European Journal of Clinical Pharmacology
Europ. J. clin. Pharmacol. 15, 293-298 (1979)
@ by Springer-Verlag I979
Comparison of Once and Twice Daily Administration of Sotalol in the Treatment of Hypertension I. Parvinen and E. Paukkala H~irk~itieHealth Center, Lieto, Finland, and First Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland
Summary. Thirty patients with mild to severe essential hypertension, satisfactorily controlled by twice daily Sotalol 80 to 320 mg/day, entered a doubleblind, crossover study comparing the efficacy, tolerability and safety of their usual twice daily dose of Sotatol with the same total dose given once daily. Each double-blind period was eight weeks long; during it blood pressure and pulse rate were measured in each patient's home at 8-10 a. m., 12-2 p. m. and 8--10 p. m., on alternate days during the last week of each treatment period. There was no significant difference in blood pressure or pulse rate between each regime for the three readings during the day. The mean serum concentration of Sotalol twenty-four hours after once daily administration was not significantly lower than the concentration 12 h after twice daily administration. Once daily dosage did not cause any problems of tolerance.
studies have given encouraging results (Gatley, 1968; Porter, 1969). Sotalol is a non-cardioselective beta-adrenoceptor antagonist, devoid of significant membrane stabilising and partial agonist activity (Shanks, 1966), which is effective in the treatment of hypertension (Prichard and Boakes, 1974; Shaw', 1976; Tuomilehto et al., 1977). Sotalol has been administered twice daily, but its half-life of fifteen hours (Anttila et al., 1976; Brown et al., 1976) would indicate that once daily Sotalol should be effective in controlling blood pressure throughout the day. The present study explored the possibility that once daily Sotalol would maintain blood pressure control on several occasions during the day in patients whose previous regimen had included Sotalol given twice daily.
Key words: sotalol, hypertension; once and twice daily dose, three daily BP-readings, plasma concentration
Patients and Methods
Since the first report in 1964 (Prichard and Gillam), beta-adrenergic-receptor blocking drugs have become well accepted in the treatment of hypertension (Simpson, 1977). They are effective agents and have the advantage of a lower incidence of side effects than most other hypotensive agents. Nevertheless, the therapeutic value of any antihypertensive drug is related to the compliance of the patients with the prescribed treatment. It seems reasonable to expect that a reduction in the frequency of dosing would improve compliance, but this has not yet been formally tested (Haynes et al., 1977), although some
The study was conducted in the out-patient clinic of the H/irk/itie Health Centre in Lieto, Finland. Thirty patients, thirteen males and seventeen females, aged 31 to 71 years (mean 51.6 years), with mild to severe essential hypertension, participated in the study. The degree of hypertension in 13 patients was WHO I, in 11 it was WHO II and in 6 WHO III. No patient had significant renal damage. Informed consent was obtained from all patients. The blood pressure of all patients had been satisfactorily controlled with twice daily Sotalol 80 to 320 mg/day (mean 176 mg/day) without any change in dose for a period of at least two months before the trial. Thirteen subjects had their blood pressure controlled on Sotalol alone, fifteen received concomitant diuretics and two received diuretics plus dihydrallazine. The dose of diuretics and of dihydralazine was 0031-6970/79/0015/0293/$01.20
294
I. Parvinen and E. Paukkala: Frequency of Sotalol Administration
Table 1. Effects of twice and once daily sotalol on average blood pressure and heart rate (_+ SD) of all patients (n = 30) Randomised double-blind crossover phase
Supine systolicblood pressure Supine diastolic blood pressure Standing heart rate Standing systolicblood pressure Standing diastolic blood pressure
(ram Hg) (mmHg) (beats/min) (ram Hg) (mmHg)
Last week of 8 weeks twice daily therapy
Last week of 8 weeks twice daily therapy
Last week of 8 weeks once daily therapy
139.9_+17.0 87.3_+ 9.9 67.3_+10.1 133.0_+16.5 88.7_+10.4
138.3_+13.7 86.0_+ 8.1 66.7_+ 9.4 132.7+12.4 88.2_+ 9.2
136.8_+14.8 85.4+ 8.8 67.3_+ 8.8 131.5_+13.6 88.1+ 9.4
Table 2. Average blood pressure (mm Hg) and heart rate (_+ SEM) of all patients from three readings in the eight week of therapy with twice and once daily sotalol Systolic
Diastolic
Heart rate
Supine
Standing
Supine
Standing
Standing
Sotalol twice daily (8 a.m. and 8 p. m.) 8a.m. 12 p.m. 8p.m.
139.7+ 1.9 137.7+2.0 137.1_+2.2
133.7+1.7 131.8+1.0 132.4_+2.1
86.5__+1.3 86.1__+1.5 85.2_+1.5
88.1__+1.4 87.7+1.8 88.6_+1.5
67.4+ 1.4 66.9__+1.6 67.6_+1.6
Sotalol once daily (8 a.m.) 8 a.m. 12 p.m. 8 p.m.
137.7+2.8 134.8+2.1 137.9_+2.1
132.2+2.3 129.6_+1.9 132.5+2.0
86.0+1.4 84.5_+1.6 86.7±1.4
87.9+1.4 87.4_+1.6 88.8_+1.5
66.3+1.4 67.6_+1.1 67.7_+1.4
not altered during the study. Prior to therapy, the diastolic blood pressure in all patients exceeded 100 m m H g . T h e m e a n p r e - t r e a t m e n t supine blood pressure was 186.9 + 3.8/111.7 + 1 . 4 m m H g . The study was divided into three periods. A f t e r a single-blind run-in period of eight weeks to familiarize the patients with the trial procedure, each subject entered a double-blind crossover phase of 2 × 8 w e e k periods, in which either Sotalol twice daily ( 8 - 1 0 a. m. and 8 - 1 0 p. m.), or the same total dose of Sotalol once daily ( 8 - 1 0 a. m.), was administered. Standing (5 min) and supine (10 min) blood pressure and standing heart rates were m e a s u r e d in triplicate between 8 and 10 a. m., 12 and 2 p. m. and 8 and 10 p. m., on alternate days during the last week of each treatment period and before administration of the next dose. Blood pressure was m e a s u r e d with a s p h y g o m o m a n o m e t e r , diastolic pressure being taken at the point of disappearance of Korotkoff sounds (phase 5). A t the same time, possible unwanted subjective effects of treatment were sought: no systemic questionnaire was used. The measurements were
always m a d e by the same nurse in the patient's h o m e or place of employment. The patients continued to be seen by the physician in the usual fashion. A blood sample for m e a s u r e m e n t of serum Sotalol was collected on the last morning visit of each trial period, immediately before the patient took the morning dose of Sotalol. Venous blood samples were taken for haematological and biochemical measurements at the end of each treatment period. The medication was supplied in identical bottles with different coloured labels to distinguish the morning and evening dose. In the once daily treatm e n t period, placebo tablets were supplied in the evening box, which matched the active tablets. Sotalol in blood was determined fluorimetrically by the method of Sundquist et al. (1974), which is a modification of the m e t h o d of G a r r e t t and Schnelle, (1971). Serum determinations were equated with plasma concentrations, since no difference has been found between serum and plasma samples (Anttila et al., 1976). The blood pressure measurements for each treat-
I. Parvinen and E. Paukkala: Frequency of Sotalol Administration
295
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Europ. J. clin. Pharmacol. 15, 293-298 (1979)
@ by Springer-Verlag I979
Comparison of Once and Twice Daily Administration of Sotalol in the Treatment of Hypertension I. Parvinen and E. Paukkala H~irk~itieHealth Center, Lieto, Finland, and First Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland
Summary. Thirty patients with mild to severe essential hypertension, satisfactorily controlled by twice daily Sotalol 80 to 320 mg/day, entered a doubleblind, crossover study comparing the efficacy, tolerability and safety of their usual twice daily dose of Sotatol with the same total dose given once daily. Each double-blind period was eight weeks long; during it blood pressure and pulse rate were measured in each patient's home at 8-10 a. m., 12-2 p. m. and 8--10 p. m., on alternate days during the last week of each treatment period. There was no significant difference in blood pressure or pulse rate between each regime for the three readings during the day. The mean serum concentration of Sotalol twenty-four hours after once daily administration was not significantly lower than the concentration 12 h after twice daily administration. Once daily dosage did not cause any problems of tolerance.
studies have given encouraging results (Gatley, 1968; Porter, 1969). Sotalol is a non-cardioselective beta-adrenoceptor antagonist, devoid of significant membrane stabilising and partial agonist activity (Shanks, 1966), which is effective in the treatment of hypertension (Prichard and Boakes, 1974; Shaw', 1976; Tuomilehto et al., 1977). Sotalol has been administered twice daily, but its half-life of fifteen hours (Anttila et al., 1976; Brown et al., 1976) would indicate that once daily Sotalol should be effective in controlling blood pressure throughout the day. The present study explored the possibility that once daily Sotalol would maintain blood pressure control on several occasions during the day in patients whose previous regimen had included Sotalol given twice daily.
Key words: sotalol, hypertension; once and twice daily dose, three daily BP-readings, plasma concentration
Patients and Methods
Since the first report in 1964 (Prichard and Gillam), beta-adrenergic-receptor blocking drugs have become well accepted in the treatment of hypertension (Simpson, 1977). They are effective agents and have the advantage of a lower incidence of side effects than most other hypotensive agents. Nevertheless, the therapeutic value of any antihypertensive drug is related to the compliance of the patients with the prescribed treatment. It seems reasonable to expect that a reduction in the frequency of dosing would improve compliance, but this has not yet been formally tested (Haynes et al., 1977), although some
The study was conducted in the out-patient clinic of the H/irk/itie Health Centre in Lieto, Finland. Thirty patients, thirteen males and seventeen females, aged 31 to 71 years (mean 51.6 years), with mild to severe essential hypertension, participated in the study. The degree of hypertension in 13 patients was WHO I, in 11 it was WHO II and in 6 WHO III. No patient had significant renal damage. Informed consent was obtained from all patients. The blood pressure of all patients had been satisfactorily controlled with twice daily Sotalol 80 to 320 mg/day (mean 176 mg/day) without any change in dose for a period of at least two months before the trial. Thirteen subjects had their blood pressure controlled on Sotalol alone, fifteen received concomitant diuretics and two received diuretics plus dihydrallazine. The dose of diuretics and of dihydralazine was 0031-6970/79/0015/0293/$01.20
294
I. Parvinen and E. Paukkala: Frequency of Sotalol Administration
Table 1. Effects of twice and once daily sotalol on average blood pressure and heart rate (_+ SD) of all patients (n = 30) Randomised double-blind crossover phase
Supine systolicblood pressure Supine diastolic blood pressure Standing heart rate Standing systolicblood pressure Standing diastolic blood pressure
(ram Hg) (mmHg) (beats/min) (ram Hg) (mmHg)
Last week of 8 weeks twice daily therapy
Last week of 8 weeks twice daily therapy
Last week of 8 weeks once daily therapy
139.9_+17.0 87.3_+ 9.9 67.3_+10.1 133.0_+16.5 88.7_+10.4
138.3_+13.7 86.0_+ 8.1 66.7_+ 9.4 132.7+12.4 88.2_+ 9.2
136.8_+14.8 85.4+ 8.8 67.3_+ 8.8 131.5_+13.6 88.1+ 9.4
Table 2. Average blood pressure (mm Hg) and heart rate (_+ SEM) of all patients from three readings in the eight week of therapy with twice and once daily sotalol Systolic
Diastolic
Heart rate
Supine
Standing
Supine
Standing
Standing
Sotalol twice daily (8 a.m. and 8 p. m.) 8a.m. 12 p.m. 8p.m.
139.7+ 1.9 137.7+2.0 137.1_+2.2
133.7+1.7 131.8+1.0 132.4_+2.1
86.5__+1.3 86.1__+1.5 85.2_+1.5
88.1__+1.4 87.7+1.8 88.6_+1.5
67.4+ 1.4 66.9__+1.6 67.6_+1.6
Sotalol once daily (8 a.m.) 8 a.m. 12 p.m. 8 p.m.
137.7+2.8 134.8+2.1 137.9_+2.1
132.2+2.3 129.6_+1.9 132.5+2.0
86.0+1.4 84.5_+1.6 86.7±1.4
87.9+1.4 87.4_+1.6 88.8_+1.5
66.3+1.4 67.6_+1.1 67.7_+1.4
not altered during the study. Prior to therapy, the diastolic blood pressure in all patients exceeded 100 m m H g . T h e m e a n p r e - t r e a t m e n t supine blood pressure was 186.9 + 3.8/111.7 + 1 . 4 m m H g . The study was divided into three periods. A f t e r a single-blind run-in period of eight weeks to familiarize the patients with the trial procedure, each subject entered a double-blind crossover phase of 2 × 8 w e e k periods, in which either Sotalol twice daily ( 8 - 1 0 a. m. and 8 - 1 0 p. m.), or the same total dose of Sotalol once daily ( 8 - 1 0 a. m.), was administered. Standing (5 min) and supine (10 min) blood pressure and standing heart rates were m e a s u r e d in triplicate between 8 and 10 a. m., 12 and 2 p. m. and 8 and 10 p. m., on alternate days during the last week of each treatment period and before administration of the next dose. Blood pressure was m e a s u r e d with a s p h y g o m o m a n o m e t e r , diastolic pressure being taken at the point of disappearance of Korotkoff sounds (phase 5). A t the same time, possible unwanted subjective effects of treatment were sought: no systemic questionnaire was used. The measurements were
always m a d e by the same nurse in the patient's h o m e or place of employment. The patients continued to be seen by the physician in the usual fashion. A blood sample for m e a s u r e m e n t of serum Sotalol was collected on the last morning visit of each trial period, immediately before the patient took the morning dose of Sotalol. Venous blood samples were taken for haematological and biochemical measurements at the end of each treatment period. The medication was supplied in identical bottles with different coloured labels to distinguish the morning and evening dose. In the once daily treatm e n t period, placebo tablets were supplied in the evening box, which matched the active tablets. Sotalol in blood was determined fluorimetrically by the method of Sundquist et al. (1974), which is a modification of the m e t h o d of G a r r e t t and Schnelle, (1971). Serum determinations were equated with plasma concentrations, since no difference has been found between serum and plasma samples (Anttila et al., 1976). The blood pressure measurements for each treat-
I. Parvinen and E. Paukkala: Frequency of Sotalol Administration
295
S.P. ] 17(
SUPINE
71 STANDING
16(
4r
-k
13[
&
/
120, 110
/ / /
/ / /
//
t/ /
/
/
Z
~z 10(
/
/i
:.i.4
b~
90`
