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Current Medical Research and Opinion

Vol. 5, No. 8, 1978

Labetalol in the difficult hypertensive patient in general practice

C. Harris, L.R.C.P., L.R.C.S.(Ed.), L.R.F.P.S.(Glas.)

Curr. Med. Res. Opin., (1978), 5, 618.

Maidstone,England

Received: 6th July 1978

Summary An open study was carried out in general practice to assess the effectiveness and tolerance of tabetalot in the treatment of 53 di3cutt hypertensive patients, most of whom had failed to respond to previous hypotensive therapy. The results showed that in the 49 patients receiving treatment for more than 3 months good blood pressure control was readily achieved, and with labetalol alone in all but 6 of them. The majority were controlled on doses ranging from 300 to 600 mg per day. Treatment was discontinued in 3 patients because of severe side-effects. Mild, tolerable side-effects, similar to those found with beta-adrenergic blocking agents, were reported by 35 patients. Key words: Labetalol - antihypertensive agents - hypertension

Introduction Most of the early clinical trials of new drugs are carried out mainly in hospital and, when these compounds are marketed, this can leave the general practitioner, who is commonly the largest prescriber, at a disadvantage. This is particularly so in the treatment of hypertension because, as general practitioners refer only a very small proportion of their hypertensive patients for consultant opinion, the results of trials from hospitals can only refer to a small fraction of the whole. Thus, the relevance of the new drug in every day general practice may not be evident from the results of hospital studies. This has certainly occurred with labetalol (‘Trandate’t), a new alpha- and betaadrenoceptor blocking drug, which appears to have the theoretical advantages of simplicity of dosage and the range of activity necessary for the treatment of hypertension in general practice. Labetalol was made available on prescription in the U.K. in April 1977 with only one report of its usage in general practice.’ It was decided, therefore, to study the activity of labetalol in the most troublesome and difficult hypertensive patients in this practice to determine if its theoretical advantages were real. Most of these patients had been referred for consultant opinion and investigation, but this had resulted in little improvementin the control of their hypertension. ttrade mark, Allen & Hanburys Ltd.

618

C. Harris

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Patients and methods Fifty-three patients were studied, 11 males and 42 females, with a mean age of 55.6 years (range 39 to 75 years). All had an initial supine diastolic pressure above 100 mmHg. Forty-seven patients were considered to have essential hypertension, 6 renal or post-toxaemia of pregnancy hypertension. Thirteen patients were newly diagnosed and 40 were inadequately controlled by their previous treatment regimen (diuretic plus beta-blocker and/or methyldopa). This failure to control blood pressure was due to dose limiting side-effects in 32 of these patients. Concurrent disease requiring treatment was present in 33 patients. A history of thyroid disturbance was present in 4, hyperlipidaemia in 2 and obesity1 diabetes in 6. The other conditions were unrelated to hypertension. Treatment for all concurrent disease was continued throughout the study period. New patients had their blood pressure recorded on at least three occasions before acceptance into the study. All measurements were made on the same arm, by the same person, and as near as possible at the same time of day. Blood pressure was recorded standing and supine, after 3-minutes’ rest at each visit. Fifth phase diastolic pressure was recorded. Patients already on treatment had to have an indication of side-effects and/or poor control before transfer to the study. The retinae ol all patients were examined at each visit and the findings recorded according to the Keith, Wagner classification. Assessments were made at 2 weeks and 4 weeks, then at 3 , 6 and 9 months into the study. Treatment was started at 100 mg labetalol 3-times daily in all except 1 patient. This dosage was adjusted at each visit, as indicated by the level of the blood pressure and symptoms. All other antihypertensive medication was withdrawn during the first 14 days of labetalol treatment, apart from 5 patients who continued on a diuretic. One patient had a diuretic added to his treatment at 3 months, but no other antihypertensive medicaments were required.

Results Details of the mean and range of dosage of labetalol during the trial period are given in Table I. Although the dosage range was great (100 to 900 mg/day), the majority of the patients were controlled in the 300 to 600 mg daily dosage range. Table I. Dosage of labetalol used during trial period: mg/day Time

Mean

Range

On entry (n =53) After 14 days (n =53) After 1 month (n =52) After 3 months (n =51) After 6 months (n =38) After 9 months (n =28)

306 300 444 455 466 493

300 to 600 300 300 to 600 200 to 900 200 to 900 100 to 900

Mean values for blood pressure and pulse rate before and after treatment are given in Table 11, and Figure 1 shows graphically the mean changes in systolic and diastolic blood pressure (standing and supine), mean arterial pressure and pulse rate. 619

151.33+ 16.79

149.006 17.15

146.93& 18.10

After 3 months (n = 5 1 )

After 6 months (n =38)

After 9 months (n = 28)

91.93A11.01

90.79k9.76

94.671 12.75

97.92k15.5

148.711-17.34

148.53%14.79

153.57%17.83

158.23%18.43

72.323Z3.14 73.86~t5.58

92.07 110.18

72.00+3.71

72.4614.17

91.05 %9.14

95.96113.75

100.85%16.06

73.861-5.39

72.4213.26

72.98 13.70

73.02%4.01

73.722~4.12

154.551 19.34

73.28k3.85

After 1 month (n = 52)

107.40% 19.79

162.68%22.92

After 14 days (n=53)

167.66+25.22

78.5615.12

79.0415.75

121.15 15.53

188.41h21.27

120.671- 16.20

183.83%22.13

On entry (n =53) 104.11 117.93

Supine

Pulse rate Standing

Supine blood pressure Diastolic

~~

Systolic

~ _ _ _

Diastolic

~~

Standing blood pressure

before and after labetalol treatment: mean (1S.D.) values

Systolic

Measurement

____

Table II. Blood pressure (mmHg) and pulse rate (beats/&)

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C . Harris

Figure 1.

Mean change in blood pressure and pulse rate during treatment with labetalol Blood pressure

2ool 190 Curr Med Res Opin Downloaded from informahealthcare.com by University of Adelaide on 11/13/14 For personal use only.

180: I70

Supine systolic Standing systolic

150

120-

Supine MAP Standing MAP

110100-

?O

.-e

E . v1 *

j

80-

70-

Supine diastolic Standing diastolic

1

1 Pulserate

3

Figures 2 and 3 show, in patient serial order, the changes in individual values for standing systolic and diastolic blood pressure from entry to completion in those patients completing more than 3-months' treatment. Clinically, in terms of blood pressure control, all patients benefitted from treatment. There was little difference between standing and supine blood pressures and there was an improvement both in systolic and diastolic pressures, except in 2 patients. In one of these, there was a considerable improvement in standing diastolic blood pressure (from 120 to 106 mmHg), but the standing systolic blood pressure rose (from 160 to 176 mmHg). In the other patient, the standing systolic blood pressure was reduced (from 220 to 156 mmHg) but there was no change in the diastolic (1 I0 mmHg). The pulse rate remained unchanged throughout the study. An improvement was noted in the appearance of the retinal vasculature in 6 patients during treatment. No deterioration was observed in any patient, 621

Labetalol in the difficult hypertensive patient in general practice

Figure 2. Scattergram of individual values for standing systolic blood pressure, before and after 3-months' treatment: 49 patients in serial order On entry

Afier

3 months

250,

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240, 230 220 210

sE E

200 190 180 170 160 150

... . . .. . . . = . ........ * . . .. . . . 0.

.

*

* .

..

. * .. . . ......

0 .

.**

...

jigi 110

Figure 3. Scattergramof individual values for standing diastolic blood pressure, before and after 3-months' treatment:49 patients in serial order On entry 190 180 170]

Afrer 3 months

160

...... 100

.

.. ..

.. I0 "V

622

.

C. Harris

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There was no evidence of drug interactions between labetalol and any other medication used during the trial period. Side-effects Table III gives details of the incidence of side-effects reported during treatment with labetalol. Also shown, for comparison, is the incidence of severe side-effects on previous therapy in the 32 patients who were transferred to labetalol treatment because of this. Table III. Incidence of side-effectsreported on labetalol and on previous antihypertensivetherapy Side-effect Palpitations Bronchospasm Dyspnoea on exertion Postural hypotension Weak limbs Tirednessllethargy Headache Insomnia Depression** Cramps Dizziness/giddiness Visual disturbance Nausea/vomiting Constipation Dry mouth Purpura, transient Pruritus Flushes Urinary symptoms Lightheadedness Tingling of scalp Memory lapses Skin rash Sexual difficulties

No. reports No. patients *Patients withdrawn

Previous

Labetalol

therapy*

Mild/moderate

Severe*

:1 :1

2 12 36 14 12

4

7 7 5 14 18 6 5 5 19 4 4 2 2 1 4 10 1 2 1 1

Stopped at 10 weeks Stopped at 5 weeks

1, stopped at 12 days

2 4

84 32

120 35

5 3

**All these patients had a history of depression

In 35 (66 %) patients, there were mild, tolerable symptoms reported, which tended to occur initially and were transient. No unwanted effects were noted in 15 (28 %) patients. Three patients (6 %) had to be withdrawn because of severe side-effects. The first patient, male aged 45 years, had a blood pressure of 165/110 mmHg whilst being treated with oxprenolol and a diuretic, and treatment was changed because of inadequate control, tiredness, lethargy and postural hypotensive symptoms. His blood pressure was unstable, and he had previously reported impotence whilst on methyldopa. Labetalol (100 mg 3-times daily), although controlling his blood 623

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Labetalol in the difficult hypertensive patient in general practice

pressure (130/80 mmHg), caused painful and hesitant micturition. The second patient, aged 42 years and the wife of the first patient, was inadequately controlled (180/142 mmHg) by methyldopa and a diuretic, and complained of tiredness, lethargy, depression and sexual difficulties. Labetalol, increasing to 900 mg/day, failed to control her blood pressure (196/146 mmHg), and complaints of weak limbs, tiredness, headache and insomnia contra-indicated a further increase in dosage. It should be noted that she had a history of tiredness, palpitations, headache and dizziness. The third patient, a 54-years’ old male, was a newly diagnosed hypertensive (190/124 mmHg) complaining of dyspnoea, bronchitis and gout. He was controlled on 200 mg labetalol3-times daily (156/94 mmHg) and returned to work after 4 weeks. Ten weeks later, however, he complained of severe dyspnoea, and chest X-rays showed the onset of pulmonary congestion and cardiac enlargement. His blood pressure was 190/130 mmHg. The consultant to whom he was referred advised withdrawal of labetalol because the congestion and enlargement may have been due to the drug’s beta-blocking activity. It is more likely, however, that the patient had entered into a malignant phase of his condition.

Discussion The results of this small study carried out on 53 severe and difficult hypertensive patients certainly appear to support the findings of other investigators,2.4 and suggest that, in general practice, labetalol has real practical and not just theoretical advantages.’ 3 3 . 6 Good blood pressure control was obtained easily and the treatment regimen was simpler than that with previous therapy received by the patients. Few incremental changes in dosage were required and all but 6 (10 %) patients were controlled by labetalol alone. A pleasing feature was the lack of any marked postural drop in blood pressure whilst patients were being treated with labetalol. This suggests that smoother control may be obtained throughout the 24 hours. Although the list of side-effects reported is lengthy, most side-effects were mild and transient and had disappeared by the next visit. The pattern of side-effects was very similar to that found with simple beta-blocking drugs. References 1. Breckenridge, A. M., Macnee, C. M., Orme, M. L‘E., Richards, D. A., and Serlin, M. J., (1977). Rate of onset of hypotensive response with oral labetalol. Br. J. Clin. Pharmacol., 4,388. 2. Ghose, R. R., and Sampson, A., (1977). Rapid onset of action of oral labetalol in severe hypertension. Curr. Med. Res. Opin.,5, 147. 3. Joeks, A. M., and Thompson, F. D., (1976). Acute haemodynamic effects of labetalol and its subsequent use as an oral hypotensive agent. Br. J. Clin. Pharmacol., 3, Suppl. 3,789. 4. Kane, J., Gregg, I., and Richards, D. A., (1976). A double-blind trial of Iabetalol. Br. J. Cfiiz. Pharmacol., 3, Suppl. 3, 737. 5. Koch, G., (1976). Combined c- and P-adrenoceptor blockade with oral labetalol in hypertensive patients with reference to haemodynamic effects at rest and during exercise. Br. J. Clin. Pharmacol., 3, Suppl. 3,729. 6. Richards, D. A., Tuckman, J., and Prichard, B. N. C., (1976). Assessment of alpha- and betaadrenoceptor blocking actions of labetalol. Br. J. Clin.Pharmacol., 3, Suppl. 3,849.

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Labetalol in the difficult hypertensive patient in general practice.

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