| Indication |
For the treatment of mild or moderate (NYHA class II or III) heart failure of ischemic or cardiomyopathic origin. |
| Pharmacodynamics |
Carvedilol is a nonselective beta-adrenergic blocking agent with
alpha1-blocking activity and is indicated for the treatment of
hypertension and mild or moderate (NYHA class II or III) heart failure
of ischemic or cardiomyopathic origin. Carvedilol is a racemic mixture
in which nonselective b-adrenoreceptor blocking activity is present in
the S(-) enantiomer and a-adrenergic blocking activity is present in
both R(+) and S(-) enantiomers at equal potency. Carvedilol has no
intrinsic sympathomimetic activity. The effect of carvedilol's
b-adrenoreceptor blocking activity has been demonstrated in animal and
human studies showing that carvedilol (1) reduces cardiac output in
normal subjects; (2) reduces exercise-and/or isoproterenol-induced
tachycardia and (3) reduces reflex orthostatic tachycardia. |
| Mechanism of action |
Carvedilol is a racemic mixture in which nonselective
beta-adrenoreceptor blocking activity is present in the S(-) enantiomer
and alpha-adrenergic blocking activity is present in both R(+) and S(-)
enantiomers at equal potency. Carvedilol's beta-adrenergic receptor
blocking ability decreases the heart rate, myocardial contractility, and
myocardial oxygen demand. Carvedilol also decreases systemic vascular
resistance via its alpha adrenergic receptor blocking properties.
Carvedilol and its metabolite BM-910228 (a less potent beta blocker, but
more potent antioxidant) have been shown to restore the inotropic
responsiveness to Ca2+ in OH- free radical-treated myocardium. Carvedilol and its metabolites also prevent OH- radical-induced decrease in sarcoplasmic reticulum Ca2+-ATPase
activity. Therefore, carvedilol and its metabolites may be beneficial
in chronic heart failure by preventing free radical damage. |
| Absorption |
Carvedilol is rapidly and extensively absorbed following oral
administration, with an absolute bioavailability of approximately 25% to
35% due to a significant degree of first-pass metabolism. |
| Volume of distribution |
|
| Protein binding |
98% |
| Metabolism |
Hepatic. Carvedilol is metabolized primarily by aromatic ring
oxidation and glucuronidation. The oxidative metabolites are further
metabolized by conjugation via glucuronidation and sulfation.
Demethylation and hydroxylation at the phenol ring produce three active
metabolites with b-receptor blocking activity. The 4'-hydroxyphenyl
metabolite is approximately 13 times more potent than carvedilol for
b-blockade. |
| Route of elimination |
Carvedilol is extensively metabolized. Less than 2% of the dose
was excreted unchanged in the urine.
Carvedilol is metabolized primarily by aromatic ring oxidation and
glucuronidation. The oxidative metabolites are further metabolized by
conjugation via glucuronidation and sulfation. The metabolites of
carvedilol are excreted primarily via the bile into the feces. |
| Half life |
7-10 hours |
| Clearance |
|
| Toxicity |
Not expected to be toxic following ingestion. |
