Source: Health Products Regulatory Authority (ZA) Revision Year: 2016 Publisher: Pharmaco Distribution (Pty) Ltd., 3 Sandown Valley Crescent, South Tower, 1st Floor, Sandton, 2196, South Africa Ethical assistance Line: +27 (0)11 784 0077
A 7.1.3 Other – hypotensives
Carvedilol is an adrenergic receptor blocker with α1, β1, and β2 adrenergic receptor blockade properties. Carvedilol is racemic, and both R(+) and S(-) enantiomers have the same α-adrenergic receptor blocking properties and antioxidant properties. Carvedilol’s β-adrenergic receptor blocking properties are non-selective for the β1 and β2adrenoceptors and are associated with the S() enantiomer. Carvedilol suppresses the renin-angiotensin-aldosterone system through β-blockade, which reduces the release of renin. Carvedilol reduces peripheral vascular resistance via selective blockade of α1-adrenoceptors. Carvedilol attenuates the increase in blood pressure induced by phenylephrine, an α1-adrenoceptor agonist, but not that induced by angiotensin II.
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 hours (tmax). The Cmax values are linearly related to the dose. Following oral administration, carvedilol undergoes extensive first pass metabolism that results in an absolute availability of about 25% in healthy male subjects. Carvedilol is a racemate and the S-() enantiomer appears to be metabolised more rapidly than the R-()- enantiomer, showing an absolute oral availability of 15% compared to 31% for the R-()- enantiomer. The maximal plasma concentration of Rcarvedilol 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 also confirmed in vivo in healthy subjects.
Eating a meal does not influence carvedilol bioavailability. The time to reach maximum serum concentration is delayed by eating a meal. Carvedilol is an antihypertensive agent with vasodilating and non-selective betablocking properties in the same dose range.
In vitro and in vivo animal studies have indicated that carvedilol is a competitive, non-selective antagonist of both beta1- and beta2-adrenoreceptors.
Carvedilol is a highly lipophilic compound, showing a plasma protein binding of around 95%. The distribution volume ranges between 1,5 and 2 l/kg.
In humans, carvedilol is extensively metabolised in the liver via oxidation and conjugation into a variety of metabolites that are eliminated mainly in the bile. Demethylation and hydroxylation at the phenol ring produce 3 metabolites with β-adrenergic receptor blocking activity. Based on pre-clinical studies, the 4'-hydroxyphenol metabolite is approximately 13 times more potent than carvedilol for β-blockade. Compared to carvedilol, the three active metabolites exhibit weak vasodilating activity. In humans, the concentrations of the three active metabolites are about 10 times lower than that of the parent substance.
Pharmacokinetic studies in humans have shown that the oxidative metabolism of carvedilol is stereo-selective. The results of an in vitro study suggested that different cytochrome P450 isoenzymes may be involved in the oxidation and hydroxylation processes including CYP2D6, CYP3A4, CYP2E1, CYP2C9 as well as CYP1A2. Studies in healthy volunteers and in patients have shown that the R-enantiomer is predominantly metabolised by CYP2D6. The S-enantiomer is mainly metabolised by CYP2D6 and CYP2C9.
The results of clinical pharmacokinetic studies in human subjects have shown that CYP2D6 plays a major role in the metabolism of R and of S-carvedilol. As a consequence plasma concentrations of R and S-carvedilol are increased in CYP2D6 slow metabolisers. However, CYP2D6 genetic polymorphism may be of limited clinical significance.
Following a single oral administration of 50 mg carvedilol, around 60% is 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% is excreted into the urine in form of carvedilol or its metabolites. The urinary excretion of unaltered carvedilol 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 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 patients with hypertension and renal insufficiency, the area under the plasma level-time curve, elimination halflife and maximum plasma concentration does not change significantly. Renal excretion of the unchanged medicine decreases in the patients with renal insufficiency; however pharmacokinetic parameters are modest. Carvedilol is not eliminated during dialysis because it does not cross the dialysis membrane, probably due to its high plasma protein binding.
In patients with cirrhosis of the liver, the systemic availability of the medicine is increased by up to 80 % because of reduction in the first-pass effect. See CONTRAINDICATIONS and DOSAGE AND DIRECTIONS FOR USE, Hepatic impairment.
In a study of 24 Japanese 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 Scarvedilol is significantly altered by heart failure.
Age has no statistically significant effect on the pharmacokinetics of carvedilol in hypertensive patients.
Investigation in paediatrics has shown that the weight adjusted clearance is significantly larger in paediatric as compared to adults.
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