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Drug Interactions

3.1

3. Drug Interactions

Definition of Drug Interaction

A drug interaction occurs when the effects of a drug that has been given to a patient are alteredby the presence of another drug, a chemical or food. Drugs may also interact with laboratorytests to render them inaccurate. Not all drug interactions produce an adverse effect and morethan two drugs can be involved, but for the purpose of this Tutorial we will deal only withinteractions between pairs of drugs that could have negative consequences for patients. Theseform the majority of drug interactions encountered in Medicines Information.

Mechanisms of Drug Interaction

The four most important mechanisms are outlined below:

1. Absorption

� One drug decreases the absorption from the gut of a second drug.– Antacids can decrease the absorption of many drugs (e.g. ciprofloxacin, iron,

oxytetracycline).

2. Metabolism

� One drug increases or decreases the metabolism of a second drug.– Rifampicin enhances the metabolism of female sex hormones, making the

contraceptive pill unreliable.– Allopurinol inhibits the metabolic destruction of a cytotoxic metabolite of

azathioprine, so that this can accumulate to cause toxicity.

3. Elimination

� One drug increases or decreases the rate at which a second drug is removed from thebody.– Amiodarone reduces the elimination of digoxin by the kidney.– Cholestyramine enhances the biliary excretion of the active metabolite of

leflunomide.

4. Pharmacodynamic

� Two drugs have additive or opposing pharmacological effects.– NSAIDs cause fluid retention, which may at least partially counteract the action

of diuretics.– Sedative drugs have additive CNS depressant effects with alcohol.

© Wessex MI, University Hospital Southampton NHS Foundation Trust 2014

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Drug Interactions

Predicting Interactions

It is not always easy to find information to show with a reasonable degree of certainty that aninteraction does or does not occur. If you can’t find any specific information, you may be ableto predict whether an interaction is likely or unlikely, using these points as a guide:1. Are the drugs metabolised by the same enzyme? Is one of the drugs known to inhibit or

induce it?2. Is there any information on how pairs of related drugs behave when given together?3. Do the two drugs have any frequent side effects in common? These effects may be

additive when the two drugs are given together.

Interactions Involving Cytochrome p450

Cytochrome p450 is a very large family of related enzymes; each individual one is called anisoenzyme. The isoenzymes are named using an agreed method of nomenclature involvingnumbers and letters of the alphabet. The four most commonly involved in metabolising drugsare:

CYP1A2 (clozapine, theophylline) CYP2C9 (phenytoin, warfarin)CYP2D6 (fluoxetine, chlorpromazine) CYP3A4 (ciclosporin, carbamazepine)

A knowledge of which isoenzyme metabolises a particular drug can make understanding ofinteractions easier. Individual drugs are not metabolised exclusively by one isoenzyme, but oneusually predominates. Theophylline, for example, is metabolised by CYP1A1, 1A2, 2D6 and2E1, but 1A2 is the main one. This means that drugs inducing CYP1A2 (e.g. tobacco) will speedup the main route of theophylline metabolism resulting in a shorter duration of action andlower peak plasma concentrations. This may reduce efficacy. Drugs which inhibit CYP1A2 (e.g.ciprofloxacin) will slow theophylline metabolism, giving a longer half-life and higher peaklevels. This may cause toxicity.Note that while some enzyme inhibitors or inducers affect the isoenzymes responsible for theirown metabolism (e.g. ciclosporin), others can affect completely different isoenzymes or are notmetabolised at all (e.g. ciprofloxacin).

Ways to Reduce Risk

� Certain drugs have a narrow therapeutic range or require careful monitoring, andinteractions involving them are more likely to cause harm to the patient (e.g. ciclosporin,lithium, phenytoin, warfarin, digoxin). Starting a new drug in patients taking thesemedicines requires a check for interactions.

� Some drugs are particular liable to interact with lots of drugs and you should be aware ofthis (e.g. cimetidine, erythromycin, ritonavir, MAOIs).

� Different drugs in the same therapeutic class can have different potentials to interact. Forexample, cimetidine or fluoxetine are more likely to interact with a range of other drugsthan ranitidine or citalopram. Swapping to a different drug in the same class may avoidan interaction.

� If a potentially interacting combination must be used, knowing the possible result mayallow the patient to be monitored for potential adverse effects.

� Clinical pharmacists in a specialist field often have a good working knowledge ofpractical ways to avoid, monitor or reduce the effects of potentially interactingcombinations of drugs.

3.2© Wessex MI, University Hospital Southampton NHS Foundation Trust 2014


Drug Interactions

3.3

Questions to Ask an Enquirer

� Which of the drugs involved is the patient already taking? How long have they beentaken for?

� Has the enquirer or patient read a warning about the combination somewhere? If so,where?

� If the patient is already taking both drugs, have any problems been identified orinvestigated?

� If there is an interaction, is there any reason why alternative drugs can’t be used to avoid it?� What is the patient’s liver and renal function like? (This may affect clearance.)� Is the patient taking any other drugs?� If any monitoring would be required who would do this?

Example Sources to Use in Answering Enquiries

� Stockley’s Drug Interactions should normally appear fairly early on in your searchstrategy.

� Check the SPCs for all the drugs involved as the information may differ between them. Inaddition some interactions may be listed because they could occur in theory rather thanbeing an actual problem in practice (such as those involving cytochrome p450).

� Martindale, AHFS, Lexicomp and Micromedex (if your centre has access), can be usefuladditional resources for interaction enquiries.

� For enquiries where you need to establish whether a drug is an inducer, inhibitor orsubstrate of cytochrome p450, then the Indiana University cytochrome p450 website athttp://medicine.iupui.edu/clinpharm/ddis/ is very helpful. Alternatively the ‘Drugmetabolism interactions’ chapter in the introductory section of Stockley’s is really usefultoo.

� Researching enquiries involving antiretroviral regimes can be complex because of thenumber of drugs involved. Fortunately www.hiv-druginteractions.org/ makes thisprocess much easier as you can enter all the antiretrovirals in question, together with theother drug(s) of interest and it will cross-check them all for you.

� Embase and Medline may be helpful, usually towards the end of your search.� If your enquiry involves an alternative medicine, then you may need to refer to some of

the example sources listed in Tutorial 12.

Further Reading

� The General considerations and mechanisms sections of Stockley’s.

Exercises

� Work through the drug interactions enquiries on MiCAL (questions 8 and 13).� Look at previous interactions enquiries that have been answered in your MI centre.� Have a go at the questions on page 3.4 (‘Test Yourself!’). Answers at the back of this book.� There is an example enquiry with a model answer on page 3.6.� .7 has some real enquiries that you might like to tackle with your MI tutor.


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Drug Interactions

Test Yourself!

1. Drugs can interact with other drugs, but what else can they interact with?

2. Where would you find information on interactions between medicines and alcohol,tobacco or illicit drugs?

3. How would you look for information about interactions involving a newly licenseddrug? If you were asked to check whether a new drug was compatible with apatient’s existing regimen, what would you do?

4. What is an isoenzyme?



Drug Interactions

3.5

5. If a drug induces the metabolism of a second drug, what will happen to the half-lifeof the second drug? What are the implications of this for the patient?

6. Why might you check the patient’s kidney and liver function when answering anenquiry about an interaction?

7. From memory, or using a book, list six drugs that can interact with theophylline.What effect do they have on theophylline levels?

Interacting Drug Effect on Theophylline Levels

8. Using your clinical knowledge, or a book, give two examples of pharmacodynamicinteractions, other than those given in the Tutorial.



Drug Interactions

Example Enquiry

The following e-mail was sent in response to a telephone call from a GP asking about the riskof QT interval prolongation with domperidone and pregabalin, and is typical of the druginteractions that flag up on prescribing systems.



Drug Interactions

3.7

Real Enquiries

This section helps you to think about the enquiry answering process. Below are given thedetails of three real enquiries, as received by a regional MI centre. Decide with your tutorwhich of these enquiries to do. Then for each one describe:(a) Any further questions you would like to ask the enquirer.(b) The top sources that you would use to answer the enquiry.Your tutor will go through these with you when you have finished. If you like, research a fullanswer using the MiDatabank Trainer on MiCAL to document it, but discuss this with yourtutor first.

1. Herbal interactions

AGP asks if it is OK for his elderly patient to take Ginkgo biloba. She is takingramipril, aspirin, simvastatin, bisoprolol and a salbutamol inhaler when required.

Further questions for enquirer Sources to use



Drug Interactions

2. Interaction on the internet

A patient’s mother has seen information on the internet that vigabatrin interacts withomeprazole. Her one year old son is taking both drugs and she tells you that she isgoing to stop one of them. She asks for advice on which one to stop.


3. Amiodarone and digoxin

A clinical pharmacist drops into Medicines Information for advice on how to managea patient who is taking amiodarone and digoxin for atrial fibrillation.




workbook tutorial 3 8pp - ukmi

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