COMPARISON OF LABETALOL

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1 Br. J. clin. Pharmac. (198), 9, COMPARISON OF LABETALOL AND PROPRANOLOL IN HYPERTENSION D.P. NICHOLLS* & M.H. HUSAINI Tameside General Hospital, Ashton-under-Lyne OL69RW C.J. BULPITT London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT M.D.B. STEPHENS & A.G. BUTLER Medical Department, Glaxo-Allenburys Research Limited, Ware, Herts SG12ODJ 1 has been compared with propranolol in a double-blind, double-dummy study of 24 patients with mild or moderate essential hypertension. 2 Two patients were unable to tolerate propranolol and five labetalol, because of symptom sideeffects; this difference was not significant (P >.1). 3 On a self-administered questionnaire, labetalol was associated with a greater number of side effects per patient than propranolol, but no individual side effect was significantly more common with either drug. 4 There was no difference in the number of spontaneously reported side effects between the two drugs. 5 Both drugs impaired pulmonary function, but propranolol caused a greater reduction than labetalol after 8 weeks of treatment. 6 We conclude that labetalol and propranolol are similarly effective and acceptable to the patient. Introduction Since the therapeutic use of propranolol in patients with hypertension was first described (Prichard & Gillam, 1964), the role of fl-adrenoceptor blocking drugs has become well established (Lorimer, Dunn, Jones & Lawrie, 1976; Barritt & Marshall, 1977). Their precise mode of action is not yet defined (Lewis, 1976). Peripheral resistance in the long term remains unchanged or possibly reduced (Tarazi & Dustan, 1972). Reduction of peripheral resistance by the addition of a-adrenoceptor blockade is an effective therapeutic combination (Majid, Meeran, Benaim, Sharma & Taylor, 1974; Johnson, La Brooy & Munro-Faure, 1976; Koch, 1976) although postural hypotension and unwanted side-effects may occur (Beilin & Juel-Jensen, 1972). has been shown to produce a- and /- adrenoceptor blockade in animals (Brittain & Levy, 1976) and in man (Richards, Prichard, Boakes, Tuckman & Knight, 1977). Previous studies have indicated that it is an effective hypotensive agent with * Present address: Tutor in Medicine, Hope Hospital, Salford M6 8HD /8/ $1., relatively few side-effects (Frick & Porsti, 1976; Sanders, Routledge, Rao, Gales, Davies & Rawlins, 1978; Pugsley, Nassim, Armstrong & Beilin, 1979). We have compared the side-effects of labetalol and propranolol in 24 patients with mild or moderate hypertension which had previously failed to respond to a thiazide diuretic alone. Methods The trial protocol was reviewed by the Tameside Area Ethical Committee in June Nine women and 15 men, aged (mean 47.4) years, were studied. Thirteen had WHO grade 1 hypertension, and 11 WHO grade II (World Health Organisation, 1962). Nine patients had previously received treatment for hypertension, but not in the month preceding entry into the trial. Patients were excluded if they had diabetes mellitus, chronic liver disease, chronic renal failure, asthma, heart failure, heart block, accelerated phase hypertension, or were taking monoamine oxidase inhibitors. Patients were included in the trial ) Macmillan Journals Ltd 198

2 234 D.P. NICHOLLS, M.H. HUSAINI, C.J. BULPITT, M.D.B. STEPHENS & A.G. BUTLER if the diastolic blood pressure was 1 mmhg or greater when measured lying, standing, and after exercise after 2 and 4 weeks' therapy with a thiazide diuretic (Navidrex K, two tablets; cyclopenthiazide.5 mg with potassium 16 mmol daily). The diuretic was then continued throughout the trial, as we felt it was unethical to include a placebo period of treatment. The blood pressures after this initial diuretic therapy were / supine, / standing and / after exercise (mmhg, mean+ s.e. mean). After informed consent had been obtained, the patients were randomly allocated to treatment groups. One group of twelve received active labetalol 2 mg twice daily with placebo propranolol tablets, and the other group active propranolol 8 mg twice daily with placebo labetalol tablets. The active and the placebo tablets were identical in size and taste. The equivalent dose ratio of 2.5: 1 was suggested by previous clinical experience (Frick & P6rsti, 1976). The patients attended every 2 weeks for eight visits. Therapy was then withdrawn, and the diuretic alone continued for a 4-week 'washout' period. At the end of this period, the blood pressures (mmhg, mean + s.e. mean) were / supine, / standing and / after exercise. The patients then crossed over to the other treatment group. Neither the doctors nor the patients knew which drug was active at any given time. The duration of the trial was 4 weeks. At each visit blood pressure was recorded after 3 min supine, 1 min erect, and after exercise at 5 Watts on a bicycle ergometer until a steady pulse rate was achieved. The pulse supine and after exercise was counted over 3 s. All blood pressure measurements were made with a random zero sphygmomanometer (Wright & Dore, 197), with a standard 13 cm cuff, and diastolic pressures were taken at Korotkoff phase IV. If the diastolic pressure was 1 mmhg or greater in any two of the three readings, therapy was increased on a fixed dose schedule up to a maximum of labetalol 24 mg or propranolol 96 mg daily. If control was regarded as satisfactory (diastolic pressure 95 mmhg or less in any two of the three readings), the same dose was maintained until the next visit. If control remained satisfactory, the same dose was continued until the end of the treatment period, but if the blood pressure rose again, further dose increments were made. All patients had a chest radiograph, intravenous urogram, and urinary 3-methoxy-4-hydroxymandelic acid (VMA) estimation before entering the trial. Nine patients (38%) had anatomical abnormalities of the urinary tract. In addition to the above investigations, the following were carried out at varying intervals during the trial: haemoglobin, differential white cell count, ESR, antinuclear factor (ANF, assayed by immunofluorescence), LE cells, serum urea, electrolytes, liver function tests, creatinine clearance, ECG, MSSU, urine sugar and protein, and body weight (kg). Peak expiratory flow rate (PEFR, 1/min) was measured with a Wright peak flow meter, and FEV1/FVC using a dry spirometer (Vitalograph Ltd). Side-effects were monitored by direct reporting, and also by a self-administered questionnaire completed by the patient after assessment, and at the end of each treatment period (Bulpitt & Dollery, 1973; Bulpitt, Dollery & Carne, 1974). Statistical analysis of the questionnaire was carried out using McNemar's test for paired proportions, except for certain questions where Wilcoxon's signed rank test was used. Analysis of blood pressure and pulse readings, and laboratory data, used Wilcoxon's rank sum test, after allowing for order of treatment effect. Results Fourteen patients completed both treatment periods. Twenty-one patients completed at least four visits on both treatments, and three failed to complete four visits on both. Therapy was stopped on eleven occasions in ten patients, for the reasons set out in Table 1. Table 2 shows the blood pressure and pulse measurements after 8 and 16 weeks of treatment. We compared the readings after initial assessment and after the 'washout' period, when the readings should be the same. In fact, the blood pressure values were significantly lower at the end of the 'washout' period than at the end of the assessment period (P <.5, supine and standing diastolic; P <.1, other readings). The resting pulse was higher (P <.5). These changes did not depend on which treatment was given first. Possibly as a result of these changes the reduction in exercise blood pressure after four visits was less during the second treatment period than during the first (P <.1, systolic; P <.5, diastolic), but all other reductions were not significantly different. Blood pressure was controlled (diastolic in two positions 95 mmhg or less) by both drugs in 11 patients (46%). The average dose of labetalol required was 66 mg (range 4-16) and of propranolol 46 mg (range 16-72) giving a dose ratio of Seven patients (29%) were controlled on the minimum dose of labetalol, and 2 (8%) with the minimum dose of propranolol. Three patients (13%) were not controlled on the maximum dose of labetalol, and 4 (17%) on the maximum dose of propranolol. One patient was not controlled with either drug. Two patients who failed to respond to labetalol were controlled with propranolol and three patients who failed to respond to propranolol were controlled by labetalol. The side-effects are listed in Table 3. Completed questionnaires were available from 22 patients (92%).

3 LABETALOL AND PROPRANOLOL IN HYPERTENSION 235 Therapy was withdrawn due to side-effects on seven occasions (see Table 1), five due to labetalol and two due to propranolol, but this difference was not significant (P >.1). One patient, unable to tolerate labetalol due to postural dizziness, had asymptomatic bradycardia on propranolol. From the questionnaire, the total number of symptom complaints per patient was 5.4 on labetalol and 3.6 on propranolol (P <.5). Thirteen had more symptoms when on labetalol and five when on propranolol (P>.1). Table 1 Withdrawals from trial (n = 11, ten patients) Drug Daily dose (mg) Blood pressure on withdrawal Effect Supine Standing Impotence 16/9 135/9 Nausea, cramps, palpitations(!) 18/1 2/11 Tired, purple vision, tingling scalp, dry mouth 15/9 135/9 Symptomatic postural hypotension 13/9 75/55 Depression, loss of libido 16/11 125/85 Depression, dyspepsia, impotence 145/95 115/8 Depression, dyspepsia 17/ /15 Asymptomatic bradycardia (supine pulse < 5/min) 125/7 12/8 Asymptomatic bradycardia 16/9 14/85 Asymptomatic bradycardia 145/85 135/95 Poor control 21/125 2/12 Table 2 Blood pressure and pulse rate after treatment (mean+ s.e. mean) Supine blood pressure Standing blood pressure Exercise blood pressure Pulse (beats/min) Rest Exercise * = P <.5, ** = P <.1 (labetalol v propranolol comparisons) Mean after 8 weeks (n = 21) Mean after 16 weeks (n = 14) ** ** ** * * Table 3 Side-effects overall Side-effect None Tiredness Impotence (males) Depression Headaches Dry eyes Blocked nose Cold fingers Cramps Dyspepsia 16 Questionnaire (%) n = 22 (14 males) Thiazide alone Thiazide alone Not asked Spontaneous reporting (%) n=24 (15 males)

4 236 D.P. NICHOLLS, M.H. HUSAINI, C.J. BULPITT, M.D.B. STEPHENS & A.G. BUTLER Our trial was primarily intended to compare labetalol and propranolol, but it was felt to be of interest to include the number of side-effects on diuretic alone in Table 3. However, it is not possible to make valid statistical comparison of this and subsequent data, as diuretic therapy was given first and not in random order, and was not accompanied by a placebo. On spontaneous reporting, there was an average of 1.6 symptom complaints per patient on labetalol, and 1.5 on propranolol. No individual symptom was significantly more frequent with either drug, either in the questionnaire, or on direct reporting, but owing to the numbers in our trial, there was less than a 5% chance of observing a significant difference at the 5% level even if one drug caused a side-effect in 2% of patients and the other drug in 5%. Of the eighteen patients who expressed a definite preference, seven preferred labetalol and eleven preferred propranolol. Two patients developed a low-grade positive ANF on labetalol. LE cells were not seen in either case. One of these patients reverted to negative on propranolol, but the other continued to have a positive test. Minor variations were found in several other laboratory tests, but none were felt to be of clinical significance. The effect on pulmonary function is shown in Table 4. All changes are relative to the appropriate pre-treatment values, that is after assessment for the first treatment period, or washout for the second treatment period. After 8 weeks, labetalol (mean dose 82 mg) had no effect on pulmonary function, whereas propranolol caused a significant reduction in PEFR and FEV1. However, after 16 weeks labetalol (mean dose 139 mg) also reduced PEFR. Two patients complained of dyspnoea during labetalol therapy, but in neither case was there any change in pulmonary function tests. Discussion This study shows that labetalol is an effective antihypertensive agent, comparable with propranolol in its action on mild and moderate hypertension. For comparative data on side effects to be valid, the blood pressure must be reduced to the same extent, and both drugs did cause a similar fall in supine, standing, and exercise pressures. The absolute blood pressures are presented in Table 2 as the trial did not include a random order placebo-treatment period, which would be required to give the fall in blood pressure induced by active treatment. Although the incidence of side-effects from the questionnaire appears high, surveys of normal subjects show that many will report symptoms on a questionnaire (Bulpitt et al., 1974), but not as frequently as our patients. It has been suggested (Lancet, 1977) that the a-adrenoceptor blocking activity of labetalol could limit its use because of sideeffects, and five of our patients could not tolerate labetalol. The most obvious clinical manifestation of a-adrenoceptor blockade is postural hypotension, but at 16 weeks the mean postural fall in blood pressure was 7/5 mmhg, and subjective postural dizziness leading to cessation of treatment was found in only one patient. However, it is interesting to note that most of the patients who were withdrawn from labetalol treatment were on low doses, and some had an appreciable fall in systolic pressure on standing (Table 1). One complained of tingling scalp, an interesting symptom which has been reported previously (Frick & P6rsti, 1976; Hua, Thomas & Kincaid-Smith, 1977; Bailey, 1977). We feel that some subjects may be sensitive to a-adrenoceptor blockade, and that the recommended starting dose of 1 mg 3 times daily, rather than 2 mg twice daily that we used, should help to avert some of these effects. Other workers have noted similar effects after a single 2 mg oral dose (Louis, Brignell, McNeil, Christophidis & Vajda, 1978). No serious toxic effects were noted. An isolated positive ANF is worrying, but of doubtful clinical significance, and has been reported before with several fl-adrenoceptor blockers as well as labetalol (Louis et al., 1978; Sanders et al., 1978). We found no evidence of a reduction in total white cell count, which has been reported previously (Sanders et al., Table 4 Change in pulmonary function tests after treatment Mean dose (mg) PEFR (1/min) FEV1 (1) FVC (1) Pre-trial (n = 24) (Mean +±s.e. mean) After 8 weeks (n = 21) Lcabetalol B ** * After 16 weeks (n = 14) ** Changes significantly different from zero = *P <.5, **P <.1. The changes are relative to the appropriate non-treatment values, either initial or washout ** -.21 * -.16

5 LABETALOL AND PROPRANOLOL IN HYPERTENSION ). No patients had evidence of a lichenoid skin eruption, which has recently been reported after treatment with labetalol (Gange & Jones, 1978). Our study suggests that propranolol reduces pulmonary function more than labetalol in non-asthmatic subjects. Previous studies have shown that labetalol does not produce bronchoconstriction in asthmatics (Skinner, Gaddie & Palmer, 1975), despite inducing f32-adrenoceptor blockade (Richards et al., 1977). It has been postulated that cx-adrenoceptor blockade prevents bronchoconstriction (Skinner et al., 1975). proved to be a useful antihypertensive drug, with an effect comparable to propranolol. A fifth of our patients were unable to tolerate labetalol due to symptom side-effects, but in those who continued with the drug, it seemed to be well tolerated. We are grateful to the Pathology Department at the Tameside General Hospital for their co-operation with the large number of investigations. We would like to thank especially Mrs G. Crane and Mrs N. Armitage for their technical assistance, Miss D. Miller for secretarial help, and Mr D. Robinson of Glaxo-Allenburys Research Ltd for the statistical analyses. Requests for reprints should be addressed to MDBS. References BAILEY, R.R. (1977). Scalp tingling and difficulty in micturition in patients on labetalol. (Letter). Iancet, ii, BARRITT, D.W. & MARSHALL, A.J. (1977). Editorial: Treating hypertension. The place of beta blockade. Br. Heart J. 39, BEILIN, L.J. & JUEL-JENSEN, B.E. (1972) Alpha and beta adrenergic blockade in hypertension. Lancet, i, BRITTAIN, R.T. & LEVY, G.P. (1976). A review of the animal pharmacology of labetalol, a combined a- and,badrenoceptor blocking drug. Br. J. clin. Pharmac. 3, BULPITT, C.J. & DOLLERY, C.T. (1973). Side effects of hypotensive agents evaluated by a self-administered questionnaire. Br. med. J., 3, BULPITT, C.J., DOLLERY, C.T. & CARNE, S. (1974). A symptom questionnaire for hypertensive patients. J. chronic Dis., 27, FRICK, M.H. & PORSTI, P. (1976). Combined alpha- and beta-adrenoceptor blockade with labetalol in hypertension. Br. med. J. 1, GANGE, R.W. & JONES, E.W. (1978). Bullous lichen planus caused by labetalol. Br. med. J. 1, HUA, A.S.P., THOMAS, G.W. & KINCAID-SMITH, P. (1977). Scalp tingling in patients on labetalol. (Letter). Lancet, ii, 295. JOHNSON, B.F., LABROOY, J. & MUNRO-FAURE, A.D. (1976). Comparative anti-hypertensive effects of labetalol and the combination of oxprenolol and phentolamine. Br. J. clin. Pharmac., 3, KOCH, G. (1976) Haemodynamic adaptation at rest and during exercise to long-term antihypertensive treatment with combination of beta-receptor blocking and vasodilator agent. Br. Heart. J., 38, LANCET (1977). Editorial. in hypertension. Lancet, i, LEWIS, P. (1976). The essential action of propranolol in hypertension. Am. J. Med. 6, LORIMER, A.R., DUNN, F.G., JONES, J.V. & LAWRIE, T.D.V. (1976). Beta-adrenoreceptor blockade in hypertension. Am. J. Med., 6, LOUIS, W.J., BRIGNELL, M.J., McNEIL, J.J., CHRISTO- PHIDIS, N. & VAJDA, F.J.E. (1978). in hypertension. (Letter). Lancet, i, MAJID, P.A., MEERAN, M.K., BENAIM, M.E., SHARMA, B. & TAYLOR, S.H. (1974). Alpha- and beta-adrenergic receptor blockade in the treatment of hypertension. Br. Heart J. 36, PRICHARD, B.N.C. & GILLAM, P.M.S. (1964). Use of propranolol (Inderal) in the treatment of hypertension. Br. med. J. 2, PUGSLEY, D.J., NASSIM, M., ARMSTRONG, B.K. & BEILIN, L. (1979). A controlled trial of labetalol (Trandate), propranolol and placebo in the management of mild to moderate hypertension. Br. J. clin. Pharmac., 7, RICHARDS, D.A., PRICHARD, B.N.C., BOAKES, A.J., TUCKMAN, J. & KNIGHT, E.J. (1977). Pharmacological basis for antihypertensive effects of intravenous labetalol. Br. Heart. J., 39, SANDERS, G.L., ROUTLEDGE, P.A., RAO, J.G., GALES, G.M., DAVIES, D.M. & RAWLINS, M.D. (1978)., a cross-over double-blind controlled trial. Eur. J. clin. Pharmac., 14, SKINNER, C., GADDIE, J. & PALMER, K.N.V. (1975). Comparison of intravenous AH5158 (ibidomide) and propranolol in asthma. Br. med. J., 2, TARAZI, R.C. & DUSTAN, H.P. (1972). Beta adrenergic blockade in hypertension: practical and theoretical implications of long-term hemodynamic variations. Am. J. Cardiol., 29, WORLD HEALTH ORGANIZATION. (1962). Arterial hypertension and ischaemic heart disease: preventive aspects. Technical Report Series, 231, 7-9. WRIGHT, B.M. & DORE, C.F. (197). A random-zero sphygmomanometer. Lancet, i, (Received June 1, 1979)