Drugs Interactions General Practice

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MeReC Bulletin Volume 10, Number 4, 1999 13

Contents: Drug interactions in general practice Nurse prescribing

N UMBER 4, 1999V OLUME 10

Drug interactions in general practiceAn in te rac t ion o ccurs when th eeffects of one drug are changedby another drug, food, drink orexposure to an env i ronmenta lchemica l . 1 However, not al l

drug interact ions are cl inical lysignif icant . This B u l l e t i n

discusses d rug in te rac t ionsand explores ho w they c an bemanaged in general pract ice.

What are drug interactions?

A drug interaction occurs whentwo or more drugs interact insuch a way that the effectivenessor toxicity of one or more of thedrugs 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, anadditive effect is seen whendiuretics and beta-blockers arecombined to treat hypertension.

Are interactions a significantproblem in general practice?

It is not known exactly how common drug interactions are.Several studies in over 370,000primary and secondary carepatients found that between2.2% 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 theeffects of an interaction. 2

Drug interactions may causehospital admission, although

this may be relatively infrequent.In one ten week study of 691admissions, 68 (9.8%) weredrug related and three (0.4%)

were due to drug interactions. 3

N ATIONAL P RESCRIBING C ENTRE

SUMMARY

* Drug interactions occur when two or more drugsinteract 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 aremore likely to be involved will act as a useful alert.

* Drugs most likely to be involved in interactions arethose with a narrow margin between the therapeuticand toxic dose, those requiring careful dosage controland 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 areparticularly susceptible to drug interactions.

* Interactions are most likely when an interacting drugis being introduced or stopped. However, the timecourse of interactions can vary, depending, for example, on the half-lives of the drugs involved.

* If the potential hazards of starting an interacting drugoutweigh the benefits, an alternative drug should bechosen if possible. Other courses of action includeadjusting the dose of one or both drugs when aninteracting drug is stopped or started. Monitoring thepatient may be necessary, where practical.

* It is important to report a n y suspected druginteractions involving newly introduced products ( ),or serious interactions involving established products,to the Committee on Safety of Medicines (CSM).

The MeReC Bulletin is producedby the NHS for the NHS



14 MeReC Bulletin Volume 10, Number 4, 1999

Pharmacokinetic interactions

Absorption Protein binding Metabolic Renal

Rate Extent Free Bound Enzyme Enzyme Excretion Excretiondrug drug induction inhibition increased decreased

Displacement Decreased Increased Decreased Increasedinteractions levels levels levels levels

What mechanisms are involved?

Drug interactions often occur by more than one mechanism at thesame time. They are not alwayseasy to predict.

Pharmacodynamic in te rac t ionsare those where the effects of onedrug are changed by another at the site of action. 1 Additive effectsoccur when two drugs with thesame pharmacological effectsare given together. For example,the concurrent use of alcohol

with benzodiazepines may causean enhanced sedative effect.

Conversely, antagonism occurs when interacting drugs haveopposing actions.

Pharmacokine t ic in te rac t ionsaffect the processes by whichdrugs are absorbed, distributed,metabolised or excreted. 1

There are several types of pharmacokinetic interaction(see below and figure 1 ).

Antacids and binding agentssuch as cholestyramine may

impair absorption of other drugsfrom the gastrointestinal tract by forming complexes with them.For example, antacids reducethe absorption of quinolonessuch as ciprofloxacin. Other drugs, such as metoclopramideor opiates, may affect gut transit time. This generally influencesthe rate, rather than the extent,of drug absorption. Most absorp-tion interactions are not clinically significant and can be managed

by separating the administrationof the drugs.

Drug displacement interactionsoccur when two drugs competefor the same protein binding

site and one or both is displaced. This results in an increase inthe concentration of free (active)drug, but is usually compensatedfor by an increase in excretion.

These interactions usually involvehighly protein bound drugs suchas phenytoin, warfarin andtolbutamide. However, the effectsof displacement interactions areusually minor and transient.

Many drugs are metabolisedin the liver, mainly by thecytochrome P450 enzymesystem. Induction of enzymes by one drug can increase the rate of metabolism of another, resultingin a reduced effect. Conversely,enzyme inhibitors may result inaccumulation and increasedtoxicity of other drugs ( table 1 ).

Finally, drugs that alter renalexcretion can affect plasma levelsof other drugs. For example,methotrexate and non-steroidalanti-inflammatory drugs competefor renal excretion. Concomitant use of these agents may result inraised methotrexate levels and

an increased risk of toxicity,although this combination may be used successfully under specialist supervision. Theimportance of this type of inter-action depends on the extent to which a drug and/or itsmetabolites are renally excreted.

Which patients are likely to beaffected?

The effect and severity of drug interactions may vary considerably from one patient toanother. Various factors canaffect patient susceptibility todrug interactions.

Patient characteristics

Elderly patients may beat increased risk of druginteractions, as they are morelikely to be taking multipledrugs and may have impairedrenal and hepatic function.

Genetic characteristics may also affect some interactions;for example, grapefruit juicemay inhibit the metabolism of terfenadine, possibly increasingthe risk of cardiotoxicity. 4

However, this only appearsto be important in the small

number of patients who arepoor metabolisers of terfenadine.

Disease

Both the disease being treated,and any concomitant disease caninfluence drug interactions. For example, although diuretics may reduce lithium excretion, patientscan be successfully stabilised onthe combination. However, any subsequent illness affecting fluid

and electrolyte balance may alter lithium levels, causing either lossof effect or toxicity.

The importance of a druginteraction may also dependupon the patient's pre-existingclinical status. For example,plasma concentrations of digoxinmay be increased by diltiazemand verapamil. If digoxin levelsare low before one of these drugsis started, the interaction couldproduce beneficial effects.However, if levels are withinor above the therapeuticrange when the interactingdrug is introduced, digoxintoxicity may result.

Figure 1 . Types of pharmacokinetic interaction.



MeReC Bulletin Volume 10, Number 4, 1999 15

When are interactions most likelyto occur?

Drug interact ions are mostl ikely when an interact ing drugis being introduced, or wheni t i s s topped . The time courseof an interaction can vary

depending on the dosage, routeof administration, importanceof active metabolites and thehalf-lives of the drugs involved(particularly the drug that has

been recently started). For example, amiodarone andmonoamine oxidase inhibitorshave very long half-lives and theeffects of interactions involvingthese drugs can persist for

weeks after therapy has beenintroduced or discontinued.

The mechanism of an interactioncan also have an effect on itstime course. 5 Enzyme inducersstimulate the production of new metabolising enzymes and it often takes between one andthree weeks before their effectsare at a maximum. In contrast,enzyme inhibitors usually havean effect on hepatic metabolism

within 24 hours.

The time course of interactionsmay also be affected when drugsare given ‘as required’, sincepatients will take different quantities at different times,depending on their requirements.

Which interactions areimportant?

Not all drug interactions areclinically significant. Some aretheoretical, while others require

either avoidance of a combinationof drugs or careful monitoring.

Many potentially harmful druginteractions occur only in a smallproportion of patients. For example, the risk of terfenadineand astemizole prolonging the

QT interval and causing cardiacarrhythmias may be increased

when they interact with other drugs. Only a few patients areaffected at therapeutic doses, but the interactions are potentially life-threatening, particularly in those with QT prolongationor electrolyte imbalances.

There are various classes of drugs that are likely to beinvolved in clinically significant drug interactions (see table 1 ).Drugs which have a narrow margin between the therapeuticand toxic dose, those that requirecareful dosage control and those

which either induce or inhibit liver enzymes are often involved.

Many substances involved ininteractions may not be thought of as drugs by the public. It isimportant to remember that patients may be taking over-the-counter or herbal products

which could have the potential tointeract with prescribed drugs.

What action should be taken?

The first step in managing druginteractions is to be aware of patients taking potentially inter-acting drugs. It is then necessary to assess the clinical significanceof the interaction and find thepatients actually at risk. Varioussteps can then be taken to

minimise any potential adverseeffects (see table 2 ).

Avoid the combination

If the potential hazards of addingan interacting drug outweighthe benefits, an alternative drugshould be chosen. However,if there is no alternative to thenew drug, then the existingtherapy may occasionally need to be changed.

The choice of an alternative agent may depend on whether or not an interaction is a classeffect. For example, cimetidine is

more likely to cause interactionsthan other H 2-antagonists

because it is an enzyme inducer.Conversely, most interactionsinvolving loop and thiazidediuretics are due to their diureticand hypotensive effects. Althoughthese drugs may have different mechanisms of action andpotencies, they all have thepotential to exert these effectsto some extent.

Adjust the dose

If the net effect of an interactionis to increase or reduce the effect of a drug, then modification of the dose of one or both drugsmay compensate for this. Dosemodi f ica t ion may be necessarywhen an interact ing drug iss ta rted or s topped .

If an interaction is relatively minor and there are nopredisposing patient factors,dose adjustment may not benecessary. In addition, if theinteraction is rare or theoretical,

it may not be appropriate toadjust the dosage in most patients taking the drugs.

Monitor

If an interacting combination of drugs is used, then monitoringmay be required, if practical.

The decision around whether or not to monitor dependson various factors such aspatient characteristics,

concomitant diseases, thetiming of introduction of theinteracting drug and theexpected time course of the interaction.

Avoid the combination

choose an alternative drug

Adjust the dose• may be needed when starting or

stopping an interacting drug

Monitor the patient

• if relevant and practical

Continue medication as before

• if interacting drugs are the optimaltherapy for a condition or if theinteraction is not clinically significant

Table 1 . Some drugs likely to be involvedin clinically significant interactions.

Table 2 . Managing drug interactions.

Drugs with a narrow therapeuticmargine.g. warfarin, digoxin, antiepileptics,

theophylline, cyclosporin.

Drugs which require carefuldosage controle.g. antihypertensives,

antidiabetic drugs.

Enzyme inducerse.g. rifampicin, phenytoin,

carbamazepine, barbiturates.Enzyme inhibitorse.g. cimetidine, ketoconazole,

ciprofloxacin, erythromycin.



16 MeReC Bulletin Volume 10, Number 4, 1999

©©©©© The National Prescribing Centre, The Infirmary, 70 Pembroke Place, Liverpool, L69 3GF.Te l e ph o n e : 0 1 5 1 - 7 9 4 8 1 4 6 / 8 1 4 0 / 8 1 4 3 / 8 1 4 5 F ax : 0 1 5 1 - 7 9 4 -8 1 3 9 / 4 4

Date of preparation: June 1999

Refe rences1 Stockley IH. Chapter 1, General considerations

and an outline survey of some basic interactionmechanisms. In: Drug interactions, 4th Ed.

The Pharmaceutical Press, London 1996; 1-152 Jankel CA, Speedie SM. Detecting drug

interactions: a review of the literature. AnnPharmacother 1990; 2 4 : 982-989

3 Stanton LA, Peterson GM, et al . Drug-relatedadmissions to an Australian hospital. J ClinPharm Ther 1994; 1 9 : 341-347

4 Stockley IH. Chapter 24, Miscellaneous drug

interactions. In: Drug interactions, 4th Ed. ThePharmaceutical Press, London 1996; 900

5 Anastasio GD, Cornell KO, Menscer D. Druginteractions: keeping it straight. ClinicalPharmacology 1997; 5 6 : 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 fromthe interaction justifies it.

• Measurement of markersfor an interaction, such asinternational normalised ratio(INR) for oral anticoagulants .

Continue medication as before

If an interaction is not clinically significant, or if interactingdrugs are the optimal therapy for a condition, the patient'smedication may be continuedunchanged. It may be useful todocument the reasons for thisin the patient's notes.

Report the interaction

There may be few data on druginteractions of newly licenseddrugs, as only around 1,500patients will have taken the drugduring clinical trials. Mibefradil(Posicor ; Roche) was voluntarily

withdrawn worldwide in 1998due to reports of serious

interactions with other drugs. The extent of the problem only became apparent post-launch.I t is important to report anysuspec ted drug in te rac t ionsinvolv ing new produc ts ( ), orse r ious in te rac t ions involv inges tab l i shed produc ts , to the

Co m m i t t e e o n S a fe t y o f Medicines (CSM) .

Sources of information on druginteractions

The most widely available sourceof information on interactions isappendix 1 of the British NationalFormulary (BNF), where thesymbol • denotes those that arepotentially hazardous. However,few data are available on the

background to the interaction, which can range from a largeclinical trial to a case-report.

The electronic version of the BNF is also useful for searching for information on specific drugs.

Other resources include druginformation centres, whichoften hold specialist textbookson drug interactions. Community pharmacists are another valuableresource, especially on interac-tions involving over-the-counter drugs. Most pharmacy and GPcomputer systems will also flagup interactions.

Conclusion

Although not all druginteractions are clinically significant, it is important to

be alert for those that are. It isimpossible to remember all theknown important drug interac-

tions. However, a knowledge of the main types of drugs that aremore likely to be involved will act as a useful alert when prescrib-ing. In addition, it is important toremember that various groupssuch as the elderly are moresusceptible to drug interactions.

Application of these principlesshould reduce serious druginteractions when prescribing.

Acknowledgement: Adaptedwi th permiss ion f rom an

art icle published in MedicinesResource, by the Informationand S ta t i s t i cs Div i s ion of theCommon Serv ices Agency,NHS in Scotland.

Nurse prescribingAfter successful pi lot ing of thes c h e m e f r o m 1 9 9 4 , c o m m u n i t ynurse prescribing is beingintroduced in England. This isbased on the recommendat ionsof the 1 98 9 Crown Report onimproving nursing care int h e c o m m u n it y.

Nurses working in community NHS Trusts or as practicenurses, and who hold the Health

Visitor or District Nurse qualifica-tions (or equivalents), an d whohave completed an approvedtraining course are entitled toprescribe from a limited Nurse Prescribers’ Formu lary (NPF).Nurse prescribing should befully 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 theBritish National Formulary. Most of the products can be purchasedfrom 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 therequest of nurses. This aimsto legitimise existing practice,resulting in more effectivepatient care and better use of GP, nurse and patient time. Asa result, part of GPs’ unified

budgets have been allocatedto nurse prescribing.

To aid newly qualified nurseprescribers in England, theNational Prescribing Centre iscurrently publishing a series of educational support materials.

Seven Prescribing Nurs e bulletins(s e e p a n e l ) will be sent to allqualified 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 andthe NHSNet:

Internet - http://www.npc.co.ukNHSNet - http://nww.npc.ppa.nhs.uk

Prescribing Nurse Bulletins• General principles of good prescribing• Modern wound management

dressings• Scabies and threadworms

• Head louse infection• Urinary incontinence• Pain relief• Constipation

Drugs Interactions General Practice

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