diltiazem

Mechanism

Additive bradycardia and AV block. Third-degree AV block with syncope has been reported. Both drugs slow AV nodal conduction.

Symptoms

Bradycardia (heart rate below 50/min), dizziness, syncope. ECG: first- to second-degree AV block. Older patients: fall risk.

Management

Avoid the combination. In atrial fibrillation, choose one strategy: amiodarone for rhythm control, diltiazem for rate control. Alternatives: a beta-blocker + digoxin or catheter ablation.

Mechanism

Diltiazem moderately inhibits CYP3A4 – a partial atorvastatin metabolic route. Atorvastatin plasma levels rise 2- to 3-fold. The effect is smaller than with simvastatin (atorvastatin's CYP3A4 dependence is weaker).

Symptoms

Pain and weakness in large muscle groups (thighs, shoulders, calves), dark urine, elevated creatine kinase. Severe cases progress to rhabdomyolysis with acute kidney injury. Symptoms appear within 1–4 weeks of co-administration.

Management

Cap atorvastatin at 20 mg/day when combined. If LDL targets are missed, switch to pravastatin or rosuvastatin. Alternative to diltiazem: amlodipine or a beta-blocker.

Mechanism

Non-dihydropyridine calcium channel blocker (diltiazem) + beta-blocker (bisoprolol) – additive AV node blockade and negative inotropic effect.

Symptoms

Bradycardia (heart rate below 50/min), dizziness, syncope. ECG: first- to second-degree AV block. Older patients: fall risk.

Management

Avoid the combination. For atrial fibrillation rate control, choose bisoprolol + digoxin (without diltiazem) or diltiazem with bisoprolol withdrawn.

Mechanism

Diltiazem blocks CYP3A4 – the main carbamazepine metabolic route. Carbamazepine plasma levels rise 1.5-fold. Neurotoxicity risk emerges (ataxia, diplopia, sedation).

Symptoms

Ataxia, diplopia, nausea, drowsiness, tremor. Severe cases: cardiac conduction abnormalities and AV block.

Management

Avoid the combination. Alternative calcium channel blocker without CYP3A4 inhibition: amlodipine (with caution). If unavoidable, check carbamazepine level at 1 and 4 weeks.

Mechanism

Non-dihydropyridine calcium channel blocker (diltiazem) + beta-blocker (carvedilol) – additive AV node blockade and negative inotropic effect. Carvedilol's α1-blockade amplifies hypotension.

Symptoms

Bradycardia (heart rate below 50/min), dizziness, syncope. ECG: first- to second-degree AV block. Older patients: fall risk.

Management

Avoid the combination. Alternative for combined heart failure and angina: carvedilol + amlodipine (dihydropyridine, no AV effect) or diltiazem with carvedilol withdrawn.

Mechanism

Diltiazem blocks CYP3A4 and P-glycoprotein – cyclosporine clearance routes. Cyclosporine plasma levels rise by 50–100%. The combination is sometimes used intentionally in transplant patients to reduce cyclosporine dose (sparing effect), but requires monitoring.

Symptoms

Acute nephrotoxicity: rising creatinine, hypertension, tremor, headache. In transplant patients: accelerated graft function decline.

Management

For intentional sparing, reduce cyclosporine by 25–50% when starting diltiazem; check trough (C0) at days 3 and 7. For incidental combination: monitor cyclosporine and creatinine.

Mechanism

Additive bradycardia and atrioventricular (AV) block. Clonidine lowers sympathetic tone and slows conduction; diltiazem directly blocks the AV node.

Symptoms

Bradycardia (heart rate below 50/min), dizziness, syncope. ECG: first- to second-degree AV block. Older patients: fall and fracture risk.

Management

Avoid the combination, especially in older patients. Alternative calcium channel blockers in hypertension: amlodipine or nifedipine (no AV effect). Alternative to clonidine: an ACE-I or ARB with a diuretic.

Mechanism

Diltiazem is a moderate CYP3A4 and P-glycoprotein inhibitor. Colchicine is a substrate of both with a narrow therapeutic window. Colchicine plasma levels rise 2- to 3-fold; myelosuppression and neuromyopathy risk.

Symptoms

Profuse diarrhoea, vomiting, abdominal pain. With prolonged combination: muscle weakness, peripheral neuropathy, falling leukocytes and platelets.

Management

In chronic kidney disease or hepatic impairment, the combination is not prescribed. With preserved function, colchicine 0.3 mg every other day for no more than 5 days. Alternative for gout: intra-articular glucocorticoid.

Mechanism

Diltiazem blocks intestinal P-glycoprotein – a key digoxin absorption route. Digoxin plasma levels rise by 20–30%. Diltiazem also slows AV conduction.

Symptoms

Nausea, anorexia, visual disturbances (yellow-green halos around lights), arrhythmias ranging from premature beats to ventricular tachycardia. Older adults: confusion, dizziness. Symptoms appear within 1–2 weeks of co-administration.

Management

When diltiazem starts, reduce digoxin by 25%; check level at 1 week. Alternatives: amlodipine (no P-glycoprotein effect) or a beta-blocker for rate control.

Mechanism

Non-dihydropyridine calcium channel blocker (diltiazem) + beta-blocker (metoprolol) – additive AV node blockade and negative inotropic effect. Diltiazem also raises metoprolol levels via a minor CYP route.

Symptoms

Bradycardia (heart rate below 50/min), dizziness, syncope. ECG: first- to second-degree AV block. Older patients: fall risk.

Management

Avoid the combination. For atrial fibrillation rate control: metoprolol + digoxin (without diltiazem) or diltiazem with metoprolol withdrawn. Alternative beta-blockers without CYP2D6 dependence: bisoprolol or carvedilol.

Mechanism

Non-dihydropyridine calcium channel blocker (diltiazem) + non-selective beta-blocker (propranolol) – marked additive bradycardia, AV block, negative inotropic effect. Risk of symptomatic AV block, especially in older patients and left ventricular dysfunction.

Symptoms

Bradycardia (heart rate below 50/min), dizziness, syncope. ECG: first- to second-degree AV block. Older patients: fall risk.

Management

Avoid the combination. For atrial fibrillation rate control, propranolol + digoxin (without diltiazem) or diltiazem with propranolol withdrawn. In heart failure, a selective beta-blocker (bisoprolol) or carvedilol is preferable.

Mechanism

Rifampicin is the most potent available CYP3A4 inducer. Diltiazem plasma levels fall 5- to 10-fold. The antianginal and antihypertensive effect practically disappears.

Symptoms

Return of hypertension, anginal episodes in ischaemic heart disease. Rate control in atrial fibrillation is lost.

Management

During anti-TB therapy, replace diltiazem with amlodipine (at higher than usual dose, since induction also affects it) or an ACE-I + beta-blocker. After rifampicin stops, induction persists for 2 weeks.

Mechanism

Diltiazem moderately inhibits CYP3A4 – the main simvastatin metabolic route. Simvastatin plasma levels rise 3- to 5-fold. FDA Zocor caps simvastatin at 10 mg/day with diltiazem.

Symptoms

Pain and weakness in large muscle groups (thighs, shoulders, calves), dark urine, elevated creatine kinase. Severe cases progress to rhabdomyolysis with acute kidney injury. Symptoms appear within 1–4 weeks of co-administration.

Management

Cap simvastatin at 10 mg/day when combined. If LDL targets are missed, switch to pravastatin or rosuvastatin (no CYP3A4 dependence). Alternative to diltiazem: amlodipine (with simvastatin capped at 20 mg/day) or a beta-blocker.