Half-Life of Carvedilol
The half-life of carvedilol ranges from 7 to 10 hours following oral administration, with significant first-pass metabolism resulting in an absolute bioavailability of approximately 25% to 35%. 1
Pharmacokinetic Profile
Carvedilol is a beta-blocker with additional alpha-1 blocking properties that exhibits the following pharmacokinetic characteristics:
- Absorption: Rapidly and extensively absorbed after oral administration
- Bioavailability: 25-35% due to significant first-pass metabolism 1
- Peak concentration: Reached within 1-2 hours post-dose 2
- Food effect: Taking carvedilol with food delays absorption but does not affect overall bioavailability; this is recommended to minimize orthostatic hypotension risk 1
- Protein binding: >98% bound to plasma proteins, primarily albumin 1
- Volume of distribution: Approximately 115 L, indicating substantial distribution into extravascular tissues 1
- Plasma clearance: 500-700 mL/min 1
Metabolism and Elimination
Carvedilol undergoes extensive metabolism with several important characteristics:
- Metabolic pathway: Primarily metabolized by aromatic ring oxidation and glucuronidation 1
- Enzymes involved: CYP2D6 and CYP2C9 are the primary P450 enzymes responsible for metabolism, with lesser contributions from CYP3A4, 2C19, 1A2, and 2E1 1
- Stereoselective metabolism: Carvedilol is a racemic mixture with the R(+)-enantiomer having plasma levels approximately 2-3 times higher than the S(-)-enantiomer 1
- Active metabolites: Three active metabolites with β-receptor blocking activity are produced, with the 4'-hydroxyphenyl metabolite being approximately 13 times more potent than carvedilol for β-blockade 1
- Elimination: Less than 2% of the dose is excreted unchanged in urine; metabolites are primarily excreted via bile into feces 1
Special Populations
The pharmacokinetics of carvedilol are affected by various patient factors:
- Elderly: Plasma levels average about 50% higher compared to young subjects 1
- Hepatic impairment: Severe liver impairment (cirrhosis) results in a 4-7 fold increase in carvedilol levels; carvedilol is contraindicated in these patients 1
- Renal impairment: Patients with moderate to severe renal impairment show approximately 40-50% higher plasma concentrations compared to those with normal renal function 1, 3
- Hemodialysis: Due to high protein binding, carvedilol is not significantly cleared by hemodialysis 1
Clinical Implications
Understanding carvedilol's half-life has important clinical implications:
- Dosing frequency: Typically administered twice daily due to its half-life 4
- Controlled-release formulation: A controlled-release formulation has been developed for once-daily dosing 5
- Starting dose: For heart failure, recommended starting dose is 3.125 mg twice daily 4
- Target dose: 25-50 mg twice daily for heart failure management 4
- Discontinuation: Should not be stopped suddenly due to risk of rebound increases in myocardial ischemia/infarction and arrhythmias 4
Comparison to Other Beta-Blockers
Different beta-blockers have varying half-lives that affect their dosing schedules:
- Carvedilol: 7-10 hours (twice daily dosing) 1
- Metoprolol tartrate: Shorter half-life requiring twice daily dosing 6
- Metoprolol succinate: Extended-release formulation allowing once-daily dosing 6
- Bisoprolol: Longer half-life allowing once-daily dosing 4
The half-life of carvedilol makes it suitable for twice-daily dosing in most clinical scenarios, with careful consideration needed for patients with hepatic or renal impairment due to potential accumulation.