What are the properties of Coreg (carvedilol)?

Properties of Coreg (Carvedilol)

Pharmacological Mechanism

Carvedilol is a nonselective beta-blocker with combined β1, β2, and α1-adrenergic receptor blocking activity, distinguishing it from traditional beta-blockers through its vasodilatory properties. 1

• Beta-blocking effects: Blocks β1 receptors (primarily cardiac) and β2 receptors (vascular and bronchial smooth muscle), reducing heart rate, myocardial contractility, and AV node conduction velocity 2, 1
• Alpha-blocking effects: Blocks α1-adrenergic receptors, producing vasodilation and reducing both peripheral vascular resistance and intrahepatic resistance 2
• Receptor selectivity: Carvedilol has approximately 7 times higher potency for β1 and β2 receptors compared to α1 receptors, but at clinical doses (50-100 mg/day) it is essentially nonselective 3
• No intrinsic sympathomimetic activity: Unlike some beta-blockers (acebutolol, pindolol), carvedilol lacks partial agonist activity 2, 3

Hemodynamic Effects in Portal Hypertension

• Superior portal pressure reduction: Carvedilol produces greater reduction in portal pressure compared to traditional nonselective beta-blockers (propranolol, nadolol) due to its dual mechanism—reducing portal flow via beta-blockade while decreasing both porto-collateral and intrahepatic resistance via α1-blockade 2
• Mechanism in cirrhosis: Beta-blockade decreases cardiac output and splanchnic blood flow, while unopposed α1-adrenergic activity causes splanchnic vasoconstriction, reducing portal pressure 2
• Trade-off: The more profound α1-blocking effects produce greater systemic arterial hypotension, particularly problematic in decompensated cirrhosis patients 2

Cardiovascular Pharmacokinetics

• Bioavailability: Absolute bioavailability is only 25-35% due to extensive first-pass metabolism 1
• Absorption: Rapidly absorbed after oral administration; taking with food slows absorption rate (delays time to peak) but does not significantly affect extent of bioavailability—food administration minimizes orthostatic hypotension risk 1
• Half-life: Apparent mean terminal elimination half-life ranges from 7-10 hours 1
• Protein binding: More than 98% bound to plasma proteins, primarily albumin 1
• Volume of distribution: Approximately 115 L, indicating substantial distribution into extravascular tissues 1
• Metabolism: Extensively metabolized primarily by aromatic ring oxidation and glucuronidation; only 7% of total radioactivity in plasma is unchanged carvedilol 1
• Excretion: Less than 2% excreted unchanged in urine; metabolites excreted primarily via bile into feces 1

Metabolic Pathways and Drug Interactions

• Primary enzymes: CYP2D6 and CYP2C9 are the primary P450 enzymes responsible for metabolism, with lesser contributions from CYP3A4, 2C19, 1A2, and 2E1 1
• Genetic polymorphism: Poor metabolizers of debrisoquin (CYP2D6 deficient) exhibit 2-3 fold higher plasma concentrations of R(+)-carvedilol but only 20-25% higher S(-)-carvedilol levels 1
• Stereoselective metabolism: R(+)-carvedilol plasma levels are 2-3 times higher than S(-)-carvedilol; R(+) half-life is 5-9 hours versus 7-11 hours for S(-)-enantiomer 1
• Active metabolites: Demethylation and hydroxylation produce 3 active metabolites with β-receptor blocking activity; the 4'-hydroxyphenyl metabolite is approximately 13 times more potent than carvedilol for β-blockade but has weak vasodilating activity 1

Special Population Considerations

• Elderly patients: Plasma levels average 50% higher in elderly compared to young subjects 1
• Severe hepatic impairment: Patients with cirrhosis exhibit 4-7 fold increase in carvedilol levels; carvedilol is contraindicated in severe liver impairment 1
• Renal impairment: Plasma concentrations increase 40-50% in patients with moderate to severe renal impairment, though peak levels increase only 12-26%; not significantly cleared by hemodialysis due to high protein binding 1

Metabolic Profile Advantages

• Favorable metabolic effects: Carvedilol has a more favorable metabolic profile compared to traditional beta-blockers, with less negative impact on glycemic control 4, 5
• Lipid neutrality: Unlike β2-selective blockers, carvedilol's α-blocking properties offset adverse effects on lipid status 5, 6
• Glucose metabolism: The α-blocking component may overcome β2-mediated adverse effects on glycemic control 5

Additional Pharmacological Properties

• Antioxidant activity: Carvedilol and its metabolites inhibit lipid peroxidation, scavenge oxygen free radicals, and prevent depletion of endogenous antioxidants (vitamin E, glutathione) 7
• LDL oxidation inhibition: Blocks oxidation of low-density lipoproteins, potentially preventing foam cell formation and atherosclerotic plaque development 7
• Antiproliferative effects: Inhibits vascular smooth muscle cell proliferation and migration induced by various mitogens (growth factors, angiotensin II, endothelin, thrombin) 7
• Neurohumoral effects: Little effect on plasma catecholamines, aldosterone, or electrolyte levels, but significantly reduces plasma renin activity after at least 4 weeks of therapy; increases atrial natriuretic peptide levels 1

Clinical Dosing

• Standard dosing range: 6.25 mg twice daily, uptitrated to a maximum of 25 mg twice daily for angina 2
• Heart failure target dose: 25-50 mg twice daily 4, 8
• Initiation strategy: Start low and titrate slowly, particularly in elderly patients and those with heart failure 4

Contraindications and Precautions

• Absolute contraindications: Severe liver impairment, asthma (as with all nonselective beta-blockers) 1, 5
• Relative contraindications: Marked first-degree AV block (PR interval >0.24 seconds), second- or third-degree AV block without pacemaker, severe LV dysfunction or heart failure during acute initiation, high risk for cardiogenic shock 2
• Major adverse effect: Postural dizziness, especially in elderly patients, related to α1-blocking vasodilatory properties 5, 6