PHA 301

FACTORS AFFECTING DRUG ACTION

&
PRINCIPLES OF BIOASSAY
DR. J. A. BADEJO
DEPARTMENT OF PHARMACOLOGY AND THERAPEUTICS
FACULTY OF BASIC MEDICAL SCIENCES
COLLEGE OF MEDICINE
UNIVERSITY OF IBADAN
FACTORS MODIFYING DRUG ACTION

I. Physiological Factors.
II. Pathological Factors (Diseases).
III. Genetic Factors.
IV. Environmental Factors.
V. Interaction with other drugs.
 I. Physiological Factors

• Age
• Sex
• Pregnancy
• Body weight
• Lactation
• Food
 Physiological Factors
1. AGE
Newborn
– ↓ gastric acid secretion.
– ↓ liver microsomal enzymes (glucuronyl
transferase).
– ↓ Plasma protein binding.
– ↓ GFR & tubular secretion.
– Immaturity of BBB in neonates.
• GIT absorption of ampicillin and
amoxicillin is greater in neonates due to
decreased gastric acidity.

• Chloramphenicol ----- Grey baby syndrome

Inadequate glucouronidation of
chloramphenicol with drug accumulation.

• Sulfonamides ------ Hyperbilirubinemia &

Kernicterus
CHILDREN

• Tetracyclines
Permanent teeth staining

• Corticosteroids
Growth & development retardation

• Antihistaminics
Hyperactivity
Old Age
– ↓ Liver function
diazepam, theophylline.

– ↓ Kidney function
Gentamycin, Digoxin, Pencillins are contraindicated in the
aged.

– ↓ Plasma protein binding

– ↑ sensitivity to CNS depressants

diazepam, morphine
2. SEX
• Testosterone increases the rate of
biotransformation of drugs.

• Decreased metabolism of some drugs in

female (Diazepam).

• Females are more susceptible to autonomic

drugs ( estrogen inhibits choline estrase).
3. Pregnancy

• ↑ Cardiac output
• ↑ GFR and renal elimination of drugs
• ↑ Vd
• ↑ Metabolic rate of some drugs
• Lipophilic drugs cross placental barrier &
slowly excreted.
II. Pathological Factors
Diseases cause individual variation in drug
response
– ↓ Plasma protein binding for warfarin,
tolbutamide → adverse effects.

– ↓ Hepatic blood flow → ↓ clearance of

morphine, propanolol.

– Impaired liver microsomal enzymes

↓ Diazepam, rifampicin, theophylline
(B) Renal Disease
– ↓GFR.
– ↓tubular function.
– ↓Plasma albumin
↓excretion of digoxin, lithium, gentamycin,
penicillin.

(C) Malnutrition
– ↓plasma protein binding of drugs.
– ↓amount of microsomal enzymes.
– ↑Increases portion of free, unbound drug
e.g. warfarin
III. Genetic Factors GENETIC POLYMORPHISM
The existence in a population of two or more
phenotype with respect to the effect of a drug.
e.g. Acetylation enzymes deficiency

• Acetyl transferase (non-microsomal).

(SHIP)
Sulphonamides, Hydralazine, Isoniazid,
Procainamide etc. metabolized by
acetylation.

• Slow acetylator phenotype → peripheral

neuropathy in INH .
• Rapid acetylator phenotype can decrease
effect of drug.
Pseudocholinesterase deficiency

• Succinyl choline ( Sk. muscle relaxant )

→ Succinylcholine apnea due to
paralysis of respiratory muscles.
Malignant hyperthermia

• By succinyl choline due to inherited inability

to chelate calcium by sarcoplasmic reticulum.

• ↑ Ca release, muscle spasm, ↑ Temp.

Deficiency of Glucose–6 phosphate
dehydrogenase (G-6-PD).

G-6-PD Deficiency in RBCs → hemolytic

anemia upon exposure to some oxidizing
drugs.

–Antimalarial drug, primaquine.

–Long acting sulphonamides.
 IV. Environmental Factors
Microsomal Enzyme Inducers

– Tobacco Smoke

– Smokers metabolize drugs more rapidly

than non smoker.
 ADVERSE DRUG EVENT
Is an undesired or harmful
occurrence that results from taking
a medication correctly and needs a
reduction of dose or drug
withdrawal .
• Nausea and vomiting
• Deafness with gentamycin
• Death with penicillin
 SIDE EFFECTS
• A side effect is an undesired effect that occurs when a
medication is administered regardless of the dose.
• Unlike adverse events, side effects are mostly foreseen
by the physician and the patient is told to be aware of
the effects that could happen while on the therapy.
• Side effects differ from adverse events and later resolve
on their own with time after taking the medication for
several weeks.
• Side effects are tracked and investigated extensively
during clinical trials before entering the market.
• Adverse events require interventions whereas most side
effects spontaneously resolve with time, e.g. Morphine
causes constipation during its use as analgesic.
Types of adverse drug reactions
A, B, C, D and E
I) Type A reactions
– Excessive therapeutic effect
– Common
– 75 % of all adverse reaction
– Related to pharmacological actions
– Dose-dependent
– Predictable
– Can be avoided by adjusting the dosage regimen
– Most of them are reversible upon stopping drug
e.g.
Hypotension (antihypertensives)
Hypoglycemia (insulin)
Type A reactions

Excessive therapeutic effect. Unwanted effects

related to the main pharmacological actions of
the drug that occur when the drug produces
greater therapeutic effect than is necessary.

• Warfarin → Anticoagulant → Bleeding

• Insulin → Normoglycemia → Hypoglycemia
II) Type B reactions
–Are bizarre reactions
–Not related to the normal pharmacological
actions of the drug.
–Unpredictable
–Not dose-related.
–Occur only in minority of patients.

Types
–Allergic reactions (Hypersensitivity )
–Genetic disorders (Idiosyncrasy)
 Type B
1) Hypersensitivity ( allergic reactions)
Abnormal response to the drug due to
antigen-antibody reactions e.g. Penicillin

• Allergic response to a drug

• Rashes, hypotension and bronchospasm

(anaphylactic reaction)
 Types of allergic reactions
• Type –I immediate type/acute hypersensitivity/anaphylatic –
Ig E mediated
• Type -II reaction/cytotoxic reaction – cause damage to cells
e.g. haemolytic anemia due to methyldopa or penicillin.

• Type- III/immune complex mediated – antigen-antibody react

to make immune complex which is engulfed by leukocytes and
initiate inflammatory process- e.g. serum sickness,
nephropathy and vasculitis.

• Type IV/delayed hypersensitivity/cell mediated- occurs 2-3

days after exposure to antigen - T lymphocytes are involved-
e.g. contact dermatitis, urticarial rash and fever.
 Type B
2) Idiosyncrasy
is an abnormal response to the drug due to
genetic disorders.

•Succinylcholine apnea
•Malignant hyperthermia – a hereditary condition in which
certain anaesthetics (e.g., halothane) cause high body temperatures and muscle
rigidity

•Porphyria – a genetic abnormality of metabolism causing pains and

mental confusion
Type C reactions ( Continuous reaction)

– Due to long term use e.g. NSAIDs

analgesic nephropathy
Type D reactions (Delayed adverse reactions)

Teratogenesis
congenital malformations occurring in the fetus
due to exposure to drugs during pregnancy
e.g. Thalidomide → Phocomelia

Carcinogenesis
Ability of some substances to induce cancer.
e.g. Stilbesterol → adenocarcinoma of vagina in
female off springs.
Mechanisms of Delayed Adverse Reactions

1. DNA alteration
Griesofulvin & alkylating cytotoxics

2. Immunosuppression
Immunosuppressants increase incidence of cancer
e.g. organ transplantation & rheumatoid arthritis

3. Hormonal
Long term use of estrogen replacement in Post
Menopausal Women induces endometrial cancer
Type E reactions (Ending of drug)

• Sudden discontinuation (abrupt withdrawal).

• Rebound adrenal insufficiency

• e.g. Corticosteroids
• Antihypertensive
• Antiepileptics
 Treatment of drug allergy

• The offending drug must be immediately stopped.

• Most mild reactions (like skin rashes) subside by

themselves and do not require specific treatment.

• Antihistamines (H1) are beneficial in some Type I

reactions (urticaria, rhinitis, swelling of lips, etc.) and
some skin rashes.
 Treatment of drug allergy
• In case of anaphylactic shock or angioedema of larynx the
following measures are recommended:

• Put the patient in reclining position, administer oxygen at high

flow rate and perform cardiopulmonary resuscitation if
required.

• Inject adrenaline 0.5 mg (0.5 ml of 1 in 1000 solution) i.m.

• Repeat every 5-10 min in case patient does not improve or

improvement is transient. This is the only life saving measure.
 Treatment of drug allergy

• Adrenaline should not be injected i.v. (can itself be

fatal) unless shock is immediately life threatening.

• If adrenaline is to be injected i.v., it should be diluted to

1:10,000 or 1:100,000 and infused slowly with
constant monitoring.

• Administer a H1 antihistaminic (chlorpheniramine 10-

20 mg) i.m./slow i.v.
 Treatment of drug allergy

• Intravenous glucocorticoid (hydrocortisone sodium

succinate 100-200 mg) should be added in
severe/recurrent cases.

• Intravenous glucocorticoid acts slowly, but is specially

valuable for prolonged reactions and in asthmatics.

• Glucocorticoids are the only drug effective in type II,

type III and type IV reactions.
 Photosensitivity
• It is a cutaneous reaction resulting from drug induced
sensitization of the skin to UV radiation.

• Phototoxic Drug or its metabolite accumulates in the skin,

absorbs light and undergoes a photochemical reaction resulting
in local tissue damage (sunburn-like), i.e. erythema, edema,
blistering followed by hyperpigmentation and desquamation.

• The shorter wave lengths (290-320 nm, UV-B) are responsible.

• Drugs involved in acute phototoxic reactions are tetracyclines

(especially demeclocycline) and tar products.
 Photosensitivity

• Photoallergic Drug or its metabolite induces a cell mediated

immune response which on exposure to light of longer wave
lengths (320- 400 nm, UV -A) produces a papular or
eczematous contact dermatitis-like picture.

• Drugs involved are sulfonamides, sulfonylureas, griseofulvin,

chloroquine, chlorpromazine.
 Drug dependence

• Psychological dependence

• Physical dependence

• Drug abuse
 Drug interactions
• This is the modification of the effect of one
drug (the object drug ) by the prior or
concomitant administration of another
(precipitant drug).
 Outcomes of drug interactions

1) Loss of therapeutic effect

2) Toxicity
3) Unexpected increase in pharmacological activity
4) Beneficial effects e.g. additive & potentiation
(intended) or antagonism (unintended).
5) Chemical or physical interaction
e.g. IV incompatibility in fluid or syringes mixture
 Mechanisms of drug interactions
Pharmacokinetic Pharmacodynamic
Involve the effect of a Are related to the
drug on another from the pharmacological activity
point of view that of the interacting drugs
includes absorption, e.g. synergism,
distribution, metabolism antagonism, altered
and excretion. cellular transport, effect
on the receptor site.
 Pharmacodynamic interactions
1. Excessive sedation, respiratory depression, motor
incoordination due to concurrent administration of a
benzodiazepine, a sedating antihistaminic
(promethazine), a neuroleptic (chlorpromazine), an
opioid (morphine) or drinking alcoholic beverage while
taking any of the above drugs.

2. Fall in BP and fainting due to concurrent administration

of α1 adrenergic blockers, vasodilators, ACE inhibitors,
high ceiling diuretics and cardiac depressants.
 Pharmacodynamic interactions

3. Pronounced and asymptomatic hypoglycaemia

can occur when propranolol is administered to
diabetics receiving insulin/sulfonylureas, due to
blockade of β adrenoceptors which contribute to
recovery from hypoglycaemia as well as some
hypoglycaemic symptoms.

4. Increased risk of bleeding due to concurrent use

of antiplatelet drugs (aspirin, clopidogrel) with
anticoagulants (warfarin).
 Pharmacodynamic interactions

5. Severe hyperkalaemia by concurrent use of ACE

inhibitors and K+ sparing diuretics.

6. Additive ototoxicity due to use of an aminoglycoside

antibiotic in a patient receiving furosemide.

7. Antagonism of bactericidal action of β lactam

antibiotic by combining it with a bacteriostatic drug
like tetracycline, erythromycin or clindamycin.
 Drug interactions before administration
• Certain drugs react with each other and get inactivated if their solutions
are mixed before administration.
• In practical situations, these in vitro interactions occur when injectable
drugs are mixed in the same syringe or infusion bottle. Some examples
are:
1. Penicillin G or ampicillin mixed with gentamicin or another
aminoglycoside antibiotic.
2. Thiopentone sodium when mixed with succinylcholine or
morphine.
3. Heparin when mixed with penicillin/ gentamicin/hydrocortisone.
4. Noradrenaline when added to sodium bicarbonate solution.

• In general, it is advisable to avoid mixing of any two or more parenteral

drugs before injecting.
Fixed dose ratio combination preparations
Advantages
1. Convenience and better patient compliance

2. Certain drug combinations are synergistic, e.g.

sulfamethoxazole + trimethoprim
levodopa + carbidopa/benserazide
combination oral contraceptives.

3. The therapeutic effect of two components being same may add up while the
side effects being different may not, e.g. amlodipine + atenolol as
antihypertensive.

4. The side effect of one component may be counteracted by the other, e.g.
a thiazide + a potassium sparing diuretic.

5. Combined formulation ensures that a single drug will not be administered.

This is important in the treatment of tuberculosis and HIV-AIDS.
DISADVANTAGES OF FIXED DOSE RATIO COMBINATIONS
1. The patient may not actually need all the drugs present in a combination: he is
subjected to additional side effects and expenses.
2. The dose of most drugs needs to be adjusted and individualised. When a combined
formulation is used, this cannot be done without altering the dose of the other
component(s).
3. The time course of action of the components may be different: administering them at
the same intervals may be inappropriate.
4. Altered renal or hepatic function of the patient may differently affect the
pharmacokinetics of the components.
5. Adverse effect, when it occurs, cannot be easily ascribed to the particular drug
causing it.
6. Contraindication to one component (allergy, other conditions) contraindicates the
whole preparation.
7. Confusion of therapeutic aims and false sense of superiority of two drugs over one is
fostered, specially in case of antimicrobials whose combinations should be avoided.
8. Corticosteroids should never be combined with any other drug meant for internal use.
Bibliography
• Essentials of Medical Pharmacology -7th edition by KD Tripathi
• Goodman & Gilman's the Pharmacological Basis of Therapeutics 12th
edition by Laurence Brunton (Editor)
• Lippincott's Illustrated Reviews: Pharmacology - 6th edition by Richard A.
Harvey
• Basic and Clinical pharmacology 11th edition by Bertram G Katzung
• Rang & Dale's Pharmacology -7th edition
by Humphrey P. Rang
• Clinical Pharmacology 11th edition By Bennett and Brown, Churchill
Livingstone
• Principles of Pharmacology 2nd edition by HL Sharma and KK Sharma
• Review of Pharmacology by Gobind Sparsh
THANK YOU