Kerlone - Clinical Pharmacology
Kerlone is a β1-selective (cardioselective) adrenergic receptor blocking agent that has weak membrane-stabilizing activity and no intrinsic sympathomimetic (partial agonist) activity. The preferential effect on β1 receptors is not absolute, however, and some inhibitory effects on β2 receptors (found chiefly in the bronchial and vascular musculature) can be expected at higher doses.
Pharmacokinetics and metabolism
In man, absorption of an oral dose is complete. There is a small and consistent first-pass effect resulting in an absolute bioavailability of 89% ± 5% that is unaffected by the concomitant ingestion of food or alcohol. Mean peak blood concentrations of 21.6 ng/ml (range 16.3 to 27.9 ng/ml) are reached between 1.5 and 6 (mean about 3) hours after a single oral dose, in healthy volunteers, of 10 mg of Kerlone. Peak concentrations for 20-mg and 40-mg doses are 2 and 4 times that of a 10-mg dose and have been shown to be linear over the dose range of 5 to 40 mg. The peak to trough ratio of plasma concentrations over 24 hours is 2.7. The mean elimination half-life in various studies in normal volunteers ranged from about 14 to 22 hours after single oral doses and is similar in chronic dosing. Steady state plasma concentrations are attained after 5 to 7 days with once-daily dosing in persons with normal renal function.
Kerlone is approximately 50% bound to plasma proteins. It is eliminated primarily by liver metabolism and secondarily by renal excretion. Following oral administration, greater than 80% of a dose is recovered in the urine as betaxolol and its metabolites. Approximately 15% of the dose administered is excreted as unchanged drug, the remainder being metabolites whose contribution to the clinical effect is negligible.
Steady state studies in normal volunteers and hypertensive patients found no important differences in kinetics. In patients with hepatic disease, elimination half-life was prolonged by about 33%, but clearance was unchanged, leading to little change in AUC. Dosage reductions have not routinely been necessary in these patients. In patients with chronic renal failure undergoing dialysis, mean elimination half-life was approximately doubled, as was AUC, indicating the need for a lower initial dosage (5 mg) in these patients. The clearance of betaxolol by hemodialysis was 0.015 L/h/kg and by peritoneal dialysis, 0.010 L/h/kg. In one study (n=8), patients with stable renal failure, not on dialysis, with mean creatinine clearance of 27 ml/min showed slight increases in elimination half-life and AUC, but no change in Cmax. In a second study of 30 hypertensive patients with mild to severe renal impairment, there was a reduction in clearance of betaxolol with increasing degrees of renal insufficiency. Inulin clearance (mL/min/1.73 m2) ranged from 70 to 107 in 7 patients with mild impairment, 41 to 69 in 14 patients with moderate impairment, and 8 to 37 in 9 patients with severe impairment. Clearance following oral dosing was reduced significantly in patients with moderate and severe renal impairment (26% and 35%, respectively) when compared with those with mildly impaired renal function. In the severely impaired group, the mean Cmax and the mean elimination half-life tended to increase (28% and 24%, respectively) when compared with the mildly impaired group. A starting dose of 5 mg is recommended in patients with severe renal impairment.
Clinical pharmacology studies have demonstrated the beta-adrenergic receptor blocking activity of Kerlone by (1) reduction in resting and exercise heart rate, cardiac output, and cardiac work load, (2) reduction of systolic and diastolic blood pressure at rest and during exercise, (3) inhibition of isoproterenol-induced tachycardia, and (4) reduction of reflex orthostatic tachycardia.
The β1-selectivity of Kerlone in man was shown in three ways: (1) In normal subjects, 10- and 40-mg oral doses of Kerlone, which reduced resting heart rate at least as much as 40 mg of propranolol, produced less inhibition of isoproterenol-induced increases in forearm blood flow and finger tremor than propranolol. In this study, 10 mg of Kerlone was at least comparable to 50 mg of atenolol. Both doses of Kerlone, and the one dose of atenolol, however, had more effect on the isoproterenol-induced changes than placebo (indicating some β2 effect at clinical doses) and the higher dose of Kerlone was more inhibitory than the lower. (2) In normal subjects, single intravenous doses of betaxolol and propranolol, which produced equal effects on exercise-induced tachycardia, had differing effects on insulin-induced hypoglycemia, with propranolol, but not betaxolol, prolonging the hypoglycemia compared with placebo. Neither drug affected the maximum extent of the hypoglycemic response. (3) In a single-blind crossover study in asthmatics (n=10), intravenous infusion over 30 minutes of low doses of betaxolol (1.5 mg) and propranolol (2 mg) had similar effects on resting heart rate but had differing effects on FEV1 and forced vital capacity, with propranolol causing statistically significant (10% to 20%) reductions from baseline in mean values for both parameters while betaxolol had no effect on mean values. While blood levels were not measured, the dose of betaxolol used in this study would be expected to produce blood concentrations, at the time of the pulmonary function studies, considerably lower than those achieved during antihypertensive therapy with recommended doses of Kerlone. In a randomized double-blind, placebo-controlled crossover (4X4 Latin Square) study in 10 asthmatics, betaxolol (about 5 or 10 mg IV) had little effect on isoproterenol-induced increases in FEV1; in contrast, propranolol (about 7 mg IV) inhibited the response.