Cardiovascular drugs have some of the most clinically important drug interactions in medicine — combining narrow therapeutic windows, electrolyte-sensitive mechanisms, and multiple shared metabolic pathways. This guide covers digoxin, antiarrhythmics, QT-prolonging combinations, diuretic electrolyte effects, warfarin, and anticoagulant-antiplatelet interactions.
Digoxin is a P-gp substrate with a narrow therapeutic index. P-gp inhibitors increase digoxin by reducing renal tubular secretion and intestinal efflux. Hypokalaemia and hypomagnesaemia markedly potentiate toxicity by increasing Na+/K+-ATPase inhibition.
| Interacting drug | Mechanism | Digoxin AUC change | Management |
|---|---|---|---|
| Dronedarone | P-gp inhibition | +150–250% | Reduce digoxin 50%; level check |
| Quinidine | P-gp + renal inhibition | +100–200% | Reduce digoxin 50%; level check |
| Amiodarone | P-gp inhibition | +50–70% Cmin | Reduce digoxin 30–50%; long-term monitoring |
| Verapamil | P-gp + renal | +50–75% | Reduce digoxin; frequent monitoring |
| Clarithromycin | P-gp inhibition | +75% | Short course: monitor carefully |
| Rifampicin | P-gp induction | −30% | May need digoxin dose increase |
| Loop diuretics | Electrolyte depletion (hypokalaemia) | Pharmacodynamic (toxicity ↑) | K+ supplementation; target K+ 4–5 mmol/L |
CYP2C9 inhibition → warfarin INR doubles (reduce warfarin 30–50%); P-gp inhibition → digoxin ↑ (reduce 30–50%); CYP3A4 inhibition → statin/ciclosporin ↑; interactions persist months after stopping due to 40–55 day half-life.
P-gp inhibition → dabigatran AUC +2.4× (contraindicated per label); digoxin +2.5×; CYP3A4/2D6 inhibition → rivaroxaban/apixaban modestly increased; do NOT combine with amiodarone (additive QT + hepatotoxicity).
CYP2D6 substrate — paroxetine, fluoxetine, bupropion (CYP2D6 inhibitors) increase flecainide levels; additive QT with other class I/III agents; avoid in structural heart disease (post-MI), use only in structurally normal heart.
Beta-blocker + class III (hERG block); additive QT with any other QT-prolonging drug; hypokalaemia dramatically increases TdP risk — potassium must be normalised before and during sotalol; avoid with drugs causing QT prolongation.
QT-prolonging drugs inhibit hERG (KCNH2/Kv11.1) potassium channel, delaying cardiac repolarisation. Risk is additive when multiple QT-prolonging drugs are combined, especially with electrolyte disturbances and CYP3A4 inhibition increasing drug levels.
Risk escalates dramatically with combinations. QTc >500 ms or rise >60 ms from baseline requires clinical review. Check CredibleMeds risk database ↗. See full guide: drug-induced QT prolongation.
Loop and thiazide diuretics deplete K+ and Mg2+, potentiating digoxin toxicity and QT prolongation. NSAIDs blunt diuretic response and worsen HF; avoid in HF patients. Loop diuretics + aminoglycosides = additive nephrotoxicity and ototoxicity. ACE inhibitors can cause AKI in volume-depleted patients — withhold diuretic before first ACE inhibitor dose in acute decompensated HF. See renal dosing adjustments.
Warfarin (S-warfarin — active enantiomer) is primarily metabolised by CYP2C9. Dozens of drugs interact; the most clinically significant:
Amiodarone (CYP2C9 inh.); fluconazole (CYP2C9/3A4 inh.); metronidazole (CYP2C9 inh.); trimethoprim; clarithromycin; erythromycin; aspirin (GI bleed risk + mild INR effect); paracetamol >2 g/day (mechanism unclear)
Rifampicin (CYP2C9/2C19 induction — massive effect: may need 5–10× warfarin dose); carbamazepine; phenytoin; St John's Wort; oral vitamin K (food or supplements); sucralfate (reduces absorption)
See anticoagulation reversal guide and warfarin CYP2C9 pharmacogenomics news.
Anticoagulant + antiplatelet combinations significantly increase bleeding risk and require clinical justification. Dual antiplatelet therapy (DAPT: aspirin + P2Y12 inhibitor) + anticoagulant (triple therapy) is highest risk — limit duration to the minimum required post-PCI (typically 1–4 weeks), then reduce to single antiplatelet + anticoagulant. See anticoagulation reversal and anticoagulant therapy guide.
P-gp inhibitors (dronedarone, quinidine, amiodarone, verapamil, clarithromycin) increase digoxin plasma levels 1.5–3-fold — reduce dose 30–50% and monitor levels. Electrolyte disturbances (hypokalaemia from loop diuretics, hypomagnesaemia) potentiate toxicity at any digoxin concentration — maintain K+ 4–5 mmol/L. Signs of toxicity: nausea, xanthopsia (yellow vision), bradyarrhythmias, junctional tachycardia.
Sotalol, dofetilide, and quinidine carry known risk. Azithromycin, clarithromycin, moxifloxacin, fluconazole, voriconazole, haloperidol, quetiapine, and ziprasidone carry conditional/possible risk. Combinations are additive — two conditional-risk drugs together approach known risk. Hypokalaemia and hypomagnesaemia amplify risk significantly. QTc >500 ms or ≥60 ms increase from baseline requires drug review.
Amiodarone inhibits CYP2C9 (warfarin — reduce 30–50%), P-gp (digoxin — reduce 30–50%), and CYP3A4 (statins); interactions persist months after stopping. Dronedarone inhibits P-gp (dabigatran ×2.4 — generally contraindicated) and CYP3A4. Flecainide is a CYP2D6 substrate — paroxetine/fluoxetine increase levels. All class I/III agents add QT risk when combined.
Loop diuretics deplete K+ and Mg2+ — potentiating digoxin toxicity and QT prolongation; supplement K+ in HF patients on digoxin (target K+ 4.0–5.0 mmol/L). ACE inhibitors after loop diuretics can cause first-dose hypotension and AKI in volume-depleted HF patients — start ACE inhibitor low and slow. NSAIDs blunt diuretic response via prostaglandin inhibition and worsen HF — avoid in HF. Aminoglycosides + loop diuretics = additive nephrotoxicity and ototoxicity.