Pharmacokinetic and blood pressure effects of carvedilol in patients with chronic renal failure

Abstract

Summary.The pharmacokinetic and acute systemic haemodynamic effects of a single oral dose of 50 mg carvedilol has been studied in 24 hypertensive patients with chronic renal failure. The patients were stratified into 3 groups according to the creatinine clearance: 1 51-90 ml-min-~; II 26-50 ml. min-1; III 425 ml-rain-1.The area under plasma level time curve AUC, the elimination half-life tl/2, the maximum plasma concentration Cm~, the time to peak concentration tm~x were not significantly different between groups, whereas the amount of unchanged drug or metabolite excreted in urine A~ and the renal clearance CLR of carvedilol and its metabolites M2, M4, M5 were significantly decreased in Group III. Blood pressure and heart rate decreased in all 3 groups of patients after acute administration of 50 mg carvedilol. Mild adverse effects were reported in 6 patients. Despite a decrease in the renal clearance of carvedilol and of its metabolites with decreasing kidney function, its main pharmacokinetic parameters remained unchanged. The present results suggest that the dose of carvedilol need not be reduced in hypertensive patients with chronic renal failure.Key words: Hypertension, Carveditol; chronic renal failure, pharmacokinetics, adverse effects Carvedilol is a non-selective /3-adrenoceptor blocking drug with vasodilating activity primarily due to c¢~-adrenoceptor blocking properties, and to a minor extent to calcium channel blocking activity (little or no contribution to the antihypertensive effect) at a high concentration [1]. The total clearance of carvedilol is 590 ml-min-1, its renal clearance is 4 ml. rain-1, and the distribution volume is 132 1 [6,7]. The absolute bioavailability of carvedilol has been estimated to be 24 %, indicating some degree of first pass extraction, and the protein binding is 95 % [6,7].Carvedilol has been shown to be effective in the treatment of patients with essential and renal hypertension, and angina pectoris [2][3][4][5]. Extensive pharmacokinetic studies of carvedilol have been done in healthy volunteers, in hypertensive patients and in patients with liver cirrhosis, but its pharmacokinetics in hypertensive patients with chronic renal failure has only been reported in a preliminary paper [6][7][8][9][10][11][12]. In addition, little information is available in the literature about the pharmacokinetics of the metabolites of carvedilol in hypertensive patients with chronic renal failure [12]. Pharmacological activity is attributed only to carvedilol metabolites M2, M4 and M5 (Sponer, unpublished). The chemical structures of carvedilol and its metabolites are displayed in Fig. 1.The pharmacokinetics and effects of acute oral administration of 50 mg carvedilol in hypertensive patients with chronic renal failure of differing severity have now been investigated. Patients and methods

Steady‐State Pharmacokinetics of Carvedilol and Its Enantiomers in Patients with Congestive Heart Failure

“…These data for M2, M4, and M5 are consistent with results previously observed in healthy volunteers and patients with hypertension. 14,21 Preclinical studies in conscious rabbits have demonstrated that these metabolites possess β-adrenoceptor blocking activity. 18 Compared to carvedilol, metabolite M4 is approximately 13 times more potent, and metabolite M2 is about 2.5-fold more potent.…”

Clinical Pharmacokinetics and Pharmacodynamics of Carvedilol

“…The pharmacokinetics of carvedilol are not altered significantly in patients with renal disease (Kramer et al 1992). However, in patients with liver disease there are marked alterations in the pharmacokinetics of the drug (table III).…”

Carvedilol

“…Patients with liver disease also have high plasma carvedilol concentrations, 24 but the half-life of the drug is unchanged. Patients with renal disease have slightly increased plasma carvedilol concentrations 25 ; the pharmacokinetics of carvedilol are not altered in patients undergoing hemodialysis. 26 Drugs that increase cytochrome P-450 activity, such as rifampin, can accelerate the clearance of carvedilol.…”