How do you approach an interaction question?
Find the newly started or stopped drug first, because most interactions follow a recent change. Then name the mechanism and the likely outcome.
- Pharmacokinetic: absorption (chelation), metabolism (CYP450 induction or inhibition), excretion (renal competition).
- Pharmacodynamic: additive or opposing effects at the same target or in the same organ.
- Inhibitors act within days; inducers take one to two weeks to reach full effect and wear off over weeks after stopping.
- Prefer substitution of the interacting drug over dose adjustment when a safe alternative exists.
In the BNF, each drug has an Interactions link, and the Appendix on interactions lists pairs by severity. Severe interactions are those to avoid or to manage with specialist advice.
Which drugs induce or inhibit CYP450?
Inducers lower the levels of other drugs and inhibitors raise them. The classic exam inducers are rifampicin, carbamazepine, phenytoin and St John's wort. The classic inhibitors are clarithromycin and erythromycin, ciprofloxacin, azole antifungals, ritonavir and grapefruit juice.
- Inducers reduce the effect of warfarin, DOACs, the combined and progestogen-only pills, ciclosporin and many others.
- Inhibitors increase levels of warfarin, statins, carbamazepine, theophylline, ciclosporin, tacrolimus and DOACs.
- Ciprofloxacin increases theophylline levels through CYP1A2 inhibition.
- St John's wort is available over the counter, so ask about herbal remedies.
High-yield interaction pairs: effect and action
| Pair | Effect | What to do |
|---|---|---|
| Warfarin with macrolides, quinolones, azoles, metronidazole | INR rises; bleeding | Avoid or monitor INR closely; miconazole oral gel also interacts |
| Warfarin with rifampicin or carbamazepine | INR falls; clots | Increase monitoring; dose adjustment needed |
| Simvastatin or atorvastatin with clarithromycin | Statin levels rise; myopathy and rhabdomyolysis | Simvastatin: do not combine; suspend it during the course or choose another antibiotic. Atorvastatin: suspend or limit the dose per the BNF |
| Methotrexate with trimethoprim or co-trimoxazole | Marrow suppression | Avoid |
| Methotrexate with NSAIDs | Reduced methotrexate excretion | Caution; monitor, especially with renal impairment |
| ACE inhibitor or ARB with spironolactone, potassium or trimethoprim | Hyperkalaemia | Check potassium; avoid or monitor |
| ACE inhibitor or ARB, diuretic and NSAID | Acute kidney injury | Avoid the combination |
| SSRI with MAOI, linezolid, tramadol or triptans | Serotonin syndrome | MAOI contraindicated; avoid or use caution |
| Macrolide, quinolone, citalopram or antipsychotic with each other | QT prolongation; torsades | Avoid combining; correct potassium and magnesium; ECG |
| Opioid with benzodiazepine or gabapentinoid | Sedation and respiratory depression | Use lowest doses; warn; avoid where possible |
| Omeprazole or esomeprazole with clopidogrel | Reduced activation of clopidogrel | Avoid; the BNF suggests other PPIs |
| Enzyme inducer with contraceptive pill or implant | Contraceptive failure | Use a non-affected method such as an IUD or injection |
| Quinolone or tetracycline with calcium, iron or antacids | Chelation; poor absorption | Separate doses; check the BNF interval |
| Nitrate with sildenafil | Severe hypotension | Contraindicated |
| Azathioprine with allopurinol | Severe myelosuppression | Major azathioprine dose reduction, with specialist advice |
Which combinations cause hyperkalaemia, QT prolongation or serotonin syndrome?
Hyperkalaemia combinations stack potassium-retaining drugs. ACE inhibitors, ARBs, spironolactone, eplerenone, trimethoprim, NSAIDs, heparin, ciclosporin and potassium supplements all raise potassium, and renal impairment multiplies the effect.
QT prolongation is additive and worsened by low potassium and magnesium. Macrolides, quinolones, antipsychotics, citalopram, escitalopram, ondansetron, amiodarone, sotalol and methadone are common culprits. Diuretics add risk through hypokalaemia.
Serotonin syndrome causes agitation, tremor, clonus, hyperthermia and diarrhoea. It follows combining serotonergic drugs, such as an SSRI with tramadol, linezolid, St John's wort or an MAOI. A washout period is required between an MAOI and an SSRI.
What about sedation, contraception and absorption interactions?
Opioids, benzodiazepines, gabapentinoids, sedating antihistamines and alcohol add central nervous system and respiratory depression, which is a recognised cause of death.
Enzyme inducers reduce contraceptive pill and implant efficacy, so the pill is not reliable and a method such as the copper IUD or an injection is preferred. Absorption chelation is solved by timing: separate the cations from quinolones, tetracyclines, levothyroxine and bisphosphonates.
Pharmacodynamic opposition also matters. Beta-blockers with verapamil or diltiazem risk bradycardia and heart block, and NSAIDs oppose antihypertensive therapy.
Check yourself
- Name four CYP450 inducers and what they do to warfarin.
- Name four CYP450 inhibitors.
- Which antibiotic is the classic trap with simvastatin?
- Which antibiotic should not be combined with methotrexate?
- What is the triple whammy?
- Which two PPIs should be avoided with clopidogrel?
- Which contraceptive methods are not affected by enzyme inducers?
- Which drugs separate from calcium or iron by timing?
Questions people ask
Which antibiotics interact with warfarin?
Macrolides, quinolones, metronidazole and co-trimoxazole commonly raise the INR. Rifampicin lowers it. Monitor the INR whenever an antibiotic is started or stopped.
Why is clarithromycin avoided with simvastatin?
Clarithromycin inhibits CYP3A4 and raises statin levels, increasing the risk of myopathy and rhabdomyolysis. Simvastatin is not combined with it (suspend the statin or choose another antibiotic), and atorvastatin is suspended or dose-limited per the BNF.
What is the triple whammy?
An NSAID with an ACE inhibitor or ARB and a diuretic, which together greatly increase the risk of acute kidney injury.
Which PPIs interact with clopidogrel?
Omeprazole and esomeprazole reduce clopidogrel activation, so the BNF advises avoiding them and choosing another PPI if one is needed.
Do enzyme inducers affect all contraceptives?
They reduce the efficacy of the combined and progestogen-only pills and the implant. The copper IUD and levonorgestrel IUS are not affected by enzyme induction.
Related revision notes
Sources: BNF interactions guidance; MHRA Drug Safety Update; Faculty of Sexual and Reproductive Healthcare guidance on drug interactions with hormonal contraception. These notes are for exam revision and are not patient-specific advice; in the exam and in practice, the BNF is the authority.
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