By Duy Thai: www.geocities.com/d.

thai 1997 Pharmacology Semester 1 page 1 of 3

DRUG METABOLISM II

• What happens when there is a parcetamol overdose?

Paracetamol

Glucuronide Sulphate
Overdose

Phase I reactions

Toxic intermediates

Low overdose High overdose

Glutathine

Mercapturic acid Nucleophilic cell

macromolecules

Cell death

• Note that in a low overdose, the enzyme glutathine may be limiting (there may not be enough glutathine)
and so a low overdose may follow the path of a high overdose and cause cell death.

Factors affecting drug metabolism

• Internal factors
• Species differences
• Studies of how drugs behave in lab animals may not give a good indication of how the
drugs will behave in humans, due to species differences in the enzymes used in drug
metabolism.
• Genetic differences
• Differences in the enzymes of metabolism within species (between individuals)
• The differences mainly lie in a defect in the amount of enzyme or the activity of an
enzyme.
• E.g. Some people have a defect in pseudocholinesterase which breaks down
succinylchloride (a neuromuscular blocker). Therefore, people with this defect who are
given this drug will have prolonged neuromuscular blockade, and potentially respiratory
failure.
• E.g. The enzyme acetyl transferase is used to conjugate (via acetylation) isoniazid (an anti
microbial drug). Some people are said to be “slow acetylators” because they have an
autosomal recessive defect in this enzyme, resulting in mutations (genetic polymorphism).
• Other examples of genetic polymorphism:
• Alcohol undergoes a dehydrogenase reaction. Some people have a defect in the
dehydrogenase enzyme, and so are more sensitive to the effects of alcohol, having
intense facial blushing.
• Tolbutamide is used to decrease blood sugar. It undergoes an oxidation reaction.
A defect in the enzyme may lead to increased concentrations, and can be
cardiotoxic.
• Hydrallazine, a vasodilator, is acetylated in phase II reactions.
• Age
By Duy Thai: www.geocities.com/d.thai 1997 Pharmacology Semester 1 page 2 of 3

• Metabolism of drugs is different in the very young and very old.

• Phase I reactions develop very early in the foetus, however phase II conjugation reactions
develop perinatally. Thus, in a neonate, drugs such as chloramphenicol and morphine can
accumulate to toxic levels (lack glucuronyl transferase).
• The metabolism of some drugs may be enhanced in children. E.g. Theophaline
metabolism may be enhanced in children ages 6 – 12.
• In the elderly, the liver enzymatic ability is reduced (degradation of liver function). In addition,
there may be reduced blood flow to the liver and kidneys (the two important organs of drug
removal) as a result of cardiac impairment. A defective liver may cause hypoalbuminaemia.
• If a drug binds heavily to plasma proteins, its free (and active) concentration will rise.
• A reduced cardiac output will reduce GFR in the kidney.
• Also, in a 70 year old, there is only 50% of functional nephrons left.
• This is important in drugs which rely on kidney’s as their main route of excretion, e.g.
erythromycin or digoxin (both cardiac glycosides – very toxic).
• Diazepam is often given to elderly patients as an anti anxiolytic. The dosage for elderly patients
needs to be reduced as it is not metabolised by the liver as rapidly.
• Gender differences
• There are some differences in alcohol and estrogen metabolism in females as compared to males
• Hormonal effects
• A hypothyroid person has a reduced metabolic activity. This may increase the half life of drugs
such as digoxin. If normal doses of digoxin were given, the concentrations may rise to toxic
levels. Digoxin levels must be monitored closely as it has a small therapeutic window.
Hypothyroid people require lower doses of digoxin to reach therapeutic levels.
• Co-existing disease
• Diseases affecting the liver will generally reduce its metabolic capabilities.
• E.g. cirrhosis, hepatitis, hepatocellular carcinoma.
• Cardiac disease will reduce the amount of blood flow to the liver and kidneys

• External factors
• Drug – drug interactions
• Often, more than one drug is simultaneously administered. Drug – drug interactions may cause:
• Competition for the same enzyme involved in metabolism
• Induction of an enzyme involved in metabolism
• Inhibition of an enzyme involved in metabolism
• E.g. Ethanol may affect the metabolism of diazepam
• In an acutely intoxicated state, ethanol will inhibit the enzymes required for the
metabolism of diazepam. The half life of diazepam will increase.
• In a sober state, but chronically alcoholic, there is induction of phase I and II enzymes
and so the metabolism of diazepam will increase. Thus higher concentrations of the
drug are required.
• In a chronic alcoholic with cirrhosis, there is liver damage and so enzyme activity
would be reduced.
• E.g. Disulfram (antabuse) is used to inhibit the enzyme aldehyde dehydrogenase (ALDH), an
enzyme involved in the breakdown of ethanol.

Ethanol ADH Acid aldehyde ALDH acetic acid

• A buildup of acid aldehyde causes unpleasant reactions, often used to deter heavy
drinking.
• E.g. Digitoxin is used to increase the cardiac contractility. Its toxic levels are close to its
therapeutic levels. If phenobarbital is given in conjunction with digitoxin, it will increase the
metabolism, resulting in a reduction in digitoxin concentrations. More digitoxin is thus required
to obtain a therapeutic level. However, if phenobarbital is removed whilst taking this increased
dosage, the digitoxin concentration will exceed toxic levels.
By Duy Thai: www.geocities.com/d.thai 1997 Pharmacology Semester 1 page 3 of 3

• Remember that the enzymes involved in drug metabolism are normally required for the
metabolism of endogenous substrates (they did not evolve just for drug metabolism). Thus, you
can have competition for an enzyme between a drug and the enzyme’s natural substrate.

• Dietary factors
• Smokers can induce the enzymes required in the breakdown of theophaline
• A protein deficiency may affect enzyme production. Also may affect the production of plasma
proteins.
• Charcoal meat may induce enzymes.
• Environment