Pharmacodynamic Actions of Diethylcarbamazine in the Dog with Particular Reference to Nicotine - Like Properties

PHARMACODYNAMIC ACTIONS OF DIETHYLCARBAMAZINE IN THE DOG WITH PARTICULAR REFERENCE TO NICOTINE - LIKE PROPERTIES

L.S. FORBES Department of Physiology and Anatomy, Massey University, Palmerston North, New Zealand.

INTRODUCTION The dog is regarded very suitable for drug studies preliminary to use in man and the Diethylcarbamazine, a derivative of pipera purpose of this short communication is to zine, was introduced in 1947 as a fiIaricidal report observations made during studies of agent in man and its outstanding anthelmin pharmacology of diethylcarbamazine, which thic action is against filarial worms, notably are significant because of the continuing Wuchereria bancro/ti, Brugia malayi, Loa-loa chemotherapeutic role of the drug in filaria of man (Rollo, 1965) and Dirofilaria immitis sis control. of the dog. At the present time, the most important use is for mass treatment of human MATERIALS AND METHODS communities in endemic areas. The aim of the therapy is to reduce the reservoir of Young dogs of mixed breeding were .used. microfilariae in the popUlation to a level at Anaesthesia was induced with thiamylal which infection of mosquitos is prevented and sodium (Surital, Parke Davis) and maintained transmission to fresh individuals ceases by infusion with chloralose. Blood pressure (Wilson, 1968). This method of control is was recorded with a mercury manometer reported to be showing considerable promise connected to a common carotid artery and of success (Sasa, 1968). respiration from a tambour attached to the side-arm of aT-shaped tracheal cannula. In addition, the drug has been suggested Injections of drugs were made through a for treatment of cutaneous larva migrans and cannula in the femoral vein and tracings were dracunculosis in man and has proved a recorded on smoked kymograph paper useful remedy for various lungworm infec (Forbes, 1964). tions - notably Dictyocaulus viviparous in cattle, D. filaria in sheep, Metastrongylus in Diethylcarbamazine citrate (Boots) was pigs, D. arnfieldi in horses and Aleurostrongy used in the form of a 40 %solution prepared Ius abstrusus in cats. for subcutaneous injection in cattle; hexame thonium bromide as Vegolysen (May and Comprehensive pharmacodynamic studies, Baker) phentolamine mesylate B.P., as Rogi with several species of animals, were carried tine (Ciba) and adrenaline hydrochloride as out by Harned et al.,(1948) and more recently, adrenaline injection, B.P. the action of the drug on levels of circulating eosinophils has been reported by Thevathasan RESULTS (1970). A. Effects of Diethylcarbamazine citrate and This work was supported partly by a esearch grant Adrenaline hydrochloride from May & Baker (New Zealand) Ltl. Some of the equipment used was purchased with a grant from Intravenous dosages of diethylcarbamazine the Golden Kiwi Lottery Distribution Committee for Scientific Research. ' citrate of from 2.5 to 10 mg/kg caused a pre-

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cipitous rise in blood pressure and a well The vasomotor effects of adrenaline (For defined increase in rate and depth of respi bes, 1971a) are identical to those of diethyl ration (Fig. 1). Respiration was sometimes carbamazine, but respiration is often in inhibited, slightly at the peak of the pressor hibited, because adrenaline has no stimulatory response, particularly when the highest dose effects on the chemoreceptors and reflex was given-probably as a result of reflex inhibition predominates. inhibition of respiration arising from the effects of hypertension on the baroreceptors B. Effects of Hexamethonium bromide and of the carotid and aortic bodies. These Diethylcarbamazine citrate responses, are identical to those given by nicotine and are attributable to: excitation This ganglionic blocking agent, antagonizes of sympathetic ganglia giving vasoconstric the action of acetylcholine, nicotine and tion,stimulation of the adrenal medullae nicotine-like drugs; at the autonomic ganglia, releasing catecholamines and stimulation of the adrenal medullae and the respiratory the respiratory chemoreceptors affecting res chemoreceptors. In a'dosage of 1 mg/kg, piration. it causes a moderate fall in blood pressure,

Fig. l-Showing the effects of diethylcarbamazine citrate at a dosa~ of 5 mg/kg on the blood pressure (upper tracing) and respiration (lower tracing). Dog anaesthetiied with chloralose.

94 Vol. 3 No. 1 March 1972 DIETHYLCARBAMAZINE IN THE DOG as a result of blockade of sympathetic ganglia derably reduced when given after phentola and consequent removal of normal vaso mine, but the respiratory effects are not constrictor tone (Forbes, 1971a). However, altered (Fig. 3). with simultaneous administration of hexame thonium, the actions of diethylcarbamazine DISCUSSION are virtually abolished (Fig. 2). The actions of endogenous acetylcholine C. Effects of Phentolamine mesylate and at autonomic ganglia, adrenal medullae and Diethylcarbamazine citrate the neuromuscular junction, are described as nicotine-like, because they are mimicked The adrenergic blocking agent, phentola by nicotine. Moreover, nicotine-like drugs, mine, specifically antagonizes the alpha stimulate the chemoreceptors of the carotid effects of sympathomimetic amines and when and aortic bodies to bring about an increase given at a dosage of 1 mg/kg, causes a small in the rate and depth of respiration: fall in blood pressure (Fig. 3) probably as a result of blockade of alpha receptors in The experiments show clearly, that diethyl peripheral vessels and consequent removal carbamazine possesses certain pharmacolo of normal vasoconstrictor tone. The vasomo . gical actions which are identical to those of tor effects of diethylcarbamazine are consi nicotine and the finding that these actions are

Fig. 2-Showing the effects of diethylcarbamazine citrate on the blood pressure (upper tracing) and respiration (lower tracing) when given simultaneously with hexamethonium bromideJat a dosage of 1 mg/kg. Dosages of diethylcarbamazine citrate at A, 10 mg/kg and at B, 20 mg/kg. Dog anaesthetized with choralose.

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\Fig. 3-Showing the effects on blood pressure (upper tracing) and respiration (lower tracing) of: A. phentolamine mesylate at a dosage of 1 mg/kg, followed by: B. diethylcarbamazine citrate at a dosage of 10 mg/kg. Dog anaesthetized with chloralose. antagonized by hexamethonium, indicates zine is capable of evoking endogenous amine that the sites of actions are the ganglia, the release from adrenergic nerves by virtue of adrenal medullae and the respiratory chern ore its ganglion stimulant properties and the ceptors. In addition, the observation that catecholamines could influence the level of the vasomotor effects are substantially in circulating eosinophils. hibited by the alpha adrenergic blocking agent, is confirmatory evidence that these In man, diethylcarbamazine has proved a effects are elicited by endogenous amines, very safe drug at therapeutic levels. However, that is, catecholamines from adrenergic it does frequently cause nausea and vomiting nerve endings and the adrenal glands. and these effects have been reported as the principal cause of the failure of mass treat Thevathasan (1970) reported that diethyl ment control projects in some cOUlltries, carbamazines produces an eosinophilia in such as India (Sasa, 1968). These gastro adrenalectomised - splenectomised rats and intestinal side effects could arise from local remarked that this response duplicates that irritant and spasmogenic effects or from obtained with adrenaline by Thevathasan stimulation of parasympathetic ganglia and and Gordon (1954). the symptoms might be controlled readily The results given above indicate that, in by atropine. A small dose of atropine given adrenalectomised . animals, diethylcarbama by mouth with the anthelminthic could exert

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sufficient local action on the gut to alleviate Care should be taken when prescribing the symptoms without producing systemic . the anthelminthic to patients exposed to effects. This procedure could be of benefit other drugs or substances with nicotine-like in assisting medication in mass treatment propensities, such as cholinergics or anti control programmes. cholinesterases.

In the dog, the drug is extremely well REFERENCES tolerated and the only side effect is a low incidence of vomiting (Link, 1965; Gibson FORBES, L.S., (1964). The relation between 1965). In cattle, doses twenty times higher method of administration, route of than normal caused nervous symptoms, absorption, inhibitory actions and acute manifest by excitability and muscle twitching, toxicity of arecoline hydrobromide in but recovery was rapid and palliative treat dogs. Ann. Trop. Med. Parasit., 58: 119. ment was not required. (Gibson, 1965). FORBES, L.S., (1971a). Some aspects of the However, diethylcarbamazine apparently pharmacology of pyrantel tartrate in exacerbates the potential toxicity of methy the dog. New Zeal. Vet. J., (lnpress). ridine and animals given the two drugs together may show severe purgation, FORBES, L.S., (197lb). Toxicological and dyspnoea, muscle spasm and may die. pharmacological relations between leva misole, pyrantel and diethylcarbamazine Other experiments (Forbes, 1971b) show and their significance in helminth chemo that several other modern anthelminthics therapy. (In press). are capable of evoking nicotinic responses GIBSON, T.E., (1965). "Veterinary Anthel and care should be exercised when pre mintic Medication", 2nd ed., Tech. scribing such drugs to patients receiving Comm. No. 33 Comm. Bur. Helminth. other drugs or exposed to substances capable HARNED, B.K., CUNNlNGHAM, RW., HALLI of exacerbating toxic propensities. The DAY, S., VESSEY, R.E., YUDA, N.N., latter group of chemicals include cho1inergics CLARK, M.C., HINE, C.H., COSGROVE, R. and substances with anticholinesterase pro and SUBBAROW, Y., (1948). Studies on perties-such as chloral and phenothiazine the chemotherapy of filariasis VI. Some derivatives and organophosphorus com pharmacodynamic properties of 1- die pounds. thylcarbamyl-4-methyl piperazine hy drochloride, Hetrazan. J. Lab. CUn. SUMMARY Med., 33 : 216. Diethylcarbamazine citrate, when given LlNK, RP., (1965). In "Veterinary Pharma intravenously to dogs anaesthetized with cology and Therapeutics". 3rd ed., chloralose, evoked precipitous hypertension Ed. L. Meyer Jones. Iowa State Univer and pronounced increase in rate and depth sity Press, Ames., U.S.A. of respiration. These effects were all abolish ROLLO, I.M., (1965). In "The Pharmacolo ed by the ganglion blocking agent, hexame gical Basis of Therapeutics" 3rd ed., thonium, and the hypertension was almost Eds. Goodman, L.S. and Gilman, A. completely antagonized by the alpha adrener The Macmillan Company, New York. gic blocking agent, phentolamine. The SASA, M., (1968). An introduction to epi results indicate that diethylcarbamazine has demiology and control of filariasis. nicotine-like properties, in common with Proc. of Seminar on Filariasis and Im several other modern anthelminthics. munology ofParasitic Infections & Labo

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ratory Meeting. Eds. A.A. Sandosham renalectomised-splenectomised rats with and V. Zaman. Singapore, p. 89. and without hydrocortisone. Southeast THEVATHASAN, OJ. and GORDON, A.S., Asian J. Trop. Med. Pub. Hlth., 1 : 123. (1954). Adrenocortical - epinephrine WILSON, T., (1968). The chemotherapy and interactions upon the circulating eosin control of filariasis. Proc. of Seminar 011 ophils in the adrenalectomized rat. Anat. Filariasis and Immunology of Parasitic Rec.,120 : 780. infections & Laboratory Meeting. Eds. THEVATHASAN, 0.1., (1970). The action of A.A. Sandosham and V. Zaman. Singa diethylcarbamazine (Hetrazan) on ad pore, p. 139.

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