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RENAL GLYCOSURIA AND AZOTAEMIA AFTER ENALAPRIL MALEATE (MK-421)
440 COMBINATION MONOAMINE OXIDASE INHIBITOR/ TRICYCLIC ANTIDEPRESSANT INTERACTION
SIR,-We describe here an adverse reaction due to the interaction a tricyclic with a monoamine oxidase inhibitor (MAOI) anti-
of
depressant. The patient had been treated uneventfully for 3 weeks a phenelzine/trimipramine combination, but experienced a severe reaction when imipramine was substituted for trimipramine. An 18-year-old girl had had a refractory form of anorexia nervosa for over 2 years. At the time of the reaction she was an inpatient in a closed psychiatric ward, and weighed 42 kg (ideal body weight 52 kg). In view of the reports of parallel neurochemical changes in depressive illness and anorexia nervosa,and the reports of weight gain with combined MAOI/tricyclic therapy,2she was put on trimipramine 50 mg at night with phenelzine 15 mg in the morning. After 5 days the dosage of each drug was doubled and after a further 5 days the dose was increased to trimipramine 150 mg at night plus phenelzine 30 mg twice daily. After 3 weeks on the higher dosage of combined antidepressants, with neither unwanted effects nor improvement, she was one evening inadvertently given imipramine 150 mg instead of trimipramine 150 mg. 20 min later she complained of nausea and felt she was losing touch with reality. When seen (by P.G.) 75 min after ingestion, her mental state was much impaired; she was disoriented and talking incomprehensibly. She was restless and shivering violently with an axillary temperature of 37 - 8°C. Her skin was pale, cold, and cyanosed and she was breathing rapidly. She had tachycardia (140 min) and a blood pressure of 140/70 mm Hg. Her pupils were dilated, she was hypertonic, and she had extensor plantar reflexes. She was transferred to an accident and emergency department. 2 h after ingestion of imipramine there had been no improvement so she was given chlorpromazine 50 mg intramuscularly. Over the next 30 min she showed dramatic improvement; her restlessness subsided, her pulse fell to normal, and it was possible for her to explain events of earlier that evening. Her recovery was uneventful, apart from postural hypotension the following day. Despite many reports of the safe use of MAOI/tricyclic combinations, clinicians familiar with this treatment have advised that particular care be exercised with imipramine,.2,3 We have found only nine published reports of MAOI/tricyclic adverse reactions when the drugs were taken orally and in therapeutic doses. Three involved phenelzine and imipramine, and the clinical reactions were similar to those observed in our case.4-6 Intramuscular imipramine 25 mg caused a similar reaction in a girl with anorexia nervosa who was being treated with phenelzine (15 7 mg three times daily), thioridazine, and oxyphencyclimine.
with
Most reports of adverse interactions between MAOI and incriminate imipramine.4The tricyclic antidepressants affect bioamine handling in the central nervous system in many ways, including inhibition of uptake of both noradrenaline and
tricyclics
5-hydroxytryptamine (5-HT). Drawing
on
pharmacological
propertiesand clinical reports, an attempt can be made to rank and correlate the two factors. A feature of the MAOI/tricyclic interaction appears to be hyperthermia, being greatest with imipramine, less with amitriptyline, and absent with trimipramine.9 The hyperthermia produced by p-methoxyamphetamine, which results in release of endogenous 5-HT, may be blocked by combined blockade of dopamine and 5-HT receptors.1O Likewise the hyper-
thermia of 5-hydroxytryptophan and MAOI is due to 5-HT and catecholamine stimulation. t°Published data8suggest that the ratio of the inhibition of 5-HT uptake to inhibition of dopamine uptake best fits the incidence of reported serious side-effects:
clomipramine 0-007, imipramine 0-02, amitryptyline 0-06, trimipramine 3-94. Chlorpromazine is useful in treatment of the clinical syndrome and has been shown to inhibit dopamine and also 5-HT receptors. We predict that trimipramine is unlikely to produce the interaction whereas the risk would be high with imipramine, and this is borne out by our case-report. Additionally, we would predict that nomifensine (calculated ratio inhibition 5-HT to dopamine uptake 320) would be unlikely to cause the interaction. Mental Health Services, 3 Havelock Street, West Perth, Western Australia 6005
PETER M. GRAHAM
Department of Pharmacology, University of Western Australia
JULIA M. POTTER J. W. PATERSON
RENAL GLYCOSURIA AND AZOTAEMIA AFTER ENALAPRIL MALEATE (MK-421) have observed an episode of azotaemia and renal in glycosuria a 42-year-old man with mild uncomplicated essential
SIR,—We
treated with enalapril maleate (MK-421). Discontinuation of the drug was associated with return to baseline renal function and disappearance of glycosuria. The patient, who had had essential hypertension for 18 years, was taking part in a study to assess the safety and efficacy of MK-421 in the treatment of mild to moderate essential hypertension. Serum creatinine was I.33 mg/dl during a 4-week placebo control period. Urinalysis was unremarkable. Diastolic blood pressure remained greater than 90 mm Hg after 8 weeks of therapy with MK-421 in doses of up to 20 mg twice daily. Adequate blood-pressure control was achieved by the addition of hydrochlorothiazide 50 mg twice daily. During the sixteenth week of drug therapy, serum creatinine rose to 3 -7mg/dl and 4 + glycosuria was present despite a fasting blood sugar of 102 mg/dl. The tubular reabsorption of uric acid, bicarbonate, and phosphorus seemed normal and aminoaciduria was not demonstrated. MK-421 was withdrawn and hydrochlorothiazide was continued at 50 mg twice daily. 10 days later the serum creatinine was 1’8mg/dl and a trace of glycosuria was detectable. 18 days after discontinuation of MK-421, serum creatinine was 1-2 mg/dl and glycosuria had disappeared. This patient was not rechallenged with MK-421 because of the azotaemia which accompanied the glycosuria. Since MK-421 is a non-sulphydryl-containing convertingenzyme inhibitor, nephrotoxicity was predicted to be less prominent than that associated with captopril. We are unaware of other reports of renal glycosuria with or without azotaemia induced by MK-421 or captopril. Continued clinical investigation of MK-421 will necessitate close observation for evidence of
hypertension being
nephrotoxicity. Department of Hypertension and Nephrology, Cleveland Clinic Foundation, Cleveland, Ohio 44106 U.S.A.
M. D. CRESSMAN D. G. VIDT C. ACKER
1 Gwirtsman HE, Gerner RH. Neurochemical abnormalities in anorexia nervoxa: Similarities to affective disorders Biol Psychiat 1981; 16: 991-95. 2 Gander DR. Treatment of depressive illnesses with combined antidepressants. Lancet
1965;
ii: 107-09
Sargant W, Slater E, Kelly D. An introduction to physical methods of treatment in psychiatry, 5th ed Edinburgh Churchill Livingstone, 1972: 53-54. 4. Schuckit M, Robins E, Feighner J. Tricyclic antidepressants and monoamine oxidase inhibitors. Arch Gen Psychiat 1971; 24: 100-03. 5. Howarth E. Possible synergistic effects of the new thymoleptics in connection with poisoning. J Ment Sci 1961; 107: 100-03. 6. Davies G. Side effects of phenelzine. Br Med J 1960, ii. 1019. 7. Hills NF. Combining the antidepressant drugs. Br Med J 1965; i: 859. 8. Møller Nielsen I. Tricyclic antidepressants: General pharmacology. In Hoffmeister F, Stille G, eds. Psychotropic agents: Part I. Berlin: Springer-Verlag, 1980: 399-414. 9. Loveless AH, Maxwell DR. A comparison of the effects of imipramine, trimipramine, and some other drugs in rabbits treated with a monoamine oxidase inhibitor. Br J 3
10.
Pharmacol 1965, 25: 158-70. Fjalland B. Neuroleptic influence on hyperthermia induced by 5-hydroxytryptophan and p-methoxy-amphetamine in MAOI-pretreated rabbits. Psychopharmacology 1979, 63: 113-17.
KETANSERIN IN ACUTE SUPERFICIAL THROMBOPHLEBITIS
SIR,-We wish to report our experience with ketanserin, an investigational serotonin S2 receptor antagonist, 1,2 in patients with acute superficial thrombophlebitis. The study was placebo controlled, double blind, 1.
and
crossover.
Leysen JE, Awouters F, Kennis L, Laduron PM, Vandenberk J, Janssen PAJ. Receptor binding profile of 41468, a novel antagonist at 5-HT 2, receptors Life Sci 1981: 28: 1015-22.
2. Van Nueten
JM, Janssen PAJ, Van Beek J, Xhonneux R, Verbeuren TJ, Vanhoutte PM. Vascular effects of ketanserin (R 41468), a novel antagonist of 5-HT serotonergic receptors. J Pharmacol Exp Ther 1981; 218: 217-30.
SIR,-We describe here an adverse reaction due to the interaction a tricyclic with a monoamine oxidase inhibitor (MAOI) anti-
of
depressant. The patient had been treated uneventfully for 3 weeks a phenelzine/trimipramine combination, but experienced a severe reaction when imipramine was substituted for trimipramine. An 18-year-old girl had had a refractory form of anorexia nervosa for over 2 years. At the time of the reaction she was an inpatient in a closed psychiatric ward, and weighed 42 kg (ideal body weight 52 kg). In view of the reports of parallel neurochemical changes in depressive illness and anorexia nervosa,and the reports of weight gain with combined MAOI/tricyclic therapy,2she was put on trimipramine 50 mg at night with phenelzine 15 mg in the morning. After 5 days the dosage of each drug was doubled and after a further 5 days the dose was increased to trimipramine 150 mg at night plus phenelzine 30 mg twice daily. After 3 weeks on the higher dosage of combined antidepressants, with neither unwanted effects nor improvement, she was one evening inadvertently given imipramine 150 mg instead of trimipramine 150 mg. 20 min later she complained of nausea and felt she was losing touch with reality. When seen (by P.G.) 75 min after ingestion, her mental state was much impaired; she was disoriented and talking incomprehensibly. She was restless and shivering violently with an axillary temperature of 37 - 8°C. Her skin was pale, cold, and cyanosed and she was breathing rapidly. She had tachycardia (140 min) and a blood pressure of 140/70 mm Hg. Her pupils were dilated, she was hypertonic, and she had extensor plantar reflexes. She was transferred to an accident and emergency department. 2 h after ingestion of imipramine there had been no improvement so she was given chlorpromazine 50 mg intramuscularly. Over the next 30 min she showed dramatic improvement; her restlessness subsided, her pulse fell to normal, and it was possible for her to explain events of earlier that evening. Her recovery was uneventful, apart from postural hypotension the following day. Despite many reports of the safe use of MAOI/tricyclic combinations, clinicians familiar with this treatment have advised that particular care be exercised with imipramine,.2,3 We have found only nine published reports of MAOI/tricyclic adverse reactions when the drugs were taken orally and in therapeutic doses. Three involved phenelzine and imipramine, and the clinical reactions were similar to those observed in our case.4-6 Intramuscular imipramine 25 mg caused a similar reaction in a girl with anorexia nervosa who was being treated with phenelzine (15 7 mg three times daily), thioridazine, and oxyphencyclimine.
with
Most reports of adverse interactions between MAOI and incriminate imipramine.4The tricyclic antidepressants affect bioamine handling in the central nervous system in many ways, including inhibition of uptake of both noradrenaline and
tricyclics
5-hydroxytryptamine (5-HT). Drawing
on
pharmacological
propertiesand clinical reports, an attempt can be made to rank and correlate the two factors. A feature of the MAOI/tricyclic interaction appears to be hyperthermia, being greatest with imipramine, less with amitriptyline, and absent with trimipramine.9 The hyperthermia produced by p-methoxyamphetamine, which results in release of endogenous 5-HT, may be blocked by combined blockade of dopamine and 5-HT receptors.1O Likewise the hyper-
thermia of 5-hydroxytryptophan and MAOI is due to 5-HT and catecholamine stimulation. t°Published data8suggest that the ratio of the inhibition of 5-HT uptake to inhibition of dopamine uptake best fits the incidence of reported serious side-effects:
clomipramine 0-007, imipramine 0-02, amitryptyline 0-06, trimipramine 3-94. Chlorpromazine is useful in treatment of the clinical syndrome and has been shown to inhibit dopamine and also 5-HT receptors. We predict that trimipramine is unlikely to produce the interaction whereas the risk would be high with imipramine, and this is borne out by our case-report. Additionally, we would predict that nomifensine (calculated ratio inhibition 5-HT to dopamine uptake 320) would be unlikely to cause the interaction. Mental Health Services, 3 Havelock Street, West Perth, Western Australia 6005
PETER M. GRAHAM
Department of Pharmacology, University of Western Australia
JULIA M. POTTER J. W. PATERSON
RENAL GLYCOSURIA AND AZOTAEMIA AFTER ENALAPRIL MALEATE (MK-421) have observed an episode of azotaemia and renal in glycosuria a 42-year-old man with mild uncomplicated essential
SIR,—We
treated with enalapril maleate (MK-421). Discontinuation of the drug was associated with return to baseline renal function and disappearance of glycosuria. The patient, who had had essential hypertension for 18 years, was taking part in a study to assess the safety and efficacy of MK-421 in the treatment of mild to moderate essential hypertension. Serum creatinine was I.33 mg/dl during a 4-week placebo control period. Urinalysis was unremarkable. Diastolic blood pressure remained greater than 90 mm Hg after 8 weeks of therapy with MK-421 in doses of up to 20 mg twice daily. Adequate blood-pressure control was achieved by the addition of hydrochlorothiazide 50 mg twice daily. During the sixteenth week of drug therapy, serum creatinine rose to 3 -7mg/dl and 4 + glycosuria was present despite a fasting blood sugar of 102 mg/dl. The tubular reabsorption of uric acid, bicarbonate, and phosphorus seemed normal and aminoaciduria was not demonstrated. MK-421 was withdrawn and hydrochlorothiazide was continued at 50 mg twice daily. 10 days later the serum creatinine was 1’8mg/dl and a trace of glycosuria was detectable. 18 days after discontinuation of MK-421, serum creatinine was 1-2 mg/dl and glycosuria had disappeared. This patient was not rechallenged with MK-421 because of the azotaemia which accompanied the glycosuria. Since MK-421 is a non-sulphydryl-containing convertingenzyme inhibitor, nephrotoxicity was predicted to be less prominent than that associated with captopril. We are unaware of other reports of renal glycosuria with or without azotaemia induced by MK-421 or captopril. Continued clinical investigation of MK-421 will necessitate close observation for evidence of
hypertension being
nephrotoxicity. Department of Hypertension and Nephrology, Cleveland Clinic Foundation, Cleveland, Ohio 44106 U.S.A.
M. D. CRESSMAN D. G. VIDT C. ACKER
1 Gwirtsman HE, Gerner RH. Neurochemical abnormalities in anorexia nervoxa: Similarities to affective disorders Biol Psychiat 1981; 16: 991-95. 2 Gander DR. Treatment of depressive illnesses with combined antidepressants. Lancet
1965;
ii: 107-09
Sargant W, Slater E, Kelly D. An introduction to physical methods of treatment in psychiatry, 5th ed Edinburgh Churchill Livingstone, 1972: 53-54. 4. Schuckit M, Robins E, Feighner J. Tricyclic antidepressants and monoamine oxidase inhibitors. Arch Gen Psychiat 1971; 24: 100-03. 5. Howarth E. Possible synergistic effects of the new thymoleptics in connection with poisoning. J Ment Sci 1961; 107: 100-03. 6. Davies G. Side effects of phenelzine. Br Med J 1960, ii. 1019. 7. Hills NF. Combining the antidepressant drugs. Br Med J 1965; i: 859. 8. Møller Nielsen I. Tricyclic antidepressants: General pharmacology. In Hoffmeister F, Stille G, eds. Psychotropic agents: Part I. Berlin: Springer-Verlag, 1980: 399-414. 9. Loveless AH, Maxwell DR. A comparison of the effects of imipramine, trimipramine, and some other drugs in rabbits treated with a monoamine oxidase inhibitor. Br J 3
10.
Pharmacol 1965, 25: 158-70. Fjalland B. Neuroleptic influence on hyperthermia induced by 5-hydroxytryptophan and p-methoxy-amphetamine in MAOI-pretreated rabbits. Psychopharmacology 1979, 63: 113-17.
KETANSERIN IN ACUTE SUPERFICIAL THROMBOPHLEBITIS
SIR,-We wish to report our experience with ketanserin, an investigational serotonin S2 receptor antagonist, 1,2 in patients with acute superficial thrombophlebitis. The study was placebo controlled, double blind, 1.
and
crossover.
Leysen JE, Awouters F, Kennis L, Laduron PM, Vandenberk J, Janssen PAJ. Receptor binding profile of 41468, a novel antagonist at 5-HT 2, receptors Life Sci 1981: 28: 1015-22.
2. Van Nueten
JM, Janssen PAJ, Van Beek J, Xhonneux R, Verbeuren TJ, Vanhoutte PM. Vascular effects of ketanserin (R 41468), a novel antagonist of 5-HT serotonergic receptors. J Pharmacol Exp Ther 1981; 218: 217-30.