Calcium channel blockers

Calcium channel blockers (CCBs) are drugs that bind to and block L-type calcium channels, which are the predominant calcium channels in the myocardium and vascular smooth muscles. By blocking these channels, CCBs cause peripheral arterial vasodilation (leading to a drop in blood pressure) and myocardial depression (leading to negative chronotropic, inotropic, and dromotropic effects on the myocardium). CCBs are classified into two major groups according to the main site of action: Dihydropyridines (e.g., nifedipine, amlodipine) are potent vasodilators, and nondihydropyridines (e.g., verapamil) are potent myocardial depressants. Diltiazem, a common nondihydropyridine, has moderate vasodilatory and myocardial depressant effects. Nondihydropyridines are also categorized as class IV antiarrhythmic drugs and are used in the treatment of supraventricular arrhythmias. The most common indications for CCB use are arterial hypertension and stable angina. The main side effects of dihydropyridines are caused by vasodilation (e.g., headache, peripheral edema); those of nondihydropyridines are caused by myocardial depression (e.g., bradyarrhythmias, atrioventricular block). CCBs are contraindicated in patients with preexisting cardiac conduction disorders, symptomatic hypotension, and/or acute coronary syndrome.

• CCBs bind to and block L-type calcium channels in cardiac and vascular smooth muscle cells; → decreased frequency of Ca²⁺ channel opening in response to cell membrane depolarization; → decreased transmembrane Ca²⁺ current
• Effects of decreased Ca²⁺ influx
  • Vascular smooth muscle relaxation; → vasodilation → decreased peripheral vascular resistance → decreased afterload → decreased blood pressure
  • Decreased cardiac muscle contractility (negative inotropic action) → decreased cardiac output → decreased blood pressure
  • Decreased SA node discharge rate (negative chronotropic action); → decreased heart rate (bradycardia) → decreased cardiac output → decreased blood pressure
  • Decreased AV node conduction (negative dromotropic action) → termination of supraventricular arrhythmias
• Dihydropyridines act mainly on vascular smooth muscle. The order of potency is nifedipine/amlodipine followed by the nondihydropyridines verapamil and diltiazem.
• Nondihydropyridines act mainly on the heart. The order of potency is verapamil > diltiazem > amlodipine/nifedipine.

Dihydropyridine CCBs (nifedipine and amlodipine) primarily act on vascular smooth muscles. Nondihydropyridine CCBs (verapamil > diltiazem) primarily act on the heart.

Verapamil mainly acts on Ventricles and Amlodipine mainly acts on Arteries.

All CCBs ^[4]

• Arterial hypertension (esp. amlodipine )
• Stable angina: for patients with contraindications for beta blockers or who are not responsive to beta blockers
• Vasospastic angina (Prinzmetal angina)
• Achalasia
• Diffuse esophageal spasm

Dihydropyridines

• Raynaud phenomenon (e.g., nifedipine, felodipine)
• Subarachnoid hemorrhage; (e.g., nimodipine; , nicardipine) to prevent secondary vasospasm
• Tocolysis
• Gestational hypertension
• Hypertensive urgency/hypertensive emergency (e.g., nicardipine, clevidipine)
• Thromboangiitis obliterans

Nondihydropyridines

• Supraventricular arrhythmias (verapamil and diltiazem ;)
  • Supraventricular tachycardia
  • Atrial fibrillation, atrial flutter
• Cardiomyopathy (hypertrophic obstructive cardiomyopathy, restrictive cardiomyopathy)
• Migraine
• Verapamil: cluster headache

Short-acting CCBs (e.g., nifedipine) are not indicated for monotherapy of angina because they cause hypotension and secondary reflex tachycardia, which can worsen cardiac ischemia.

Dihydropyridines ^[5][6]

• Effects due to vasodilation
  • Peripheral edema (esp. amlodipine)
  • Headaches, dizziness
  • Facial flushing, feeling of warmth
  • Reflex tachycardia: a condition of tachycardia secondary to a decrease in blood pressure (esp. nifedipine)
    • Vasodilation lowers the blood pressure, which stimulates baroreceptors of the sympathetic nervous system, resulting in reflex tachycardia. ^[7]
    • May worsen symptoms of angina
• Gingival hyperplasia

Nondihydropyridines ^[6]

• Benzothiazepines: similar to those of the other CCB classes, but milder
• Phenylalkylamines
  • Reduced contractility
  • Bradycardia
  • AV block ^[8]
  • Gingival hyperplasia
  • Verapamil
    • Constipation
    • Hyperprolactinemia ^[9]

We list the most important adverse effects. The selection is not exhaustive.

All CCBs ^[10]

• Allergy/hypersensitivity to CCBs
• Symptomatic hypotension ^[11]
• Acute coronary syndrome ^[12]

Dihydropyridines

• Hypertrophic obstructive cardiomyopathy (HOCM) ^[13]
• Severe stenotic heart valve defects ^[11][14][15]

Nondihydropyridines ^[16]

• Preexisting cardiac conduction disorders
  • Wolff-Parkinson-White syndrome ^[17]
  • Sick sinus syndrome
  • Systolic dysfunction (in congestive heart failure)
  • Bradycardia
  • 2° AV block/3° AV block
• Combination with beta blockers: risk of AV block, bradycardia, and/or decreased cardiac contractility

Nondihydropyridine CCBs should not be combined with beta blockers because CCBs can enhance the negative inotropic, chronotropic, and dromotropic effects of beta blockers.

Phenylalkylamines (e.g., verapamil), which primarily affect the calcium channels of the heart, are contraindicated in cases of heart failure because of their negative effect on myocardial contractility.

We list the most important contraindications. The selection is not exhaustive.

Clinical features ^[18]

Patients are usually symptomatic but those who present early or have only consumed a small quantity of CCBs may be asymptomatic.

• Cardiovascular
  • Hypotension: may be profound, including cardiogenic shock
  • Cardiac arrhythmias
  • Cardiac arrest
• Respiratory: respiratory depression (including apnea), pulmonary edema
• Gastrointestinal: nausea and vomiting
• Central nervous system: confusion, lethargy, and coma

Diagnostics ^[19]

• Diagnosis is based on clinical observation and a thorough history
  • Determine the time of intake, type, amount, and preparation (extended-release vs. immediate-release) of the drug.
  • Assess for risk of self harm.
• Any ingestion exceeding the maximum therapeutic dosage is usually clinically relevant.

Laboratory tests ^[18]

• BMP: typically shows mild hyperglycemia and hyperkalemia
• VBG/ABG: metabolic acidosis

ECG ^[20]

May show any of the following associated arrhythmias:

• AV block
• AV dissociation
• Junctional rhythm
• Sinus bradycardia
• Tachycardia

Acute management ^[21]

Approach

• Assess hemodynamic stability.
  • Pulseless
    • Start CPR (see “Advanced cardiac life support”).
    • Give calcium IV.
    • Consider lipid emulsion therapy and VA-ECMO (see “Management of a refractory overdose of CCB”).
  • Hemodynamically unstable: combination therapy for stabilization (e.g., IV fluids, calcium, atropine, vasopressors)
  • Hemodynamically stable or asymptomatic patients: 24 hours of inpatient observation
• All patients
  • Consider decontamination.
  • Evaluate for ingestion of other substances (e.g., beta blockers)
  • Contact poison control center.
  • Admit for continuous cardiac monitoring.
  • Frequent blood pressure checks
  • Cardiology consult
  • All potentially intentional overdoses: psychiatry consult

Patients with CCB overdose require continuous cardiac monitoring because they can develop severe cardiovascular complications and deteriorate quickly.

Hemodynamically unstable patients

Management is complicated and specialists should be involved early. A combination of therapies is frequently required and should be tailored to the predominant symptoms.

• IV fluids
• Evidence of myocardial dysfunction
  • Calcium IV ^[21]
    • Calcium chloride
    • OR calcium gluconate
  • High-dose insulin therapy (with regular insulin) ^[20][21][22]
    • Patients are at risk of hypokalemia and hypoglycemia; treat prior to starting infusion and monitor throughout.
    • Blood glucose < 200 mg/dL (< 11.1 mmol/L): give dextrose IV
• Symptomatic bradycardia or conduction disorders: atropine
• Shock: vasopressor therapy
  • Norepinephrine
  • Consider the addition of another vasopressor for refractory shock
    • Epinephrine
    • Dobutamine

Patients on high-dose insulin infusions must have glucose regularly monitored.

Refractory overdose

• Escalating high-dose insulin therapy while maintaining euglycemia and normokalemia ^[22]
• Lipid emulsion therapy ^[21]
• Consider transcutaneous pacing in patients with unstable bradycardia or high-grade AV block.
• Consider VA-ECMO if available for patients in refractory shock and significant myocardial dysfunction.

Decontamination

Consider in all patients who present within the following time frames or who have taken sustained or extended-release preparations.

• Ingestion in the last hour: activated charcoal ^[23]
• Sustained or extended-release preparations: whole bowel irrigation