Clinical Pharmacology and Therapeutics

Figure 1.5 Plot of concentration versus time illustrating the accumulation to steady state when a drug is administered by regular oral doses.

Figure 1.6 Semi‐logarithmic plot of concentration versus time after a bolus intravenous injection. The slope of this line is −k; the elimination rate constant and the elimination half‐life of the drug can be determined from such a plot by noting the time at which the concentration has fallen to half its original value.

As previously mentioned, most drugs display first‐order kinetics where the rate of elimination is proportional to the amount of drug in the body. However, drugs such as ethanol, phenytoin and heparin have zero‐order kinetics. Here, a constant amount of drug is eliminated per unit time, independent of plasma drug concentration. This occurs when the enzymes responsible for metabolism become saturated and the rate of elimination does not increase in response to an increase in concentration (or an increase in the amount of drug in the body) but becomes constant.

The clinical relevance of non‐linear kinetics is that a small increase in dose can lead to a large increase in concentration. This is particularly important when toxic side effects are closely related to concentration, as with phenytoin.

Drugs are eliminated from the body by two principal mechanisms: (i) liver metabolism and (ii) renal excretion. Drugs that are already water‐soluble are generally excreted unchanged by the kidney. Lipid‐soluble drugs are not easily excreted by the kidney because, following glomerular filtration, they are largely reabsorbed from the proximal tubule. The first step in the elimination of such lipid‐soluble drugs is metabolism to more polar (water‐soluble) compounds. This is achieved mainly in the liver, but can also occur in the gut and may contribute to first‐pass elimination. Metabolism generally occurs in two phases:

Phase 1 – Mainly oxidation, but also reduction or hydrolysis to a more polar compound:Oxidation can occur in various ways at carbon, nitrogen or sulphur atoms and N‐ and O‐dealkylation. These reactions are catalysed by the cytochrome P450‐dependent system of the endoplasmic reticulum. Knowledge of P450, which exists as a superfamily of similar enzymes (isoforms), has increased greatly recently and is divided into a number of families and subfamilies. Although numerous P450 isoforms are present in human tissue, only a few of these have a major role in the metabolism of drugs. These enzymes, which display distinct but overlapping substrate specificity, include CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4. Induction or inhibition of one or more of these enzymes may form the basis of clinically relevant drug interactions. Phase 1 metabolites usually have only minor structural differences from the parent drug, but may exhibit totally different pharmacological actions. For example, the metabolism of azathioprine produces the powerful antimetabolite 6‐mercaptopurine.

Phase 2 – Conjugation usually by glucoronidation or sulphation to make the compound more polar: This involves the addition of small endogenous molecules to the parent drug, or to its Phase 1 metabolite, and almost always lead to abolition of pharmacological activity. Multiple forms of conjugating enzymes are also known to exist, although these have not been investigated to the same extent as the P450 system.

The wide range of drugs metabolised by the P450 system provides the opportunity for interactions of two types, namely enzyme induction and inhibition.

A 24‐year‐old woman goes to a family planning clinic for advice about contraception. The patient has a history of epilepsy which is stable on carbamazepine 200 mg bd. What options are available to the general practitioner?

Enzyme induction, which may be defined as the increase in amount and activity of drug‐metabolising enzymes, is a consequence of new protein synthesis resulting from prolonged exposure to the inducing drug. While a drug may induce its own metabolism, it can also accelerate the metabolism and clearance of unrelated compounds. Many compounds are known to act as enzyme inducers in animals at toxicological dose levels, but relatively few drugs produce clinically significant induction in humans when used at therapeutic dose levels. For practical purposes, anticonvulsants (carbamazepine, phenytoin) and rifampicin are the most potent enzyme inducers in clinical use and have produced numerous clinically significant drug interactions, related primarily to increases in the metabolism of CYP2C9, CYP2C19 and CYP3A4 substrates (including, for example, oestrogen and progesterone, the constituents of a combined oral contraceptive pill). Enzyme induction is not, however, limited to administration of prescription drugs. St John's wort, a herbal remedy, can also cause enzyme induction as can cigarette smoking (induction of CYP1A2 substrates, e.g. theophylline) and ethanol (induction of CYP2E1 but unlikely to be clinically relevant).

Enzyme induction produces clinical changes over days or weeks, but the effects of enzyme inhibition are usually observed immediately. In most circumstances, these changes are manifest as:

Therapeutic failure resulting from induction

Adverse effects resulting from inhibition

Clinical relevance occurs when drug therapy needs to be altered to avoid the consequences of the drug interaction and this is most common and most serious in compounds that have a narrow therapeutic index.

A 58‐year‐old man with chronic obstructive pulmonary disease is admitted to hospital with an infective exacerbation. He is on three different inhalers and additionally takes simvastatin for hypercholesterolaemia. He is allergic to penicillin. The admitting doctor prescribes nebulised salbutamol, prednisolone and clarithromycin along with the patient's usual medications. The next day the patient complains of general aches and pains. Could this be due to a drug interaction?

Concurrently administered drugs can also lead to inhibition of enzyme activity, with many P450 inhibitors showing considerable isoform selectivity. Some of the most clinically relevant inhibitors are listed in Table 1.1, together with the isoform inhibited. In some cases this can lead to potentially dangerous adverse events, e.g. ketoconazole decreases the metabolism of the CYP3A4 substrate, terfenadine, leading to QT interval prolongation and torsades de pointes.