Drug–Drug Interactions — 30

Do not memorise interactions as pairs alone. Ask what changes: bleeding, potassium, QT interval, sedation, drug concentration, renal clearance or therapeutic failure. Then decide whether to avoid, substitute, dose-reduce or monitor.

• Warfarin + TMP-SMX / metronidazole / amiodarone: INR may rise substantially. Prefer an alternative when reasonable; if unavoidable, arrange early and repeated INR review and individualise warfarin adjustment.
• Anticoagulant + NSAID / antiplatelet: pharmacodynamic bleeding risk rises even when INR is unchanged. Use only for a clear indication, minimise duration and assess GI/renal risk.
• Nitrate + sildenafil/vardenafil/tadalafil: potentially profound hypotension from excessive cGMP-mediated vasodilation. Avoid the combination; the nitrate-free interval depends on the PDE5 inhibitor used.
• ACEI/ARB + spironolactone/eplerenone or potassium supplements: hyperkalaemia and AKI risk. Check creatinine/eGFR and potassium after initiation or dose change, especially in CKD/dehydration.
• Simvastatin/atorvastatin + strong CYP3A4 inhibitor: statin exposure and myopathy/rhabdomyolysis risk increase. Pause, reduce, or choose a less interaction-prone statin according to the interacting drug.
• Digoxin + amiodarone/verapamil: digoxin concentration and bradyarrhythmia risk may rise. Review dose, renal function, pulse/ECG and level when clinically indicated.
• Lithium + thiazide / ACEI / ARB / NSAID: lithium clearance falls and toxicity may occur. Avoid casual co-prescribing; monitor lithium and renal function closely if essential.
• Methotrexate + trimethoprim: additive antifolate effect can cause severe marrow suppression and mucositis; generally avoid.
• Opioid + benzodiazepine/other sedative: additive respiratory depression. Use the lowest necessary doses with explicit monitoring and avoid routine combination.
• Linezolid + serotonergic medicines: serotonin toxicity is possible. Review necessity, alternatives and monitoring rather than treating the interaction as automatically harmless.
• Rifampicin + DOAC/warfarin/oral contraceptive/tacrolimus: potent enzyme induction can markedly reduce exposure to many drugs; anticipate therapeutic failure and choose alternatives/monitor appropriately.
• Levothyroxine + iron/calcium: absorption falls. Separate administration and recheck TSH after clinically meaningful changes.
• Fluoroquinolone/tetracycline + iron/calcium/antacid: chelation reduces antibiotic absorption; separate dosing according to the specific product.
• Multiple QT-prolonging drugs: risk is amplified by hypokalaemia, hypomagnesaemia, bradycardia and structural heart disease. Correct reversible factors and obtain ECG monitoring when risk is meaningful.

The most dangerous interaction is often not the longest list in an interaction checker—it is the interaction that changes a narrow-therapeutic-index drug in a physiologically vulnerable patient.