BRITISH MEDICAL JOURNAL
17 APRIL 1976
The cyclic AMP response in patients with shunts indicates the possibility of predicting the patency of the shunt by a noninvasive procedure, but this obviously requires further study. The reduced response in six of the eight patients with portacaval shunts may have been due to the dynamic changes in the hepatic circulation reducing the "bolus" effect of the 60-second injection of glucagon. Actual hepatic arterial blood flow is increased in cirrhosis owing to intrahepatic shunting'0 and all our patients with cirrhosis of varying severity and aetiology showed normal cyclic AMP responses. Total hepatic blood flow falls after portacaval shunts, the actual fall varying considerably (mean 50"'',);" the effect on hepatic arterial flow is less certain. Glucagon causes gastrointestinal vasodilation'2 but the effect of this on hepatic blood flow is again unknown. Constant hepatic stimulation by glucagon results in a reduced or absent cyclic AMP response'3 14 and thus patients with raised basal glucagon levels may not be able to achieve a normal cyclic AMP response. Patients with portacaval shunts are known to have particularly raised plasma glucagon levels compared with cirrhotic patients.6 A third possibility for the reduced response is damage to the glucagon receptors or the adenylate cyclase system on the cell membrane. There is a large difference between the concentration of glucagon which gives a maximal effect on glucagon output and that which gives maximal binding and activation of adenylate cyclase. Glucagon interacting with only 1I0 of available receptors can stimulate sufficient cyclic AMP to achieve maximal glucose production.'5 This may have happened in two of our
933
patients who showed a reduced plasma cyclic AMP response but maintained a reasonable rise in blood glucose. This work was supported by the Scientific and Research Committee of the Royal Victoria Infirmary, Newcastle upon Tyne.
References 1 Hardman, J G, Davils, J W, and Sutherland, E W, Journal of Biological
Chemistry, 1969, 244, 6354. Broadus, A E, et al, Journal of Clinical Investigation, 1970, 49, 2237. 3Strange, R C, and Mjos, 0 D, European Journal of Clinical Investigation. 1975, 5, 147. 4Latner, A L, and Prudhoe, K, Clinica Chimica Acta, 1973, 48, 353. 5 Schneider, W, and Jutller, G A, New England Journal of Medicine, 1974, 291, 155. 6 Marco, J, Diego, J, and Villanereva, M L, New England Journal of Medicine, 1973, 289, 1107. Sherwin, R, et al, New England Journal of Medicine, 1974, 291, 239. 8 Broe, M E, Be Borgers, M, and Wieme, R J, Clinica Chimica Acta, 1975, 59, 369. 9 Elkeles, R S, et al, Clinical Science and Molecular Medicine, 1975, 48, 27. 10 Takahashi, T, and Fumiaki, T, Tohoku Journal of Experimental Medicine, 1974, 113, 113. Redeker, A G, Geller, H M, and Reynolds, T B, Journal of Clinical Investigation, 1958, 37, 606. 12 Krarup, N, Larsen, J A, and Anders, M, Acta Physiologica Scandinavica, 1975, 95, 110. 3Lilenquist, J E, et al, Journal of Clinical Investigation, 1974, 53, 198. 14 Plas, C, and Funez, J, J'ournal of Biological Chemistry, 1975, 250, 5304. 15 Lefebvre, P J, and Unger, R H, in Glucagon, p 79. Oxford, Pergammon Press, 1972. 2
Trial of combination of guanethidine and oxprenolol in hypertension R M PEARSON, M R BENDING, C J BULPITT, C F GEORGE, D R HOLE, F M WILLIAMS, A M BRECKENRIDGE
British Medical Journal, 1976, 1, 933-936
trations were of value in determining compliance with the protocol.
Summary
Thirteen hypertensive patients entered a double-blind crossover trial of guanethidine and oxprenolol in combination. In nine patients who completed the trial there was an additive effect on blood pressure, but the combination had a smaller effect on heart rate than was expected from the individual effects, and side effects were not increased. During treatment with oxprenolol the plasma potassium concentration rose from 3 6 mmol (mEq)/l to 3-9 mmol (mEq)/l. No correlation was found between the plasma oxprenolol concentration and changes in blood pressure or response to injected isoprenaline, but measurements of plasma oxprenolol concen-
Department of Clinical Pharmacology, Royal Postgraduate Medical School, Hammersmith Hospital, London W12 R M PEARSON, MB, MRCP, research fellow (now honorary lecturer, Medical Unit, Royal Free Hospital, London NW3) M R BENDING, MB, MRCP, research fellow C 1 BULPITT, MSC, MRCP, honorary consultant physician C F GEORGE, MD, MRC1', senior registrar (now professor of clinical pharmacology, Faculty of Medicine, University of Southampton) D R HOLE, BSC, technician F M WILLIAMS, PHD, assistant lecturer A M BRECKENRIDGE, MD, FRCP, senior lecturer in medicine (now professor of clinical pharmacology, New Medical School, Liverpool)
Introduction Drug combinations are often used in hypertension both to improve control of blood pressure and to diminish dose-related side effects. Guanethidine, an adrenergic neurone blocking drug, is a powerful hypotensive agent but postural hypotension, diarrhoea, failure of ejaculation, and impotence may limit its use.' Oxprenolol, a beta-adrenergic receptor blocking agent, also lowers blood pressure.2 3When two drugs are given together their effects may be equal to, greater than, or less than the sum of the effects of each drug given separately. This study aimed to show whether guanethidine and oxprenolol, which act by different mechanisms, when given in combination would produce an additive effect or potentiate or antagonise one another's action in lowering blood pressure.
Patients and methods Thirteen outpatients (five men and eight women) with essential hypertension were selected for study. Their ages ranged from 40 to 65 (mean 45 6) years. Their average lying blood pressure at presentation was 203/120 mm Hg. Apart from two patients whose blood pressure was inadequately controlled with guanethidine alone none were on treatment before the trial. No patient had a history of angina, myocardial infarction, heart failure, stroke, or asthma. All had grade 1 or 2 hypertensive retinal changes and a plasma urea of less than 10
934 mmol/l (60 mg/100 ml). The study was approved by the hospital's ethics committee, and informed consent was obtained from each patient. DESIGN OF TRIAL
The trial had a double-blind crossover design with four treatment periods. Before entry to the trial the patient's blood pressure was controlled with guanethidine alone, so that the lying diastolic pressure was between 90 and 100 mm Hg on at least two outpatient visits. Each patient then entered the first of four randomly allocated treatment periods, when they received either guanethidine alone, oxprenolol alone, guanethidine in combination with oxprenolol, or placebo. The placebo and active drugs were identical in appearance, and the number of tablets and times of dosing were the same in each treatment period. Each treatment period lasted six weeks. The same dose of guanethidine initially used for stabilisation was used in the guanethidine alone and guanethidine plus oxprenolol treatment periods. A fixed dose of oxprenolol-namely, 40 mg three times a day in the first two weeks, and 80 mg three times a day for the succeeding four weeks-was used in the oxprenolol alone and oxprenolol plus guanethidine treatment periods. Patients were seen at two-weekly intervals. At each visit blood pressure was measured with a Hawksley (random zero) sphygmomanometer in the lying and standing positions and after standard exercise (40 yards (36-5 m) of fast walking). Diastolic pressure was recorded at the point of muffling of sound (Korotkoff IV). Blood pressure was measured by the same person throughout. Pulse rate was measured after blood pressure in all positions. The patient's weight and peak expiratory flow were recorded at each visit and the fundi were examined. At each visit blood was taken for measurement of the plasma oxprenolol concentration. The samples were obtained one to two hours after taking the tablets. At the end of each treatment period blood was also taken for haematological and biochemical tests (haemoglobin; packed cell volume; white cell count; plasma sodium, potassium, and urea; and serum albumin, globulin, bilirubin, aspartate transferase, and alkaline phosphatase). For five patients dose-response curves were constructed to determine the chronotropic effect of rapid intravenous injections of isoprenaline in the last week of each treatment period.4 Blood was taken for measurement of the plasma oxprenolol concentration at the beginning of each isoprenaline dose-response study. Tablet containers were collected at each visit, their contents counted, and new tablets issued. A validated side-effect questionnaire5 provided details of symptomatic side effects, including diarrhoea (loose motions), increased frequency of defecation, nocturia, blurred vision, weakness of limbs, and depression. Criteria for withdrawal from the trial, which were established before it began, were: (1) occurrence of troublesome side effects; (2) unacceptable blood pressures-defined as a lying diastolic pressure above 120 mm Hg on two successive visits; (3) deterioration of cardiac, respiratory, renal, or hepatic function; (4) development of angina, myocardial infarction, or stroke; and (5) deterioration of fundal appearance.
the remaining nine patients (two men and seven women) were therefore analysed. Blood pressure-The average lying blood pressure before treatment was 203/120 mm Hg. Before entry to the trial, when stabilised on guanethidine alone, the average lying pressure was 172/101 mm Hg. The dose of guanethidine needed to achieve this ranged from 10 to 100 mg (average 27 mg) daily. The average of the last two blood pressure measurements for each patient in each of the four treatment periods was used to calculate the average blood pressure for the group in each position and after exercise (table I). The fall in blood pressure produced by the drugs in combination was not different from the sum of the effects of each drug used alone (table II), which was confirmed by analysis of variance. Guanethidine significantly reduced the diastolic blood pressure in the lying position and both systolic and diastolic blood pressures on standing and after exercise (P
17 APRIL 1976
The cyclic AMP response in patients with shunts indicates the possibility of predicting the patency of the shunt by a noninvasive procedure, but this obviously requires further study. The reduced response in six of the eight patients with portacaval shunts may have been due to the dynamic changes in the hepatic circulation reducing the "bolus" effect of the 60-second injection of glucagon. Actual hepatic arterial blood flow is increased in cirrhosis owing to intrahepatic shunting'0 and all our patients with cirrhosis of varying severity and aetiology showed normal cyclic AMP responses. Total hepatic blood flow falls after portacaval shunts, the actual fall varying considerably (mean 50"'',);" the effect on hepatic arterial flow is less certain. Glucagon causes gastrointestinal vasodilation'2 but the effect of this on hepatic blood flow is again unknown. Constant hepatic stimulation by glucagon results in a reduced or absent cyclic AMP response'3 14 and thus patients with raised basal glucagon levels may not be able to achieve a normal cyclic AMP response. Patients with portacaval shunts are known to have particularly raised plasma glucagon levels compared with cirrhotic patients.6 A third possibility for the reduced response is damage to the glucagon receptors or the adenylate cyclase system on the cell membrane. There is a large difference between the concentration of glucagon which gives a maximal effect on glucagon output and that which gives maximal binding and activation of adenylate cyclase. Glucagon interacting with only 1I0 of available receptors can stimulate sufficient cyclic AMP to achieve maximal glucose production.'5 This may have happened in two of our
933
patients who showed a reduced plasma cyclic AMP response but maintained a reasonable rise in blood glucose. This work was supported by the Scientific and Research Committee of the Royal Victoria Infirmary, Newcastle upon Tyne.
References 1 Hardman, J G, Davils, J W, and Sutherland, E W, Journal of Biological
Chemistry, 1969, 244, 6354. Broadus, A E, et al, Journal of Clinical Investigation, 1970, 49, 2237. 3Strange, R C, and Mjos, 0 D, European Journal of Clinical Investigation. 1975, 5, 147. 4Latner, A L, and Prudhoe, K, Clinica Chimica Acta, 1973, 48, 353. 5 Schneider, W, and Jutller, G A, New England Journal of Medicine, 1974, 291, 155. 6 Marco, J, Diego, J, and Villanereva, M L, New England Journal of Medicine, 1973, 289, 1107. Sherwin, R, et al, New England Journal of Medicine, 1974, 291, 239. 8 Broe, M E, Be Borgers, M, and Wieme, R J, Clinica Chimica Acta, 1975, 59, 369. 9 Elkeles, R S, et al, Clinical Science and Molecular Medicine, 1975, 48, 27. 10 Takahashi, T, and Fumiaki, T, Tohoku Journal of Experimental Medicine, 1974, 113, 113. Redeker, A G, Geller, H M, and Reynolds, T B, Journal of Clinical Investigation, 1958, 37, 606. 12 Krarup, N, Larsen, J A, and Anders, M, Acta Physiologica Scandinavica, 1975, 95, 110. 3Lilenquist, J E, et al, Journal of Clinical Investigation, 1974, 53, 198. 14 Plas, C, and Funez, J, J'ournal of Biological Chemistry, 1975, 250, 5304. 15 Lefebvre, P J, and Unger, R H, in Glucagon, p 79. Oxford, Pergammon Press, 1972. 2
Trial of combination of guanethidine and oxprenolol in hypertension R M PEARSON, M R BENDING, C J BULPITT, C F GEORGE, D R HOLE, F M WILLIAMS, A M BRECKENRIDGE
British Medical Journal, 1976, 1, 933-936
trations were of value in determining compliance with the protocol.
Summary
Thirteen hypertensive patients entered a double-blind crossover trial of guanethidine and oxprenolol in combination. In nine patients who completed the trial there was an additive effect on blood pressure, but the combination had a smaller effect on heart rate than was expected from the individual effects, and side effects were not increased. During treatment with oxprenolol the plasma potassium concentration rose from 3 6 mmol (mEq)/l to 3-9 mmol (mEq)/l. No correlation was found between the plasma oxprenolol concentration and changes in blood pressure or response to injected isoprenaline, but measurements of plasma oxprenolol concen-
Department of Clinical Pharmacology, Royal Postgraduate Medical School, Hammersmith Hospital, London W12 R M PEARSON, MB, MRCP, research fellow (now honorary lecturer, Medical Unit, Royal Free Hospital, London NW3) M R BENDING, MB, MRCP, research fellow C 1 BULPITT, MSC, MRCP, honorary consultant physician C F GEORGE, MD, MRC1', senior registrar (now professor of clinical pharmacology, Faculty of Medicine, University of Southampton) D R HOLE, BSC, technician F M WILLIAMS, PHD, assistant lecturer A M BRECKENRIDGE, MD, FRCP, senior lecturer in medicine (now professor of clinical pharmacology, New Medical School, Liverpool)
Introduction Drug combinations are often used in hypertension both to improve control of blood pressure and to diminish dose-related side effects. Guanethidine, an adrenergic neurone blocking drug, is a powerful hypotensive agent but postural hypotension, diarrhoea, failure of ejaculation, and impotence may limit its use.' Oxprenolol, a beta-adrenergic receptor blocking agent, also lowers blood pressure.2 3When two drugs are given together their effects may be equal to, greater than, or less than the sum of the effects of each drug given separately. This study aimed to show whether guanethidine and oxprenolol, which act by different mechanisms, when given in combination would produce an additive effect or potentiate or antagonise one another's action in lowering blood pressure.
Patients and methods Thirteen outpatients (five men and eight women) with essential hypertension were selected for study. Their ages ranged from 40 to 65 (mean 45 6) years. Their average lying blood pressure at presentation was 203/120 mm Hg. Apart from two patients whose blood pressure was inadequately controlled with guanethidine alone none were on treatment before the trial. No patient had a history of angina, myocardial infarction, heart failure, stroke, or asthma. All had grade 1 or 2 hypertensive retinal changes and a plasma urea of less than 10
934 mmol/l (60 mg/100 ml). The study was approved by the hospital's ethics committee, and informed consent was obtained from each patient. DESIGN OF TRIAL
The trial had a double-blind crossover design with four treatment periods. Before entry to the trial the patient's blood pressure was controlled with guanethidine alone, so that the lying diastolic pressure was between 90 and 100 mm Hg on at least two outpatient visits. Each patient then entered the first of four randomly allocated treatment periods, when they received either guanethidine alone, oxprenolol alone, guanethidine in combination with oxprenolol, or placebo. The placebo and active drugs were identical in appearance, and the number of tablets and times of dosing were the same in each treatment period. Each treatment period lasted six weeks. The same dose of guanethidine initially used for stabilisation was used in the guanethidine alone and guanethidine plus oxprenolol treatment periods. A fixed dose of oxprenolol-namely, 40 mg three times a day in the first two weeks, and 80 mg three times a day for the succeeding four weeks-was used in the oxprenolol alone and oxprenolol plus guanethidine treatment periods. Patients were seen at two-weekly intervals. At each visit blood pressure was measured with a Hawksley (random zero) sphygmomanometer in the lying and standing positions and after standard exercise (40 yards (36-5 m) of fast walking). Diastolic pressure was recorded at the point of muffling of sound (Korotkoff IV). Blood pressure was measured by the same person throughout. Pulse rate was measured after blood pressure in all positions. The patient's weight and peak expiratory flow were recorded at each visit and the fundi were examined. At each visit blood was taken for measurement of the plasma oxprenolol concentration. The samples were obtained one to two hours after taking the tablets. At the end of each treatment period blood was also taken for haematological and biochemical tests (haemoglobin; packed cell volume; white cell count; plasma sodium, potassium, and urea; and serum albumin, globulin, bilirubin, aspartate transferase, and alkaline phosphatase). For five patients dose-response curves were constructed to determine the chronotropic effect of rapid intravenous injections of isoprenaline in the last week of each treatment period.4 Blood was taken for measurement of the plasma oxprenolol concentration at the beginning of each isoprenaline dose-response study. Tablet containers were collected at each visit, their contents counted, and new tablets issued. A validated side-effect questionnaire5 provided details of symptomatic side effects, including diarrhoea (loose motions), increased frequency of defecation, nocturia, blurred vision, weakness of limbs, and depression. Criteria for withdrawal from the trial, which were established before it began, were: (1) occurrence of troublesome side effects; (2) unacceptable blood pressures-defined as a lying diastolic pressure above 120 mm Hg on two successive visits; (3) deterioration of cardiac, respiratory, renal, or hepatic function; (4) development of angina, myocardial infarction, or stroke; and (5) deterioration of fundal appearance.
the remaining nine patients (two men and seven women) were therefore analysed. Blood pressure-The average lying blood pressure before treatment was 203/120 mm Hg. Before entry to the trial, when stabilised on guanethidine alone, the average lying pressure was 172/101 mm Hg. The dose of guanethidine needed to achieve this ranged from 10 to 100 mg (average 27 mg) daily. The average of the last two blood pressure measurements for each patient in each of the four treatment periods was used to calculate the average blood pressure for the group in each position and after exercise (table I). The fall in blood pressure produced by the drugs in combination was not different from the sum of the effects of each drug used alone (table II), which was confirmed by analysis of variance. Guanethidine significantly reduced the diastolic blood pressure in the lying position and both systolic and diastolic blood pressures on standing and after exercise (P
