Calcium Channel Blockers

Calcium channel blockers inhibit L-type voltage-gated calcium channels, reducing calcium entry into vascular smooth muscle and cardiac cells. They lower blood pressure, relieve angina and control supraventricular rate. The class divides into dihydropyridines, which act mainly on vessels, and non-dihydropyridines, which act on the heart.

Classification. Dihydropyridines: amlodipine, nifedipine, felodipine, lercanidipine, nicardipine, nimodipine, isradipine and clevidipine. Phenylalkylamine: verapamil. Benzothiazepine: diltiazem.

Mechanism. Blocking the alpha-1 subunit of the L-type channel relaxes arteriolar smooth muscle, lowering afterload and coronary resistance. In the sinoatrial and atrioventricular nodes verapamil and diltiazem slow conduction and in the myocardium reduce contractility. Verapamil shows use-dependent block, which is greater at faster rates.

Tissue selectivity. Dihydropyridines are vascular selective with little direct cardiac effect. Verapamil is cardiac selective. Diltiazem is intermediate.

Pharmacokinetics. High first pass metabolism by CYP3A4 for most agents. Amlodipine has a long half-life of 30 to 50 hours and a slow onset. Verapamil and diltiazem inhibit CYP3A4 and P-glycoprotein.

• Dihydropyridines: hypertension, angina, Raynaud phenomenon, subarachnoid haemorrhage (nimodipine), and hypertension in pregnancy (nifedipine). Reflex tachycardia and ankle oedema are common.
• Verapamil: supraventricular tachycardia, rate control, angina, cluster headache prevention, hypertrophic cardiomyopathy. Constipation is frequent.
• Diltiazem: angina, hypertension, rate control, anal fissure (topical).

• Hypertension: a dihydropyridine is first line in patients aged 55 years or over and in patients of African ancestry. Amlodipine 5 to 10 mg daily.
• Angina: a dihydropyridine, or verapamil or diltiazem when a beta blocker is not suitable. Do not combine verapamil or diltiazem with a beta blocker.
• Rate control: verapamil or diltiazem when beta blockers are contraindicated and ejection fraction is preserved.
• Heart failure with reduced ejection fraction: non-dihydropyridines are contraindicated. Amlodipine and felodipine are neutral and can be used for blood pressure.
• Overdose: calcium chloride 10% 10 to 20 mL intravenously (or calcium gluconate 10% 30 to 60 mL), repeated, with high-dose insulin and glucose (1 unit/kg bolus then 0.5 to 1 unit/kg/hour), noradrenaline, glucagon and lipid emulsion in refractory cases. Sustained release products delay presentation by up to 24 hours.

Contraindications. Cardiogenic shock, severe aortic stenosis (dihydropyridines with caution), unstable angina and acute myocardial infarction (immediate release nifedipine), sick sinus syndrome and atrioventricular block (non-dihydropyridines), and heart failure with reduced ejection fraction (non-dihydropyridines).

Adverse effects. Headache, flushing, ankle oedema, dizziness, reflex tachycardia, constipation (verapamil), bradycardia and atrioventricular block (non-dihydropyridines), gingival hyperplasia, and hypotension.

Interactions. CYP3A4 inhibitors (clarithromycin, azole antifungals, ritonavir, grapefruit juice) raise levels. CYP3A4 inducers (rifampicin, carbamazepine, phenytoin, St John's wort) lower them. Simvastatin should not exceed 20 mg with amlodipine and 10 mg with verapamil or diltiazem. Ciclosporin and tacrolimus levels rise. Beta blockers add bradycardia with non-dihydropyridines.

Overdose features. Hypotension, bradycardia, hyperglycaemia (insulin inhibition), and non-cardiogenic pulmonary oedema.

Monitoring. Blood pressure, heart rate, electrocardiogram for PR interval with non-dihydropyridines, oedema and liver tests.

Referral and escalation. Symptomatic bradycardia, hypotension or suspected overdose needs urgent care and toxicology advice.

Special groups. Pregnancy: nifedipine is used for hypertension and preterm labour. Breastfeeding: nifedipine, verapamil and diltiazem are compatible. Hepatic impairment: reduce doses. Older adults: lower starting doses. Children: weight-based doses.