Chemical formula: C₂₄H₂₆N₂O₄ Molecular mass: 406.474 g/mol PubChem compound: 2585
Carvedilol, a racemic mixture of two enantiomers (R- and S-carvedilol), is a multiple action alpha- and beta-adrenergic receptor blocker. The beta-adrenergic receptor blockade is associated with the S-enantiomer and non-selective for beta1- and beta2-adrenoceptors, while both enantiomers have the same blocking properties specific for alpha1-adrenergic receptors. At higher concentrations, carvedilol also has a weak to moderate calcium-channel blocking activity. It has no intrinsic sympathomimetic activity and (like propranolol) it has membrane-stabilising properties.
Carvedilol reduces peripheral vascular resistance by selective blockade of alpha1-adrenoreceptors. Through its beta-blocking action, carvedilol suppresses the renin-angiotensin-aldosterone system, reducing the release of renin and making fluid retention rare. It attenuates the increase in blood pressure induced by phenylephrine, an alpha1-adrenoceptor agonist, but not that induced by angiotensin II. Carvedilol’s calcium-channel blocking activity may increase blood flow in specific vascular beds such as the cutaneous circulation
Carvedilol has organ-protective effects likely resulting at least in part from additional properties beyond its adrenergic receptor blockade action. It has potent antioxidant properties associated with both enantiomers, is a scavenger of reactive oxygen radicals and has antiproliferative effects on human vascular smooth muscle cells. Carvedilol has no adverse effect on the lipid profile.
Carvedilol is rapidly absorbed after oral administration. In healthy subjects, maximum serum concentration is achieved approximately 1 hour after administration. The absolute bioavailability of carvedilol in humans is approximately 25%.
There is a linear relationship between dose and serum concentrations of carvedilol. Food intake did not affect the bioavailability or the maximum serum concentration, although the time needed to reach maximum serum concentration is prolonged.
Following oral administration of a 25 mg capsule to healthy subjects, carvedilol is rapidly absorbed with a peak plasma concentration Cmax of 21 mg/L reached after approximately 1.5 hour (tmax). The Cmax values are linearly related to the dose. Following oral administration, carvedilol undergoes extensive first pass metabolism that results in an absolute bioavailability of about 25% in healthy male subjects. Carvedilol is a racemate and the S ( - ) enantiomer appears to be metabolized more rapidly than the R ( + ) enantiomer, showing an absolute oral bioavailability of 15% compared to 31% for the R ( + ) enantiomer. The maximal plasma concentration of R-carvedilol is approximately 2 fold higher than that of S-carvedilol.
In vitro studies have shown that carvedilol is a substrate of the efflux transporter P-glycoprotein. The role of P-glycoprotein in the disposition of carvedilol was also confirmed in vivo in healthy subjects. Food does not affect bioavailability, residence time or the maximum serum concentration, although the time to reach maximum serum concentration is delayed.
Carvedilol is highly lipophilic. The plasma protein binding is about 98 to 99%. The volume of distribution is approximately 2 l/kg and increases in patients with liver cirrhosis.
In humans and in animal species studied, carvedilol is extensively metabolized to several metabolites which are excreted primarily in bile. The first pass effect after oral administration is about 60-75%. The enterohepatic circulation of the parent substance was demonstrated in animals.
Carvedilol is extensively metabolized in the liver, glucuronidation being one of the main reactions. The demethylation and hydroxylation at the phenol ring produce 3 active metabolites with blocking activity of beta-adrenergic receptors.
According to preclinical studies, the beta-blocking activity of the metabolite 4-hydroxyphenol is approximately 13 times higher than that of carvedilol. The three active metabolites have a weak vasodilating activity, compared with carvedilol. In humans, their concentrations are about 10 times lower than the parent substance. Two of the carbazole-hydroxy metabolites are extremely potent antioxidants, showing a potency 30-80 times that of carvedilol.
The average half-life of elimination of carvedilol is approximately 6 hours. The plasma clearance is approximately 500-700 ml/min. Elimination is mainly via the bile, and excretion mainly via the faeces. A minor part is eliminated renally in the form of various metabolites.
Following a single oral administration of 50 mg carvedilol, around 60% are secreted into the bile and eliminated with the faeces in the form of metabolites within 11 days. Following a single oral dose, only about 16% are excreted into the urine in form of carvedilol or its metabolites. The urinary excretion of unaltered drug represents less than 2%. After intravenous infusion of 12.5 mg to healthy volunteers, the plasma clearance of carvedilol reaches around 600 mL/min and the elimination half-life around 2.5 hours. The elimination half-life of a 50 mg capsule observed in the same individuals was 6.5 hours corresponding indeed to the absorption half-life from the capsule. Following oral administration, the total body clearance of the S-carvedilol is approximately two times larger than that of the R-carvedilol.
In some of the hypertensive patients with moderate to severe renal impairment (creatinine clearance <30 ml/min), an increase in plasma carvedilol concentrations of approximately 40-50% was seen compared to patients with normal renal function. Peak plasma concentrations in patients with renal insufficiency increased also by an average of 10-20%. However, there was a large variation in the results. Since carvedilol is primarily excreted via the faeces, significant accumulation in patients with renal impairment is unlikely.
In patients with moderate to severe renal impairment there is no need to modify carvedilol dosage.
In patients with liver cirrhosis, the systemic availability of carvedilol is increased 80% due to reduced first pass effect. Therefore, carvedilol is contraindicated in patients with clinically manifest hepatic impairment.
Age had a statistically significant effect on pharmacokinetic parameters of carvedilol in hypertensive patients. A study in elderly hypertensive patients showed no difference between the adverse event profile of this group and younger patients. Another study involving elderly patients with coronary artery disease showed no difference in reported adverse reactions vs. those that were reported by younger patients.
The available information on pharmacokinetics in subjects younger than 18 years is limited.
In hypertensive patients with type 2 diabetes was not observed effect of carvedilol on blood glucose (fasting or postprandial) and glycosylated haemoglobin A1, it was not necessary to change the dose of antidiabetic drugs.
In patients with type 2 diabetes, carvedilol had no statistically significant influence on the glucose tolerance test. In nondiabetic hypertensive patients with altered insulin sensitivity (Syndrome X), carvedilol increased insulin sensitivity. The same results were observed in hypertensive patients with type 2 diabetes.
In a study in 24 patients with heart failure, the clearance of R-and S-carvedilol was significantly lower than previously estimated in healthy volunteers. These results suggested that the pharmacokinetics of R-and S-carvedilol is significantly altered by heart failure.
Carvedilol demonstrated no mutagenic or carcinogenic potential.
High doses of carvedilol impaired fertility and affected pregnancy in rats (increased resorptions). Decreased fetal weight and delayed skeletal development were also seen in rats. Embryotoxicity (increased post-implantation loss) occurred in rats and rabbits.
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