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Sunday, July 27, 2025

Diltiazem


Diltiazem is a calcium channel blocker (CCB) belonging to the benzothiazepine class, used extensively in the management of hypertension, angina pectoris, and certain cardiac arrhythmias such as atrial fibrillation and supraventricular tachycardia. It exhibits both vasodilatory and negative chronotropic effects, making it unique among CCBs for its combined use in both vascular and cardiac rate control settings.

Pharmacological Classification

  • Therapeutic class: Antihypertensive, Antianginal, Antiarrhythmic

  • Pharmacologic class: Calcium channel blocker (Non-dihydropyridine type)

  • Chemical class: Benzothiazepine derivative

  • ATC code: C08DB01

  • Legal status: Prescription-only medication (Rx)

Brand Names and Formulations

  • Cardizem®

  • Dilzem®

  • Tildiem®

  • Tiazac®

  • Adizem® SR / XL, Angitil® SR, Viazem® XL, Zemret® XL

Available Forms:

  • Immediate-release tablets: 30 mg, 60 mg

  • Modified-release (MR/SR/XL) capsules/tablets: 90 mg, 120 mg, 180 mg, 240 mg, 300 mg

  • Injectable solution: 5 mg/mL (used in arrhythmias, IV bolus or infusion)

Mechanism of Action

Diltiazem acts by inhibiting the influx of calcium ions (Ca²⁺) through L-type calcium channels in:

  1. Cardiac muscle:

    • ↓ Myocardial contractility (negative inotropy)

    • ↓ SA node automaticity → ↓ heart rate (negative chronotropy)

    • ↓ AV node conduction (negative dromotropy) → useful in arrhythmia control

  2. Vascular smooth muscle:

    • Promotes vasodilation of coronary and peripheral arteries

    • ↓ Total peripheral resistance → ↓ systemic blood pressure

Because diltiazem acts on both cardiac conduction and vascular tone, it bridges the pharmacological gap between verapamil (more cardioselective) and amlodipine/nifedipine (more vascular selective).

Therapeutic Indications

1. Hypertension (High Blood Pressure)

  • Monotherapy or in combination

  • Helps reduce systemic vascular resistance without reflex tachycardia

2. Chronic Stable Angina

  • Reduces myocardial oxygen demand via ↓ HR and ↓ afterload

  • Also improves oxygen delivery via coronary vasodilation

3. Vasospastic (Prinzmetal’s) Angina

  • Relieves and prevents coronary artery spasm

4. Atrial Fibrillation or Flutter

  • Used intravenously or orally for rate control by slowing AV nodal conduction

5. Paroxysmal Supraventricular Tachycardia (PSVT)

  • Acute IV treatment for AV nodal re-entrant tachycardia (AVNRT)

Dosage and Administration

Oral – Adults

Hypertension

  • Initial: 180–240 mg once daily (extended-release preferred)

  • Maintenance: 180–360 mg once daily or in divided doses

  • Titrate based on BP response

Angina

  • Immediate-release: 30 mg four times daily, up to 360 mg/day

  • SR/XL: 180–360 mg/day in single or divided doses

Atrial Fibrillation (chronic rate control)

  • Oral sustained-release: 120–360 mg/day

IV – Arrhythmia (Adults)

  • Initial bolus: 0.25 mg/kg over 2 minutes

  • If needed: second bolus of 0.35 mg/kg after 15 minutes

  • Maintenance infusion: 5–15 mg/h for up to 24 hours

Special populations

  • Elderly: Start at lower doses due to increased sensitivity

  • Hepatic impairment: Reduce initial dose and monitor closely

  • Renal impairment: No specific adjustment, but use caution

Contraindications

  • Second- or third-degree AV block (without pacemaker)

  • Severe bradycardia (<50 bpm)

  • Sick sinus syndrome (unless paced)

  • Left ventricular dysfunction (EF <40%) or acute heart failure

  • Hypotension (SBP <90 mmHg)

  • Concurrent use with intravenous beta-blockers

  • Known hypersensitivity to diltiazem or components

Warnings and Precautions

  • Heart failure: May exacerbate systolic dysfunction due to negative inotropy

  • Conduction abnormalities: Monitor ECG, especially if combined with other AV-nodal blocking agents

  • Hypotension: Risk of dizziness, syncope

  • Hepatic function: Regular monitoring during long-term therapy

  • Discontinuation: Taper gradually to avoid rebound hypertension or angina

  • Surgery: Inform anesthetist due to interaction with anesthetic agents

  • Grapefruit juice: Avoid due to CYP3A4 inhibition → ↑ serum diltiazem levels

Adverse Effects

Very Common (≥10%)

  • Bradycardia, edema (especially ankle swelling)

  • Headache, dizziness, flushing

Common (1–10%)

  • Nausea, vomiting, constipation

  • Fatigue, weakness

  • Palpitations, hypotension

  • Erythema, rash

  • Hepatic enzyme elevation

Rare (<1%)

  • AV block, heart failure exacerbation

  • Gynecomastia, impotence

  • Photosensitivity, exfoliative dermatitis

  • Lupus-like syndrome

Drug Interactions

Pharmacodynamic Interactions

  • Beta-blockers: Additive effects → AV block, bradycardia, hypotension

  • Amiodarone, digoxin: May potentiate bradycardia or AV conduction delay

  • Ivabradine: Risk of severe bradycardia

Pharmacokinetic Interactions

  • CYP3A4 inhibitors (e.g., ketoconazole, erythromycin): ↑ diltiazem levels

  • CYP3A4 inducers (e.g., rifampicin, phenytoin): ↓ efficacy

  • Diltiazem inhibits CYP3A4 → may raise levels of cyclosporine, statins (simvastatin, atorvastatin), tacrolimus, and carbamazepine

  • Grapefruit juice: Avoid due to CYP3A4 inhibition

Use in Pregnancy and Lactation

Pregnancy

  • Category C (US FDA)

  • Use only if clearly needed and benefits outweigh potential fetal risks

  • Animal studies show some risk, but no controlled human data

Lactation

  • Excreted in breast milk in low levels

  • Manufacturer recommends caution or avoiding use while breastfeeding

Use in Special Populations

  • Elderly: Increased sensitivity to hypotension and bradycardia

  • Hepatic impairment: Reduced metabolism → dose adjustment needed

  • Renal impairment: No major dose changes, but monitor closely

  • Pediatrics: Not routinely used; limited data; IV used in specific arrhythmias

Comparative Pharmacology (No Tables)

Diltiazem vs. Verapamil

  • Both are non-dihydropyridine CCBs

  • Diltiazem has milder cardiac depressant effects → less risk of heart block

  • Verapamil is more negative inotropic and used more frequently for arrhythmias

  • Diltiazem causes less constipation than verapamil

Diltiazem vs. Amlodipine

  • Amlodipine is a dihydropyridine CCB → stronger vasodilation, but minimal cardiac effect

  • Diltiazem is suitable for rate control and angina, while amlodipine is ideal for pure hypertension

  • Diltiazem may cause bradycardia, amlodipine may cause reflex tachycardia

Diltiazem vs. Beta-blockers

  • Both reduce heart rate and myocardial oxygen demand

  • Beta-blockers are preferred post-MI; diltiazem preferred in asthma/COPD patients (beta-blocker contraindicated)

  • Combination use is cautious due to additive bradycardia risk

Overdose Management

Symptoms

  • Severe hypotension

  • Bradycardia

  • AV block

  • Cardiac arrest

  • CNS depression

Treatment

  • Gastric lavage and activated charcoal (if early)

  • Atropine for bradycardia

  • IV calcium gluconate or calcium chloride to reverse calcium channel blockade

  • Vasopressors (dopamine, norepinephrine) for hypotension

  • Temporary pacing in case of AV block

  • High-dose insulin-euglycemia therapy in severe cardiotoxicity

Patient Counseling Points

  • Take extended-release formulations whole; do not crush or chew

  • Monitor blood pressure and heart rate regularly

  • Rise slowly from a seated or lying position to avoid dizziness

  • Avoid grapefruit juice

  • Report symptoms of dizziness, palpitations, fainting, or swelling

  • Do not stop the medication suddenly

  • Discuss use with dentist/surgeon due to anesthesia interactions

  • Inform provider of all current medications due to multiple drug interaction risks




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