Bisoprolol Fumarate and Hydrochlorothiazide (Page 2 of 8)

Pharmacodynamics

Bisoprolol Fumarate

Findings in clinical hemodynamics studies with bisoprolol fumarate are similar to those observed with other beta-blockers. The most prominent effect is the negative chronotropic effect, giving a reduction in resting and exercise heart rate. There is a fall in resting and exercise cardiac output with little observed change in stroke volume, and only a small increase in right atrial pressure, or pulmonary capillary wedge pressure at rest or during exercise.

In normal volunteers, bisoprolol fumarate therapy resulted in a reduction of exercise-and isoproterenol-induced tachycardia. The maximal effect occurred within 1-4 hours post-dosing. Effects generally persisted for 24 hours at doses of 5 mg or greater.

In controlled clinical trials, bisoprolol fumarate given as a single daily dose has been shown to be an effective antihypertensive agent when used alone or concomitantly with thiazide diuretics (see CLINICAL STUDIES).

The mechanism of bisoprolol fumarate’s antihypertensive effect has not been completely established. Factors that may be involved include:

  1. Decreased cardiac output,
  2. Inhibition of renin release by the kidneys,
  3. Diminution of tonic sympathetic outflow from vasomotor centers in the brain.

Beta 1 -selectivity of bisoprolol fumarate has been demonstrated in both animal and human studies. No effects at therapeutic doses on beta 2 -adrenoreceptor density have been observed. Pulmonary function studies have been conducted in healthy volunteers, asthmatics, and patients with chronic obstructive pulmonary disease (COPD). Doses of bisoprolol fumarate ranged from 5 to 60 mg, atenolol from 50 to 200 mg, metoprolol from 100 to 200 mg, and propranolol from 40 to 80 mg. In some studies, slight, asymptomatic increases in airway resistance (AWR) and decreases in forced expiratory volume (FEV 1 ) were observed with doses of bisoprolol fumarate 20 mg and higher, similar to the small increases in AWR noted with other cardioselective beta-blocking agents. The changes induced by beta-blockade with all agents were reversed by bronchodilator therapy.

Electrophysiology studies in man have demonstrated that bisoprolol fumarate significantly decreases heart rate, increases sinus node recovery time, prolongs AV node refractory periods, and, with rapid atrial stimulation, prolongs AV nodal conduction.

Hydrochlorothiazide

Acute effects of thiazides are thought to result from a reduction in blood volume and cardiac output, secondary to a natriuretic effect, although a direct vasodilatory mechanism has also been proposed. With chronic administration, plasma volume returns toward normal, but peripheral vascular resistance is decreased.

Thiazides do not affect normal blood pressure. Onset of action occurs within 2 hours of dosing, peak effect is observed at about 4 hours, and activity persists for up to 24 hours.

CLINICAL STUDIES

In controlled clinical trials, bisoprolol fumarate/hydrochlorothiazide 6.25 mg has been shown to reduce systolic and diastolic blood pressure throughout a 24-hour period when administered once daily. The effects on systolic and diastolic blood pressure reduction of the combination of bisoprolol fumarate and hydrochlorothiazide were additive. Further, treatment effects were consistent across age groups (< 60, ≥ 60 years), racial groups (black, nonblack), and gender (male, female).

In two randomized, double-blind, placebo-controlled trials conducted in the U.S., reductions in systolic and diastolic blood pressure and heart rate 24 hours after dosing in patients with mild-to-moderate hypertension are shown below. In both studies mean systolic/diastolic blood pressure and heart rate at baseline were approximately 151/101 mm Hg and 77 bpm.

Sitting Systolic / Diastolic Pressure ( BP ) and Heart Rate ( HR )
Mean Decrease ( Δ ) After 3 - 4 Weeks
Study 1 Study 2
Placebo B 5 / H 6 . 25 mg Placebo H 6 . 25 mg B 2 . 5 / H 6 . 25 mg B 10 / H 6 . 25 mg

a) Observed mean change from baseline minus placebo

n= 75 150 56 23 28 25
Total ΔBP (mm Hg) -2.9/-3.9 -15.8/-12.6 -3.0/-3.7 -6.6/-5.8 -14.1/-10.5 -15.3/-14.3
Drug Effect a -/- -12.9/-8.7 -/- -3.6/-2.1 -11.1/-6.8 -12.3/-10.6
Total ΔHR(bpm) -0.3 -6.9 -1.6 -0.8 -3.7 -9.8
Drug Effect a - -6.6 - +0.8 -2.1 -8.2

Blood pressure responses were seen within 1 week of treatment but the maximum effect was apparent after 2 to 3 weeks of treatment. Overall, significantly greater blood pressure reductions were observed on bisoprolol fumarate and hydrochlorothiazide than on placebo. Further, blood pressure reductions were significantly greater for each of the bisoprolol fumarate plus hydrochlorothiazide combinations than for either of the components used alone regardless of race, age, or gender. There were no significant differences in response between black and nonblack patients.

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