Drug interactions are an avoidable cause of patient harm. Harm may occur due to either increased drug effect causing toxicity or decreased drug effect leading to therapeutic failure. Drug interactions should be considered both in the differential diagnosis of symptoms (for interactions that have already occurred) and when prescription changes are made (for potential interactions). Software checkers for drug interactions are widely available, but have limited clinical utility. Patient harm from drug interactions can be reduced by:
A drug interaction occurs when a patient’s response to a drug is modified by food, nutritional supplements, formulation excipients, environmental factors, other drugs or disease. Interactions between drugs (drug–drug interactions) may be beneficial or harmful. Harmful drug–drug interactions are important as they cause 10–20% of the adverse drug reactions requiring hospitalisation and they can be avoided.1 Elderly patients are especially vulnerable – with a strong relationship between increasing age, the number of drugs prescribed and the frequency of potential drug–drug interactions.2 Knowing how drug–drug interactions occur and how to manage them is an important part of clinical practice.
Interactions between drugs may be categorised by the underlying mechanism (see Box):
Pharmacokinetics is ‘what the body does to the drug’. These interactions occur when one drug (the perpetrator) alters the concentration of another drug (the object) with clinical consequences. Altered bioavailabilityThis occurs when the amount of the object drug reaching the systemic circulation is affected by a perpetrator drug. For orally administered drugs this occurs when absorption or first-pass metabolism is altered. Drugs with low oral bioavailability are often affected while those with high bioavailability are seldom affected. For example, alendronate and dabigatran have low oral bioavailability. Alendronate co-administration with calcium decreases bioavailability and can result in no alendronate being absorbed. Conversely, dabigatran co-administration with verapamil increases bioavailability and can result in an increased risk of bleeding. Altered clearance |
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Altered distribution
This occurs when the concentration of drug at the site of action is changed without necessarily altering its circulating concentration. This is particularly an issue for drugs with intracellular or central nervous system targets. Some drugs cause significant changes in the cell membrane transport of other drugs. For example, verapamil inhibits efflux transporters (e.g. P-glycoprotein) increasing the concentrations of substrates such as digoxin and cyclosporin. Probenecid inhibits anion transporters (e.g. OAT-1) increasing the concentrations of substrates such as methotrexate and penicillins. Drug interactions involving transport are less well understood than drug interactions involving metabolism.
Pharmacodynamics is ‘what the drug does to the body’. These interactions occur between drugs with additive or opposing effects. The brain is the organ most commonly compromised by pharmacodynamic interactions.
Pharmacodynamic interactions between drugs with additive effects may be intentional, for example when combining antihypertensives, or unintentional, for example serotonin syndrome caused by adding tramadol to a selective serotonin reuptake inhibitor (SSRI). Conversely, combining drugs with opposing effects can result in loss of drug effect, for example reduced bronchodilation by a beta2 agonist prescribed with a non-selective beta blocker.9
Considering drug effects by organ is a useful way to recognise pharmacodynamic interactions. Ask yourself – might any of these drugs affect the same organ (for example the brain)? This approach allows you to consider interactions between drugs with different modes of action, for example an anticholinergic and a benzodiazepine.10
Ensure you have a full drug history including over-the-counter and herbal products. Pharmacodynamic drug–drug interactions can be anticipated based on knowledge of the clinical effects of the drugs involved. The better your pharmacological knowledge, the easier it is! Prescribe few drugs and know them well.
Pharmacokinetic drug–drug interactions are more difficult to anticipate since they are not predictable from the clinical effects of the drugs involved. Recognition of drugs that have a narrow therapeutic index (Table 1) and the major perpetrators of pharmacokinetic interactions (see Table 2) will help identify most of these.
We use five ‘rules’ to manage potential drug–drug interactions in clinical practice:
- Any interactions between existing drugs in a given patient have already occurred. Hence they are part of differential diagnosis.
- Knowledge of the pharmacological effects of drugs and of patient physiology together allows recognition of potential pharmacodynamic drug– drug interactions.
- Drugs with a narrow therapeutic index are particularly susceptible to pharmacokinetic drug–drug interactions (Table 1).
- A small number of drugs are important ‘perpetrators’ of pharmacokinetic drug–drug interactions (see Table 2).
- Starting or stopping a drug is a prescribing decision that may cause a drug interaction.
Monitoring patients for drug toxicity or loss of efficacy is part of routine care. Checking for changes in symptoms, biomarkers of effect, or drug concentrations soon after prescription changes helps identify drug interactions early and can reduce harm.
A number of resources are available to help clinicians with drug–drug interactions:
- individual drug monographs in formularies, such as the Australian Medicines Handbook, are a useful starting point for learning about new drugs
- tables listing the major perpetrators of pharmacokinetic drug–drug interactions are available in the Australian Medicines Handbook or online (www.pkis.org)
- prescribing and dispensing software mostly generates alerts from tables of information about drug pairs. The time involved and the amount of irrelevant information retrieved may cause ‘alert fatigue’ and limit their clinical utility.11
- drug information services have access to reference information such as Stockley’s Drug Interactions and Micromedex.
Most potential drug interactions can be recognised by applying principles of clinical pharmacology and good clinical care. Increased vigilance by clinicians at the time of changing drugs improves the chance of identifying unwanted drug interactions before they cause significant harm. Knowing a few drugs well and making judicious use of available information is more effective for managing drug interactions than relying solely on electronic decision support.
Conflict of interest: Dr Polasek has consulted for Genelex Corporation on the GeneMedRX Drug Interaction Checker. Dr Snyder, Dr Doogue: none declared.
The following statements are either true or false.
1. Drugs with high oral bioavailability are often affected by pharmacokinetic drug interactions.
2. Fluvoxamine is a strong inhibitor of cytochrome P450 2C19.
Answers to self-help questions
1. False
2. True
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