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.
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
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.
considerably from year to year but no definite trend emerged. Rodin’s dictum’ that modern drug therapy has not seriously affected the incidence of epileptic control was, unfortunately, confirmed. I report this not as a negative observation but to draw attention to the effect of ageing on seizure frequency; for in any study of the positive aspects of long-term anticonvulsant therapy we must be aware of the natural history of chronic epilepsy. In the randomised sample (group 2) the effect of ageing on seizure frequency was clearly seen. Between the 20-29 year decade, and the 30-39 decade the fall was approximately 38%. Over the next two decades the frequency fell by a further 34%. When, in group 1, the same sample population was studied
than epilepsy, to show whether those with seizures fared less well in terms of health care than their non-epileptic counterparts. Measurements of outcome of health care are difficult enough without attempting to compare the management ot two totally different disorders-epilepsy and migraine, for example, or multiple sclerosis. It seems more appropriate to define a standard of acceptable care and assess how nearly.that standard is achieved. For those disabled by multiple sclerosis, the standard is physical and financial support within the community, and Dr and Mrs Johnson have lately shown (Jan. 1, p..31) how far from reaching that standard are the services in the West of Scotland. For those with epilepsy, one standard is abolition of seizures, and we showed how feeble were attempts to reach that standard. Dr Critchley’s letter (see below) shows the difficulties of controlling seizures in institutionalised patients but considerable control of seizures of those in the community is entirely possible, with only one drug properly used.I Dr Stores (Feb. 12, p. 359) argues that it is unreasonable to expect a general practitioner to cope with the psychological and social complications which people with epilepsy often experience. Our view is the reverse-the general practitioner is often the only person in possession of sufficient information about the patient and, as such, is the person most likely to help. There is no evidence that the bureaucratic organisation of psychological and social aid within an institutional framework is beneficial to those distressed.:2
Department of Neurological St Bartholomew’s Hospital, London EC1A 7BE
lacia induced by anticonvulsants. In addition she had hepatomegaly, with granulomas on biopsy; and chest X-ray revealed miliary mottling. The differential was that of sarcoid and tuberculosis, and while awaiting a Kveim test she collapsed
ANTHONY HOPKINS GRAHAM SCAMBLER
SIR,-Dr Hopkins and Mr Scambler (Jan. 22, p. 183)
that all too often a physician’s honour is satisfied so long as some tablets are taken. Unfortunately it cannot be claimed that we can always control epilepsy by properly monitored modern drug therapy. Using the criteria of complete seizure cessation, the 2 year, 5 year, and 10 year terminal remissionrate has hardly altered since the beginning of the century. Modern drug therapy is kinder, with fewer side-effects and less damage to the intellect, but it is not yet more effective. An attempt was made to show trends in the treatment of chronic epilepsy at an epileptic centre by a retrospective study of the number of recorded seizures. It was hoped to show the influence of regular sessions by interested neurologists, the introduction of new drugs, the monitoring of anticonvulsant levels, the correction of side-effects and the performance of drug trials on the seizure-frequency pattern of the residents over the past 10 years (1967-76). Such patients pose different problems to those living in the community who were the subject of Dr Hopkins and Mr Scambler’s report. In 10 years the number of residents has dwindled from over 400 to 360 and many are now in their 60s or 70s, The average intelligence of newcomers to the centre has possibly fallen, but the problem of epileptic control has not altered essentially. Two groups of residents were studied. The first group consisted of 80 residents (40 males and 40 females) equally divided into age decades 20-29, 30-39, 40-49, and 50-59-10 males and 10 females in each decade-and followed through, noting their seizure frequency in 1967, 1972, and 1976. To eliminate the factor of an ageing population, a second ’group comprised of 40 residents for each of the 10 years, similarly divided with 5 males and 5 females in each age range, and selected by a randomised rotation through the whole population, were also examined. There were rather fewer females than males, and in certain age-ranges a resident might be picked twice or possibly three times. In the comparison of the same population (group 1) in 1967, 1972, and 1976, there was a decrease in the number of seizures, but in the second group the seizure-frequency rate ftuc1.Reynolds, E H., Chadwick, D., Galbraith, A. W. Lancet, 1976, 2 Mayer, J E., Timms, N. The Client Speaks. London, 1970.
10 years, the percentage decrease in seizures was even greater but these residents can be regarded as survivors and,
ideally, the figures should be corrected for mortality. Department of Neurology, Royal Infirmary,
E. M. R. CRITCHLEY
Preston PRI 6PS
AMIKACIN RESISTANCE DEVELOPING IN PATIENT WITH PSEUDOMONAS ÆRUGINOSA BRONCHOPNEUMONIA
SIR,-A 57-year-old woman was admitted in November, 1976, with a history of bone pain found to be due to osteoma-
admitted to intensive care on Dec. 21. She was put and isoniazid, but liver failure prompted the withdrawal of isoniazid, which was later replaced by ethambutol. Acid-fast bacilli were isolated after 3-4 weeks’ incubation from gastric aspirate, sputum, and urine obtained during the November admission. The miliary mottling had faded from the chest radiograph after 2-3 weeks’ treatment. At the beginning of the third week after her admission an acute abdomen developed, and perforated bowel was suspected. Metronidazole therapy was started and Jan. 9 a laparotomy was performed. A perforated colonic ulcer was found but and
M.I.C.S OF AMINOGLYCOSIDE ANTIBIOTICS AGAINST PS. AERUGINOSA ISOLATED FROM SPUTUM* BEFORE AND AFTER DEVELOPMENT OF PYOGENIC PNEUMONIA ON
*Similar M.r.c. patterns were obtained for 1’s. aeruginosa isolated from rectal and tracheal swabs (Jan. 10) and abdominal drain (Jan. 13). j2 days later the M.i.C. pattern for S. marcescens was 12.5, 0.78, 25,
12.5, 25,50. $Amikacin was started on Jan. 13, 500mg immediately, then 2x250 mg/day. A=amikacin; G=gentamicin; T=tobramycin; S=srsomycin; N=netilmicin ; K=kanamycin.
peritonitis. The peritoneum was washed out with saline and colostomy was fashioned. The patient showed a slight improvement postoperatively but on the third postoperative day she appeared septicmmic and had fresh signs of chest infection with consolidation in the no
1. Rodin, E. A. Epilepsia,