828 To dismiss them as clinically irrelevant at this stage would, we feel, be premature. We wholeheartedly endorse George’s plea for individualisation of dosage, adding the caveat that a dose should be the lowest required to achieve the desired therapeutic effect. ROY DAVIES* T. G. PICKERING A. MORGANTI G. BIANCHETTI P. L. MORSELLI Hypertension and Cardiovascular Center, J. ROMANKIEWICZ New York Hospital Cornell Medical Center, New York, N.Y. 10021, U.S.A. J. H. LARAGH *
Present address: Middlesex Hospital, London W1N 8AA.
HYPOTENSION AFTER INTRAVENOUS CIMETIDINE
SIR,—A 34-year-old male was admitted with an 85% burn of both 3rd and 2nd degree caused by an explosion. On the third day after admission he had a gastrointestinal bleed, the gastric pH was 1 8, and he was therefore given cimetidine (300 mg as a bolus intravenous injection given over 4 min). The gastric pH did not rise above 3.0and the dose was increased after 4 doses of 300 mg to 600 mg, again given intravenously over 4 min. After the second 600 mg dose the blood-pressure fell dramatically from an average of 100/50 to 30/0 mm Hg. This occurred on three further occasions and was not at first attributed to cimetidine. Blood-pressure declined when the patient had a heart-rate of 130 beats/min and this did not change at the time of hypotension. Central venous pressure was 20-25 cm of water and showed no changes coincident with the hypotension. The rapid intravenous infusion of plasma in varying quantities reversed the hypotension and although the patient was in a positive cumulative fluid balance of 10-12 it was felt that he might have a reduced intravascular volume. Additional colloid was given and the hypotensive episodes coincident with cimetidine gradually decreased in severity, although bloodpressure did not return fully to normal. Intravenous injection of the diluent had no effect. Gentamicin and carbenicillin were also given for infection with gram-negative organisms and morphine alkaloids were given for relief of pain. The second patient was a 49-year-old male admitted for respiratory intensive care 6 days after clinical signs of tetanus appeared. The patient was ventilated and treated with large doses of diazepam intravenously, and with pancuronium bromide and penicillin. On the fifth day after admission the patient had a gastrointestinal bleed and 300 mg cimetidine was given intravenously over 5 min. The gastric pH rose from 1.5 to 3.0 and after two doses of 300 mg, 600 mg cimetidine was given intravenously After the first dose of 600 mg the bloodpressure fell abruptly from 170/100 to 120/60. The patient’s blood-pressure had varied considerably both spontaneously and when he was disturbed and the fall in blood-pressure was not initially attributed to cimetidine. However, subsequent doses of cimetidine produced similar effects. Hypotension lasted 5-25 min. 300 mg cimetidine reduced blood-pressure less than 600 mg and for a shorter time. A variety of other drugs for control of blood-pressure had been given but were stopped when cimetidine was given. Heart-rate or central venous pressure did not change during hypotensive episodes. It is difficult to explain the mechanism of cimetidine-induced hypotension; in the second patient considerable alterations in sympathetic activity were evident, with swings in bloodpressure and heart-rate and profuse sweating, but in the first patient the usual blood-pressure of 100/50 was maintained despite large doses of plasma. Cimetidine in a number of clinical disorders might act as a partial histamine agonist, producing vasodilation, but this has not been previously reported. The possibility that excessive secretion of histamine might have occurred in both the patients, and that cimetidine had a vasodilator effect, seems unlikely. Cimetidine did not induce hypotension in 50—60 other patients in the intensive-care unit.
now infuse the drug rather than give bolus injections, and have not seen any haemodynamic changes.
We
Respiratory Intensive Care Unit, Toronto General Hospital, Toronto, Ontario, Canada
W. A. MAHON M. KOLTON
CIMETIDINE AND BRADYCARDIA
SIR,—Reding et al.’ described a patient who developed bradycardia and atrioventricular dissociation while on oral cimetidine. We have seen two cases of bradycardia associated with cimetidine. A 39-year-old man with a radiologically proven gastric ulcer responded well to a 4 week course of cimetidine (1 g daily) but symptoms recurred on a maintenance dose of 400 mg at night. 2 days after restarting a 1 g daily dose he developed malaise and dizziness which persisted until he was seen as an outpatient 4 weeks later. Examination was normal except that the pulse-rate was 48/min (previously 76/min) and an electrocardiogram confirmed a sinus bradycardia. The symptoms disappeared and his pulse-rate rose to 72/min on stopping cimetidine. A 62-year-old man was admitted with a melama after taking aspirin. 4 h after being given cimetidine (200 mg intravenously) a sinus bradycaria was noted (42/min). There was no electrocardiographic or enzyme evidence of myocardial infarction. Cimetidine (1 g) was given orally for the next 3 days and bradycardia persisted. On the third day the patient complained of thirst and had glycosuria (blood-sugar 14.2 mmol/1). He had no history of diabetes mellitus, his bloodsugar was normal on admission, and he was not receiving Intravenous glucose. Cimetidine-induced , hyp.erglyca:mia has been noted by us previously (Feb. 18, p. 383), and therefore the drug was discontinued. Over the following 10 h his pulse rose from 44/min to 64/min. 3 days later the patient was challenged with an intravenous bolus of 200 mg cimetidine. His heart-rate fell from 70/min to 44/min over 3 h and subsequently returned to normal over 10 h. Cimetidine may induce sinus bradycardia by blocking the H2-receptor sites present in the heart.2 We thank Dr G. W. Scott for tients under his care.
allowing
us to
report details of paD. B.
JEFFERYS J. A. VALE
Guy’s Hospital, London SE1
NOMIFENSINE OVERDOSE
SIR,—Nomifensine3is one of a number of new antidepresNo reports of overdosage have been published and we report here one case in which the patient made an uneventful sants.
recovery.
28-year-old woman was admitted to hospital 3 h after tak5 g (sixty 25 mg capsules) of nomifensine. She had a history of attempted suicide and had previously received antidepressant drugs and electroconvulsive therapy. Her drug treatment had been changed by her general practitioner from imipramine to nomifensine a few days before the overdose because of failure to respond. On admission she was conscious; pulse, blood-pressure, and respiration were normal, and there were no abnormal neurological signs. A stomach wash-out was done but no capsules could be identified in the washings. Although clinically not severely poisoned, she was transferred to the intensive therapy unit for further observation. Apart from a sinus tachycardia of 140/min which rapidly resolved, A
ing
1. 2.
1
P. Lancet, 1977, ii, 1227. Black, J. W., and others. Nature, 1972, 236, 385. 3. Symposium on Nomifensine Br. J. Pharmac. 1977, 4, Suppl. 2 (edited by P. A. Nicholson and P. Turner).
Reding, P., Devroede, C., Barbier,
Present address: Middlesex Hospital, London W1N 8AA.
HYPOTENSION AFTER INTRAVENOUS CIMETIDINE
SIR,—A 34-year-old male was admitted with an 85% burn of both 3rd and 2nd degree caused by an explosion. On the third day after admission he had a gastrointestinal bleed, the gastric pH was 1 8, and he was therefore given cimetidine (300 mg as a bolus intravenous injection given over 4 min). The gastric pH did not rise above 3.0and the dose was increased after 4 doses of 300 mg to 600 mg, again given intravenously over 4 min. After the second 600 mg dose the blood-pressure fell dramatically from an average of 100/50 to 30/0 mm Hg. This occurred on three further occasions and was not at first attributed to cimetidine. Blood-pressure declined when the patient had a heart-rate of 130 beats/min and this did not change at the time of hypotension. Central venous pressure was 20-25 cm of water and showed no changes coincident with the hypotension. The rapid intravenous infusion of plasma in varying quantities reversed the hypotension and although the patient was in a positive cumulative fluid balance of 10-12 it was felt that he might have a reduced intravascular volume. Additional colloid was given and the hypotensive episodes coincident with cimetidine gradually decreased in severity, although bloodpressure did not return fully to normal. Intravenous injection of the diluent had no effect. Gentamicin and carbenicillin were also given for infection with gram-negative organisms and morphine alkaloids were given for relief of pain. The second patient was a 49-year-old male admitted for respiratory intensive care 6 days after clinical signs of tetanus appeared. The patient was ventilated and treated with large doses of diazepam intravenously, and with pancuronium bromide and penicillin. On the fifth day after admission the patient had a gastrointestinal bleed and 300 mg cimetidine was given intravenously over 5 min. The gastric pH rose from 1.5 to 3.0 and after two doses of 300 mg, 600 mg cimetidine was given intravenously After the first dose of 600 mg the bloodpressure fell abruptly from 170/100 to 120/60. The patient’s blood-pressure had varied considerably both spontaneously and when he was disturbed and the fall in blood-pressure was not initially attributed to cimetidine. However, subsequent doses of cimetidine produced similar effects. Hypotension lasted 5-25 min. 300 mg cimetidine reduced blood-pressure less than 600 mg and for a shorter time. A variety of other drugs for control of blood-pressure had been given but were stopped when cimetidine was given. Heart-rate or central venous pressure did not change during hypotensive episodes. It is difficult to explain the mechanism of cimetidine-induced hypotension; in the second patient considerable alterations in sympathetic activity were evident, with swings in bloodpressure and heart-rate and profuse sweating, but in the first patient the usual blood-pressure of 100/50 was maintained despite large doses of plasma. Cimetidine in a number of clinical disorders might act as a partial histamine agonist, producing vasodilation, but this has not been previously reported. The possibility that excessive secretion of histamine might have occurred in both the patients, and that cimetidine had a vasodilator effect, seems unlikely. Cimetidine did not induce hypotension in 50—60 other patients in the intensive-care unit.
now infuse the drug rather than give bolus injections, and have not seen any haemodynamic changes.
We
Respiratory Intensive Care Unit, Toronto General Hospital, Toronto, Ontario, Canada
W. A. MAHON M. KOLTON
CIMETIDINE AND BRADYCARDIA
SIR,—Reding et al.’ described a patient who developed bradycardia and atrioventricular dissociation while on oral cimetidine. We have seen two cases of bradycardia associated with cimetidine. A 39-year-old man with a radiologically proven gastric ulcer responded well to a 4 week course of cimetidine (1 g daily) but symptoms recurred on a maintenance dose of 400 mg at night. 2 days after restarting a 1 g daily dose he developed malaise and dizziness which persisted until he was seen as an outpatient 4 weeks later. Examination was normal except that the pulse-rate was 48/min (previously 76/min) and an electrocardiogram confirmed a sinus bradycardia. The symptoms disappeared and his pulse-rate rose to 72/min on stopping cimetidine. A 62-year-old man was admitted with a melama after taking aspirin. 4 h after being given cimetidine (200 mg intravenously) a sinus bradycaria was noted (42/min). There was no electrocardiographic or enzyme evidence of myocardial infarction. Cimetidine (1 g) was given orally for the next 3 days and bradycardia persisted. On the third day the patient complained of thirst and had glycosuria (blood-sugar 14.2 mmol/1). He had no history of diabetes mellitus, his bloodsugar was normal on admission, and he was not receiving Intravenous glucose. Cimetidine-induced , hyp.erglyca:mia has been noted by us previously (Feb. 18, p. 383), and therefore the drug was discontinued. Over the following 10 h his pulse rose from 44/min to 64/min. 3 days later the patient was challenged with an intravenous bolus of 200 mg cimetidine. His heart-rate fell from 70/min to 44/min over 3 h and subsequently returned to normal over 10 h. Cimetidine may induce sinus bradycardia by blocking the H2-receptor sites present in the heart.2 We thank Dr G. W. Scott for tients under his care.
allowing
us to
report details of paD. B.
JEFFERYS J. A. VALE
Guy’s Hospital, London SE1
NOMIFENSINE OVERDOSE
SIR,—Nomifensine3is one of a number of new antidepresNo reports of overdosage have been published and we report here one case in which the patient made an uneventful sants.
recovery.
28-year-old woman was admitted to hospital 3 h after tak5 g (sixty 25 mg capsules) of nomifensine. She had a history of attempted suicide and had previously received antidepressant drugs and electroconvulsive therapy. Her drug treatment had been changed by her general practitioner from imipramine to nomifensine a few days before the overdose because of failure to respond. On admission she was conscious; pulse, blood-pressure, and respiration were normal, and there were no abnormal neurological signs. A stomach wash-out was done but no capsules could be identified in the washings. Although clinically not severely poisoned, she was transferred to the intensive therapy unit for further observation. Apart from a sinus tachycardia of 140/min which rapidly resolved, A
ing
1. 2.
1
P. Lancet, 1977, ii, 1227. Black, J. W., and others. Nature, 1972, 236, 385. 3. Symposium on Nomifensine Br. J. Pharmac. 1977, 4, Suppl. 2 (edited by P. A. Nicholson and P. Turner).
Reding, P., Devroede, C., Barbier,
