Labetalol and Hydrochlorothiazide for Ventilatory Function of Hypertensive Patients Outcomes and Deliberations

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Patient Characteristics

Of the 41 patients who entered the treatment phase of the study, 21 received therapy with labetalol and 20 received hydrochlorothiazide treatment (Table 1). The ratio of men to women was similar in both groups. Mean age was 54 years in the labetalol group and 59 years in the hydrochlorothiazide group. The preponderance of middle-aged males reflects the fact that two of the participating hospitals were Veterans Administration hospitals. Three of the 21 patients in the labetalol group and five of the 20 in the hydrochlorothiazide group were black. There were no significant differences in mean baseline systolic blood pressure, diastolic blood pressure, FEVb or FEV/FVC levels between the two treatment groups.

Propranolol Challenge

The responses of the 41 patients to oral propranolol challenge are shown in Table 2. In the labetalol group, mean FEVj decreased from 1,707 ml to 1,180 ml two hours after receiving propranolol, a decrease of 32 percent. A similar decrease was seen, from a mean value of 1,823 ml to 1,250 ml, in the patients receiving hydrochlorothiazide, a decrease of 31 percent. The fall in FEV1 after administration of propranolol was significant in both groups.
Heart Rate Estimation

Control of Hypertension

Of the 21 patients who received therapy with labetalol, 18 completed the four-week treatment phase; the remaining three were dropped due to lack of blood pressure control. Of the 20 patients who received therapy with hydrochlorothiazide, 18 completed the treatment phase; the other two were dropped due to lack of blood pressure control. Average maximum daily dose of labetalol in the 18 patients who completed the study was 557 mg, while the average maximum daily dose of hydrochlorothiazide was 72 mg.

Ventilatory Function

Short-term effects of therapy with labetalol and hydrochlorothiazide were evaluated by comparing FEVi levels before and two hours after administration of the maximum antihypertensive drug dose on the last treatment visit. The results of this comparison are shown in Table 3. Pretreatment FEVj on the last treatment day was 1,578 ml in the labetalol group, a value significantly lower than the mean pretreatment value of 1,905 ml in the hydrochlorothiazide group. Two hours after administration of the highest dose of labetalol, mean FEVj was 1,554 ml, a decrease of 1.5 percent; in the hydrochlorothiazide group, mean FEVj decreased only 1 ml (0.05 percent). Mean change in FEVx two hours after maximum dose was not significant in either group.

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Long-term effects of the two antihypertensive agents are shown in Table 4. Initial mean FEVj was lower in the labetalol group (1,682 ml vs 1,760 ml), and there was a gradual drop in mean baseline FEVj in the labetalol group, reaching a maximum of 156 ml after three weeks of therapy. There was an increase in mean baseline FEVj in patients receiving hydrochlorothiazide, reaching a maximum of 145 ml at the last treatment visit. Although there was a decline in mean baseline FEVj with increasing doses in the labetalol group, the change was not significant in either group.

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Other Side Effects

Neither antihypertensive agent was discontinued because of the presence of significant side effects. One patient who received hydrochlorothiazide complained of dryness of the mouth, and one patient in the labetalol group had leg cramps. One patient in each group noted increased fatigue.

Discussion

The decision to include a propranolol challenge as a part of the protocol was made after considerable debate. A drop in FEVj following oral administration of propranolol was added to the criteria for patient entry in order to increase the significance of the results. Exercise was used previously by the authors as a nonspecific challenge and was found to be unreliable in older patients. At the beginning of the study, all candidates were challenged with 80 mg of oral propranolol; however, one patient at each of the three study centers developed severe bronchospasm requiring therapy with bronchodilators and lasting up to three days. Following this event, the protocol was amended so that patients first received a 40 mg dose of propranolol, and if the FEVi did not decrease by 20 percent or more, the larger dose was given on a separate day.

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The results of this study indicate that a majority of patients with mild-to-moderate hypertension can be controlled successfully with oral labetalol twice daily. These results are consistent with previous reports that labetalol is an effective antihypertensive agent. While no previous studies have reported the chronic effects of therapy with labetalol on ventilatory function in asthmatic subjects, the acute effects have been evaluated in both normal and asthmatic subjects. In six healthy volunteers, Maconochie et al found that administration of 400 mg of oral labetalol did not enhance the fall in FEVj after a histamine challenge. They hypothesized that the alpha-adrenergic receptor blocking activity of labetalol should make it less likely to cause bronchoconstriction in asthmatic subjects. Skinner et al found that mean FE Vi decreased only 20 ml 15 min after the intravenous administration of 20 mg of labetalol to ten asthmatic subjects.

Bronchodilator MedicationWhile the effects of a single dose of labetalol on air flow are minimal, there was a trend toward decrease in FEVj over the four-week period of this trial. This trend may be important in that the dosage was titrated upward at each of the four visits until blood pressure was satisfactorily controlled; thus, the average daily dose was highest at the last visit. This suggests that there may be a decrease in ventilatory function in some propranolol-sensitive asthmatic subjects when higher doses of labetalol are administered, as has been reported with the cardioselective beta-adrenergic blocking drugs, metoprolol and atenolol. In spite of the gradual drop in FEVi, patients did hot require more bronchodilator medication and did not report an increase in dyspnea or wheezing. Long-term deterioration of lung function following labetalol administration was not seen in patients with hypertension and chronic obstructive pulmonary disease in one study, although in a separate study using the same protocol, there was a gradual deterioration in ventilatory function with labetalol therapy.

Because of the availability of other effective antihypertensive agents, beta-adrenergic antagonist drugs are not recommended for the initial treatment of hypertension in asthmatic subjects, especially those with marked airway responsiveness. Alternative agents which might be considered in these patients include diuretics, alpha-adrenergic antagonist drugs and calcium channel-blocking agents. Although the calcium inhibitor drugs have not been approved for use as antihypertensive agents, they are frequently used for this purpose with good results. These agents have been shown to protect against nonspecific bronchial challenges and, in a recent report, verapamil compared favorably with labetalol for the treatment of hypertension in a group of patients with obstructive airways disease.

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If a decision is made to use a beta-adrenergic antagonist drug because of failure to obtain a satisfactory response with alternative agents or because of patient intolerance, then labetalol is recommended over other currently available agents because of its effectiveness and relative safety. Because of the trend toward a decrease in FEVj with increasing doses of labetalol, patients with asthma (read more) should be observed closely with spirographic examinations or peak flow determinations for the first few weeks, while the dose is being adjusted for blood pressure control.

Table 1 — Population Characteristics

Labetalol group Hydrochlorothiazide group
Number 21 20
Male/female 16/5 15/5
Mean age (Yrs) 54 59
Systolic BP (mm Hg) 146 ±3* 155 ±4*
Diastolic BP (mm Hg) 100 ±1* 102 ±1*
Baseline FEVj (ml) 1,689 ±128* 1,763 ±176*
Baseline FEVj/FVC 0.58 ±0.03* 0.58 ±0.03*

Table 2 — Changes in FEVl (ml) After Oral Propranolol

Labetalolgroup Hydrochlorothiazide group
Before propranolol 1,707 ±133* 1,823 ±181*
2 hr s. after propranolol 1,180±1252 1,250 ±132*
% decrease 32 31
Pt <0.001 <0.001

Table 3—FEVj (ml) Before and Two Hours After Highest Dose of Antihypertensive Agent

Labetalol (n = 19) Hydrochlorothiazide (n = 18)
Before highest dose 1,578 ±135* 1,905 ± 256*
After highest dose 1,554 ±137* 1,904 ± 242*
Change (%) — 1.5 “0.05
P >0.5 >0.5

Table 4 — Effects of Hydrochlorothiazide and Labetalol on FEVj During Four-Week Treatment Period

No. of subjects Hydrochlorothiazide FEVj (ml) No. of subjects Labetalol FEV, (ml)
Baseline 20 1,760 ±176* 21 1,682 ±118*
Visit 1 20 1,802 ±184* 21 1,665 ±116*
Visit 2 20 1,782 ± 203* 19 1,654 ±121*
Visit 3 19 1,824 ± 225* 19 1,526 ±137*
Visit 4 18 1,905 ±256* 19 1,578 ±135*
Maximum change 145 -156