Class 4 Antiarrhythmic Drugs (Calcium Channel Blockers)

Calcium channel blockers (CCBs) are a class of medications that inhibit voltage-dependent L-type calcium channels of cardiac and vascular smooth muscle cells. The inhibition of these channels produces vasodilation and myocardial depression. There are 2 major classes of CCBs: dihydropyridines and non-dihydropyridines, which differ in their selectivity for cardiac or vascular smooth muscle cells. Broadly, these agents are used to treat hypertension, angina, and tachyarrhythmias. Side effects are from vasodilation (headache, peripheral edema, reflex tachycardia) or a consequence of reduced myocardial contractility and nodal conduction velocity (bradycardia).

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Calcium channel blockers (CCBs)

  • Medications that block the L-type calcium channels (mostly found in the myocardium, vascular smooth muscles, and pancreatic β islet cells)
  • Common uses: hypertension, angina, and supraventricular dysrhythmias

Pharmacologic classes

  • Dihydropyridine: 
    • Binds more selectively to vascular smooth muscle calcium channels (vasodilator)
    • Can lead to reflex tachycardia
    • Example: amlodipine
  • Non-dihydropyridine:
    • Affects the heart contractility and conduction and with less effect on vasodilation
    • Does not lead to reflex tachycardia
    • Benzothiazepine:
      • Mainly acts on the myocardium (myocardial depressant), with some effect on vascular smooth muscles 
      • Acts as a cardiac depressant and a vasodilator
      • Example: diltiazem 
    • Phenylalkylamine:
      • Acts on cardiac myocytes (strong myocardial depressant), with minimal effect on the vascular smooth muscles
      • Example: verapamil


  • Cardiac muscle contraction involves:
    • Action potential generation produced by the sinoatrial (SA) node 
    • Impulse conduction to the atrial cardiac myocytes → the atrioventricular node → ventricular myocytes
  • Contractile cardiac myocyte action potential:
    • Depolarization: Fast-voltage gated sodium channels open, and sodium enters the cell. 
    • Plateau: 
      • Sodium channels close; some potassium moves outward.
      • Calcium ions enter via the L-type calcium channels. 
      • Release of calcium from the sarcoplasmic reticulum is triggered, facilitating myocyte contraction.
    • Repolarization: 
      • Calcium channels close and with increased potassium efflux. 
      • Intracellular calcium decreases and myocytes relax.
  • Cardiovascular effects of calcium entry to the cells:
    • Myocardial contraction
    • Smooth muscle contraction (vascular smooth muscles are the most sensitive)
    • SA node impulse generation 
    • Atrioventricular (AV) node conduction
Cardiac myocyte action potential

Cardiac myocyte action potential:
1. Sodium channels open, and sodium enters the cell.
2. Sodium channels close; some potassium moves outward. Intracellular calcium increases from entry through L-type calcium channels and release of calcium from the sarcoplasmic reticulum.
3. Calcium channels close and with increased potassium efflux. Cardiac myocytes relax.

Image: “Action Potential in Cardiac Contractile Cells” by Philschatz. License: CC BY 4.0, edited by Lecturio

Pharmacology of CCB

Mechanism of action

  • CCBs bind the L-type calcium channels in cardiac myocytes, cardiac nodal tissues, and vascular smooth muscle cells leading to:
    • Closed L- type channels
    • Decreased calcium entry
Antiarrhythmics mechanism of action

Diagram demonstrating a cardiac action potential and the phases of action for different antiarrhythmic drug classes:
The cycle begins with phase 4, the resting potential. Phase 0 is when rapid depolarization happens due to an influx of sodium ions into the cell. Repolarization follows, with an efflux of potassium through fast potassium channels in phase 1, calcium influx in phase 2 causing a plateau (site of action for calcium channel blockers), and an efflux of potassium through delayed potassium channels in phase 3.

Image by Lecturio.


  • Smooth muscle relaxation (especially vascular muscles) → systemic vasodilation:
    • Reduction of cardiac afterload: ↓ blood pressure (effective in hypertension) 
    • Dihydropyridines > diltiazem > verapamil
  • Reduced myocardial contractility:
    • Negative inotropic effect
    • ↓ cardiac output (CO), ↓ blood pressure 
    •  Reduces the oxygen demand of the myocardium (effective in angina)
    • Verapamil, diltiazem 
  • Decreased atrioventricular node conduction velocity:
    • Negative dromotropic effect
    • Slows conduction through AV node (used in supraventricular arrhythmia)
    • Verapamil, diltiazem
  • Decreased automaticity (SA node effect):
    • Negative chronotropic effect
    • ↓ heart rate, ↓ CO, ↓ blood pressure 
    • Verapamil, diltiazem
Cardiovascular effects of calcium channel blockers (CCBs)

Cardiovascular effects of calcium channel blockers
1. Calcium channel blockers slow down the sinoatrial node, causing lowered heart rate.
2. Calcium channel blockers intake leads to vascular smooth muscle relaxation, causing vasodilation.

Image by Lecturio.

Absorption and excretion

  • Dosage forms: oral, intravenous
  • Metabolism: hepatic first-pass metabolism, primarily by CYP3A4
  • Drug interactions:
    • Rifampicin: accelerates CCB breakdown
    • Protease inhibitors, macrolide antibiotics, fluconazole, and grapefruit juice: inhibit CCB breakdown
  • Excretion: renal 


Drug classExamplesIndicationsKey points
DihydropyridinesNifedipine, nicardipine, amlodipine, felodipine, nimodipine
  • Hypertension
  • Stable angina
  • Vasospastic angina/coronary vasospasm
  • Cerebral vasospasm (especially nimodipine prophylaxis after subarachnoid hemorrhage)
  • Raynaud’s phenomenon (especially amlodipine)
  • Vasodilators; + risk of reflex tachycardia
  • Amlodipine: long half-life (up to 50 hours); safer and preferred
  • Nifedipine: short half-life (2–5 hours); can be infused
  • Hypertension
  • Stable angina
  • Vasospastic angina/coronary vasospasm
  • Supraventricular tachyarrhythmias without accessory pathways (atrial fibrillation)
  • Esophageal hyperperistalsis
  • Myocardial depression; blunts the reflex tachycardia caused by vasodilation
  • Stable angina
  • Coronary vasospasm
  • Supraventricular tachyarrhythmias without accessory pathways (atrial fibrillation)
  • Cluster headache prophylaxis
  • Migraine prophylaxis
  • Much less vasodilation than other classes
  • Among CCBs, verapamil has the most potent negative inotropic effect.

Adverse Effects

  • Dihydropyridines:
    • Headache (cerebral vasodilation)
    • Reflex tachycardia (especially with short-acting nifedipine)
    • Hypotension
    • Flushing
    • Peripheral edema (dose-dependent; usually with amlodipine)
    • Gingival hyperplasia
  • Non-dihydropyridines:
    • Constipation (dose-dependent)
    • Fatigue
    • Bradycardia
    • AV nodal block
    • Worsening of cardiac output
    • Gingival hyperplasia


  • Common contraindications:
    • Hypotension
    • Hypersensitivity to CCBs
    • Acute coronary syndrome:
      • Avoid nifedipine or short-acting dihydropyridines.
      • Short-acting dihydropyridines cause reflex tachycardia and worsen myocardial ischemia.
  • Contraindications to non-dihydropyridines:
    • Heart failure with a reduced ejection fraction 
    • Sick sinus syndrome
    • 2nd and 3rd AV block
    • Supraventricular tachyarrhythmias caused by an accessory pathway (i.e., Wolff-Parkinson-White syndrome)
    • Avoid using with β-blockers.
  • Contraindications to dihydropyridines:
    • Moderate to severe aortic stenosis
    • Hypertrophic obstructive cardiomyopathy


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  3. Katzung B.G. (2017). Vasodilators & the treatment of angina pectoris. Katzung B.G.(Ed.), Basic & Clinical Pharmacology, 14th ed. McGraw-Hill.
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