Beta adrenergic antagonists are widely used antihypertensive agents with therapeutic effectiveness similar to that of methyldopa and thiazide diuretics. Their advantages over other antihypertensive medications include a lack of postural hypotension, effectiveness in the supine position, and their potential cardioprotective ability. An important consideration with currently available beta-adrenergic antagonist drugs is their ability to block the betas adrenergic receptors in the lungs, resulting in worsened ventilatory function in patients with obstructive lung disease. Two currently available beta-adrenergic antagonist drugs, metoprolol and atenolol, have relative cardioselectivity and, at low doses, have minimal effects on bronchial smooth muscles; however, in higher doses, these drugs may increase the degree of airway obstruction in patients with lung disease. Labetalol hydrochloride is a new beta-adrenergic blocking agent which competitively inhibits both alpha- and beta-adrenergic receptors. This agent has been marketed in Europe since 1975 and has recently become available commercially for the treatment of hypertension in this country. Previous studies have shown that labetalol is relatively safe for use in hypertensive patients who have obstructive airways disease. The present study was designed to evaluate the effectiveness and safety of therapy with oral labetalol in a group of patients with both hypertension and asthma who had a significant increase in obstruction to air flow after a single dose of oral propranolol.
Materials and Methods
Selection of Subjects
Patients between the ages of 18 and 70 years with mild-to-moderate essential hypertension and bronchial asthma were selected for the study. Hypertension was defined as a sitting diastolic blood pressure of 95 to 115 mm Hg on two consecutive visits while taking no antihypertensive medication. All patients had mild-to-moderate asthma, as defined by the American Thoracic Society criteria, with a history of at least one attack of acute bronchospasm requiring medication within the previous year. Patients were excluded if they had congestive heart failure, cardiac conduction block, previous cerebrovascular accident, recent myocardial infarction or significant hepatic, hematologic or renal disease. This study was approved by the institutional review committees for human studies at each hospital, and informed consent was obtained.
The study consisted of initial two-to-four week placebo washout phase, propranolol challenge, and a four-week treatment phase (Fig 1). During the two-to-four week placebo washout phase, patients were treated with a placebo tablet twice daily and were examined at weekly intervals. All antihypertensive and bronchodilator drug therapy was discontinued except for oral or inhaled corticosteroid and oral theophylline therapy, which was continued at stable maintenance levels, provided the patient had been on long-term therapy with these agents. In addition, metered dose inhalers containing albuterol were given to each subject for use only in the event of an acute asthma attack. The cannisters were weighed at each weekly evaluation to determine usage during the previous week. All bronchodilator therapy was discontinued for at least six hours prior to pulmonary function tests.
Patients who did not maintain a sitting diastolic blood pressure between 95 and 115 mm Hg on at least two consecutive weekly visits were dropped from the study. All patients who successfully completed the washout phase underwent an oral propranolol challenge. They were first given 40 mg of propranolol and, if their FEV1 failed to decrease by 20 percent or more, they were given 80 mg of propranolol on a separate study day. If once again their FEV1 did not decrease by at least 20 percent, they were dropped from the study.
Subjects who responded to treatment with propranolol entered the four-week treatment phase, during which they received labetalol or hydrochlorothiazide and continued to be evaluated weekly. Labetalol was titrated at each visit, from 100 up to 600 mg twice daily, the end point being a drop in diastolic blood pressure below 90 mm Hg and at least 10 mm Hg from baseline. Hydrochlorothiazide was titrated from 25 to 50 mg twice daily until the same end point was reached. Patients received diary cards on which they recorded any adverse symptoms or experiences between evaluation periods.
At each weekly visit, subjects were asked about adverse reactions and diary cards were collected. Baseline heart rate, blood pressure and spirometric measurements were repeated and the appropriate dose of medication, based on diastolic blood pressure level, was then administered. Spirographic studies were performed, and blood pressure and heart rate were determined two hours after ingestion of the medication.
The two treatments (with labetalol and hydrochlorothiazide) were compared using analysis of variance. The immediate effects of administration of both drugs on ventilatory function were evaluated by comparing FEV1 level two hours after the largest dose of antihypertensive medication given on the last treatment day to baseline FEV1 prior to drug administration on the same day. Long-term effects were evaluated by comparing FEV1 before treatment on each evaluation day during phase two with the mean of the last two pretreatment FEV1 levels during the placebo washout period. Antihypertensive effects of the drugs were evaluated by comparing the sitting diastolic blood pressure prior to drug administration on each treatment day with the mean of the last two sitting diastolic blood pressures during the placebo washout period.
Figure 1. Outline of the study plan.