little, if at all, and the termination of their actions depends mainly on renal excretion.
Liver
The main organ of drug metabolism is the liver, but other organs, such as the gastrointestinal tract and lungs, have considerable activity. Drugs given orally are usually absorbed in the small intestine and enter the portal system to travel to the liver, where they may be extensively metabolized (e.g. lidocaine, morphine, propranolol). This is called first‐pass metabolism, a term that does not refer only to hepatic metabolism. For example, chlorpromazine is metabolized more in the intestine than by the liver.
Phase I reactions
The most common reaction is oxidation. Other, relatively uncommon, reactions are reduction and hydrolysis.
The P450 monooxygenase system
Cytochrome P450 enzymes form a superfamily of related enzymes that differ in amino acid sequence. Each is referred to as CYP followed by defining numbers and a letter. There are over 70 CYP gene families but only three are involved in hepatic drug metabolism (CYP1, CYP2 and CYP3). Oxidation by the P450 monooxygenase system is complex but the result is simple, the addition of an –OH group to the drug. Numerous (CYP) isoforms of P450 exist with different, but often overlapping, substrate specificities. About half a dozen P450 isoforms account for most hepatic drug metabolism. CYP3A4 is worth remembering because it metabolizes more than 50% of drugs.
Phase II reactions
These usually occur in the liver and involve conjugation of a drug or its phase I metabolite with an endogenous substance. The resulting conjugates are almost always less active and are polar molecules that are readily excreted by the kidneys.
Factors affecting drug metabolism
Enzyme induction
The activity of some drugs, for example, oestrogen and progesterone may be significantly reduced by a second drug that increases the activity of drug‐metabolizing enzymes (primarily CYP2C9, CYP2C19 and CYP3A4). Phenytoin, carbamazepine and rifampicin are the most potent enzyme inducers. The mechanism involved is unclear but is similar to hormones that bind to response elements in DNA and promote transcription of the appropriate gene. However, not all enzymes subject to induction are microsomal. For example, hepatic alcohol dehydrogenase occurs in the cytoplasm.
Enzyme inhibition
Enzyme inhibition may cause adverse drug interactions. These interactions tend to occur more rapidly than those involving enzyme induction because they occur as soon as the inhibiting drug reaches a high‐enough concentration to compete with the affected drug. Drugs may inhibit different forms of cytochrome P450 and so affect the metabolism only of drugs metabolized by that particular isoenzyme. Cimetidine inhibits the metabolism of several potentially toxic drugs including phenytoin, warfarin and theophylline. Erythromycin also inhibits the cytochrome P450 system and increases the activity of theophylline, warfarin, carbamazepine and digoxin. Substances in the diet can also affect the metabolism of drugs. For example, a component of grapefruit juice inhibits CYP3A4 and may increase the effects of several drugs, such as midazolam, simvastatin.
Genetic polymorphisms
The study of how genetic determinants affect drug action is called pharmacogenetics. The response to drugs may vary significantly between individuals. For example, about 8% of the population has faulty expression of CYP2D6, the P450 isoform responsible for debrisoquine hydroxylation. These poor hydroxylators show exaggerated and prolonged responses to drugs such as propranolol and metoprolol (Chapter 15), which undergo extensive hepatic metabolism.
Drug‐acetylating enzymes
Hepatic N‐acetylase displays genetic polymorphism. About 50% of the population acetylate isoniazid (an antitubercular drug) rapidly, whereas the other 50% acetylate it slowly. Slow acetylation is caused by an autosomal recessive gene that is associated with decreased hepatic N‐acetylase activity. Slow acetylators are more likely to accumulate the drug and to experience adverse reactions.
Plasma pseudocholinesterase
Rarely, a deficiency (<1:2500) of this enzyme occurs and this extends the duration of action of suxamethonium (a frequently used neuromuscular blocking drug) from about 6 min to over 2 h or more.
Age
In the elderly, hepatic metabolism of drugs may be reduced, but declining renal function is usually more important. By 65 years, the glomerular filtration rate (GFR) decreases by 30%, and every following year it falls a further 1–2% (as a result of cell loss and decreased renal blood flow). Thus, older people need smaller doses of many drugs than do younger persons, especially centrally acting drugs (e.g. opioids, benzodiazepines, antidepressants), to which the elderly seem to become more sensitive (by unknown changes in the brain). Hepatic microsomal enzymes and renal mechanisms are reduced at birth, especially in preterm babies. Both systems develop rapidly during the first 4 weeks of life. There are various methods for calculating paediatric doses (see British National Formulary).
Metabolism and drug toxicity
Occasionally, reactive products of drug metabolism are toxic to various organs, especially the liver. Paracetamol, a widely used weak analgesic, normally undergoes glucuronidation and sulphation. However, these processes become saturated at high doses and the drug is then conjugated with glutathione. If the glutathione supply becomes depleted, then a reactive and potentially lethal hepatotoxic metabolite accumulates (Chapter 46).
5 Local anaesthetics
Local anaesthetics (top left) are drugs used to prevent pain by causing a reversible block of conduction along nerve fibres. Most are weak bases that exist mainly in a protonated form at body pH (bottom left). The drugs penetrate the nerve in a non‐ionized (lipophilic) form (
All nerve fibres are sensitive to local anaesthetics but, in general, small‐diameter fibres are more sensitive than large fibres. Thus, a differential block can be achieved where the smaller pain and autonomic fibres are blocked, whereas coarse touch and movement fibres are spared. Local anaesthetics vary widely in their potency, duration of action, toxicity and ability to penetrate mucous membranes.
Local anaesthetics depress other excitable tissues (e.g. myocardium) if the concentration in the blood is sufficiently high, but their main unwanted systemic effects involve the central nervous system. Lidocaine is the most widely used agent.