Diltiazem hydrochloride is a cornerstone calcium channel blocker medication, classified as a benzothiazepine derivative, prescribed for the management of various cardiovascular conditions. Its primary mechanism of action involves the selective inhibition of calcium ion influx across the cell membranes of cardiac and vascular smooth muscle, without significantly altering serum calcium concentrations. This expert-level overview details its pharmacological profile, clinical applications, and essential management protocols for healthcare professionals to ensure optimal therapeutic outcomes and patient safety.

Features

• Pharmaceutical Class: Benzothiazepine-derived calcium channel blocker.
• Mechanism of Action: Inhibits the transmembrane influx of calcium ions into cardiac and vascular smooth muscle cells during depolarization.
• Available Formulations: Immediate-release tablets, extended-release capsules (CD, XR, XT), and intravenous solution.
• Bioavailability: Approximately 40% following oral administration, subject to significant first-pass metabolism.
• Protein Binding: 70–80%, primarily to alpha-1-acid glycoprotein and albumin.
• Metabolism: Extensive hepatic metabolism via the cytochrome P450 system, primarily CYP3A4, producing active and inactive metabolites.
• Elimination Half-life: Biphasic; initial phase 3–5 hours, terminal phase 5–8 hours. Extended-release formulations alter pharmacokinetics.
• Excretion: Primarily renal (35%) and secondarily fecal (65%) as metabolites.

Benefits

• Reduces myocardial oxygen demand by decreasing heart rate, systemic vascular resistance, and cardiac contractility, effectively managing chronic stable angina.
• Controls ventricular rate in patients with atrial fibrillation or atrial flutter by slowing conduction through the atrioventricular (AV) node.
• Provides sustained antihypertensive effects through vasodilation of peripheral arterioles, reducing systemic vascular resistance and blood pressure.
• Offers a favorable side effect profile compared to some other antiarrhythmics and antihypertensives, particularly regarding lipid and glucose metabolism.
• Available in multiple extended-release formulations to support 24-hour coverage, enhance adherence, and minimize peak-to-trough fluctuations in plasma concentration.

Common use

Diltiazem is indicated for the management of chronic stable angina pectoris, alone or in combination with other antianginal agents. It is also approved for the treatment of essential hypertension, either as monotherapy or as part of a combination regimen. A critical application is the control of rapid ventricular rate in patients with atrial fibrillation or atrial flutter. Off-label uses may include the treatment of supraventricular tachycardias, Raynaud’s phenomenon, and as part of a medical management strategy for certain types of coronary vasospasm (Prinzmetal’s angina).

Dosage and direction

Dosage is highly individualized based on indication, patient response, and formulation. For hypertension or angina, initial oral doses typically range from 120 to 240 mg daily for extended-release formulations, or 30 mg three or four times daily for immediate-release, titrated upward at 1- to 2-week intervals. The maximum recommended daily dose is 540 mg. For atrial fibrillation/flutter, an intravenous loading dose of 0.25 mg/kg actual body weight over 2 minutes may be administered, followed by a second dose of 0.35 mg/kg after 15 minutes if needed, and a continuous infusion of 5–15 mg/hour. Oral maintenance therapy is then initiated. All doses must be adjusted in patients with hepatic impairment. Tablets and capsules should be swallowed whole, not crushed or chewed; some extended-release formulations may be opened and sprinkled on applesauce.

Precautions

Close monitoring of heart rate, blood pressure, and ECG is mandatory, especially during initiation and titration. Use with extreme caution in patients with heart failure (HF) with reduced ejection fraction, as negative inotropic effects may exacerbate symptoms. Hepatic impairment significantly reduces clearance; dosage reduction is required. Renal impairment necessitates cautious use. May prolong AV nodal refractory periods; caution is advised in patients with sick sinus syndrome or AV block (unless a pacemaker is present). Can occasionally cause symptomatic hypotension. Abrupt withdrawal may precipitate angina in patients with coronary artery disease; therapy should be tapered under supervision.

Contraindications

Diltiazem is contraindicated in patients with known hypersensitivity to the drug or any component of the formulation. It must not be used in patients with sick sinus syndrome or second- or third-degree AV block, except in the presence of a functioning ventricular pacemaker. It is contraindicated in patients with severe hypotension (systolic pressure < 90 mm Hg), acute myocardial infarction, and pulmonary congestion documented by x-ray on admission. Concomitant use with ivabradine is contraindicated. Intravenous diltiazem is contraindicated in patients with atrial fibrillation/flutter associated with an accessory bypass tract (e.g., Wolff-Parkinson-White syndrome).

Possible side effect

Common adverse reactions (≥2%) include headache, dizziness, asthenia, edema (lower extremity), bradycardia, AV block (first-degree), flushing, and nausea. Less common but serious side effects include symptomatic hypotension, exacerbation of heart failure, severe bradycardia, syncope, sinoatrial node dysfunction, and elevated liver enzymes (AST, ALT). Rash, constipation, and gingival hyperplasia have also been reported. The incidence and severity of side effects are often dose-dependent.

Drug interaction

Diltiazem is a moderate inhibitor of CYP3A4 and a P-glycoprotein inhibitor, leading to numerous clinically significant interactions. Coadministration with other CYP3A4 substrates can lead to increased plasma levels of the coadministered drug. Key interactions include:

• Simvastatin/Lovastatin: Increased risk of myopathy/rhabdomyolysis; avoid concomitant use or strictly limit statin dose.
• Beta-blockers/Digoxin: Additive effects on cardiac conduction (bradycardia, AV block) and contractility; monitor heart rate and PR interval closely.
• Cyclosporine, Sirolimus, Tacrolimus: Can significantly increase levels of these immunosuppressants; monitor levels and adjust doses.
• Buspirone, Triazolobenzodiazepines (e.g., midazolam, triazolam), Sildenafil: Increased effects and potential toxicity.
• Carbamazepine, Phenytoin, Rifampin: Strong CYP3A4 inducers can significantly reduce diltiazem plasma levels, reducing efficacy.
• Anesthetics: Additive hypotensive effects.
• Ivabradine: Contraindicated due to risk of excessive bradycardia.

Missed dose

If a dose of an immediate-release formulation is missed, it should be taken as soon as possible. However, if it is almost time for the next scheduled dose, the missed dose should be skipped, and the regular dosing schedule resumed. The dose should not be doubled. For once-daily extended-release formulations, take the missed dose as soon as remembered on the same day. If remembered the next day, skip the missed dose and resume the normal schedule. Do not take two doses on the same day. Patients should be counseled on the importance of adherence and the specific instructions for their prescribed formulation.

Overdose

Manifestations of overdose are primarily extensions of its pharmacological effects and include severe bradycardia, hypotension, heart failure, AV block, and cardiac arrest. Symptomatic management is primary. Treatment includes:

• Cardiovascular support: Administer IV fluids for hypotension. Vasopressors (e.g., dopamine, norepinephrine) may be required.
• Bradycardia/AV Block: Atropine, isoproterenol, or cardiac pacing.
• Calcium: Administration of calcium gluconate (1 g IV) or calcium chloride (10% solution) can help counteract the effects of calcium channel blockade, though effects may be transient.
• Inotropic support: In cases of decreased cardiac output, inotropic agents like dobutamine or dopamine may be necessary.
• General supportive measures, including airway management, should be instituted. Since diltiazem is highly protein-bound, hemodialysis is not likely to be beneficial.

Storage

Store at controlled room temperature, 20°C to 25°C (68°F to 77°F), in a tight, light-resistant container as defined in the USP. Protect from moisture and excessive heat. Keep all medications out of the reach of children and pets. Do not use after the expiration date printed on the container. Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Consult a pharmacist on proper disposal methods.

Disclaimer

This information is intended for educational purposes and as a professional reference for healthcare providers. It is not a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of a qualified physician or other authorized health provider with any questions regarding a medical condition or before initiating, altering, or discontinuing any course of treatment. Never disregard professional medical advice or delay in seeking it because of something contained in this document. The author and publisher are not responsible for any errors or omissions or for any outcomes resulting from the use of this information.

Reviews

• “Diltiazem remains a first-line agent in our cardiology practice for rate control in AFib. Its predictable pharmacokinetics and generally well-tolerated profile make it a reliable choice, especially in its extended-release forms for outpatient management.” – Cardiologist, 15 years experience
• “As a clinical pharmacist, I appreciate its role in hypertension management, particularly in patients where beta-blockers are contraindicated. The drug interaction profile is significant but manageable with careful review and patient monitoring.” – Clinical Pharmacist, Hospital Setting
• “From a primary care perspective, diltiazem is a versatile tool. However, it requires vigilant monitoring for bradycardia and edema in our elderly population. Patient education on not crushing ER tablets is crucial.” – Family Nurse Practitioner
• “The intravenous formulation is invaluable in the ICU for rapid, controlled rate reduction. Its short half-life allows for quick titration, but it demands continuous hemodynamic monitoring to avoid overshoot hypotension.” – Critical Care Intensivist