FACTORS AFFECTING BIOTRANSFORMATION OF

DRUGS

PRESENTED BY:

HADIA ARSHAD

TYPES OF FACTORS

• Chemical • Biological• Altered Physiological• Temporal• Route of Drug Administration• Enviornmental

Chemical Factors

1. Enzyme Induction

2. Enzyme Inhibition

Enzyme Induction

It is a process in which a drug induces or enhances the expression of an enzyme.

Rifampicin If taken by female patients taking contraceptives, causes decreased therapeutic effect, leading to pregnancy.

Phenobarbitone If administered to patients taking warfarin, may cause therapeutic failure, leading to increased bleeding tendency.

Auto induction: The phenomenon in which adrug induces metabolism of other drugs as well as its own E.g. carbamazepine-antiepileptic.

Enzyme Inhibition

Decrease in the drug metabolizing ability of enzymes. Competition for the active sites takes place between the inhibitor and the drugs. When enzyme inhibitor attaches, less metabolism occurs. E.g. Sulfonamides decrease the metabolism of phenytoin so that its

blood levels become toxic. Cimetidine decreases the metabolism of propanolol leading to

enhanced bradycardia. Oral contraceptives inhibit metabolism of antipyrine.

Biological Factors

Age

Gender

Genetics

Race

Diet

AGE

In infants microsomal enzyme system is not fully developed. The rate of metabolism is very low. Care should be taken in administering drugs in younger patients.

Chloramphenicol does not have great efficacy in infants. Toxic effects in the form of grey baby syndrome might occur. The baby may be cyanosed, hypothermic, flaccid and grey in color. Shock and even death might occur if toxic levels get accumulated.

Diazepam may result in floppy baby syndrome in which flaccidity of the baby is seen.

AGE

In elderly, most processes slow down which leads to decreased metabolism. Shrinkage of organs occurs as well along with decreased liver functions and decreased blood flow through the liver. All these factors decrease the metabolism.

The drug doses should be decreased in the elderly

GENDER

Gender related differences in the rate of metabolism are attributed to sex hormones and are generally observed following puberty.

Male have a higher BMR as compared to the females, thus can metabolize drugs more efficiently, e.g. salicylates and others might include ethanol, propanolol, benzodiazepines.

Women on oral contraceptives metabolize drugs at a slower rate

GENETICS

Drugs behave differently in different individuals due to genetic variations

Succinyl choline, which is a skeletal muscle relaxant, is metabolized by pseudocholine esterase. Some people lack this enzyme, due to which lack of metabolism of succinyl choline might occur. When administered in those individuals, prolonged Apnea might result.

Different groups of populations might be classified as fast metabolizers and poor metabolizers of drugs.

For drugs, like Isoniazid, fast acetylators as well as slow acetylators are present. Fast acetylators cause rapid acetylation, while poor metabolizers metabolize less. Hepatic acetyl transferrase catalyzes acetylation. Slow acetylation might occur due to genetic malformation leading to decreased production.

RACE/SPECIES

Asians, Orientals, Blacks and Whites might have different drug metabolizing capacity. Examples include difference in drug metabolizing capacity of certain anti malarial.

Eskimos metabolize drugs faster than Asians.

Laboratory animals can metabolize drugs faster than man e.g. barbiturates.

DIET

The enzyme content and activity is altered by a number of dietary components.

Low protein diet decreases and high protein content in diet increases the drug metabolizing ability.

Dietary deficiency of vitamins and minerals retard the metabolic activity of enzymes.

ALTERED PHYSIOLOGICAL FACTORS

Pregnancy

Hormonal Imbalance

Disease states

PREGNANCY

During pregnancy, metabolism of some drugs is increased while that of others is decreased due to the presence of steroid hormones e.g.

Phenytoin Phenobarbitone Pethidine

HORMONAL IMBALANCE

Higher levels of one hormone may inhibit the activity of few enzymes while inducing that of others. E.g.

Hypothyroidism increases drug metabolizing capacity (increased half life of antipyrine, digoxin, methimazole, practolol) while hyperthyroidism decreases it.

DISEASE STATES

Liver disease such as hepatic carcinoma, cirrhosis, hepatitis, obstructive jaundice etc reduce the hepatic drug metabolizing ability and thus increase the half lives of almost all drugs.

In renal diseases conjugation of salycylates, oxidation of vitamin D and hydrolysis of Procaine are impaired.

Cardiovascular diseases, although have no direct effect, decrease the blood flow, which may slow down biotransformation of drugs like isoniazid, morphine and propanolol.

Pulmonary conditions may decrease biotransformation. Procaine and procainamide hydrolysis is impaired.

TEMPORAL FACTOR

Diurnal variations and variations in enzyme activity with light cycle is circadian rhythm.

Enzyme action is maximum during early morning and minimum in late afternoon which is probably due to high levels of coticosterone.

ROUTE OF ADMINISTRATION

Oral route can result in extensive hepatic metabolism of some drugs (first pass effect).

Lignocaine is almost completely metabolized if taken by oral route therefore the preferable route is Topical.

ENVIRONMENTAL FACTORS

Aromatic hydrocarbon contained in Cigarette smokers act as enzyme inducers.

Chronic alcoholism might lead to enzyme induction as well.

Pesticides or Organophosphate insecticides may act as enzyme inducers.

In hot and humid climate biotransformation is decreased and vice versa.

At high altitude decreased biotransformation occurs due to decreased oxygen leading to decreased oxidation of drugs.

THANK YOU

STAY HEALTHYEAT A BIG BREAKFASTAVERAGE LUNCH AND

A TINY DINNER

AND DON’T FORGET TO DRINK PLENTY OF WATER