Diltiazem: Efficacy in Hypertension and Angina

Diltiazem (brand names Dilzem, Dilzem retard, Diltahexal and generics) is a calcium antagonist from the benzothiazepine class. Together with verapamil, it forms the subgroup of non-dihydropyridine calcium antagonists and combines vasodilatory and cardiac effects. Compared to verapamil, diltiazem has a somewhat more balanced profile, with moderate heart rate reduction and less pronounced negative inotropic effect. Diltiazem is often chosen as a better tolerated alternative when heart rate control is desired and beta blockers are not suitable.

Therapeutically, diltiazem is established in the treatment of hypertension, angina pectoris including vasospastic Prinzmetal angina, and heart rate control in atrial fibrillation and flutter. Diltiazem also plays a role in supraventricular tachycardias. Due to CYP3A4 inhibition, relevant drug interactions exist that must be carefully evaluated in clinical practice.

Mechanism of Action

Diltiazem blocks voltage-dependent L-type calcium channels, primarily in vascular smooth muscle and the heart. In the vasculature, it dilates mainly coronary and peripheral arteries, leading to a reduction in peripheral resistance and improved coronary perfusion. At the heart, diltiazem reduces conduction in the AV node, causing heart rate to decrease and allowing interruption of supraventricular reentry tachycardias.

Compared to verapamil, the negative inotropic effect is somewhat less pronounced, which is why diltiazem is better tolerated in patients with borderline pump function. In manifest heart failure with reduced left ventricular ejection fraction, it remains contraindicated.

Pharmacokinetically, diltiazem undergoes significant first-pass metabolism, with oral bioavailability of approximately 40 percent. The half-life is approximately 3 to 4 hours, and extended-release formulations allow once or twice daily dosing. Metabolism occurs predominantly via hepatic CYP3A4 to several active metabolites. Diltiazem itself inhibits CYP3A4 and P-glycoprotein, which explains the drug interactions.

Indications

• Arterial hypertension as monotherapy or combination therapy, especially when moderate heart rate control is simultaneously desired
• Stable angina pectoris including vasospastic angina (Prinzmetal angina)
• Atrial fibrillation and flutter for heart rate control in patients with preserved systolic pump function
• Supraventricular tachycardias, intravenously for acute treatment, orally for recurrence prophylaxis
• Migraine prophylaxis off-label, less well established than verapamil in cluster headache
• Anal fissure, topical as 2 percent ointment in specialized use

As with verapamil, diltiazem is not first-line for heart failure with reduced left ventricular function and atrial fibrillation with preexcited conduction in the context of Wolff-Parkinson-White syndrome.

Dosage and Administration

Hypertension and angina, oral: 60 mg three times daily or 90 to 180 mg extended-release once or twice daily. Escalation up to 360 mg per day is possible.

Heart rate control in atrial fibrillation, oral: 180 to 360 mg per day.

Acute supraventricular tachycardia, intravenous: Initial dose 0.25 mg per kg body weight over 2 minutes, repeat if needed with 0.35 mg per kg after 15 minutes, followed by continuous infusion 5 to 15 mg per hour according to heart rate target. ECG monitoring is mandatory.

Topical in anal fissure: 2 percent ointment applied to the anal margin twice daily, typically for 6 to 8 weeks. Improved tolerability compared to glyceryl trinitrate ointment due to fewer headaches.

Renal impairment: usually no dose adjustment required due to hepatic elimination. Hepatic impairment: dose reduction in moderate impairment. Elderly patients: lower starting dose, slow titration.

Administration: with or without food. Do not crush extended-release formulations, as controlled drug release would be disrupted. Avoid grapefruit and grapefruit juice.

Side Effects

Common: headache, dizziness, ankle edema, facial flushing, nausea, fatigue, constipation (less frequent than with verapamil).

Occasional: bradycardia, first or second-degree AV block, hypotension, sleep disturbances, gingival hyperplasia, skin rash, pruritus.

Rare, but relevant: cardiac decompensation in patients with borderline pump function, severe AV block or asystole especially in combination with beta blockers, allergic skin reactions including Stevens-Johnson syndrome (very rare).

With intravenous administration: hypotension, bradycardia and asystole are possible; emergency equipment with calcium chloride, atropine and pacemaker capability is a prerequisite.

Topical administration: generally well tolerated, local skin irritation possible, systemic effects rare and usually mild.

Drug Interactions

• Beta blockers: additive bradycardia and negative inotropic effects, AV block possible, combination requires critical evaluation, intravenous not recommended.
• Digoxin: diltiazem increases digoxin levels, serum level monitoring and dose adjustment required.
• Other antiarrhythmics (amiodarone, flecainide, sotalol): additive bradycardia and QT effects.
• Statins (simvastatin, atorvastatin, lovastatin): level elevation via CYP3A4 inhibition, risk of myopathy and rhabdomyolysis, alternatively pravastatin or rosuvastatin.
• Direct oral anticoagulants (apixaban, rivaroxaban, edoxaban, dabigatran): level elevation via CYP3A4 and P-glycoprotein, bleeding risk, observe dose adjustments.
• Immunosuppressants (ciclosporin, tacrolimus, sirolimus): elevated levels, therapeutic drug monitoring.
• Carbamazepine, phenytoin: elevated levels and neurotoxic symptoms possible.
• CYP3A4 inhibitors and inducers: significantly alter diltiazem levels, adjustment needed.
• Grapefruit juice: level elevation, avoid.

Special Precautions

Pregnancy: Data limited; methyldopa, nifedipine extended-release and labetalol are established in pregnancy. Diltiazem only for clear indications and after individual counseling. Breastfeeding: Transfer into breast milk, breastfeeding during therapy is generally not recommended.

Children: Limited data, in pediatric cardiology only in specialized centers.

Elderly patients: Caution due to bradycardia, hypotension and constipation. Low starting dose, regular blood pressure and heart rate monitoring.

Before starting therapy: ECG with assessment of sinus rhythm, AV conduction and QT interval. Diltiazem is contraindicated in patients with AV block without pacemaker, sick sinus syndrome, manifest heart failure or Wolff-Parkinson-White syndrome with atrial fibrillation.

Surgery and anesthesia: preoperative notification of the anesthesia team. Sudden discontinuation of diltiazem therapy should be avoided in patients with cardiac disease if possible, as rebound effects may occur.

Driving ability: during dose titration, dizziness and hypotension are possible; usually maintained in stable condition.

Lifestyle: Lifestyle measures such as salt reduction, regular exercise, weight management and smoking cessation supplement pharmacological therapy and may help reduce dose long-term.

You might also be interested in

• Verapamil, phenylalkylamine calcium antagonist with similar profile
• Nifedipine, dihydropyridine calcium antagonist with predominantly vasodilatory effect
• Propranolol, classic beta blocker
• Amiodarone, class III antiarrhythmic
• Blood pressure medications, overview of drug classes

Frequently Asked Questions

Sources

• Gelbe Liste, Diltiazem active ingredient profile
• BfArM, Federal Institute for Drugs and Medical Devices
• AWMF, Guidelines for hypertension and atrial fibrillation
• European Society of Cardiology, cardiology guidelines