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. it no longer worries them. Similarly chlorpro- tion, but there is still room for really well controlled mazine has no analgesic effects of its own-but experiments in the clinical field. Recent experi- good results have been reported in such cases as mental work has shown that vomiting results from post-herpetic neuralgias and the effects have been stimulation of the centre by a reflex arc arising described as an indifference to, rather than an from ' chemoreceptor trigger zone ' situated on the absence of, pain (Sigwald and Bouttier, I953). surface of the medulla in the floor of the fourth When chlorpromazine-treated animals are given ventricle. This trigger zone is activated by so- hypnotic or anaesthetic drugs such as barbiturates called central acting drugs such as apomorphine, or ether, sleep time is prolonged. This so-called morphine, etc., and by those stimuli from the 'potentiation' also occurs in man. A similar vestibular apparatus which are respopsible for effect with the analgesia of morphine has been motion sickness. Chlorpromazine is thought to claimed but could not be demonstrated by Kopera act by competitive blocking of the receptors at this and Armitage (I954) in mice. The results of trigger zone when given in moderate doses. Much alcohol are the excitement doses are said to have a direct taking modified, phase larger depressant http://pmj.bmj.com/ being eliminated, the subject passing directly into effect on the actual vomiting centre and will the stage of collapse. diminish the response to direct gastric irritation by copper sulphate or to stimulation of the vagus Effects on Body Temperature by veriloid. Man's first protection against cold is by con- striction of the blood vessels of the skin. When Cardiovascular Effects this defence is overcome and the temperature of The effects of chlorpromazine on the cardio- the blood drops °o C. a second delayed mechan- vascular system are mainly the result of its action on September 29, 2021 by guest. ism, shivering, comes into action. In dogs mild in lowering the peripheral resistance by vasodilata- shivering increases oxygen consumption twice and tion. The heart becomes more rapid presumably severe shivering three times; by this means the in an attempt to maintain the blood pressure. heat production of the body may be raised 300 per There is usually an increase in the cardiac output cent. These two defensive reactions, vasoconstric- but in the vast majority of cases the blood pressure tion and shivering may be prevented by drugs; falls and becomes orthostatic. most anaesthetic agents produce a certain degree The blood flow in the hand has been shown, by of vasodilation of the skin vessels and deep Foster (1954) and his co-workers, to be increased anaesthesia or curarization will completely abolish 284 per cent. after intravenous chlorpromazine. shivering. Chlorpromazine is an effective vaso- The intra-arterial injection of adrenalin produces dilator and reduces but does not always entirely constriction of the hand vessels, chlorpromazine abolish shivering. Both general anaesthesia and given intra-arterially prevents this as does intra- Postgrad Med J: first published as 10.1136/pgmj.31.359.451 on 1 September 1955. Downloaded from 454 POSTGRADUATE MEDICAL JOURNAL September I955 venous administration. The effect of noradrenalin living with hypometabolism, muscular relaxation is not blocked to anything like the same degree as and a state of twilight sleep which resembles that of adrenalin (Kopera and Armitage, I954), and narcosis' (Huguenard, 1953). The substance and in those cases in which hypotension following the manner of expression of the assumptions and administration of chlorpromazine is too great or theories upon which these workers base their too prolonged, it would seem better to treat it method have not proved acceptable to most by noradrenalin rather than by adrenalin. When anaesthetists in this country, who feel, moreover, noradrenalin is given to a patient, slowing of the that the method is unduly complicated and often pulse is usual presumably due to vagal reflexes carried further than is reasonable. excited by the raised pressure; after chlorpro- The author has used a much simplified modifica- mazine the rise in pressure is less marked but is not tion of his technique for over 200 cases undergoing accompanied by slowing of the pulse. There is thoracic surgery. Premedication with prometha- evidence then that chlorpromazine is a powerful zine (phenergan), 50 mgm. given by mouth four adrenalin blocking agent, it may be called a hours before operation, and pethidine, o00 mgm. sympathetic blocking agent; it is in some measure given intramuscularly one hour before arrival in a parasympathetic blocking agent and it has effects the theatre, has given reasonably satisfactory seda- on the mid brain. Some would therefore go tion. A mixture of promezathine, 50 mgm., further and say that it is an autonomic blocking chlorpromazine, 50 mgm., and pethidine, o00 agent. But we should, I think, be careful to mgm. in 250 cc. of 5 per cent. dextrose in water, is distinguish it in our minds from such drugs as given intravenously in the anaesthetic room. After hexamethonium, which are true ganglion blocking some ten minutes the patient becomes apathetic agents. and drowsy; should the rapid and forceful heart In haemorrhagic shock, vaso-constriction of action cause any distress the patient may be made sympathogenic origin, if persistent, may be a comfortable by a' sleep dose ' of ioo to I50 mgm.Protected by copyright. factor in making the shock irreversible: the vaso- of thiopentone. A fall in blood pressure to about constriction in the tissues being so extreme as to 80 mm. of mercury is common in healthy adults cause anoxic tissue damage so severe that even if and the dose of' mixture' is therefore reduced in the blood volume were completely restored re- the frail or elderly. A further 00oo to I50 mgm. of covery would, in any case, be impossible. It has thiopentone and a suitable dose of relaxant allow been suggested that preventing this vasoconstric- intubation with or without bronchial aspiration and tion lessens the incidence of irreversible shock. blocking to be carried out carefully. Anaesthesia Chlorpromazine has been shown to have a shock is maintained with nitrous oxide and oxygen with sparing effect in experimental animals subjected relaxant added as needed. While respiration is to haemorrhage and trauma. But similar effects rather less depressed than with some other are seen with a wide variety of agents including sequences the bronchial reflexes are quiet. This atropine, barbiturates and some, but not all, anti- reduction in irritability has seemed of particular adrenaline drugs, and it seems that ' protection is value in difficult cases with secretions and broncho- not a function of increased blood flow in the After in successful the spasm. operation, cases, http://pmj.bmj.com/ tissues created by autonomic blockade' (Hershey patients are pale, lying quietly with eyes closed et al.). In the case of chlorpromazine there is apparently untroubled by pain but capable of usually a fall in blood pressure which in itself is responding to requests to move or cough, shutting a factor in reducing blood loss. In man controlled their eyes again when the physiotherapist leaves. experiment is difficult and it has yet to be proved The pressure tends to remain low while the drugs that, provided blood is adequately transfused, are active, and pain when it comes on some chlorpromazine gives any better protection against after an operation may be resented by a patient who operative shock than does good conventional has been, until then, comfortable. Relative com- on September 29, 2021 by guest. modern anaesthesia. Many feel encouraged, how- fort may be restored by pethidine or occasionally ever, by the condition of bad risk cases given by a further dose of chlorpromazine given chlorpromazine for very major operations. intramuscularly. Laborit and Huguenard were the first to use The incidence of vomiting after thoracic surgery chlorpromazine when they added it to their so- when using a barbiturate, relaxant and nitrous called ' artificial hibernation' in 195I. This they oxide sequence is low and is still further reduced defined as ' a pharmacodynamic technique which, when chlorpromazine is used. It is not, however, by using autonomicolytic drugs aims at establish- abolished completely. Of our cases three with ing a " controlled inhibition" of the autonomic persistent hypotension were treated by intravenous system, a neuroplegia of homeostasis and, as a infusion of nor-adrenalin and three developed consequence, an attenuation of the regulatory transient auricular fibrillation. These six com- reactions; it amounts to an economical method'of plications all followed resection for carcinoma of 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 455 the lung, when such sequelae may occur irrespec- While conventional methods in skilled hands tive of the anaesthesia. The method seems to allow a more rapid return to normality and make have been responsible for several cases of urinary assessment of the patient's condition easier, there retention occurring in men, several of whom is no doubt that several of the effects of chlor- required catheterization. promazine can conveniently fit into the pattern of Many of the nursing and resident medical staff anaesthetic requirements for major surgery. While have come to prefer this technique for thoracic grateful for this it would seem preferable to be able work. It is significant that when the routine use to control the extent of those various effects of this method was stopped after a trial period the independently by manipulating the dosage of surgeon at one hospital asked if it could be con- several different and shorter acting drugs. A tinued one week longer as he was operating on a sawn off shot gun may be effective but it is neither surgical colleague; and that when the sister of one a weapon of precision nor is its use appropriate on of the thoracic surgical wards herself underwent all occasions. lobectomy, and later thoracoplasty, she chose chlorpromazine for herself. BIBLIOGRAPHY ANTON-STEVENS, D. (I954), J. Ment. Sc., 00oo, 543. BURNS, J. H. (I95o), Brit. med. Y., ii, 691. An Assessment BURNS, J. H. (1954), Proc. Roy. Soc. Med., 47, No. 8, 617. The has undoubted value as an anti- BURNS, J. H., and DUTTA, N. K. (1948), Brit. J. Pharmacol., drug 3, 354. emetic and has a place in the management of DECOURT, P. (1953), Thdrapie, 8, 846. painful conditions and in psychiatry, but its con- DEWS and GRAHAM (I946), Brit. J. Pharmacol., I, 278. tinued administration carries the risk of to DOBKIN, A. B., GILBERT, R. G. B., and LAMOUREUX, L. damage (i954), Anaesthesia, 9, 157. the liver and bone marrow. In anaesthesia the HUGUENARD (1953), Anaes. Analg., Paris, Io, i6. author's is limited to its use in KOPERA, J., and ARMITAGE, A. K. (1954), Brit. J. Pharmacol., experience largely 9, No. 4, 392. surgery of the lung. Here the combination of LEHMAN, H. E., and HANRAHAN, G. E. (1954), Arch. Neurol.Protected by copyright. used allows endobronchial instru- Psychirat., Chicago, 71, 227. drugs repeated MAGOUN, H. W. (I950), Physiol. Rev., 30, 459. mentation, provides satisfactory operating con- SHACKMAN, R., WOOD-SMITH, F. G., GRABER, I. G., ditions and seems to lessen the discomforts of the MELROSE, D. G., and LYNN, R. B. (I954), Lancet, ii, 617. With after care SIGWALD, J., and BOUTTIER, D. (1953), Ann. Med., 54, 150. post-operative period. adequate VAN OMMEN, R. A., and BROWN, C. H. (1954), J. Amer. Med. significant complications have not been increased. Assoc., 157, 321.

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Bibliography continued from page 439--. B. Wyman iI. NEFF, W., MAYER, E. C., and THOMSON, R. (x950),, I3. LEE, J. ALFRED (I947), 'A Synopsis of Anaesthesia,' John Brit. med. J., i, 1400. J. Wright & Sons Ltd., Bristol. L. CURRIE, T. T. (I954), The Broad Way Clinical Supplement 12. MUSHIN, W. W., and RENDELL-BAKER, (1949) 14. iii. Ibid., ii, 472. , (Westminster Hospital), I, (No. 7),