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EFFECT OF DIARRHOEA ON A PATIENT TAKING CAPTOPRIL
581
(3) Proteinuria can often be observed in hypertensive patients in association with end-organ damage. The frequency of proteinuria demonstrable in the population studied with enalapril was not different from that seen with other antihypertensive drugs.3 The criteria used for defining proteinuria in the studies of captopril,2 when applied to studies with enalapril in hypertension, reveal no cases of proteinuria with that drug. In about 140 patients with renal impairment treated with enalapril, not a single instance of proteinuria developedand in those patients with pre-existing proteinuria the proteinuria tended to decrease on enalapril treatment. Nephrotic syndrome and membranous glomerulopathy have not been reported in association with enalapril. Thus although both captopril and enalapril are ACE inhibitors they appear to have a different safety profile. They differ chemically in that captopril contains a sulphydryl group whereas enalapril does not. Captopril has been shown to have some efficacy in rheumatoid arthritis5 as do several other sulphydryl-containing compounds while enalapril does not.6 Captopril, unlike enalapril to date, has also been associated with pemphigus7,8 and cholestatic jaundice,99 both of which may have an immunological mechanism.
baroceptor reflexes4,5 and interference with thirst6 and ADH
responses. We wonder whether we can expect to see more instances of
Hoddesdon, Herts 1 Studer
2 3
4 5 6 7 8 9
when sudden gastro-
develops
in
hypertensive patients being
treated with ACE
inhibitors. Department of Medicine, Royal Infirmary, Edinburgh EH3 9YW
JOHN MCMURRAY DAVID M. MATTHEWS
1. Clough DP, Collis MG, Conway J, Hatton R, Keddie JR. Interaction of angiotensin converting enzyme inhibitors with the function of the sympathetic nervous system. Am J Cardiol 1982; 49: 1410-14. 2. Timmermans PBMWM, Wilffer TB, Kalkan HO, Thoolen MJMC Selective inhibition of CX2 Adreno receptor mediated vasoconstriction in vivo by captopril and MK-421. Br J Pharmacol 1982; 75 (suppl) 135P. 3. Imai Y, Keishi A, Masamide S, et al Captopril attenuates pressor responses to norepinephrine and vasopressin through depletion of endogenous angiotensin II Am J Cardiol 1982; 49: 1537-39. 4 Clough DP, Hatton R, Conway J, Adigun SA. Angiotensin activates sympathetic reflexes
in the anaesthetised cat Clin Sci 1980; 59: 287s-89s. G, Parati G, Pomidossi G, et al. Modification of arterial baroreceptor reflexes by Captopril in essential hypertension. Am J Cardiol 1982, 49: 1415-19. Fitzsimons JT, Elfont RM. Angiotensin does contribute to drinking induced by caval ligation in rat. Am JPhysiol 1982; 243: R558-62.
5 Mancia 6.
Merck Sharp & Dohme Ltd, Hertford Road,
life-threatening complications
severe
enteritis, acute haemorrhage, or diabetic metabolic decompensation
W. J. C. CURRIE W. D. COOPER
A, Vetter
W Reversible leucopenia associated with angiotens in-converting enzyme inhibitor MK-421. Lancet 1982; i: 458. Frohlich ED, Cooper RA, Lewis EJ. Review of the overall experience of captopril in hypertension. Arch Intern Med 1984; 144: 1441-44. Tempero KF, Kramsch DM, Moncloa F. The safety profile of enalapril. In: Proceedings of the XVII International Congress of Therapy (Rome, Sept 27-30, 1983). 60-64 Moncloa F, Sromovasky JA, Walker JF, Davies RO. Enalapril in hypértension and congestive heart failure: Overall review of efficacy and safety. Drugs (in press). Martin MFR, Surall K, McKenna F, Dixon JS, Bird HA, Wright V. Captopril: a new long-term agent for treating rheumatoid arthritis. Ann Rheum Dis 1983; 42: 231. Jaffe I. Angiotensin converting inhibitors in rheumatoid arthritis. Arthritis Rheum 1984; 27: 840. Parfrey PS, Clement M, VandenBurg MJ, Wright F. Captopril induced pemphigus. Br Med J 1980; 281: 194. Clement M. Captopril-induced eruptions. Arch Dermatol 1981; 117: 525-26. Rahmat J, Gelfand RL, Gelfand MC, Winchester JF, Schreiner GE, Zimmerman HJ. Captopril-associated cholestatic jaundice. Ann Intern Med 1985; 102: 56-58.
EFFECT OF DIARRHOEA ON A PATIENT TAKING CAPTOPRIL
SIR,-We welcome the survey of angiotensin converting enzyme inhibitors by Professor Edwards and Dr Padfield (Jan 5, p 30). We would, however, counsel caution regarding the inevitable increase in prescribing of such drugs.
(ACE)
A 66-year-old man presented as an emergency, stuporose and unable to provide a history. On examination, he was apyrexial (36’4°C) and peripherally underperfused, with an unrecordable blood-pressure, but his pulse rate was normal (75/min). Elevation from the supine position caused syncope. Further examination and chest X-ray and excluded serious haemorrhage, electrocardiogram were normal. Laboratory investigations revealed a urea of 20 mmol/1, sodium of 137 mmol/1, potassium 5 - 4 mmol/l, total bicarbonate of 20 mmol/1, and glucose of 83mmol/1. Haemoglobin was 21-44 g/dl, haematocrit 0658, and white-cell count 22.4 4 109/1. Severe salt and water depletion of uncertain cause was diagnosed and the patient recovered completely after 2 units of’Haemacel’ and 8 litres of normal saline over the next 72 h. While recovering he revealed that he had had recurrent diarrhoea in the 18 h before presentation and that he had been treated for essential hypertension by his general practitioner with captopril 25 mg twice a day for the past 15 months. The results of initial blood and stool cultures were negative and plasma cortisol and amylase were normal. This patient clearly had life-threatening severe hypotension with pre-renal uraemia as a result of a trivial diarrhoeal illness on a background of pharmacological ACE inhibition. Unlike most antihypertensive drugs, captopril uniquely mterferes with all the important homoeostatic responses to extracellular fluid volume loss. Blockade of the renin-angiotensinaldosterone sequence, including the direct effect of angiotensin II on the arterial system, is the prime effect. Other effects are inhibition of the autonomic-catecholamine responsel-3 and
GASTROINTESTINAL LESIONS AND POTASSIUM CHLORIDE SUPPLEMENTS
SiR,-Dr Leijonmarck and Dr Raf (Jan 5, p 56) report an incidence of small-bowel ulceration associated with slow release (wax matrix) potassium chloride (KCI) several times higher than any previously published figure. They suggest that a microencapsulated preparation may be safer in this respect. It would seem likely that the ulcerogenic potential of different formulations or release mechanisms of KCl can be predicted by comparing their irritant effects in more endoscopically accessible areas of the gastrointestinal tract. We have examined endoscopically a series of 45 healthy volunteers, comparing three different formulations of KCI wax matrix (’Slow K’), microencapsulated (’Micro K’), and controlled release (’K-Contin’) systems. The oesophagus, stomach, and duodenum were examined before and at the end of 7 days’ consumption of one tablet three times daily of one of the above. This was combined with glycopyrrolate 2 mg three times daily in the hope of enhancing irritant action. The tablets were prepackaged with random allocation, the endoscopist being unaware of which preparation any individual was taking. 7 out of 15 volunteers taking wax matrix KCI showed erosions and 2 showed hyperaemia only,-, of the 15 taking microencapsulated KCI 1 showed erosions and 2 showed hyperaemia only; and none of those given controlled release KCI showed erosions, 4 having hyperaemia. McMahon et all found a similar difference between wax matrix and microencapsulated KCI, while Alsop et al2 did not. In two previous studies, an open3 and a controlled one,4 no gastric erosions were demonstrated with a combined tablet of frusemide 40 mg and controlled release KCI (’Diumide K Continus’) in 20 and 10 subjects, respectively. In the controlled study,46of 10 subjects taking frusemide 40 mg and wax matrix KCI in separate tablets had erosions compared with 4 of 10 when a combined frusemide/wax matrix formulation was used. There are clearly considerable differences in the erosive action of different KCl slow release mechanisms on the upper gastrointestinal tract. It seems likely that intestinal ulceration would follow a similar pattern, although extensive observations of the newer preparations in clinical use is required. It would seem advisable, however, to use a less irritant KCI formulation than the wax matrix one, not only to reduce gastric erosive changes but also in the hope of averting the potentially lethal complication of intestinal ulceration. -
Mater Infirmorum Belfast BT14 6AB
Hospital,
J. C. MCLOUGHLIN
FG, Akdamar K, Ryan JR, Ertan A. Upper gastrointestinal lesions after potassium chloride supplements: a controlled clinical trial. Lancet 1982; i: 1059-61. 2. Alsop WR, Moore JG, Rollin DE, Tolman KG. The effects of five potassium chloride preparations on the upper gastrointestinal mucosa in healthy subjects receiving glycopyrrolate J Clin Pharmacol 1984; 24: 235-39. 1. McMahon
(3) Proteinuria can often be observed in hypertensive patients in association with end-organ damage. The frequency of proteinuria demonstrable in the population studied with enalapril was not different from that seen with other antihypertensive drugs.3 The criteria used for defining proteinuria in the studies of captopril,2 when applied to studies with enalapril in hypertension, reveal no cases of proteinuria with that drug. In about 140 patients with renal impairment treated with enalapril, not a single instance of proteinuria developedand in those patients with pre-existing proteinuria the proteinuria tended to decrease on enalapril treatment. Nephrotic syndrome and membranous glomerulopathy have not been reported in association with enalapril. Thus although both captopril and enalapril are ACE inhibitors they appear to have a different safety profile. They differ chemically in that captopril contains a sulphydryl group whereas enalapril does not. Captopril has been shown to have some efficacy in rheumatoid arthritis5 as do several other sulphydryl-containing compounds while enalapril does not.6 Captopril, unlike enalapril to date, has also been associated with pemphigus7,8 and cholestatic jaundice,99 both of which may have an immunological mechanism.
baroceptor reflexes4,5 and interference with thirst6 and ADH
responses. We wonder whether we can expect to see more instances of
Hoddesdon, Herts 1 Studer
2 3
4 5 6 7 8 9
when sudden gastro-
develops
in
hypertensive patients being
treated with ACE
inhibitors. Department of Medicine, Royal Infirmary, Edinburgh EH3 9YW
JOHN MCMURRAY DAVID M. MATTHEWS
1. Clough DP, Collis MG, Conway J, Hatton R, Keddie JR. Interaction of angiotensin converting enzyme inhibitors with the function of the sympathetic nervous system. Am J Cardiol 1982; 49: 1410-14. 2. Timmermans PBMWM, Wilffer TB, Kalkan HO, Thoolen MJMC Selective inhibition of CX2 Adreno receptor mediated vasoconstriction in vivo by captopril and MK-421. Br J Pharmacol 1982; 75 (suppl) 135P. 3. Imai Y, Keishi A, Masamide S, et al Captopril attenuates pressor responses to norepinephrine and vasopressin through depletion of endogenous angiotensin II Am J Cardiol 1982; 49: 1537-39. 4 Clough DP, Hatton R, Conway J, Adigun SA. Angiotensin activates sympathetic reflexes
in the anaesthetised cat Clin Sci 1980; 59: 287s-89s. G, Parati G, Pomidossi G, et al. Modification of arterial baroreceptor reflexes by Captopril in essential hypertension. Am J Cardiol 1982, 49: 1415-19. Fitzsimons JT, Elfont RM. Angiotensin does contribute to drinking induced by caval ligation in rat. Am JPhysiol 1982; 243: R558-62.
5 Mancia 6.
Merck Sharp & Dohme Ltd, Hertford Road,
life-threatening complications
severe
enteritis, acute haemorrhage, or diabetic metabolic decompensation
W. J. C. CURRIE W. D. COOPER
A, Vetter
W Reversible leucopenia associated with angiotens in-converting enzyme inhibitor MK-421. Lancet 1982; i: 458. Frohlich ED, Cooper RA, Lewis EJ. Review of the overall experience of captopril in hypertension. Arch Intern Med 1984; 144: 1441-44. Tempero KF, Kramsch DM, Moncloa F. The safety profile of enalapril. In: Proceedings of the XVII International Congress of Therapy (Rome, Sept 27-30, 1983). 60-64 Moncloa F, Sromovasky JA, Walker JF, Davies RO. Enalapril in hypértension and congestive heart failure: Overall review of efficacy and safety. Drugs (in press). Martin MFR, Surall K, McKenna F, Dixon JS, Bird HA, Wright V. Captopril: a new long-term agent for treating rheumatoid arthritis. Ann Rheum Dis 1983; 42: 231. Jaffe I. Angiotensin converting inhibitors in rheumatoid arthritis. Arthritis Rheum 1984; 27: 840. Parfrey PS, Clement M, VandenBurg MJ, Wright F. Captopril induced pemphigus. Br Med J 1980; 281: 194. Clement M. Captopril-induced eruptions. Arch Dermatol 1981; 117: 525-26. Rahmat J, Gelfand RL, Gelfand MC, Winchester JF, Schreiner GE, Zimmerman HJ. Captopril-associated cholestatic jaundice. Ann Intern Med 1985; 102: 56-58.
EFFECT OF DIARRHOEA ON A PATIENT TAKING CAPTOPRIL
SIR,-We welcome the survey of angiotensin converting enzyme inhibitors by Professor Edwards and Dr Padfield (Jan 5, p 30). We would, however, counsel caution regarding the inevitable increase in prescribing of such drugs.
(ACE)
A 66-year-old man presented as an emergency, stuporose and unable to provide a history. On examination, he was apyrexial (36’4°C) and peripherally underperfused, with an unrecordable blood-pressure, but his pulse rate was normal (75/min). Elevation from the supine position caused syncope. Further examination and chest X-ray and excluded serious haemorrhage, electrocardiogram were normal. Laboratory investigations revealed a urea of 20 mmol/1, sodium of 137 mmol/1, potassium 5 - 4 mmol/l, total bicarbonate of 20 mmol/1, and glucose of 83mmol/1. Haemoglobin was 21-44 g/dl, haematocrit 0658, and white-cell count 22.4 4 109/1. Severe salt and water depletion of uncertain cause was diagnosed and the patient recovered completely after 2 units of’Haemacel’ and 8 litres of normal saline over the next 72 h. While recovering he revealed that he had had recurrent diarrhoea in the 18 h before presentation and that he had been treated for essential hypertension by his general practitioner with captopril 25 mg twice a day for the past 15 months. The results of initial blood and stool cultures were negative and plasma cortisol and amylase were normal. This patient clearly had life-threatening severe hypotension with pre-renal uraemia as a result of a trivial diarrhoeal illness on a background of pharmacological ACE inhibition. Unlike most antihypertensive drugs, captopril uniquely mterferes with all the important homoeostatic responses to extracellular fluid volume loss. Blockade of the renin-angiotensinaldosterone sequence, including the direct effect of angiotensin II on the arterial system, is the prime effect. Other effects are inhibition of the autonomic-catecholamine responsel-3 and
GASTROINTESTINAL LESIONS AND POTASSIUM CHLORIDE SUPPLEMENTS
SiR,-Dr Leijonmarck and Dr Raf (Jan 5, p 56) report an incidence of small-bowel ulceration associated with slow release (wax matrix) potassium chloride (KCI) several times higher than any previously published figure. They suggest that a microencapsulated preparation may be safer in this respect. It would seem likely that the ulcerogenic potential of different formulations or release mechanisms of KCl can be predicted by comparing their irritant effects in more endoscopically accessible areas of the gastrointestinal tract. We have examined endoscopically a series of 45 healthy volunteers, comparing three different formulations of KCI wax matrix (’Slow K’), microencapsulated (’Micro K’), and controlled release (’K-Contin’) systems. The oesophagus, stomach, and duodenum were examined before and at the end of 7 days’ consumption of one tablet three times daily of one of the above. This was combined with glycopyrrolate 2 mg three times daily in the hope of enhancing irritant action. The tablets were prepackaged with random allocation, the endoscopist being unaware of which preparation any individual was taking. 7 out of 15 volunteers taking wax matrix KCI showed erosions and 2 showed hyperaemia only,-, of the 15 taking microencapsulated KCI 1 showed erosions and 2 showed hyperaemia only; and none of those given controlled release KCI showed erosions, 4 having hyperaemia. McMahon et all found a similar difference between wax matrix and microencapsulated KCI, while Alsop et al2 did not. In two previous studies, an open3 and a controlled one,4 no gastric erosions were demonstrated with a combined tablet of frusemide 40 mg and controlled release KCI (’Diumide K Continus’) in 20 and 10 subjects, respectively. In the controlled study,46of 10 subjects taking frusemide 40 mg and wax matrix KCI in separate tablets had erosions compared with 4 of 10 when a combined frusemide/wax matrix formulation was used. There are clearly considerable differences in the erosive action of different KCl slow release mechanisms on the upper gastrointestinal tract. It seems likely that intestinal ulceration would follow a similar pattern, although extensive observations of the newer preparations in clinical use is required. It would seem advisable, however, to use a less irritant KCI formulation than the wax matrix one, not only to reduce gastric erosive changes but also in the hope of averting the potentially lethal complication of intestinal ulceration. -
Mater Infirmorum Belfast BT14 6AB
Hospital,
J. C. MCLOUGHLIN
FG, Akdamar K, Ryan JR, Ertan A. Upper gastrointestinal lesions after potassium chloride supplements: a controlled clinical trial. Lancet 1982; i: 1059-61. 2. Alsop WR, Moore JG, Rollin DE, Tolman KG. The effects of five potassium chloride preparations on the upper gastrointestinal mucosa in healthy subjects receiving glycopyrrolate J Clin Pharmacol 1984; 24: 235-39. 1. McMahon