Br. J. clin. Pharmac. (1979), 8, 149S-151S
A COMPARATIVE STUDY OF METHYLDOPA AND LABETALOL IN THE TREATMENT OF HYPERTENSION G.L. SANDERS, D.M. DAVIES, G.M. GALES, J.G. RAO, M.D. RAWLINS & P.A. ROUTLEDGE Department of Pharmacological Sciences (Wolfson Unit of Clinical Pharmacology), The University, Newcastle upon Tyne, and Department of Clinical Pharmacology Shotley Bridge General Hospital, County Durham, UK.
1 Twenty patients with essential hypertension completed a double-blind, dose-tritrated, cross-over comparison of methyldopa and labetalol. 2 Average lying BPs (systolic/diastolic) were reduced by 28/15 mmHg with methyldopa and by 23/15 mmHg with labetalol. 3 Average standing BPs (systolic/diastolic) were reduced by 29/14 mmHg with methyldopa and by 29/15 mmHg with labetalol. 4 Both lying and standing heart rates were reduced with labetalol. 5 It is concluded that the antihypertensive properties of labetalol and methyldopa are similar but that larger patient populations are needed to study the relative incidence of subjective adverse effects.
Introduction
A NUMBER of studies have demonstrated the antihypertensive properties of labetalol after single (Rosei et al., 1975), and during chronic, treatment (Kane et al., 1976; Pugsley et al., 1976; Johnson et al., 1976). The present investigation was undertaken to compare its efficacy and short-tenn toxicity with methyldopa. Methods Twenty-two patients (13 women; mean age 52.8 + 2.6 y) were included in the trial. All were receiving antihypertensive treatment at the time of entry into the study, but all had had diastolic BPs between 95 and 129 mmHg before treatment. None had had evidence of accelerated hypertension, a surgically correctable cause for their hypertension, heart block, cardiac failure, ischaemic heart disease, cerebrovascular disease, obstructive airways disease, or diabetes mellitus. The study received approval from the local Ethical Committee. All antihypertensive therapy was withdrawn (except for one patient who continued to take hydrochlorthiazide throughout the study) for a 3 week 'run in' period, and patients were then randomly allocated to start treatment with either labetalol 100 mg three times daily or methyldopa 100 mg three times daily, which were supplied in identical capsules. Patients were seen at fortnightly intervals,
0306-5251/79/17014903 3
$01.00
and the doses of both were increased stepwise (200, 300, 400, 600, 800 and 1000 mg three times daily) until lying and standing diastolic BPs were less than 90 mmHg, or the maximum dose (1000 mg three times daily) had been reached, or presumed adverse effects precluded further dosage increments. Dosage adjustments were made by an observer who was unaware of patients' treatment allocations, but who knew the patients' BPs. This observer recorded patients' spontaneously reported symptoms. Once patients' optimum dosage requirements had been defined, they were maintained on this dose for a further 6 weeks before transferring 'blindly' to placebo treatment for 6 weeks. Patients were then changed to the other drug for dosage titration, and the trial ended after 6 weeks' treatment at the optimum level. At the end of the two optimum dose periods, and after the placebo phase, venous blood was withdrawn for routine haematological, biochemical and immunological estimations. At the same time an adverse effects questionnaire (Bulpitt & Dollery, 1973) was given to each patient to complete at home and to return by post. At each visit, systolic and diastolic BPs and heart rate, were measured in triplicate after 15 mins recumbency and 3 min standing by an independent observer who was unaware of the patients' treatment. BPs (first and fourth Korotkoff sounds) were measured using a random zero sphygmomanometer
(o Macmillan Journals Ltd 1979
150S
G.L. SANDERS, D.M. DAVIES, G.M. GALES, J.G. RAO, M.D. RAWLINS & P.A. ROUTLEDGE
(Wright & Dore, 1970), and heart rate was measured by palpation of the radial artery. Results are expressed as mean + s.e.m. The significance of differences between means were determined using student's t test (BPs, heart rate), or using Wilcoxon's sign rank test (laboratory data). McNemar's test for paired data was used in the analysis of the questionnaire. Results Two patients failed to complete the trial: one because of poor compliance, and one because his diastolic BP was consistently less than 90 mmHg during the placebo period. In four patients, the placebo period was curtailed because of an increase in arterial BP to more than 120 mmHg. Two patients failed to complete the methyldopa phase because of drug induced lethargy (one patient), and therapeutic failure (one patient). The average time to achieve optimai BP control was similar (P> 0.5) with labetalol (5.7 weeks) and methyldopa (6.2 weeks), and compliances assessed from tablet count) were 95 + 1% and 96 + 1% respectively. Maintenance doses for labetalol and methyldopa averaged 810 + 166 mg daily, and 1183 + 201 mg daily, respectively. Labetalol and methyldopa produced similar changes in average lying and standing BPs during the maintenance dose periods (Table 1), but there was a significant postural fall in systolic BP only with labetalol. Labetalol produced a significant (P < 0.00 1) fall in lying and standing heart rate (Table I) compared with placebo, whereas methyldopa caused a significant (P 1/16) were detected during labetalol treatment (two patients) and during placebo (one patient) and methyldopa (one patient) phases. No other significant changes in the laboratory tests were encountered. There was no significant differences in adverse effects reported spontaneously by patients, or elicited by questionnaire, during any of the treatment periods. Discussion The results of this double-blind, placebo-controlled, trial confirm that labetalol is an effective antihypertensive drug, and no patient proved refractory to treatment. Labetalol and methyldopa reduced supine and standing BPs, on average, by the same extent. The time taken to achieve adequate BP control was similar for the two drugs, but one patient proved resistant to methyldopa. A significant postural fall in systolic BP was observed among patients receiving labetalol (Table 1) which we attribute to the aadrenoceptor blocking activities of the compound (Boakes et al., 1971). However, this was niether doselimiting, nor did it give rise to symptoms. A small change in white blood cell count was observed during labetalol treatment. Although there was an increase in patients' weight with labetalol which is likely to have been due to fluid retention (Weidmann et al., 1978), there was no alteration in haematocrit or haemoglobin concentration. The change in white blood cell count does not therefore seem to be related to dilution. A large patient population will need to be studied for this
BPs, heart rates, daily dosages, compliance and body weights during placebo, labetalol and
methyldopa treatment Placebo
Maintenance dose (mg daily) Compliance (%) Weight (kg) Lying Systolic BP (mmHg) Diastolic BP (mmHg) Heart rate (beats/min) Standing Systolic BP (mmHg) Diastolic BP (mmHg) Heart rate (beats/min) Postural change Systolic BP (mmHg) Diastolic BP (mmHg) *P
A COMPARATIVE STUDY OF METHYLDOPA AND LABETALOL IN THE TREATMENT OF HYPERTENSION G.L. SANDERS, D.M. DAVIES, G.M. GALES, J.G. RAO, M.D. RAWLINS & P.A. ROUTLEDGE Department of Pharmacological Sciences (Wolfson Unit of Clinical Pharmacology), The University, Newcastle upon Tyne, and Department of Clinical Pharmacology Shotley Bridge General Hospital, County Durham, UK.
1 Twenty patients with essential hypertension completed a double-blind, dose-tritrated, cross-over comparison of methyldopa and labetalol. 2 Average lying BPs (systolic/diastolic) were reduced by 28/15 mmHg with methyldopa and by 23/15 mmHg with labetalol. 3 Average standing BPs (systolic/diastolic) were reduced by 29/14 mmHg with methyldopa and by 29/15 mmHg with labetalol. 4 Both lying and standing heart rates were reduced with labetalol. 5 It is concluded that the antihypertensive properties of labetalol and methyldopa are similar but that larger patient populations are needed to study the relative incidence of subjective adverse effects.
Introduction
A NUMBER of studies have demonstrated the antihypertensive properties of labetalol after single (Rosei et al., 1975), and during chronic, treatment (Kane et al., 1976; Pugsley et al., 1976; Johnson et al., 1976). The present investigation was undertaken to compare its efficacy and short-tenn toxicity with methyldopa. Methods Twenty-two patients (13 women; mean age 52.8 + 2.6 y) were included in the trial. All were receiving antihypertensive treatment at the time of entry into the study, but all had had diastolic BPs between 95 and 129 mmHg before treatment. None had had evidence of accelerated hypertension, a surgically correctable cause for their hypertension, heart block, cardiac failure, ischaemic heart disease, cerebrovascular disease, obstructive airways disease, or diabetes mellitus. The study received approval from the local Ethical Committee. All antihypertensive therapy was withdrawn (except for one patient who continued to take hydrochlorthiazide throughout the study) for a 3 week 'run in' period, and patients were then randomly allocated to start treatment with either labetalol 100 mg three times daily or methyldopa 100 mg three times daily, which were supplied in identical capsules. Patients were seen at fortnightly intervals,
0306-5251/79/17014903 3
$01.00
and the doses of both were increased stepwise (200, 300, 400, 600, 800 and 1000 mg three times daily) until lying and standing diastolic BPs were less than 90 mmHg, or the maximum dose (1000 mg three times daily) had been reached, or presumed adverse effects precluded further dosage increments. Dosage adjustments were made by an observer who was unaware of patients' treatment allocations, but who knew the patients' BPs. This observer recorded patients' spontaneously reported symptoms. Once patients' optimum dosage requirements had been defined, they were maintained on this dose for a further 6 weeks before transferring 'blindly' to placebo treatment for 6 weeks. Patients were then changed to the other drug for dosage titration, and the trial ended after 6 weeks' treatment at the optimum level. At the end of the two optimum dose periods, and after the placebo phase, venous blood was withdrawn for routine haematological, biochemical and immunological estimations. At the same time an adverse effects questionnaire (Bulpitt & Dollery, 1973) was given to each patient to complete at home and to return by post. At each visit, systolic and diastolic BPs and heart rate, were measured in triplicate after 15 mins recumbency and 3 min standing by an independent observer who was unaware of the patients' treatment. BPs (first and fourth Korotkoff sounds) were measured using a random zero sphygmomanometer
(o Macmillan Journals Ltd 1979
150S
G.L. SANDERS, D.M. DAVIES, G.M. GALES, J.G. RAO, M.D. RAWLINS & P.A. ROUTLEDGE
(Wright & Dore, 1970), and heart rate was measured by palpation of the radial artery. Results are expressed as mean + s.e.m. The significance of differences between means were determined using student's t test (BPs, heart rate), or using Wilcoxon's sign rank test (laboratory data). McNemar's test for paired data was used in the analysis of the questionnaire. Results Two patients failed to complete the trial: one because of poor compliance, and one because his diastolic BP was consistently less than 90 mmHg during the placebo period. In four patients, the placebo period was curtailed because of an increase in arterial BP to more than 120 mmHg. Two patients failed to complete the methyldopa phase because of drug induced lethargy (one patient), and therapeutic failure (one patient). The average time to achieve optimai BP control was similar (P> 0.5) with labetalol (5.7 weeks) and methyldopa (6.2 weeks), and compliances assessed from tablet count) were 95 + 1% and 96 + 1% respectively. Maintenance doses for labetalol and methyldopa averaged 810 + 166 mg daily, and 1183 + 201 mg daily, respectively. Labetalol and methyldopa produced similar changes in average lying and standing BPs during the maintenance dose periods (Table 1), but there was a significant postural fall in systolic BP only with labetalol. Labetalol produced a significant (P < 0.00 1) fall in lying and standing heart rate (Table I) compared with placebo, whereas methyldopa caused a significant (P 1/16) were detected during labetalol treatment (two patients) and during placebo (one patient) and methyldopa (one patient) phases. No other significant changes in the laboratory tests were encountered. There was no significant differences in adverse effects reported spontaneously by patients, or elicited by questionnaire, during any of the treatment periods. Discussion The results of this double-blind, placebo-controlled, trial confirm that labetalol is an effective antihypertensive drug, and no patient proved refractory to treatment. Labetalol and methyldopa reduced supine and standing BPs, on average, by the same extent. The time taken to achieve adequate BP control was similar for the two drugs, but one patient proved resistant to methyldopa. A significant postural fall in systolic BP was observed among patients receiving labetalol (Table 1) which we attribute to the aadrenoceptor blocking activities of the compound (Boakes et al., 1971). However, this was niether doselimiting, nor did it give rise to symptoms. A small change in white blood cell count was observed during labetalol treatment. Although there was an increase in patients' weight with labetalol which is likely to have been due to fluid retention (Weidmann et al., 1978), there was no alteration in haematocrit or haemoglobin concentration. The change in white blood cell count does not therefore seem to be related to dilution. A large patient population will need to be studied for this
BPs, heart rates, daily dosages, compliance and body weights during placebo, labetalol and
methyldopa treatment Placebo
Maintenance dose (mg daily) Compliance (%) Weight (kg) Lying Systolic BP (mmHg) Diastolic BP (mmHg) Heart rate (beats/min) Standing Systolic BP (mmHg) Diastolic BP (mmHg) Heart rate (beats/min) Postural change Systolic BP (mmHg) Diastolic BP (mmHg) *P
