Drug interactions

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4 Drug interactions

H.K.R. Thanacoody

• Drug interactions can cause significant patient harm and are an important cause of morbidity.

• Most clinically important drug interactions occur as a result of either decreased drug activity with diminished efficacy or increased drug activity with exaggerated or unusual effects. Drugs with a narrow therapeutic range, such as theophylline, lithium and digoxin, or a steep dose–response curve, such as anticoagulants, oral contraceptives and anti-epileptics, are often implicated.

• The most important pharmacokinetic interactions involve drugs that can induce or inhibit enzymes in the hepatic cytochrome P450 system.

• Pharmacodynamic interactions are difficult to classify but their effects can often be predicted when the pharmacology of co-administered drugs is known.

• In many cases, potentially interacting drugs can be given concurrently provided the possibility of interaction is kept in mind and any necessary changes to dose or therapy are initiated promptly. In some situations, however, concurrent use of potentially interacting drugs should be avoided altogether.

• Suspected adverse drug interactions should be reported to the appropriate regulatory authority as for other adverse drug reactions.

Drug interactions have been recognised for over 100 years. Today, with the increasing availability of complex therapeutic agents and widespread polypharmacy, the potential for drug interactions is enormous and they have become an increasingly important cause of adverse drug reactions (ADR).

Despite regulatory requirements to define the safety profile of new medicines including their potential for drug–drug interactions before marketing, the potential for adverse interactions is not always evident. This was illustrated by the worldwide withdrawal of the calcium channel blocker mibefradil, within months of launch, following reports of serious drug interactions (Li Wan Po and Zhang, 1998). In the past decade, a number of medicines have been either withdrawn from the market, for example, terfenadine, grepafloxacin and cisapride, or had their use restricted because of prolongation of the QT interval on the electrocardiogram, for example, thioridazine. Drug interactions are an important cause of QT prolongation which increases the risk of developing a life-threatening ventricular arrhythmia known as torsade de pointes (Roden, 2004).

The increasing availability and non-prescription use of herbal and complementary medicines has also led to greater awareness of their potential for adverse interactions. St John’s wort, a herbal extract used for treatment of depression, can cause serious interactions as a result of its enzyme-inducing effects. Drug interactions with food and drink are also known to occur, exemplified by the well-known interaction between monoamine oxidase inhibitor antidepressants (MAOIs) and tyramine-containing foodstuffs. Grapefruit juice is a potent inhibitor of cytochrome P450 3A4 and causes clinically relevant interactions with a number of drugs including simvastatin and atorvastatin, thereby increasing the risk of statin-induced adverse reactions such as myopathy and myositis.

Although medical literature is awash with drug interaction studies and case reports of adverse drug interactions, only a relatively small number of these are likely to cause clinically significant consequences for patients. The recognition of clinically significant interactions requires knowledge of the pharmacological mechanisms of drug interactions and a thorough understanding of high-risk drugs and vulnerable patient groups.

Definition

An interaction is said to occur when the effects of one drug are altered by the co-administration of another drug, herbal medicine, food, drink or other environmental chemical agents (Baxter, 2010). The net effect of the combination may manifest as an additive or enhanced effect of one or more drugs, antagonism of the effect of one or more drugs, or any other alteration in the effect of one or more drugs.

Clinically significant interactions refer to a combination of therapeutic agents which have direct consequences on the patient’s condition. Therapeutic benefit can be obtained from certain drug interactions, for example, a combination of different antihypertensive drugs may be used to improve blood pressure control or an opioid antagonist may be use to reverse the effect of an overdose of morphine. In this chapter, we will concentrate on clinically significant interactions which have the potential for undesirable effects on patient care.

Epidemiology

Accurate estimates of the incidence of drug interactions are difficult to obtain as published studies frequently use different criteria for defining a drug interaction, and for distinguishing between clinically significant and non-significant interactions. Some of the early studies uncritically compared prescribed drugs with lists of possible drug interactions without taking into account their potential clinical significance.

The reported incidence of drug–drug interactions in hospital admissions ranged from 0% to 2.8% in a review which included nine studies, all of which had some design flaws (Jankel and Fitterman, 1993). In the Harvard Medical Practice Study of adverse events, 20% of events in acute hospital inpatients were drug related. Of these, 8% were considered to be due to a drug interaction, suggesting that interactions are responsible for less than 2% of adverse events in this patient group (Leape et al., 1992).

In a 1-year prospective study of patients attending an Emergency Department, 3.8% resulted from a drug–drug interaction and most of these led to hospital admissions (Raschett et al., 1999). In a prospective UK study carried out on hospital inpatients, ADR were responsible for hospital admission in 6.5% of cases. Drug interactions were involved in 16.6% of adverse reactions, therefore being directly responsible for leading to hospital admission in approximately 1% of cases (Pirmohamed et al., 2004).

Few studies have attempted to quantify the incidence of drug–drug interactions in the outpatient hospital setting and in the community. In the early 1990s, a community pharmacy study in the USA revealed a 4.1% incidence of interactions, while a Swedish study reported an incidence of 1.9%. In the outpatient setting, the availability of newer drugs for a variety of chronic conditions has increased the risk of drug–drug interactions in this patient group.

Although the overall incidence of serious adverse drug interactions is low, it remains a potentially preventable cause of morbidity and mortality.

Susceptible patients

The risk of drug interactions increases with the number of drugs used. In a hospital study, the rate of ADR in patients taking 6–10 drugs was 7%, rising to 40% in those taking 16–20 drugs, with the exponential rise being largely attributable to drug interactions (Smith et al., 1969). In a high-risk group of emergency department patients, the risk of potential adverse drug interaction was 13% in patients taking 2 drugs and 82% in those taking 7 or more drugs (Goldberg et al., 1996).

Although polypharmacy is common and often unavoidable, it places certain patient groups at increased risk of drug interactions. Patients at particular risk include those with hepatic or renal disease, those on long-term therapy for chronic disease, for example, HIV infection, epilepsy, diabetes, patients in intensive care, transplant recipients, patients undergoing complicated surgical procedures and those with more than one prescriber. Critically ill and elderly patients are at increased risk not only because they take more medicines but also because of impaired homeostatic mechanisms that might otherwise counteract some of the unwanted effects. Interactions may occur in some individuals but not in others. The effects of interactions involving drug metabolism may vary greatly in individual patients because of differences in the rates of drug metabolism and in susceptibility to microsomal enzyme induction. Certain drugs are frequently implicated in drug interactions and require careful attention (Box 4.1).

Mechanisms of drug interactions

Drug interactions are conventionally discussed according to the mechanisms involved. These mechanisms can be conveniently divided into those with a pharmacokinetic basis and those with a pharmacodynamic basis. Drug interactions often involve more than one mechanism. There are some situations where drugs interact by unique mechanisms, but the most common mechanisms are discussed in this section.

Pharmacokinetic interactions

Pharmacokinetic interactions are those that affect the processes by which drugs are absorbed, distributed, metabolised or excreted. Due to marked interindividual variability in these processes, these interactions may be expected but their extent cannot be easily predicted. Such interactions may result in a change in the drug concentration at the site of action with subsequent toxicity or decreased efficacy.

Absorption

Following oral administration, drugs are absorbed through the mucous membranes of the gastro-intestinal tract. A number of factors can affect the rate of absorption or the extent of absorption (i.e. the total amount of drug absorbed).

Changes in gastro-intestinal pH

The absorption of a drug across mucous membranes depends on the extent to which it exists in the non-ionised, lipid-soluble form. The ionisation state depends on the pH of its milieu, the pK_a of the drug and formulation factors. Weakly acidic drugs, such as the salicylates, are better absorbed at low pH because the non-ionised form predominates.

An alteration in gastric pH due to antacids, histamine H₂ antagonists or proton pump inhibitors therefore has the potential to affect the absorption of other drugs. The clinical significance of antacid-induced changes in gastric pH is not certain, particularly since relatively little drug absorption occurs in the stomach. Changes in gastric pH tend to affect the rate of absorption rather than the extent of absorption, provided that the drug is acid labile. Although antacids could theoretically be expected to markedly influence the absorption of other drugs via this mechanism, in practice, there are very few clinically significant examples. Antacids, histamine H₂ antagonists and omeprazole can significantly decrease the bioavailability of ketoconazole and itraconazole, which require gastric acidity for optimal absorption, but the absorption of fluconazole and voriconazole is not significantly altered by changes in gastric pH.

The alkalinising effects of antacids on the gastro-intestinal tract are transient and the potential for interaction may be minimised by leaving an interval of 2–3 h between the antacid and the potentially interacting drug.

Adsorption, chelation and other complexing mechanisms

Certain drugs react directly within the gastro-intestinal tract to form chelates and complexes which are not absorbed. The drugs most commonly implicated in this type of interaction include tetracyclines and the quinolone antibiotics that can complex with iron, and antacids containing calcium, magnesium and aluminium. Tetracyclines can chelate with divalent or trivalent metal cations such as calcium, aluminium, bismuth and iron to form insoluble complexes, resulting in greatly reduced plasma tetracycline concentrations.

Bisphosphonates are often co-prescribed with calcium supplements in the treatment of osteoporosis. If these are taken concomitantly, however, the bioavailability of both is significantly reduced, with the possibility of therapeutic failure.

The absorption of some drugs may be reduced if they are given with adsorbents such as charcoal or kaolin, or anionic exchange resins such as colestyramine or colestipol. The absorption of propranolol, digoxin, warfarin, tricyclic antidepressants, ciclosporin and levothyroxine is reduced by colestyramine.

Most chelation and adsorption interactions can be avoided if an interval of 2–3 h is allowed between doses of the interacting drugs.

Effects on gastro-intestinal motility

Since most drugs are largely absorbed in the upper part of the small intestine, drugs that alter the rate at which the stomach empties its contents can affect absorption. Drugs with anticholinergic effects, such as tricyclic antidepressants, phenothiazines and some antihistamines, decrease gut motility and delay gastric emptying. The outcome of the reduced gut motility can either be an increase or a decrease in drugs given concomitantly. For example, tricyclic antidepressants can increase dicoumarol absorption, probably as a result of increasing the time available for its dissolution and absorption. Anticholinergic agents used in the management of movement disorders have been shown to reduce the bioavailability of levodopa by as much as 50%, possibly as a result of increased metabolism in the intestinal mucosa.

Opioids such as diamorphine and pethidine strongly inhibit gastric emptying and greatly reduce the absorption rate of paracetamol, without affecting the extent of absorption. Codeine, however, has no significant effect on paracetamol absorption. Metoclopramide increases gastric emptying and increases the absorption rate of paracetamol, an effect which is used to therapeutic advantage in the treatment of migraine to ensure rapid analgesic effect. It also accelerates the absorption of propranolol, mefloquine, lithium and ciclosporin. This type of interaction is rarely clinically significant.

Induction or inhibition of drug transport proteins

The oral bioavailability of some drugs is limited by the action of drug transporter proteins, which eject drugs that have diffused across the gut lining back into the gut. At present, the most well-characterised drug transporter is P-glycoprotein. Digoxin is a substrate of P-glycoprotein and drugs that inhibit P-glycoprotein, such as verapamil, may increase digoxin bioavailability with the potential for digoxin toxicity (DuBuske, 2005).

Malabsorption

Drugs such as neomycin may cause a malabsorption syndrome leading to reduced absorption of drugs such as digoxin. Orlistat is a specific long-acting inhibitor of gastric and pancreatic lipases, thereby preventing the hydrolysis of dietary fat to free fatty acids and triglycerides. This can theoretically lead to reduced absorption of fat-soluble drugs co-administered with orlistat. There has been recent concern about potential decreased absorption of levothyroxine and anti-epileptic drugs such as valproate sodium and lamotrigine, although the exact mechanism for the postulated interactions is presently unclear.

Most of the interactions that occur within the gut result in reduced rather than increased absorption. It is important to recognise that the majority result in changes in absorption rate, although in some instances the total amount (i.e. extent) of drug absorbed is affected. For drugs that are given chronically on a multiple dose regimen, the rate of absorption is usually unimportant provided the total amount of drug absorbed is not markedly altered. On the other hand, delayed absorption can be clinically significant where the drug affected has a short half-life or where it is important to achieve high plasma concentrations rapidly, as may be the case with analgesics or hypnotics. Absorption interactions can often be avoided by allowing an interval of 2–3 h between administration of the interacting drugs.

Drug distribution

Following absorption, a drug undergoes distribution to various tissues including to its site of action. Many drugs and their metabolites are highly bound to plasma proteins. Albumin is the main plasma protein to which acidic drugs such as warfarin are bound, while basic drugs such as tricyclic antidepressants, lidocaine, disopyramide and propranolol are generally bound to α₁-acid glycoprotein. During the process of distribution, drug interactions may occur, principally as a result of displacement from protein-binding sites. A drug displacement interaction is defined as a reduction in the extent of plasma protein binding of one drug caused by the presence of another drug, resulting in an increased free or unbound fraction of the displaced drug. Displacement from plasma proteins can be demonstrated in vitro for many drugs and has been thought to be an important mechanism underlying many interactions in the past. However, clinical pharmacokinetic studies suggest that, for most drugs, once displacement from plasma proteins occurs, the concentration of free drug rises temporarily, but falls rapidly back to its previous steady-state concentration due to metabolism and distribution. The time this takes will depend on the half-life of the displaced drug. The short- term rise in the free drug concentration is generally of little clinical significance but may need to be taken into account in therapeutic drug monitoring. For example, if a patient taking phenytoin is given a drug which displaces phenytoin from its binding sites, the total (i.e. free plus bound) plasma phenytoin concentration will fall even though the free (active) concentration remains the same.

There are few examples of clinically important interactions which are entirely due to protein-binding displacement. It has been postulated that a sustained change in steady-state free plasma concentration could arise with the parenteral administration of some drugs which are extensively bound to plasma proteins and non-restrictively cleared, that is, the efficiency of the eliminating organ is high. Lidocaine has been given as an example of a drug fitting these criteria.

Drug metabolism

Most clinically important interactions involve the effect of one drug on the metabolism of another. Metabolism refers to the process by which drugs and other compounds are biochemically modified to facilitate their degradation and subsequent removal from the body. The liver is the principal site of drug metabolism, although other organs such as the gut, kidneys, lung, skin and placenta are involved. Drug metabolism consists of phase I reactions such as oxidation, hydrolysis and reduction, and phase II reactions, which primarily involve conjugation of the drug with substances such as glucuronic acid and sulphuric acid. Phase I metabolism generally involves the cytochrome P450 (CYP450) mixed function oxidase system. The liver is the major site of cytochrome 450-mediated metabolism, but the enterocytes in the small intestinal epithelium are also potentially important.

CYP450 isoenzymes

The CYP450 system comprises 57 isoenzymes, each derived from the expression of an individual gene. As there are many different isoforms of these enzymes, a classification for nomenclature has been developed, comprising a family number, a subfamily letter and a number for an individual enzyme within the subfamily (Wilkinson, 2005). Four main subfamilies of P450 isoenzymes are thought to be responsible for most (about 90%) of the metabolism of commonly used drugs in humans: CYP1, CYP2, CYP3 and CYP4. The most extensively studied isoenzyme is CYP2D6, also known as debrisoquine hydroxylase. Although there is overlap, each cytochrome 450 isoenzyme tends to metabolise a discrete range of substrates. Of the many isoenzymes, a few (CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4) appear to be responsible for the human metabolism of most commonly used drugs.

The genes that encode specific cytochrome 450 isoenzymes can vary between individuals and, sometimes, ethnic groups. These variations (polymorphisms) may affect metabolism of substrate drugs. Interindividual variability in CYP2D6 activity is well recognised (see Chapter 5). It shows a polymodal distribution and people may be described according to their ability to metabolise debrisoquine. Poor metabolisers tend to have reduced first-pass metabolism, increased plasma levels and exaggerated pharmacological response to this drug, resulting in postural hypotension. By contrast, ultra-rapid metabolisers may require considerably higher doses for a standard effect. About 5–10% of white Caucasians and up to 2% of Asians and black people are poor metabolisers.

The CYP3A family of P450 enzymes comprises two isoenzymes, CYP3A4 and CYP3A5, so similar that they cannot be easily distinguished. CYP3A is probably the most important of all drug-metabolising enzymes because it is abundant in both the intestinal epithelium and the liver and it has the ability to metabolise a multitude of chemically unrelated drugs from almost every drug class. It is likely that CYP3A is involved in the metabolism of more than half the therapeutic agents that undergo alteration by oxidation. In contrast to other cytochrome 450 enzymes, CYP3A shows continuous unimodal distribution, suggesting that genetic factors play a minor role in its regulation. Nevertheless, the activity of the enzyme can vary markedly among members of a given population.

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