Drug interactions

In this month's article Oliver Jones describes the principles of drug interactions and how to identify and manage them

Drug interactions are common. It is important to be aware which drugs are likely to interact. Many easily accessible references exist, such as appendix 1 of the British National Formulary, but it is not practicable to consult these every time you write a prescription. Knowledge of a severe drug interaction should deter you from using the combination of treatments. However, in other circumstances, only closer clinical management or adjustment of dose is indicated. Furthermore, drug interactions may even be used therapeutically, as in the treatment of poisoning. This article describes the principles of drug interactions, their identification, and their management.

Types of drug interactions

There may be two outcomes of drug interaction. Antagonism occurs when the action of one drug opposes that of another, while synergism occurs when the effects of coadministration of drugs is additive. When the sum of two drugs is more than a simple additive effect, this is known as "potentiation." Not all drug interactions are harmful. For example, the ISIS-2 study showed that aspirin and streptokinase each improve outcome in myocardial infarction, and that the combination of both these drugs has an additive therapeutic effect.¹

Drug interactions may be divided into three main types

Pharmaceutical interactions
This is probably the least important of the types of interactions. It is the interaction of drugs on a chemical, not a pharmacological, level. An example is the formation of a complex between thiopentone and suxamethonium, which cannot therefore be mixed in the same syringe. These types of interactions are best avoided by giving drugs as bolus injections where appropriate, avoiding the mixing of drugs before administration except when this is known to be safe and making up infusions immediately before use.

Pharmacodynamic interactions
This is the reduction or enhancement of the effect of one drug by another without altering its concentration at its site of action. These are usually predictable from the knowledge of the pharmacological mechanism of action of the drugs, and usually occur through competition at receptor sites or through an action on similar physiological systems. An example of this type of interaction is that between loop diuretics and digoxin. Loop diuretics lower plasma potassium and this reduces competition between the glycoside and potassium for the sodium potassium pump in the heart muscle. The consequent increased glycoside binding enhances the risk of arrhythmias.

Pharmacokinetic interactions
This is the alteration of drug concentration reaching its target site by a second drug. The four determinants of drug pharmacokinetics may each be affected by this coadministration: absorption, distribution, metabolism, and excretion. These types of interaction are not easily predicted and the severity of interaction, unlike the pharmacodynamic variety, often differs markedly between patients.

• Absorption may be affected from the gut either because two drugs form an insoluble complex (seen sometimes with antacids and prednisolone) or because one drug alters gut motility, as seen with drugs such as loperamide or metoclopramide, and affects the time available for drug absorption to occur. In the skin, reduced absorption (and hence redistribution or metabolism) of lignocaine after subcutaneous injection is usefully achieved by combining this with the vasoconstrictor adrenaline. This prolongs the anaesthetic action of lignocaine.
• Distribution is commonly a factor in those drugs that are extensively protein bound in the plasma, where they may be displaced from their binding sites by a second drug. This is rarely important pharmacologically, because although the free drug accounts for its pharmacological action, it is this same fraction which is available for redistribution and metabolism, which usually restores free levels. Thus most serious interactions are seen when displacement from plasma proteins occurs in addition to other effects such as inhibition of drug metabolism. An example of this is sodium valproate, which not only displaces phenytoin from plasma proteins but also reduces the rate at which it is metabolised.
• Metabolism of a drug is most commonly altered by enzyme inducers such as phenytoin combined with another drug--for example, the contraceptive pill. The pill is metabolised more frequently, and the resultant reduced plasma levels may result in pregnancy. Enzyme inhibitors also exist. The most common drugs in this category are those with an action which includes inhibition of isoenzymes of cytochrome p450--for example, cimetidine and erythromycin.
• Elimination becomes a factor in those drugs sharing common transporter mechanisms in the kidney. An example of this is the lithium accumulation seen in patients treated with concomitant diuretics.

Identifying possible drug interactions
Drug interactions may manifest as a lack of effect of a newly introduced drug treatment, or more seriously as a clinical deterioration. It should always be considered in people who are severely ill, in whom interactions may be difficult to identify, and in the elderly. Both these groups are likely to be taking several medications simultaneously. Patients with renal or hepatic impairment are also more likely to suffer the effects of interactions, as metabolism and excretion will be impaired. Others at risk include those taking drugs long term where the precise plasma level is important--for example, people with epilepsy.

With so many drugs available to prescribers, it is not possible to learn all the different combinations and interactions. An understanding of the above principles should allow a reasoned approach to the problem. In general terms, certain drugs are more likely to be involved in interactions. These include drugs with a small therapeutic index (a small change in drug concentration resulting in a substantial change in therapeutic effect). Drugs that are known to be enzyme inducers or inhibitors or those with a saturable metabolism should also be used with caution.

Finally, there are several drugs that, although used for treating the same disease, are capable of causing serious drug interactions when used together. These include digoxin with thiazide or loop diuretics, theophylline with ß adrenoceptor agonists (both combinations may cause cardiac arrythmias), phenytoin with sodium valproate (phenytoin toxicity), and verapamil with ß adrenoceptor antagonists (bradycardia).

1. ISIS-2 International Study of Infarct Survival Collaborative Group. Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. Lancet 1988;2:349-60.