Drug interactions

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4 Drug interactions

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 In the past decade, a number of medicines have been either withdrawn from the market, for example, terfenadine, grepafloxacin and cisapride, or had their use restricted because of prolongation of the QT interval on the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.

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 pKa 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.

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.

The effect of a cytochrome 450 isoenzyme on a particular substrate can be altered by interaction with other drugs. Drugs may be themselves substrates for a cytochrome 450 isoenzyme and/or may inhibit or induce the isoenzyme. In most instances, oxidation of a particular drug is brought about by several CYP isoenzymes and results in the production of several metabolites. So, inhibition or induction of a single isoenzyme would have little effect on plasma levels of the drug. However, if a drug is metabolised primarily by a single cytochrome 450 isoenzyme, inhibition or induction of this enzyme would have a major effect on the plasma concentrations of the drug. For example, if erythromycin (an inhibitor of CYP3A4) is taken by a patient being given carbamazepine (which is extensively metabolised by CYP3A4), this may lead to toxicity due to higher concentrations of carbamazepine. Table 4.1 gives examples of some drug substrates, inducers and inhibitors of the major cytochrome 450 isoenzymes.

Enzyme induction

The most powerful enzyme inducers in clinical use are the antibiotic rifampicin and antiepileptic agents such as barbiturates, phenytoin and carbamazepine. Some enzyme inducers, notably barbiturates and carbamazepine, can induce their own metabolism (autoinduction). Cigarette smoking, chronic alcohol use and the herbal preparation St John’s wort can also induce drug-metabolising enzymes. Since the process of enzyme induction requires new protein synthesis, the effect usually develops over several days or weeks after starting an enzyme-inducing agent. Similarly, the effect generally persists for a similar period following drug withdrawal. Enzyme-inducing drugs with short half-lives such as rifampicin will induce metabolism more rapidly than inducers with longer half-lives, for example, phenytoin, because they reach steady-state concentrations more rapidly. There is evidence that the enzyme induction process is dose dependent, although some drugs may induce enzymes at any dose.

Enzyme induction usually results in a decreased pharmacological effect of the affected drug. St John’s wort is now known to be a potent inducer of CYP3A (Mannel, 2004). Thus, when a patient receiving ciclosporin, tacrolimus, HIV-protease inhibitors, irinotecan or imatinib takes St John’s wort, there is a risk of therapeutic failure with the affected drug. However, if the affected drug has active metabolites, this may lead to an increased pharmacological effect. The effects of enzyme induction vary considerably between patients and are dependent upon age, genetic factors, concurrent drug treatment and disease state. Some examples of interactions due to enzyme induction are shown in Table 4.2.

Table 4.2 Examples of interactions due to enzyme induction

Drug affected Inducing agent Clinical outcome
Oral contraceptives Rifampicin Therapeutic failure of contraceptives
Rifabutin Additional contraceptive precautions required
Modafinil Increased oestrogen dose required
Ciclosporin Phenytoin Decreased ciclosporin levels with possibility of transplant rejection
Carbamazepine
St John’s wort
Paracetamol Alcohol (chronic) In overdose, hepatotoxicity may occur at lower doses
Corticosteroids Phenytoin Increased metabolism with possibility of therapeutic failure
Rifampicin

Enzyme inhibition

Enzyme inhibition is responsible for many clinically significant interactions. Many drugs act as inhibitors of cytochrome 450 enzymes (see Box 4.2). A strong inhibitor is one that can cause ≥5-fold increase in the plasma area-under-the-curve (AUC) value or more than 80% decrease in clearance of CYP3A substrates. A moderate inhibitor is one that can cause ≥2- but <5-fold increase in the AUC value or 50–80% decrease in clearance of sensitive CYP3A substrates when the inhibitor is given at the highest approved dose and the shortest dosing interval. A weak inhibitor is one that can cause ≥1.25- but <2-fold increase in the AUC values or 20–50% decrease in clearance of sensitive CYP3A substrates when the inhibitor is given at the highest approved dose and the shortest dosing interval.

Concurrent administration of an enzyme inhibitor leads to reduced metabolism of the drug and hence an increase in the steady-state drug concentration. Enzyme inhibition appears to be dose related. Inhibition of hepatic metabolism of the affected drug occurs when sufficient concentrations of the inhibitor are achieved in the liver, and the effects are usually maximal when the new steady-state plasma concentration is achieved. Thus, for drugs with a short half-life, the effects may be seen within a few days of administration of the inhibitor. Maximal effects may be delayed for drugs with a long half-life.

The clinical significance of this type of interaction depends on various factors, including dosage (of both drugs), alterations in pharmacokinetic properties of the affected drug such as half-life and patient characteristics such as disease state. Interactions of this type are again most likely to affect drugs with a narrow therapeutic range such as theophylline, ciclosporin, oral anticoagulants and phenytoin. For example, starting treatment with an enzyme inhibitor such as ritonavir in a patient taking sildenafil could result in a marked increase in sildenafil plasma concentrations. Some examples of interactions due to enzyme inhibition are shown in Table 4.3.

Table 4.3 Examples of interactions due to enzyme inhibition

Drug affected Inhibiting agent Clinical outcome
Anticoagulants (oral) Ciprofloxacin Anticoagulant effect increased and risk of bleeding
Clarithromycin
Azathioprine Allopurinol Enhancement of effect with increased toxicity
Clopidogrel Lansoprazole Reduced anti-platelet effect
Carbamazepine Cimetidine Antiepileptic levels increased with risk of toxicity
Phenytoin
Sodium valproate
Sildenafil Ritonavir Enhancement of sildenafil effect with risk of hypotension

The isoenzyme CYP3A4, in particular, is present in the enterocytes. Thus, after oral administration of a drug, cytochrome 450 enzymes in the intestine and the liver may reduce the portion of a dose that reaches the systemic circulation, that is, the bioavailability of the drug. Drug interactions resulting in inhibition or induction of enzymes in the intestinal epithelium can have significant consequences. For example, by selectively inhibiting CYP3A4 in the enterocyte, grapefruit juice can markedly increase the bioavailability of some oral calcium channel blockers, including felodipine (Wilkinson, 2005). Such an interaction is usually considered to be a drug metabolism interaction, even though the mechanism involves an alteration in drug absorption. A single glass of grapefruit juice can cause CYP3A inhibition for 24–48 h and regular consumption may continuously inhibit enzyme activity. Consumption of grapefruit juice is therefore not recommended in patients receiving drugs that are extensively metabolised by CYP3A such as simvastatin, tacrolimus and vardenafil.

Enzyme inhibition usually results in an increased pharmacological effect of the affected drug, but in cases where the affected drug is a pro-drug which requires enzymatic metabolism to active metabolites, a reduced pharmacological effect may result. For example, clopidogrel is metabolised via CYP2C19 to an active metabolite which is responsible for its anti-platelet effect. Proton pump inhibitors such as lansoprazole are inhibitors of CYP2C19 and may lead to reduced effectiveness of clopidogrel when used in combination

Predicting interactions involving metabolism

Predicting drug interactions is not easy for many reasons. First, individual drugs within a therapeutic class may have different effects on an isoenzyme. For example, the quinolone antibiotics ciprofloxacin and norfloxacin inhibit CYP1A2 and have been reported to increase plasma theophylline levels, whereas moxifloxacin is a much weaker inhibitor and appears not to interact in this way. While atorvastatin and simvastatin are metabolised predominantly by the CYP3A4 enzyme, fluvastatin is metabolised by CYP2C9 and pravastatin is not metabolised by the CYP450 system to any significant extent.

Identification of cytochrome P450 isoenzymes involved in drug metabolism using in vitro techniques are now an important step in the drug development process. However, findings of in vitro studies are not always replicated in vivo and more detailed drug interaction studies may be required to allow early identification of potential interactions. Nevertheless, some interactions affect only a small proportion of individuals and may not be identified unless large numbers of volunteers or patients are studied.

Suspected drug interactions are often described initially in published case reports and are then subsequently evaluated in formal studies. For example, published case reports indicate that some antibiotics reduce the effect of oral contraceptives, although this interaction has not been demonstrated in formal studies. Another factor complicating the understanding of metabolic drug interactions is the finding that there is a large overlap between the inhibitors/inducers and substrates of the drug transporter protein P-glycoprotein and those of CYP3A4. Therefore, both mechanisms may be involved in many of the drug interactions previously thought to be due to effects on CYP3A4.

Elimination interactions

Most drugs are excreted in either the bile or urine. Blood entering the kidneys is delivered to the glomeruli of the tubules where molecules small enough to pass across the pores of the glomerular membrane are filtered through into the lumen of the tubules. Larger molecules, such as plasma proteins and blood cells, are retained. The blood then flows to other parts of the kidney tubules where drugs and their metabolites are removed, secreted or reabsorbed into the tubular filtrate by active and passive transport systems. Interactions can occur when drugs interfere with kidney tubule fluid pH, active transport systems or blood flow to the kidney, thereby altering the excretion of other drugs.

Changes in active renal tubule excretion

Drugs that use the same active transport system in the kidney tubules can compete with one another for excretion. Such competition between drugs can be used to therapeutic advantage. For example, probenecid may be given to increase the plasma concentration of penicillins by delaying renal excretion. With the increasing understanding of drug transporter proteins in the kidneys, it is now known that probenecid inhibits the renal secretion of many other anionic drugs via organic anion transporters (OATs; Lee and Kim, 2004). Increased methotrexate toxicity, sometimes life-threatening, has been seen in some patients concurrently treated with salicylates and some other non-steroidal anti-inflammatory drugs (NSAIDs). The development of toxicity is more likely in patients treated with high-dose methotrexate and those with impaired renal function. The mechanism of this interaction may be multifactorial but competitive inhibition of methotrexate’s renal tubular secretion is likely to be involved. If patients taking methotrexate are given salicylates or NSAIDs concomitantly, the dose of methotrexate should be closely monitored.

Drug transporter proteins

Drugs and endogenous substances are now known to cross biological membranes not just by passive diffusion but by carrier-mediated processes, often known as transporters. Significant advances in the identification of various transporters have been made and although their contribution to drug interactions is not yet clear, they are now thought to play a role in many interactions formerly attributed to cytochrome 450 enzymes (DuBuske, 2005).

P-glycoprotein (P-gp) is a large cell membrane protein that is responsible for the transport of many substrates, including drugs. It is a product of the ABCB1 gene (previously known as the multidrug resistance gene, MDR1) and a member of the adenosine triphosphate (ATP)-binding cassette family of transport proteins (ABC transporters). P-glycoprotein is found in high levels in various tissues including the renal proximal tubule, hepatocytes, intestinal mucosa, the pancreas and the blood–brain barrier. P-glycoprotein acts as an efflux pump, exporting substances into urine, bile and the intestinal lumen. Its activity in the blood–brain barrier limits drug accumulation in the central nervous system (CNS). Examples of some possible inhibitors and inducers of P-glycoprotein are shown in Table 4.4. The pumping actions of P-glycoprotein can be induced or inhibited by some drugs. For example, concomitant administration of digoxin and verapamil, a P-glycoprotein inhibitor, is associated with increased digoxin levels with the potential for digoxin toxicity. There is an overlap between CYP3A4 and P-glycoprotein inhibitors, inducers and substrates. Many drugs that are substrates for CYP3A4 are also substrates for P-glycoprotein. Therefore, both mechanisms may be involved in many of the drug interactions initially thought to be due to changes in CYP3A4. Digoxin is an example of the few drugs that are substrates for P-glycoprotein but not CYP3A4.

Table 4.4 Examples of inhibitors and inducers of P-glycoprotein

Inhibitors Atorvastatin
Ciclosporin
Clarithromycin
Dipyridamole
Erythromycin
Itraconazole
Ketoconazole
Propafenone
Quinidine
Ritonavir
Valspodar
Verapamil
Inducers Rifampicin
St John’s wort

Pharmacodynamic interactions

Pharmacodynamic interactions are those where the effects of one drug are changed by the presence of another drug at its site of action. Sometimes these interactions involve competition for specific receptor sites but often they are indirect and involve interference with physiological systems. They are much less easy to classify than interactions with a pharmacokinetic basis.

Additive or synergistic interactions

If two drugs with similar pharmacological effects are given together, the effects can be additive (see Table 4.5). Although not strictly drug interactions, the mechanism frequently contributes to ADR. For example, the concurrent use of drugs with CNS-depressant effects such as antidepressants, hypnotics, antiepileptics and antihistamines may lead to excessive drowsiness, yet such combinations are frequently encountered. Combinations of drugs with arrhythmogenic potential such as antiarrhythmics, neuroleptics, tricyclic antidepressants and those producing electrolyte imbalance (e.g. diuretics) may lead to ventricular arrhythmias and should be avoided. Another example which has assumed greater importance of late is the risk of ventricular tachycardia and torsade de pointes associated with the concurrent use of more than one drug with the potential to prolong the QT interval on the electrocardiogram (Roden, 2004).

Table 4.5 Examples of additive or synergistic interactions

Interacting drugs Pharmacological effect
NSAID, warfarin, clopidogrel Increased risk of bleeding
ACE inhibitors and K-sparing diuretic Increased risk of hyperkalaemia
Verapamil and β-adrenergic antagonists Bradycardia and asystole
Neuromuscular blockers and aminoglycosides Increased neuromuscular blockade
Alcohol and benzodiazepines Increased sedation
Pimozide and sotalol Increased risk of QT interval prolongation
Clozapine and co-trimoxazole Increased risk of bone marrow suppression

Serotonin syndrome

Serotonin syndrome (SS) is associated with an excess of serotonin that results from therapeutic drug use, overdose or inadvertent interactions between drugs. Although severe cases are uncommon, it is becoming increasingly well recognised in patients receiving combinations of serotonergic drugs (Boyer and Shannon, 2005). It can occur when two or more drugs affecting serotonin are given at the same time or after one serotonergic drug is stopped and another started. The syndrome is characterised by symptoms including confusion, disorientation, abnormal movements, exaggerated reflexes, fever, sweating, diarrhoea and hypotension or hypertension. Diagnosis is made when three or more of these symptoms are present and no other cause can be found. Symptoms usually develop within hours of starting the second drug but occasionally they can occur later. Drug-induced SS is generally mild and resolves when the offending drugs are stopped. Severe cases occur infrequently and fatalities have been reported.

SS is best prevented by avoiding the use of combinations of several serotonergic drugs. Special care is needed when changing from a selective serotonin reuptake inhibitor (SSRI) to an MAOI and vice versa. The SSRIs, particularly fluoxetine, have long half-lives and SS may occur if a sufficient wash-out period is not allowed before switching from one to the other. When patients are being switched between these two groups of drugs, the guidance in manufacturers’ Summaries of Product Characteristics should be followed. Many drugs have serotonergic activity as their secondary pharmacology and their potential for causing the SS may not be readily recognised, for example linezolid, an antibacterial with monoamine oxidase inhibitory activity has been implicated in several case reports of SS.

Many recreational drugs such as amfetamines and their derivatives have serotonin agonist activity and the SS may ensue following the use of other serotonergic drugs.

Drug or neurotransmitter uptake interactions

Although seldom prescribed nowadays, the MAOIs have significant potential for interactions with other drugs and foods. MAOIs reduce the breakdown of noradrenaline in the adrenergic nerve ending. Large stores of noradrenaline can then be released into the synaptic cleft in response to either a neuronal discharge or an indirectly acting amine. The action of the directly acting amines adrenaline, isoprenaline and noradrenaline appears to be only moderately increased in patients taking MAOIs. In contrast, the concurrent use of MAOIs and indirectly acting sympathomimetic amines such as amphetamines, tyramine, MDMA (ecstasy), phenylpropanolamine and pseudoephedrine can result in a potentially fatal hypertensive crisis. Some of these compounds are contained in proprietary cough and cold remedies. Tyramine, contained in some foods, for example cheese and red wine, is normally metabolised in the gut wall by monoamine oxidase to inactive metabolites. In patients taking MAOI, however, tyramine will be absorbed intact. If patients taking MAOIs also take these amines, there may be a massive release of noradrenaline from adrenergic nerve endings, causing a sympathetic overactivity syndrome, characterised by hypertension, headache, excitement, hyperpyrexia and cardiac arrhythmias. Fatal intracranial haemorrhage and cardiac arrest may result. The risk of interactions continues for several weeks after the MAOI is stopped as new monoamine oxidase enzyme must be synthesised. Patients taking irreversible MAOIs should not take any indirectly acting sympathomimetic amines. All patients must be strongly warned about the risks of cough and cold remedies, illicit drug use and the necessary dietary restrictions.

Drug–food interactions

It is well established that food can cause clinically important changes in drug absorption through effects on gastro-intestinal absorption or motility, hence the advice that certain drugs should not be taken with food, for example, iron tablets and antibiotics. Two other common examples already outlined include the interaction between tyramine in some foods and MAOIs, and the interaction between grapefruit juice and the calcium channel blocker felodipine. With improved understanding of drug metabolism mechanisms, there is greater recognition of the effects of some foods on drug metabolism. The interaction between grapefruit juice and felodipine was discovered serendipitously when grapefruit juice was chosen to mask the taste of ethanol in a study of the effect of ethanol on felodipine. Grapefruit juice mainly inhibits intestinal CYP3A4, with only minimal effects on hepatic CYP3A4. This is demonstrated by the fact that intravenous preparations of drugs metabolised by CYP3A4 are not much affected whereas oral preparations of the same drugs are. Some drugs that are not metabolised by CYP3A4 show decreased levels with grapefruit juice, such as fexofenadine. The probable reason for this is that grapefruit juice inhibits some drug transporter proteins and possibly affects organic anion-transporting polypeptides, although inhibition of P-glycoprotein has also been suggested. The active constituent of grapefruit juice is uncertain. Grapefruit contains naringin, which degrades during processing to naringenin, a substance known to inhibit CYP3A4. Although this led to the assumption that whole grapefruit will not interact, but that processed grapefruit juice will, some reports have implicated the whole fruit. Other possible active constituents in the whole fruit include bergamottin and dihydroxybergamottin.

Initial reports of an interaction between cranberry juice and warfarin, prompting regulatory advice that the international normalised ratio (INR) should be closely monitored in patients taking this combination, have not been confirmed by subsequent controlled studies.

Cruciferous vegetables, such as brussels sprouts, cabbage and broccoli, contain substances that are inducers of the CYP450 isoenzyme CYP1A2. Chemicals formed by burning (e.g. barbecuing) meats additionally have these properties. These foods do not appear to cause any clinically important drug interactions in their own right, but their consumption may add another variable to drug interaction studies, so complicating interpretation.

Drug–herb interactions

There has been a marked increase in the availability and use of herbal products in the UK over the past decade, which include Chinese herbal medicines and Ayurvedic medicines. Up to 24% of hospital patients report using herbal remedies (Constable et al., 2007). Such products often contain pharmacologically active ingredients which can give rise to clinically significant interactions when used inadvertently with other conventional drugs.

Extracts of Glycyrrhizin glabra (liquorice) used for treating digestive disorders may cause significant interactions in patients using digoxin or diuretics. It may exacerbate hypokalaemia induced by diuretic drugs and precipitate digoxin toxicity. Herbal products such as Chinese ginseng (Panax ginseng), Chan Su (containing bufalin) and Danshen may also contain digoxin-like compounds which can interfere with digoxin assays, leading to falsely elevated levels being detected.

A number of herbal products have anti-platelet and anticoagulant properties and may increase the risk of bleeding when used with aspirin or warfarin. Herbal extracts containing coumarin-like constituents include Alfalfa (Medicago sativa), Angelica (Angelica archangelica), Dong Quai (Angelica polymorpha, A. dahurica, A. atropurpurea), chamomile, horse chestnut and red clover (Trifolium pratense) which can potentially lead to interactions with warfarin. Herbal products with anti-platelet properties include Borage (Borago officinalis), Bromelain (Ananas comosus), capsicum, feverfew, garlic, Ginkgo (Ginkgo biloba) and turmeric amongst others.

Other examples of drug–herb interactions include enhancement of hypoglycaemic (for example Asian ginseng) and hypotensive (for example hawthorn) effects, and lowering of seizure threshold (for example evening primrose oil and Shankapushpi). The most widely discussed drug–herb interactions are those involving St John’s wort (Hypericum extract) used for depression but these only represent a minority of the potential interactions. It is therefore imperative that patients are specifically asked about their use of herbal medicines as they may not volunteer this information.

Conclusion

Whilst one should acknowledge the impossibility of memorising all potential drug interactions, health care workers need to be alert to the possibility of drug interactions and take appropriate steps to minimise their occurrence. Drug formularies and the Summary of Product Characteristics provide useful information about interactions. Other resources that may also be of use to prescribers include drug safety updates from regulators such as the Medicines and Health care products Regulatory Agency (available at http://www.mhra.gov.uk/index.htm), interaction alerts in prescribing software and the availability of websites which highlight interactions for specific drug classes, for example, HIV drugs (http://www.hiv-druginteractions.org/.).

Possible interventions to avoid or minimise the risk of a drug interaction include:

Overall, it is important to anticipate when a potential drug interaction might have clinically significant consequences for the patient. In these situations, advice should be given on how to minimise the risk of harm, for example, by recommending an alternative treatment to avoid the combination of risk, by making a dose adjustment or by monitoring the patient closely.

Case studies

Answers

References

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