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Sunday, July 27, 2025

Carvedilol


Carvedilol is a non-selective β-adrenergic receptor blocker with additional α1-adrenergic blocking properties, used primarily in the treatment of cardiovascular diseases such as hypertension, heart failure, and post-myocardial infarction management. Its unique vasodilatory effect sets it apart from other traditional beta-blockers, making it a preferred option in certain patient populations with both cardiac and vascular dysfunction.

This comprehensive professional monograph reviews carvedilol's pharmacological profile, mechanisms of action, clinical uses, dosing, safety considerations, contraindications, side effects, and interaction profile, with references from leading drug compendia and regulatory authorities.

Pharmacological Classification

  • Therapeutic class: Antihypertensive, Heart failure agent

  • Pharmacologic class: Non-selective beta-adrenergic antagonist with alpha-1 blockade

  • ATC code: C07AG02

Brand Names and Formulations

  • Coreg® (US)

  • Dilatrend®, Eucardic®, Carloc®, Carvipress® (various markets)

  • Generic name: Carvedilol

  • Available formulations:

    • Immediate-release tablets: 3.125 mg, 6.25 mg, 12.5 mg, 25 mg

    • Controlled-release capsules (Coreg CR): 10 mg, 20 mg, 40 mg, 80 mg

Mechanism of Action

Carvedilol exerts its therapeutic effects through dual adrenergic receptor antagonism:

  1. Beta-1 blockade:

    • Reduces heart rate (negative chronotropic effect)

    • Decreases myocardial contractility (negative inotropic effect)

    • Lowers cardiac output and oxygen demand

  2. Beta-2 blockade:

    • Causes vasoconstriction in some vascular beds (offset by α1-blockade)

    • May impair bronchodilation

  3. Alpha-1 blockade:

    • Induces peripheral vasodilation

    • Reduces systemic vascular resistance (SVR)

    • Lowers blood pressure without reflex tachycardia

Carvedilol also exhibits antioxidant, anti-inflammatory, and antiproliferative effects, which may contribute to its benefits in heart failure and myocardial remodeling.

Clinical Indications

Approved Uses

  • Hypertension: As monotherapy or in combination with other antihypertensives

  • Chronic heart failure (NYHA Class II–IV): Especially systolic dysfunction

  • Left ventricular dysfunction following myocardial infarction

  • Angina pectoris (off-label use in many regions)

Off-label or Adjunctive Uses

  • Atrial fibrillation with rapid ventricular response

  • Portal hypertension and variceal bleeding prophylaxis

  • Hypertrophic cardiomyopathy

  • Anxiety-related tachycardia

  • Migraine prophylaxis

Dosage and Administration

Hypertension

  • Initial dose: 6.25 mg orally twice daily

  • Maintenance: 6.25–25 mg twice daily

  • Maximum: 50 mg/day (25 mg twice daily)

Heart Failure

  • Initial dose: 3.125 mg twice daily for 2 weeks

  • Titration: Increase to 6.25 mg, 12.5 mg, then 25 mg twice daily at 2-week intervals if tolerated

  • Target dose:

    • ≤85 kg: 25 mg twice daily

    • 85 kg: up to 50 mg twice daily

Post-Myocardial Infarction with LV Dysfunction

  • Same titration protocol as heart failure

  • Initiate after hemodynamic stabilization

Elderly or Hepatic Impairment

  • Begin at lowest possible dose; careful titration is essential

Pharmacokinetics

  • Bioavailability: ~25–35% due to first-pass hepatic metabolism

  • Protein binding: >95%

  • Peak plasma concentration: 1–2 hours (immediate-release); 5 hours (CR)

  • Half-life: 7–10 hours

  • Metabolism: Extensive hepatic (CYP2D6, CYP2C9)

  • Excretion: Primarily fecal (biliary); minor renal

  • Onset of action: 1–2 hours for blood pressure reduction

Contraindications

  • Asthma or severe chronic obstructive pulmonary disease (COPD) with bronchospasm

  • Second- or third-degree AV block, unless pacemaker present

  • Severe bradycardia (<50 bpm)

  • Cardiogenic shock

  • Decompensated heart failure requiring IV inotropes

  • Severe hepatic impairment

  • Known hypersensitivity to carvedilol or components

Precautions and Warnings

  • Bradycardia: May require dose reduction or discontinuation

  • Hypotension: Especially postural; titrate slowly, monitor BP

  • Worsening heart failure: Fluid retention may require diuretics adjustment

  • Bronchospasm: Risk in reactive airway disease; use cardioselective agents instead

  • Hepatic dysfunction: Elevated transaminases may occur

  • Diabetes: Masks hypoglycemia symptoms (e.g., tachycardia)

  • Thyrotoxicosis: May mask hyperthyroid symptoms

  • Surgical anesthesia: Risk of bradycardia and hypotension under anesthesia

  • Abrupt withdrawal: Avoid; taper over 1–2 weeks to prevent rebound hypertension or ischemia

Adverse Effects

Very Common (>10%)

  • Dizziness, fatigue

  • Hypotension, especially orthostatic

  • Bradycardia

Common (1–10%)

  • Diarrhea, nausea, vomiting

  • Weight gain, fluid retention

  • Asthenia

  • Vision disorders

  • Hyperglycemia, especially in diabetic patients

  • Depression, insomnia

Uncommon (<1%)

  • Worsening heart failure

  • Bronchospasm

  • Syncope

  • Thrombocytopenia, leukopenia

  • Impotence, libido changes

Rare (<0.1%)

  • Hepatic dysfunction: elevated ALT, AST, bilirubin

  • Anaphylaxis, angioedema

  • Stevens-Johnson syndrome, toxic epidermal necrolysis

  • Psoriasis flare

  • Agranulocytosis

Drug Interactions

Pharmacodynamic

  • Calcium channel blockers (e.g., verapamil, diltiazem): additive bradycardia and AV block

  • Digitalis glycosides: risk of bradycardia and AV block

  • CNS depressants: additive sedation and fatigue

  • Antihypertensives: enhanced hypotensive effect

  • Clonidine: do not withdraw clonidine before discontinuing carvedilol (risk of rebound hypertension)

  • Insulin or sulfonylureas: masks hypoglycemic symptoms

Pharmacokinetic

  • CYP2D6 inhibitors (fluoxetine, quinidine, bupropion): ↑ carvedilol levels

  • Amiodarone: increased risk of bradycardia, conduction disturbances

  • Rifampin: induces metabolism → ↓ carvedilol plasma levels

  • Cimetidine: may increase carvedilol levels

  • Cyclosporine: carvedilol may increase its levels; monitor levels closely

Pregnancy and Lactation

Pregnancy

  • Category C (US FDA)

  • Animal studies show fetal harm at high doses; human data limited

  • Use only if potential benefit justifies potential risk

  • Monitor fetal growth, uteroplacental perfusion if used

Lactation

  • Unknown if carvedilol is excreted in breast milk

  • Consider alternatives or monitor infant for bradycardia/hypotension if used

Use in Special Populations

  • Elderly: Increased risk of hypotension and bradycardia; start at lower dose

  • Renal impairment: No dose adjustment typically needed; monitor renal function if used in CHF

  • Hepatic impairment: Use is contraindicated in severe impairment

  • Pediatrics: Not FDA approved; limited data available

Counseling Points

  • Take carvedilol with food to reduce risk of orthostatic hypotension

  • Do not abruptly discontinue; taper over 1–2 weeks

  • Monitor BP, pulse, and blood glucose (if diabetic)

  • Report symptoms of dizziness, worsening heart failure, cold extremities, or breathing difficulty

  • Rise slowly from sitting or lying position

  • Avoid alcohol, OTC cold remedies, and NSAIDs without clinician approval

  • Inform surgeon/anesthetist before surgery if taking carvedilol

  • Store tablets at room temperature, away from moisture and heat

Comparison to Other Beta Blockers

  • Compared to atenolol or metoprolol: has additional alpha-1 blocking (vasodilating) action

  • Less cardioselective: caution in asthma/COPD

  • Preferred in heart failure (with bisoprolol and metoprolol succinate)

  • Longer half-life than atenolol

  • Offers better blood pressure reduction due to vasodilation



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