Drugs interactions in general practice


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Material per realitzar el seminari d'interaccions farmacològiques.

Farmacologia general. U.D. de la vall d'Hebron. Medicina. UAB

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Drugs interactions in general practice

  1. 1. MeReC Bulletin Volume 10, Number 4, 1999 13 Contents: Drug interactions in general practice Nurse prescribing NUMBER 4, 1999VOLUME 10 Drug interactions in general practice An interaction occurs when the effects of one drug are changed by another drug, food, drink or exposure to an environmental chemical.1 However, not all drug interactions are clinically significant. This Bulletin discusses drug interactions and explores how they can be managed in general practice. What are drug interactions? A drug interaction occurs when two or more drugs interact in such a way that the effectiveness or toxicity of one or more of the drugs is altered.2 Interactions can be harmful, either by in- creasing the toxicity of a drug or by reducing its efficacy. However, some drug interactions can also be beneficial; for example, an additive effect is seen when diuretics and beta-blockers are combined to treat hypertension. Are interactions a significant problem in general practice? It is not known exactly how common drug interactions are. Several studies in over 370,000 primary and secondary care patients found that between 2.2% and 70.3% may be affected by potential drug interactions.2 Up to 11.1% of patients actually experienced symptoms that may have been attributable to the effects of an interaction.2 Drug interactions may cause hospital admission, although this may be relatively infrequent. In one ten week study of 691 admissions, 68 (9.8%) were drug related and three (0.4%) were due to drug interactions.3 NATIONAL PRESCRIBING CENTRE SUMMARY * Drug interactions occur when two or more drugs interact in such a way that the effectiveness or toxicity of one or more of the drugs is altered. * Although not all drug interactions are clinically significant, it is important to be alert for those that are. A knowledge of the main types of drugs that are more likely to be involved will act as a useful alert. * Drugs most likely to be involved in interactions are those with a narrow margin between the therapeutic and toxic dose, those requiring careful dosage control and those which either induce or inhibit liver enzymes. Over-the-counter or herbal products may also interact with prescribed medicines. * The effect and severity of drug interactions may vary considerably from one patient to another. Elderly patients and those taking multiple medications are particularly susceptible to drug interactions. * Interactions are most likely when an interacting drug is being introduced or stopped. However, the time course of interactions can vary, depending, for example, on the half-lives of the drugs involved. * If the potential hazards of starting an interacting drug outweigh the benefits, an alternative drug should be chosen if possible. Other courses of action include adjusting the dose of one or both drugs when an interacting drug is stopped or started. Monitoring the patient may be necessary, where practical. * It is important to report any suspected drug interactions involving newly introduced products (J), orseriousinteractionsinvolvingestablishedproducts, to the Committee on Safety of Medicines (CSM). The MeReC Bulletin is produced by the NHS for the NHS
  2. 2. 14 MeReC Bulletin Volume 10, Number 4, 1999 Pharmacokinetic interactions Absorption Protein binding Metabolic Renal Rate Extent Free Bound Enzyme Enzyme Excretion Excretion drug drug induction inhibition increased decreased Displacement Decreased Increased Decreased Increased interactions levels levels levels levels What mechanisms are involved? Drug interactions often occur by more than one mechanism at the same time. They are not always easy to predict. Pharmacodynamic interactions are those where the effects of one drug are changed by another at the site of action.1 Additive effects occur when two drugs with the same pharmacological effects are given together. For example, the concurrent use of alcohol with benzodiazepines may cause an enhanced sedative effect. Conversely, antagonism occurs when interacting drugs have opposing actions. Pharmacokinetic interactions affect the processes by which drugs are absorbed, distributed, metabolised or excreted.1 There are several types of pharmacokinetic interaction (see below and figure 1). Antacids and binding agents such as cholestyramine may impair absorption of other drugs from the gastrointestinal tract by forming complexes with them. For example, antacids reduce the absorption of quinolones such as ciprofloxacin. Other drugs, such as metoclopramide or opiates, may affect gut transit time. This generally influences the rate, rather than the extent, of drug absorption. Most absorp- tion interactions are not clinically significant and can be managed by separating the administration of the drugs. Drug displacement interactions occur when two drugs compete for the same protein binding site and one or both is displaced. This results in an increase in the concentration of free (active) drug, but is usually compensated for by an increase in excretion. These interactions usually involve highly protein bound drugs such as phenytoin, warfarin and tolbutamide. However, the effects of displacement interactions are usually minor and transient. Many drugs are metabolised in the liver, mainly by the cytochrome P450 enzyme system. Induction of enzymes by one drug can increase the rate of metabolism of another, resulting in a reduced effect. Conversely, enzyme inhibitors may result in accumulation and increased toxicity of other drugs (table 1). Finally, drugs that alter renal excretion can affect plasma levels of other drugs. For example, methotrexate and non-steroidal anti-inflammatory drugs compete for renal excretion. Concomitant use of these agents may result in raised methotrexate levels and an increased risk of toxicity, although this combination may be used successfully under specialist supervision. The importance of this type of inter- action depends on the extent to which a drug and/or its metabolites are renally excreted. Which patients are likely to be affected? The effect and severity of drug interactions may vary considerably from one patient to another. Various factors can affect patient susceptibility to drug interactions. Patient characteristics Elderly patients may be at increased risk of drug interactions, as they are more likely to be taking multiple drugs and may have impaired renal and hepatic function. Genetic characteristics may also affect some interactions; for example, grapefruit juice may inhibit the metabolism of terfenadine, possibly increasing the risk of cardiotoxicity.4 However, this only appears to be important in the small number of patients who are poor metabolisers of terfenadine. Disease Both the disease being treated, and any concomitant disease can influence drug interactions. For example, although diuretics may reduce lithium excretion, patients can be successfully stabilised on the combination. However, any subsequent illness affecting fluid and electrolyte balance may alter lithium levels, causing either loss of effect or toxicity. The importance of a drug interaction may also depend upon the patient's pre-existing clinical status. For example, plasma concentrations of digoxin may be increased by diltiazem and verapamil. If digoxin levels are low before one of these drugs is started, the interaction could produce beneficial effects. However, if levels are within or above the therapeutic range when the interacting drug is introduced, digoxin toxicity may result. Figure1.Typesofpharmacokineticinteraction.
  3. 3. MeReC Bulletin Volume 10, Number 4, 1999 15 When are interactions most likely to occur? Drug interactions are most likely when an interacting drug is being introduced, or when it is stopped. The time course of an interaction can vary depending on the dosage, route of administration, importance of active metabolites and the half-lives of the drugs involved (particularly the drug that has been recently started). For example, amiodarone and monoamine oxidase inhibitors have very long half-lives and the effects of interactions involving these drugs can persist for weeks after therapy has been introduced or discontinued. The mechanism of an interaction can also have an effect on its time course.5 Enzyme inducers stimulate the production of new metabolising enzymes and it often takes between one and three weeks before their effects are at a maximum. In contrast, enzyme inhibitors usually have an effect on hepatic metabolism within 24 hours. The time course of interactions may also be affected when drugs are given ‘as required’, since patients will take different quantities at different times, depending on their requirements. Which interactions are important? Not all drug interactions are clinically significant. Some are theoretical, while others require either avoidance of a combination of drugs or careful monitoring. Many potentially harmful drug interactions occur only in a small proportion of patients. For example, the risk of terfenadine and astemizole prolonging the QT interval and causing cardiac arrhythmias may be increased when they interact with other drugs. Only a few patients are affected at therapeutic doses, but the interactions are potentially life-threatening, particularly in those with QT prolongation or electrolyte imbalances. There are various classes of drugs that are likely to be involved in clinically significant drug interactions (see table 1). Drugs which have a narrow margin between the therapeutic and toxic dose, those that require careful dosage control and those which either induce or inhibit liver enzymes are often involved. Many substances involved in interactions may not be thought of as drugs by the public. It is important to remember that patients may be taking over- the-counter or herbal products which could have the potential to interact with prescribed drugs. What action should be taken? The first step in managing drug interactions is to be aware of patients taking potentially inter- acting drugs. It is then necessary to assess the clinical significance of the interaction and find the patients actually at risk. Various steps can then be taken to minimise any potential adverse effects (see table 2). Avoid the combination If the potential hazards of adding an interacting drug outweigh the benefits, an alternative drug should be chosen. However, if there is no alternative to the new drug, then the existing therapy may occasionally need to be changed. The choice of an alternative agent may depend on whether or not an interaction is a class effect. For example, cimetidine is more likely to cause interactions than other H2 -antagonists because it is an enzyme inducer. Conversely, most interactions involving loop and thiazide diuretics are due to their diuretic and hypotensive effects. Although these drugs may have different mechanisms of action and potencies, they all have the potential to exert these effects to some extent. Adjust the dose If the net effect of an interaction is to increase or reduce the effect of a drug, then modification of the dose of one or both drugs may compensate for this. Dose modification may be necessary when an interacting drug is started or stopped. If an interaction is relatively minor and there are no predisposing patient factors, dose adjustment may not be necessary. In addition, if the interaction is rare or theoretical, it may not be appropriate to adjust the dosage in most patients taking the drugs. Monitor If an interacting combination of drugs is used, then monitoring may be required, if practical. The decision around whether or not to monitor depends on various factors such as patient characteristics, concomitant diseases, the timing of introduction of the interacting drug and the expected time course of the interaction. Avoidthecombination • chooseanalternativedrug Adjustthedose • may be needed when starting or stoppinganinteractingdrug Monitorthepatient • ifrelevantandpractical Continuemedicationasbefore • if interacting drugs are the optimal therapy for a condition or if the interactionisnotclinicallysignificant Table 1. Some drugs likely to be involved inclinicallysignificantinteractions. Table2.Managingdruginteractions. Drugs with a narrow therapeutic margin e.g. warfarin,digoxin,antiepileptics, theophylline,cyclosporin. Drugswhichrequirecareful dosagecontrol e.g. antihypertensives, antidiabeticdrugs. Enzymeinducers e.g. rifampicin,phenytoin, carbamazepine,barbiturates. Enzymeinhibitors e.g. cimetidine,ketoconazole, ciprofloxacin,erythromycin.
  4. 4. 16 MeReC Bulletin Volume 10, Number 4, 1999  The National Prescribing Centre, The Infirmary, 70 Pembroke Place, Liverpool, L69 3GF. Telephone: 0151-794 8146/8140/8143/8145 Fax: 0151-794-8139/44 Date of preparation: June 1999 References 1 Stockley IH. Chapter 1, General considerations and an outline survey of some basic interaction mechanisms. In: Drug interactions, 4th Ed. The Pharmaceutical Press, London 1996; 1-15 2 Jankel CA, Speedie SM. Detecting drug interactions: a review of the literature. Ann Pharmacother 1990; 24: 982-989 3 Stanton LA, Peterson GM, et al. Drug-related admissions to an Australian hospital. J Clin Pharm Ther 1994; 19: 341-347 4 Stockley IH. Chapter 24, Miscellaneous drug interactions. In: Drug interactions, 4th Ed. The Pharmaceutical Press, London 1996; 900 5 Anastasio GD, Cornell KO, Menscer D. Drug interactions: keeping it straight. Clinical Pharmacology 1997; 56: 883-894 Monitoring may involve: • Clinical monitoring to detect any adverse effects, either by examining the patient or by warning them about possible symptoms. • Measurement of drug levels, if appropriate monitoring facilities are available and if the potential danger from the interaction justifies it. • Measurement of markers for an interaction, such as international normalised ratio (INR) for oral anticoagulants. Continue medication as before If an interaction is not clinically significant, or if interacting drugs are the optimal therapy for a condition, the patient's medication may be continued unchanged. It may be useful to document the reasons for this in the patient's notes. Report the interaction There may be few data on drug interactions of newly licensed drugs, as only around 1,500 patients will have taken the drug during clinical trials. Mibefradil (Posicor; Roche) was voluntarily withdrawn worldwide in 1998 due to reports of serious interactions with other drugs. The extent of the problem only became apparent post-launch. It is important to report any suspected drug interactions involving new products (J), or serious interactions involving established products, to the Committee on Safety of Medicines (CSM). Sources of information on drug interactions The most widely available source of information on interactions is appendix 1 of the British National Formulary (BNF), where the symbol • denotes those that are potentially hazardous. However, few data are available on the background to the interaction, which can range from a large clinical trial to a case-report. The electronic version of the BNF is also useful for searching for information on specific drugs. Other resources include drug information centres, which often hold specialist textbooks on drug interactions. Community pharmacists are another valuable resource, especially on interac- tions involving over-the-counter drugs. Most pharmacy and GP computer systems will also flag up interactions. Conclusion Although not all drug interactions are clinically significant, it is important to be alert for those that are. It is impossible to remember all the known important drug interac- tions. However, a knowledge of the main types of drugs that are more likely to be involved will act as a useful alert when prescrib- ing. In addition, it is important to remember that various groups such as the elderly are more susceptible to drug interactions. Application of these principles should reduce serious drug interactions when prescribing. Acknowledgement: Adapted with permission from an article published in Medicines Resource, by the Information and Statistics Division of the Common Services Agency, NHS in Scotland. Nurse prescribing After successful piloting of the scheme from 1994, community nurse prescribing is being introduced in England. This is based on the recommendations of the 1989 Crown Report on improving nursing care in the community. Nurses working in community NHS Trusts or as practice nurses, and who hold the Health Visitor or District Nurse qualifica- tions (or equivalents), and who have completed an approved training course are entitled to prescribe from a limited Nurse Prescribers’ Formulary (NPF). Nurse prescribing should be fully implemented by mid-2001, when around 26,000 nurses will be qualified to prescribe. The NPF consists of a list of drugs, dressings and appliances published as an appendix of the British National Formulary. Most of the products can be purchased from pharmacies, although a few are prescription-only medicines. Nurse prescribing is intended to be substitute, not additional, prescribing as it will mainly involve those products histori- cally prescribed by GPs at the request of nurses. This aims to legitimise existing practice, resulting in more effective patient care and better use of GP, nurse and patient time. As a result, part of GPs’ unified budgets have been allocated to nurse prescribing. To aid newly qualified nurse prescribers in England, the National Prescribing Centre is currently publishing a series of educational support materials. Seven Prescribing Nurse bulletins (see panel) will be sent to all qualified nurse prescribers. All of these bulletins will be available by the end of October 1999. They are also available to browse or download from the Internet and the NHSNet: Internet-http://www.npc.co.uk NHSNet-http://nww.npc.ppa.nhs.uk PrescribingNurseBulletins • Generalprinciplesofgoodprescribing • Modernwoundmanagement dressings • Scabiesandthreadworms • Headlouseinfection • Urinaryincontinence • Painrelief • Constipation