536
Letters
to
the Editor
PRESSOR RESPONSES TO
BETA-ADRENERGIC-BLOCKING DRUGS SiR,—Ihave been interested in reports indicating that betaadrenoceptor-blocking drugs may sometimes cause a paradoxical rise in pressure when used in the treatment of hypertension.’-5 . A rise in blood-pressure was first reported with the original beta blocker used to treat hypertension. The administration of pronethalol intravenously on eight occasions to five volunteer hypertensives produced a rise in blood-pressure in two patients of between 15/15 and 60/35 mm Hg. Pronethalol possesses some intrinsic sympathomimetic action (I.S.A.), and similar pressor reactions have occasionally been seen with other drugs with I.S.A. after prolonged oral use (oxprenolol’ and pindoloP 3). Reduction of the dosage of pindoloP3 has been associated with improved blood-pressure control. However, the explanation that I.S.A. is responsible for the pressor effect27 is unsatisfactory. I.S.A. in a drug acting at the beta receptor might be thought to produce responses like those of isoprenaline (i.e., reduction in peripheral resistance and fall in bloodpressure). However, it could just be argued that beta-blocking drugs with I.S.A. at larger doses facilitate noradrenaline outflow at sympathetic nerve endings by the stimulation of presynaptic beta receptors,8 4 a possible positive feedback mechanism. It would be interesting to know the levels of catecholamines in patients showing a pressor response to betablocking drugs with I.S.A. The hypothesis that I.S.A. is necessarily responsible for the pressor response becomes virtually untenable because a pressor response has been seen with propranolol4 that has no such activity. A surprising high proportion of patients (11% of 187 patients) given propranolol for their hypertension showed a significant rise in diastolic pressure. These patients, in contrast to the responders, showed a significant gain in weight (average 2.7 kg). The dosage was modest and the post-treatment heartrate (75 + 16/min) was still high. Drayer et al.4 suggested that the pressor response was due to unopposed alpha constrictor activity, which seems to be the explanation of the usual pressor response seen after propranolol in patients with pheeochromocytoma; 10 such an explanation could suffice for the other nonselective agents cited above (oxprenolol and pindolol). A substantial rise in pressure has also been seen in normotensive schizophrenics given large doses of propranolol," and, like the response seen in patients with phaeochromocytoma,1O the rise in pressure is reversed by an alpha-receptor-blocking drug. However, this hypothesis does not seem satisfactory. A rise in blood-pressure has been reported with atenolols which is relatively cardioselective and would not oppose the peripheral dilator action of circulatory amines; and atenolol also lacks i.s.A. The 6 patients of a total of 38 who showed a rise in blood-pressure towards pretreatment levels had evidence of fluid retention, and this was thought the reason for the lessening response. This could be the reason for the effect seen with propranolol. The weights of patients were not reported in those patients showing a rise in pressure with oxprenolol or B. R. H., Raftery, E. B. Circulation, 1972, 45, suppl. 11, p. 142. Waal-Manning, H. J., Simpson, F. O. Br. med. J. 1975, iii, 155. Bjerle, P., Jackson, K. A., Agert, G. ibid. p. 284. Drayer, J. I. M., Keim, H. J., Weber, M. A., Case, D. B., Laragh, J. H. Am. J. Med. 1976, 60, 897. 5. Amery, A., Billiet, L., Boel, A., Fagard, R., Reybrouck, T., Willems, J. Am. Heart J. 1976, 91, 634. 6. Prichard, B. N. C. Br. med. J. 1964, i, 1227. 7. Conolly, M. E., Kersting, F., Dollery, C. T. Progr. cardiovasc. Dis. 1976, 19, 203. 8. Adler-Graschinsky, E., Langer, S. Z. Br. J. Pharmac. 1975, 53, 43. 9. Stjarne, L., Brundin, J. Acta physiol. scandi. 1975, 94, 139. 10. Prichard, B. N. C., Ross, E. J. Am. J. Cardiol. 1966, 18, 394. 11. Blum, I., Atsmon, A., Steiner, M., Wysenbeek, H. Br. med. J. 1975, iv, 623.
1. 2. 3. 4.
Cook,
Loss of blood-pressure control has been associated with fluid retention with other antihypertensive agents." Leaving aside the special cases of phaeochromocytoma and psychosis it seems that fluid retention can occasionally occur with all beta-adrenoceptor-blocking drugs and that this could account for a rise in blood-pressure towards pretreatment levels. Perhaps this did not happen in our series of over 100 patients treated with propranolol" and in the large series of Zachariasl4 because diuretics were often given as well; the patients reported by Laragh’s group4 did not have diuretics. It is just possible that the mechanism may vary with different drugs and in different patients. As postulated above the stimulation of pre-synaptic beta receptors with increased noradrenaline production then acting on alpha receptors is a possible mechanism in drugs with I.S.A. This is on balance unlikely since plasma-noradrenaline is reduced by pindolol15 using a dosage in 8 of the 15 patients in the range that has been associated with an increase in blood-pressure on pindolol.2
pindolol.
Clinical
Pharmacology, University College Hospital Medical School,
London WC1E 6JJ
B. N. C. PRICHARD
HOW DOCTORS DEAL WITH EPILEPSY
SIR,-We were interested in the correspondence arising from our paper (Jan. 22, p. 183). Dr Scott and Dr Harris (Feb. 12, p. 358) and Dr Whitty (Feb. 26, p. 490) spring to the defence of the use of electroencephalography in the investigation of epilepsy. Dr Harris records only the ideal world. "Most electroencephalographers" she writes, "prefer to continue their investigations beyond the ’short paper record’ if this proves unhelpful". She draws attention to the value of recording during spontaneous seizures. No doubt she is correct in these statements, but all we can say is that in the sample studied-representative, we believe, of current practice in Metropolitan London-short inter-ictal paper records were all that the patient got, and in no patient was there any evidence that these records contributed to management. Our sample contains a number of patients investigated at the centres from which Dr Harris and Dr Scott write. As Dr Scott states, the diagnosis of epilepsy should be based on seizures. Management may then, in occasional cases, require the use of the E.E.G. to identify the seizure type, as Dr Whitty suggests, or to identify those rare patients likely to benefit from surgery. Our criticisms were of the unthinking and ritual use of electroencephalography, for which physicians and electroencephalographers must share the blame: , Dr Scott also wonders how our collaborating general practices were selected, and whether our conclusions are justified and applicable outside London. The general practitioners were chosen from volunteers who responded to invitations circulated through the Faculties of the Royal College of General Practitioners. More practices volunteered than could be used; selection of practices in rich, middle-class, and poor areas of London was undertaken in an attempt to produce a sample that reflected the distribution of social classes of the country as a whole. This stratification was successful in so far as the numbers of patients in any class did not differ from the expected number by more than 2. There was no evidence of downward social mobility as a result of epilepsy in our sample. Since the general practitioners who cooperated were all volunteers and keen to have their methods of work examined, it is likely that any bias in our sample is towards better management. a
Dr Scott also writes that it would have been useful to have control group of patients with neurological disorders other
12. Finnerty, F. A. Am. Heart J. 1971, 81, 563. 13. Prichard, B. N. C., Gillam, P. M. S. Br. med. J. 1969, i, 7. 14. Zacharias, F. J., Cowen, K. J., Vickers, J., Wall, B. G. Am.
Heart J. 1972,
83, 755. 15. Brecht, H. M., Bantien, F., Schoeppe, W. Klin. Wschr. 1976, 54, 1095.
Letters
to
the Editor
PRESSOR RESPONSES TO
BETA-ADRENERGIC-BLOCKING DRUGS SiR,—Ihave been interested in reports indicating that betaadrenoceptor-blocking drugs may sometimes cause a paradoxical rise in pressure when used in the treatment of hypertension.’-5 . A rise in blood-pressure was first reported with the original beta blocker used to treat hypertension. The administration of pronethalol intravenously on eight occasions to five volunteer hypertensives produced a rise in blood-pressure in two patients of between 15/15 and 60/35 mm Hg. Pronethalol possesses some intrinsic sympathomimetic action (I.S.A.), and similar pressor reactions have occasionally been seen with other drugs with I.S.A. after prolonged oral use (oxprenolol’ and pindoloP 3). Reduction of the dosage of pindoloP3 has been associated with improved blood-pressure control. However, the explanation that I.S.A. is responsible for the pressor effect27 is unsatisfactory. I.S.A. in a drug acting at the beta receptor might be thought to produce responses like those of isoprenaline (i.e., reduction in peripheral resistance and fall in bloodpressure). However, it could just be argued that beta-blocking drugs with I.S.A. at larger doses facilitate noradrenaline outflow at sympathetic nerve endings by the stimulation of presynaptic beta receptors,8 4 a possible positive feedback mechanism. It would be interesting to know the levels of catecholamines in patients showing a pressor response to betablocking drugs with I.S.A. The hypothesis that I.S.A. is necessarily responsible for the pressor response becomes virtually untenable because a pressor response has been seen with propranolol4 that has no such activity. A surprising high proportion of patients (11% of 187 patients) given propranolol for their hypertension showed a significant rise in diastolic pressure. These patients, in contrast to the responders, showed a significant gain in weight (average 2.7 kg). The dosage was modest and the post-treatment heartrate (75 + 16/min) was still high. Drayer et al.4 suggested that the pressor response was due to unopposed alpha constrictor activity, which seems to be the explanation of the usual pressor response seen after propranolol in patients with pheeochromocytoma; 10 such an explanation could suffice for the other nonselective agents cited above (oxprenolol and pindolol). A substantial rise in pressure has also been seen in normotensive schizophrenics given large doses of propranolol," and, like the response seen in patients with phaeochromocytoma,1O the rise in pressure is reversed by an alpha-receptor-blocking drug. However, this hypothesis does not seem satisfactory. A rise in blood-pressure has been reported with atenolols which is relatively cardioselective and would not oppose the peripheral dilator action of circulatory amines; and atenolol also lacks i.s.A. The 6 patients of a total of 38 who showed a rise in blood-pressure towards pretreatment levels had evidence of fluid retention, and this was thought the reason for the lessening response. This could be the reason for the effect seen with propranolol. The weights of patients were not reported in those patients showing a rise in pressure with oxprenolol or B. R. H., Raftery, E. B. Circulation, 1972, 45, suppl. 11, p. 142. Waal-Manning, H. J., Simpson, F. O. Br. med. J. 1975, iii, 155. Bjerle, P., Jackson, K. A., Agert, G. ibid. p. 284. Drayer, J. I. M., Keim, H. J., Weber, M. A., Case, D. B., Laragh, J. H. Am. J. Med. 1976, 60, 897. 5. Amery, A., Billiet, L., Boel, A., Fagard, R., Reybrouck, T., Willems, J. Am. Heart J. 1976, 91, 634. 6. Prichard, B. N. C. Br. med. J. 1964, i, 1227. 7. Conolly, M. E., Kersting, F., Dollery, C. T. Progr. cardiovasc. Dis. 1976, 19, 203. 8. Adler-Graschinsky, E., Langer, S. Z. Br. J. Pharmac. 1975, 53, 43. 9. Stjarne, L., Brundin, J. Acta physiol. scandi. 1975, 94, 139. 10. Prichard, B. N. C., Ross, E. J. Am. J. Cardiol. 1966, 18, 394. 11. Blum, I., Atsmon, A., Steiner, M., Wysenbeek, H. Br. med. J. 1975, iv, 623.
1. 2. 3. 4.
Cook,
Loss of blood-pressure control has been associated with fluid retention with other antihypertensive agents." Leaving aside the special cases of phaeochromocytoma and psychosis it seems that fluid retention can occasionally occur with all beta-adrenoceptor-blocking drugs and that this could account for a rise in blood-pressure towards pretreatment levels. Perhaps this did not happen in our series of over 100 patients treated with propranolol" and in the large series of Zachariasl4 because diuretics were often given as well; the patients reported by Laragh’s group4 did not have diuretics. It is just possible that the mechanism may vary with different drugs and in different patients. As postulated above the stimulation of pre-synaptic beta receptors with increased noradrenaline production then acting on alpha receptors is a possible mechanism in drugs with I.S.A. This is on balance unlikely since plasma-noradrenaline is reduced by pindolol15 using a dosage in 8 of the 15 patients in the range that has been associated with an increase in blood-pressure on pindolol.2
pindolol.
Clinical
Pharmacology, University College Hospital Medical School,
London WC1E 6JJ
B. N. C. PRICHARD
HOW DOCTORS DEAL WITH EPILEPSY
SIR,-We were interested in the correspondence arising from our paper (Jan. 22, p. 183). Dr Scott and Dr Harris (Feb. 12, p. 358) and Dr Whitty (Feb. 26, p. 490) spring to the defence of the use of electroencephalography in the investigation of epilepsy. Dr Harris records only the ideal world. "Most electroencephalographers" she writes, "prefer to continue their investigations beyond the ’short paper record’ if this proves unhelpful". She draws attention to the value of recording during spontaneous seizures. No doubt she is correct in these statements, but all we can say is that in the sample studied-representative, we believe, of current practice in Metropolitan London-short inter-ictal paper records were all that the patient got, and in no patient was there any evidence that these records contributed to management. Our sample contains a number of patients investigated at the centres from which Dr Harris and Dr Scott write. As Dr Scott states, the diagnosis of epilepsy should be based on seizures. Management may then, in occasional cases, require the use of the E.E.G. to identify the seizure type, as Dr Whitty suggests, or to identify those rare patients likely to benefit from surgery. Our criticisms were of the unthinking and ritual use of electroencephalography, for which physicians and electroencephalographers must share the blame: , Dr Scott also wonders how our collaborating general practices were selected, and whether our conclusions are justified and applicable outside London. The general practitioners were chosen from volunteers who responded to invitations circulated through the Faculties of the Royal College of General Practitioners. More practices volunteered than could be used; selection of practices in rich, middle-class, and poor areas of London was undertaken in an attempt to produce a sample that reflected the distribution of social classes of the country as a whole. This stratification was successful in so far as the numbers of patients in any class did not differ from the expected number by more than 2. There was no evidence of downward social mobility as a result of epilepsy in our sample. Since the general practitioners who cooperated were all volunteers and keen to have their methods of work examined, it is likely that any bias in our sample is towards better management. a
Dr Scott also writes that it would have been useful to have control group of patients with neurological disorders other
12. Finnerty, F. A. Am. Heart J. 1971, 81, 563. 13. Prichard, B. N. C., Gillam, P. M. S. Br. med. J. 1969, i, 7. 14. Zacharias, F. J., Cowen, K. J., Vickers, J., Wall, B. G. Am.
Heart J. 1972,
83, 755. 15. Brecht, H. M., Bantien, F., Schoeppe, W. Klin. Wschr. 1976, 54, 1095.
