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| __NOTOC__
| | #REDIRECT [[Carvedilol#Pharmacology]] |
| {{Carvedilol}}
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| {{CMG}}; {{AE}} {{AZ}}
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| ==Clinical Pharmacology==
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| ===Mechanism of Action===
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| COREG is a racemic mixture in which nonselective β-adrenoreceptor blocking activity is present in the S(-) enantiomer and α1-adrenergic blocking activity is present in both R(+) and S(-) enantiomers at equal potency. COREG has no intrinsic sympathomimetic activity.
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| ===Pharmacodynamics===
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| ====Heart Failure====
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| :*The basis for the '''beneficial effects''' of COREG in heart failure is '''not established.'''
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| :*Two placebo‑controlled trials compared the acute hemodynamic effects of COREG with baseline measurements in 59 and 49 subjects with NYHA class II‑IV heart failure receiving [[diuretics]], [[ACE inhibitors]], and [[digitalis]]. There were significant reductions in systemic blood pressure, pulmonary artery pressure, pulmonary capillary wedge pressure, and heart rate. Initial effects on cardiac output, stroke volume index, and systemic vascular resistance were small and variable.
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| :*These trials measured hemodynamic effects again at 12 to 14 weeks. COREG significantly '''reduced systemic blood pressure, pulmonary artery pressure, right atrial pressure, systemic vascular resistance, and heart rate''', while stroke volume index was increased.
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| :*Among 839 subjects with NYHA class II‑III heart failure treated for 26 to 52 weeks in 4 US placebo‑controlled trials, average left ventricular ejection fraction (EF) measured by radionuclide ventriculography increased by 9 EF units (%) in subjects receiving COREG and by 2 EF units in placebo subjects at a target dose of 25 to 50 mg twice daily.
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| :*'''The effects of carvedilol on ejection fraction were related to dose'''. <u>Doses of 6.25 mg twice daily, 12.5 mg twice daily, and 25 mg twice daily</u> were associated with placebo‑corrected increases in EF of 5 EF units, 6 EF units, and 8 EF units, respectively; each of these effects were nominally statistically significant.
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| ====Left Ventricular Dysfunction Following Myocardial Infarction====
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| The basis for the beneficial effects of COREG in patients with left ventricular dysfunction following an [[acute myocardial infarction]] is not established.
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| ====Hypertension====
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| The mechanism by which β-blockade produces an antihypertensive effect has not been established.
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| :*β-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]]. Significant β-adrenoreceptor blocking effect is usually seen within 1 hour of drug administration.
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| :*α1-adrenoreceptor blocking activity has been demonstrated in human and animal studies, showing that carvedilol (1) attenuates the pressor effects of [[phenylephrine]]; (2) causes vasodilation; and (3) reduces peripheral vascular resistance. These effects contribute to the reduction of blood pressure and usually are seen within 30 minutes of drug administration.
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| :*Due to the α1-receptor blocking activity of carvedilol, blood pressure is lowered more in the standing than in the supine position, and symptoms of postural hypotension (1.8%), including rare instances of syncope, can occur. Following oral administration, when [[postural hypotension]] has occurred, it has been transient and is uncommon when COREG is administered with food at the recommended starting dose and titration increments are closely followed [see Dosage and Administration (2)].
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| :*In hypertensive patients with normal renal function, therapeutic doses of COREG decreased renal vascular resistance with no change in glomerular filtration rate or renal plasma flow. Changes in excretion of sodium, potassium, uric acid, and phosphorus in hypertensive patients with normal renal function were similar after COREG and placebo.
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| :*COREG has little effect on plasma [[catecholamines]], plasma [[aldosterone]], or electrolyte levels, but it does significantly reduce plasma renin activity when given for at least 4 weeks. It also increases levels of [[atrial natriuretic peptide]].
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| ===Pharmacokinetics===
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| :*COREG is rapidly and extensively absorbed following oral administration, with absolute bioavailability of approximately 25% to 35% due to a significant degree of first-pass metabolism. Following oral administration, the apparent mean terminal elimination half-life of carvedilol generally ranges from 7 to 10 hours. Plasma concentrations achieved are proportional to the oral dose administered. When administered with food, the rate of absorption is slowed, as evidenced by a delay in the time to reach peak plasma levels, with no significant difference in extent of bioavailability. Taking COREG with food should minimize the risk of[[ orthostatic hypotension]].
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| :*'''Carvedilol is extensively metabolized'''. Following oral administration of radiolabelled carvedilol to healthy volunteers, carvedilol accounted for only about 7% of the total radioactivity in plasma as measured by area under the curve (AUC). 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. Demethylation and hydroxylation at the phenol ring produce 3 active metabolites with β-receptor blocking activity. Based on preclinical studies, the 4'-hydroxyphenyl metabolite is approximately 13 times more potent than carvedilol for β-blockade.
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| :*Compared with carvedilol, the 3 active metabolites exhibit weak vasodilating activity. Plasma concentrations of the active metabolites are about one-tenth of those observed for carvedilol and have pharmacokinetics similar to the parent.
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| :*Carvedilol undergoes stereoselective first-pass metabolism with plasma levels of R(+)-carvedilol approximately 2 to 3 times higher than S(-)-carvedilol following oral administration in healthy subjects. The mean apparent terminal elimination half-lives for R(+)-carvedilol range from 5 to 9 hours compared with 7 to 11 hours for the S(-)-enantiomer.
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| :*The primary P450 enzymes responsible for the metabolism of both R(+) and S(-)-carvedilol in human liver microsomes were CYP2D6 and CYP2C9 and to a lesser extent CYP3A4, 2C19, 1A2, and 2E1. CYP2D6 is thought to be the major enzyme in the 4’- and 5’-hydroxylation of carvedilol, with a potential contribution from 3A4. CYP2C9 is thought to be of primary importance in the O-methylation pathway of S(-)-carvedilol.
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| :*Carvedilol is subject to the effects of genetic[[ polymorphism]] with poor metabolizers of debrisoquin (a marker for cytochrome P450 2D6) exhibiting 2- to 3-fold higher plasma concentrations of R(+)-carvedilol compared with extensive metabolizers. In contrast, plasma levels of S(-)-carvedilol are increased only about 20% to 25% in poor metabolizers, indicating this enantiomer is metabolized to a lesser extent by cytochrome P450 2D6 than R(+)-carvedilol. The pharmacokinetics of carvedilol do not appear to be different in poor metabolizers of S-mephenytoin (patients deficient in cytochrome P450 2C19).
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| :*Carvedilol is more than 98% bound to plasma proteins, primarily with [[albumin]]. The plasma-protein binding is independent of concentration over the therapeutic range. Carvedilol is a basic, lipophilic compound with a steady-state volume of distribution of approximately 115 L, indicating substantial distribution into extravascular tissues. Plasma clearance ranges from 500 to 700 mL/min.<ref name="dailymed.nlm.nih.gov">{{Cite web | last = | first = | title = COREG (CARVEDILOL) TABLET, FILM COATED [GLAXOSMITHKLINE LLC] | url =http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=c57982f2-c7da-488a-7ea9-b9609439ac68#nlm34089-3 | publisher = | date = | accessdate = }}</ref>
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| ===Special Populations===
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| ====Heart Failure====
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| [[Steady‑state ]]plasma concentrations of carvedilol and its enantiomers increased proportionally over the 6.25 to 50 mg dose range in subjects with heart failure. Compared with healthy subjects, heart failure subjects had increased mean AUC and Cmax values for carvedilol and its enantiomers, with up to 50% to 100% higher values observed in 6 subjects with NYHA class IV heart failure. The mean apparent terminal elimination half‑life for carvedilol was similar to that observed in healthy subjects.
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| ====Geriatric====
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| Plasma levels of carvedilol average about 50% higher in the elderly compared with young subjects.
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| ====Hepatic Impairment====
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| Compared with healthy subjects, patients with severe liver impairment ([[cirrhosis]]) exhibit a 4- to 7-fold increase in carvedilol levels.
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| Carvedilol is contraindicated in patients with severe liver impairment.
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| ====Renal Impairment====
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| Although carvedilol is metabolized primarily by the liver, plasma concentrations of carvedilol have been reported to be increased in patients with renal impairment. Based on mean AUC data, approximately 40% to 50% higher plasma concentrations of carvedilol were observed in hypertensive subjects with moderate to severe renal impairment compared to a control group of hypertensive subjects with normal renal function. However, the ranges of AUC values were similar for both groups. Changes in mean peak plasma levels were less pronounced, approximately 12% to 26% higher in subjects with impaired renal function.
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| Consistent with its high degree of plasma protein‑binding, carvedilol does not appear to be cleared significantly by [[hemodialysis]].
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| ==References==
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| {{Reflist}}
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| {{FDA}}
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| | [[Category:Beta Blockers]] |
| | [[Category:Cardiovascular Drugs]] |
| [[Category:Drugs]] | | [[Category:Drugs]] |