In the neonatal period, drug-metabolizing enzymes may be deficient for at least a month after birth, particularly in the premature neonate. Neonates have problems in effectively metabolizing vitamin K analogues, sulphonami des, barbiturates, morphine and curare. One of the most dramatic examples is the production of the ‘grey baby’ syndrome by chloramphenicol in premature infants. This consists of circulatory collapse and muscular hypotonia and is thought to be due to a combination of defective hepatic conjugation of chloramphenicol and accumulation of unconjugated drug because of immature renal excretion.
In addition to hepatic immaturity, newborn infants have a relatively lower glomerular fi.ltration rate and renal plasma flow than adults, which results in reduced excretion of drugs such as aminoglycosides and digoxin.

The elderly

Adverse drug reactions occur commonly in the elderly. They receive more drugs on average because of their increased incidence of disease conditions, and are therefore more likely to experience drug interactions. They are also more susceptible to most dose-related adverse drug reactions. Reduced hepatic drug extraction and metabolism occurs with increasing age. This contributes to the increased incidence of adverse effects in older patients following the administration of central depressant drugs such as sedatives, tranquillizers and hypnotics. Agerelated changes in the sensitivity of the central nervous system to the effects of these compounds may also be involved.

Drugs that may have unwanted
Drugs that may have unwanted
Some factors which influence drug response in elderly patients.
Some factors which influence drug response in
elderly patients.

Glomerular filtration rate falls with age, leading to the accumulation of drugs principally excreted unchanged by the kidney. In view of this, doses of digoxin, lithium and aminoglycosides have to be reduced in elderly patients. Increasing age is also associated with changes in body composition, as well as with a general tendency to a decrease in body weight. Both of these may influence the distribution and tissue levels of administered drugs.

Differences in enzyme activity

Differences in enzyme activity between individuals may be either inherited or acquired.


There are marked differences in the rates of drug metabolism between individuals. Some of these are known to be due to polymorphic genetic control of the metabolic pathways involved. Other examples include the exacerbation of acute intermittent porphyria by barbiturates and the occurrence of a rare familial resistance to coumarin anticoagulants.

Acquired enzyme inhibition

Many adverse drug reactions occur due to the administration of drugs which cause inhibition of enzymes.
MONOAMINE OXIDASE. This is a widely distributed enzyme that is responsible for the intercellular degradation of, amongst other monoamines, adrenaline, noradrenaline, dopamine and 5-hydroxytryptamine (serotonin). Its inhibition by monoamine oxidase inhibitors (MAOIs) may, therefore, give rise to serious adverse effects from the following agents if taken concurrently:
INDIRECTLY ACTING SYMPATHOMIMETIC AMINES such as ephedrine and phenylpropanolamine, whose pressor and cardiac actions are due to the release of noradrenaline from adrenergic nerve terminals, are potentiated by monoamine oxidase inhibition.

Adverse drug reactions associated with inherited enzyme deficiencies.
Adverse drug reactions associated with inherited enzyme deficiencies.

FOODS THAT CONTAIN TYRAMINE, such as cheeses, wines, meat and yeast products. Tyramine is an indirectly acting amine with similar actions to phenylpropanolamine.
MONOAMINE-REUPTAKE INHIBITING (TRICYCLIC) ANTIDEPRESSANTS can cause serious central nervous stimulation, convulsions and circulatory collapse if given together with an MAOI.
ANTIHYPERTENSIVE DRUGS such as reserpine, guanethidine and bethanidine release noradrenaline from its neuronal stores and so can produce serious hypertension if given with an MAOI.
PETHIDINE may produce severe narcotic effects with coma and hyperthermia in patients receiving MAOIs, possibly owing to raised levels of cerebral 5-hydroxytryptamine. Reversible inhibition of monooxidase type A (RIMA) drugs are now available causing less adverse effects.
XANTHINE OXIDASE. Inhibition of xanthine oxidase by allopurinol can lead to reduced breakdown of purines such as 6-mercaptopurine and azathioprine, with an increased risk of their dose-dependent adverse effects, for example on the bone marrow.
ALDEHYDE DEHYDROGENASE. This is inhibited by disulfiram, resulting in an accumulation of acetaldehyde after ingestion of alcohol, with the resulting ‘antabuse’ reaction of flushing, hypotension, headache, sweating, nausea, vomiting and even cardiovascular collapse. This forms the basis of one approach to the management of alcohol dependence. A similar reaction may occur with the antimicrobial drug metronidazole. Competition by drugs for hepatic drug-metabolizing pathways is not uncommon and is recognized as a basis for adverse drug interactions. For example, cimetidine increases the anticoagulant effect of warfarin, the sedative effect of diazepam and the f3-adrenoreceptor blocking action of propranolol by inhibiting their hepatic metabolism. Sulphonamides decrease phenytoin metabolism so that toxic levels may be reached.

Mechanism by which monoamine
Mechanism by which

Acquired enzyme induction

The activity of hepatic drug-metabolizing enzymes may be increased by a large number of common substances, including insecticides, pesticides, polycyclic aromatic hydrocarbons, and some drugs such as barbiturates, phenytoin, carbamazepine and rifampicin. Such enzyme induction results in increased drug metabolism and breakdown, reducing the therapeutic activity of certain drugs. Examples include oral anticoagulants, corticosteroids and the contraceptive pill. The importance of enzyme induction lies in the exaggerated effects that can occur if the inducing drug is discontinued and the drug whose metabolism was being induced, e.g. warfarin, continues to be given in an increased dosage.

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