Introduction
Diltiazem is a calcium channel blocker belonging to the benzothiazepine class that is widely used in cardiovascular medicine. First approved by the FDA in 1982, it has become a cornerstone therapy for various cardiac conditions including hypertension, angina pectoris, and certain arrhythmias. Diltiazem exerts its therapeutic effects primarily through vascular smooth muscle relaxation and modulation of cardiac conduction.
Mechanism of Action
Diltiazem inhibits the influx of calcium ions through slow channels during membrane depolarization of cardiac and vascular smooth muscle. This inhibition results in:
- Coronary and peripheral arterial vasodilation
- Reduction in peripheral vascular resistance
- Negative chronotropic effects (decreased heart rate)
- Negative dromotropic effects (slowed AV nodal conduction)
- Mild negative inotropic effects (decreased myocardial contractility)
The drug preferentially acts on vascular smooth muscle and the AV node, making it particularly useful for both hypertension and supraventricular arrhythmias.
Indications
FDA-approved indications:- Hypertension (monotherapy or combination therapy)
- Chronic stable angina
- Vasospastic angina (Prinzmetal's variant angina)
- Paroxysmal supraventricular tachycardia
- Atrial fibrillation/flutter for ventricular rate control
- Raynaud's phenomenon
- Prevention of migraine headaches
- Esophageal spasm
- Hypertrophic cardiomyopathy
Dosage and Administration
Hypertension:- Immediate-release: 180-240 mg daily in divided doses (maximum 360 mg/day)
- Extended-release: 180-240 mg once daily (maximum 540 mg/day)
- Immediate-release: 30 mg TID or QID (maximum 360 mg/day)
- Extended-release: 120-180 mg once daily (maximum 360 mg/day)
- IV bolus: 0.25 mg/kg (average 20 mg) over 2 minutes
- IV infusion: 5-15 mg/hour
- Oral: 120-360 mg daily in divided doses
- Renal impairment: Reduce dose by 30-50% for CrCl <30 mL/min
- Hepatic impairment: Use with caution; consider dose reduction
- Geriatric patients: Start with lowest recommended dose
- Pediatric use: Safety and effectiveness not established
Pharmacokinetics
Absorption: Well absorbed from GI tract (≈80% bioavailability); extensive first-pass metabolism Distribution: Volume of distribution 3-13 L/kg; 70-80% protein bound Metabolism: Extensive hepatic metabolism via CYP3A4; active metabolites (desacetyldiltiazem) Elimination: Half-life 3-4.5 hours (immediate-release), 5-10 hours (extended-release); primarily excreted in urine (2-4% unchanged) and feces Onset of action: Oral: 30-60 minutes; IV: 2-3 minutes Duration of action: Immediate-release: 4-8 hours; Extended-release: 12-24 hoursContraindications
- Sick sinus syndrome (except with functioning ventricular pacemaker)
- Second- or third-degree AV block (except with functioning ventricular pacemaker)
- Hypotension (SBP <90 mmHg)
- Acute myocardial infarction with pulmonary congestion
- Hypersensitivity to diltiazem or any component of the formulation
- Concurrent use with strong CYP3A4 inhibitors in patients with LV dysfunction
Warnings and Precautions
Black Box Warning: None Cardiac: May precipitate heart failure in patients with impaired ventricular function; can cause bradycardia, AV block Hepatic: Hepatic enzymes may increase; rare cases of hepatic injury reported Withdrawal: Abrupt discontinuation may cause rebound angina Peripheral edema: Common side effect (up to 10% of patients) Dermatologic: Rash reported in 1-3% of patients Pregnancy: Category C; use only if potential benefit justifies potential risk Lactation: Excreted in human milk; use cautiously in nursing mothersDrug Interactions
Major interactions:- Beta-blockers: Enhanced bradycardia and AV block
- Digoxin: Increased digoxin levels (15-20%)
- Statins (simvastatin, lovastatin): Increased risk of myopathy
- CYP3A4 inhibitors (ketoconazole, clarithromycin): Increased diltiazem levels
- CYP3A4 inducers (rifampin, phenytoin): Decreased diltiazem levels
- Cyclosporine: Increased cyclosporine levels
- Anesthetics: Enhanced cardiovascular effects
- Alpha-blockers: Enhanced hypotensive effects
- Benzodiazepines: Increased sedation
- Carbamazepine: Increased carbamazepine levels
Adverse Effects
Common (≥1%):- Headache (5-12%)
- Dizziness (3-10%)
- Peripheral edema (5-10%)
- Fatigue (3-8%)
- Flushing (2-5%)
- Nausea (2-4%)
- Constipation (2-3%)
- Symptomatic bradycardia
- AV block (first, second, or third degree)
- Heart failure exacerbation
- Hepatotoxicity
- Severe hypotension
- Stevens-Johnson syndrome (rare)
- Gingival hyperplasia (chronic use)
Monitoring Parameters
Baseline:- Blood pressure and heart rate
- ECG (assess PR interval and rhythm)
- Liver function tests
- Renal function
- Signs/symptoms of heart failure
- Blood pressure at each dose adjustment, then every 3-6 months
- Heart rate and rhythm
- Signs of peripheral edema
- Liver enzymes annually or if symptoms develop
- Therapeutic response (angina frequency, exercise tolerance)
- Adverse effects assessment
Patient Education
- Take with food to minimize GI upset
- Do not crush or chew extended-release formulations
- Rise slowly from sitting/lying position to prevent dizziness
- Monitor weight regularly and report sudden increases
- Report symptoms of slow heart rate, dizziness, or shortness of breath
- Avoid grapefruit juice (may increase drug levels)
- Inform all healthcare providers about diltiazem use
- Do not stop medication abruptly without medical supervision
- Use caution when driving or operating machinery until effects are known
- Maintain regular follow-up appointments
References
1. FDA Prescribing Information: Diltiazem Hydrochloride 2. Brunton LL, Hilal-Dandan R, Knollmann BC. Goodman & Gilman's: The Pharmacological Basis of Therapeutics. 13th ed. 3. Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults. J Am Coll Cardiol. 2018;71(19):e127-e248. 4. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation. J Am Coll Cardiol. 2014;64(21):e1-e76. 5. Micromedex Solutions: Diltiazem Drug Information 6. Lexicomp Online: Diltiazem Monograph 7. Clinical Pharmacology: Diltiazem Database
This monograph is for educational purposes only and should not replace professional medical advice. Always consult with a healthcare provider for personalized medical guidance.