FACTORS MODIFYING DRUG ACTION

BY SANDIP MAITY

A multitude of host & environmental factors influence drug response. Understanding of these factors can guide choice appropriate drug & dose for individual patient.

VARIATION IN RESPONSE OF DRUGVariation in response to the same dose of a drug between different patients and even in the same patient on different occasions will occur. The range of variability may be marked or limited depending on the pharmacokinetic & Pharmacodynamic characteristics of the drug.

The factors are broadly classified as: Physiological Factors. Pathological Factors (Diseases) Genetic Factors. Environmental Factors. Interaction with other drugs.

o There exists no specific dose. Giving optimum dose is mandatory for desired results. Pharmacopoeia gives the guidelines and ranges.

Physiological Factors: 1. Age: The adult dose is for people between 18 and 60 years of age. The tissues of an infant & child are highly sensitive to large number of drugs. Children under 12 years require fraction of adult dose. DOSE TO BE PRESCRIBED TO ADULTS: By body size, obese or lean, the individual dose = [Body weight(kg)/70 χ Average adult dose]By body size, Body surface area (BSA) provides a more accurate basis for dose calculation.BSA(m2)=[Body weight(kg)0.425 χ height(cm)0.725 χ 0.007184]The individual dose = [BSA (m2) / 1.7 χ Average adult dose]Child dose is calculated by, Young’s formula = [age / age + 12 χ adult dose] Dilling’s formula = [ age/20 χ adult dose ]

2. Sex:• Testosterone increases the rate of biotransformation of drugs.• Decreased metabolism of some drugs in female (Diazepam)

occurs. Females are more susceptible to autonomic drugs. Drugs used for ulcer may cause increased prolactin.

• During menstruation, salicylates and strong purgatives should be avoided as they may increase bleeding.

3. Pregnancy• In pregnancy following are to be considered:• Cardiac output.• GFR and renal elimination of drugs.• Metabolic rate of some drugs.

4. Plasma Protein Binding• Malnutrition causes decreased amino acids, decreased proteins

leading to decreased binding sites for drugs. 5. Lactation• During lactation, drugs may be excreted through milk and may

affect the infant e.g. some purgatives, penicillin, chloramphenicol and oral anticoagulants.

6. Food• Drugs are better absorbed in empty stomach. To prevent gastric

irritation most drugs are taken after or between foods, which affects the outcomes.

7. Allergy• Allergy is the abnormal response of drug resulting from antigen-

antibody reaction, leading to liberation of histamine and histamine-like substances.

8. Drug Dependence (Drug addiction)• Drug dependence is a state of periodic or chronic

intoxication which is detrimental to person and society. It becomes almost impossible to carry out normal physical functions without the drug.

• Components of phenomenon of addiction include:• Euphoria- sense of happiness and forgetfulness• Tolerance- due to increased production of enzymes• Psychic dependence (Habituation)- person desires but

in absence of drug no harm occurs.

Pathological Factors:Diseases cause individual variation in drug response 1. Liver Disease• In liver diseases, prolong duration of action occurs.• Plasma protein binding for warfarin, tolbutamide is decreased leading to

adverse effects. 2. Renal Disease• GFR, tabular function and plasma albumin may be affected leading to abnormal

effects of digoxin, lithium, gentamycin and penicillin 3. Genetic Factors• Genetic abnormalities influence the dose of a drug and response to drugs. It

affects the drug response in individuals at 2 levels.• At the level of receptors• At the level of drugs metabolizing enzyme

4. Idiosyncrasy• Idiosyncrasy is the abnormal drug reaction due to genetic

disorder. It is the unpredictable response seen on first dose of drug on hereditary basis. This may be due to

• Acetylation.• Oxidation.• Glucose 6-phosphate dehydrogenase deficiency.

Environmental Factors: 1. Route of Administration• Some drugs are incompletely absorbed after oral intake, when

given intravenously; their dose has to be reduced.

2. Time of Administration • Hypnotics (producing sleep) act better when administered at night

and smaller doses are required. 3. Effect of Climate• Metabolism is low in hot and humid climate. Purgatives act better in

summer while diuretics act better in winters 4. Preparation of Drug• Drugs in solid forms disintegrate slowly. Onset of action is rapid when

drug is given in liquid form. 5. Age of Drug• Action may be modified if kept for longer durations. Outdated

tetracyclines give rise to excretion of amino acids in urine. Chloroform and carbon tetrachloride become toxic if kept for long durations.

6. Acidic or Basic Medium• If GIT has decreased acidity, acidic drugs like benzyl penicillin are not effective

orally. 7. Effect of Disease• Certain drugs are only effective in disease conditions. These include antipyretics

like aspirin and paracetamol, which do not reduce temperature in case of healthy individuals.

8. Hyper susceptibility to Drugs• Variations in individuals leading to prolonged effects of drugs. Examples include

diazepam, 2 mg of which are used as antianxiety producing no hang overs. In hyper susceptible individuals, the drug has prolonged action causing hangovers and hypnotic actions.

9. Hypersensitivity• Hypersensitivity is the quantitatively abnormal response with certain groups of

drugs.

10. Tolerance• Resistance to normal therapeutic dose of drug, producing lesser response

to normal therapeutic dose is known as tolerance. eg: Alcoholics do not respond to hypnotics and analgesics, dose of which has to be increased many folds.

Interactions of Drugs: 1. Synergism• Synergism is the facilitation/potentiation of pharmacological response by

concomitant use of two drugs. Potentiation• The total effect will be more than the sum of their individual effects. Eg:

Sulfonamide (effective against some microorganisms) when combined with trimethoprim is effective against a wider range of microorganisms.

Additive Effect (Summation)• In this case the total pharmacological action of two drugs will

be equal to the sum of their individual effect on simultaneous administration. The response is not more than their total algebraic sum. Eg: Nitrous oxide + ether as general anesthetic.

2. Antagonism• When two drugs, administered simultaneously, oppose the

action of each other on the same physiological system, the phenomenon is called antagonism. Eg: In iron poisoning deproxamine is given which binds sulphydral groups forming insoluble complexes which can be easily detoxified.

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