Verapamil: Efficacy in Hypertension and Arrhythmias

Verapamil (brand names Isoptin, Verahexal, Falicard and generics) is a calcium antagonist from the class of phenylalkylamines. Unlike dihydropyridines, verapamil acts on both vascular smooth muscle and directly on the heart, with inhibition of conduction in the sinoatrial node and AV node. This results in a dual action profile: blood pressure reduction and heart rate control in a single substance. Verapamil has been available since the 1960s and is established in several indications.

In clinical practice, verapamil is used primarily for supraventricular tachyarrhythmias, heart rate control in atrial fibrillation, angina pectoris, and migraine prophylaxis. In classical arterial hypertension without concomitant indications, verapamil is not first line because dihydropyridines such as amlodipine are equivalent or superior for blood pressure reduction alone and do not cause constipation. Prescribers of verapamil should be very familiar with its interaction profile, as verapamil is a potent inhibitor of CYP3A4 and P glycoprotein.

Mechanism of Action

Verapamil blocks voltage dependent L type calcium channels. In vascular smooth muscle, this reduces calcium influx, causing vasodilation and thus lowering peripheral vascular resistance. Compared to dihydropyridines, the vasodilatory effect is less pronounced, but verapamil acts significantly on the heart.

At the sinoatrial node and AV node, verapamil slows impulse generation and conduction. This lowers heart rate and interrupts supraventricular reentry tachycardias. In working myocardium, verapamil additionally reduces contractility (negative inotropic effect), which represents a risk in patients with impaired pump function. These properties explain why verapamil is contraindicated in heart failure with reduced left ventricular ejection fraction (HFrEF).

Oral bioavailability is low at approximately 10 to 20 percent due to pronounced first pass metabolism. The half life is 3 to 7 hours, with extended release formulations allowing once daily administration. Metabolism occurs predominantly hepatically via CYP3A4. Verapamil itself inhibits CYP3A4 and P glycoprotein, explaining numerous drug interactions.

Indications

• Supraventricular tachycardias including AV node reentry tachycardia, intravenously for conversion and orally for recurrence prevention
• Atrial fibrillation and atrial flutter for rate control, especially in patients with preserved systolic pump function and without Wolff Parkinson White syndrome
• Stable angina pectoris including vasospastic Prinzmetal angina
• Arterial hypertension as add on therapy, especially when simultaneous heart rate control is desired
• Migraine prophylaxis, particularly for cluster headache, in specialized neurology settings
• Hypertrophic obstructive cardiomyopathy, in specialized settings for symptom control

Verapamil is not first line for heart failure with reduced ejection fraction and for atrial fibrillation with preexcited conduction (WPW), as paradoxical acceleration via accessory pathways may occur.

Dosage and Administration

Hypertension and angina, oral: 240 mg per day in an extended release form in the morning, alternatively 120 mg twice daily as an immediate release tablet. Increase to 360 or 480 mg per day is possible.

Rate control in atrial fibrillation, oral: 240 to 360 mg per day.

Acute supraventricular tachycardia, intravenous: 5 mg slowly over 2 minutes, repeat with 5 to 10 mg after 10 to 30 minutes if needed. Attempt vagal maneuver before administration, ECG monitoring is mandatory. Adenosine is often the faster alternative.

Migraine prophylaxis and cluster headache: Start with 80 mg three times daily, slow titration. Some patients require doses up to 720 mg per day, ECG checks are then mandatory.

Renal impairment: Usually no dose adjustment required due to hepatic elimination. Hepatic impairment: Dose reduction required as half life is prolonged. Elderly patients: Lower starting dose, ECG before therapy and during follow up.

Administration: With water, with or without food. Avoid grapefruit juice as it inhibits CYP3A4 and increases levels. Do not split or chew extended release formulations.

Side Effects

Very common: Constipation, dizziness, fatigue, headache, ankle edema.

Common: Hypotension, bradycardia, nausea, facial flushing, nausea, general weakness.

Uncommon to rare: AV block, cardiac decompensation in patients with impaired pump function, bronchospasm, gynecomastia, hyperprolactinemia, elevated liver enzymes, gingival hyperplasia.

With intravenous administration: Pronounced blood pressure drop, asystole with bolus injection, emergency preparedness with calcium chloride, atropine and possibly pacemaker.

Constipation is the typical and often limiting side effect. High fiber diet, adequate fluid intake and if needed mild laxatives help.

Drug Interactions

• Beta blockers: Additive bradycardia and negative inotropy, AV block, asystole possible, assess combination critically, avoid intravenous administration.
• Digoxin: Verapamil increases digoxin levels by 50 to 75 percent, dose reduction and level monitoring required.
• Other antiarrhythmics (amiodarone, flecainide, sotalol): Additive effects with bradycardia and conduction delay.
• Statins (simvastatin, atorvastatin, lovastatin): Verapamil inhibits CYP3A4, statin levels increase, risk of myopathy and rhabdomyolysis, limit dose or switch to pravastatin or rosuvastatin.
• Direct oral anticoagulants (dabigatran, apixaban, edoxaban, rivaroxaban): Verapamil inhibits P glycoprotein, levels increase, bleeding risk, observe dose adjustments.
• Immunosuppressants (ciclosporin, tacrolimus, sirolimus): Level increase, regular therapeutic drug monitoring.
• Carbamazepine, phenytoin: Increased levels, neurotoxic symptoms possible.
• Grapefruit juice: CYP3A4 inhibition, verapamil levels increase.
• CYP3A4 inducers (rifampicin, carbamazepine, St John's wort): Verapamil levels decrease, loss of efficacy possible.

Special Precautions

Pregnancy: Verapamil is among the most well studied antiarrhythmics in pregnancy. When needed, for example for rate control, it can be used, ideally after individual counseling at a specialized center. Breastfeeding: Passage into breast milk in small amounts, breastfeeding under therapy usually possible.

Children: Established in pediatrics, especially for supraventricular tachycardias. In infants under one year, intravenous administration is contraindicated due to risk of severe bradycardia.

Elderly patients: Caution regarding bradycardia, hypotension and constipation. Low starting dose, monitor concomitant beta blocker therapy closely.

Before starting therapy: ECG with assessment of sinus rhythm, heart rate, AV conduction. Verapamil is contraindicated in atrial fibrillation with preexcitation, manifest AV block, or sick sinus syndrome without pacemaker.

Emergency aspect: Verapamil toxicity threatens severe bradycardia, AV block and hypotension. Treatment with calcium chloride, atropine, high dose insulin glucose and possibly pacemaker.

Driving ability: Dizziness and hypotension possible during dose titration. Usually preserved in stable state, individual assessment advisable.

You may also be interested in

• Diltiazem, another non dihydropyridine calcium antagonist with rate effects
• Nifedipine, dihydropyridine calcium antagonist with predominantly vasodilatory effect
• Propranolol, classical beta blocker
• Amiodarone, Class III antiarrhythmic for complex arrhythmias
• Blood pressure medications, overview of drug classes

Frequently Asked Questions

Sources

• Gelbe Liste, Verapamil drug profile
• BfArM, Federal Institute for Drugs and Medical Devices
• AWMF, Guidelines for hypertension, atrial fibrillation and cluster headache
• European Society of Cardiology, cardiological guidelines