Non Dihydropyridine Calcium Channel Blockers

Non-dihydropyridine calcium channel blockers (verapamil and diltiazem) block L-type channels in the heart and also in vessels. They slow sinoatrial and atrioventricular nodal conduction, reduce contractility and lower afterload, so they treat supraventricular tachycardia, atrial fibrillation rate control, angina and hypertension.

Verapamil. A phenylalkylamine with the strongest effect on the atrioventricular node and myocardium, and a strong inhibitor of CYP3A4 and P-glycoprotein.

Diltiazem. A benzothiazepine with intermediate cardiac and vascular effects and moderate CYP3A4 inhibition.

Mechanism. Use-dependent blockade is greater at fast rates, which slows conduction at the atrioventricular node and terminates re-entrant supraventricular tachycardia. Negative inotropy lowers oxygen demand, and arterial dilation lowers afterload.

Pharmacokinetics. Both undergo extensive first pass metabolism. Verapamil has a half-life of 3 to 7 hours (longer with long-term use) and diltiazem 3 to 5 hours. Modified release forms allow once or twice daily dosing.

• Verapamil: more negative inotropy; constipation in up to a quarter of patients; raises digoxin by 50% to 75%.
• Diltiazem: fewer constipating and inotropic effects; common alternative for rate control.

• Supraventricular tachycardia (narrow complex, after vagal manoeuvres and adenosine): verapamil 5 to 10 mg intravenously over 2 minutes, with a further 5 mg after 5 to 10 minutes if needed. Diltiazem 0.25 mg/kg intravenously over 2 minutes, repeated at 0.35 mg/kg if needed.
• Atrial fibrillation rate control: diltiazem modified release 120 to 360 mg daily or verapamil 120 to 480 mg daily in divided doses, in preserved ejection fraction. Acute intravenous diltiazem infusion 5 to 15 mg/hour after a bolus.
• Angina: verapamil 80 to 120 mg 3 times daily, or diltiazem modified release 180 to 360 mg daily. Variant angina responds well.
• Hypertension: verapamil modified release 120 to 240 mg daily; diltiazem modified release 180 to 360 mg daily.
• Cluster headache prevention: verapamil 240 to 480 mg daily, titrated to higher doses by a specialist with electrocardiogram surveillance for PR prolongation.
• Hypertrophic cardiomyopathy: verapamil for obstructive symptoms when beta blockers are not tolerated.
• Anal fissure: topical diltiazem 2%.
• Selection: use only with preserved ejection fraction. Do not combine with a beta blocker.

Contraindications. Heart failure with reduced ejection fraction, sick sinus syndrome, second or third degree atrioventricular block without a pacemaker, systolic pressure under 90 mmHg, cardiogenic shock, atrial fibrillation with a pre-excitation syndrome (Wolff-Parkinson-White), and wide complex tachycardia of uncertain origin, where verapamil can precipitate collapse. Intravenous verapamil within hours of an intravenous beta blocker risks asystole. Ivabradine is contraindicated with either drug.

Adverse effects. Bradycardia, atrioventricular block, hypotension, constipation, ankle oedema, headache, dizziness, gingival hyperplasia, and raised transaminases. Diltiazem may cause rash.

Interactions. Beta blockers (bradycardia and block), digoxin (verapamil raises levels), dabigatran and other direct oral anticoagulants, simvastatin (maximum 10 mg daily), ciclosporin and tacrolimus, colchicine (toxicity), carbamazepine, midazolam, lithium neurotoxicity, ticagrelor (raised by diltiazem), and amiodarone. Rifampicin and phenytoin lower levels.

Overdose. Profound bradycardia, hypotension and hyperglycaemia. Give calcium chloride 10% 10 to 20 mL intravenously, high-dose insulin with glucose, atropine, noradrenaline and glucagon, and consider pacing or extracorporeal support.

Monitoring. Heart rate, blood pressure, electrocardiogram (PR interval) at start and after dose change, signs of heart failure, and bowel function.

Referral and escalation. Symptomatic bradycardia, block, hypotension or suspected overdose needs urgent hospital care.

Special groups. Pregnancy: verapamil is used for supraventricular tachycardia. Breastfeeding: both are compatible. Hepatic impairment: reduce doses substantially (verapamil to about 30% of the usual dose in severe impairment). Older adults: start low. Renal impairment: usual doses with monitoring.