Calcium channel blockers

1. Introduction

• Calcium channel blockers are a class of drugs that inhibit the influx of calcium ions (Ca²⁺) through voltage-gated calcium channels in cell membranes.

• Primarily used in the management of hypertension, angina pectoris, and certain cardiac arrhythmias.

• Reduce myocardial oxygen demand and vascular tone by affecting cardiac and vascular smooth muscle.

• Also known as calcium antagonists.

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2. Mechanism of Action

• Block L-type calcium channels in vascular smooth muscle, cardiac muscle, and cardiac conduction tissue.

• Vascular smooth muscle: inhibition → relaxation → vasodilation → reduced systemic vascular resistance (afterload).

• Cardiac muscle: decreased calcium entry → reduced contractility (negative inotropy).

• Cardiac conduction system: slowed conduction through the AV node (negative dromotropy) and reduced heart rate (negative chronotropy) in non-dihydropyridine CCBs.

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3. Classification

A. Dihydropyridines (DHPs) – potent vasodilators, minimal cardiac conduction effects

• Amlodipine

• Felodipine

• Nifedipine

• Nicardipine

• Lercanidipine

• Clevidipine

B. Non-Dihydropyridines (Non-DHPs) – significant effects on cardiac conduction and contractility

• Phenylalkylamine: Verapamil – strong cardiac effects, moderate vasodilation

• Benzothiazepine: Diltiazem – intermediate cardiac and vascular effects

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4. Pharmacokinetics (General Trends)

• Absorption: well absorbed orally; bioavailability affected by first-pass metabolism.

• Distribution: high protein binding.

• Metabolism: hepatic via CYP3A4 for most agents.

• Elimination: renal and biliary; dose adjustments may be needed in hepatic impairment.

• Half-life: varies widely (e.g., amlodipine ~30–50 hours, verapamil ~3–7 hours).

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5. Therapeutic Indications

Cardiovascular

• Hypertension (first-line for many patients, particularly older adults and those of African descent).

• Chronic stable angina.

• Vasospastic (Prinzmetal’s) angina.

• Supraventricular tachyarrhythmias (e.g., atrial fibrillation, atrial flutter – non-DHPs).

• Hypertrophic cardiomyopathy (symptom control with verapamil).

Other

• Raynaud’s phenomenon (vasospastic disorder).

• Certain cerebrovascular conditions (nimodipine for subarachnoid hemorrhage vasospasm prevention).

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6. Contraindications

General

• Severe hypotension (SBP < 90 mmHg).

• Known hypersensitivity to the drug.

Non-DHP specific

• Severe left ventricular dysfunction.

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

• Sick sinus syndrome (without pacemaker).

• Acute decompensated heart failure.

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7. Adverse Effects

Common – DHPs

• Peripheral edema (ankles, feet).

• Flushing, headache.

• Reflex tachycardia (more with short-acting agents).

Common – Non-DHPs

• Bradycardia, AV block.

• Constipation (notably with verapamil).

• Worsening heart failure in susceptible patients.

Serious (all types)

• Severe hypotension.

• Exacerbation of myocardial ischemia (if excessive hypotension).

• Rare hepatic dysfunction.

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8. Drug Interactions

• CYP3A4 inhibitors (e.g., ketoconazole, grapefruit juice) ↑ CCB levels.

• CYP3A4 inducers (e.g., rifampin, carbamazepine) ↓ CCB levels.

• Beta-blockers: additive cardiac depressant effects with non-DHPs → risk of bradycardia, AV block.

• Digoxin: verapamil and diltiazem increase digoxin levels by reducing clearance.

• Statins: some CCBs increase statin concentrations, raising myopathy risk.

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9. Special Precautions

• Monitor blood pressure, heart rate, and signs of heart failure during therapy.

• Dose adjustments in hepatic impairment due to metabolism changes.

• Avoid abrupt withdrawal in angina patients – risk of rebound ischemia.

• In elderly patients, start at lower doses to minimize hypotension.

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10. Advantages and Limitations

Advantages

• Effective across diverse populations for hypertension control.

• Do not cause electrolyte disturbances like diuretics.

• Useful in patients with concurrent angina and hypertension.

Limitations

• Peripheral edema can limit tolerance.

• Non-DHPs not suitable for patients with certain conduction disorders or systolic heart failure.

• Some agents have significant drug–drug interaction potential.