ANTAGONISM OF IMIPRAMINE INDUCED FATAL HYPERPYREXIA IN MAO INHIBITOR TREATED RABBITS

ANTAGONISM

OF IMIPRAMINE IN MAO INHIBITOR

INDUCED

FATAL HYPERPYREXIA

TREATED

RABBITS

J.N. SINHA, K.M. DHASMANA, K.S. DIXIT AND K.P. BHARGAVA Department of Pharmacology & Therapeutics, K.G's MedicalCollege Lucknow-3, India Receivedfor publicationJune 23, 1969 Extensiveuseof monoamineoxidaseinhibitorsand imipraminein psychiatricpracticehasrevealedserious toxicreactions. It has been observedthat combinationof monoamineoxidaseinhibitorand imipramine producesa symptomcomplexcharacterizedby hyperexcitement, motorrestlessness and hyperpyrexia(1-6). Furthermore,hypertensivecrisis,subarachnoidhaemorrhageand pulmonaryoedemahas beenreportedto occurin patientswhoweremaintainedon monoamineoxidaseinhibitorand tookcheeseor broadbeans(7, 8). High contentsof tyraminein cheeseand 3-4 dihydroxyphenylalanine (dopa)in broadbeanshavebeensug gestedto be responsiblefor theabovementionedserioussideeffects. Sinceit is knownthat in MAOinhibitor pretreatedanimalsadministrationof both, tyramineand dopa increasecirculatingcatecholaminecontent

of the body, it seems likely that catecholamines might be playing a key role in the causation of these side effects. Loveless and Maxwell (9) have studied MAO inhibitor-imipramine not come to any definite conclusion regarding its mechanism.

induced fatal hyperpyrexia but they could As all above observations suggest a possible

role of catecholamines in these side effects, it was thought worthwhile to investigate the role of catecholamines by studying the effect of specific a and ~-adrenergic blockers on the fatal hyperpyrexia induced by MAO inhibitor-imipramine

combination.

The present study was carried out on thirty-five adult albino rabbits of either sex.

The animals were

pretreated with niamid (100 mg/kg i.p.) for two days. On the following days the rabbits were placed in stocks for recording the rectal temperatures. Control recordings of the temperature were taken for one hour before the administration of imipramine vein at a rate of 2.5 mg/kg/min. hour.

(the incompatible agent).

Imipramine was infused into a marginal ear

Rectal temperatures were recorded at 30 minute intervals for one and a half

Two groups of controls were used in this study.

intravenous saline infusion was given.

In the first control group instead of imipramine only

In the second control group intravenous infusion of imipramine was

given in untreated animals. Either the rise of rectal temperature to more than 3°C or the occurrence of mortality during the period of observations was taken as the criterion of fatal hyperpyrexia. The a-adrenergic

blockade was achieved by treating the animals with dibenzyline (10 mg/kg i.p.) given

half an hour before the imipramine infusion. and INPEA (5.0 mg/kg i.p.) was used. fatal hyperpyrexia

*Each rectal

Similarly for j3-receptor blockade propranolol (5.0 mg/kg i.p.)

The effect of prior a and n-receptor blockade was studied on the

caused by MAO inhibitor-imipramine

star

denotes

the

death

of

one

rabbit

combination.

before

the

time

of

observation

of

the

temperature.

The results of the present study are shown in Table 1.

It was observed that the control groups (which

received either only niamid or imipramine with saline) did not exhibit fatal hyperpyrexia. received niamid (100 mg/kg i.p.) for two days and then imipramine in three out of six animals. higher dose of imipramine

The group which

(2.5 mg/kg i.v.) showed hyperpyrexia

The other group which received niamid (100 mg/kg i.p.) for two days and a (5.0 mg/kg i.v.) exhibited fatal hyperpyrexia in 100% animals.

Two out of six

rabbits died during the study. Pretreatment with dibenzyline (10.0 mg/kg i.p.) half hour before imipramine infusion completely prevents the development of the fatal hyperpyrexial response and also the mortality is reduced. Prior n-receptor blockade by propranolol (5.0 mg/kg i.p.) markedly enhances the toxicity, as all the six animals showed hyperpyrexia and expired during the study. INPEA, another /3-receptor blocking agent did not significantly alter the development of fatal hyperpyrexial response. The results of the present study clearly show that a combination of niamid (a MAO inhibitor) with imi

pramine produces fatal hyperpyrexia. Blockade of hyperpyrexia by a-receptor blocking agent, dibenzyline, suggests the role of catecholamines and involvement of a-adrenergic receptors in this response . However, further study is required to prove this contention.

Alpha receptor blocking agents may prove life saving for

the cases of fatal hyperpyrexia due to MAO inhibitor-imipramine

combination . Since out of two a-receptor blocking agent only propranolol enhanced the toxicity , such a potentiation does not seem to be related to the n-receptor blockade. It is more likely that prepranolol does so by virtue of its catecholamine releasing action. Acknowledgements: The authors are grateful to the Indian Council of Medical Research , New Delhi for We also gratefully acknowledge free gift of propranolol from ICI (England), INPEA

financial assistance.

from Selvi and Co. (Italy) and imipramine from Geigy Research Laboratories (Switzerland). REFERENCES 1) DAVIES,G.: Br. med. J. 11, 1019 (1960) ; 2) F.I.: Br. med.J. 1, 338 (1961) ; 4)

SINGH,H.: Am. J. Psychiat. 117, 360 (1960) ; 3)

LEE, 5)

LUBY,E.D. ANDDOMINO,E.F.: J. Am. med. Ass. 177, 68 (1961) ;

BRACHEFIELD, J., WIRSTSHAFTER, A. ANDWOLFE, S.: J. Am. med. Ass. 186, 1 172 (1963) ; 6) ANDPAL, N.R.: Br. med. J. 11, 1011 (1964); Lancet 1, 1076 (1964) ;

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STANLEY , B. CUTHILL,J.M. GRIFFITHS,A.B. AND POWELL , D.E.B.:

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