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Kerledex

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Kerledex

CLINICAL PHARMACOLOGY

Kerledex

Data supporting the efficacy of once-daily administration of Kerledex include those derived from five double-blind, randomized, controlled trials, involving a total of 1,146 patients. Two of these trials were concurrent placebo-controlled.

The first placebo-controlled trial was a factorial design, parallel fixed-dose study (n = 408). The study consisted of an initial 3 week double-blind period evaluating placebo, chlorthalidone 12.5 mg, and chlorthalidone 25 mg, followed by a second 3 week double-blind period in which betaxolol 5 mg, betaxolol 10 mg, or placebo was added to the medication received during the first period. Placebo-subtracted reductions in trough supine diastolic blood pressures (SDBP) in mmHg at endpoint were:

  Placebo Betaxolol 5 mg Betaxolol 10 mg
Placebo 0 – 5.0 – 7.3
Chlorthalidone 12.5 mg –3.2 – 9.2 –10.4
Chlorthalidone 25 mg –4.9 –11.1 –12.8

The second placebo controlled trial (n = 261) was a parallel, fixed-dose study with a 6 week double-blind treatment period. Patients were randomized to receive either placebo, betaxolol 10 mg, chlorthalidone 12.5 mg, or the combination betaxolol 10 mg/chlorthalidone 12.5 mg. Placebo-subtracted reductions in SDBP (mmHg) were:

betaxolol 10 mg –6.7
chlorthalidone 12.5 mg –4.6
betaxolol 10 mg/chlorthalidone 12.5 mg –9.4

The results of these two studies demonstrate that the combination of betaxolol plus chlorthalidone has a greater effect than either of the individual components. The three nonconcurrent placebo controlled studies, each of which used betaxolol 20 mg, chlorthalidone 25 mg, and the combination of these treatments, support the superior antihypertensive efficacy of the combination of betaxolol plus chlorthalidone, when compared to either of its individual components.

Results of the factorial design study indicate that the administration of the low-dose combination (betaxolol 5 mg/chlorthalidone 12.5 mg) is associated with a lower incidence of hypokalemia than the same dose, or a higher dose, of chlorthalidone used alone. The incidence of hypokalemia (serum potassium < 3.5 mEq/L) as a percentage of randomized patients was:

 

  Placebo Betaxolol 5 mg Betaxolol 10 mg
Placebo 0% 2% 0%
Chlorthalidone 12.5 mg 23% 17% 11%
Chlorthalidone 25 mg 45% 28% 30%

Also in this study, the overall incidence of bradycardia (heart rate < 50 bpm) tended to be lower in patients whose treatment included the 5 mg dose (1.5%) of betaxolol than in those whose treatment included betaxolol 10 mg (3.7%). Regimens which combine low doses of betaxolol and chlorthalidone are less likely to be associated with dose-dependent adverse effects (eg, hypokalemia, bradycardia) than higher doses of the individual components, while still achieving equal or greater reductions in blood pressure.

In a retrospective subgroup analysis of the data from the large factorial study, the blood pressure response and the effect on serum potassium levels were compared between white and black patients. In general, blacks and whites showed a greater decrease in blood pressure with the combination than either component alone. This is shown in the table below which provides reduction in SDBP (mmHg) from baseline for white and black subgroups in this trial.

  Placebo Betaxolol 5 mg Betaxolol 10 mg
Placebo
  White – 6.3 –12.6 –14.4
  Black – 4.8 – 6.9 –10.0
Chlorthalidone 12.5 mg
  White – 8.5 –15.5 –17.6
  Black –10.9 –13.8 –12.3
Chlorthalidone 25 mg
  White –10.7 –16.8 –18.3
  Black –12.9 –15.6 –17.5

In white patients, adding betaxolol decreases the potassium loss associated with chlorthalidone (at any dose of chlorthalidone) and this potassium-sparing effect was seen at all doses of betaxolol. This effect was not observed in the subgroup of black patients.

Overall, in clinical trials involving betaxolol/chlorthalidone, the average change in serum potassium was approximately –0.26 mEq/L in subjects who received betaxolol 10 mg and chlorthalidone 12.5 mg. The average subject who received betaxolol 10 mg and chlorthalidone 25 mg experienced a reduction in serum potassium less than that experienced by the average subject receiving the same dose of chlorthalidone monotherapy.

Pharmacokinetics and metabolism

A clinical study conducted in normal volunteers indicates that the pharmacokinetic profiles of betaxolol and chlorthalidone, when administered concurrently, do not differ from the observations in the same subjects when each agent was administered alone.

Betaxolol: Betaxolol 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 of betaxolol 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 betaxolol. 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.

Betaxolol 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 betaxolol 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.

Studies in elderly patients (n = 10) gave inconsistent results but suggest some impairment of elimination, with one small study (n = 4) finding a mean half-life of 30 hours. A starting dose of 5 mg is suggested in older patients.

Pharmacodynamics

Clinical pharmacology studies have demonstrated the beta-adrenergic receptor blocking activity of betaxolol 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 betaxolol in man was shown in three ways: (1) In normal subjects, 10- and 40-mg oral doses of betaxolol, 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 betaxolol was at least comparable to 50 mg of atenolol. Both doses of betaxolol, 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 betaxolol 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 to 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 betaxolol. 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.

Consistent with its negative chronotropic effect, due to beta-blockade of the SA node, and lack of intrinsic sympathomimetic activity, betaxolol increases sinus cycle length and sinus node recovery time. Conduction in the AV node is also prolonged.

Significant reductions in blood pressure and heart rate were observed 24 hours after dosing in double-blind, placebo-controlled trials with doses of 5 to 40 mg administered once daily. The antihypertensive response to betaxolol was similar at peak blood levels (3 to 4 hours) and at trough (24 hours). In a large randomized, parallel dose-response study of 5, 10, and 20 mg, the antihypertensive effects of the 5-mg dose were roughly half of the effects of the 20-mg dose (after adjustment for placebo effects) and the 10-mg dose gave more than 80% of the antihypertensive response of the 20-mg dose. The effect of increasing the dose from 10 mg to 20 mg was thus small. In other trials, there was little evidence of a greater antihypertensive response to 40 mg than to 20 mg. The maximum effect of each dose was achieved within 1 or 2 weeks. In comparative trials against propranolol, atenolol, and chlorthalidone, betaxolol appeared to be at least as effective as the comparative agent.

Betaxolol has been studied in combination with thiazide-type diuretics and the blood pressure effects of the combination appear additive. Betaxolol has also been used concurrently with methyldopa, hydralazine, and prazosin.

The mechanism of the antihypertensive effects of beta-adrenergic receptor blocking agents has not been established. Several possible mechanisms have been proposed, however, including: (1) competitive antagonism of catecholamines at peripheral (especially cardiac) adrenergic-neuronal sites, leading to decreased cardiac output, (2) a central effect leading to reduced sympathetic outflow to the periphery, and (3) suppression of renin activity.

The results from long-term studies have not shown any diminution of the antihypertensive effect of betaxolol with prolonged use.

Chlorthalidone

Chlorthalidone is a diuretic with prolonged activity and low toxicity. The diuretic effect of the drug occurs within two hours of an oral dose and continues for 48 to 72 hours. Thiazides reduce the reabsorption of sodium and chloride in the first half of the distal convoluted tubule and a portion of the cortical ascending limb of the loop of Henle.

Pharmacokinetics and metabolism

In man, chlorthalidone has a mean plasma half-life of 40 hours following a 25 mg to 200 mg dose and an oral availability of approximately 64%. Approximately 65% of the intravenous dose is renally excreted unchanged and chlorthalidone has a reported volume of distribution of 3.9 L/Kg. Approximately 75% of the drug is bound to plasma proteins; 68% of the drug is bound to albumin. Due to the high affinity of chlorthalidone to erythrocyte carbonic anhydrase, red blood cells contain much higher levels of chlorthalidone than plasma. Data indicate that chlorthalidone crosses the placental barrier and appears in human milk.

Last reviewed on RxList: 9/6/2011
This monograph has been modified to include the generic and brand name in many instances.

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