Clinical Science and Molecular Medicine (1975) 48, 97s-100s.
Some haemodynamic effects of compound AH 5158 compared with propranolol, propranolol plus hydrallazine, and diazoxide: the use of AH 5158 in the treatment of hypertension B. N. C. P R I C H A R D , F. 0. T H O M P S O N , A . J . B O A K E S
AND
A. M. JOEKES
Departnrent of Clinical Pharmacology, Medical Unit, University College Hospital Medical School and Hypertension Clinic, Unicersity College Hospital, London, and St Peters Group of Hospitals, Institute of Urology, London
Key words: compound AH 5158, hypertension.
properties (Boakes, Knight & Prichard, 1971). Compound AH 5158 produced a parallel shift in the dose-response curve to isoprenaline-induced tachycardiaand phenylephrine-induced hypertension. In the present study, with non-invasive techniques, we have compared some haemodynamic effects of compound AH 5158 with those of beta-adrenergic blockade alone (propranolol), with the effects of a beta-blocking agent in combination with a vasodilator (propranolol plus hydrallazine), and finally with those of vasodilatation from diazoxide. We also report our experience in the treatment of hypertension with compound AH 51 58 in a series of thirty-one patients.
Introduction
Methods
Summary 1. Intravenous administration of compound AH 51 58, which possesses alpha- and beta-adrenergic
receptor-blocking properties, produces haemodynamic effects similar to those seen from the combined effects of propranolol and hydrallazine. 2. Chronic oral administration has demonstrated that compound AH 5158 is an effective hypotensive agent capable of controlling the blood pressure in patients previously requiring large doses of drugs such as methyldopa. Some postural and exercise hypotension may be seen with larger doses.
Beta-adrenoceptor-blocking drugs have been used in the treatment of hypertension for over 10 years (Simpson, 1974). The experience of some investigators has indicated that they are of similar potency to bethanidine, guanethidine or methyldopa (Prichard & Gillam, 1969; Prichard, Gillam & Graham, 1970; Zacharias, Cowen, Vickers & Wall, 1972). There have also been reports of the use of beta-receptor-blocking drugs in combination with an alpha-receptor-blocking drug (Beilin & JuelJensen, 1972). Compound AH 5 158, 5-{I-hydroxy-2-[(1-methyl 3-phenylproypl)amino]ethyl) salicylamide, was found to possess beta- and alpha-adrenergic receptor-blocking properties in animals, and preliminary human pharmacological studies confirmed these
Haemodynamic studies Twelve patients were studied supine at rest. Changes in thoracic impedance were used to calculate the stroke volume, two tape electrodes being placed around the neck and two around the lower thorax (Kubicek, Patterson & Witsoe, 1970). The impedance method for cardiac output measurement correlates well with that of the standard isotopic technique, giving a correlation coefficient of 0.82 (Hill & Thompson, 1975). Blood pressure was measured by a standard arm sphygmomanometer. Patients rested for 10 min and base-line readings of the stroke volume, pulse rate and blood pressure were taken. Twelve patients were given 0.5 mg (0.001 mmol)/kg of compound AH 5158 intravenously over 10-20 min. The total dose ranged from 22 mg (0.06 mmol) to 70 mg (0.19 mmol). The blood pressure was taken at 5 min intervals and when the maximum hypotensive effect was obtained the
Correspondence: D r B. N. C. Prichard, Department of Clinical Pharmacology, Medical Unit, University College Hospital Medical School, University Street, London, W.C.I.
97s
B. N. C. Prichard et al.
98s
cardiac output and pulse rate measurements were repeated. Twelve other patients were given propranolol intravenously, 8 mg (0.028 mmol)-16 mg (0.056 mmol) injected over 10-20 min, sufficient to produce a fall of heart rate to 60 beatsimin. When the fall in the cardiac output and pulse rate had stabilized, 20 mg (0.0125 mmol) of hydrallazine was given intravenously over 1-2 min. The effects of 300 mg (1.31 mmol) of intravenous diazoxide was studied in a further twelve patients. The cardiovascular measurements were repeated before and after d iazoxide but with these patients the cardiac output was estimated by more standard isotopic technique employing praecordial radioactivity counting (Veal & Vetter, 1965). Treattilent of hypertensioti
Patients were seen in the hypertension clinic under standardized conditions. Blood pressures were taken by a physician after the patient had rested supine on a couch for 3 min. Readings were Mean blood pressure
Pulse rote
repeated after standing for 1 min and again after 1 min of 8 in steps up and down at the rate of 1 cycle in 2.5 s, i.e. 24 stepsimin. All blood pressures were taken with the London School of Hygiene and Tropical Medicine Sphygmomanometer (Rose, Holland & Crowley, 1964). Calculations were based on the average of three readings before and the latest three during the administration of compound AH 5158. A large number of the patients in this study were already under treatment with a variety of drugs (see below). Although not a formal comparative study this made it possible to obtain some idea of the Comparative efficiency of compound A H 5158. Full blood count, standard biochemical investigations and urine analysis were performed at I , 3 and 6 months, at I year and thereafter at yearly intervals. Dosage was commenced at 25 mg t.d.s. Increments usually of 25 mg a dose were made up to 200 mg, of 50 mg a dose up to 400 mg and thereafter of 100 mg a dose, up to a maximum of 3200 mg daily. Cardiac
outpur
Stroke volume
Peripheral resistance
T
I1 40
+
30
T
20
10
10
20
30
0 01 P < O O O l 0001 P 5158 P D H
1 0 001
0001 P 5158 P D H
001 0 01 P 5158 P D
a
H
P 5158 P
a
H
D
0001 0001 0 0 2 0 001 P 5158 P D
a
H
I . A comparison of the haernodynarnic response to intravenous propranolol (P), compound A H 5158, propranol plus hydrallazine (P & H), and diazoxide (D). Vertical lines indicate SD. FIG.
Haernodynamic effects of compound AH 51 58
Results Haemodyrianiic studies (Fig. 1) The hypotensive effect of compound AH 5158 ( n = 12) developed over 15 min and was usually maximal within 30 min. The average systolic pressure fell from its initial value of 176 (SD 31) mmHg to 146 (SD 23) mmHg, with the diastolic pressure falling from 1 13 (SD 19) mmHg to 92 (sD 18) mmHg. The mean pressure fell by 26 (SD 9) mmHg which represented a percentage fall of 18.5 (P
Some haemodynamic effects of compound AH 5158 compared with propranolol, propranolol plus hydrallazine, and diazoxide: the use of AH 5158 in the treatment of hypertension B. N. C. P R I C H A R D , F. 0. T H O M P S O N , A . J . B O A K E S
AND
A. M. JOEKES
Departnrent of Clinical Pharmacology, Medical Unit, University College Hospital Medical School and Hypertension Clinic, Unicersity College Hospital, London, and St Peters Group of Hospitals, Institute of Urology, London
Key words: compound AH 5158, hypertension.
properties (Boakes, Knight & Prichard, 1971). Compound AH 5158 produced a parallel shift in the dose-response curve to isoprenaline-induced tachycardiaand phenylephrine-induced hypertension. In the present study, with non-invasive techniques, we have compared some haemodynamic effects of compound AH 5158 with those of beta-adrenergic blockade alone (propranolol), with the effects of a beta-blocking agent in combination with a vasodilator (propranolol plus hydrallazine), and finally with those of vasodilatation from diazoxide. We also report our experience in the treatment of hypertension with compound AH 51 58 in a series of thirty-one patients.
Introduction
Methods
Summary 1. Intravenous administration of compound AH 51 58, which possesses alpha- and beta-adrenergic
receptor-blocking properties, produces haemodynamic effects similar to those seen from the combined effects of propranolol and hydrallazine. 2. Chronic oral administration has demonstrated that compound AH 5158 is an effective hypotensive agent capable of controlling the blood pressure in patients previously requiring large doses of drugs such as methyldopa. Some postural and exercise hypotension may be seen with larger doses.
Beta-adrenoceptor-blocking drugs have been used in the treatment of hypertension for over 10 years (Simpson, 1974). The experience of some investigators has indicated that they are of similar potency to bethanidine, guanethidine or methyldopa (Prichard & Gillam, 1969; Prichard, Gillam & Graham, 1970; Zacharias, Cowen, Vickers & Wall, 1972). There have also been reports of the use of beta-receptor-blocking drugs in combination with an alpha-receptor-blocking drug (Beilin & JuelJensen, 1972). Compound AH 5 158, 5-{I-hydroxy-2-[(1-methyl 3-phenylproypl)amino]ethyl) salicylamide, was found to possess beta- and alpha-adrenergic receptor-blocking properties in animals, and preliminary human pharmacological studies confirmed these
Haemodynamic studies Twelve patients were studied supine at rest. Changes in thoracic impedance were used to calculate the stroke volume, two tape electrodes being placed around the neck and two around the lower thorax (Kubicek, Patterson & Witsoe, 1970). The impedance method for cardiac output measurement correlates well with that of the standard isotopic technique, giving a correlation coefficient of 0.82 (Hill & Thompson, 1975). Blood pressure was measured by a standard arm sphygmomanometer. Patients rested for 10 min and base-line readings of the stroke volume, pulse rate and blood pressure were taken. Twelve patients were given 0.5 mg (0.001 mmol)/kg of compound AH 5158 intravenously over 10-20 min. The total dose ranged from 22 mg (0.06 mmol) to 70 mg (0.19 mmol). The blood pressure was taken at 5 min intervals and when the maximum hypotensive effect was obtained the
Correspondence: D r B. N. C. Prichard, Department of Clinical Pharmacology, Medical Unit, University College Hospital Medical School, University Street, London, W.C.I.
97s
B. N. C. Prichard et al.
98s
cardiac output and pulse rate measurements were repeated. Twelve other patients were given propranolol intravenously, 8 mg (0.028 mmol)-16 mg (0.056 mmol) injected over 10-20 min, sufficient to produce a fall of heart rate to 60 beatsimin. When the fall in the cardiac output and pulse rate had stabilized, 20 mg (0.0125 mmol) of hydrallazine was given intravenously over 1-2 min. The effects of 300 mg (1.31 mmol) of intravenous diazoxide was studied in a further twelve patients. The cardiovascular measurements were repeated before and after d iazoxide but with these patients the cardiac output was estimated by more standard isotopic technique employing praecordial radioactivity counting (Veal & Vetter, 1965). Treattilent of hypertensioti
Patients were seen in the hypertension clinic under standardized conditions. Blood pressures were taken by a physician after the patient had rested supine on a couch for 3 min. Readings were Mean blood pressure
Pulse rote
repeated after standing for 1 min and again after 1 min of 8 in steps up and down at the rate of 1 cycle in 2.5 s, i.e. 24 stepsimin. All blood pressures were taken with the London School of Hygiene and Tropical Medicine Sphygmomanometer (Rose, Holland & Crowley, 1964). Calculations were based on the average of three readings before and the latest three during the administration of compound AH 5158. A large number of the patients in this study were already under treatment with a variety of drugs (see below). Although not a formal comparative study this made it possible to obtain some idea of the Comparative efficiency of compound A H 5158. Full blood count, standard biochemical investigations and urine analysis were performed at I , 3 and 6 months, at I year and thereafter at yearly intervals. Dosage was commenced at 25 mg t.d.s. Increments usually of 25 mg a dose were made up to 200 mg, of 50 mg a dose up to 400 mg and thereafter of 100 mg a dose, up to a maximum of 3200 mg daily. Cardiac
outpur
Stroke volume
Peripheral resistance
T
I1 40
+
30
T
20
10
10
20
30
0 01 P < O O O l 0001 P 5158 P D H
1 0 001
0001 P 5158 P D H
001 0 01 P 5158 P D
a
H
P 5158 P
a
H
D
0001 0001 0 0 2 0 001 P 5158 P D
a
H
I . A comparison of the haernodynarnic response to intravenous propranolol (P), compound A H 5158, propranol plus hydrallazine (P & H), and diazoxide (D). Vertical lines indicate SD. FIG.
Haernodynamic effects of compound AH 51 58
Results Haemodyrianiic studies (Fig. 1) The hypotensive effect of compound AH 5158 ( n = 12) developed over 15 min and was usually maximal within 30 min. The average systolic pressure fell from its initial value of 176 (SD 31) mmHg to 146 (SD 23) mmHg, with the diastolic pressure falling from 1 13 (SD 19) mmHg to 92 (sD 18) mmHg. The mean pressure fell by 26 (SD 9) mmHg which represented a percentage fall of 18.5 (P
