General Pharma
General Pharma
GENERAL PHARMACOLOGY
GENERAL PHARMACOLOGY
(Introduction to
Pharmacology)
Index
Introduction
pharmacokinetics
absorption
Distribution
Metabolism
Excretion
Questions
Routs of administration
Fundamental principles of pharmacokinetics
a)
b)
c)
d)
Pharmacodynamics
Types of receptors
Factors modifying dose & action of the drug
Adverse drug effects
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Pharmacology:
Drugs:
These are chemical agents used for:
Source
Chemistry
Pharmacokinetics (and Routes of Administration)
Pharmacodynamics
Pharmacotherapeutics: Indications (Therapeutic uses) and dosage
Adverse effects
Contraindications
Drug Interactions
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I- Sources of Drugs:
1) Plant sources: e.g. Atropine is obtained from Atropa belladonna and other plants,
Morphine is obtained from Papaver somniferum, Ephedrine is obtained from Ephedra
plant, etc
2) Animal sources: e.g. animal Insulin was prepared from pigs (known as porcine insulin)
and from cattle (known as bovine insulin), Heparin (unfractionated heparin = UFH) is
obtained from the lungs and intestines of cattle and pigs. These drugs are highly
antigenic and are replaced now by human insulin and low molecular weight heparins
(LMWHs); respectively.
3) Microorganisms: Antibiotics (as penicillin G) are prepared from microorganisms as fungi
and bacteria.
4) Mineral sources: e.g. iodine and magnesium sulphate, and also radioactive isotopes as
I131 (therapeutic) and I132 (diagnostic).
5) Synthetic drugs: most drugs are chemically synthesized, e.g. Aspirin, Propranolol,
Sulphonamides, Benzodiazepines, Paracetamol, etc
6) Biotechnology (genetic engineering): some drugs are prepared using "recombinant
DNA technology" as Human insulin, Growth hormone, recombinant tissue Plasminogen
Activator (r- tPA = Alteplase).
The main disadvantage of these drugs is their high cost (expensive).
II- Chemistry:
Some drugs as Aspirin (Acetyl Salicylic Acid) and Barbiturates- are weak acids, whereas
others- as Ephedrine and Amphetamine- are weak bases.
Most drugs are organic compounds but few drugs are inorganic elements as Lithium
and Iron.
Some drugs contain a specific chemical ring, e.g. Steroid hormones as Cortisone contain
a steroid ring, and catecholamines as Adrenaline contain a catechol ring.
III- Pharmacokinetics:
The term "pharmacokinetics" describes the movement of drugs inside the body, and is
usually referred to as "what the body does to the drug".
Pharmacokinetics includes:
1) Absorption
2) Distribution
3) Metabolism = Biotransformation
4) Excretion
(N.B.: Pharmacokinetics is sometimes referred to as "absorption and fate", and
metabolism and excretion are called together "elimination" or "clearance").
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IV- Pharmacodynamics:
The term pharmacodynamics is referred to as "what the drug does to the body" and it
includes:
1) Mechanism of Action:
The most important mechanism of action is on specific "receptors", but some drugs
may act on enzymes, cell membrane, DNA, chemically, physically, etc. (see later).
2) Pharmacological Actions:
The actions of the drug may be:
1) Local actions (also known as topical actions) where the drug acts at the site of
application, e.g. skin ointments and eye drops.
2) Systemic actions: the drug reaches the systemic circulation and is distributed to
different systems as CNS, CVS, respiratory system, etc.
3) Reflex actions (also called remote actions): e.g. drugs that elevate arterial blood
pressure as Noradrenaline lead to "reflex bradycardia" through vagal stimulation.
The diseases for which the drug is prescribed to treat or prevent, e.g. Aspirin is indicated in
treatment of headache and fever, and to prevent thromboembolism.
N.B.: "Pharmacotherapeutics" includes therapeutic uses and dosage of drugs.
This term describes the unwanted drug effects and is sometimes referred to as "side
effects" or "toxic effects" (see later).
VII- Contraindications:
The diseases in which the drug should be avoided, e.g. Aspirin is contraindicated in peptic
ulcer.
1) Drug-Drug interactions: when 2 or more drugs are prescribed to the patient, these
interactions may be beneficial (favorable) or harmful (unfavorable).
2) Drug-Food interactions, e.g. MAO inhibitors (used in treatment of depression) interact
with food containing tyramine as cheese and yoghurt and lead to serious and may be
fatal elevation of arterial blood pressure.
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Pharmacokinetics
1-Absorption:
Definition: it is the passage (transfer) of the drug from the site of administration to the
systemic circulation.
It is obvious that absorption from any site (GIT, lung, skeletal muscles, skin, and mucous
membranes) occurs by passage of the drug across the cell membrane (which is made of
phospholipid bi-layer and contains minute water-filled channels and ion channels).
Passage of drugs across cell membranes "transmembrane movement of drugs":
occurs by one of the following methods:
a) Passive transfer:
1) Simple diffusion (the most important method for drug absorption).
2) Filtration (important for drug excretion by the kidney).
b) Special transfer (Specialized transport):
1) Active transport.
2) Facilitated diffusion.
N.B. Active transport and facilitated diffusion are known as "carrier-mediated
transport".
3) Pinocytosis (Endocytosis or Cell drinking): it is an active process (energydependent) in which the drug is "engulfed" inside the cell, e.g. absorption of
vitamin B12/ intrinsic factor complex by the ileum.
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Method
1-Simple
diffusion:
2-Filtration:
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Characteristics
Factors and forces affecting
1) The drug passes through the lipid 1) Lipid solubility (lipid/water or
bi-layer of the cell membrane.
oil/ water partition
2) The drug moves from the higher to
coefficient): the more the
the lower concentration = along
lipophilicity of the drug, the
(with) concentration gradient.
more the absorption.
3) No energy is needed.
2) Degree of ionization: the
4) No carrier is needed.
more the unionized (non5) No saturation occurs.
ionized) form of the drug, the
6) No competition with other drugs
more its lipid solubility and
or endogenous substances.
accordingly the more its
absorption.
3) Molecular size: the smaller
the molecular size, the better
the absorption.
4) Concentration gradient: the
higher the gradient, the
higher the rate of passage of
the drug.
5) Water solubility is a must.
1) The drug passes through the
1) Water solubility.
aqueous pores (channels) in the
2) Molecular weight: the pores
cell membrane.
have minute size and allow
2) The drug moves from the higher to
only the passage of drugs of
the lower osmotic pressure =
low molecular weight (< 500).
along (with) osmotic pressure
3) The drug must be free
gradient.
(unbound to plasma
3) No energy is needed.
proteins).
4) No carrier is needed.
4) Blood flow.
5) No saturation occurs.
5) Hydrostatic and osmotic
6) No competition with other drugs
gradient.
or endogenous substances.
(Glomerular filtration is essential for
renal excretion of most drugs).
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3-Active
transport:
4-Facilitated
diffusion:
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Un ionized form
Ionized form
Ionized form
Unionized form
8) The same rules are applied to renal excretion of drugs: alkalinization of urine by
NaHCO3 enhances (increases) renal excretion of acidic drugs as aspirin because aspirin
will be mostly ionized so it will be hydrophilic and excreted not reabsorbed (ion
trapping), but if urine is made more acidic by vitamin C (ascorbic acid) or NH4Cl, most of
aspirin will be unionized and lipid soluble so it will be "reabsorbed" by renal tubules.
On the other hand, basic drugs as amphetamine and ephedrine will be more excreted
by acidification of urine.
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The factors that influence drug absorption can be classified into factors related to the drug
and factors related to the patient.
a) Factors related to the drug:
1) Lipid solubility and lipid-water partition coefficient: the more the lipid solubility (i.e.
the higher the lipid-water partition coefficient), the better the absorption.
2) Degree of ionization: the more the unionized form of the drug, the more the lipid
solubility and hence the better the absorption.
3) Valency: ferrous salts (Fe2+) are better absorbed than ferric salts (Fe3+).
4) Chemical nature: inorganic drugs are better absorbed than organic drugs (due to
smaller molecules).
5) Pharmaceutical formulation:
Aqueous solutions are better absorbed than suspensions.
Drugs that are rapidly disintegrated (dissolved) in the stomach as paracetamolare better absorbed than slowly disintegrated drugs as digoxin.
Important notes:
1) Quaternary ammonium drugs as Neostigmine are ionized and so poorly absorbed orally.
2) Tertiary amine drugs as Physostigmine are unionized and lipid soluble, and accordingly
are well absorbed orally.
3) Aminoglycosides-as Streptomycin-have high pKa, so they are always ionized in any
medium in the body including the alkaline medium of the intestine, and accordingly are
almost not absorbed orally.
4) Some drugs are not absorbed orally although they are unionized, e.g. Sulfaguanidine.
b) Factors related to the patient:
1) Route of administration:
Intravenous injection (I.V.): 100% of the drug reaches the systemic circulation
almost immediately.
Intramuscular injection (I.M.): most of the drug is rapidly absorbed due to the
high vascularity of skeletal muscles.
Subcutaneous injection (S.C.): absorption is less than after I.M. injection because
the S.C. tissue is much less vascular than the skeletal muscles.
Inhalation: lipid soluble drugs as inhalation general anaesthesia are rapidly and
almost completely absorbed because the alveoli have a very wide surface area
and very rich blood supply.
Sublingual: drugs given as sublingual pellets as nitroglycerin in treatment of
acute anginal attacks-are better and more rapidly absorbed than orally
administered drugs because they reach the systemic circulation directly and
avoid passage through GIT and the liver.
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2)
3)
4)
5)
6)
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Oral absorption is usually variable due to the effect of GIT and the liver on the
drug before reaching the systemic circulation; this is known as
"1st pass effect" (see later).
(I.V. > Inhalation > I.M. > S.C. > Intact skin).
Surface area of the absorbing surface: the more the surface area exposed to the
drug, the better the absorption; e.g. small intestine (about 1000 times the surface
area of the stomach due to the presence of microvilli) and lung alveoli.
Vascularity (blood supply) of the absorbing surface: the richer the blood supply of
the absorbing surface, the better the absorption; e.g. the small intestine and the
lung alveoli.
State of health of the absorbing surface: oral absorption is greatly decreased in the
presence of diseases of GIT as malabsorption.
State of general circulation: in cases of shock; blood flow to the subcutaneous (S.C.)
tissues is markedly reduced due to diminished tissue perfusion and sympathetic
stimulation causing vasoconstriction of subcutaneous blood vessels. That is why
drugs as morphine should be given I.V. in case of shock.
Specific factors: oral vitamin B12 is absorbed only in the presence of intrinsic factor
synthesized by the gastric parietal cells.
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Exceptionally; irritant drugs-as aspirin and other NSAIDs, and iron preparationsshould be given after meals.
Food containing Ca2+ (as milk and dairy products), and antacids containing Al3+
and Mg2+ decrease absorption of tetracyclines due to chelation.
Tetracyclines and tannic acid (in tea and coffee) decrease absorption of iron.
Cholestyramine and activated charcoal decrease absorption of most drugs
(activated charcoal adsorbs drugs).
Tannic acid in tea and coffee decreases absorption of iron.
Grape fruit inhibits P-glycoprotein-which is responsible for reversed transport of
drugs from gut mucosa into gut lumen-and so grape fruit increases drug
absorption.
P-glycoprotein also causes efflux of anticancer drugs as Methotrexate out of the
cancer cells. It was found that Verapamil-a calcium channel blocker-inhibits Pglycoprotein and so it increases uptake of methotrexate
8) First pass effect (first pass metabolism or pre-systemic metabolism): orallyadministered drugs may be partially or completely metabolized while passing in GIT
(gut first pass) or the liver (hepatic first pass) before reaching the systemic
circulation.
a) Gut first pass effect:
Some penicillins are destroyed by gastric acidity and are known as "acidsensitive penicillins", e.g. benzyl penicillin (penicillin G).
Polypeptide hormones as insulin are destroyed by the digestive enzymes.
Some drugs are metabolized by the gut mucosa as chlorpromazine and methyl dopa.
b) Hepatic first pass effect (much more important than gut first pass):
Lipophilic drugs are metabolized by the liver (see later).
Some of these drugs are largely metabolized by first pass hepatic effect, e.g.
propranolol. Other drugs are extensively metabolized, as nitroglycerin, or
almost completely metabolized as lidocaine and natural sex hormones.
Hydrophilic drugs as Atenolol and Nadolol are minimally metabolized by the
liver.
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Bioavailability:
The factors affecting bioavailability are the same factors affecting absorption of
drugs (see before).
Bioequivalence: two drugs or two forms of the same drug show bioequivalence if
they have the same bioavailability and the same rate of absorption (they reach the
peak plasma concentration at the same time).
Therapeutic equivalence: two drugs have the same efficacy and safety.
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2- Distribution:
Once the drug is absorbed from any site, i.e. it reaches the systemic circulation; it may be
distributed to the body fluids and tissues as follows:
A) Compartment Model:
The body fluids = 42 L. representing 60% of the total body weight (TBW) of an average 70
Kg. person and include: plasma (4 L.), interstitial fluid (10 L.), and intracellular fluid (28 L.).
The plasma is referred to as "intravascular compartment", whereas the plasma and the
interstitial fluid together (14 L.) are referred to as "extracellular compartment".
28 Liters
10 Liters
4 Liters
PLASMA
INTERSTITIAL INTRACELLULAR
Drugs are distributed according to one of the following patterns of distribution:
1) One Compartment Model:
Drugs that are extensively bound to plasma proteins and drugs that have a very high
molecular weight as high molecular weight heparin (HMWH) and dextran (plasma
expander) can not pass through the capillary endothelium and are distributed in plasma
only = intravascular compartment = 4 L.
2) Two Compartment Model:
Drugs that are hydrophilic and with low molecular weight can pass through the
capillary endothelium but can not pass the cell membranes being lipid insoluble and
ionized-as quaternary ammonium compounds (neostigmine)-and accordingly are
distributed in 2 compartments: plasma and interstitial fluid =extracellular compartment
= 14 L.
3) Multicompartment Model:
Drugs that are of low molecular weight, non-ionized, and lipophilic are distributed in all
compartments-both extracellular and intracellular-and accordingly are distributed in
42L.
4) Special Distribution=Tissue reservoir:
Some drugs are concentrated in certain tissues, e.g. tetracyclines are concentrated in
bone and teeth (Ca2+-containing)-iodine is concentrated in thyroid tissue-thiopentone
in fatty tissues-heavy metals as lead and arsenic in hair and skin-digitalis in cardiac
muscles-thiopentone in fat-Vitamin B12 and chloroquine in the liver.
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Free Form
Diffusible.
Active.
Liable to liver metabolism.
Liable to renal excretion (mostly by
glomerular filtration).
Bound Form
Non-diffusible (confined to plasma).
Inactive.
Not liable to liver metabolism.
Not liable to renal excretion.
Acts as a "reservoir".
Drugs are bound reversibly mainly to albumin and to a lesser extent to globulin and acid glycoprotein.
Some drugs as aspirin and sulphonamides have a highly affinity (are highly bound) to
plasma proteins and they displace other drugs with lower affinity as digoxin,
sulphonylureas (oral hypoglycemics), and warfarin (oral anticoagulant) if administered
together, which results in increase in the free "active" form of the latter drugs and this
may lead to severe adverse (toxic) effects:
Aspirin and sulphonamides displace digoxin leading to digitalis toxicity.
Aspirin and sulphonamides displace sulphonylureas (as Tolbutamide) leading to
hypoglycemia.
Aspirin and sulphonamides displace warfarin leading to bleeding.
Sulphonamides displace bilirubin from plasma proteins, which increases free bilirubin
causing hyperbilirubinemia and may be kernicterus in neonates.
In conditions causing "hypoalbuminemia" as in old age, liver diseases, malnutrition or
starvation; the free form of drugs as phenytoin (antiepileptic) is higher than in normal
individuals and toxic effects may occur with therapeutic doses.
The more the bound form of the drug, the longer its duration. This is shown with some
sulphonamides.
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Significance of Vd:
1) The term "apparent" indicates that it is a hypothetical - not always a true value -as in
the case of digoxin which has a Vd of 500 liters which is much higher that the total fluid
volume (42 L. in an average 70 Kg. person).
2) High Vd indicates that the drug is distributed as a multicompartment model or has high
tissue concentration (highly bound to tissue proteins). Drugs with very high Vd have
slow rate of elimination and long T1/2.
3) Low Vd indicates that the drug is retained in plasma (intravascular, one compartment
model) mostly due to high binding to plasma proteins.
4) Knowing the Vd allows the estimation of the "loading dose" which is the initial dose
required to reach a specific drug concentration, and also allows measurement of the
total amount of the drug in the body: A = Vd X C
5) Drugs with low Vd as aspirin are highly bound to plasma proteins meaning that they a
have high plasma concentration, that is why hemodialysis is useful in treatment of
acute toxicity by these drugs.
It is clear that hemodialysis is not beneficial in treatment of acute toxicity by drugs with
high Vd because they have low plasma concentration being highly distributed or highly
concentrated in tissues.
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3-Metabolism=Biotransformation:
These are chemical reactions that occur mainly in the liver.
The aim of biotransformation reactions is to "convert lipophilic (lipid soluble) drugs into
water-soluble (hydrophilic, ionized,or polar) metabolites to be easily excreted in urine.
It is clear that water-soluble drugs do not undergo metabolism and are excreted
"unchanged" in urine.
On the other hand; lipophilic drugs-after filtration through the renal glomeruli-will
undergo "reabsorption" by the renal tubular cells, making renal excretion of these
drugs very slow. So, they are metabolized to be converted into water soluble form to
promote their renal excretion.
a) Phase I Reactions:
These are "Non-Synthetic" reactions.
The drug undergoes either: oxidation, reduction, or hydrolysis.
Phase I reactions will result in one of the following:
1) Conversion of an active drug into an "inactive" metabolite.This is the most
common result, e.g.:
Hydrolysis
Acetylcholine
choline + acetic acid
2) Conversion of an active drug into an "active" metabolite, e.g.:
oxidation
3) Conversion of an "inactive" drug into an "active" metabolite and in this case the
parent drug is known as a "prodrug", e.g. cortisone (inactive) is changed into
cortisol=hydrocortisone (active), and enalapril(inactive) is metabolized into
enalaprilate (active).
Oxidation
Imipramine
desipramine.
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b) Phase II Reactions:
These are "Synthetic" or "Conjugation" reactions.
The drug or a metabolite resulting from phase I reaction is "conjugated" with an
endogenous polar compound as glucuronic acid, sulphate, glycine, acetate, glutathione
or methyl group.
Phase II reactions mostly result in drug inactivation, with some exceptions as morphine
(active) which is partially converted into morphine 6-glucuronide (active metabolite),
and minoxidil (inactive) is conjugated into minoxidil sulphate (active).
N.B. most drugs are metabolized by phase I reactions followed by phase II reactions,
undergo phase I reaction only, or phase II reactions only. Few drugs as isoniazid is
metabolized by conjugation (phase II) followed by hydrolysis (phase I), i.e. there is
"reversal of order of the phases".
Sites of biotransformation reactions:
1) The liver: it is the main site of drug metabolism.
2) The plasma: e.g. plasma cholinesterase (pseudo cholinesterase) is responsible for
metabolism of some drugs as Succinylcholine.
3) Other sites: the lung, the kidney, the skin, and GIT.
Types of Enzymes Responsible for Biotransformation Reactions:
Microsomal Enzymes
1) Found in smooth endoplasmic reticulum of
liver cells, that is why they are referred to as
"Hepatic" microsomal enzymes (HME).
Non-Microsomal Enzymes
1) Found in the cytoplasm and
mitochondria of liver cells, skin, GIT,
lungs, and in plasma.
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2) Age:
The activity of HME is lower in extremities of age; i.e. neonates (especially if premature)
and old age, so they should be treated with lower doses than adults.
3) Sex (Gender):
Male sex hormones (androgens) act as HME inducers whereas female sex hormones
(estrogen and progesterone) act as HME inhibitors. This is an important cause why females
receive lower doses than males (of the same age and weight).
4) Pathological conditions:
Liver diseases as cirrhosis markedly reduce the activity of HME and the dose of drugs
metabolized by these enzymes should be adjusted according to liver function tests.
Cancer and starvation have the same effect on HME activity.
5) Genetic factors (Pharmacogenetics):
There is marked variation (polymorphism) in the enzyme activity among the population
which influences drug action and toxicity.
In addition, genetic abnormalities may result in defective or abnormal enzymes; e.g.
genetic defect in pseudocholinesterase enzyme greatly reduces metabolism and
increases the action- of succinylcholine (skeletal muscle relaxant) and may lead to
"apnea". This abnormal drug response due to genetic defect is known as "idiosyncrasy".
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4- Excretion:
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2-GIT:
Some drugs may be excreted by:
a) Bile:
Some drugs are excreted in bile; either as free drugs (active), as ampicillin and
rifampicin, or conjugated drugs, as morphine and phenolphthalein (a chemical
laxative).
Ampicillin and Rifampicin are effective in treatment of GIT infections and gall
bladder infections (cholecystitis) being excreted in an active form in bile.
Some drugs excreted by bile (as phenolphthalein and rifampicin) may be reabsorbed
from GIT undergo, i.e. undergo "entero-hepatic recycle" which prolongs the
duration of action of such drugs.
The unabsorbed drugs are excreted in feces.
b) Saliva: e.g. morphine, iodine (which may cause a metallic taste and inflammation of the
salivary glands), aspirin, and rifampicin.
c) Stomach: morphine is partially excreted in the stomach; that is why stomach wash is
performed in case of acute morphine poisoning despite the fact that morphine is
administered intravenously.
d) Large Intestine (Stools): drugs that are poorly absorbed orally as aminoglycosides (e.g.
streptomycin) and some tetracyclines are excreted in stools.
3-Respiratory System: inhaled general anaesthetics, whether gases as nitrous oxide, or
volatile liquids as halothane, are excreted by lungs.
4-Sweat: very few drugs are excreted in sweat as rifampicin and B12.
5-Breast milk: many drugs can be excreted in breast milk and can affect suckling infants,
e.g. laxatives (as phenolphthalein), antihistaminics (in common cold medications), oral
anticoagulants (as warfarin), antibiotics (as chloramphenicol, tetracyclines and
fluroquinolones), morphine, antithyroid drugs, etc.
It is well known that basic drugs as amphetamine and morphine are "trapped" and
excreted in breast milk (see before).
N.B.
1) Rifampicin is excreted in urine, sweat, saliva, and even in tears causing orangered discoloration of all the fluids.
2) Sweat glands and mammary glands are called "skin glands".
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The drug
should be
Advantages
1-Enteral:
a)Oral
1) Stable.
2) Not irritant.
3) Absorbable (if
systemic action is
needed).
1)
2)
3)
4)
5)
b)Sublingual
(S.L.): e.g.
nitroglycerin
pellets in
acute anginal
attacks.
1-Stable.
2-Soluble in saliva.
3-Palatable.
4-Effective in small
doses.
1-Rapid onset of
action.
2-Avoids first pass
effect.
3-Overdose effects
can be avoided by
swallowing or
spitting.
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Easy.
Convenient.
Economic.
Safe.
Suitable for most
drugs.
Disadvantages
Not suitable for:
1) Emergencies (due to
delayed onset of action).
2) Unconscious patients (for
fear of aspiration
pneumonia).
3) Irritant drugs.
4) Unabsorbable drugs as
aminoglycosides
(streptomycin).
5) Uncooperative patients (as
children, insane patients).
6) In presence of vomiting.
7) Drugs with almost complete
first pass effect (as
lidocaine).
8) Absorption is affected by
the presence of food and
other drugs
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c)Rectal:
In the form of
suppository and
enema. Enema is
either:1-retention
enema (MgSO4,
glucose,steroids)
2-evacuant enema
( in constipation).
2-Injection:
a)I.V.:
(bolus or
infusion)
b)I.M.:
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1)Solutions.
2)Suspensions.
3)Oily preparations.
4)Moderately irritant.
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Can be used if oral
route is ineffective as
in:
UnconsciousVomiting-Irritant
drugs-Uncooperative
patients-Drugs with
extensive first pass.
1-Psychologically inconvenient
for most patients.
2-may cause rectal
inflammation (proctitis).
3-variable absorption
especially when the rectum if
full of stools.
4-Not suitable in diarrhea.
1)Allergic reactions as
anaphylactic shock.
2)Rapid injection of
aminophylline causes severe
hypotension and
arrhythmias=velocity reaction.
3)Pyrogenic reaction may
occur.
4)Thrombophlebitis.
5)Transmission of diseases as
hepatitis B and C.
6)Extravasation of the drug
may cause necrosis (see
noradrenaline).
7)Avoid oily preparations and
suspensions to avoid
embolism.
1)Avoid highly irritant drugs (to
avoid inflammation).
2)Heparin should never be
given IM to avoid hematoma.
3)Pain, irritation.
4)Phenytoin and
benzodiazepines as Diazepam
strongly bind to muscle
proteins leading to irregular
absorption after IM injections.
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c)S.C.:
3-Inhalation
4-Topical:
A-Skin:
B-Mucous
membranes:
1) Nose.
2) Ear.
3) Eye.
4) Mouth.
1-Ointments, creams,
and powders are
applied for local
actions.
2-Transdermal
delivery system (TDS)
as transdermal
patches which are
applied for systemic
actions as
nitroglycerin. It
avoids 1st pass and
has long duration.
N.B.: Drugs given orally are liable to 1st pass metabolism, whereas drugs given S.L.,
injection, inhalation, and by TDS avoid 1st pass effect.
Skin absorption can be increased by:
1) Inunction (rubbing off oily drugs).
2) Iontophoresis (galvanic current for water soluble drugs).
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Pharmacodynamics
Examples
b) Osmosis:
c) Demulcent:
d) Astringent:
2-Chemical:
a) Neutralization (Chemical
Antagonism)
b) Chelation:
Combination of organic
compound with a heavy metal
to form non-toxic easily
excreted complex.
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3-Inhibition of cell division
(cytotoxic action):
4-Interference with normal
metabolic pathway:
5- Interference with selective
passage of ions through ion
channels:
7-Action on Receptors:
(The most important mechanism
of drug action).
2011/2012
Cancer chemotherapy as Methotrexate and Nitrogen
mustard.
Sulphonamides inhibit bacterial folic acid synthesis
by competition with PABA.
1) Na+ channel blockers as lidocaine (lead to
membrane stabilization, used as local
anaesthetics and antiarrhythmics).
2) Ca2+ channel blockers as verapamil which block
voltage gated Ca2+ channels, L-type (used as antianginals, antiarrhythmics and antihypertensives).
1) Aspirin irreversibly inhibits cyclooxygenase (COX)
enzymes.
2) Organophosphprous compounds irreversibly
inhibit cholinesterase enzyme.
3) Neostigmine and physostigmine inhibit reversibly
cholinesterase
4) Allopurinol inhibits reversibly xanthine oxidase
enzyme.
Acetylcholine (agonist) and atropine (antagonist) act
on muscarinic receptors.
Adrenaline (agonist) and propranolol (antagonist) act
on -receptors.
RECEPTORS:
Receptors are specific chemo-sensitive, chemo-selective protein macromolecules
present on the cell membrane (e.g. - and -adrenergic receptors, and muscarinic and
nicotinic receptors), inside the cytoplasm (e.g. receptors for steroid hormones and
vitamin D), and inside the nucleus (e.g. receptors for thyroid hormones).
Any chemical substance that has the ability to bind to a receptor is called a "ligand".
Ligands may be: drugs, hormones, or chemical transmitters (neurotransmitters).
The ability of the ligand to bind to the receptor is called "affinity".
Affinity may be due to the fact that the shapes of the ligand and the receptor are
complementary (Key and Lock theory), which allows the drug to "fit" onto the receptor.
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Dissociation
Kd
(D: drug- R: receptor Ka: rate of association- Kd: rate of dissociation).
Examples of agonists: Acetylcholine-Adrenaline-Noradrenaline.
The response (effect or action) of the agonist depends on:
1) The number of receptors occupied by the agonist: the more the number the more
the response. This is known as "occupation theory ".
2) The rate of association / dissociation of the agonist with / from the receptors: the
more rapid the rate, the more the response of the agonist. This is known as "rate
theory of Paton".
N.B.: a number of receptors remains unoccupied even with maximum response of
an agonist and are called "spare receptors".
Receptors regulation: Under normal conditions; the number of receptors is fixed. This may
vary in the following conditions:
1) Long use of an agonist leads to decrease in the number (and sensitivity) of
receptors, this is known as "down-regulation".
2) Long use of an antagonist or deficiency of an endogenous agonist as
neurotransmitters leads to increase in the number (and sensitivity) of receptors.
This is known as "up-regulation".
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2-ANTAGONISTS = BLOCKERS:
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Antagonists are drugs that block the receptors thus preventing the action of the agonist,
and are characterized by the following:
1) Affinity.
2) No efficacy (zero efficacy): no change in the activity of the cell in the absence of an
agonist, but they prevent the action of the agonist.
3) Slow rate of association and dissociation.
Types of Pharmacological antagonists:
1) Competitive Antagonists: there is competition between the agonist and antagonist on
the same receptor, and excess agonist can displace the antagonist. Examples: AtropinePropranolol-Prazosin-Curare. Competitive antagonists cause "parallel shift to the right
with same efficacy" of the log dose/ response curve of the agonist.
2) Non-competitive Antagonists: the antagonist cannot be displaced by excess agonist.
They cause "non-parallel shift to the right with reduced efficacy" of the agonist
log dose/ response curve.
Non-competitive antagonists are further subdivided into:
a) Reversible Antagonists: the effect of the antagonist is of short duration because it is
rapidly metabolized, e.g. succinylcholine (non-competitive neuro-muscular blocker).
b) Irreversible Antagonists: the effect of the antagonist is prolonged because it binds to
the receptor by a "covalent bond", and its effect is terminated by synthesis of new
receptors, e.g. phenoxybenzamine (irreversible -blocker).
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Receptors have 2 main functions; to bind ligands and to initiate a "response" or effect in
the cells by signal transduction.
There are (4) types of receptors according to the signal transduction mechanism
responsible for inducing the response of agonists:
1) Ion-channel linked receptors= Ligand-gated ion channels
They are located in the cell membrane on the gates of ion channels. Activation of this type
of receptors by specific agonists leads to change in the shape of the receptor
(conformational change) followed by opening of the gates of specific ion channels.
Examples include:
1) Nicotinic receptors (N): They are formed of 5 subunits: 2 , 1 , 1 , and 1 .
Activation of this receptor by acetylcholine (which binds to both subunits) induces
opening of Na+-channels Na+ influx and depolarization.
2) GABA receptors: There are 2 types of GABA receptors in CNS: GABAA receptors
which open Cl- channels leading to Cl- influx and hyperpolarization, and GABAB
receptors which open K+-channels also leading to K+ efflux and hyperpolarization
and may also block Ca2+-channels.
2) G-protein-linked receptors:
They are serpentine in shape, made up of 7 polypeptide loops that span the cell
membrane (7 helical segments).
Type of GReceptors
Signal transduction
Protein
1) All -receptors.
Activation of adenyl cyclase and
Gs
Gi
Gq
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2)
3)
1)
2)
3)
4)
1)
2)
3)
4)
H2-receptors.
D1-receptors.
2-receptors.
M2-receptors.
5-HT1-receptors.
D2-receptors.
1-receptors.
M1 and M3 (except on blood vessels).
H1-receptors (except on blood vessels).
5HT2 receptors.
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B-Pharmacological Actions:
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Percent of Adult
Dose
10%.
25%.
33%.
50%.
75%.
Elderly between 60 and 70 years require 2/3 of the adult dose and those over 70 years
require 1/2 of the adult dose due to:
1) Weakness of hepatic microsomal enzymes.
2) Reduced renal excretory functions.
2) Body Weight:
The more the body weights the higher the dose except in cases of edema or fat which
are not taken into consideration.
In obese patients due to excessive body fat increase the dose of lipophilic drugs and
reduce that of hydrophilic drugs.
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6) Tolerance:
Definition: failure to obtain the usual response by the usual dose.
Types:
a) Congenital which is either:
1) Racial: Negros are tolerant to the mydriatic action of ephedrine.
2) Species: rabbits are tolerant to the systemic actions of atropine due to the
presence of atropine esterase (atropinase) in their plasma.
3) Individual: this is due to genetic variations.
b) Acquired: long use of drugs as morphine, barbiturates, nicotine, ethyl alcohol, and
amphetamine leads to acquired tolerance which is usually reversible, and may occur
to some not all- actions of the drug (see morphine).
Causes of acquired tolerance:
a) Pharmacokinetic causes: HME inducers as nicotine and barbiturates increase their
own metabolism.
b) Pharmacodynamic causes: long use of drugs leads to "down-regulation" of receptors
or depletion of endogenous transmitters. Animal insulin induces antibody formation
Special types of acquired tolerance:
Tachyphylaxis: acute acquired tolerance (see effect of ephedrine on ABP).
Cross tolerance: occurs between drugs having similar effects as morhine, barbiturates,
or ethyl alcohol with general anaesthesia (all are CNS depressants).
7) Dependence:
It is either:
a) Psychic dependence = Habituation: sudden cessation of the drug does not cause
withdrawal symptoms but may cause emotional distress for a short time, e.g.
methylxanthine beverages as tea and coffee.
b) Psychic and Physical dependence = Addiction:
Sudden cessation of the drug leads to severe and may be fatal- withdrawal symptoms
"Abstinence syndrome" which are the reverse of the drug actions, e.g. opiates
(morphine, heroin, and codeine), ethyl alcohol, barbiturates, and nicotine.
8) Supersensitivity =Intolerance:
It is an exaggerated normal drug response. It is due to upregulation of receptors, due to
inhibition of metabolizing enzymes, or due to diseases as thyrotoxicosis (see adrenaline). It
requires reduction of the dose.
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9) Hypersensitivity = Allergy:
It is an abnormal unpredictable drug response due to antigen-antibody reaction (the
drug or a metabolite acts as an antigen or binds to a hapten).
It does not occur on the first exposure to the drug which sensitizes the patient but
occurs on subsequent exposures, and is not dose-dependent.
Manifestations: skin rash, urticaria, photosensitivity (skin rash on exposure to sunlight), asthma, angioneurotic edema, anaphylactic shock, bone marrow depression
(blood dyscrasias) by chloramphenicol, sulphonamides, dipyrone and thioamide
antithyroids-cholestatic hepatitis and jaundice by chlorpropamide, testosterone,
chlorpromazine, and alpha methyldopa.
Cross allergy occurs between drugs having the same chemical structure as
sulphonamides and thiazide diuretics, or between drugs having the same mechanism of
action as aspirin and other NSAIDs in asthmatics.
10) Idiosyncracy:
It is an abnormal unpredictable drug response due to genetic defects.
Drugs
Succinylcholine
Halothane
Idiosyncratic reaction
1-Succinylcholine apnea in patients with
pseudocholinesterase deficiency.
2-Malignant hyperthermia.
Malignant hyperthermia.
Hydralazine
Corticosteroids
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