Class IV Antiarrhythmic Drugs

Class IV antiarrhythmic drugs are the non-dihydropyridine calcium channel blockers, verapamil and diltiazem. They block L-type calcium channels in the sinoatrial and atrioventricular nodes, slowing nodal conduction, lengthening the nodal refractory period and reducing ventricular rate in supraventricular tachyarrhythmia. They also lower blood pressure and myocardial oxygen demand.

Members. Verapamil (phenylalkylamine) and diltiazem (benzothiazepine).

Mechanism. Block of L-type channels reduces calcium entry into nodal cells, which depend on calcium for phase 0 depolarisation. Conduction slows and re-entry circuits that include the atrioventricular node terminate. Use dependence makes block stronger at fast rates. Both drugs also reduce myocardial contractility and vascular tone, with verapamil more negatively inotropic.

Pharmacokinetics. Both drugs undergo extensive first pass metabolism by CYP3A4 and inhibit CYP3A4 and P-glycoprotein. Intravenous onset is within 2 to 5 minutes. Oral half-lives are 3 to 7 hours for verapamil immediate release and 3 to 5 hours for diltiazem, longer for modified release forms.

• Verapamil: stronger atrioventricular block and negative inotropy; constipation; supraventricular tachycardia, atrial fibrillation, fascicular ventricular tachycardia, angina, cluster headache prophylaxis.
• Diltiazem: less negative inotropy; rate control and angina; fewer cardiac arrhythmia effects but similar risk in reduced ejection fraction.

• Supraventricular tachycardia after failure of vagal manoeuvres or adenosine: verapamil 5 to 10 mg intravenously over 2 minutes (2.5 to 5 mg in older adults), repeated once after 15 to 30 minutes; or diltiazem 0.25 mg/kg intravenously over 2 minutes, repeated at 0.35 mg/kg after 15 minutes.
• Atrial fibrillation rate control: diltiazem 120 to 360 mg daily or verapamil 120 to 480 mg daily in modified-release forms, in patients with preserved ejection fraction.
• Idiopathic fascicular ventricular tachycardia: verapamil 5 to 10 mg intravenously terminates the arrhythmia.
• Angina and hypertension: modified-release preparations.
• Cluster headache prophylaxis: verapamil 240 to 480 mg daily with electrocardiogram monitoring.
• Selection: use when beta blockers are not tolerated or are contraindicated, for example in asthma, and when ejection fraction is preserved.

Contraindications. Heart failure with reduced ejection fraction, second or third degree atrioventricular block, sick sinus syndrome, severe hypotension, cardiogenic shock, atrial fibrillation with pre-excitation (Wolff-Parkinson-White syndrome), wide-complex tachycardia of uncertain origin (treated as ventricular tachycardia until proved otherwise), and concurrent intravenous beta blockade.

Adverse effects. Bradycardia, heart block, hypotension, heart failure, constipation (verapamil), peripheral oedema, headache, flushing, gingival hyperplasia, and liver enzyme rise.

Overdose. Calcium gluconate 10% 30 to 60 mL (or calcium chloride 10 mL) intravenously, atropine, high-dose insulin euglycaemia therapy, glucagon, vasopressors, and lipid emulsion in refractory cases. Modified-release overdose may need whole bowel irrigation and prolonged monitoring.

Interactions. Beta blockers (severe bradycardia and block), digoxin (levels rise by 50% to 75% with verapamil), simvastatin (limit to 10 mg daily with verapamil and diltiazem), ciclosporin, carbamazepine, dabigatran, apixaban and rivaroxaban (verapamil raises levels), clarithromycin, rifampicin (lowers levels) and grapefruit juice.

Monitoring. Heart rate, blood pressure, PR interval, electrocardiogram after dose changes, and signs of heart failure.

Referral and escalation. Profound bradycardia, hypotension or block needs emergency treatment and drug withdrawal.

Special groups. Pregnancy: verapamil and diltiazem are used for supraventricular tachycardia, with monitoring. Hepatic impairment: reduce doses. Older adults: lower doses and heart block risk. Children: verapamil is avoided under 1 year because of cardiovascular collapse.