FACTORS MODIFYING DRUG RESPONSE

Mr. A. S .KhairnarAssistant. Professor

Ali –Allana college of pharmacy,Akkalkuwa (M.S.)

FACTORS MODIFYING DRUG RESPONSE

• variations in response to same dose of a drug between different patients• in the same patient on different occasions •The dose of drug is generally expressed in the range, which gives therapeutic effect in majority of patients. • The dose range is usually based on the average requirements of an adult and is not strictly applicable under all circumstances

• IMPORTANT FACTORS MODIFYING DRUG ACTION ARE:

• • BODY WEIGHT • • AGE • • SEX • • ROUTE OF DRUG ADMINISTRATION • • TIME OF DRUG ADMINISTRATION • • GENETIC FACTORS • • METABOLIC DISTURBANCES • • PATHOLOGICAL CONDITIONS • • TOLERANCE • • TACHYPHYLAXIS • • CUMMULATION • • DRUG INTERACTIONS

BODY WEIGHT :

• average dose of a drug is mentioned in terms of mg/Kg body weight. However, the dose mentioned may not be applicable to all cases.

• in cases of edema weight of patient increases due to the accumulation of ECF

• in malnutrition metabolizing capacity of drug is reduced

• these factors should be kept in mind while calculating the dose of drug.

AGE: Pharmacokinetics of many drugs change with age. - Newborn: liver and renal function less developed– Elderly: hepatic and renal functions decline– Glomerular filtration rate: low in infants– Blood brain barrier: more permeable in infants & may cause

accumulation

SEX: • Females: smaller body size, require doses that are on lower

side of the range.• Consideration given to menstruation, pregnancy and

lactation.• Drugs given during pregnancy may affect the fetus. • Physiological changes during pregnancy alter drug

disposition.• drugs like methyldopa and blockers interfere with sexual

function in males but not in females.

• Gynecomastia produced by drugs like Digitalis, Cimetidine, and Metoclopramide occurs in males not in females

ROUTE OF DRUG ADMINISTRATION: • governs the speed and intensity of drug response.

• In general, intravenous dose of drug is usually smaller than oral, and time of onset of action is quick with intravenous route.

• A drug may have entirely different uses through different routes. For example Magnesium sulfate given orally produce purgation, applied locally on inflamed area decreases the swelling while intravenously it produces CNS depression and hypotension.

GENETIC FACTORS: • The dose of a drug to produce same effects may vary 4–6

folds among different individuals. This is mainly due to the differing rates of drug metabolism as the amount of microsomal enzymes is genetically controlled.

• There are some specific genetic defects that lead to variation in drug response. Example;

• Hemolysis by Primaquine and Sulfonamides in persons with G.6.P.D. deficiency.

• Slow metabolism of Isoniazid in slow acetylators.

• Example; • Hemolysis by Primaquine and Sulfonamides in persons with G.6.P.D. deficiency.

• Slow metabolism of Isoniazid in slow acetylators.

TIME OF ADMINISTRATION: There is delayed drug absorption when drug is given orally after meals,

which slows down the effects of drug. Under certain circumstances drugs must be given before meals.

• To prevent mixing of drug with food Anthelminthics. • To get immediate effect: Drugs used for prevention of motion sickness. • To prevent formation of insoluble complexes: Tetracycline's. • To prevent specific side effects, for example to prevent hypoglycemia

insulin and sulfonylureas are given before meals

METABOLIC DISTURBANCES: Changes in water and electrolyte balance body temperature and

acid base balance may modify the effects of drug.

• For example aspirin reduces body temperature only in presence of fever and have no effect on body temperature when it is normal.

• Iron is well absorbed in states of iron deficiency.

PATHOLOGICAL CONDITIONS

several diseases influence drug disposition and action. • Hepatic, renal and cardiovascular diseases have important

influence on drug clearance and drug actions. • Drugs must be carefully used in presence of diseases of these

organs.

DRUG INTERACTIONS:

Drug interaction:• Drugs may modify the response to each other by pharmacokinetic or

pharmacodynamics interaction between them.

• Drug interaction does not necessarily mean that their concurrent use

is contraindicated; many drugs can be used beneficially and some with dose adjustment.

• Drug combinations can produce:

» Additive effect.» Synergism.

» Potentiation. » Antagonism.

ADDITIVE EFFECT OR SUMMATION When total pharmacological effect produced by concomitant use of two or more drugs is equal to the sum of their individual effects, it is called “Additive effect.” 1 + 1 = 2. Example: Combination of ephedrine and Theophylline in the treatment of asthma. The individual side effects of an additive pair may be different, and may not add up. The combination is better tolerated than higher dose of one component.

SYNERGISM • When total pharmacological effect produced by

concomitant use of two or more drugs is higher than the sum of their individual effects, it is called “Synergism”.

• 1 + 1 = > 2. • Example: • Codeine + Aspirin > Analgesia.

• Sulfonamide + Trimethoprim > Antibacterial effect.

POTENTIATION • Enhancement of effect of one agent by another; so that the

combined effect is more than the sum of their individual effects is called “Potentiation.”

• In case of potentiation one agent has no effect when given alone but increases the effects of other co-administered drug.

• 0 + 1 = > 2.

• Example: • Levodopa + Carbidopa => Parkinsonism.

• Ampicillin + Clavulanic acid = > Antibacterial effect.

ANTAGONISM • The phenomenon of opposing effects when two or more drugs are

given together is called “Antagonism.”

There are three types of antagonism • Chemical antagonism. • Physiological antagonism. • Pharmacological antagonism. CHEMICAL ANTAGONISM • In this type of antagonism two or more drugs react chemically to form inactive product, it occurs without involvement of drug receptors. Examples: Acids react with Alkalis, Heparin and Protamine sulfate.

PHARMACOLOGICAL ANTAGONISM

• When two drugs produce opposite effects on same physiological function by acting on same receptors it is called “Pharmacological antagonism.” PHARMACOLOGICAL ANTAGONISM

• Competitive antagonist • Non competitive antagonism Equilibrium (reversible). Non

equilibrium (irreversible).

COMPETITIVE EQUILIBRIUM ANTAGONISM

• agonist and antagonist compete for same receptor site. • Drug receptor binding is weak & non-covalent.

• The extent to which the antagonist opposes the action of agonist is dependent upon the number of receptors occupied by agonist and antagonist.

• The antagonism is surmountable i.e. the antagonism can be reversed by increasing the concentration of agonist at receptor site, for example atropine and acetylcholine on muscarinic receptors.

• Maximal response of agonist is achieved by increasing the concentration of agonist at receptor site.

COMPETITIVE NON-EQUILIBRIUM ANTAGONISM

• agonist and antagonist compete with one another for same receptor site.

• Antagonist binds with receptor by covalent bond.

• Example: Epinephrine and Phenoxybenzamine on receptors.

NON COMPETITIVE ANTAGONISM

• Agonist and antagonist bind at different sites on the same receptors.

• The antagonist inactivates the receptor so that effective complex with agonist cannot be formed irrespective of the concentration of agonist.

• Example: Acetylcholine and Decamethonium on nicotinic

receptors

TOLERANCE • Reduction in the response due to continued use or repeated

administration of drug is called TOLERANCE

CROSS TOLERANCE: • It is the development of tolerance to pharmacologically related drugs, e.g. alcoholic need relatively large doses of barbiturates, as they are tolerant to this class of drugs.

• Closer the drugs are, more complete is the cross-tolerance between them; e.g. there is partial tolerance between morphine and barbiturates but complete cross tolerance between morphine and pethidine.

MECHANISM OF TOLERANCE:

• Reduction in response may be due to the changes in absorption, distribution, metabolism and excretion leading to the decreased effective concentration of drug at the site of action, e.g. barbiturates on repeated administration enhance their own metabolism due to enzyme induction, this is called DISPOSITIONAL OR PHARMACOKINETIC TOLERANCE.

• Reduction in response may be due to the reduced responsiveness of target tissues due to down regulation of receptors; this called FUNCTIONAL OR PHARMACODYNAMIC TOLERANCE.

TACHYPHYLAXIS • Rapid reduction in responsiveness due to repeated

administration of drug at frequent intervals is called TACHYPHYLAXIS.

• It is also known as ACUTE TOLERANCE.• This is usually seen with indirectly acting drugs, e.g.

ephedrine, tyramine, and amphetamine act by releasing catecholamine in the body, synthesis of which does not match release and stores deplete rapidly.

• Slow dissociation of drug from receptors is another mechanism responsible for the development of Tachyphylaxis.

•Thank you