Postgrad Med J: first published as 10.1136/pgmj.31.359.451 on 1 September 1955. Downloaded from 451 IV CHLORPROMAZINE AND ALLIED SUBSTANCES By JOHN BEARD, M.D., M.B., B.S., M.R.C.S., L.R.C.P., D.A., F.F.A., R.C.S., D.C.H. Chlorpromazine (largactil) was synthesized in Chlorpromazine Hydrochloride 1950 by Charpentier at the Rhone-Poulenc (4560 R.P.) Laboratories. It is a phenothiazine derivative (Largactil) closely related to promethazine (phenergan). Formulae / /\ Promethazine Hydrochloride (Phenergan) /\ /S /\ N\ Protected by copyright. \/ \/ \N/ CH2 CH2 CH2 / / CH2 CH3 http://pmj.bmj.com/ CH3 / CH3 1N HC1. Promethazine (phenergan) has two methyl groups, which in these derivatives are associated CH3 with strong antihistaminic power, while chlor- on September 29, 2021 by guest. promazine is a propylamine phenothiazine, which demonstrated in the case of chlorpromazine has more marked central nervous system effects (Burns, I954). Their very multiplicity makes the but only one-hundredth of the antihistamine assessment of the action of chlorpromazine difficult potency of promezathine. when it is given alone; when given in conjunction The Department of Pharmacology at Oxford with other drugs the confusion becomes greater has pointed out (Burns, 1948; Burns and Dutta, and there have been times when it has seemed that 1948; Dews and Graham, 1946) that atropine, this confusion has in some measure affected the pethidine, procaine, quinidine and also the anti- critical powers of its administrator. histamine drugs share many properties-incommon; Chlorpromazine is well absorbed by mouth, its spasmolytic, analgesic, 'quinidine-like,' hypo- effect, maximal in about three hours, being main- thermic and antihistamine effects are all seen. tained for several hours. Intramuscular irrjection These multiple effects were expected and later produces sedation in some 30 minutes lasting four Postgrad Med J: first published as 10.1136/pgmj.31.359.451 on 1 September 1955. Downloaded from 452 POSTGRADUATE MEDICAL JOURNAL September I955 or five hours, while intravenously the effects are part in a million concentration in the body tissues seen within five to ten minutes. The drug is very of an adult. After oral administration all the soluble in water, forming an acid solution irritant absorbed drug must travel via the portal circulation to the tissues. It is therefore given by injection to the liver where most probably the local con- either well diluted intravenously or deeply into a centration is over I:4oo,ooo, and continued muscle; repeated intramuscular administration administration is likely to be followed by toxic may, however, give rise to pain with local indura- effects in a proportion of cases. While the in- tion, leucocytosis and fever. Only about 8 per cidence of liver damage is not high the risk is cent of the total dose is excreted in the urine. The sufficiently great to make the administration of way in which the drug is broken down is not chlorpromazine for more than very short periods known but it is probable that the liver is con- a step requiring serious consideration. A few ceined since the drug's effect is more marked in cases of agranulocytosis have been reported and cases of liver disease. one has caused death but others have responded In animals very large doses cause death which to the withdrawal of the drug and penicillin may occur rapidly with convulsions or be more administration. Finally the makers warn us of delayed when muscular hypotonia is marked. In the possibilities of contact dermatitis and perhaps man, attempted suicide by taking 70 25 mgm. we would be wise to avoid prolonged contact, by tablets (i,750 mgm.) was followed by complete washing after handling the drug. recovery in three days. More serious effects have followed prolonged administration and are there- Sedative Effects fore not so likely to be seen by the anaesthetists Drowsiness is a side effect of several of the as by psychiatrists or general physicians. antihistamine drugs especially diphenhydramine from which is and With Phenothiazine, chlorpromazine (benadryl) promethazine (phenergan). Protected by copyright. derived, contains a benzene ring which is well chlorpromazine it occurs even more strongly. The recognized as a possible cause of liver and bone sedation in these cases differs from that seen after marrow damage. Minor liver changes are not barbiturates. In the latter, conditioned reflex unusual if chlorpromazine is given for several responses in rats persist until drowsiness is obvious, weeks as in psychiatric work. In an early series while in the case of chlorpromazine and some (Anton Stevens, I954) jaundice occurred several antihistamines, the rats cease to respond at a times but always cleared up on stopping the drug, dosage which did not cause drowsiness. The but recently reports of more persistent jaundice sedation of chlorpromazine is marked by a listless lasting up to five months have been published. In apathy. The patient is usually calm and may several carefully studied cases the jaundice has appear to sleep. The closed eyes and even snoring been of obstructive type (Van Ommen and Brown, are largely due to muscular hypotonia. The I954), and it was impossible to differentiate be- patient will answer questions intelligently if asked tween chlorpromazine jaundice and obstructive firmly, but larger doses will usually cause actual jaundice from other causes, by liver function sleep. This sleep effect differs from that of the tests; on histological examination there was no barbiturates. Lehman and Hanrahan (I954) pointhttp://pmj.bmj.com/ evidence of liver cell damage, but bile thrombi out that chlorpromazine seems to act selectively were noted in the ducts. -A transient eosinophilia on the subcortical centres of the brain which (up to 40 per cent. of white cells) and the history normally maintain wakefulness and psychomotor of drug administration were helpful points in 'drive.' It is suggested that this area is in the diagnosis and should be kept in mind to avoid 'reticular structure' of the mid brain, about unnecessary surgical interventions. These find- which so much is being written today (Magoun, resemble those in cases This while of no ings reported receiving 1950). hypothesis, great prac- on September 29, 2021 by guest. arsphenamine and methyltestosterone therapy. A tical importance, perhaps fits in with electro- few deaths from liver failure have been reported encephalographic findings, which in the case of and I have recently heard of a doctor who has died chlorpromazine resemble those of sleep rather than after self administration of chlorpromazine to re- those of the barbiturates, which are thought to act lieve the vomiting of digitalis. Not only was not only on the mid brain but also on the cortex. chlorpromazine contra-indicated because of the Large doses of chlorpromazine and also anti- passive congestion of his liver due to heart failure, histamines in animals cause convulsions. It is of but he had, in addition, a history of infective interest that antihistamines have been thought to hepatitis within the last four years. Decourt precipitate epileptic attacks and that coramine (i953) has stated that chlorpromazine in con- given to a patient who had had a full dose of centration of I :4oo,ooo is a general depressor of chlorpromazine was followed by prolonged con- cellular activity. A quite usual dose in medicine vulsions. These findings contrast with the known and psychiatry is 75 mgm. daily representing one sedative effect of barbiturates in convulsive states Postgrad Med J: first published as 10.1136/pgmj.31.359.451 on 1 September 1955. Downloaded from September 1955 BEARD: Chlorpromazine and Allied Substances 453 which are thought to be cortical in origin. This chlorpromazine will each allow increased heat loss relative freedom from cortical effects of chlor- if the body is exposed. In view of the known promazine may explain the clearness of the mind effect of chlorpromazine in reducing the tone of which persists while the apathy and lack of the blood vessels and muscles it seems unnecessary ' drive ' are noticeable. This can be demonstrated to postulate a central effect on the thermo- experimentally in man and in some measure in regulatory centre. The drug may thus be con- animals. I have seen no excitement stage as is seen veniently employed to facilitate cooling and by sometimes with barbiturates. Psychiatrists find this means to reduce the oxygen consumption of that while at. first large doses quieten many excited the body. Apart from cooling, however, no such patients inducing sleep, this sleep effect diminishes reduction of oxygen .consumption has been found and after a few days patients can sit about while after administration of chlorpromazine in vivo taking doses which made them almost comatose (Dobkin et al., 1954; Shackman et al., 1954). earlier on. In the favourable cases excitement and confusion may remain controlled in ambulant Anti-Emetic Properties patients as long as the drug is continued, but when It often appears that the effects of a drug are it is stopped many cases relapse (Stevens, 1953). increased in proportion to the strength of the There seems to be a disinterestedness and a de- administrator's convictions, and any recent remedy tachment in these patients, some of whom may still is likely to be effective in a good proportion of experience their hallucinations but are no longer cases. Persistent hiccup, for example, has stopped disturbed by them. The term ' a chemical dramatically three minutes after an intramuscular leucotomy' has been used and it will be re- injection of chlorpromazine. Similarly the value membered that the operation of leucotomy has of drugs in post-operative vomiting is difficult to been performed for pain in incurable disease. The assess. There is considerable evidence that chlor- patients are then said to experience their pain but promazine reduces the frequency of this complica-Protected by copyright.