Cardiovascular Drugs and Therapy 2: 363-367, 1988 © Kluwer Academic Publishers. Printed in the U.S.A.

LABETALOL IN NORMOTENSIVE PATIENTS WITH ANGINA PECTORIS

SUMMARY. Labetalol, an alpha-beta-blocker, has been shown to have vasodi lat ing as wel l as beta-blocking proper- ties. From the theoretical point of v iew such a drug is l ikely to be beneficial in the treatment of angina pectoris. There are very few studies invest igat ing the effects of labetalol in normotensive patients wi th angina pectoris. The three major controlled trials that have been published show that labetalol reduces angina frequency and prolongs exercise duration. In one study the effects of labetalol in anginal subjects us ing am- bulatory monitoring w a s performed and showed a reduction in si lent i sebemia as wel l as a reduction in angina pectoris. Thus labetalol would appear to be an effective ant ianginal agent. Further studies are necessary to determine i f the anti- anginal effect is ent irely due to the beta-receptor-blocking activity of the drug or whether labetalol 's vasedi lat ing prop- erty has important additional benefit.

KEY WORDS. labetalol, beta-blocker, alpha-blocker, angina pectoris, ischemia, vasodi lat ion

I t has become clear in recent years that the mech- anisms causing angina include not only an increase in myocardial oxygen demand but alterations in coronary blood flow. While coronary spasm in patients with nor- mal coronary arteries is relatively uncommon, angina pectoris is not infrequently modulated both by cor- onary artery tone and by alterations in myocardial ox- ygen demand. This proposal has important implica- tions in the selection of drug therapy.

Pharmacodynamic Effects of Beta- Blocking and Alpha-Beta-Blocking Agents

Beta-receptor antagonists have been widely used in the t reatment of angina [1]. Blockade of the beta-l- receptor cause a fall in heart rate and blood pressure together with a negative inotropic effect. The net result is reduction of the myocardial oxygen consumption. However, these agents also increase peripheral vas- cular resistance which theoretically can increase myocardial oxygen demand [2]. Blockade of beta- receptors is likely directly to cause coronary vaso- constriction, while combined blockade of beta-l- and beta-2-receptors, particularly during increased cate- cholamine release, leads to unopposed alpha-adrener-

Kim Fox, Arshed A. Quyyumi National Heart Hospital, London, England

gic activity [3, 4]. These events would tend to increase coronary tone and to reduce coronary blood flow and may be detrimental particularly when increased cor- onary tone plays an important role in the mechanism of angina pectoris.

Alpha-adrenoreceptor-blocking agents increase cor- onary blood flow and reduce coronary and peripheral vascular resistance [5, 6]. However, pure alpha- adenergic blockade may be a disadvantage to patients with angina pectoris. The alpha-receptor antagonist phentolamine can cause a reduction in peripheral vas- cular resistance and a fall in blood pressure, yet any potential benefit in terms of reduction of myocardial oxygen demand obtained by the fall in blood pressure will be counterbalanced by the reflex tachycardia that occurs [7]. Thus in some patients the use of pure alpha- blocking agents may actually exacerbate angina. Selective alpha-l-receptor blockade with prazosin tends to cause less tachycardia but even with this drug exacerbation of angina has been described [8].

Labetalol is a unique compound since it possesses both beta-blocking and alpha-l-receptor blocking ac- tivities [9, 10]. Labetalol's beta-blocking activities are nonselective in isolated tissue preparation and the drug is about three times more potent in beta-blocking than in alpha-blocking activity. Theoretically, there- fore, labetalol should have advantages not available using conventional beta-blockade, particularly where coronary tone is important. Labetalol decreases pe- ripheral vascular resistance by its alpha-blocking ac- tivity and may be useful in those patients with angina pectoris who have either mild congestive heart failure or peripheral vascular disease.

Address correspondence and reprint requests to: Dr. Kim Fox, National Heart Hospital, London WIM 8BA, England

364 Fox and Quyyumi

Effects of Labetalol in Hypertensive Angina

In patients with hypertension and angina pectoris an improvement of exercise capacity has been found using labetalol in dosages ranging from 300 to 1,600 rag/day [11, 12]. In these studies labetal reduced the frequency of anginal attacks, increased exercise time, and in- creased exercise workload. There was a reduction in the resting supine and standing blood pressure and heart rate; the increments in systolic blood pressure with exercise were blunted. A reduction in resting heart rate × blood pressure product and inhibition of the heart rate × blood pressure increments with exercise was also found.

However, these studies were performed in hyperten- sive subjects and there are very few control data in nor- motensive anginal subjects.

Effects of Labetalol in Normotensive Angina

Upward and colleagues investigated 12 normotensive patients with stable angina pectoris in a single-blind dose-ranging study [13]. After a 2-week placebo period, labetalol was given in increasing doses up to a max- imum of 600 mg daily. There was a reduction in both the frequency of angina attacks and glyceryl trinitrin consumption. Maximal symptom-limited exercise tests were performed 3 and 12 hours after dosage, there was an improvement in exercise tolerance accom- panied by a blunting of the heart rate/blood pressure response to exercise. Trough exercise tolerance did not differ from that performed 3 hours after the dosage.

We investigated the effects of labetalol in the treat- ment of normotensive patients with angina [14]. The purpose of our study was to determine the dose re- quired to treat angina patients using labetalol using an open single-blind dose titration. Each patient subse- quently entered a double-blind crossover study com- paring labetalol with placebo. Recordings were taken of the frequency of angina and exercise tolerance was measured using a treadmill. In addition we determined the effects of labetalol on the frequency of both painful and silent ischemia.

Ten patients were investigated; all received 200 and 400 mg/day of labetalol and six who remained asymp- tomatic on 400 mg/day were given 600 mg/day. Labetalol caused a dose-related reduction in resting heart rate throughout the 24 hours and a reduction of both the systolic and diastolic arterial pressure. All patients continued to have angina with labetalol 200

mg daily but three patients became pain-free with 400 mg/day and three of the six patients treated with 600 mg/day had no chest pain while the other three patients had a greatly decreased frequency of pain at 600 mg/day.

Labetalol significantly reduced episodes of angina pain (Figure 1). The optimum dose was 200 rag/day in one patient, 400 mg/day in four patients, and 600 mg/ day in five patients (mean 480 mg/day). There was an increase in the duration of exercise before the develop- ment of ST segment depression when compared to placebo {Figure 2) and also there was an increase in the total duration of exercise (p < 0.01) (Figures 2 and 3). The mean heart rate and systolic blood pressure at the onset of 1-mm ST segment depression and at the ter- mination of exercise was lower using labetalol treat- ment. The blood pressure effect was found to occur at 400 mg/day; the effect on exercise duration continued to 600 mg/day (Figure 4).

In addition to reducing the frequency of angina, labetalol reduced the frequency of ST segment depres- sion recorded by 48-hour ambulatory monitoring at the end of each of the treatment phases. There was a reduc-

Fig. 1. Effects of labetalol on angina frequency. There was a significant reduction in the weekly number of episodes of angina during treatment with labetalol. Reproduced from [15] by courtesy of British Heart Journal.

Angina episodes/wk

11

10-

9-

8-

7 -

6 -

5 Placebo

p < 0.01

Labetalol 480 mg

Heart rate to 1-mm ST-segment depression Systolic blood pressure

Time to 1-mm ST-segment depression (min)

8

7 ~

6 ¸

[ ~ - F , 2OO

J

4O0

Labetalol (mq)

5 ,1 I g u v

6OO 2O0 400 600

Labetalol (mg)

Fig. 2. Effects of labetalol on exercise duration to myocardial ischemia. During the double blind crossover phases labetalol pro- duced a significant increase in the exercise time to I mm S T segment depression when compared to placebo. Reproduced from [15] by courtesy of B r i t i s h H e a r t J o u r n a l .

Fig. 3. Effects of labetalol on total exercise duration. During the double-blind crossover phases labetalol produced signifi- cant prolongation in the total exercise duration when com- pared to placebo. Reproduced from [15] by courtesy of B r i t i s h

H e a r t J o u r n a l .

Time to 1-mm ST-segment depression (rain)

8 -

p < 0.01

7 -

6"

Placebo Labetalol 480 mg

FiE. 4. Effects of labetalol on exercise duration, heart rate, and blood pressure to I mm ST segment depression during dose titration. There was a dose-related increase in the exer- cise time to I mm S T segment depression. Reproduced from [15] by courtesy of B r i t i s h H e a r t J o u r n a l .

Exercise duration (min)

9.0

8.5.

8.0-

7.5-

7.0-

6.5

p < 0.01

Placebo Labetalol 480 mg

366 Fox and Quyyumi

Episodes of ST-segment depression 4

I Total

I Pain

p < 0.01

Placebo Labetalol 480 mg

Fig. 5. Effects of labetalol on silent and painful episodes of ST segment depression. There was a significant reduction in the frequency of ST segment changes during treatment with labetalol when cmpared with placebo. This reduction affected not only the total episodes of ST segment depression but also those episodes that were not accompanied by chest pain. Reproduced from [15] by courtesy of British Heart Journal.

tion not only in those episodes of ST segment depres- sion accompanied by chest pain but also in the silent episodes of ST segment depression {Figure 5). Silent ischemia occurred approximately three times as fre- quently as painful ST segment depression, a similar in- cidence to previous studies reporting on the frequency of silent ischemia [16].

Although this study has shown that labetalol is ef- fective in the treatment of normotensive angina in patients with chronic stable effort-related angina, it is not possible to determine how much of this effect is due to the beta-blocking properties of the drug and how much is due to the additional alpha-blocking proper- ties. It may be entirely possible that the entire an- tianginal effect with labetalol is due to beta-adrenergic blockade. Recently the systemic and coronary haemo- dynamic effects of combined alpha- and beta-adrener- gic blockade was assessed in 12 normotensive patients with angina [17]. Labetalol produced systemic and cor- onary vasodilatation, reduced aortic pressure, and in-

creased cardiac output; coronary flow and heart rate did not change. These authors also found that exercise duration was prolonged in a substantial number of patients. During exercise, tachycardia was blunted as was the increase in aortic pressure, left ventricular end-diastolic pressure and coronary sinus flow. The cardiac output, systemic, and coronary vascular resis- tance was similar to values obtained during controlled exercise. Thus these authors concluded that the hemodynamic effects of labetalol appeared to be beneficial, and that the hemodynamic effects of labetalol differ from those of classic beta-adrenergic receptor blocking drugs principally by its vasodilating actions. Some of labetalol's hemodynamic effects are normally associated with calcium antagonist drugs. However, in contrast to the dihydropyridine calcium antagonists, labetalol does not cause a reflex tachycar- din. The following effects of labetalol resemble those of diltiazem [18]: 1) acute decrease in aortic pressure without reflex tachycardia, 2) preservation of coronary blood flow, and 3) decrease in both systemic and cor- onary resistance. Although diltiazem and verapamil may both blunt exercise-induced tachycardia they do so only by a small amount while labetalol tends to blunt it more.

Conclusions

Thus labetalol appears to be effective in the manage- ment of angina pectoris. It has characteristics in com- mon with both beta-receptor blocking drugs and some calcium antagonists. Further work needs to be done to determine the place of labetolol in relation to the com- monly used antianginal drugs. In particular, studies comparing labetalol with calcium antagonists and beta-receptor-blocking drugs are necessary.

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Labetalol in Angina Pectoris 367

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