.S.
Propionic acid derivatives
Ibuprofen Peak Cp 15-30 min 10-15% discontinue due Equipotent
Protein binding to adverse effects.
99% Children’s dosing
Metabolites - Antipyretic: 5-10mg/kg
232 | Unit 5.
conjugates of every 6 hours (max:
hydroxyl and 40mg/kg/day)
carboxyl Anti-inflammatory: 20-
metabolites 40mg/kg/day in 3-4
T1/2 2-4 hours divided doses
Naproxen Peak Cp 1 hour Peak and anti- More potent in
Protein binding inflammatory effects may vitro; usually
99% (less in not be seen until 2-4 better tolerated;
elderly) weeks of use variably
Metabolites - 6- prolonged T1/2
demethyl and other may afford
metabolites cardioprotectio
T1/2 14 hours n in some
individuals
Fenoprofen Peak Cp 2 hours 15% experience
Protein binding side effects;
99% few
Metabolites - discontinue use
glucuronide, 4-OH
metabolite
T1/2 2 hours
Ketoprofen Peak Cp 1-2 hours 30% develop
Protein binding side effects
98% (usually GI,
Metabolites - usually mild)
glucuronide
conjugates
T1/2 2 hours
Flurbiprofen Peak Cp 1-2 hours Available as a 0.03%
Protein binding ophthalmic solution
99%
Metabolites -
hydroxylates and
conjugates
T1/2 6 hours
Oxaprozin Peak Cp 3-4 hours Long T1/2 alows for daily
Protein binding administration; slow onset
99% of action; inappropriate
Major metabolites - for fever/ acute analgesia
oxydates and
glucuronide
conjugates
T1/2 40-60 hours
Enolic acid derivatives
Piroxam Peak Cp 3-4 hours May inhibit activation of Equipotent;
Protein binding neutrophils, activity of perhaps better
Chapter 13. | 233
99%
proteoglycanase, tolerated
Metabolites - collagenases 20% develop
hydroxylates and side effects;
then conjugated 5% discontinue
T1/2 45-50 hours drug
Meloxicam Peak Cp 5-10 hours Some COX 2
Protein binding selectivity,
99% especially at
Metabolites - lower doses
hydroxylation
T1/2 15-20 hours
Nabumetone Peak Cp 3-6 hours A prodrug, rapidly Shows some
(naphthyl Protein binding metabolized to 6- COX 2
alkanone) 99% methoxy-2-naphthyl selectivity
Metabolites - O- acetic acid; (active
demethylation then pharmacokinetiks reflect metabolite does
conjugation active compound not) Fewer GI
T1/2 24 hours side effects than
many NSAIDs
Diaryl heterocyclic NSAIDs (COX 2 selective)
Evidance for Decrease in GI
cardiovascular adverse side effects and
events in platelet
effects
Celecoxib [diaryl Peak Cp 2-4 hours Substrate for CYP2C9, see the text for
substituted Protein binding inhibor of CYP2D6 an overview of
pyrazone; 97% Coadministration with COX 2
(sulfonamide Metabolites - inhibitor CYP2C9 or inhibitors
derivative)] carboxylic acid and substrates of CYP2D6
glucuronide should be done with
conjugates caution
T1/2 6-12 hours
Paracoxib Not approved for
Etoricoxib use in U.S.
Lumaricoxib
* adopted from Goodman & Gilman’s The Pharmacological Bases of THERAPEUTICS. 12 th
edition. Medical. 2011. – 2084 P. with autor’s changes and additions.
a - Time to peak plasma drug concentration (Cp) after a single dose.
b - The majority of NSAIDs undergo hepatic metabolism, and the metabolites are excreted in the
urine.
c - Typical t1/2 is listed for therapeutic doses; if t1/2 is much different with the toxic dose, this is
also given.
Classification of NSAIDs according mechanism of action
1. Selective COX 1 inhibitors:

Acetylsalicylic acid in dose less than 300 mg
Selective (Specific) COX 2 inhibitors:
Lornoxicam
Meloxicam
Nimesulide
Nabumetone
Etodolac
Highly selective COX 2 inhibitors:
Celecoxib
Parecoxib
Valdecoxib
Etoricoxib
Rofecoxibe
Nonselective (Nonspecific) COX inhibitors (COX 1 and COX 2):
Acetylsalicylic acid in dose more than 300 mg
Diclofenac sodium
Indometacin
Ibuprofen
Piroxicam
Classification of NSAIDs according their action on

articular cartilage metabolism
Inhibitors of glycosaminoglycan biosynthesis:

Acetylsalicylic
acid Indometacin
Ibuprofen
Fenoprofen
Phenylbutazone
No effect on glycosaminoglycan biosynthesis:
Meloxicam
Piroxicam
Diclofenac
sodium Sulindak
Stimulators of glycosaminoglycan biosynthesis:
Paracetamol
Tiaprofenic acid
Classification under the influence of some NSAIDs on the metabolism of

articular cartilage is presented in connection with the use of these drugs mainly in
the pathology of joints. When inflammation of the articular cartilage is excessive
destruction of molecules of glycosaminoglycans (GAG) and collagen fibers,

resulting in an articular cartilage becomes thinner and is unable to effectively
perform its biological functions. Unlike corticosteroids, NSAIDs differently affect
the biosynthesis of GAG, the processes of cell proliferation, collagen biosynthesis,
and catabolic processes in cartilage. And if you do not consider the effects of
NSAIDs on the metabolism of articular cartilage, can worsen the articular
syndrome.
In summary, tNSAIDs and COX 2 selective inhibitors have anti-
inflammatory, analgesic, and antipyretic activity due to inhibition of PG
biosynthesis. Nonselective inhibitors of COX (tNSAIDs) induce GIT adverse
effects. Selective inhibitors of COX 2 were synthesized to reduce these GIT
adverse effects, but have never been shown advantages in efficiency of COX 2
selective inhibitors over tNSAIDs. Besides, COX 2 selective inhibitors most have
been eliminated from the market due to cardiovascular and hepatic toxicities. They
provide an increased risk of heart attack and stroke. The mechanism of the
cardiovascular hazard is based on acceleration of atherogenesis directly via
inhibition of PGI2 and indirectly by virtue of elevate in BP due to inhibition of
COX 2-derived PGE2 and PGI2. The patients with risk of cardiovascular diseases
or prone to thrombosis (including Leiden mutation or concomitant therapy, such as
oral contraceptives, smoking, alcohol abuse, etc.) should be treated by analgesics
that do not interfere with platelet action.
The NSAIDs with more rapid onset of action, shorter duration of action are
preferable for a temperature control in case of acute viral diseases, and of a pain
control after minor musculoskeletal injuries, or headache. At the same time
NSAIDs with a longer duration action may be preferable for management of
postoperative and arthritic pain.
Table 44. Medicinal forms of NSAIDs.

Acetylsalicylic acid Аспро, Acesal, Tablets; 0.1, 0.25, 0.5
Aceticyl, Acetol,
Acetophen, Acetosal,
Acetylin, Acetylsal,
Acetysal, Acylpyrin,
Aspirin, Aspisol,
Asposal, Aspro, Astrin,
Ataspin, Bayaspirin,
Bebaspin, Benaspir,
Bispirine, Caprin,
Cetasal, Citopyrine,
Clariprin, Darosal,
Durasal, Easprin,
Endosalil, Endospirin,
Eutosal, Genasprine,
Helicon, Isopirin,
Istopirin, Monasalyl,
236 | Unit 5.
Novosprin, Panspiril,
Polopiryna, Prodol,
Rodopyrin, Ruspirin,
Salacetin, Saletin,
Temperal, Vicapirine,
Zorprin, etc.
Aspirin cardio;
Thrombo ASS;
Aspilite, Aspirin
“York”, Aspirin
“Quolity”, Aspirin-
Milton, Aspirin UPSA, Tablets; 0.1, 0.3;
Bufferan, Bufferin, Tablets; 0.05, 0.1;
Novandol, NU-seals 75 Tablets 0.325
cardio-aspirin
Acetylsalicylic acid, lysine Acelysin, Aspisol- Powder for per 1.6, 2.6;
salt - Lysine acetylsalicilat Aspirinum solubile, oral solution;
Aspidol, Delgesic, Powder for
Draspir, Egalgic, injections (i/m,
Flectadol, Injesprin, i/v) in flacons 1.0; 2.0
Laspal, Laboprin,
Lasdol, Lisaspin,
Lysoprin, Salisyn,
Solpirin, Solusprin,
Venopirin etc.
Sodium salicylate Enterosalyl, Glutosalyl, Tablets; 0.25, 0.5;
Nadisal, Natrii Parenteral 10% - 5.0 ml,
salicylas, Salicine, solution (i/v) in 10 ml
Saliglutin, Salitin, etc. ampoules
Salicylamide Algamon, Salamide, Tablets 0.25, 0.5
Saliamid, Salopur,
Urtosal, etc.
Methylii salicylas; Methylis salicylas, Ointment; 10% - 25.0;
Methylium salicylicum;
Camphor + Methyl Sanitas; Liniment; 50.0;
salicylate + Terbinthinae
oleum + Eucalypti oleum;
Methyl salicylate + menthol Boum-Benge; Ointment; 20.0, 25.0, 35.0,
+ vaseline + paraffin; 40.0;
Methyl salicylate + Analgin
+ petroleum + cachalot fat; Naphthalginum Liniment; 100.0;
Hyoscyami oleum + Methyl
salicylate + Capsici tinctura;
Hyoscyami oleum + Methyl Capsinum; Liniment; 50.0, 100.0,
salicylate + Chloroform; Liniment; 50.0;
Hyoscyami oleum + Methyl
salicylate + Chloroform Linimentum Methylii Liniment 30.0, 40.0, 50.0,
salicylatis compositum; 80.0
Salinimentum
Metamizole sodium Analginum, Tablets; 0.05, 0.1, 0.15,
Algocalmin, Algopyrin, 0.5;
Chapter 13. | 237
Analgetin, Baralgin M, Calsules; 0.25;
Devalgin, Dipyrone, Rectal 0.1, 0.2, 0.3;
Ilvagin, Metamizole suppositories;
sodium, Metapyrin, Parenteral 25%, 50% - 1 ml,
Methylmelubrin, solution (i/m) in 2 ml;
Minalgin, Nebagin, ampoules;
Neomelubrin, Nobol, Peroral solution 50% - 1 ml, 20 ml,
Novaldin, Novalgin, in flacons 50 ml
Novamidazophen,
Novaminosulfon,
Novapyrin, Optalgin,
Pantalgan, Pyralgin,
Pyretin, Pyridone,
Pyrisan, Ronalgin,
Spasdolgin, Sulpyrin,
Toralgin, Totalgine,
Vetalgin, etc.
Phenylbutazone; Butadionum, Alindor, Tablets; 0.03, 0.05, 0.15;
Antadol, Arthril, Ointment; 5% - 20.0;
Arthrizon, Artrizin,
Artropan, Azobutil,
Butalan, Butapirazol,
Butartril, Butazolidin,
Butazone, Butofar,
Butosal, Butylpyrin,
Colbutan, Curosoladin,
Delbutan, Deltabutanyl,
Dibutone,
Diphenylbutazon,
Elmedal, Eributazone,
Fenibutasan,
Fenibutazona,
Fenylbutazon,
Mephabutazon,
Merizone, Nadozone,
Novophenyl, Panazone,
Phebutan, Phenbutazol,
Phenopyrine,
Phenylbutazone,
Rheumaphen,
Rubatone, Sedazole,
Todalgil, Zolaphen,
etc.;
Phenylbutazone + Pyrabutol; Dragee; 0.125 + 0.125;
aminofenazon;
Phenylbutazone + Rheopyrin Dragee, 0.125 + 0.125;
aminofenazon Parenteral 5 ml
solution (i/m) in
ampoules
Acetaminophen Paracetamol; Tablets; 0.125, 0.2, 0.325,
Abesanil, Acamol, 0.5, 0.008;
238 | Unit 5.
Acelifen, Acemol, 0.08, 0.15, 0.24;
Acetalgin, Powder for
Acetaminophen, peroral solution;
Acetaminophenol, Peroral 2.4% - 70 ml;
Actasol, Adol, Aldolor, suspension; 10 0ml; 300 ml;
Algotropyl, Alvedon, 5% - 100 ml;
Aminadol, Aminophen, 10% - 15 ml;
Amphenol, Apamide, Peroral solution 2.4%- 60 ml;
Apanol, Bartell drugs in flacons; 100 ml;
analgetic apap, Syrup; 3% - 90 ml;
Bindard, Biocetamol, 2.4% - 50 ml;
Calpol, Celifen, 100 ml;
Cetadol, Cetanil, 2.5% - 60 ml;
Chemcetaphen, 100 ml; 120 ml;
Daleron, Dapirex, 3.2% - 30 ml;
Datril, Deminofen, 120 ml;
Dexa-mol, Dimindol, 4% - 60ml; 120ml;
Dolamin, Dolanex,
Dolipram, Dolo, Rectal 0.05, 0.08, 0.1;
Dolomol, Dominophen, suppositories; 0.125, 0.15, 0.25,
Dynafed, Efferalgan, 0.3, 0.5;
Erocetamol, Febricet, Parenteral 15% - 2 ml
Febridol, Febrinil, solution in (i/m,
Febrinol, Fendon, i/v) ampoules;
Ifimol, Lekadol, Eye films
Lupocet, Medipyrin,
Mexalen, Minoset,
Myalgin, Napa,
Napamol, Naprinol,
Nasprin, Nysacetol,
Opradol, Pacemol,
Pacimol, Pamol,
Panadol, Panadon,
Paracetamol, Paracinol,
Paramol, Perfalgan,
Prohodolum, Pyranol,
Pyrimol, Pyrinazin,
Rolocin, Sanidol,
Strimol, Tempramol,
Tralgon, Tylemin,
Tylenol, Ushamol,
Valadol, Valgesic,
Valorin, Volpan,
Winadol, etc.
Indomethacin Algometacin, Articin, Tablets; 0.005, 0.01, 0.025,
Artrizinal, Artrocid, 0.025;
Bonatol, Cidalgon, Dragee; 0.025, 0.03, 0.05;
Cinodocin, Capsules; 0.075;
Cosmocalm, Dolopas,
Dolovin, Elmetacin, Capsules retard; 0.05, 0.1;
Fortarthrin, Inacid, Rectal
Chapter 13. | 239
Indacin, Indocid, suppositories; 3% - 2ml;
Indometacin, Parenteral
Indomethacin, solution (i/m) in
Indomin, Indopal, ampoules; 1%, 10% - 50.0;
Indren, Inteban, Gel in tubes; 100.0;
Melitex, Metacen, 5%, 10% - 30.0;
Mataril, Matartril, Ointment; 40.0;
Methacid, Mathindol, 0.1%, 1%
Metindol, Nuricon, Eye suspension
Peralgon, Phenotacin,
Rumacid, Reumadolon,
Reumatin, Sadoreum,
Valicent, Vellopan, etc.
Diclofenac-natrium Voltaren, Ortophen, Tablets; 0.015, 0.025;
Aflamin, Almiral, Apo- Rectal 0.05;
Diclo, Arthrex, Batafil, suppositories;
Betaren, Bioran, Parenteral 2.5% - 3 ml;
Blesin, Clofenac, solution (i/m) in
Delimon, Diclac, Diclo, ampoules;
Diclobene, Dicloberl, Ointment in 2% - 30.0;
Diclofen, Diclofenac, tubes;
Diclogen, Diclogesic, Eye drops in - 0.1% - 1 ml;
Diclomax, Diclomelan, dropper –
Diclonac, Diclonat, flacons;
Dicloran, Diclorium,
Diclovit, Difisal,
Dignofenac,
Diklofenak, Diphen,
Diralon, Ecofenac,
Effecton, Feloran,
Forgenac, Inflanac,
Linobol, Naklof,
Naklofen, Neodol,
Novo-Difenac, Olfen,
Panamor, Prophenatin,
Remetan, Rewodina,
Rheumavek,
Rumaphen, Sanfinac,
Skip, Sofarin,
Sorelmon, Ultrafen,
Umeran, Valetan,
Veral, Vernac,
Voltaren, Voltarol,
Vonafec, Votaxil,
Votrex, Youfenac;
Dicloberl retard,
Diclonat P retard,
Difisal-SR, Rewodina
retard, Rumaphen-SR,
Feloran retard,
Voltaren retard 100; Tablets; 0.1;
240 | Unit 5.
Voltaren Emulgel Gel 1%
Aceclofenac Airtal Tablets 0.1
Ibuprophen Advil, Algofen, Tablets; 0.2, 0.4, 0.6, 0.05,
Anflagen, Artofen, 0.1;
Artril, Bren, Brufanic, Dragee; 0.2;
Brufen, Bufigen, Tablets retard; 0.8;
Burana, Children’s Capsules retard;
Motrin, Deef Relief, Syrup in 0.3;
Dolgit, Ebufac, flacons;
Iborufen, Ibalgin, Sispension for 100 ml, 200 ml;
Ibumetin, Ibuprofen, peroral
Ibupron, Ibusan, introduction;
Ibutad, Ibutop, Inflam, Peroral solution 2% - 60ml, 100ml;
Ipren, Lamidon, in flacons;
Marcofen, MIG 200, Cream in tubes; 4% - 15ml;
Mortifen, Motrin, Gel 5% - 20.0, 50.0,
Napacetin, Nobfen, 100.0;
Nuprin, Nurofen, 10% - 30.0
Paxofen, Profen,
Profinal, Rebugen,
Relcofen, Reumafen,
Ruprin, Seclodin,
Sednafen, Solpaflex
Naproxen Aleve, Anaprox, Tablets; 0.22, 0.25, 0.275,
Antalgin, Feminax 0.375, 0.5, 0.55;
Ultra, Flanax, Inaprol,
Inza, Midol Extended, Peroral 2.4%, 2.5% -
Methoxypropriocin, suspension in 100 ml;
Relief, Nalgesin, flacons;
Naposin, Naprelan, Rectal 0.25, 0.5
Naprogesic, Naprosyn, suppositories
Narocin, Proxen,
Pronaxen, Synflex,
Sanaprox, Xenobid,
Xenar, etc.
Etodolac Elderin Tablets 0.2, 0.3
Fenoprofen Nalfon Tablets 0.2, 0.3
Tolmetin Tolеctin Tablets; 0.2, 0.6;
Capsules 0.4
Ketoprofen Alreumant, Artrozilen, Tablets; 0.05, 0.1;
Asozal, Dexal, Tablets retard; 0.15;
Febrofid, Flamax, Capsules; 0.05;
Flexen, Kefenid, Capsules retard; 0.2;
Ketolist retard, Rectal
Ketoprosil, Meprofen, suppositories; 0.1;
Niflam, Oruvеil, Sprey; 5% - 50 ml;
Ostofen, Reumoquin, Powder for 0.1
Synpofen, Orudis, parenteral
Oruvail, Ketoflam, injections (i/m,
Ketorin, Keto, i/v) in
Ketomex, Orudis', ampoules;
Chapter 13. | 241
Profénid, Bi-Profénid, Parenteral 5% - 2 ml;
Ketum, Ketodol, solution (i/m,
Fastum Gel, Lasonil, i/v) in
Orudis, Oki, Knavon, ampoules;
Ketonal, Arthril, Zon, Gel in tubes; 2.5% - 30.0, 50.0,
Orudis, OKI, Gesiket 60.0;
"ATM", Actron, Cream in tubes; 5% - 30.0;
Ketoprofeno, etc.;
Dexalgin 25;
Dexalgin Tablets; 25 mg;
Dexketoprofen Parenteral 25 mg/1 ml - 2 ml
solution (i/m,
i/v) in ampoules
Flurbiprophen Urbifen, Ansaid, Tablets; 0.1;
Flurwood, Froben,
Raxtan-Sanovel,
Strepsils intensive, Lingual tablets; 8.75 mg;
Tablets; 0.05, 0.1;
Flugalin Capsules retard; 0.2;
Rectal
suppositories; 0.1;
Gel 5% - 15.0; 30.0
Pyroxycam Piroxicam, Doblexan, Tablets; 0.01, 0.02;
Piroksan, Roxicam, Rectal 0.01; 0.02;
Zunden, Algitrat, Pirox, suppositories;
Androxicam, Apo- Gel in tubes; 0.5% - 35.0; 50.0;
Piroxicam, Brexic-DT, 2% - 1ml; 2ml
Calmapirol, Parenteral
Calmopirol, Erason, solution (i/m) in
Feldene, Flexase, Gen- ampoules
Piroxicam, Hotemin,
Novo-Piricam,
Pirocam, Piroflam,
Pirorheum,
Piroxiferum,
Piroxiflam, Pro-naxen,
Remoxicam, Reucam,
Sanicam, Toldin, etc.
Tenoxycam Tenicam, Tenoktil, Capsules; 0.02;
Tilcotil, Tobitil Tablets; 0.02;
Rectal 0.02
suppositories
Meloxycam Lem, Melox, Meloxam, Tablets; 0.0075, 0.015;
Mirlox, Movalis. Rectal 0.015
suppositories
Lornoxycam Xefocam Tablets; 0.004, 0.008;
Powder for 0.008
parenteral
injections (i/m,
i/v) in ampoules
Amizon Amizon Max Capsules; 0.5;
242 | Unit 5.
Tablets; 0.25;
Syrup in flacons 10mg/1ml - 100ml
Celecoxib Celebrex Capsules 0.1; 0.2
Rofecoxib Viox Tablets; 0.0125; 0.025;
Peroral 0.25%, 0.5% -
suspension in 150 ml
flacons
Parecoxib Dynastat Lyophilized 0.04
powder for
parenteral
injections (i/m,
i/v) in flaconis
Valdecoxib Bextra Tablets 0.01, 0.02, 0.04
Etoricoxib Arcoxia Tablets 0.06, 0.09, 0.12
Nimesulide Aponil, Coxtral, Flolid, Tablets; 0.1, 0.2;

Mesulid, Nimfast, Granules for 2.0;
Nimica, Nimulide, peroral solution
Nize in sachets;
Peroral
suspension in 1% - 60 ml;
flacons;
Transdermal gel
in tubes 1% - 20.0
Niflumic acid Donalgin, Acidum Capsules; 0.25;
niflumicum, Artricid, Rectal 0.4; 0.7;
Dimepon, Dontalgan, suppositories;
Felalgyl, Flaminor, Gel in tubes; 2.5% - 60.0;
Forenol, Inflaril, Cream in tubes 3% - 60.0
Niduran, Niflamol,
Nifluran, Niflux,
Panreumal, Pefamexan
Nabumetone Relafen, Rodanol S Tablets 0.5, 0.75, 1.0
Tiaprofenic acid Surgam Tablets for 0.1; 0.15;
children;
Tablets for 0.3;
adults;
Tablets and 0.3;
capsules retard;
Rectal 0.15;
suppositories
for children;
Rectal 0,3;
suppositories
for adults;
Powder for 0.2
injections (i/m)
in flacons
Mephenamic acid Coslan, Lysalgo, Tablets 0.25, 0.5
Parkemed, Ponstan,
Chapter 13.
Non-opioid analgetics | 243
Ponstel, Ponstyl,
Pontal, Tanston etc.
Ketorolac Adolor, Dolak, Tablets; 0.01;
Ketanov, Ketorol, Parenteral 3% -1 ml
Ketorolac solution (i/m,
Trometamine, i/v) in ampoules
Ketrodol, Nato,
Toradol, Torolac.
Diphlunizolum Adomal, Algobid, Tablets 0.25, 0.5
Cididol, Di-flonid,
Diflunil, Dolisal,
Dolobid, Flovacil,
Flunidor, Flu-o-donil,
Noalodol
Nefopam Oxadol; Tablets; 30 mg;
Parenteral 2% - 1 ml;
solution (i/m,
i/v) in
ampoules;
Akupan-Biocodex Parenteral 2% - 2 ml
solution (i/m,
i/v) in ampoules
Combined analgesics
Metamizole + Pitofenone + Renalgan Tablets; 0.5 + 0.005 +
Fenpiverinium 0.0001;
Parenteral 2 ml
solution (i/m,
i/v) in ampoules
Diclofenac + Misoprostol Artrotec Tablets
Paracetamol + Codeine Prodein Tablets 0.5 + 0.03
Acetylsalicylic acid + Citramonum P, Capsules 0.24 + 0.18 + 0.03
Paracetamol + Caffeine Citraparum
Acetylsalicylic acid + Citrapacum Tablets 0.24 + 0.18 + 0.03
Paracetamol + Caffeine + + 0.05 + 0.005
Accorbic acid + Citric acid
Acetylsalicylic acid + Ascophenum P Tablets 0.2 + 0.2 + 0.04
Paracetamol + Caffeine
Paracetamol + Caffeine + Gripocide Capsules
Chlorphenamine + Vit.C
Paracetamol + Dicyclomine Cyclopar Tablets 0.5 + 0.02
hydrochloride
Paracetamol + Grippostad Capsules 0.2 + 0.15 + 0.025
Acetylsalicylic acid + + 0.0025
Caffeine +
Chlorpheniramine
Paracetamol + Methamisol Sedalgin-Neo Tablets 0.3 + 0.15 + 0.05
sodium + Caffeine + + 0.015 + 0.01
Phenobarbitale + Codeine
phosfas
Methamisol sodium + Baralginum Tablets;
Pitofenone + Fenpiverinium Parenteral 5ml
244 | Unit 5.
bromide solution (i/m,
i/v) in ampoules
Propiphenason + Spasmoveralgin-Neo Tablets 0.15 + 0.02 + 0.03
Phenobarbitale Papaverine + 0.015 + 0.005 +
hydrochloride + Codeine 0.0005
dihydrophosfas +
Ephedrinum chloride +
Atropine metabromide
Codeine + Methamisol Tempalgin Tablets 0.008 + 0.03 +
sodium + Caffeine + 0.05 + 0.01
Phenobarbitale
Phenylbutason + Pyrabutol Tablets aa 0.125
Aminophenosonum
Phenylbutason + Rheopyrin Dragee; aa 0.125;
Amydasophenum Parenteral 5 ml
solution (i/m,
i/v) in ampoules
Phenylbutazone + Ambene
dexametazone
Clofexamide + Clofezone Rectal 0.4
Phenylbutason suppositories
Acetylsalicylic acid + Thomapyrin Tablets 0.25 + 0.2 + 0.05
Paracetamol + Caffeine
Acetylsalicylic acid + Thomapyrin C Tablets 0.25 + 0.2 + 0.2
Paracetamol + Vit.C
Acetylsalicylic acid + Citric Alka-Seltzer Tablets 0.324 + 0.965 +
acid + Sodium bicarbonate 1.625
Acetylsalicylic acid + Alka-prim Tablets 0.330 + 0.1 +
Glycine + Sodium 1.685 + 0.685
bicarbonate + Citric acid
Acetylsalicylic acid + Aspirin plus C Tablets 0.4 + 0.24
ascorbic acid
Acetylsalicylic acid + Aspirin UPSA with Tablets 0.330 + 0.2
ascorbic acid Vit.C
Acetylsalicylic acid + Aspro with Vit.C Tablets 0.5 + 0.3
ascorbic acid
Paracetamol + Caffeine + Coldrex Tablets 0.5 + 0.025 + 0.05
Phenylephrine + + 0.02 + 0.03
Terpinhydrate + Ascorbic
acid
Paracetamol + Caffeine + Solpadein Tablets 0.5 + 0.03 + 0.008
Codeine
Paracetamol + Caffeine Panadol extra Tablets 0.5 + 0.065
Paracetamol + Caffeine + Gewadal Tablets 0.25 + 0.05 + 0.25
Propyphenazone
Paracetamol + Caffeine + Saridon Tablets 0.25 + 0.05 + 0.15
Propyphenazone
Paracetamol + Caffeine + Coldrin Tablets 0.3 + 0.003 + 0.01
Phenylephrine + + 0.002
Chlorphenamine maleate
Paracetamol + Anacold, Rinzasip Tablets 0.3 + 0.01 + 0.002
Phenylephrine +
Chlorphenamine maleate
Paracetamol + Ibuprophen Brustan Tablets 0.325 + 0.4
Paracetamol + Mefenamic Lanagesic Tablets 0.5 + 0.25
acid
Paracetamol + Diclophenac Panoxen Tablets 0.5 + 0.005
Paracetamol + pyrilamine Femizol Tablets 0.5 + 15 mg +
maleate + pamabrom 25 mg +
Analgin + Quinine Analgin-Chinin Tablets 0.2 + 0.05
Analgin + Bendazol + Аndipalum Tablets 0.25 + 0.02 + 0.02
Papaverine hydrochloride
Analgin + Thiamin + Benalgin Tablets 0.5 + 38.75 mg +
Caffeine 0.05
Chapter 14. Antipsychotics (Neuroleptics)

Neuroleptics are the drugs, that depress the central nervous system without
disturbing consciousness, remove hallucinations, motor and verbal excitation.
Classification of Antipsychotics (neuroleptics)
Typical
Phenothiazine derivatives
Chlorpromazine
Fluphenazine
Perphenazine
 Periciazine
Derivative thioxanthenes
Chlorprothixenum
 Zuklopentiksol
Derivative butyrophenones
Haloperidol
 Droperidolum
 Indole derivatives
Dicarbine
Rauwolfia Alkaloid
Reserpine

Atypical
 Benzamide
Sulpiride
 Tiapride
Derivatives benzodiazepine
Clozapine
Olanzapine
The mechanism of antipsychotic action and adverse effects.

All antipsychotics are known today have a common mechanism of
antipsychotic action as reduce the transmission of nerve impulses in the brain
systems, where the nerve impulse transmitter is dopamine. There are: mesolimbic
pathway, mesocortical pathway, nigrostriatal pathway, tuberoinfundibular
pathway.
It is believed that a reduction of dopaminergic transmition in mesolimbic
pathway (antipsychotic action) lead to removal of productive symptoms (delusions,
hallucinations, etc.), and the most effective for this are haloperidol and
chlorpromazine, but they cause extrapyramidal disorders.
It is known that a decrease in dopamine level in mesocortical pathway
causes symptoms such as negative disorders (flattening of affect, apathy, poverty
of speech, anhedonia, desocialization, etc.), and cognitive impairment (deficits in
attention, working memory, executive functions). Dopamine receptors blockage in
mesocortical pathway with prolonged therapy by typical nuroleptics may elicit an
enhancement of cognitive dysfunction and violation of higher integrative functions
of the brain.
It is obvious that the blockage of dopamine in nigrostriatal pathway adducts
to typical adverse effects for neuroleptics use, namely extrapyramidal disorders,
acathisia, early dyskinesia, trismus, drooling, tardive dyskinesia.
There is evidence that the blockage of dopamine in tuberoinfundibular
pathway lead to elevation in prolactine level in the blood, and might result in a
number of other side effects galactorrhoea, gynecomastia, menstrual disorders,
sexual dysfunction, depression, increased risk of osteoporosis, the risk of cancer
pathology, infertility, tumors of the pituitary gland.
Acting on the hypothalamus, neuroleptics inhibit the secretion of growth
hormone (GH) and corticotropin (CTH). Reduction of nervous impulse
transmission in dopamine neurons of trigger zone and the vomiting center provides
antiemetic effect.
α1-adrenoceptor blockade with neuroleptics leads to lower blood pressure,
orthostatic hypotension, vasodilation, dizziness, drowsiness; blockade of H1-
histamine receptors causes hypotension, increased demand for carbohydrates and
weight gain, sedation. With the blockade of acetylcholine receptors are associated
anticholinergic side effects of some antipsychotics: the possibility of cognitive
impairment, dry mouth, constipation, disturbance of accommodation, increased
intraocular pressure, increased heart rate. Blockade of 5-HT1A receptors causes
antidepressant and anxiolytic effect of some antipsychotic drugs, and blockade of
5-HT2A lead to prevention of extrapyramidal disorders, and reduction of negative
symptoms. The influence of antipsychotics on lipid metabolism in high dosage
determines a significant risk of cardiovascular disease, the risk of myocardial
infarction and stroke, dyslipidemia, and a sharp increase in body weight while
taking antipsychotic drugs can trigger the emergence of diabetes mellitus type 2.
Particularly high risk of cardiovascular events in patients receiving combination
therapy with typical and atypical antipsychotics. Atypical antipsychotics are more
Chapter 14. Antipsychotics (Neuroleptics) | 247
likely to cause stroke and diabetes mellitus than the typical, and cause more weight
gain than haloperidol. There is evidence that in older people antipsychotics cause
an increased risk of pneumonia by 60%.
Neuroleptic action of Neuroleptics (antipsychotics) is due to α-adrenergic
blocking effects and to a lesser degree is due to H1 blocking effects. These effects
provide the peripheral actions of Neuroleptics also. Antipsychotic action of
Neuroleptics is ensured by influence on dopaminergic processes, blockage of
dopaminergic receptors and impact on serotoninergic processes.
Typical Antipsychotics act due to blockage of dopamine receptors that
associate with the risk for extrapyramidal side effects.
Atypical antipsychotic agents there are the newer Antipsychotics. They
potently antagonize the 5HT2 receptors, while blocking D2 receptors less potently
than older typical antipsychotic agents, resulting in the atypical clinical profile of
antipsychotic efficacy with limited extrapyramidal side effects. Also promising are
medications that target glutamate and 5HT7 receptors subtypes, receptors for γ-
aminobutiric acid (GABA) and acetylcholine (M- and N-) and even peptide
hormone receptors (e.g., oxytocin).
Group of typical antipsychotics affects mainly on dopamine receptors and
blocks typically, 75-80% D2-receptors, in the treatment of psychosis is redundant;
atypical group affects the metabolism of dopamine to a lesser extent, more - on the
metabolism of serotonin and other neurotransmitters; accordingly, they are less
likely cause extrapyramidal disorders, and negative symptoms and neurocognitive
deficits.
Summing up the above, can be said that adverse effects predicted by
monoamine receptor affinities. So, excluding the D2 partial agonist aripiprazole,
all antipsychotic agents possess D2 antagonist properties that lead to
extrapyramidal disorders, akathisia, long-term tardive dyskinesia risk, and
hyperprolactinemia. Two side effects such as sedation and weight gain via appetite
stimulation are associated with central antagonism of H1 receptors. M1
antagonism is responsible for central and peripheral anticholinergic effects of
antipsychotics. But, most of atypical antipsychotic agents, including risperidone,
paliperidone, asenapine, iloperidone, ziprasidone and aripiprazole, have not
affinity to muscarinic receptors and do not elicit perceptible anticholinergic effects.
Albeit, clozapine and low-potency phenothiazines have considerable
anticholinergic adverse effects, quetiapine has moderate muscarinic affinity, but its
active metabolite norquetiapine causes anticholinergic side effects. Adrenergic
antagonism is associated with risk of orthostatic hypotension. In comparison with
high-potency typical antipsychotics, low-potency typical agents have much greater
affinities for α1 receptors and therefore significantly greater risk for orthostasis.
Typical antipsychotics have all pharmacological effects. Atypical
antipsychotics have not neuroleptic effect, do not cause extrapyramidal disorders
(Parkinson's syndrome), or cause in lesser degree.
Pharmacological effects of Antipsychotics:

Antipsychotic
Neuroleptic
Sedative
Antidepressant
Potentiating
Antiemetic
Hypothermic
Hypotensive
Adrenolytic
Cholinolytic (dry mouth, urinary retention, constipation, blurred vision,
increased intraocular pressure)
blockade of serotonin receptors
blockade of histamine receptors
Myorelax
Cataleptic
Analgesic
Indications for Antipsychotics use:
Psychosis, schizophrenia, bipolar disorder, mania, treatment-resistant major
depression
Tourette’s disorders (tics in patients with Tourette’s disorders)
Huntington’s disease
Autism
Anesthesia, premedication
Anacatharsis (uncontrollable vomiting, pernicious vomiting)
Hypertensive crisis
Neurodermatosis
Neuroleptanalgesia
Hyperthermia, resistant to antipyretics
Shock
Migraine, dizziness
Adverse effects of Antipsychotics:
Extrapyramidal disorders (Parkinson's syndrome)
Orthostatic (postural) hypotension
Endocrine disorders: inhibition of pituitary hormone production - CTH, GH and
increase secretion of ADH (edema), and prolactin (hyperprolactinemia)
Antipsychotics, particularly atypicals, appear to cause changes in insulin levels
by blocking the muscarinic M3 receptor (which is a key regulator of insulin
secretion) expressed on pancreatic β cells and in regions of the brain that
regulate glucose homeostasis. Altered insulin levels can lead to diabetes
mellitus and fatal diabetic ketoacidosis, especially (in US studies) in African
Americans
Pancreatitis
Overweight (especially atypical antipsychotics – olanzapine and clozapine)

due to occupancy of the histamine receptor and changes to neurochemical
signaling in regions of the brain that regulate appetite
Clozapine also has a risk of inducing agranulocytosis, a potentially
dangerous reduction in the number of white blood cells in the body. Because
of this risk, patients prescribed clozapine may need to have regular blood
checks to catch the condition early if it does occur, so the patient is in no
danger
Tardive dyskinesia. It is believed that there is a greater risk of developing
tardive dyskinesia with the older, typical antipsychotic drugs, although the
newer antipsychotics are now also known to cause this disorder
A potentially serious side effect of many antipsychotics is that they tend to
lower an individual's seizure threshold. Chlorpromazine and clozapine, in
particular, have a relatively high seizurogenic potential. Fluphenazine,
haloperidol, pimozide and risperidone exhibit a relatively low risk. Caution
should be exercised in individuals that have a history of seizurogenic
conditions such as epilepsy, or brain damage.
Neuroleptic malignant syndrome (muscle rigidity, fever, autonomic
instability, and cognitive changes such as delirium, and is associated with
elevated plasma creatine phosphokinase)
Dysphoria (it is a state of feeling unwell or unhappy; a feeling of emotional
and mental discomfort as a symptom of discontentment, restlessness,
dissatisfaction, malaise, depression or anxiety)
Sexual dysfunction, which may rarely continue after withdrawal, similar to
Post-SSRI (selective serotonin reuptake inhibitor) sexual dysfunction.
Both typical and atypical can lead to akathisia
Dystonia, a neurological movement disorder in which sustained muscle
contractions cause twisting and repetitive movements or abnormal postures
Sedation
Local tissue irritation
Pharyngitis
Mental disorders – reduction of intelligence, emotional lability, seizures, and
excitation.
Ventricular arrhythmia and sudden cardiac death due to inhibition of K + ion
channels and elongation of QT interval, especially for thioridazine,
mesoridazine, pimozide, i/m injection of droperidole, i/v injection of
haloperidol. At the same time the newer atypical antipsychotics have less
impact on heart electrophysiology than typical agents. Note that the risk
of sudden cardiac death is dose-dependent for both as the typical and

atypical antipsychotic drugs.
Withdrawal symptoms from antipsychotics may emerge during dosage
reduction and discontinuation. Withdrawal symptoms can include nausea,
emesis, anorexia, diarrhea, rhinorrhea, diaphoresis, myalgia, paresthesia,
anxiety, agitation, restlessness, and insomnia.
The side effects are based on potencies of the selected agent to inhibit
neurotransmitter receptors. Adverse effects such as extrapyramidal disorders,
orthostatic hypotension, sedation, hyperprolactinemia may respond to drug dose
reduction, but metabolic anomalies improve only with termination of provocative
agent and a transfer to a more metabolically benign medication (table 38,39).
Overdose with typical antipsychotics is of particular concern with low-

potency drugs (e.g. chlorpromazine) by reason of the risk of torsades de pointes,
sedation, anticholinergic effects, and orthostasis. Along with this the high-potency
typical antipsychotics (e.g. haloperidol) and substituted benzamides are at higher
risk for extrapyramidal disorders by virtue the high D2 affinity. Overdose with
newer atypical antipsychotics much less leads to torsades de pointes ventricular
arrhythmias as opposed to older antipsychotic drugs.
Drug-Drug interactions. Antipsychotic agents are not appreciable
inhibitors of CYP enzymes (microsomal liver enzymes) with a few exceptions
(chlorpromazine, perphenazine, thioridazine).Whereas, antipsychotics are highly
protein bound, there is no evidence of significant displacement of other protein
bound drugs, thus dosage correction is not needed for agents with narrow
therapeutic indices. It is important to consider the influence of smoking,
nutraceuticals, grapefruit juice and changes in these behaviors.
Antipsychotics are unsuitable for use during pregnancy and lactation. Some
antipsychotics (risperidone, aripiprazole) can be used in pediatric practice for the
treatment of autism, bipolar disorder (acute mania), schizophrenia.
Neuroleptics are incompatible with the anticholinesterases,
cholinomimetics, adrenomimetics, MAO inhibitors, antihypertensive drugs, and
drugs that depress the central nervous system. Phenothiazine derivatives are
incompatible with the tricyclic antidepressants. Chlorpromazine is incompatible
with epinephrine, caffeine, morphine, vitamin B12, Cardiac glycosides.
Haloperidol is incompatible with epinephrine, propanidid, reduces the effects of
indirect anticoagulants, and potentiates the effect of hypnotics, analgesics.
Chapter 14.
Table 45*. Neurological Side Effects of AntipsychoticAntipsychoticsDrugs(Neuroleptics)

| 251
Reaction Features Time of Proposed Treatment
Onset and mechanism
Risk INFO
Acute Spasm of muscles 1-5 days; Acute Anti-parkinsonian
dystonia of tongue, face, Young, dopamine (D) agents are
neck, back. antipsychotic antagonism diagnostic and
naïve patients curative
at highest risk (diphenhydromine,
or benztropine with
the possible re-
dosing of these
drugs due to long
antipsychotic T1/2).
Akathisia Subjective and 5-60 days Unknown Reduce dose or
objective change drug;
restlessness; not clonazepam,
anxiety or propranolol in
”agitation”. relatively low doses
more effective than
anti-parkinsonian
agents;
β1 selective
adrenergic receptor
antagonists are less
effective; non-
lipophilic β
adrenergic receptor
antagonists have
limited CNS
penetration and are
of no benefit (e.g.,
atenolol).
Parkinsonism Bradykinesia, 5-30 days D antagonism Dose reduction;
rigidity, variable Elderly at change medication;
tremor, mask greatest risk anti-parkinsonian
facies, shuffling agents (use of
gait. amantadine avoids
anticholinergic
effects of
benztropine or
diphenhydromine).
Neuroleptic Extreme rigidity, weeks- D antagonism Stop antipsychotic
malignant fever, unstable BP, months immediately;
syndrome myoglobinemia; Can persist supportive care;
can be fatal. for days after dantrolene and
252 | Unit 5.
stopping bromocriptine; with
antipsychotic persistent
antipsychotic affects
(e.g., long-action
injectable agents),
bromocriptine may
be tolerated in large
doses. Anti-
parkinsonian agents
are not effective.
Perioral Perioral tremor months or Unknown Anti-parkinsonian
tremor (may be a late years of agents often help
(“rabbit variant of treatment (use of amantadine
syndrome”) parkinsonism). avoids
anticholinergic
effects of
benztropine or
diphenhydromine).
Tardive Orofacial months, years Postsynaptic Prevention crucial;
dyskinesia dyskinesia; rarely of treatment D-receptor treatment
widespread Elderly at 5- supersensitivi unsatisfactory. May
choreoathetosis or fold greater ty, be reversible with
dystonia. risk. Risk > up-regulation early recognition
potency of and drug
D2 blockade discontinua
tion
* adopted from Goodman & Gilman’s The Pharmacological Bases of THERAPEUTICS. 12tth
Table 46*. Potencies of Antipsychotic Agents at Neurotransmitter Receptors** and Metabolic Risk Profile.
Musc Hista
Dopa
mine
Serotonine Dopamine arinic Adrenergic mine Metabolic Risk Profile
Antipsychotic 5HT/
Agents D2
Ra
D2 5HT 5HT 5HT tio D1 D4 M1 α1A α2A H1 Weig Lipid Glucos
1A 2A 2C ht gain s e
Typical Agents
Haloperidol 1.2 2100 57 4500 47 120 5.5 >10,000 12 1130 1700 +/- - -
Fluphenazine 0.8 1000 3.2 990 3.9 17 29 1100 6.5 310 14 +/- - -
Thiothixene 0.7 410 50 1360 72 51 410 >10,000 12 80 8
Perphenazine 0.8 420 5.6 130 7.4 37 40 1500 10 810 8.0 +/- - -
Loxapine 11 2550 4.4 13 0.4 54 5.1 120 42 150 4.9 + - -
Molindone 20 3800 >5000 10,000 >250 >10,000 >20006.4 >10,000 2600 1100 2130 - - -
Thioridazine 8.0 140 28 53 3.5 94 12 13 3.2 130 16

Chlorpromazine 3.6 2120 3.6 16 1 76 32 0.3 250 3.1 +++ +++ ++
Atypical Agents
Asenapine*** 1.4 2.7 0.1 0.03 0.05 1.4 1.1 >10,000 1.2 1.2 1.0 +/- - -
Ziprasidone 6.8 12 0.6 13 0.1 30 39 >10,000 18 160 63 +/- - -
Sertindole*** 2.7 280 0.4 0.90 0.2 12 13 >5000 1.8 640 130 +/- - -
Zotepine*** 8.0 470 2.7 3.2 0.3 71 39 330 6.0 210 3.2
Risperidone 3.2 420 0.2 50 0.05 240 7.3 >10,000 5.0 16 20 + +/- +/-
Paliperidone 4.2 20 0.7 48 0.2 41 54 >10,000 2.5 4.7 19 + +/- +/-
Iloperidone 6.3 90 5.6 43 0.9 130 25 4900 0.3 160 12 + +/- +/-
Aripiprazole 1.6 6.0 8.7 22 5.0 1200 510 6800 26 74 28 +/- - -
Sulpiride*** 6.4 >10,000 >10,000 >10,000 >1000 >10,000 54 >10,000 >10,000 >5000 >10,000
Olanzapine 31 2300 3.7 10 0.1 70 18 2.5 110 310 2.2
Quetiapine 380 390 640 1840 2.0 990 2020 37 22 2900 6.9 + + +/-
Clozapine 160 120 5.4 9.4 0.03 270 24 6.2 1.6 90 1.1 ++++ +++ +++
th
* - adopted from Goodman & Gilman’s The Pharmacological Bases of THERAPEUTICS. 12 edition. Medical. 2011. – 2084 P.
- Data are averaged Ki values (nM) from published sources determined by competition with radioligands for bonding to the indicated cloned human
receptors. Data derived from receptor binding to human or rat brain tissue is used when cloned human receptor data is lacking.
- Not available in the US.
The classification and peculiarities of some antipsychotics,

and other agents with antipsychotic activity
Commonly used antipsychotic medications are listed below by drug group
Trade names appear in parentheses.
First generation antipsychotics
Main article: Typical antipsychotics:
 Butyrophenones
Haloperidol (Haldol, Serenace)
Droperidol (Droleptan, Inapsine)
 Phenothiazines
Chlorpromazine (Thorazine, Largactil)
Fluphenazine (Prolixin) - Available in decanoate (long-acting) form
Perphenazine (Trilafon)
Prochlorperazine (Compazine)
Thioridazine (Mellaril)
Trifluoperazine (Stelazine)
Mesoridazine (Serentil)
Periciazine
Promazine
Triflupromazine (Vesprin)
Levomepromazine (Nozinan)
Promethazine (Phenergan)
Pimozide (Orap)
Cyamemazine (Tercian)
 Thioxanthenes
Chlorprothixene (Cloxan, Taractan, Truxal)
Clopenthixol (Sordinol)
Flupenthixol (Depixol, Fluanxol)
Thiothixene (Navane)
Zuclopenthixol (Cisordinol, Clopixol, Acuphase)
Second generation antipsychotics
Main article: Atypical antipsychotics:
Clozapine (Clozaril) – Requires weekly to biweekly complete blood count due
to risk of agranulocytosis
Olanzapine (Zyprexa) – Used to treat psychotic disorders including
schizophrenia, acute manic episodes, and maintenance of bipolar disorder
Risperidone (Risperdal) – Divided dosing is recommended until initial titration
is completed, at which time the drug can be administered once daily. Used
off-label to treat Tourette syndrome and anxiety disorder.
Quetiapine (Seroquel) – Used primarily to treat bipolar disorder and
schizophrenia, and "off-label" to treat chronic insomnia; it is a powerful
sedative.
Ziprasidone (Geodon) – Approved in 2004 to treat bipolar disorder. Side-effects

include a prolonged QT interval in the heart, which can be dangerous for
patients with heart disease or those taking other drugs that prolong the QT
interval.
Amisulpride (Solian) – Selective dopamine antagonist. Higher doses (greater
than 400 mg) act upon post-synaptic dopamine receptors resulting in a
reduction in the positive symptoms of schizophrenia, such as psychosis.
Lower doses, however, act upon dopamine autoreceptors, resulting in
increased dopamine transmission, improving the negative symptoms of
schizophrenia. Lower doses of amisulpride have also been shown to have
antidepressant and anxiolytic effects in non-schizophrenic patients, leading
to its use in dysthymia and social phobias. Amisulpride has not been
approved for use by the Food and Drug Administration in the United States.
Asenapine (Saphris) is a 5-HT2A- and D2-receptor antagonist under
development for the treatment of schizophrenia and acute mania associated
with bipolar disorder.
Paliperidone (Invega) – Derivative of risperidone that was approved in 2006, it
offers a controlled release once-daily dose, or a once-monthly depot
injection.
Iloperidone (Fanapt, Fanapta, and previously known as Zomaril) – Approved by
the FDA in 2009, it is fairly well tolerated, although hypotension, dizziness,
and somnolence were very common side effects.
Zotepine (Nipolept, Losizopilon, Lodopin, Setous) – An atypical antipsychotic
indicated for acute and chronic schizophrenia. It was approved in Japan circa
1982 and Germany in 1990.
Sertindole (Serdolect, and Serlect in Mexico). Sertindole was developed by the
Danish pharmaceutical company H. Lundbeck. Like the other atypical
antipsychotics, it is believed to have antagonist activity at dopamine and
serotonin receptors in the brain.
Lurasidone (Latuda), recently approved by the FDA for schizophrenia and
pending approval for bipolar disorder. Given once daily, it has shown mixed
Phase III efficacy results but has a relatively well-tolerated side effect
profile.
Third generation antipsychotics
Aripiprazole (Abilify) – Mechanism of action is thought to reduce susceptibility
to metabolic symptoms seen in some other atypical antipsychotics. The
extent to which these effects differ from other atypical antipsychotics is
debated.
Partial agonists of dopamine receptors.
Other options
Cannabidiol is one of the main components of Cannabis sativa. Cannabidiol
differs from the active drug in cannabis, tetrahydrocannabinol, in that
cannabidiol lacks the typical mind altering and recreational effects. One
study has suggested that cannabidiol may be as effective as atypical
antipsychotics in treating schizophrenia. Some further research has

supported these results, and found fewer side effects with cannabidiol than
with amisulpride.
Tetrabenazine is similar in function to antipsychotic drugs, though is not, in
general, considered an antipsychotic itself. Its main usefulness is the
treatment of hyperkinetic movement disorders such as Huntington's disease
and Tourette syndrome, rather than for conditions such as schizophrenia.
Also, rather than having the potential to cause tardive dyskinesia, which
most antipsychotics have, tetrabenazine can be an effective treatment for the
condition.
Metabotropic glutamate receptor 2 agonism has been seen as a promising
strategy in the development of novel antipsychotics. When tested in patients,
the research substance LY2140023 yielded promising results and had few
side effects. The active metabolite of this prodrug targets the brain glutamate
receptors mGluR2/3 rather than dopamine receptors.
Glycine transporter 1 inhibition. RG1678 has been shown in phase 2 clinical
trials to be selectively effective for the negative symptoms of schizophrenia.
A placebo-controlled trial has suggested that adding L-theanine, an amino acid
found in green tea and available as supplement, to ongoing antipsychotic
medication may be helpful in reducing some symptoms of schizophrenia.
Table 47. Medicinal forms of Antipsychotics (Neuroleptics)

Chlorpromazine Aminazinum, Ampliactil, Tablets; 0.01;
Amplictil, Chlorazin, Dragee; 0.025; 0.05; 0.1;
Chlorpromanyl, 0.25;
Chlorpromazine, Contomin, Parenteral 2.5% - 1ml, 2ml,
Fenactil, Hibanil, Hibernal, solution (i/m, 5ml, 10ml
Kloproman, Largactil, i/v) in ampoules
Megaphen, Plegomazin,
Promactil, Propaphenin,
Thorazine, etc.
Fluphenazine Phthorphenazinum, Moditen, Tablets; 0.001; 0.0025;

Anatensol, Dapotum, Elinol, 0.005;
Flumazine, Flumezin, Lyogen, Dragee; 0.00025; 0.001;
Lyorodin, Mirenil, Pacinol, 0.0025; 0.005;
Pacinone, Permitil, Prolixin, Parenteral 0.25% - 1ml
Sevinal, Sevinol, Sevinon, solution (i/m) in
Siqualine, Siqualone, Tensofin, ampoules
Teviral, Trancin, Vespazin, etc.
Chapter 14. | 257
Antipsychotics (Neuroleptics)
Perphenazine Aethaperazinum, Chlorpiprazin, Tablets 0.004; 0.006; 0.01
h/chl. Chlorpiprozine, Decentan,
Fentazin, Neuropax, Perphenan,
Perphenazine, Trilafon, Trilifan,
etc.
Periciazine Neuleptile, Aolept, Apamin, Capsules; 0.01;
Nemactil, Neulactil, Pericyazine, Peroral solution 4% - 30ml, 125ml
Propericiazine in flacons
Chlorprothixene Truxal, Chlothixen, Minithixen, Tablets; 0.005; 0.015;

Tactaran, Taractan, Tarasan, 0.025; 0.05;
Trictal, Truxil, Vetacalm, etc. Parenteral 2.5% - 1ml
solution (i/m) in
ampoules
Zuclopentixol Clopixol, Clopixol-accuphase Tablets; 0.002; 0.01; 0.025;

5% - 1ml, 2ml
Parenteral oil
solution (i/m) in
ampoules
Haloperidol Halopidol, Halophen, Haloper, Tablets; 0.0005; 0.001;
Aloperidin, Apo-Haloperidol, 0.0015; 0.002;
Haldol, Halopidol, Senorm, 0.005; 0.01;
Seranase, Serenace, Trancodol, Tablets forte; 0.005;
etc. Peroral solution 0.2% - 10ml;
in flacons;
Parenteral
solution (i/m, 0.5% - 1ml;
i/v) in
ampoules;
Parenteral oil
solution (i/m) in 5% - 1ml
ampoules
Droperidol DehydrobenzperidolDridol, Parenteral 0.25% - 2ml, 5ml,
Droleptan, Droperidol, Inapsin, solution (s/c, 10ml
Sintodril, etc i/m, i/v) in
ampoules
Dicarbine Carbidinum Tablets; 0.025;
Parenteral 1.25% - 2ml
solution (i/m) in
ampoules
Reserpine see page 150-151, 154
Sulpiride Abilit, Betamax, Depral, Digton, Capsules; 0.05; 0.1; 0.2;
Dobren, Dogmalid, Dogmatil, Tablets forte; 0.2;
Eglonyl, Eusulpid, Lisopiride, Peroral solution 0.5% - 100ml;
Megotyl, Miradon, Mirbanil, in flacons;
Nivelan, Norestran, Omperan, Parenteral
Prosulpin, Sulpiril solution (i/m) in 5% - 2ml
ampoules
258 | Unit 5.
Clozapine Azaleptin, Alemoxan, Clazaril, Tablets; 0.025; 0.1;
Iprox, Lapenax, Lepotex, Granules for 0.5; 1.0;
peroral solution
Leponex, in sachets;
Parenteral
solution (i/m) in 2.5% - 2ml;
Alemoxan. ampoules;
Tablets 0.05
Olanzapine Ziprexa Tablets 0.005, 0.0075,
0.01
Asenapine Saphris Sublingual 5mg
tablets
Ziprasidone Zipsila, Zeldox Capsules; 40mg, 80mg;
Powder for 30mg
parenteral
solution (i/m) in
ampoules
Sertindole Serdolect Tablets 4mg, 12mg, 16mg,
20mg
Zotepine Nipolept, Zoleptil, Lodopin Tablets; 25mg, 50mg,
100mg;
Dragee; 25mg, 50mg,
100mg;
Granules for 10%, 50%
peroral solution
Risperidone Risperdal, Ridal, Sizodon, Tablets 1mg, 2mg, 4mg
Riscalin, Risdone, Riswel,
Rispolept, Zepidone,
Riperidone, Rispen Risperidona,
Apexidone, Rissar, Torendo Q,
Belivon,
Paliperidone Invega Sustenna, Tablets; 3mg, 6mg, 9mg,
12mg;
Xeplion Suspension for 25mg/0.25ml;
i/m introduction 50mg/0.5ml;
in the syringes 75mg/0.75ml;
100mg/1ml;
150mg/1.5ml
Iloperidone Fanapt, Fanapta, Zomaril Tablets 1mg, 2mg, 4mg,
6mg, 8mg, 10mg,
12mg
Aripiprazole Zilaxera, Abilify, Aripiprex, Tablets 5mg, 10mg, 15mg,
Amdoal 30mg
Quetiapine Seroquel, Xeroquel, Ketipinor, Tablets 25mg, 100mg,
Quepin, Syquel, Nantarid, 150mg, 200mg,
Ketilept, Victoel, Seroquel 300mg, 400mg
prolong, Kventiax, Lakvel,
Gedonin
Chapter 15. Anxiolitics (Tranquilizers) | 259
Chapter 15. Anxiolytics (Tranquilizers)

Anxiolytics are psychotropic drugs that remove the fear, anxiety, irritability,
aggressiveness. They are also called ataractics (ataraxia – equanimity,
indifference), antifears (phobos – fear). Anxiolytics depress CNS. Unlike
antipsychotics anxiolytics have no antipsychotic activity, practically no influence
on the autonomic nervous system (except benactyzine); they do not provide
extrapyramidal disorders.
Classification of Anxiolytics according the chemical structure
Benzodiazepines derivatives (benzodiazepine receptor agonists)

Chlordiazepoxide
Diazepam
Bromdihydrochlorphenylbenzodiazepine (Phenazepam)
Oxazepam
Lorazepam
Medazepam
Hydrazinecarbonylmethylbromphenyldihydrobenzadiazepine
(Gidazepam) Alprazolam
Carbamic (butyl) esters of substituted propanediol
Meprobamate
Diphenylmethane derivatives
Benactyzine
Hydroxyzine
Different chemical groups
Benzoclidine
Tetramethyltetraazocycloocyandione
(Mebicar) Buspirone
DAILY Anxiolytics
Medazepam
Gidazepam
Mebikar
Benzoclidine
In clinical practice, anxiolytics are divided into typical and atypical.

Benzodiazepines belong to the typical anxiolytics, whereas derivatives of other
chemical groups of anxiolytics belong to the atypical agents. Moreover a
significant number of drugs possess anxiolytic activity. There are some
antidepressants, neuroleptics, nootrops, central myorelaxants, drugs pro narcosis,
opioids, central α2 adrenergic agonists, β adrenergic blockers, calcium channels
blockers, et al.
From a clinical point of view anxiolytics are divided into: sedative agents
that have expressed sedative and hypnotic effects (benzodiazepines); daily
anxiolytics that have anxiolytic effect and a low sedative, hypnotic, anticonvulsive
and antispasmodic activity. They can be used in out-patients because the daily
anxiolytics have a little effect on the rate of physical and mental reactions.
The mechanism of action of Anxiolytics. The mechanism of anxiolytic
action of anxiolytics is insufficiently studied. It is believed that anxiolytics reduce
the excitability of the limbic system, pituitary and hypothalamus, i.e. those brain
structures that are responsible for emotional state. In addition, they inhibit the
process interaction of these structures with the cerebral cortex of the brain, and
oppress the polysynaptic spinal reflexes.
Benzodiazepine anxiolytics are the agonists of benzodiazepine receptors that
are closely related to the γ-aminobutyric acid (GABA) receptors, and affect
GABA-ergic system, activating the specific GABA receptors. In other words,
activation of benzodiazepine receptors leads to activation of GABA receptors that
promotes disclosing of chloride channels, increasing the flow of chloride ions into
the neuron, and inhibition of neurons of the CNS, especially in the limbic system,
cortex, hypothalamus, thalamus, reticular formation, spinal cord. This process
causes a membrane hyperpolarization and suppressed neuronal activity in CNS and
it is called the GABA-benzodiazepine chloride complex (complex Costa). Today
there are several subtypes of benzodiazepine receptors: BZ1, BZ2, BZ3, or w1, w2,
w3. Endogenous ligands for these are many of the physiologically active
compounds: peptides, purines, nicotinamide hypoxanthine, β-carbolines, etc.
Anxiolytics have little effect on noradrenergic, dopaminergic, serotoninergic
systems; moderately inhibit the synthesis of norepinephrine and dopamine
(Benzodiazepine derivatives). Also it was found that benzodiazepine derivatives
inhibit the release of excitatory amino acids (glutamine, asparagine) of axon
terminals, and some of them reduce inactivation of adenosine, and block Ca+ and
Na+ channels.
Several subtypes of benzodiazepine receptors have been allocated on the
membrane of the neurons of the brain structures that regulate the emotional state
(the limbic system, hypothalamus, nucleus of the thalamus, the spinal cord).
Therefore, benzodiazepines have multifaceted activity: anxiolytic, sedative,
hypnotic, anticonvulsive and antispasmodic.
Diphenylmethane derivatives inhibit the cholinergic system in the brain, as a
result they are called central cholinolytics. Their use nowadays is restricted due to
the adverse effects.
The mechanism of action of carbamic esters of substituted propanediol today
remains unsolved, although the representative of this group Meprobamate – is a
founder of tranquilizers and was synthesized in finding central muscle relaxants. It
is known that drugs of this group have no expressed action on benzodiazepine and
cholinergic receptors.
In accordance with the different mechanisms of action, all anxiolytics were

separated into: agonists of benzodiazepine receptors; agonists of serotonine
receptors; and other mechanisms of action.
Pharmacological effects of Anxiolytics:
Anxiolytic
Sedative
Hypnotic
Amnesic
Antispasmodic (they decrease the smooth muscle tone)
Anticonvulsive
Stabilization of vegetative nervous system and endocrine system
All pharmacological effects of benzodiazepines are dose-dependent.
Indications for the Anxiolytics use:
 Neurosis
Light psychosis
Neurogenic diseases (hypertension, angina pectoris, peptic ulcer and
 dvenadtsatipaloy intestine, etc.)
Premedication
Spastic states
Sleep disturbances associated with negative emotions
Depression
Withdrawal syndrome in alcoholism and narcotic drug addiction
Neurodermatitis
Parkinson disease
Climacteric neuroses
Epileptic status
In general, the therapeutic uses of the benzodiazepines depend on its T 1/2.
Anti-axyety benzodiazepines should have a long T1/2 despite the drawback of the
risk of neuropsychological deficits caused by drug accumulation.
Adverse effects of Anxiolytics:
Drowsiness, fatigue, dizziness, weakening of memory, impaired concentration
of attention, headache, nervousness, discoordination movement, addiction,
increased reaction time, motor incoordination, anterograde amnesia
(benzodiazepine derivatives)
Withdrawal syndrome, addictive/habitation, addiction (especially
 meprobamate), euphoria (benactyzine, meprobamate)
Dry mouth, hypotension, tachycardia, mydriasis, constipation, nausea, allergic
 reactions
Overdose of tranquilizers leads to motor and mental excitement, anger, sleep
disorders, vision disorders, convulsions (especially benactyzine,
hydroxyzine)
The specific antagonist of benzodiazepine receptors is flumazenil. It is a
competitive antagonist of the benzodiazepines, and is used in case of
benzodiazepine tranquilizer overdoses to reduce their central effects (except

anticonvulsive).
Anxiolytics can not be used during the work, which requires more attention,
rapid mental and motor reaction.
Undesirable is the use of anxiolytics with MAO inhibitors (reinforce their
effects), antipsychotic agents, alcohol, etc., that depress the CNS functions
(summation of the inhibitory effect on the CNS).
Undesirable is the use of anxiolytics with peripheral muscle relaxants
(increased peripheral myorelax effect).
The solution of diazepam is not compatible in the same syringe with any
drugs (to prevent formation of precipitate).
Characteristics of certain groups of Anxiolytics
Benzodiazepines are the weak bases and have a good absorption in

duodenum. Maximal their concentration in plasma is in 1-2 hours. The binding of
the benzodiazepines with plasma proteins is from 60% to 95%. Benzodiazepines
penetrate biological barriers; form a high concentration especially in cortex,
cerebellum, midbrain and spinal cord. Besides, benzodiazepines have a high
affinity to fat tissue. Benzodiazepines are metabolized in the liver: most of them by
microsomal enzimes with the formation of active metabolites that prolong the
action of the agent. In order to reduce the duration of tranquilizers in clinic are
used their active metabolites (e.g., a metabolite of diazepam – oxazepam). They
are named as prodrugs. T1/2 depends on age of patients: from 31 hours in newborns
to 100 hours in older people; and depends on function of internal organs (e.g., in
patients with liver cirrhosis T1/2 is doubled. Based on the characteristics of
pharmacokinetics, benzodiazepines can be divided into the following groups: the
average duration of activity (T1/2 6-24 hours) – oxazepam, lorazepam; long-action
(T1/2 more than 24 hours) - diazepam, Phenazepam.
Due to the intensity and the ratio of the pharmacological effects and
therefore in clinical use the benzodiazepines are divided into the following groups:
agents with expressed anxiolytic action (e.g., diazepam, lorazepam), agents with
moderate anxiolytic action (e.g., chlordiazepoxide, oxazepam, Gidazepam); agents
with expressed sedative and hypnotic action (e.g., Phenazepam, diazepam,
lorazepam, chlordiazepoxide, oxazepam); agents with expressed anticonvulsive
action (e.g., chlonazepam, diazepam, Phenazepam, lorazepam); agents with
expressed antispasmodic action (they decrease the smooth muscle tone) (e.g.,
diazepam, chlordiazepoxide, lorazepam).
The sequence of manifestations of the tranquilizer central effects is:
anticonvulsive, anxiolitic, light sedation, reduce attention, intelligence, amnestic
effect, deep sedation, relaxation, sleep.
Table 48. Medicinal forms of Anxiolytics

Chlordiazepoxide Ansiacal, Apo-Benzodiapin, Tablets; 0.005, 0.01; 0.025
Chlordiazepoxide, Decadil, Dragee;
Droxol, Elenium, Equinbral, Capsules
Labiton, Librium, Lixin,
Napoton, Novosed, Radepur,
Sonimen, Timosin, Viansin,
Chlozepidum,
Angirex, Klopoxid, Librax ,
Libritabs, Mesural, Multum,
Novapam, Risolid, Silibrin,
Tropium
Diazepam Valium, Antenex, Anstolin, Tablets; 0.001; 0.002;
Apaurin, Apo-Diazepam, 0.005; 0.01;
Apozepam, Bensedin, Parenteral 0.5% - 2ml
Calmpose, Diapam, solution (i/m,
Diazepam, Diazepex, Diazex, i/v) in ampoules
Dicam, Dizep, Eridan,
Faustan, Lembrol, Novo-
Dipam, Pacitrian, Quetinil,
Relanium, Relium, Saromet,
Seduxen, Sibazonum,
Serenamin, Serensin,
Sonacon, Stesolin, Ushamir,
Valitran, Vatran, Vival, etc.
Oxazepam Adumbran, Oxazepam, Tablets 0.01; 0.015; 0.03
Praxiten, Psicopax, Rondar,
Serax, Serenal, Tazepam,
Alepam, Medopam, Murelax,
Noripam, Nozepam, Opamox,
Ox-Pam, Purata, Serepax,
Vaben, Sobril, Oxascand,
Zaxpam etc.
Bromdihydrochlorphe Phenazepam Tablets; 0.0005; 0.001;
nylbenzodiazepine 0.0025;
Parenteral 0.1%, 0.3% - 1ml
solution (i/m,
i/v) in ampoules
Lorazepam Ansilor, Apo-Lorazepam, Tablets; 0.0005, 0.001,
Ativan, Kalmalin, Lorafen, 0.002, 0.0025;
Loram, Lorenin, Lorsedal, Dragee 0.001, 0.0025
Lorsilan, Sidenar, Tavor,
Temesta, Trapex, Lorax,
Lorivan, Merlit, Trapax, etc.
Medazepam Mezapamum, Rudotel, Tablets; 0.01;
Ansilan, Anxitol, Benson, Granules for
Emopan, Enobrin, Imazepam, peroral
Medaurin, Medazepol, suspension in
Megasedan, Nivelton, banks 150ml
264 | Unit 5.
Nobritem, Nobrium, Pazital,
Stratium, etc.
Hydrazinecarbonylme Gidazepam Tablets 0.02; 0.05

thylbromphenyldihydr
obenzadiazepine
Alprazolam Alprox, Alzolam, Cassadan, Tablets; 0.00025, 0.0005,
Chelex, Frontin, Lamoz, 0.001, 0.002
Neurol, Prinax, Restil,
Solanax, Tafil, Trankimazin,
Tricca, Xanor, Zoldac,
Zotran,
Xanax
Tablets retard 0.0005, 0.001,
0.002, 0.003
Meprobamate Andaxin, Aneural, Apo- Tablets 0.2
Meprobamate, Biobamat,
Equanil, Gadexyl, Harmonin,
Mepavlon, Meprotanum,
Meproban, Meprospan,
Miltown, Nephentine,
Pankalma, Pertranquile,
Procalmadiol, Quanil,
Restenil, Sedanyl, Sedazil,
Sedral, Tensonal, Tranquil,
Tranquilan, Tranquiline,
Tranquisan, etc.
Benactyzine Amisylum, Actozine, Tablets 0.001, 0.002
Amitakon, Benactina,
Benactyzine, Cafron,
Cevanol, Lucidil, Nervatil,
Neurobenzile, Parasan,
Phobex, Procalm, Suavitil,
Tranquilline, etc.
Hydroxyzine Alamon, Arcanax, Atarax, Tablets; 0.01, 0.025;
Atara, Aterax, Atazin, Syrup in 0.2% - 200ml;
Clorixin, Disron, Durrax, flacons;
Quiess, Forticalman, Parenteral 5% - 2ml
Tranquizine, Hyzine, solution (i/m) in
Iremoxin, Multipax, ampoules
Neocalma, Neurolax,
Orgatrax, Placidol, Quiess,
Ucerax, Vistaril, Equipose,
Masmoran, Paxistil.
(Vistaril, Equipose,
Masmoran, Paxistil are
preparations of the pamoate
salt, while Atarax, Alamon,
Aterax, Durrax, Tran-Q,
Chapter 15.
Anxiolitics (Tranquilizers) | 265
Orgatrax, Quiess, and
Tranquizine are of the
hydrochloride salt
Benzoclidine Oxylidinum Tablets; 0.02, 0.05;
Parenteral 2%, 5% - 1ml
solution (s/c,
i/m) in
ampoules
Tetramethyltetraazabi Mebicar, Adaptol, Mebix Tablets 0.3, 0.5
cyclooctandione
Buspirone Bespar, Buspar, Spitomin Tablets 0.005, 0.01
Flumazenil Anexate, Romazicon Parenteral 0.01% -5ml, 10ml
solution (i/v) in
ampoules
Chapter 15. Hypnotic drugs

Hypnotics can depress the function of CNS and elicit calming and
drowsiness (sedation). They inhibit the CNS in dose-dependent fashion: from mild
sedation to coma and death. Hypnotics promote the onset of sleep and support a
sleep which is similar to the physiological sleep in it electroencephalographic
characteristics and from which the patient can be awakened easily.
Classification of Hypnotics
I. Barbiturates:
Phenobarbital
Cyclobarbital
Reladorm (Cyclobarbital + Diazepam)
Benzodiazepines:
Triazolam
Midazolam
Brotizolam*
Temazepam
Nitrazepam*
Flurazepam
Flunitrazepam
*- not available for clinical use in the U.S.
III. Different chemical groups:
Methaqualone
Doxylamine
Bromizoval
“Z compounds”:
Zopiclone
Eszopiclone (Lunesta)
Zolpidem (Ambien)
Zalepton (Sonata)
Mechanisms of action of different classification groups of Hypnotics. All

benzodiazepines (table 37) are the agonists of benzodiazepine receptors, and as a
result they also are agonists GABA receptors which exist as multi-subunit, ligand-
gated chlorine channels, thereby enhancing the GABA-induced ionic flow through
these channels. Heterogeneity among sites of binding and action of
benzodiazepines, GABA-gated chlorine channels expressed in different neurons
allowed developing the new hypnotic drugs, so called “Z compounds”. There are
zolpidem (Ambien), an imidazopyridine, the pyrazolopyrimidines zalepton
(Sonata) and the cyclopyrrolones zopiclone and eszopiclone (Lunesta). They
evidently invoke sedative-hypnotic effects due to interaction with a subset of
benzodiazepine binding sites.
Pharmacological effects of Benzodiazepine Hypnotics:
central effects:
 Sedative
Hypnotic
Muscle-relaxant
Anxiolytic
Anticonvulsive
Anterograde amnesia
 peripheral effects:
Coronary vasodilatation (after i/v administration of therapeutic doses)
Decrease BP and increase heart rate
Neuromuscular blockade (only after administration of a very high doses).
All benzodiazepines have similar pharmacological profiles, but drugs differ

in selectivity, and clinical use of the individual benzodiazepines varies
considerably. If the benzodiazepine dose is increased, sedation progresses to
hypnosis and then to stupor. Benzodiazepines do not cause general anesthesia due
to the fact that consciousness usually persists, however, “preanesthetic” doses
induce amnesia for events subsequent to administration of the drug. In
“preanesthetic” doses (e.g., for endoscopy) benzodiazepines slightly depress
alveolar ventilation and cause rerspiratory acidosis, can cause apnea during
anesthesia or when given with opioids. Hypnotic doses of benzodiazepines may
worsen sleep-related brething disorders, may cause hypoventilation and
hypoxemia. In patients with obstructive sleep apnea, hypnotic doses of
benzodiazepines may increase alveolar hypoxia , pulmonary hypertension, and
cardiac ventricular load. Diazepam decreases noctural gastric secretion in
humans.
All benzodiazepines have high lipid-water distribution coefficients in the
non-ionized form. According to the duration of action the benzodiazepines are
divided in 4 groups: ultra-short-acting benzodiazepines; short-action agents (T1/2 <
6 hours), including triazolam, midazolam, zolpidem, eszopiclone; intermediate-
acting agents (T1/2 6-24 hours), including estazolam, temazepam; long-acting
agents (T1/2 < 24 hours), including flurazepam, diazepam and quazepam.
Chapter 16. Hypnotics | 267
The ideal hypnotic agent would have a rapid onset of action, cause stable
sleep throughout the night, and no residual action till the following morning.
Indications for Benzodiazepines use:
Insomnia
Anxiety disorders
Preanesthetic medication
Status epilepticus
Convulsions
Management of alcohol withdrawal syndrome
Adjunctive treatment in acute mania and certain movement disorders
Mostly benzodiazepines can be used interchangeability. In general, the
therapeutic use of the benzodiazepines depends on its T1/2. A short
elimination T1/2 is desirable for hypnotics, although it carries the drawback
of increased abuse liability and severity of withdrawal syndrome after drug
discontinuation.
Adverse effects of Benzodiazepines:
Withdrawal syndrome: dysphoria, irritability, sweating, unpleasant dreams,
 tremors, anorexia, and faintness or dizziness
Lassitude
Increased reaction time
Motor incoordination
Impairment of mental and motor functions
Confusion
Anterograde amnesia
Euphoria
Dependence and abuse
Restlessness
Hallucinations
Sleep-walking
Sleep-talking
Hypomanic behavior
Residual effects
Weakness
Headache
Blurred vision
Nausea, vomiting
Epigastric distress, diarrhea
Joint pains
Chest pains
Incontinence
Paradoxical effects: increase the frequency of seizures in patients with
epilepsy; garrulousness, anxiety, irritability, tachycardia, sweating
Hepatotoxic effect
Allergic reaction
Hematologic reaction
Hypothermia, hypotonia, and mild respiratory depression may be in the
neonate in case of use benzodiazepines before or during labor
When the drugs are given at the intended time of sleep, the persistence of
these effects during the waking hours is adverse. The residual effects and degree of
impairment may be underestimated.
Drug-Drug interactions. Ethanol increases both the rate of absorption of
benzodiazepines and the associated CNS depression. Valproates and
benzodiazepines in case of combination may cause psychotic episodes.
Original benzodiazepine receptor agonists (“Z compounds”). Z
compounds (zolpidem, zaleplon, zopiclone, eszopiclone) are not structurally related
to each other and to benzodiazepines; however they have hypnotic effect due to the
agonist effects on the benzodiazepine site of the GABA receptor. In comparison to
benzodiazepines, Z compounds are less effective as anticonvulsants or muscle
relaxants. Lately Z compounds replace benzodiazepines in the treatment of
insomnia by virtue its less potential for dependence and abuse than traditional
benzodiazepines. And nevertheless, long-term use of Z compounds, especially in
high doses leads to tolerance and physical dependence. Overdose with Z
compounds is similar to that of benzodiazepine overdose and can be treated with
the benzodiazepine antagonist flumazenil.
Melatonine congeners. In US ramelteon (Rozerem) is used for treatment of
insomnia, especially sleep onset difficulties. Ramelteon is an analog of melatonine.
It is known that melatonin plays a critical role in the regulation of the circadian
rhythms of several biological functions including sleep – awake. Mechanism of
action of ramelteon is to bind to specific melatonin receptors in the
suprachiasmatic nucleus – M1 and M2. Ramelteon binds these receptors with high
affinity. Ramelteon is not known to bind to any other types of receptors, such as
benzodiazepine-binding site on GABA receptors, opiate, dopamine,
acethylcholine, neuropeptide receptors.
Barbiturates. The barbiturates were once used widely as sedative-hypnotic
drugs, but they are now replaced with safer benzodiazepines, except for a few uses
(table 43). The barbiturates reversibly inhibit the activity of all excitable tissues,
however direct its effects on peripheral excitable tissues are weak. Together with
that, the acute barbiturate intoxication causes serious malfunctions in
cardiovascular system and respiratory system.
Barbiturates act throughout the CNS; they depress polysynaptic responses
primarily at synapses where neurotransmission is mediated by GABA acting at
GABA receptors. The site of inhibition is postsynaptic in cortical and cerebellar
pyramidal cells, in the cuneate nucleus, substantia nigra, thalamic neurons, or
presynaptic in spinal cord. Hypnotic doses of barbiturates increase the total sleep
time and alter the stages of sleep in dose-dependent manner. The barbiturates are
the inductors of the liver microsomal enzymes which control the biotransformation
of barbiturates. That's why the repeated introduction of barbiturates leads to the
tolerance to the effects on sleep which occurs within a few days, and the effect on
total sleep time may be reduced by as much as 50% after 2 weeks of use. Tolerance
to the effects on mood, sedation, hypnosis develops more rapidly and is more
significant than tolerance to the anticonvulsive and lethal effects.
Pharmacodynamic tolerance to barbiturates gives cross-tolerance to all CNS
depressants, including ethanol.
Pharmacological effects that limit the use of barbiturates as hypnotics now:
Barbiturates alter the physiological structure of sleep
They cause dreaming, nightmares, fitful sleep
Barbiturates provoke aftereffect: violation of motor coordination, drowsiness,
 muscle weakness
Barbiturates induce abuse, drug addiction, and require greater and greater doses
 to the soporific effect and large doses of them are toxic to the humans
In some persons, barbiturates may cause paradoxical effect: excitement,
insomnia, inebriation, restlessness, delirium, an increase the patient’s
perception of pain
Hypersensitivity
As the inductors of the liver microsomal enzymes, barbiturates alter the
pharmacokinetics and pharmacodynamics of drugs that are metabolized by
microsomal liver enzymes
Action of barbiturates on peripheral nervous system. The barbiturates
selectively suppress neurotransmission in autonomic ganglia and decrease nicotinic
excitation by choline esters. This mechanism has a value in the fall of BP in case of
intravenous introduction of barbiturates. Barbiturates enchance the blocking effects
of both depolarizing and nondepolarizing neuromuscular blocking agents during
barbiturate anesthesia. Barbiturates depress respiratory system in doses more than
hypnotic; in case of i/v administration, barbiturates may increase the risk of
ventricular arrhythmias, especially when epinephrine or halothane is also present.
Besides, anesthetic concentration of barbiturates has direct electrophysiological
effects on the heart, change the function of Na+ and K+ channels. But, direct
depression of cardiac contractility occurs only when acute barbiturate poisoning.
Barbiturates elicit dose-dependent decrease of GIT tone and contractility. In the
liver barbiturates induce the microsomal enzymes. Severe oliguria or anuria may
occur in acute barbiturate poisoning.
Contraindications for Barbiturates use:
 Kidney and liver disease
Pregnancy, lactation
Arterial hypotension
Atherosclerosis
Chronic alcoholism
Barbiturates are absolutely contraindicated in patients with porphyria,
because these agents enchance porphyrin synthesis.
Barbiturate poisoning is a significant clinical problem, problem of suicide,
and accidental poisonings in children or drug abusers. The treatment of barbiturate
poisoning is based on symptomatic therapy. CNS stimulators are contraindicated
because they increase the mortality rate. In severe cases of barbiturate poisoning,
the hemodialysis or hemoperfusion is necessary.
Table 49*. Trade names, Routs of administration, and Therapeutic Uses of
Benzodiazepines
b a
Compound Routs of T1/2 Therapeutic Uses Comments
administ hours
ration
Alprazolam Oral 12±2 Anxiety disoders, Withdrawal symptoms
agoraphobia may be especially
severe
Chlordiazepo Oral, i/m, 10±3.4 Anxiety disoders, Long-acting and self-
xide i/v management of alcohol tapering because of
withdrawal, anesthetic active metabolites
premedication
Clonazepam Oral 23±5 Seizure disoders, Tolerance develops to
adjunctive treatment in anticonvulsant effects
acute mania and certain
movement disoders
Clorazepate Oral 2.0±0. Anxiety disoders, Prodrug; activity due to
9 seizure disorders formation of
nordazepam during
absorption
Diazepam Oral, i/m, 43±13 Anxiety disoders, Prototypical
i/v, rectal status epilepticus, benzodiazepine
skeletal muscle
relaxation, anesthetic
premedication
Estazolam Oral 10-24 Insomnia Contains triazoloring;

adverse effects may be
similar to those of
triazolam
Flurazepam Oral 74±24 Insomnia Active metabolites
accumulate with
chronic use
Lorazepam Oral, i/m, 14±5 Anxiety disoders, Metabolites solely by
i/v preanesthetic conjugation
medication
Midazolam i/m, i/v 1.9±0. Preanesthetic and Rapidly inactivated
6 intraoperative
medication
Oxazepam Oral 8.0±2. Anxiety disorders Metabolites solely by
4 conjugation
Quazepam Oral 39 Insomnia Active metabolites
accumulate with
Chapter 16. | 271
Hypnotics
chronic use
Temazepam Oral 11±6 Insomnia Metabolized mainly by
conjugation
Triazolam Oral 2.9±1. Insomnia Rapidly inactivated;
0 may cause disturbing
daytime side effects
* - adopted from Goodman & Gilman’s The Pharmacological Bases of THERAPEUTICS.
12th edition. Medical. 2011. – 2084 P.
a - The therapeutic uses are identified as examples to emphasize that most benzodiazepines
can be used interchangeability.
b - Half-life of active metabolite may differ.
Table 50*. Trade names, Routs of administration, and Therapeutic Uses of

Barbiturates
Compound Routs T1/2 Therapeutic Uses Comments

(Trade names) of hours
adminis
tration
Amobarbital i/m, i/v 10-40 Insomnia, preoperative Only Na+ salt
(Amytal) sedation, emergency administered
management of seizures parenterally
Butabarbital Oral 35-50 Insomnia, preoperative Redistribution

(Butisol, others) sedation shortens duration of
action of single dose
to 8 hours
Mephobarbital Oral 10-70 Seizures disorders, daytime Second-line
(Mebaral) sedation anticonvulsant
Methohexital i/v 3-5** Induction and maintenance Only Na+ salt
(Brevital) of anesthesia available; single dose
provides 5-7 min of
anesthesia**
Pentobarbital Oral, 15-50 Insomnia, preoperative Only Na+ salt
(Nembutal) i/m, i/v, sedation, emergency administered
rectal management of seizures parenterally
Phenobarbital Oral, 80-120 Seizures disorders, status First-line

(Luminal, others) i/m, i/v epilepticus, daytime anticonvulsant, only
sedation Na+ salt administered
parenterally
Secobarbital Oral 15-40 Insomnia, preoperative Only Na+ salt
(Seconal) sedation available
Thiopental i/v 8-10** Induction/maintenance of Only Na+ salt
(Pentothal) anesthesia, preoperative available; single dose
sedation, emergency provides brief of
management of seizures anesthesia**

th
12 edition. Medical. 2011. – 2084 P.
** - value represents terminal T1/2 due to metabolism by the liver; redistribution following
parenteral administration produces effects lasting only a
few minutes.
Table 51. Medicinal forms of Hypnotics

Phenobarbital Barbiphen, Dormiral, Epanal, Powder;
Fenemal, Gardenal, Hypnotal, Tablets; 0.005; 0.05;
Lepinal, Luminal, Mephabarbital, Peroral 0.1;
Neurobarb, Nirvonal, solution in 0.2% -
Phenobarbitone, Sedonal, Sevenal, flacons 100ml
etc.
Cyclobarbital Aethylhexabital, Cavonyl, Powder Cyclobarbita

Cyclobarbitone, Cyclohexal, l is excluded
Cyclonal, Cyclosedal, Dormiphan, from the
Dormiphene, Fanodorm, Hexemal, nomenclatur
Hypnoval, Normanox, Palinum1, e of
Panodorm, Phanoctal, Phanodorm, medicines
Phriodorm, Prodorm, Somnokalan,
etc.
Cyclobarbital + Reladorm Tablets 0.1 + 0.01

Diazepam
Triazolam Apo-Triazo, Apo-Triolam, Tablets 0.00025
Clorazolam, Halcion, Insomnium,
Novidorm, Nuctan, Somneton,
Songar, etc.
Midazolam Dormicum, Dormonid, Flormidal, Tablets; 0.0075;

Fulsed, Versed Parenteral 0.015;
solution 0.1% - 5ml,
(i/m, i/v) in 10ml;
flacons;
ampoules
0.5% - 1ml,
3ml
Brotizolam Lendormin Tablets 0.00025

Temazepam Signopam Tablets 0.01
Nitrazepam Apodorm, Benzalin, Berladorm, Tablets 0.005; 0.01
Calsmin, Dumolid, Epibenzalin,
Epinelbon, Eunoctin, Hipnax,
Hipsal, Insomin, Livetan, Magadon,
Mitidin, Mogadan, Mogadon,
Nelbon, Neozepam, Nitram,
Nitrazepam, Nitrenpax,
Nitrodiazepam, Nitrosam, Pacidrim,
Pacisyn, Radedorm, Serenex,
Somitran, Sonipam, Sonnolin, etc.
Flurazepam Apo-Flurazepam Capsules 0.015; 0.03

Flunitrazepam Hypnodorm, Hypnosedon, Narcozep, Tablets; 0.001; 0.002;
Primum, Rohypnol, Sedex, Parenteral 0.2% - 1ml
Somnubene, Valsera, etc. solution
(i/m, i/v) in
ampoules
Zopiclone Imovan, Zimovane Tablets 0.0075
Eszopiclone (is the Lunesta Tablets 1mg, 2mg,
S(+) enantiomer of 3mg
zopiclone)
Zolpidem Ivadal, Sanval, Ambien Tablets 0.005; 0.01
Zalepton Sonata Capsules 0.005
Methaqualone Aqualon, Bendor, Citexal, Tablets 0.2
Dormigen, Dormilone, Dormised,
Dormotil, Dorsedine, Holodorm,
Ipnolan, Ipnosed, Mandrax,
Mekvalon, Melsomin, Mequalon,
Mezulon, Motolon, Mynal,
Nobadorm, Noctilene, Normorest,
Optinoxan, Orthonal, Quaalude,
Revonal, Ronqualone, Somberol,
Somnidon, Somnomed,
Somnotropon, Tolinon, Toquilone,
Toraflon, Torinal, etc.
Doxylamine Donormil Tablets 0.015

Bromisoval Abroval, Albroman, Alluval, Alural,
Bromodorm, Bromuralum,
Bromuresan, Dormigene, Isobromyl,
Isoneurin, Isoval, Leunerval,
Sedural, Somnibrom, Somnurol,
Valurea, etc.
Ramelteon Rozerem Tablets 8mg

Chapter 17. Antiepileptic drugs and Antiparkinsonian drugs

Antiepileptic drugs and Antiparkinsonian drugs belong to group of
anticonvulsant drugs.
Antiepileptic drugs
More than 40 separate forms of epilepsy have been identified. The defective
synaptic function might lead to convulsions. Namely, improving of excitatory
synaptic activity or oppression of inhibitory synaptic activity may evoke a
convulsion. In this way, the drugs for therapy of epilepsy should oppress the
activating amino acids (glutamate, aspartate), or increase the activity of GABA.
More over, antagonists of the GABAA receptor or agonists of glutamat receptors
elicit seizures in experimental animals, and vice versa. The drugs described as
antiepileptic guarantee the symptomatic therapy and not effective as anti-
epileptogenic agents. So, therapy of epilepsy is symptomatic in that available drugs
inhibit seizures. A major problem of this therapy is the length of its duration, and
as a result, the unfavorable effects are possible. The ideal anticonvulsant drug
would depress all convulsions without causing adverse effects. Unfortunately, the
drugs that are used currently provoke undesirable effects from minimal impairment
of CNS to death from aplastic anemia or hepatic failure. Anti-seizure drugs interact
with oral contraceptives and lead to teratogenic effects, and effects on vitamin K
metabolism in pregnant women. Anti-seizure drugs have been associated with
vitamin K deficiency in newborns, which can result in a coagulopaty and
intracerebral hemorrhage. And that is why treatment with vitamin K, 10mg/day
during the last month of gestation, has been recommended for prophylaxis.
Classification of Antiepileptic drugs according the mechanism of action
Barbiturates: Phenobarbital (see above in table 44)

Benzobarbital
Primidone
Stimulators of GABA: Valproic acid
Vigabatrin
Tiagabine
Valpromide
Inhibitors of neuromediator acids – aspartate & glutamate: Lamotrigine
Topiramate
Drugs of “hybrid” neuromediator action: Carbamazepine
Oxcarbazepine
Phenytoin
Felbamate
Benzodiazepines: Clonazepam
Diazepam
Chapter 17. Antiepleptic and Antiparkinsonian drugs | 275
Different drugs: Ethosuximide

Beclamide
Gabapentine
Puphemide
Pregabalin
Lacozamide
Table 52*. Proposed Mechanisms of Action of Anti-Seizure Drugs
Molecular Target and Drug Consequences of Action

Activity
NA+ channels modulatos
that: phenitoin, · block action potential propagation
enhance fast inactivation carbamazepine, · stabilize neuronal membranes
lamotrigine, · reduce neurotransmitter release,
felbamate, focal firing, and seizure spread;
oxcarbazepine,
topiramate, · increases spike frequency adaptation
enhance slow inactivation valproic acid · reduces action potential bursts, focal
firing, and seizure spread
lacozamide · stabilizes neuronal membranes
2+
Ca channel blockers ethosuximide, · reduce neurotransmitter release
valproic acid, · reduce slow-depolarization and
lamotrigine spike-wave discharges
α2δ ligands gabapentin, · modulate neurotransmitter release
pregabalin
GABAA receptor benzodiazepine · increase membrane
allosteric modulators s, hyperpolarization and seizure
phenobarbital, threshold
felbamate, · reduce focal firing
topiramate, benzodiazepines - attenuate spike-
carbamazepine, wave discharges
oxcarbazepine phenobarbital, carbamazepine,
oxcarbazepine - aggravate spike-wave
discharges
GABA uptake inhibitors/ tiagabine, · increase GABA level and membrane
GABA-transaminase vigabatrin hyperpolarization
inhibitors · reduce focal firing
· aggravate spike-wave discharges
N-Methyl-D-aspartate felbamate · reduces slow excitatory
(NMDA) receptor neurotransmission
antagonists · reduces excitatory amino acid
neurotoxicity
· delays epileptogenesis
α-amino-3-hydroxy-5- phenobarbital, · reduce fast excitatory

methyl-4- topiramate neurotransmission and focal firing
isoxazolepropionic acid
(AMPA)/kainate receptor
antagonists
Enhancers of lamotrigine · buffers large hyperpolarizing and
Hyperpolarization- depolarizing inputs
activated cyclic · suppresses action potential initiation
nucleotide-gated (HCN) by dendritic inputs
channel activity
Synaptic vesicle levetiracetam · unknown; may decrease transmitter
glycoprotein 2A (SV2A) release
protein ligand
Inhibitors of brain acetazolamide, · increase HCN-mediated currents
carbonic anhydrase topiramate, · reduce NMDA-mediated currents
zonisamide · increase GABA-mediated inhibition
th
12 edition. Medical. 2011. – 2084 P.
Table 53*. Classification of Epileptic Seizures and Indications for Anti-Seizure

Drugs
Seizure Features Conventional Recently

Type Anti-Seizure Developed
Drugs Anti-Seizure
Drugs
Partial Seizures
Simple Diverse manifistations determined carbamazepin gabapentin,
partial by the region of cortex activated by e, phenytoin, lacosamide,
the seizure (e.g., if motor cortex valproate lamotrigine,
representing left thumb, clonic jerking of levetiracetam,
left thumb results; if somatosensory cortex rufinamide,
representing left thumb, paresthesia of left tiagabine,
thumb results), lasting approximating
topiramate,
20-60 seconds.
Key feature is represervation of zonisamide
consciousness.
Complex Impaired consciousness lasting 30
partial seconds to 2 minutes, often
associated with purposeless
movements such as lip smacking or
hand wringing.
Partial with Simple or complex partial seizure carbamazepin
secondary evolves into a tonic-clonic seizure e,
generalized with loss of consciousness and phenobarbital,
tonic-clonic sustained contractions (tonic) of phenytoin,

seizure muscles throughout the body primidone,
followed by periods of muscles valproate
contraction alternating with period
of relaxation (clonic), typically
lasting 1-2 minutes.
Generalised Seizures
Absence Abrupt onset of impaired ethosuximide, lamotrigine
seizure consciousness associated with valproate,
staring and cessation of ongoing clonazepam
activities typically lasting less than
30 seconds.
Myoclonic A brief (perhaps a second), valproate, levetiracetam
seizure shocklike contraction of muscles that clonazepam
may be restricted to part of one
extremity or may be generalized.
Tonic- As described earlier in table for carbamazepin lamotrigine,
clonic partial with secondarily generalized e, levetiracetam,
seizure tonic-clonic seizures except that it is phenobarbital, topiramate
not preceded by partial seizure. phenytoin,
primidone,
valproate
Table 54. Medicinal forms of Antiepileptic drugs

Benzobarbital Benzonal Tablets 0.05; 0.1
Primidone Hexamidinum, Tablets 0.125; 0.25
Desoxyphenobarbitone,
Lepimidin, Lespiral,
Liskantin, Mylepsin,
Mysoline, Prilepsin,
Primaclone, Primidone,
etc.
Phenobarbital Luminalum Tablets 0.1; 0.05; 0.005
Valproic acid Apilepsin, Acediprol, Tablets; 0.3;
Convulex, Depakene, Syrup 5% - 100ml
Depakin, Depakote,
Deprakine, Diplexin,
Divalproex, Encorate,
Encorate Chrono,
Epikine, Epilim,
Everiden, Lepeilan,
Orfilept, Orfiril,
Propymal, Valpakine,
278 | Unit 5.
Valparine XR,
Valporin, Valprin,
Valproate sodium,
Valpron, etc.
Vigabatrin Sabril Tablets; 500 mg;
Powder 500 mg/ sachet
Valpromide Depamide Tablets 0.3
Tiagabine Gabitril Tablets 5mg, 10mg, 15mg
Lamotrigine Lamictal, Lamitor Tablets; 0.025, 0.05, 0.1;
Chewable 0.005, 0.025, 0.1
tablets
Topiramate Topamax Tablets; 25 mg, 50 mg,
100 mg, 200 mg;
Capsules 15 mg, 25 mg,
50 mg
Carbamazepine Actinerval, Apo- Tablets; 0.1, 0.2;
Carbamazepin,
Carbadac, Carbapin,
Carbasan, Carbatol,
Epial, Gen-Carbasan,
Gen-Carpaz, Mazepine,
Novo-Carbamaz,
Stazepin, Storilat,
Tegretol, Timonil,
Zagretol, Zeptol,
Finlepsin, etc. Tablets retard 0.2, 0.4
Oxcarbazepine - is keto Trileptal, Trexapin, etc. Tablets; 0.15, 0.3, 0.6;
analog of carbamazepine Peroral 0.3/5 ml
suspension
Phenytoin Alepsin, Dihydantoin, Tablets; 0.117 Phenytoin +
Diphenin, Dilantin 0.032 Sodium
sodium, Diphantoine, hydrocarbonate;
Diphedan, Epanutin, Parenteral 250 mg – 5 ml;
Eptoin, Hydantal, solution (i/v) in
Hydantoinal, Phenytek, ampoules;
Sodanton, Solantoin, Capsules; 25 mg, 50 mg,
etc. 100 mg;
Peroral 30 mg – 5 ml;
suspension;
Coated tablets; 100 mg;
Chewable
tablets 50 mg
Felbamate Felbatol Tablets; 0.4, 0.6;
Peroral 60%
suspension
Clonazepam Antelepsin, Clonotril, Tablets; 0.00025, 0.0005,
Iktoril, Iktorivil, 0.001, 0.002;
Ravatril, Ravotril, Peroral 0.25%;
Rivatril, Rivotril, solution;
others Parenteral 0.05% -2 ml
solution (i/v) in
Chapter 17. | 279
Antiepleptic and Antiparkinsonian drugs
ampoules
Ethosuximide Aethosuximid, Asamid, Capsules 0.25
Ethymal, Etomal,
Pemalin, Petinimid,
Pyknolepsin, Ronton,
Succimal, Suxilep,
Zarontin, others
Beclamide Chloracon, Tablets 0.25
Benzchlorpropamide,
Hibicon, Nydrane,
Posidrine
Gabapentin Neurontin, Convalis, Capsules; 0.1, 0.3, 0.4;
Gabagamma, Tablets 0.6, 0.8
Gapentek, Lepsitin,
Tebantin
Pregabalin Lyrica Capsules; 25 mg, 50 mg,
100 mg, 200 mg,
300 mg;
Oral solution 20mg/1ml - 473ml
Levitiracetam Keppra, others Tablets; 250 mg, 500 mg;
Oral solution 100 mg/1 ml -
300 ml
Zonosamide Zonegran Capsules 25 mg, 50 mg,
100 mg
Puphemide Tablets 0.25
Lacozamide Vimpat Tablets; 50 mg, 100mg,
150 mg, 200 mg;
Syrup; 100 mg/1 ml -
200 ml;
Parenteral 10 mg/ 1ml
solution (i/v) in
ampoules
Rufinamide Banzel, Inovelon Tablets; 100 mg, 200 mg,
400 mg;
Peroral 40 mg/1 ml -
suspension 460 ml
Drugs for treatment Parkinson disease
Parkinson disease is characterized by several features:

Bradykinesia
Muscular rigidity
Resting tremor
An impairment of postural balance leading to disturbances of gait and
falling.
Patogenic base of PD is insufficiency of dopaminergic nervous transmission.
The distinctive feature of PD is loss of pigmented, dopaminergic neurons of
substantia nigra pars compacta, with the appearance of intracellular inclusions
known as Lewy bodies. Loss of 70%-80% of dopaminergic neurons causes
symptoms of PD that are progressed over 5-10 years to a rigid, akinetic state and
inability to care for themselves. Causes of death are immobility, aspiration
pneumonia or pulmonary embolism. Loss of dopaminergic neurons affects other
areas of the brain, namely, brainstem, hippocampus, and cerebral cortex that is
likely responsible for “non-motor” peculiarities of PD, such as sleep disorders,
depression, and memory impairment. In addition to idiopathic Parkinson's disease
and Parkinson's syndrome exists, which may be the cause of neurodegenerative
disoders, stroke, intoxication with dopanin receptor antagonists, the use of
antipsychotics, like haloperidol and thorazine, anti-emetics such as
prochloperazine and metoclopramide.
The treatment of Parkinson disease is based on the drugs that may increase
the dopaminergic nervous transmission. In other words, these drugs should
enhance dopamine levels in dopaminergic neurons; or inhibit Mono-amino
oxydase (MAO) and Catecol-O-Methyltransferase (COMT), because after release,
dopamine is transported back into dopaminergic terminals by the presynaptic
uptake mechanism or metabolized by the actions of MAO and COMT; or activate
dopamine receptors. There are following medications: dopamine precursors, MAO
inhibitors, COMT inhibitors, dopamine receptor agonists.
Dopamine precursors are the short-acting drugs. They cause “Wearing off”
symptoms. ‘Wearing off’ is a common phrase used in PD. It describes the period
of time between the end of the effect of one dose of medication, and the beginning
of the next one. That is, the beneficial effects of the previous dose appear to be
‘wearing off’. There is no definite explanation for what causes wearing off.
Levodopa works by supplying dopamine to the nerve cells of people with PD.
However, as PD progresses, it is possible that the levodopa medication is less able
to compensate for the increasing loss of dopamine-producing nerve cells. Another
possibility is based on the theory that, in early PD, the extra dopamine supplied by
each levodopa dose is stored and then released when needed. In more advanced
PD, the dopamine can no longer be stored and so it is released all at once,
beginning by working well (ON time), progressing to working too well (ON with
dyskinesias), returning to working well again (ON time), and then wearing off
(OFF time). These variations are examples of motor fluctuations. The symptoms of
wearing off vary from person to person, and may not occur after every dose of
levodopa. Wearing off tends to produce a mild and gradual increase in symptoms,
with some people noticing an increase in tremor or slowness. In contrast, other
types of motor fluctuations associated with more advanced PD, such as those
known as ON–OFF fluctuations, have more rapid and sometimes unpredictable
switches between periods of good function and periods of poor function. People
may experience a return of symptoms including tremor, stiffness, anxiety,
depression, and pain.
Dopamine receptor agonists have direct action on striatal dopamine
receptors; they do not depend on the functional abilities of the nigrostriatal
neurons. Dopamine receptor agonists have duration of action longer than that of
levodopa. They are used for prevention and treatment of motor disorders in
Parkinson's disease. Dopamine receptor agonists reduce a need for exogenous

levodopa.
COMT inhibitors block peripheral conversation of levodopa to 3-O-methyl
DOPA, increasing both the plasma T1/2 of levodopa as well as the fraction of each
dose that reaches the CNS. They reduce the “Wearing off” symptoms in patients
with levodopa/carbidopa.
MAO inhibitors act on both isoemzymes MAO-A and MAO-B that are
present in the periphery, and inactivate monoamines of intestinal origin. Two
selective inhibitors MAO-B are used fot treatment of PD: seleginine and
rasagiline. They inhibit breakdown of dopamine in the striatum, but do not inhibit
peripheral metabolism of catecholamines and can be taken safely with levodopa in
contrast to non-selective MAO inhibitors. They do not provide “cheese effect”:
when tyramine-rich foods (such as mature cheese, yeast extracts and fermented
soya bean products, wine, pickled herring, broad bean pods) are ingested in
conjunction with a monoamine oxidase inhibitor, tyramine is responsible for the
so-called "cheese effect (syndrome)". The "cheese effect" is associated with the
selective inhibition of MAO-A, the enzyme responsible for intraneuronal oxidation
of noradrenaline, and may cause a dangerous rise in blood pressure. An early
warning symptom may be a throbbing headache. A consequence of action of
MAO-B inhibitors in the brain is a reduction in overal metabolism of dopamine,
and as a result, a reduction in formation of toxic free radicals.
Table 55*. Drugs for Treatment of Parkinson Disease
Agent Features of Adverse effects Comments

Pharmacokinetics
Levodopa Formulations
Carbidopa/levo Peak of plasma Dyspeptic symptoms Levodopa is
dopa; concentration 0.5-2 (nausea, vomiting, administered in
Carbidopa/levo hours; loss of appetite), combination with
dopa sustained T1/2 1-3 hours; orthostatic peripherally acting
release; The duration of action 6- hypotension, inhibitor of aromatic L-
Carbidopa/levo 8 hours; arrhythmia, chronic amino acid
dopa Rate and extent of and choreoathetoid decarboxylase, such as
orally absorption depends on hyperkinesis, carbidopa or
disintegrating the rate of gastric psychotic and benserazide, drugs that
tablets emptying, the pH of paranoid reactions, do not penetrate well
gastric juice, the length headache, blurred into the CNS, to prevent
of time the drug is vision, and decarboxylation by
exposed to the leukopenia, enzymes in the intestinal
degradative enzymes of agranulocytosis, mucosa and in other
gastric and intestinal allergic reactions; peripheral sites.
mucosa, competitors “Wearing off” Inhibition of peripheral
like dietary amino acids. symptoms. decarboxylase
More over levodopa and noticeably increases the
aromatic amino acids fraction of levodopa that
282 | Unit 5.
have the same remains unmetabolized
membrane transporter to and available to cross
overcome the BBB for the BBB. In addition,
entry into the CNS. In dopamine release into
the brain levodopa is the circulation by
converted to dopamine peripheral conversation
by decarboxylation first of levodopa creates
of all within the adverse effects,
presynaptic terminals of especially nausea and
dopaminergic neurons in hypotension.
the stratium.
COMT Inhibitors
Entacapone; It has short action, and Nausea, orthostatic
Stalevo inhibits peripheral hypotension, vivid
(combination COMT. dreams, confusion,
entacapone and hallucinations
with
levodopa/carbi
dopa)
Tolcapone It has duration action, Nausea, orthostatic Use only in patients not
and inhibits both central hypotension, vivid responding satisfactorily
and peripheral COMT. dreams, confusion, to other treatments.
and hallucinations; Requires monitoring of
May be hepatotoxic. liver function.
Carbidopa/levo
dopa/
entacapone
Dopamine Agonists
Apomorphine It penetrates the blood- May cause collaps, It has high affinity for
brain barrier, as a result loss of D4 receptors, moderate
it has a central consciousness (in affinity for D2, D3, D5
dopaminergic action. case of the and adrenergic α1D, α2B,
concomitant use and α2C receptors, and
with ondansetron), low affinity for D1
hallucinations, receptors.
neurological Apomorphine do not use
disorders, allergic for treatment PD due to
reactions, QT nausea, vomiting, toxic
prolongation, effect on kidney.
injection-site Trimethobenzamide
reactions, (Tebamide, Tigan) is an
dyskinesia, and antiemetic used to
abnormal behavior. prevent nausea and
vomiting.
Apomorphine is FDA-
approved as a “rescue
Chapter 17. | 283
therapy”. Use only in
patients not responding
satisfactorily to other
treatments.
Bromocriptine Older agent.
Pergolide Older agent. It was
withdrawn from U.S.
market in 2007 due to
cardiac valve fibrosis.
Pramipexole These are the newest They cause They have selective
Ropinirole agents. hallucination, activity at D2 class site
The duration of action 8- confusion, nausea, (specifically at D2 and
24 hours. orthostatic D3 receptors). Both are
hypotension, fatigue well absorbed orally and
and somnolence, have similar therapeutic
attacks of irresistible action.
sleepiness.
Ropinirole It is in a once-daily
sustained sustained release
release formulation, is more
convenient and may
reduce adverse effects
related to intermittent
dosing.
MAO Inhibitors
Rasagiline It is well absorbed from Often - headaches, It reduces levodopa-
the GIT. depression, related ‘Wearing off’
Fat food slows the dizziness, anorexia, symptoms.
absorption of its. convulsions, It has a neuroprotective
arthralgia, arthritis, effect.
pain in the neck, the Rasagiline at therapeutic
vesicles bullous doses does not block the
rash, contact metabolism of dietary
dermatitis, biogenic amines
stenocardia, flu-like (including tyramine) and
symptoms, fever, therefore causes no
leukopenia, rhinitis, tyramine-mediated
weakness, hypertensive syndrome.
conjunctivitis, acute It does not cause
disorders of the "tyramine syndrome",
urinary system, which allows patients to
allergic reactions; be used without
rarely - restriction in the diet
insufficiency of the foodstuffs containing
cerebral circulation, significant amounts of
skin carcinoma, tyramine (including
284 | Unit 5.
myocardial cheese, chocolate).
infarction;
dyspeptic symptoms
(nausea, vomiting,
loss of appetite).
Selegiline Metabolites of selegiline Anxiety, insomnia Orally disintegrating
include amphetamine due to metabolites; tablets (Zelapar),
and methamphetamine, May be stupor, transdermal patch
which may cause rigidity, agitation, (Emsam) allow reducing
adverse effects. and hypertermia hepatic first-pass
when selegiline metabolism and in this
administered with way limiting the
the analgesic formation of
meperidine. amphetamine
metabolites.
Selegiline may have
antidepressant effects,
especially at daily doses
20mg, and is under
investigation for
administration by
transdermal patch.
Other Medications
Trihexyphenidy Effect of the drug occurs Headache, Prescribe the drug with
l HCl within 1 hour after oral irritability, caution in patients older
(antimuscarinic administration, and the delusions, than 60 years because of
agent: central maximum effect lasts hallucinations, increased sensitivity to
M-, N- for 2-3 hours, and the mental the drug, the possibility
cholinolytic total duration of effect is disorientation of deterioration in
and peripheral 6-12 hours. After i/m (predominantly in memory and thinking.
M-cholinolytic) injection it is absorbed patients with You should regularly
within a few minutes, atherosclerosis); monitor the intraocular
the effect develops after Effects due to the pressure.
5-10 minutes and lasts anticholinergic Perhaps the
up to 12 hours. activity: dry mucous development of drug
membranes of the dependence.
mouth, visual During the period of
impairment, treatment must be
increased intraocular careful when driving and
pressure, occupation of other
constipation, potentially hazardous
difficulty urinating, activities that require
and tachycardia. high concentration of
attention and speed of
psychomotor reactions.
Chapter 17. | 285
Amantadine It is well abs orbed
from Dizziness, insomnia, It is antiviral agent for
the GIT. anxiety, irritability, prophylaxis and
It passes through the blurred vision, treatment of ingluenza
BBB, placenta, into agitation, tremor, A, but has
breast milk. T1/2 - is seizures, visual antiparkinsonian
about 15 hours. It is hallucinations; activity.
excreted primarily by heart failure,
the kidneys unchanged. tachycardia,
orthostatic
hypotension;
anorexia, nausea,
dry mouth,
dyspepsia;
urinary retention in
patients with benign
prostatic
hyperplasia,
polyuria, nocturia,
peripheral edema,
dermatitis, the
appearance of a
bluish color of the
skin of upper and
lower limbs.
Table 56. Medicinal forms of the drugs for treatment Parkinson disease

Levodopa Avodopa, Bendopa, Bio-dopa, Tablets; 0.25; 0.5
Brocadopa, Caldopa, Cicandopa, Capsules
Dalutrin, Deadopa, Dopacin,
Dopaflex, Dopal, Doparkin,
Dopastral, Doprin, Eldopar,
Eurodopa, Larodopa, L-Dopa,
Levopa, Le-vopar, Madopan,
Medidopa, Oridopa, Pardopa,
Parkidopa, Parmidin,
Speciadopa, Tonodopa, Veldopa,
others
Carbidopa/levodopa Parcopa Tablets 25/100 mg,
10/100 mg,
25/125 mg
Entacapone Comtan, Comtess Tablets 0.2
Entacapone with Stalevo Tablets 50/12.5/200 mg,
levodopa/carbidopa: 75/18.75/200 mg,
levodopa/carbidopa/ 100/25/200 mg,
entacapone
125/31.5/200 mg,
150/37.5/200 mg,
175/43.75/200 mg,
200/50/200 mg
Tolcapone Tasmar Tablets 0.1
Apomorphine Apokyn, Ixense, Spontane, Powder
Uprima Parenteral 1% - 1 ml;
solution (s/c) in
aqmpouls
Powder in 0.01, 0.02, 0.03,
gelatine 0.04, 0.06
capsules
Bromocriptine Aberginum, Bromergon, Tablets 0.0025, 0.004,
Bromocriptinum mesilat, 0.01;
Lactodel, Parlodel, Capsules 0.005, 0.01
Pravidel,
Serocriptine
Pergolide Permax Tablets as 50, 250
mesilate micrograms,
0.001
Pramipexole Mirapexin, Mirapex, 180, 350, 700
micrograms;
Mirapexin prolonged release
260, 520
micrograms,
1.05 mg, 1.57 mg,
2.1 mg, 2.62 mg,
3.15 mg
Ropinirole Requip, Adartrel, Tablets as 0.25, 0.5,
hydrochloride 0.001, 0.002,
0.005,
Ropinirole sustained Requip XL 0.002, 0.004,
release 0.008
Selegiline Eldepryl, Emsam, Zelapar Tablets 0.005, 0.01
hydrochloride
Rasagiline Azilect Tablets as 0.001
mesilate
Trihexyphenidyl HCl Artane, Apo-Trihex, Parkin, Tablets 0.001, 0.002,
Pacitane, Benzhexol, Anti-Sраs, 0.005
Аntitrem, Aparkan, Benzhexol
hydrochoride, Pacitane, Parkan,
Parkinsan, Parkopan, Peragit,
Pipanol, Romparkin, Tremin,
Trihetphenidili hydrochloridum,
Trihexyphenidyl hydrochloride,
Triphenidyl, Trixyl,
Cyclodolum, etc.
Amantadine Symmetrel, Midantan, PK-Merz Film-coated 0.1, 0.2
tablets
Chapter 18. Sedative drugs | 287
Chapter 18. Sedative drugs

Sedative drugs – are those that have a mild sedative effect by strengthening
the processes of inhibition in the CNS in dose-dependent fashion. In comparison
with the antipsychotics and tranquilizers they do not cause muscle relaxation,
ataxia, decreased muscle activity, drowsiness, drug dependence and are widely
used in clinical practice. Sedatives reduce activity, excitation of medium and mild
degree, and cause calm of patients.
Classification of Sedative drugs
I. Plant origin medications: preparations of Valeriana L., preparations of
Leonurus L., preparations of Polemonium coeruleum L. , preparations of Paeonia
L., and combined drugs: Valocordin, Valoserdin, Novo-passit, Corvalol,
Corvaldin, etc.
II. Bromides: sodium bromide, potassium bromide, bromcamphora.
Bromine is an antagonist of chlorine in human body. It has good absorption
from GIT mucosa and is distributed primarily in body fluids including blood
plasma. Bromine quantity in the cells of the body is small. Bromine excretion is
through kidney, sweat glands and GIT. T1/2 is about 2 weeks.
Pharmacological effects of Bromides:
sedative
increase the threshold of brain excitement
restoration of of reflex activity in cases of its violation
Indications for Bromides use:
neurosis
convulsion in patients with epilepsy, chorea, laryngism and other pathological
spasmodic states
The treatment begins from little doses with a gradual increase and reduction
of the salt intake.
Contraindications for Bromides use:
 idiosyncrasy
heart insufficiency
kidney diseases
expressed atherosclerosis
anemia
eczematous, bullous skin rash
Adverse effects of Bromides use:
bromism
Acne-form dermatitis and other forms of skin disease may also be seen, as
well as mucous hypersecretion in the lungs. Asthma and rhinitis may
worsen. Rarely, tongue disorder, bad breath and obstipation occur. Bromism.
Symptomes: running nose, cough, conjunctivitis, weakness,
ataxia, reducing memory, acne bromica, depression, lethargy, somnolence, loss of
appetite and cachexia, exicosis, loss of reflexes or pathologic reflexes, clonic
seizures, tremor, loss of neural sensitivity, paresis, cerebral edema with associated
headache and papilledema of the eyes, delirium: confusion, abnormal speech, loss
of concentration and memory, aggressiveness and psychosis.
Antidote of Bromides – NaCl.
Table 57. Medicinal forms of Sedative drugs

Sodium bromide Natrium Powder;
bromatum, Natrii Tablets; 0.15; 0.5;
bromidum Peroral solution cum 1%, 2%, 3% -
sirupo fructuario in 100ml;
flacons;
Parenteral solution (i/v)
in ampoules
5%, 10%, 20%
- 5ml, 10ml
Potassium bromide Kalii bromidum Powder;
Tablets; 0.05; 0.1;
Peroral solution cum 1% - 100ml
sirupo fructuario in
flacons
Bromcamphora Camphora Tablets 0.15; 0.25
monobromata
Rhizoma cum radicibus Species
Valerianae
Valerian Tinctura in flacons 25ml, 30ml,
40ml
Leonurus Tinctura in flacons 25ml
Menthae piperitae oleum + Valocordin Peroral solution in 25ml
Phenobarbital + Humuli lupuli flacons
cones oleum +
Ethylbromizovalerionate
Origani herba + Menthae Valoserdin Peroral solution in 25ml
piperitae oleum + Phenobarbital flacons
+ Ethylbromizovalerionate
Guaifenesin and extracts of Novo-passit Tablets;
hawthorn, hops, St. John's wort, Peroral solution in 100ml
lemon balm, passionflower, flacons
valerian and elderberry
Menthae piperitae oleum + Corvalol Peroral solution in 25ml
Phenobarbital + flacons
Ethylbromisovalerinate
Ethylbromisovalerinate + Corvaldin Peroral solution in 25ml
Phenobarbital + Menthae flacons
piperitae oleum + Humuli lupuli
oleum
Chapter 19. Antidepressants | 289
Chapter 19. Antidepressants

Antidepressant drugs – are used for trearment depression. In accordance
with the mechanism of action, all antidepressants are divided into first and second
generation. The most widely used modern drugs are second-generation
antidepressants, namely: selective serotonine reuptake inhibitors (SSRIs),
serotonine-norepinephrine reuptake inhibitors (SNRIs), selective norepinephrine
reuptake inhibitors (SNRIs). Reuptake of transmitter in monoamine system is the
main mechanism of action by which neurotransmission is interrupted, thus
inhibition of this reuptake can promote neurotransmission, apparently by
deceleration clearance of the transmitter from the synapse and prolonging the
dwell-time of the transmitter in the synapse. Besides, reuptake inhibitors hamper
either Se, the neuronal Se transporter - 5-HT; NE, the neuronal NE transporter or
both. In a like manner, the first generation antidepressants include monoamine
oxidase inhibitors (MAOIs) and tricyclic antidepressants (TCAs). They also
promote neurotransmission by inhibiting monoamine metabolism and thereby
facilitating neurotransmitter storage in secretory granules, TCAs by inhibiting 5-
HT and NE reuptake. These first generation agents manifest adverse effects and
drugs and food interactions that limit their use in the current treatment.
In general, antidepressants enhance serotoninergic and noradrenergic
transmission; they evoke adaptive or regulatory mechanisms to improve the
effectiveness of therapy; increase density or sensitivity of adrenergic or
serotoninergic receptors, receptor-G-protein coupling and cyclic nucleotide
signaling; cause induction of neurotrophic factors, and contribute neurogenesis in
the hippocampus.
Unfortunately, neither earlier theories of the mechanisms of antidepressant
action nor current theories have yet led to new antidepressant treatments.
Nevertheless, the potential targets for elaboration of the new antidepressants may
be glutamate, neurokinin, corticotropin releasing hormone receptors, cyclic
nucleotide pohosphodiesterases.
All antidepressants have “therapeutic lag” lasting 3-4 weeks before
therapeutic response. But, if given antidepressant is not effective after 8-week trial
in an adequate dose it should be switched to another antidepressant with different
mechanism of action.
The metabolism of most antidepressants is mediated by hepatic CYPs.
Classification of antidepressants
І. Monoamine oxidase inhibitors (MAOIs):

Nonselective inhibitors of MAO-A and MAO-B (Irreversible action):
Nialamidе
Selective inhibitors of MAO-A (Reversible action):
Pyrazidol
Tetrindolе (Hexahydrocyclohexilpyrazynocarbazol)
Metralindol
Moclobemide
Befol
Feprosidnin
ІІ. Monoamine reuptake inhibitors:

Nonselective monoamine reuptake inhibitors (tricyclic antidepressants):
Tertiary amine tricyclic antidepressants:
Imipramine
Clomipramine
Amitriptyline
Trimipramine
Doxepine
Secondary amine tricyclic antidepressants:
Maprotiline
Amoxapine
Nortriptyline
Protriptyline
Desipramine
Particular tricyclic antidepressants:
Pipofezine
Fluacizine
Selective norepinephrine reuptake inhibitors (NRIs):
Reboxetine
Viloxazine
Atomoxetine
Selective serotonine reuptake inhibitors (SSRIs):
Fluoxetine
Fluvoxamine
Sertraline
Paroxetine
Citalopram
Serotonine-norepinephrine reuptake inhibitors (SNRIs):
Milnacipran
Venlafaxine
Duloxetine
ІІІ. Selective serotonin reuptake enhancer (SSRE):

Tianeptine
ІV. Atypical antidepressants:

Trazodone
Nefazodone
Mirtazapine
Mianserin
Atomoxetine
Bupropion
Duloxetine
V. Miscellaneous preparations:
Hyperici perforati herbae extract (Negrustin, Deprim)
The main pharmacological effects:

Antidepressive
Anticholinergic
Antihistaminic
Antidiuretic
Sedative/stimulanting
Anxiolytic
Analgesic
Indications: Antidepressants are drugs used for the treatment of depression.
Despite their name, they are often used to treat a wide range of other conditions,
on- or off-label, such as:
Anxiety disorders
Obsessive compulsive disorder
Eating disorders
Chronic pain, neuropathic pain
Some hormone-mediated disorders such as dysmenorrhea
Snoring
Migraines
Attention-deficit hyperactivity disorder
Substance abuse
Occasionally even insomnia or other sleep disorders
Antidepressants can be used both alone or in combination with other medications.
Features of Antidepressant Adverse effects:
“Therapeutic lag” phenomenon –is a delay of therapeutic response to
 antidepressant treatment
“Switch” phenomenon – is the transition from a depressed episode to a manic or
hypomanic episode in patients receiving antidepressants and emergence of
bipolar illness; SSRIs, Nialamide and Bupropion may be somewhat less
 likely to induce “switch” phenomenon that other antidepressants
Antidepressants are considered as indirect risk factor of suicidal ideation or
suicide attempts and self-injurious behavior; FDA has a issued “black box”
caution especially about the use of SSRIs, and some other antidepressants in
children and adolescents
“Cheese” syndrome (tyramine, or serotonin syndrome): to avoid the
development of "cheese" syndrome during treatment by Nonselective
monoamine reuptake inhibitors (tricyclic antidepressants) should be

excluded from the diet the food containing tyramine, including cheese,
cream, coffee, beer, wine, smoked food
Nonselective monoamine reuptake inhibitors (tricyclic antidepressants) may
have antihistamine effects, sedative, analgesic, and antiparkinsonian effects,
weight gain, quinidine-like effects on cardiac conduction, hepatotoxicity
Tricyclic antidepressants may cause headache, nausea, dizziness, sweating,
tachycardia, cognitive dulling, blurred vision, dry mouth, constipation,
difficulty urinating (adverse effects mediated by antagonism of muscarinic
acetylcholine receptors); antagonism of α1 adrenergic receptors contributes
 to ortostatic hypotension and sedation
Anticholinergic effects: disturbance of accommodation, dry mouth, urinary
retention, confusion, etc.
Tolerance
Withdrawal syndrome; dizziness, headache, nervousness, nausea, insomnia
Addiction to medication
Antidepressants lower the seizure threshold
SNRIs venlafaxine in high doses can induce sustained diastolic hypertension
SSRIs may cause dyspepsia, diarrhea, anorexia, emesis – as a result of
stimulation of CNS and peripheral 5-HT3 receptors; sweating, headache,
insomnia, anxiety, irritability, tremor, impotention, decreased libido, sexual
dysfunction (erectile dysfunction, anorgasmia, ejaculatory delay) – due to
excessive stimulation of brain 5-HT2 receptors; in case of continued
treatment may be dullness of intellectual abilities and concentration
Using neuronal serotonin reuptake inhibitors with tricyclic antidepressants may
 develop a "serotonin syndrome"
Serotonin Receptor Antagonists (Atypical Antidepressants) mirtazapine may
elicit somnolence, increased appetite, weight gain, and rarely –
agranulocytosis; trazodone use is associated with priapism; nefazodone may
 cause liver failure; bupropion in high doses may cause seizures
MAOI use is associated with hypertensive crisis resulting from food or drug
 interactions
It is difficult to distinguish the adverse effects of antidepressants from
symptoms of depression
Contraindications:
Glaucoma
Prostate hypertrophy
Atherosclerosis
Infection diseases
Tuberculosis in active phase
Liver, kidney and heart insufficiency
Diseases of hematopoietic system
Pregnancy
Cerebral blood circulation insufficiency
Arterial hypotension
Idiosyncrasy
Convulsive syndrome, epilepsy

 Peculiar properties of SSRIs:
SSRIs treatment causes stimulation of 5-HT1A and 5-HT7 autoreceptors on cell
bodies in the raphe nucleus and 5-HT1D autoreceptors on serotoninergic terminals,
and this reduces serotonin synthesis and release toward pre-drug levels.
With repeated treatment with SSRIs, there is a gradual down-regulation and
desensitization of these autoreceptor mechanisms
Down-regulation of postsynaptic 5-HT2A receptors may contribute to
antidepressant efficacy directly or by influencing the function of noradrenergic and
other neurons via serotoninergic heteroreceptors
Other postsynaptic 5-HT receptors remain responsive to increased synaptic
concentration of 5-HT and contribute to the therapeutic effects of the SSRIs
SSRIs do not block histamine receptors
FDA has approved fluvoxamine for treatment of obsessive-compulsive disorder
and social anxiety disorder, but not depression
citalopram is labeled for the use in premenstrual dysphoric disorder
SSRIs are used for preventing vasovagal symptoms in post-menopausal women
SSRIs are more effective and safer in overdose than TCAs
SSRIs have affected a broad range of psychiatric, behavioral, and medical
conditions, for which they are used, on and off label
they are effective in treating major depression
SSRIs demonstrate the effectiveness in the treatment of generalized anxiety,
panic, social anxiety and obsessive-compulsive disorder
Setraline and paroxetine nave been approved for treatment of posttraumatic
strees disorder
There is no strong relationship between SSRI serum concentration and
therapeutic efficacy
CYP2D6 is involved in the metabolism of most SSRIs and the SSRIs are at
least moderately potent inhibitors of this isoenzyme. This is very important for
drug interactions.
Peculiar properties of SNRIs:
SNRIs with non-tricyclic structure have been approved for treatment of
depression, anxiety disorders and pain: venlafaxine and its demethylated
metabolite, desvenlafaxine; duloxetine; and milnacipran
Duloxetine – off-label uses include stress urinary incontinence, autism, binge
eating disoders, hot flashes, pain syndromes (fibromyalgia and neuropathic pain
associated with peripheral neuropathy), premenstrual dysphoric disorders; it is
used in the treatment of depression and anxiety,
Venlafaxine is most effective drug for preventing vasovagal symptoms in
postmenopausal women, and is used in posttraumatic stress disorders
SNRIs are eliminated by hepatic metabolism and by renal excretion.
Serotonin Receptor Antagonists of 5-HT2 family of receptors (Atypical

Antidepressants): trazodone, nefazodone, mirtazapine, mianserin are effective
antidepressants.
Trazodone blocks 5-HT2 and α1 adrenergic receptors, and also inhibits the
serotonin transporter
Trazodone have been used widely both alone and concurrently with SSRIs or
SNRIs to treat insomnia, depression
Mianserin and mirtazapine potently block histamine H1 receptors, and also have
some affinity for α2 adrenergic receptors, 5-HT2A, 5-HT2C, 5-HT3 receptors
Mianserin and mirtazapine are used as sedating and for treatment of the
depressed patients with insomnia.
Clearance of Serotonin Receptor Antagonists is decreased in the elderly and
in patients with renal or hepatic impairment.
Others Atypical Antidepressants: bupropion acts via multiple
mechanisms. It is reuptake inhibitor of both NE and D which leads to enhancement
of noradrenergic and dopaminergic neurotransmission. Bupropion is indicated for
the treatment of depression, prevention of seasonal depressive disorder, and as a
smoking cessation treatment. Bupropion has effects on sleep EEG. Bupropion may
improve symptoms of attention deficit hyperactivity and has been used off-label
for neuropathic pain and weight loss. This drug is widely used in combination with
SSRIs to reach a greater antidepressant response. The elimination of bupropion
involves both hepatic and renal routes.
TCAs cause serious side effects, but have established value for treatment of
major depression. Tertiary amine TCAs have been used for treating insomnia and a
variety of pain conditions. Majority of TCAs also block H1, 5-HT2, α1, and
muscarinic receptors. One TCA, amoxapine, also is dopaminergic receptor
antagonist and may elicit extrapyramidal side effect such as tardive dyskinesia.
TCAs are largely eliminated by hepatic CYPs. About 76% of patients metabolize
TCAs slowly due to variant CYP2D6 isoenzyme.
MAOIs are rarely used because of their toxicity and major drug and food
interactions. MAOIs are metabolized by acetylation. A significant part of
population is “slow acetylators”. Foods containing tyramine are a contributing
factor. MAO-A within the intestinal wall and MAO-A and MAO-B in the liver
degrade dietary tyramine. In case of inhibition of MAO-A the ingestion of cheeses,
red wines, sauerkraut, fava beans, and other tyramine-containing foods leads to
accumulation of tyramine in adrenergic nerve endings and neurotransmitter
vesicles and induces NE and Ep release. The released catecholamines stimulate
postsynaptic receptors in the periphery, increasing blood pressure. Thereby, the
transdermal patch is better tolerated end safer.
Table 58*. Antidepressants: INN, Amine effects, adverse effects
INN Amine effects Adverse effects

Agitatio Seizures Sedation Hypo- Anti- GI Weith Sexual Cardiac
n tension choliner effects gain effects effects
gic
effects
Monoamine oxidase inhibitors (MAOIs):
Nonselective monoamine oxidase (MAO-A and MAO-B) inhibitors
Nialamidе 3+ 0 0 2+ 3+ 2+ 3+ 2+ 2+
Selective monoamine oxidase (MAO-A) inhibitors
Pyrazidol +/- 0 +/- 0 0 2+ 0 0 +
Tetrindolе inhibitor of 3+ 0 0
deamination of
Se and NE
Metralindol NE-, Se-ergic 3+ 0 0 0/+ 0 2+ 0 0 +
activator
Moclobemide** inhibits the 3+ 0 0 hyper- 0 2+ 0 0 0
Chapter
Befol destruction of 3+ 0 0 tension 0 0 0 0 0
NE and Se, a
lesser degree, D
concentration of
.18
monoamine
295|Antidepressants
neurotransmitter
s in the CNS
Feprosidnin enhances NE and 3+ 0 paradoxic hyper- 2+ 2+ 0 0 +
Ep action al tension
sedative
effect
Monoamine reuptake inhibitors:
Nonselective monoamine reuptake inhibitors (tricyclic antidepressants):
Tertiary amine tricyclic antidepressants:
Imipramine NE, Se 0/+ 2+ 2+ 2+ 2+ 0/+ 2+ 2+ 3+
Clomipramine NE, Se 0 3+ 2+ 2+ 3+ + 2+ 3+ 3+
Amitriptyline NE, Se 0 2+ 3+ 3+ 3+ 0/+ 2+ 2+ 3+
Trimipramine NE, Se 0 2+ 3+ 2+ 3+ 0/+ 2+ 2+ 3+
Doxepine NE, Se 0 2+ 3+ 2+ 2+ 0/+ 2+ 2+ 3+
Secondary amine tricyclic antidepressants:
Maprotiline NE 0/+ 3+ 2+ 2+ 2+ 0/+ + 2+ 2+
Amoxapine NE, D 0 2+ + 2+ + 0/+ + 2+ 2+
Nortriptyline NE 0 + + + + 0/+ + 2+ 2+
Protriptyline NE 2+ 2+ 0/+ + 2+ 0/+ + 2+ 3+
Desipramine NE + + 0/+ + + 0/+ + 2+ 2+
Particular tricyclic antidepressants:
Pipofezine inhibits the NE 0 0 2+ 0 0 0 0 0 0
and Se reuptake
Fluacizine 0 0 2+ 2+ 3+ + 0 0 0
Selective norepinephrine reuptake inhibitors (NRIs):
Reboxetine NE 2+ 2+ 0 2+ + 0 0 2+ 2+
Viloxazine NE + + 0 hyper- + 0 0 0 2+
tension
Atomoxetine NE 0 0 3+ hyper- 2+ 2+ weight 2+ +
tension loss
Selective serotonine reuptake inhibitors (SSRIs):
Fluoxetine Se + 0/+ 0/+ 0 0 3+ 0/+ 3+ 0/+
Fluvoxamine Se 0 0 0/+ 0 0 3+ 0 3+ 0
Sertraline Se + 0 0/+ 0 0 3+ 0 3+ 0
Paroxetine Se + 0 0/+ 0 0/+ 3+ 0 3+ 0
Citalopram Se 0/+ 0 0/+ 0 0 3+ 0 3+ 0
Escitalopram Se 0/+ 0 0/+ 0 0 3+ 0 3+ 0
Serotonine-norepinephrine reuptake inhibitors (SNRIs):
Milnacipran NE, Se 2+ 2+ 0 hyper- 2+ 0 0 0 2+
tension
Venlafaxine Se, NE 0/+ 0 0 0 0 3+ 0 3+ 0/+
Duloxetine Se, NE, D 0/+ 0 0 2+ 2+ 2+ weight 2+ 2+
loss
Selective serotonin reuptake enhancer (SSRE):
Tianeptine Se 0 0 0/+ 0/+ 0/+ 0/+ 0 0 0/+
Atypical antidepressants:
Trazodone Se 0 0 3+ 0 0 2+ + + 0/+
Nefazodone Se 0 0 3+ 0 0 2+ 0/+ 0/+ 0/+
Mirtazapine Se, NE 0 0 4+ 0/+ 0 0/+ 0/+ 0 0
Mianserin 0 0 2+ 2+ 0 0 0 0 0
Atomoxetine NE 0 0 0 0 0 0/+ 0 0 0
Bupropion D, NE 3+ 4+ 0 0 0 2+ 0 0 0

Duloxetine NE, Se + 0 0/+ 0/+ 0 0/+ 0/+ 0/+ 0/+
Miscellaneous preparations:
Hyperici Se, D, NE, 0 0 2+ 0 + + 0 0 0
perforati herbae GABA,
extract glutaminic
acid
* - adopted from Goodman & Gilman’s The Pharmacological Bases of THERAPEUTICS. 12 edition. Medical. 2011. – 2084 P. with autor’s changes
and additions
** - it is not approved for use in U.S.
0 negligible; 0/+ minimal; + mild; 2+ moderate; 3+ moderately severe; 4+ severe; +/- agitation (activating effect) in patients with apathetic, anergic
depression and sedation in patients with agitated states
Table 59. Medicinal forms of Antidepressants

Nialamidе Espril, Nialamide, Niamid, Niaquitil, Tablets 0.025
Nuredal, Nyazin, Psicodisten, etc.
Pirlindole Lifril, Pyrazidol Tablets 0.025
0.05
Hexahydrocycloh Tetrindolе Tablets 0.025
exilpyrazynocarb 0.05
azol
Metralindol Inkazan Tablets; 0.025;
Parenteral solution in 1.25% -
ampules (i/m, i/v) 2 ml,
10 ml
Moclobemide Amira, Aurorix, Clobemix, Depnil, Tablets 0.15,
Manerix, Clorix 0.3
Befol Tablets; 0.01,
0.025;
Parenteral solution in 0,25% -
ampules (i/v) 2 ml
Feprosidnin Sydnophen Tablets 0.005
Imipramine Tofranil, Melipramine, Tablets; 0.01,
Antideprin, Depranil, Deprimin, 0.025,
Deprinol, Depsonil, Dynaprin, 0.05,
Eupramin, Imipramil, Impramine, 0.075;
Impril, Irmin, Melipramin, Norfanil, Parenteral solution in 1.25% -
Novopramine, Pryleugan, Surplix, ampules (i/m) 2 ml
Tofranil, etc.
Clomipramine Anafranil, Chlorimipramine, Clofranil, Tablets; 0.01,
Clominal, Hydiphen, Klomipramin, 0.025;
Monochlorimipramine, Neoprex Tablets retard; 0.075;
Dragee; 0.025;
ampules (i/m, i/v) 2 ml
Opipramol Dinsidon, Insidon, Opramol, Oprimol, Dragee 0.05
Pramolan
Amitriptyline Elavil, Tablets; 0.01,
Damileni maleinas, Adepril, 0.025,
Amineurin, Amiprin, Amirol, Amizol, 0.05,
Apo-Amitriptylin, Atryptal, Daprimen, 0.075;
Elatral, Elavil, Elivel, Enovil, Lantron, Capsules retard; 0.025,
Laroxal, Laroxyl, Lentizol, 0.05;
Proheptadien, Redomex, Saroten, Parenteral solution in 1%-2 ml;
Sarotex, Teperin, Triptizol, Triptopol, ampules (i/m, i/v);
Triptyl, Tryptanol, Tryptizol, etc. Capsules
0.05
Pipofezine Aza-xazin, Dizaphenum Tablets 0.025
Fluacizine Phthoracizinum Tablets; 0.01,
0,025;
ampules (i/m) 1 ml
Chapter 19. | 299
Antidepressants
Maprotiline Ladiomil, Ludiomil, Ludionil, Dragee; 0.01,
Maprotibene 0.025,
0.05,
0.075;
Doxepine Sinequan Capsules 0.01,
0.025
Reboxetine Edronax Tablets 0.002,
0.004
Fluoxetine Deprenon, Deprex, Floxet, Fludac, Capsules; 0.01,
Flunat, Fluval, Fluxonil, Framex, 0.02;
Oxedep, Portal, Prodel, Prodep, Tablets 0.01,
Prozac 0.02
Fluvoxamine Avoxin, Fevarin, Floxyfral, Myroxim Tablets 0.05,
0.1
Sertraline Zoloft, Lustral Tablets 0.05, 0.1
Paroxetine Paxil, Rexetin Tablets 0.02
Citalopram Cipral, Cipramil, Lupram, Sepram Tablets 0.02,
0.04
Trazodone Azona, Beneficat, Bi-maran, Desyrel, Capsules; 0.025,
Geripax, Menegan, Molipaxin, 0.05, 0.1;
Pragmarel, Pragmazine, Sideril, Tablets retard; 0.075,
Thombran, Tramensan, Trazolan, 0.15;
Trazone, Tresin, Trittico Parenteral solution in 1% -
Milnacipran Ixel, Savella, Dalcipran, Toledomin Capsules 0.025,
0.05
Venlafaxine Efevelon, Velafax, Velaxin, Velaxor, Tablets; 0.025,
Effexor 0.0375,
0.05,
0.075;
Capsules 0.075,
0.15
Duloxetine Cymbalta, Yentreve Capsules 0.06,
0.12
Mirtazapine Mirzaten, Remeron Tablets 0.015,
0.03,
0.045
Tianeptine Stablon, Coaxil, Tatinol Tablets 0.0125
Mianserin Bolvidon, Lerivon, Miansan, Norial, Tablets 0.01,
Tolvin, Tolvon 0.03
Herba Hyperici Negrustin, Helarium Hypericum, Capsules 0.425
Doppelherz® Nervotonik
Hyperici perforate Deprim Tablets 0.06

herbae extract
Chapter 20. Psychomotor stimulants

Psychomotor stimulants stimulate CNS, cause excitement and euphoria,
decrease feeling of fatigue, and increase motor activity.
Classification of Psychomotor stimulants
accordingly chemical structure
 Methylxanthines:
Caffeine
Caffeine end sodium benzoate
Phenylalkylamines derivatives:
Amphetamine, α-methylphenethylamine
Sydnonimine derivatives:
Mesocarb
Piperidine derivatives:
Methylphenidate
Mechanism of action of Psychomotor stimulants.
There are several mechanisms of action of Methylxanthine – caffeine,
including translocation of extracellular calcium, increase in cyclic adenosine
monophosphate and cyclic guanosine monophosphate caused by the inhibition of
phosphodiesterase and blockade of adenosine receptors.
The effects of Phenylalkylamines derivative – amphetamine on CNC and
peripheral nervous system are indirect, and both depend upon an elevation of the
level of catecholamine neurotransmitters in synaptic spaces. Amphetamine
achieves this effect by releasing intracellular stores of catecholamines, and also
inhibits MAO that leads to high level of catecholamines that are readily released
into synaptic spaces. Amphetamine has stronger effect on dopaminergic brain
structures than noradrenergic.
Sydnonimine derivative – mesocarb has stronger effect on noradrenergic
brain structures than dopaminergic, facilitating the release of norepinephrine from
stable depot, and also inhibits MAO, but it does not have peripheral adrenomimetic
effects.
Piperidine derivative – methylphenidate has CNS stimulant properties
similar to those of amphetamine and may also lead to abuse, although its addictive
potential is controversial. Methylphenidate is a more potent dopamine transport
inhibitor thus making more dopamine available.
Pharmacological effects:
Stimulant effect on CNS
Hypertensive (caffeine, amphetamine)
Thymoleptic (mesocarb)
Weakening of the action of drugs that depress CNS (hypnotics, sedatives,
tranquilizers, alcohol, etc.)
Chapter 20. Psychomotor stimulants | 301
Analeptic
Cardiostimulant
Decreasing of stomach secretion
Increasing of diuresis
Improving of glycogenolysis, lipolysis (caffeine)
 Anorexia
Indications:
For the increasing of mental and physical performance
Migraine (caffeine)
Nocturnal enuresis, or nighttime urinary incontinence (caffeine, mesocarb)
Narcolepsy, or hypersomnia (caffeine, amphetamine)
As a subsidiary drugs for treatment of apnea in children
For improvement of the effect of electroconvulsive therapy
Adverse effects:
Caffeine in moderate doses may cause insomnia, anxiety, and agitation; in high
doses it may cause nausea, vomiting, and convulsions; the lethal doses
(about 10 g – about 100 cups of coffee daily) induce cardiac arrhythmia,
tachycardia; the consumption of 600 mg of caffeine (about six cups of coffee
 daily) may produce lethargy, irritability, and headache.
Amphetamine causes addiction, leading to psychological and physiological
dependence, drug-seeking behavior; may develop tolerance to euphoric and
anorectic (due to amphetamine action on lateral hypothalamic feeding
center) effects in cause of its chronic use; amphetamine abusers often
administer the drugs by i/v injection and by smoking; the euphoria caused by
amphetamine lasts 4-6 hours. Central effects: insomnia, irritability,
weakness, dizziness, tremor, hyperactive reflexes, confusion, delirium, panic
states, suicidal tendencies. Chronic amphetamine use induces “amphetamine
psychosis” – psychotic episodes associated with schizophrenia.
Cardiovascular effects: palpitation, cardiac arrhythmias, hypertension,
anginal pain, circulatory collapse; may be headache, chills, excessive
sweating. GIT effects: anorexia, nausea, vomiting, abdominal cramps,
 diarrhea.
Mesocarb use may be associated with neuro-psychiatric disorders; it may cause
headache, irritability, restlessness, insomnia, loss of appetite, anorexia,
increased blood pressure, allergic reactions. In patients with pre-existing
psychopathology mesocarb may induce aggravation of delusions and
hallucinations.
Methylphenidate may cause abdominal pain and nausea; anorexia, insomnia,
 nervousness, and fever.
In case of a long-term using and/or a using in high doses of Psychomotor
stimulants may be developed cardiomyopathy, arterial hypertension,
psychotic reactions, impotence, weigh loss, confusion, increasing of tactile
and pain sensitivity, tremor, tinnitus, convulsions.
Contraindications:
Increased excitement
Insomnia
Arterial hypertension and atherosclerosis
Organic diseases of cardiac and vessel system
Advanced age
Glaucoma
Phobia
Liver diseases
Alcoholism
Thyrotoxicosis
Epilepsy
Idiosyncrasy
Features of psychomotor stimulants
Caffeine act on CNS: stimulates cortex and other areas of the brain that leads to
decline in fatigue, increases the mental activity. This effect of caffeine is manifested
in case of the use of two cups of coffee (100-200 mg daily). Consumption of 1.5 g of
caffeine (12-15 cups of coffee daily) induces anxiety and tremors. Very high dose of
caffeine (2-5 g daily) causes stimulation of spinal cord. The stimulating effects of
caffeine are inherent in the rapid development of tolerance, and withdrawal syndrome
is accompanied by fatigue and sedation. Acting on the cardiovascular system, caffeine
causes positive inotropic and chronotropic effects, that may be dangerous to the
patients with IHD and may result in premature ventricular contractions. Caffeine has
diuretic action due to increase urinary output of sodium, chloride, and potassium.
Caffeine stimulates secretion of hydrocholic acid from gastric mucosa. This drug and
its derivatives relax the smooth muscles of the bronchioles. Caffeine crosses BBB, PB
and is secreted into the mother's milk, it is metabolized in the liver by CYPA2
pathway, and it is excreted in the urine.
Amphetamine is a noncatecholaminergic sympathetic amine. This drug has
D and NE release-enhancing properties. Amphetamine stimulates the entire
cerebrospinal axis, cortex, brainstem, and medulla oblongata, this leads to elevate
alertness, decreased fatigue, depressed appetite, and insomnia. Amphetamine acts
on adrenergic system: indirectly stimulates adrenergic receptors through NE
release. The side effects of this drug limit the use of it. Amphetamine is absorbed
from GIT, metabolized by the liver, and excreted in the urine. Chlorpromazine or
haloperidol relieves the CNS symptoms of amphetamine overdoses as well as the
hypertension through of their α-blocking effects. Administration of sodium
bicarbonate will increase the reabsorption of dextroamphetamine from the renal
tubules into the bloodstream.
Mesocarb stimulates noradrenergic and in less degree – dopaminergic
transmission. Its action is developed gradually, not accompanied by severe euphoria
and motor excitation. Mesocarb is well absorbed from GIT. Mesocarb is used for
Chapter 20. Psychomotor stimulants | 303
treatment of asthenic conditions accompanied by lethargy, apathy, decreased

performance, increased sleepiness, but also caused by antipsychotics and
anxiolytics; hypochondria, stupor and stupor like conditions; asthenic-neurotic
syndrome after undergoing intoxication, infection, trauma, physical and mental
fatigue; sluggish schizophrenia, artificial exacerbation of schizophrenia (in order to
overcome resistance to therapy psychotropic drugs), correction of side effects
(muscle relaxation, drowsiness ) caused an benzodiazepine anxiolytics; withdrawal
syndrome in chronic alcoholism, adynamic depression; fatigue in mentally healthy
people; mental retardation in children with adynamia, aspontaneity in organic
diseases of CNS. Mesocarb cannot be used in patients with atherosclerosis, arterial
hypertension, together with MAO-inhibitors and with TCAs, in pregnant women,
and in case of idiosyncrasy.
Methylphenidate has stimulant effects similar to those of amphetamine and
may induce abuse. This drug is widely used in children with attention deficit,
hyperactivity disorder, and for the treatment of narcolepsy. Methylphenidate is
absorbed from GIT and is excreted with urine. This drug increases the seizure
frequency, especially in patients who take antidepressants. Methylphenidate is
contraindicated in patients with glaucoma.
Table 60. Medicinal forms of Psychomotor stimulants

Caffeine Guaranin, Theinum Powder for internal use 0.1
Caffeine sodium Tablets for children; 0.075;

benzoate Tablets for adults; 0.1, 0.2;
Solution for injection in 10% , 20% -
ampules; 1 ml, 2 ml;
Solution for injection in syrette 10%, 20% -
(s/c) 1ml
Amphetamine Aktedrin, Alentol, Tablets 0.01
Amfetamine,
Amphamine,
Amphedrine,
Benzedrine sulfate,
Benzopropamin,
Euphodyn, Isoamin,
Ortedrine,
Psychedrinum,
Psychoton, Racephen,
Raphetamin,
Sympamin,
Sympatedrine,
Phenaminum, etc.
Mesocarb Sidnocarb, Sydnocarb Tablets 0.005, 0.01,
0.025
Methylphenidate Centedrin, Rilatine Tablets 0.01
Chapter 21. Analeptics

Analeptics – there are the drugs that at therapeutic doses restore weakened
function of the vital centers of the medulla oblongata, ie respiratory and
vasomotor.
Classification of Analeptics
І. By action type:
Analeptics of direct action:
Bemegridе
Caffeine
Methylamide ethylilamidazolecarbonate
Analeptics of reflex action:
Lobelinе
Cytisine
Almitrine
Solutio Ammonii caustici 10%
Analeptics of mixed action:
Niketamide
Sulfocamphoric acid + procaine (Sulfacamfocainum)
Pentylenetetrazol
Camphor
ІІ. predominant action on certain areas CNS:
Cortex (caffeine)
Medulla oblongata (methylamide ethylilamidazolecarbonate, niketamide,
Sulfacamfocainum, bemegride)
Spinal cord (strychnine)
Mechanism of action of Analeptics
Analeptics of direct action activate centers of medulla oblongata, especially
respiratory center and vasomotor center through depression of GABA-A receptors.
Analeptics of reflex action stimulate chemoreceptors of carotid sinus,
activate medulla oblongata centers.
Analeptics of mixed action have direct action on CNS and reflex action due
to stimulation of chemoreceptors of carotid sinus and activation of medulla
oblongata centers. Thus, niketamide directly activates vasomotor center of medulla
oblongata, and by reflex it activates respiratory center of medulla oblongata as a
result of stimulation of chemoreceptors of carotid sinus. Sulfacamfocainum directly
excites the CNS, and especially the vital centers of the medulla oblongata:
vasomotor and respiratory, and this drug acts also indirectly through carotid sinus.
Sulfacamfocainum intensifies the exchange in the heart muscle; it increases
sensitivity of the heart muscle to sympathetic influence resulting in its cardiotonic
effect. Sulfacamfocainum has direct vasospastic effect in abdominal cavity that
Chapter 21. Analeptics | 305
lead to redistribution of blood, increasing of the veins tonus and a blood flow to the
heart, intensification of blood circulation in heart, lungs and brain.
Pentylenetetrazol arouses vasomotor and respiratory centers of medulla oblongata,
stimulates respiration, and elevates BP, blood circulation, especially in the case of
depression of the vital centers of the medulla oblongata. Pentylenetetrazol has not
direct action on the heart and the vessels. In high doses this drug causes an
excitement of the brain and spinal cord, it demonstrates “awaking” action in event
of acute poisoning by hypnotics and narcotics, and pentylenetetrazol in high doses
may elicit convulsions in virtue of its impact on motor zones of the brain and
partially – due to its influence on spinal cord.
Pharmacological effects of Analeptics:
Incitation of vasomotor and respiratory centers of medulla oblongata (all
analeptics)
Elevation of BP (bemegridе, niketamide, Sulfacamfocainum, pentylenetetrazol)
Enhancement of myocardial contractility (niketamide, caffeine,
Sulfacamfocainum, pentylenetetrazol)
Stimulation of CNS, antagonism with hypnotics (bemegridе, pentylenetetrazol),
opioid analgesics, alcohol and drugs for general anestesia (bemegridе, methylamide
ethylilamidazolecarbonate, pentylenetetrazol)
Antiphlogistic, antiallergic actions by the activation of pituitary functions
(methylamide ethylilamidazolecarbonate)
stimulation of reflex function of spinal cord, increase of skeletal muscle tonus
and smooth muscle tonus, improvement in visual acuity, taste, smelling, hearing,
tactile sensitivity (strychnine)
The ability to cause seizures (all analeptics)
Indications for Analeptics:
Acute poisoning by hypnotics and narcotics (bemegridе, methylamide
ethylilamidazolecarbonate, caffeine, pentylenetetrazol, niketamide)
Acute and chronic violations of blood circulation (niketamide, caffeine,
Sulfacamfocainum, pentylenetetrazol, cytisine)
Shock, collapse, asphyxia (niketamide, cytisine, Sulfacamfocainum, methylamide
ethylilamidazolecarbonate, pentylenetetrazol)
Acute and chronic heart failure (Sulfacamfocainum, caffeine, pentylenetetrazol)
Respiratory insufficiency (camphor, niketamide)
Fetal asphyxia, newborn asphyxia (methylamide ethylilamidazolecarbonate,
pentylenetetrazol)
Functional vision insufficiency, violation of vision, hearing, smelling; paralysis,
paresis, gastrointestinal atony (strychnine)
Adverse effects of Analeptics:
Symptoms of CNS excitement, arterial hypertension, tremor, hyperventilation,
arrhythmia, convulsion; in case of long-term action – tolerance, dyspepsia
(bemegridе, methylamide ethylilamidazolecarbonate)
Reduction of BP by procaine action (Sulfacamfocainum)
Vomiting, hyperemia of the face, clonic seizures, cardiac arrhythmia, local pain
in place of injection (niketamide)
Increase of muscle tonus and difficulties of breathing and swallowing
(strychnine)
In case of rapidly direction of pentylenetetrazol may be convulsions
Contraindications for Analeptics:
Sulfacamfocainum can not be used in patients with idiosyncrasy to procaine
Bemegridе can not be used in patients with psychosis, psychomotor excitement,
and epilepsy
Niketamide can not be used in patients with tendency to seizures
Pentylenetetrazol can not be used in patients with acute endocarditis, aortic
aneurysm, and active tuberculosis
Methylamide ethylilamidazolecarbonate can not be used in patients with
hypersensitivity to this drug, expressed CNS depression, motor and psychic
excitement, poisonings with convulsive remedies, arterial hypertension, glaucoma,
expressed atherosclerosis, circulatory and heart decompensation, in elderly people
Strychnine can not be used in patients with arterial hypertension, bronchial
asthma, IHD, acute and chronic nephritis, hepatitis, tendency to seizures,
thyrotoxicosis, in pregnant women
Cytisine can not be used in patients with acute ulcer disease of duodenum or/and
stomach, organic diseases of heart and blood circulation
Table 61. Medicinal forms of Analeptics

Camphor Oil solution for injections 20% - 1ml,
(s/c) 2 ml, 10 мл
Sulfocamph Sulfacamfocainum Solution for injections (i/v, 10% - 2 ml
oric acid + i/m, s/c) in ampoules
procaine
Niketamide Anacardone, Solution for injections (i/v, 25% - 1 ml, 2 ml;
Cardiamidum, i/m, s/c) in ampules; 25% - 1 ml
Coraethamidum, Coramin, Solution for injections (i/v,
Cormed, Corvitol, i/m, s/c) in syrette; 25% - 15 ml, 30 ml
Corvoton, Nicethamidum, Solution for peroral use in
Nicorine, Nikethamide, flacons
Nikorin, Tonocard, etc.
Bemegridе Ahypnon, Etimid, Solution for injections (i/v) 0.5% - 10 ml
Eukraton, Glutamisol, in ampoules
Malysol, Megibal,
Megimide,
Methertharmide,
Mikedimide, Zentraleptin
Almitrine Armanor Tablets 0.05
Caffeine Guaranin, Theinum Powder for peroral use 0.1
Caffeine Powder, Tablets 0.1, 0.2; 0.075 - for
Chapter 21. | 307
Analeptics
sodium children;
benzoate 10%, 20% -
Solution for injections (s/c) 1 ml, 2 ml
in ampoules
Lobelinе Lobeton, Solution for injections (i/v, 1% - 1 ml
i/m) in ampules and in
syrette;
Lobesilum Tablets 0.002
Cytisine Baptitoxine, Sophorine, Solution for injections (i/v, 0.15% - 1 ml;
Tabex i/m) in ampules;
Tablets 1.5 mg
Solutio Нашатирний спирт Solution in flacons; 10% - 10 ml,
Ammonii 40 ml, 100 ml,
caustici 10%
Solution in ampules 10% - 1 ml
for inhalation, for peroral
use, for external use
Methylamide Aethimizolum Powder, Tablets; 0.1;
ethylilamidaz Solution for injections (i/v, 1% , 1.5% - 3 ml, 5
olecarbonate i/m, s/c) in ampoules ml
Pentylenetetr Cardiazol, Angiazol, Tablets; 0.1;
azol Centrazol, Deumacar, Solution for injections (i/v, 10% - 1 ml
Diovascol, Leptazol, i/m, s/c) in ampules
Metrazol, Pentame-
thazolum, Pentazol,
Pentetrazolum, Pentrazol,
Phrenazole, Tetracor, etc.
Strychninе Strychninum nitricum Solution for injections (s/c) 0.1% - 1 ml
in ampules;
Peroral solution
Currently, in the clinic, analeptics of reflex action lobeline and cytisine are
applied as tablets for treatment of the patients with nicotine smoking addiction.
They are Lobesilum and Tabex. They are N-cholinimimetics of reflex action and
stimulate N-cholinergic receptors of vegetative ganglia and adrenal gland, and
stimulate respiration and Ep excretion from adrenal medulla. Lobeline and cytisine
have the mechanism of action similar as nicotine. Adverse effects may occur at the
beginning of treatment. There are changes in taste and appetite, dry mouth,
headache, dizziness, tremor, insomnia, increased irritability, myalgia, chest pain,
abdominal pain, nausea, dyspepsia, tachycardia, a slight increase in BP, lower
body weight, sweating. Contraindications: hypersensitivity to the drugs, IHD,
cardiac arrhythmias, atherosclerosis, gastric and duodenal ulcer, pregnancy and
lactation. Overdose of lobeline and cytisine has the symptoms of nicotine
intoxication: nausea, vomiting, mydriasis (dilated pupils), weakness, tachycardia,
clonic convulsions, and respiratory paralysis. Tabex and Lobesilum can greatly
impair driving and other psychomotor skills.
Chapter 22. Nootropics (Cognitive enhancers)
Nootropics – the drugs that activate higher integrative brain function,

improve intellection, memory, learning ability. Positive effect on higher nervous
activity only occurs during prolonged applications (2-5 months). Nootropics are
also referred to as smart drugs, memory enhancers, neuroenhancers, cognitive
enhancers, and intelligence enhancers.
Mechanism of action of Nootropics connects with stimulation of GABA-A
receptors and glutamate receptors, and with the increase of ATP synthesis, glucose
utilization, improving of synaptic mediator processes, synthesis of RNA, proteins,
membrane phospholipids. Nootropics are thought to work by altering the
availability of the brain's supply of neurochemicals (neurotransmitters, enzymes,
and hormones).
Classification of Nootropics
Pirolidone derivatives:
Piracetam
Etiracetam
Dupracetam
Aniracetam
GABA derivatives:
Acidum gamma-aminobutyricum Gamma-amino-beta-
phenilbutirate hydrochloride (Phenybutum) Hopantenic acid
Nicotinoyl gamma-aminobutiric acid (Picamilonum)
Pirodoxine derivatives:
Pyritinol
Pyridoxine + Trionin (Biotredin)
Dimethylaminoethanol derivatives (predecessors of Ach):
Deanol aceglumate
Meclofenoxate
Cerebrovascular drugs:
Ginkgo Biloba
6. Neuropeptides and their analogs:
Metionil-glutamil-gistidil-fenilalanil-prolil-glicil-prolin (Semax)
Amino acids and substances that influence on the system of excitatory
amino acids:
Aminoacetic acid (Glycine)
2-mercantobenzimidazole:
Ethylthiobenzymidazol hydrobromidе (Bemithylum)
Vitamin-like substances:
Idebenone
Polypeptides:
Cerebrolysin
Chapter 22. Nootropics | 309
Substances of other pharmacological groups with nootropic component :

Correctors of brain blood circulation insufficiency:
Nicergoline
Vinpocetine
Xantinol nicotinate
Vincamine
Cinnarizine
Restorative substances and adaptogens :
Ginseng
Melatonin
Lecithin
Psychostimulators:
Sulbutiamine
Antihypoxants and antioxidants:
Ethylmethylhydroxypyridine succinate (Mexidolum)
Drugs of other groups:
Oxydate sodium
Nootropic: improvement of thinking, attention, language
Mnemotropny: enhancement of memory, learning
Raising the level of consciousness, mental clarity (impact on the oppressed
consciousness and clouding of consciousness)
Adaptogenic: influence on tolerance to a variety of exogenous factors, including
drugs, increasing overall resistance to the action of extreme factors
Antiasthenic: the impact of weakness, lethargy, exhaustion, mental and physical
phenomena of fatigue
Psychogogic
Antidepressive
Sedative
Vegetative
Antikinetic
Antiparkinsonian
Antiepileptic
Hypoglycemic
Energetic action due to enhancing of glucose consumption by cells of the body
Increase of somatotropic hormone release
Anabolic
Lipolytic
Antitoxic
Immunostimulatory
At the core of the therapeutic action of nootropics are several mechanisms:
improvement of the energy state of neurons (increased synthesis of ATP, anti-
hypoxic and anti-oxidant effects); activation of the plastic processes in the CNS
due to increased synthesis of RNA and proteins; strengthening of the processes of

synaptic transmission in the CNS; improvement of the glucose utilization;
membrane-stabilizing action.
Indications:
Traumatic brain injury, stroke, chronic cerebral vascular disorders
Hypertension and atherosclerotic encephalopathy
Mental retardation in children, poor memory
Depression
Senile dementia
Abstinence
Alcohol poisoning
Hypoxic conditions
Open-angle glaucoma
Migraine
Stuttering, tics in children
Meniere's disease
Asthenia
Neuroses
Epilepsy
Parkinson disease
Adverse effects:
dizziness
tremor
nervousness
irritability
feeling of anxiety
sleep disorders
nausea
vomiting
dyspepsia
increased body temperature
fluctuations in blood pressure
allergic reaction
Contraindications:
the sharp increase in intracranial pressure
epileptic syndrome
hemorrhagic stroke
individual adverse reaction
pregnancy
Besides, some of the Nootropics have specific adverse reactions: piracetam is
contraindicated in acute venous insufficiency in children with diabetes, it is not
recommended for children under 1 year and acute renal failure. Sodium oxybate
improper for hypokalemia, myasthenia gravis. Due to the sedative effect it should
not be given during daylight hours to the patients whose work requires quick
Chapter 22. Nootropics | 311
physical and mental reactions. Hopantenic acid is contraindicated in severe acute

kidney disease. Phenybutum is contraindicated in hepatic impairment. Pyritinol no
need to appoint in case of psychomotor agitation, epilepsy, and increased
convulsive readiness. Picamilonum is contraindicated in acute and chronic kidney
disease.
Table 62. Medicinal forms of Nootropics

Acidum gamma- Aminalonum, Apogamma, Tablets 0.25
aminobutyricum Encefalon, GABA,
Gaballon, Gamarex,
Gammalon, Gammaneuron,
Gammar, Gammasol,
Mielogen, Mielomade, etc.
Piracetam Braintop, Breinox, Cerebril, Capsules; 0.4;
Cerebropan, Ceretran, Tablets for children; 0.2;
Ciclo-cetam, Cintilan, Tablets; 0.4; 0.5, 0.8,
Dinacel, Dinagen, 1.2;
Encefalux, Eumental, Granules for syrup
Euvifor, Fortineural, for children in jars; 56.0 (2.0);
Gabacet, Gericetam, in packages; 2.8 (0.1);
Lucetam, Memotropil, Peroral solution in 20%, 33%-125
Mera-piran, Neutrofin, flacons; ml;
Noocebril, Noocefal, Elixir for children in 3.2%-118 ml;
Nootropil, Normar-brain, flacons;
Norotrop, Norzetam, Parenteral solution for 4.8%-125 ml;
Oikamid, Pirabene, infusions in flacons; 250 ml, 500 ml,
Piracetam, Piramem, 1000 ml;
Piratam, Piratropil, Pirroxil, Parenteral solution (i/m, 20%-5 ml,
Pyramem, Stamin, i/v) in ampoules, 15 ml;
Stimocartex, Stimubral, etc. in flacons 20%-60 ml
Oxydate sodium Oxybate sodium, Sodium Parenteral solution (i/m, 20%-5 ml,
gamma-hydroxybutyrate i/v) in ampoules; 10 ml;
Syrup in flacons 5%-400 ml
Gamma-amino- Phenibutum Tablets 0.25
beta-phenilbutirate
hydrochloride
Hopantenic acid Calcium homopantothenat, Tablets; 0.25, 0.5;
Hopaten, Pantogamum Syrup in flacons 10%-50 ml, 100
ml
Nicotinoyl gamma- Picamilonum Tablets; 0.01, 0.02 , 0.05;
aminobutiric acid 5%, 10%-2 ml
Parenteral solution (i/m,
i/v) in ampoules
Pyritinol Biocephalin, Cefalogen, Tablets; 0.05, 0.1, 0.2;
Cerebol, Cervitalin, Dragee; 0.1;
Cogitan, Dipiridol, Enbol, Syrup in flacons 2%-200 ml
Encefabol, Encefort,
Encephabol, Encerebrovit,
312 | Unit 5.
Enerbol, Estisol, Neurotin,
Neuroxin, Piritinol,
Psicobolin, Pyrithioxin,
Pyritinol, Tonobrain, etc.
Meclofenoxate Analux, Centrophenoxine, Tablets 0.1
Cerutil, Claretil,
Clofenoxine, Lucidril,
Meclofenoxate, Meclon,
Mexazine, Nisantol, Pro-
seryl, Ropoxyl, etc.
Deanol aceglumate Clirigil, Dardanin, Deanol Peroral solution in 20%-50 ml, 100
Aceglumate, Nooclerin, flacons ml, 200 ml
Otrun, Risatarim, etc.
Memoplant Ginos Tablets 0.04
Aminoacetic acid Aciport, Amitone, Glicocol, Sub-lingual tablets 0.1
Glicosil, Glycine,
Glycolixir, Glycosthene,
etc.
Metionil-glutamil- Semaxum, Solution for nasal use 0.1%, 1%-3 ml
gistidil-fenilalanil- Minicem
prolil-glicil-prolin
Idebenone Noben Capsules; Film-coated 0.03
tablets
Cerebrolysin Cerebrolysinum Parenteral solution (i/m, 21.5%-1 ml,
i/v) in ampoules 5 ml, 10ml
Nicergoline Sermionum, Dasovas, Tablets; 0.005, 0.01;
Dospan, Ergotop, Fisilax, Powder for injections in 0.004
Nargoline, Nicotergoline, ampoules (i/v, i/m)
Nimergoline, Sinscleron,
Varsan, etc.
Vinpocetine Inex, Telectol, Vinpocetine Tablets; 0,005;
Parenteral solution (i/v) 0.5%-2 ml
in ampoules
Xantinol nicotinate Angioamin, Complamex, Tablets; 0.15;
Complamin, Contamex, Tablets retard; 0.5;
Mehemin, Sadamin, Parenteral solution (i/v) 15%-2 ml
Teonicol, Vedrin, Xantinol in ampoules
nicotinate, Xavin, etc.
Vincamine Vincanorum, Vincapan, Tablets 0.02
Vincamin
Cinnarizine Cinnarizine, Cinarin, Tablets, Capsules; 0.025;
Cinazin, Cinedil, Cinnaron, Tablets, Capsules forte 0,075;
Cinnasan, Cinniprine, Peroral suspension 7.5%-20 ml
Cirizin, Dimitronal, Disiron,
Glamil, Labyril, Marisan,
Midronal, Mitronal,
Stugeron, Stutgeron,
Vertizin, etc.
Melatonin Eucalin, Melapur, Tablets 0.003
Melatonum, Melaxen, etc.
Chapter 22. | 313
Nootropics
Sulbutiamine Enerion Tablets 0.2
Ethylmethylhydrox Mexidolum Tablets; 0.125;
ypyridine succinate Parenteral solution (i/m, 5%-2 і 5 ml
i/v) in ampoules
Ethylthiobenzymid Bemithylum Tablets 0.125, 0.25, 0.5
azol hydrobromid
Ginseng Tincture of Ginseng, Tincture in flacons; 50 ml;
Ginsana Capsules 0.1
Chapter 23. Adaptogens, Actoprotectors
Adaptogens – pharmacological group of drugs of natural (plant or animal)

or synthetic origin that can enhance non-specific resistance to a wide range of
harmful effects of physical, chemical and biological nature.
Mechanism of action of Adaptogens connects with:
activation of the RNA and protein synthesis resulting in an restorative processes
are observed
antioxidant action
reduction of biochemical abnormalities in stress reactions
normalization of the functions of pituitary-adrenal and immune systems.
Classification of Adaptogens
I. Adaptogens of plant origin:

Tincture of Ginseng root
Extract of Ginseng (Ginsana)
Alcoholic tincture of Ginseng
Extract of Eleutherococcus senticosus (Siberian
Ginseng) Tincture of Schisandra chinensis
Rhodiolae extract fluid – Extractum Rhodiolae fluidum (Rhodiolae roseae –
rhizomata et radices)
Tincture of Echinopanacis rhizomata
Tincture of radices Araliae mandshuricae – tincture Araliae
Tincture of Sterculia plantanifoliа – tincture Sterculiae
Extract of Rhaponticum carthamoides (Maral root or Rhaponticum),
(Extractum Leuzeae fluidum)
Ecdistenum (Rhaponticum carthamoides) – a natural compound of steroid
structure, separated from the roots and rhizomes of Leuzea carthamoides
Sараrаlum – sum of glycosides from the roots of Aralia
II. Adaptogens of animal origin:

Pantocrinum – extract from not ossified horns (antlers), Maral, Manchurian
deer and spotted deer
Rantarinum – extract from male reindeer antlers
Pharmacological effects of Adaptogens:

Improvement of physical and mental performance, reducing of fatigue, eating
disorders, recovery of the diurnal cycle of body functions
Increase of endurance of the body to the influence of the harmful effects of high
air temperature, cooling, toxic industrial poisons, ionizing radiation, etc.
Improvement of specific and nonspecific immunity
Improvement of blood circulation, respiration, vision, hearing
Cardioprotective effect
Hepatoprotective effect
Stimulation of hematopoiesis.
Indications:
Physical overloads
Physical and mental overfatigue
Asthenic syndrome
Condition after infectious and somatic diseases
Radiation exposure, radiation disease
In stomatology in the form of applications for the treatment of infectious
processes
Adverse effects:
Excessive CNS and cardiovascular system stimulation
Hyperglycemia
Contraindications:
The drugs are not recommended in the evening
Atherosclerosis
Organic diseases of heart
IHD, stenocardia (angina pectoris)
Hypercoagulability
Severe forms of glomerulonephritis
Diarrhea
Table 63. Medicinal forms of Adaptogens

Ginseng, Tincture “Bioginseng”, Tincture 1:10 in 70% ethyl 25 ml, 50 ml;
Tincture of Ginsana alcohol for peroral use in
Ginseng flacons;
Capsules 0.1
Extract of Extract 1:1 in 70% ethyl 50 ml
Eleutherococcus alcohol for peroral use in
fluidum, flacons
Acanthopanax
senticosus
Chapter 23. | 315
Adaptogens, Actoprotectors
Tincture of Tincture 1:5 in 95% ethyl 50 ml
Schisandra alcohol for peroral use in
flacons
Extract of Extract 1:1 in 40% ethyl 30 ml, 50 ml
Rhodiola fluidum alcohol for peroral use in
flacons
Tincture of Oplopanax elatus Tincture 1:5 in 70% ethyl 50 ml
Echinopanax alcohol for peroral use in
flacons
Tincture of Aralia Tincture 1:5 in 70% ethyl 50, 100 ml;
Aralia alcohol for peroral use in
mandshurica, flacons;
Aralia Saparalum Tablets 0.05
manshuricae
radices
Tincture of Tincture for peroral use in 25 ml
Sterculia flacons
platanifolia
Extract of Leuzea Rhaponticus Extract 1:1 in 70% ethyl 40 ml
fluidum carthamoides, alcohol for peroral use in
Leuzea carthamoides flacons
D.С.
Ecdistenum Ecdysterone, Tablets 0.005
20-beta- Ectysterone,
hydroxyecdystero Turkesterone,
ne Ponasterone, Ecdysone,
Ecdystene
Pantocrinum Pantocrinum Aqueous alcoholic extract 30, 50, 100 ml;
Аntlers of the for peroral use in flacons;
extract Tablets;
Parenteral solution (i/m, 0.075, 0,15;
s/c) in ampoules; 1 ml, 2 ml;
Rantarinum Tablets 0.25
Actoprotectors – not have the expressed stimulating effect on CNS, but

improve mental and physical activity, increase capacity for work, reduce
fatigability. Actoprotectors increase the body's resistance to hypoxia, to high and
low ambient temperatures.
Mechanism of action: actoprotectors belong to the metabolic drugs of
inexhaustible type of action. They have an antihypoxic activity too. Actoprotectors
directly stimulate RNA and protein synthesis in different cells including enzymatic
synthesis, structural and proteins synthesis related to the immune system; activate
synthesis of the enzymes of gluconeogenesis which provides the utilization of
lactate – the factor limiting performance and re-synthesis of carbohydrates – the
most important sources of energy under extreme stresses, leading to an increase in
physical performance. Enhancing formation of mitochondrial enzymes and
structural proteins of mitochondria provides increased energy production and
maintenance of a high degree of coupling of oxidation with phosphorylation.
Maintaining a high level of ATP synthesis in case of oxygen deficiency contributes
to severe antihypoxic and antiischemic activity of actoprotectors. Actoprotectors

increase the synthesis of antioxidant enzymes and have expressed antioxidant
activity.
This group includes: Ethylthiobenzymidazol hydrobromide (Bemithylum),
vitamins and biogenic stimulants. But, Bemithylum is standard drug for the group
of Actoprotectors.
psychogogic
antihypoxic
increase in work capacity
immunostimulating
Indications:
asthenic conditions,
neurosis
after injuries
in complex therapy of infectious diseases
in sports medicine to restore muscle activity after intense exercises
Adverse effects:
dyspepsia
headache
flushing of the face
Contraindications:
idiosyncrasy
hypoglycemia
Table 64. Medicinal forms of Actoprotectors.

Ethylthiobenzymidazol Bemithylum Tablets 0.125, 0.25, 0.5
hydrobromide
References | 317
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Ministry of Healthcare of Ukraine

National Pirogov Memorial Medical University

Germanyuk T.A., Bobruk V.P., Lysogora V.V.

G 39 General Pharmacology and Pharmacology of the drugs affecting

The tutorial "Pharmacology of the drugs affecting vegetative and central

information about the mechanisms of drug action, their pharmacological effects,

F2α (PGF2α) - prostaglandin F2α

is no equality between the pharmacological effect of opium galenic preparations

Peculiarities of marking of ready dosage forms

There are international standards (International rules-standards), which

UNIT 1. GENERAL PHARMACOLOGY

Pharmacokinetics studies the routes of administration, the processes of

with respiratory complaints (asthma, chronic obstructive pulmonary disease,

Rectal route of drug administration provides drug absorption in lower and

additional lipid membrane. In addition, on the surface of the cell membranes of

Table 1. BBB permeability to antibacterial drugs*

Penetrate well Penetrate well in Poorly penetrate even Not penetrate

Placental barrier (PB) - is the physiology barrier between maternal blood

If the substances or metabolites from PhaseI biotransformation is sufficiently polar,

urine as with bile. Process of filtration is disturbed in case of shock, collapse,

Desensitization of receptors is reduced agonist effect when prolonged or

The embryotoxic effect is developed in first days and weeks after

formation mechanism of tolerance. The rapid development of tolerance is called

decrease of affinity of microorganism’s structure to antibiotics, genetic mutations

Classification of chemical interactions*:

There are pharmaceutical, pharmacokinetic and pharmacodynamic

drug absorption, transportation, dissemination, deport, biotransformation and

competition at a receptor, as in the antagonism provided by naloxon therapy; overdose

Table 2. Some common antidotes and their indications*

Antidote Poisoning indication(s)

UNIT 2: DRUGS AFFECTING MEDIATORY PROCESSES

reported to mediate adenosine inhibition of Ca2+ conductance, whereas A2B and

improvement of methabolic and reparative processes in eye lens and for

renal insufficiency, and in elderly patients. Dopamine may precipitate toxicity in

Table 3. Places of location, mechanism and effects of activation of adenosine

Table 4*. Agonists and antagonists of adenosine receptors

An adenosine reuptake inhibitor is a type of drug which acts as a reuptake

Scheme 1. Catecholamine biosynthesis (adopted from http://en.wikipedia.org).

N-methyltransferase (PNMT) with S-adenosyl-L-methionine (SAMe) as the

(ALDH). DOPAL can also be reduced to 3,4-dihydroxyphenylethanol (DOPET;

Scheme 2. Dopamine degradation (adopted from http://en.wikipedia.org/).

Family Receptor Gene Type Mechanism Potential

Table 6. Places of location, mechanism and effects of activation of dopamine

Biological role. Dopamine has many functions in the brain, including

of renin by the kidneys, increases the secretion of prostaglandins by kidney tissue,

Table 7**. Agonists and antagonists of dopamine receptors

Receptor Agonists Antagonists

Serotonin or 5-hydroxytryptamine (5-HT) is a monoamine

influence of acetaldehydrogenase-2 – into 5-hydroxyindoleacetic acid (5-HIAA)

Circulation of serotonin. Serotonin which was synthesized by neuron is

pituitary function; to cause an increase in the secretion of prolactin and other

Local (eg, intramuscular) administration of exogenous serotonin causes

exposure to selective serotonin re-uptake inhibitors reduces fetal growth. Human

Some 5-HT3 antagonists, such as ondansetron, granisetron, and tropisetron,

Serotonin is found in mushrooms, fruits and vegetables, in nuts of the

Table 8. Places of location, mechanism and effects of activation of serotonin

Receptor Mechanism Places of location Effects of activation*

5-HT2B Uterus, trachea, small

Table 9**. Agonists and antagonists of serotonin receptors

Receptor Agonists Antagonists

At present, the physiological significance of serotonin has been

Bacteria also are capable of producing histamine using histidine

Scheme 4. Conversion of histidine to histamine by histidine decarboxylase (adopted

Storage and release. Histamine is a ubiquitous chemical messenger that can