Carvid Mechanism of Action

Beta-Adrenergic Blocker/Antihypertensive.
Pharmacology: Pharmacodynamics: Carvedilol is a racemic mixture in which nonselective beta-adrenoceptor blocking activity is present in the S(-) enantiomer and alpha-adrenergic blocking activity in both R(+) and S(-) enantiomers at equal potency. It has no intrinsic sympathomimetic activity and has membrane stabilizing properties.
Carvedilol is a potent antioxidant, a scavenger of reactive oxygen radicals, and an antiproliferative agent.
Carvedilol has no adverse effect on lipid profile. The normal ratio of high-density lipoproteins to low density lipoproteins (HDU/LDL) is maintained.
Vasodilation resulting in decreased total peripheral resistance mediated through carvedilol's alpha₁-adrenergic blockade and decreased sympathetic tone plays a major role in the drug's hypotensive effects. Carvedilol causes reductions in cardiac output, exercise-induced tachycardia, isoproterenol-induced tachycardia, and reflex orthostatic tachycardia. Significant beta-blocking activity of carvedilol is usually observed within 1 hour of oral use. Carvedilol's alpha-adrenergic blocking effects, which contribute to the drug's hypotensive effects, are seen within 30 minutes of drug administration and include reduction in phenylephrine-induced presser effects, vasodilation, and decreased peripheral vascular resistance. The dose-dependent hypotensive effect of carvedilol results in blood pressure (systolic and diastolic) reductions of 5 to 46% with little, if any, reflex tachycardia. This hypotensive effect occurs about 30 minutes after oral use and has a maximum effect 1.5 to 7 hours after oral administration.
Due to carvedilol's alpha₁-receptor blocking activity, blood pressure is reduced more in the standing than in the supine position, and symptoms of postural hypotension, including rare instances of syncope, may occur. The frequency and severity of orthostatic hypotension may be decreased by administering carvedilol with food and by strictly adhering to the usual starting dose and titration recommendations.
Therapeutic doses of carvedilol decreased renal vascular resistance with no change in glomerular filtration rate or renal plasma flow in hypertensive patients with normal renal function.
Carvedilol has little effect on plasma catecholamines, plasma aldosterone, or electrolyte levels; however, carvedilol significantly decreases plasma renin activity when given for at least 4 weeks. Carvedilol also increases atrial natriuretic peptide levels. Carvedilol has demonstrated anti-ischemic and anti-anginal properties in patients with stable angina. Acute hemodynamic studies showed that carvedilol decreases ventricular preload and afterload.
In patients with chronic heart failure and left ventricular dysfunction, carvedilol is associated with improvements in myocardial function through afterload reduction as evidenced by improved left ventricular ejection fraction, decreased left ventricular volumes, and prevention of progression of left ventricular dilatation. Reductions in systemic blood pressure, pulmonary artery pressure, pulmonary capillary wedge pressure, and heart rate were observed in patients with heart failure.
Carvedilol significantly decreases mortality and hospitalizations and improves symptoms and left ventricular function in patients with ischemic or non-ischemic chronic heart failure. Carvedilol's effect is dose dependent.
Pharmacokinetics: Carvedilol is rapidly and extensively absorbed after oral administration with absolute bioavailability of approximately 25 to 35% due to significant first-pass metabolism. After 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. The rate of absorption is slowed when administered with food, as evidenced by a delay in the time to reach peak plasma levels, with no significant difference in extent of bioavailability. Taking carvedilol with food minimizes the risk of orthostatic hypotension.
Carvedilol is extensively metabolized. After 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 is 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 three active metabolites with beta receptor blocking activity. Based on preclinical studies, the 4'hydroxyphenyl metabolite is approximately 13 times more potent than carvedilol for betablockade. Compared with carvedilol, the three 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. Carvedilol undergoes stereoselective first-pass metabolism with plasma levels of R(+) carvedilol approximately 2 to 3 times higher than S(-) carvedilol after 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. 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 a substantial distribution into extravascular tissues. Plasma clearance ranges from 500 to 700 mL/min.
The steady-state plasma concentrations of carvedilol and its enantiomers increased proportionately over the 6.25 to 50 mg dose range in patients with congestive heart failure (CHF). Compared with healthy subjects, patients with CHF had increased mean ALIC and C_max values for carvedilol and its enantiomers, with up to 50% to 100% higher values observed in a few patients with NYHA class IV heart failure. The mean apparent terminal elimination half-life for carvedilol was similar to that observed in healthy subjects.