Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Alpha- and beta-blocking agents. ATC code: C07AG02.

Mechanism of action
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 alpha 1-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.

Pharmacodynamic effects
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.

Clinical efficacy and safety
Clinical studies have shown that the balance of vasodilation and beta-blockade provided by carvedilol results in the following effects:

Hypertension
Carvedilol lowers blood pressure in hypertensive patients by beta-blockade and alpha1- mediated vasodilation, without a concomitant increase in total peripheral resistance, as observed with pure beta-blocking agents. Heart rate is slightly decreased.
Renal blood flow and renal function are maintained. Carvedilol has been shown to maintain stroke volume and reduce total peripheral resistance, without compromising blood supply to distinct organs and vascular beds e.g., kidneys, skeletal muscles, forearms, legs, skin, brain or the carotid artery. There is a reduced incidence of cold extremities and early fatigue during physical activity.

Hypertensive patients with renal impairment

Several open studies have shown that carvedilol is effective in patients with renal hypertension, chronic renal failure, on haemodialysis or after renal transplantation. Carvedilol causes a gradual reduction in blood pressure on dialysis and non-dialysis days, and blood pressure-lowering effects are comparable with those seen in patients with normal renal function.

Stable angina pectoris
In patients with stable angina, carvedilol has demonstrated anti-ischaemic (improved total exercise time, time to 1 mm ST segment depression and time to angina) and anti-anginal properties that were maintained during long-term treatment. Acute haemodynamic studies demonstrated that carvedilol significantly decreases myocardial oxygen demand and sympathetic over-activity, and reduces both cardiac pre-load (pulmonary artery pressure and pulmonary capillary wedge pressure) and after-load (total peripheral resistance) with consequent improvement in left ventricular systolic and diastolic function without substantial changes in the cardiac output.

Carvedilol has no adverse affects on the metabolic risk factors of coronary heart disease. It does not impair the normal serum lipid profile and in hypertensive patients with dyslipidaemia favourable effects on the serum lipids have been reported after six months of oral therapy.

Chronic Heart Failure
Carvedilol significantly reduces mortality and hospitalisations and improves symptoms and left ventricular function in patients with ischaemic or non-ischaemic chronic heart failure.
The effect of carvedilol is dose dependent.

Chronic Heart Failure patients with renal impairment
Carvedilol reduces morbidity and mortality in dialysis patients with dilated cardiomyopathy, as well as all-cause mortality, cardiovascular mortality and heart failure mortality or first hospitalization in heart failure patients with mild to moderate non-dialysis-dependent chronic kidney disease. A meta-analysis of placebo-controlled clinical trials including a large number of patients (>4,000) with mild to moderate chronic kidney disease supports carvedilol treatment of patients with left ventricular dysfunction with or without symptomatic heart failure to reduce rates of all cause of mortality as well as heart failure related events.

Paediatric population
The safety and efficacy of carvedilol in children and adolescents has not been established due to limited number and size of studies. Available studies focus on treatment of paediatric heart failure which differs from the disease in adults regarding characteristics and aetiology.
Because of the small number of participants compared to studies in adults and a general lack of an optimal dosing scheme for children and adolescents, available data is not sufficient to establish a paediatric safety profile for carvedilol.

Pharmacokinetic Properties

5.2 Pharmacokinetic properties

Absorption
Following oral administration of a 25 mg capsule to healthy subjects, carvedilol is rapidly absorbed with a peak plasma concentration Cmax of 21 μg/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.

Distribution
Carvedilol is highly lipophilic, showing a plasma protein binding of around 95%. The distribution volume ranges between 1.5 and 2L/kg and increased in patients with liver cirrhosis.

Biotransformation
In humans, carvedilol is extensively metabolized in the liver via oxidation and conjugation into a variety of metabolites that are eliminated mainly in the bile. Enterohepatic circulation of the parent substance has been shown in animals. Demethylation and hydroxylation at the phenol ring produce three metabolites with beta-adrenergic receptor blocking activity. Based on pre-clinical studies, the 4'-hydroxy-phenol metabolite is approximately 13 times more potent than carvedilol for beta-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. Two of the hydroxy- carbazole metabolites of carvedilol are extremely potent antioxidants, demonstrating a 30 to 80-fold greater potency than carvedilol.

Pharmacokinetic studies in humans have shown that the oxidative metabolism of carvedilol is stereoselective. 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 metabolized by CYP2D6. The S-enantiomer is mainly metabolized by CYP2D6 and CYP2C9.

Genetic polymorphism
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. The importance of CYP2D6 genotype in the pharmacokinetics of R- and S-carvedilol was confirmed in population pharmacokinetics studies, whereas other studies did not confirm this observation. It was concluded that CYP2D6 genetic polymorphism may be of limited clinical significance.

Elimination

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 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.

Special populations

Elderly: Age has no statistically significant effect on the pharmacokinetics of carvedilol in hypertensive patients.

Paediatric population: The weight-adjusted clearance in children and adolescents is significantly larger than in adults.

Hepatic impairment: In a study in patients with cirrhotic liver disease, the bioavailability of carvedilol was four times greater and the peak plasma level five times higher than in healthy subjects.

Renal impairment: Since carvedilol is primarily excreted via the faeces, significant accumulation in patients with renal impairment is unlikely.
In patients with hypertension and renal insufficiency, the area under plasma level-time curve, elimination half-life and maximum plasma concentration does not change significantly. Renal excretion of the unchanged drug decreases in the patients with renal insufficiency; however changes in 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.

Heart failure: In a study in 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 S-carvedilol is significantly altered by heart failure in Japanese patients.