Basic Principles of Pharmacology: Prof. Suheil Zmeili Faculty of Medicine Department of Pharmacology University of Jordan
Basic Principles of Pharmacology: Prof. Suheil Zmeili Faculty of Medicine Department of Pharmacology University of Jordan
Basic Principles of Pharmacology: Prof. Suheil Zmeili Faculty of Medicine Department of Pharmacology University of Jordan
Management
Drugs
•FDA approved definition of drugs
A chemical substance that is mainly used to
treat, control, prevent, or diagnose a
specific disease or to prevent pregnancy!!!
•Chemical nature of drugs
- Acidic; Aspirin, barbiturates...etc
- Basic or alkaline; Morphine, Atropine,
Alkaloids...etc
- Neutral; Steroids
MAJOR OBJECTIVE
Assessment
of safety
Pharmaceutical
Kinetics
Process
Administration
•Pharmaceutical process; drug in dosage form:
Is the drug getting into patient?
•Pharmacokinetic process:
Is the drug getting to its site of action?
•Pharmacodynamic process:
Is the drug producing the required pharmacological effect?
•Therapeutic process (clinical pharmacology):
Is the pharmacological effect being translated into therapeutic
effect?
•Phrmacogenetics
Individual variations in responding to drugs + gene therapy
Drug discovery & development
1. Starts with prediction=an idea &
hypothesis
What helps?
- Awareness of the beneficial effects of
plants and animal products (natural
sources)
- Chemical identification of a wide variety
of natural mediators and the possibility of
modifying them chemically
e.g. epinephrine, norepinehrine
acetylcholine
histamine
prostaglandins
endogenous opioids
hormones…etc
- Avoid chemicals with highly reactive
groups (toxic)
2. Design and synthesis of useful drugs or
substances through simple techniques or
with the help of advanced technology
e.g. a plant → fractionation,
chromatographic experiments →
identification of the active ingredients →
isolation → purification → good drug
(recently most drugs of plant source
could be synthesized)
An animal → isolation of a substance
(insulin)
Simple peptides → a.a sequencing
machine
Complex proteins → recombinant DNA
technology
-Receptology studies
Allowed synthesis of huge number of
agonists and antagonists
3. Preclinical studies
Studies on tissues and whole animals
-Determine efficacy
Isolated tissue e.g. bronchi → organ path
→ testing drug…etc
Animal models
→ drug ↓ BP
→ drug ↓ blood sugar level
- Determine pharmacokinetic parameters
Absorption, distribution, metabolism…etc
- Determine pharmacodynamics (MOA)
- Assessment of drug toxicity=safety
. Acute toxicity studies
Determination of LD50; Margin of safety…etc
. Subacute and chronic toxicity studies
Repeated dose studies
Daily observation of animals (wt.,
food and water intake ..)
Obtaining biological samples (blood;
urine)
Obtaining tissues (liver; spleen;
stomach…etc) for histopathological
exam or studies
-Special toxicology studies
. Mutagenicity (genotoxicity) tests
Could delineate the induction of gene
mutations (bacterial mutagenicity test or
administration of drug to pregnant
animals…etc)
Some mutations could result in the
development of cancer
. Carcinogenicity studies
Not always required prior to early studies in
man unless there is a high suspicion that the
drug could be carcinogenic e.g. suspicion of
mutagenicity; highly reactive groups on
drug; histopathological abnormalities…
Required if the use of drug in man for more
than one year or +ve mutagenic test
•Clinical drug trials ( mainly 4 phases)
- Phase 0
Phase 0 or first-in-human trials is a recent
phase approved in accordance with the
United States FDA’s 2006 Guidelines
Phase 0 trials are also known as human microdosing
studies and are designed to speed up the
development of promising drugs by establishing very
early on whether the drug or agent behaves in
human subjects as was expected from preclinical
studies
Distinctive features of Phase 0 trials include the
administration of single subtherapeutic doses of the
study drug to a small number of subjects (10 to 15)
to gather preliminary data on the agent's
pharmacokinetics and pharmacodynamics
A Phase 0 study gives no data on safety or efficacy,
being by definition a dose too low to cause any
therapeutic effect. Drug development companies
carry out Phase 0 studies to rank drug candidates in
order to decide which has the best pharmacokinetic
parameters in humans to take forward into further
development
Phase 0 studies enable go/no-go decisions to
be based on relevant human models instead
of relying on sometimes inconsistent animal
data
Questions have been raised by experts about
whether Phase 0 trials are useful, ethically
acceptable, feasible, speed up the drug
development process or save money, and
whether there is room for improvement
-Phase I
Involves the use of a drug in humans for
the first time
It establishes dose level at which signs of
toxicity first appear
Conducted on 20-80 healthy men with
ages 18-45 yrs
Usually a single dose is used initially and if
no side effects exhibited, the dose is
increased progressively until sufficient
serum level is achieved (therapeutic
level) or some toxic effects appear
Such studies are conducted in hospital
If no side effects result from single dose,
multiple dose studies should be initiated
=bioavailability-bioequivalence studies
- Phase II
If phase I studies prove that the drug is safe to
continue, the new drug is administered to
patients for the first time
All patients should have only one problem
(one disease)
It assesses efficacy and establishes optimal
dose range in patients (dose-response
studies are important)
Phase II studies are conducted on 80-100 patients
(certain countries ask for 50-300 patients)
Also patients are observed for toxicity to assess safety
of the drug
- Phase III
Similar to phase II but conducted on large number of
patients (several hundreds to thousands; 250-1000
reasonable)
It also assesses safety and efficacy
Could detect effects/side effects not observed in
phase II
-Phase IV
Post-marketing studies
Controlled and uncontrolled studies are
often conducted after drug approval and
marketing
It further assesses safety & efficacy of
drugs
It allows for comparisons between
different drugs used for the same disease
In addition, phase IV studies provide
evidence of a new use to the drug e.g.
aspirin-antiplatelet
sildenafil citrate-ED
Double-blind; single-blind placebo
controlled studies are usually conducted
AFTER ALL THESE CLINICAL DRUG
TRIALS THE DRUG IS USUALLY
APPROVED BY NATIONAL OR
INTERNATIONAL REGULATORY
AUTHORITIES AND IS LICENSED FOR
GENERAL PRESCRIBING
Ethics of the use of drugs in humans
•Full detailed protocol has to be
approved by the ethical committee, the
institutional review board (IRB)
•All subjects should sign an informed
consent form
•All subjects should be insured for life
and damage
** Branches of pharmacology usually
answer all of the following questions:
-How much of a drug to give? Dose
-How frequent a drug should be given?
Related to the biological half-life (t )
1/2
R CH3 R COOH
. O-dealkylation
R-O-CH3 R-OH+HCHO
. N-dealkylation
H
R-N-CH3 R-NH2+HCHO
. N-oxidation; N-hydroxylation
(CH3)N (CH3)3NO
H
R-CH2-NH2 R-CH2-N
OH
. Sulfoxidation O
S S
N N
. Hepatic reduction
Azo reduction
R1-N=N-R2 R1-NH2+H2N-R2
Nitroreduction
R-NO2 R-NH2
- Nonmicrosomal oxidation and reduction
Alcohol oxidation; chloral hydrate reduction
- Hydrolysis reactions
NH2 NH2
H2O
Esterases +HO-CH2-R
C-O-CH2-R C
O O OH
2. Pathway II = Conjugation reactions
Addition of certain groups to a drug to become more polar
and readily excreted
soluble enzymes in cytosole
Acceptor + Donor conjugate
(Drug) (activated) of liver (transferases)
- Metylation
- Acetylation
- Glucuronic acid conjugate
- Etheneal sulfates
- Glycine conjugate (mercaptopuric acid formation)
Inactive D
*Active D kidney
I
II
I II
II I
Characteristics of an ideal metabolite:
- Water soluble
- Pharmacologically inactive
- Not to be toxic
Sites of drug metabolism:
- Liver (major site)
- Intestine
- Lungs; brain; kidney; plasma, adrenals...etc
Factors affecting drug metabolism:
- Genetic factors and species differences (major factor)
(slow and rapid metabolizers)
- Sex
- Drug-drug interactions
- Age (paracetamol vs chloramphenicol)
- General health of patients and nutritional status
- Dose and frequency of administration
First-pass effect = rapid metabolism
Enterohepatic circulation
Drug excretion = elimination
A process by which a drug or it’s
metabolites are eliminated from the
body
Major sites:
-Kidney (most drugs)
-Liver
Kidney function (old people)!!!!!
Methods of excretion:
- Filtration
- Tubular secretion
•Specific secretory mechanism for weak acids and
another one for weak bases
•Still some drugs remain lipophylic so could be
reabsorbed (this could be inhibited by changing pH
and provides the use of alkali in enhancing excretion
of acidic drugs)
Probenecid
Penicillin
The rate of excretion of a given drug is
determined by a specific constant known
as Ke which depends on AVD and clearance
Ux (mg/ml) x V
Clearance = ـــــــــــــــــــــــــــــــــــــــــ
Px (mg/ml)
Ke = Clearance (ml/min)/AVD (ml)
Ke unit: min-1 = 1/min
Ke = 0.693/t1/2 (min)
KT = Km+ Ke
toxic
ineffective
Time (hr; min)
3hrs 3hrs 3hrs
C0 100 50 25 12.5
Blood α-phase
Conc. 50% β-phase
(%)
t1/2
Time (hr; min)
Steady state level (chronic administration)
Plateau
Blood
Conc. input=output
Time
Reached after 5 t1/2 lives
Loading dose (initial large dose) followed by
maintenance dose e.g. digitalization...etc
Steady state level could be calculated from this equation:
ƒ.D ƒ.D T1/2
Cp = = ـــــــــــــــــــــــــــــ1.44 x ــــــــــــــx ـــــــــــ
AVD . Ke .T AVD T
Cp = Average steady state plasma conc. of drug
ƒ = fraction of dose absorbed; bioavailable fraction
D = dose of given drug
Ke = first order reaction rate constant
AVD = apparent volume of distribution
T = time interval between doses
T1/2 = biological half-life
1.44 = 1/0.693
Trough and peak drug levels:
Used to establish the effectiveness of a drug
Trough is the lowest drug level that is needed to
reach therapeutic range
Peak is drawing the serum blood levels (30 min
parenteral; 1-2 hr oral) after the drug is
administered
Trough is drawing the serum blood levels right (30
min-1 hr) before the next dose
(If trough or peak levels are > than normal, the
patient is at risk for adverse effects)
Bioavailability-bioequivalence studies:
To prove that 2 drugs have the same
-Chemical structure
-Bioavailability
-Biochemical activity
-Therapeutic effects
A B AUC
Blood
Conc.
Tlag Tmax
Time (hrs; days)
KT; Km; Ke; T1/2; clearance...etc
Terms:
- Capacity limited processes
1. first-order (exponential) kinetics
All pharmacokinetic processes (abs., distr., met. excr.) occur at a
rate directly proportional to conc. of drug e.g. increasing
dose increases these processes
2. zero-order (saturation) kinetics
Apply mainly to met. And elimination where their rates reach
saturation (maximum) and a further increase in rates is
impossible despite an increase in dose (these processes are
independent of the conc. (absorption from SR tab. Or
continuous infusion are good examles)
First order kinetics may become zero order when high conc.’s of
drug are present
- Indication:
Clinical uses of drugs
- Contraindications:
Situations when not to use drugs
- Drug tolerance:
↓ response after repeated doses e.g.
drugs of addiction
- Tachyphylaxis:
Rapidly developing tolerance
- Drug interactions:
The effect of one drug on another. Takes
many forms:
↑ or ↓ absorption; ↑ or ↓ protein
binding; ↑ or ↓ metabolism; ↑ or ↓
excretion; ↑ or ↓ toxicity; ↑
or ↓ binding to receptors… etc
** Rule: one drug is better than two; two
drugs are better than three…etc
- Side effects and drug toxicity:
Unwanted, untoward, undesirable,
adverse reactions to a given drug
- Idiosynchracy:
Abnormal genetically reaction to a given
drug (inherited abnormal response to a
drug)