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Home , Orphenadrine

CENTRAL ACTIVITY OF , AND DESMETHYLIMIPRAMINE

J.N. SINHA, R.C. SRIMAL, K.S. DIXIT, OM CHANDRA AND K.P. BHARGAVA Departmentof Pharmacologyand Therapeutics,K.G. Medical College, LucknewUniversity, Luckncw-3, India Receivedfor publication October 4, 1965

The exact mechanismof action of the new thymolepticsimipramine (IMI), its derivative des methylimipramine(DMI) and its analogue amitriptyline (AMI) is still not known. These agents antagonise the muscular rigidity induced by and this has been attributed to their central anti-cholinergicaction (1). Another structurally similarantidepressant, orphenadrine, has been report ed to possesscentral (2) and peripheral (3) muscle relaxant property. We have already reported that IMI, AMI and DMI are peripheral muscle relaxants (4). The present study deals with the central musclerelaxant property of theee . Thirty adult cats (2.5-4.0kg) of either sex were employedin the study. They wereanaesthetised with pentobarbitonesodium (30mg/kg i.p.) and maintained on artificial positive pressurerespiration as a routine. Right femoral vein was cannulated and arterial pressurewas recorded from the left common carotid artery through a mercury manometer on smoked kymographpaper. Intracerebro ventricular cannula was introducedinto the lateral ventricle accordingto the technique of Feldberg and Sherwood(5). The linguomandibularreflex was recorded through a system of pulleys on the kymographpaper as describedby King and Unna (6). Movementsof the lower jaw were elicited by stimulating the root of the tongue through needle electrodesby rectangular pulses (2-4 v, 5-10 msec duration and I shock/secfrequency) derived from Grass electronicstimulator. Contractionsof gastrocnemiusmuscle due to sciaticnerve stimulationwere used as peripheralcontrol. The test drugs were dissolvedin 0.9% saline and were injected intraventricularly in a volume 0.25ml. The per centage reduction of linguomandibularreflex was determined for at least three dose levels of each and the results were subjected to probit analysisby the method of Finney (7) and the ED50, standard error and 95% fiducial limits were calculated. All the three compoundswere found to inhibit the linguomandibularreflex. Records of the typical experiments with mephenesinand imipramineare shown in Fig. 1. (1.25mg intraventricular) producedabout 50%inhibition of the linguomandibularreflex with quick recovery. Imipramine (0.25mg) administeredby the same route in another experiment also inhibited the lin guomandibularreflex by about 50% but with a longer duration of action (45minutes). In both the experiments,peripheral neuromusculartransmission remained unaffected. Activity ratio of these compoundswas calculated taking the activity of mephenesinas one (Table 1). In the present study IMI, AMI and DMI have been found to depress the linguomandibular reflex in cat. This polysynapticreflex is mediated at the medullary level and its inhibition has been found to be a good index of central musclerelaxant activity (8). Possibilityof peripheral leak of the drugs after intraventricular administration was excluded since the sciatic nerve stimulated contractionsof the gastrocnemiusmuscle remained unaffected. All the three compoundswere found to be more potent and to possesslonger duration of action than mephenesin,the control drug. Out of the three compoundstested, IMI was found to be the most potent (5.2 times) while AMI (3.12 FIG. 1. Shows responses of blood pressure, linguomandibular reflex (middle tracing) and sciatic nerve stimulated contractions of gastrocnemius muscle in cats. (A) shows inhibition of linguomandibular reflex by mephenesin (1.25 mg i.c.v.) with quick recovery. (B) shows a similar effect of imipra mine (0.25 mg i.c.v.) on linguomandibular reflex, with a long duration of action (recovery-45 minutes). Note that sciatic nerve gastrocnemius contractions (lower tracing) remined unaffected.

TABLE 1. Central muscle relaxant activity of imipramine, amitriptyline and desmethylimipramine.

times) and DMI (2.23 times) fell next in the order. Main disadvantage of mephenesin as a muscle relaxant is its short duration of action. AMI was found to be a long acting compound having dura tion of action 7.5 times that of mephenesin. IMI, the most potent of the three compounds, has a shorter duration of action as compared to AMI but is still 4.5 times more potent than mephenesin. Duration of action of DMI was only about twice as compared to mephenesin. Whether central muscle relaxant activity of these compounds has anything to do with their thymoleptic action is not known. Similar inhibition of the liguomandibular reflex has been seen with orphenadrine , another structurally similar . From the results of the present study it is apparent that these agents are potent central muscle relaxants and may prove to be more useful than mephenesin in certain spastic disorders of skeletal muscle. Acknowledgement: Authors are grateful to M/S J.R. Geigy, Switzerland , for the gift of imipramine (Tofranil) and desmethylimipramine (Pertofran) and to M/S Merck Sharp & Dohme, U.S.A., for the supply of amitriptyline (Elavil). REFERENCES

1) SUSLER, F., BICKEL, M. H. AND BRODIE, B. B.: J. Pharmacol. 144, 321 (1964)2) BIJLASMA,U. G., HARMS, A.F., FINCKE, A.B.H., TERSTEEGE,H.M. AND NAUTA, W.T.: Arch. int. Pharmacodyn. 106, 332 (1956)3) ONUAGULUCHI,G. AND LEWIS, J. J.: J. Pharm. Pharmacol. 15, 329 (1963)4) SINHA, J. N., DIXIT, K.S., SRIMAL,R.C., CHANDRA,O. AND BHARGAVA,K.P. : Arch. int. Pharmacodyn. (1965)(In press) 5) FELDBERG,W. AND SHERWOOD,S.L. : J. Physiol. 123, 148 (1954)6) KING, E.G. AND UNNA, K.R. : J. Pharmacol. 111, 293 (1954)7) FINNEY, D. J. : Probit Analysis 2nd Ed., Cambridge University Press, London (1952)8) BHARGAVA,K.P. AND SRIVASTAVA,R.K. : Brit. J. Pharmacol. 25, 751 (1965)