BJPsych Advances (2019), vol. 25, 265–268 doi: 10.1192/bja.2019.21

CLINICAL Histamine in : REFLECTION as a sedative anticholinergic John Cookson

(strongly influenced by the ideas of Claude Bernard John Cookson, FRCPsych, FRCP, is SUMMARY and Louis Pasteur). There he met Filomena Nitti, a consultant in general adult psych- iatry for the Royal London Hospital The author reflects on discoveries over the course daughter of a former prime minister of Italy. They of a century concerning histamine as a potent and East London NHS Foundation married in 1938 and she became her husband’slife- chemical signal and , the develop- Trust. He trained in physiology and long co-worker. They moved in 1947 to the at the University of ment of , including promethazine, Institute of Health in Rome. In 1957 he was Oxford and he has a career-long and from a common precursor, interest in psychopharmacology. His and the recognition of a major brain pathway awarded a Nobel Prize for his work in developing duties have included work in psychi- involving histamine. Although chlorpromazine has drugs ‘blocking the effects of certain substances atric intensive care units since 1988. been succeeded by numerous other antipsycho- occurring in the body, especially in its blood vessels He has co-authored two editions of tics, promethazine remains the and skeletal muscles’ (Oliverio 1994). He and his Use of Drugs in Psychiatry, published recommended for sedation in acutely disturbed by Gaskell. research student Marianne Staub introduced the Correspondence: Dr John Cookson, patients, largely because it is potently anticholiner- first antihistamine in 1937, developed by altering Tower Hamlets Centre for Mental gic at atropinic muscarinic receptors and therefore the structures of drugs found to block known trans- Health, Mile End Hospital, Bancroft anti-Parkinsonian: this means it is also useful in mitters – acetylcholine and – such as atro- Road, London E1 4DG, UK. Email: combination with older such as [email protected] pine. Their compound, called 929F, counteracted the haloperidol. actions of histamine on smooth muscle and reduced First received 12 Mar 2019 DECLARATION OF INTEREST anaphylactic shock; however, it was too toxic for clin- Accepted 25 Mar 2019 ical use. None. Copyright and usage © The Royal College of Psychiatrists KEYWORDS 2019. Histamine; antihistamines; tranquillisation; anti- The synthesis of promethazine psychotics; history. The synthesis of promethazine (Box 1) was first reported in 1944 by Dr Henry Gilman and David Stanley, chemists at Iowa State College, working Histamine is a small positively charged molecule on in a search for antimalarials. derived from the amino acid histidine, originating The antihistamine properties of promethazine from ergot, the fungal putrefaction of protein in rye (phenergan) were discovered in France in 1946 by (Fig. 1). It was identified as biologically active by Halpern, who was at the French National Centre one of the founding fathers of British pharmacology, for Scientific Research in . This was the most Henry Dale: working with Patrick Laidlaw in the potent of a series of antihistamines that were deriva- laboratories of Sir Henry Wellcome in London, tives of . In the 1940s academic they described all its main actions – except that of laboratories and the pharmaceutical industry stimulating gastric acid secretion (Dale 1910). strove to discover new and safer antihistamines, They very presciently compared its effect in lowering with such success that more than 50 were synthe- blood pressure to that of anaphylactic ‘shock’. sised by 1965 (Dripps 1965). Histamine was suspected to be released in allergic The sedative properties of promethazine were conditions: urticaria, hay fever, bronchospasm and studied by the French-Vietnamese surgeon-anaes- anaphylaxis. And drugs that would antagonise his- thetist and pioneer-explorer Henri Laborit. tamine had obvious therapeutic potential. Between 1948 and 1952 he developed what he called his ‘lytic cocktail’, intended to reduce the need for inhaled anaesthetic agents and to combat The first antihistamines surgical ‘shock’ and post-operative vomiting. It con- Daniel Bovet (1907–1992) led in the search for anti- tained initially , promethazine and histaminics, working first in the therapeutic chemis- opioids such as . ‘Lytic’ implied loosening try laboratory at the Pasteur Institute in Paris or relaxing (Valenstein 2002).

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Histidine Histamine

O CO 2 N N OH

N NH N NH 2 2 H H

Promethazine Chlorpromazine

S S

Cl N N

CH 3 CH N 3 N H C CH CH 3 3 3

FIG 1 The structure of histidine, histamine, promethazine and chlorpromazine, and conversion of histidine to histamine (imidazolyl ethylamine) by histidine decarboxylase.

to explore the drug. The introduction of chlorpro- BOX 1 Pharmacokinetics of promethazine mazine by psychiatrists Delay and Deniker in 1952 represented something ‘very different’ and Oral promethazine is almost completely absorbed from the the drug was also associated with Parkinsonian gut and metabolised by hydroxylation (involving the hepatic side-effects, giving rise later to the name ‘neurolep- enzyme CYP 2D6) and sulphoxidation in the liver, leading to ’– – a bioavailability of 25% and a peak concentration at 2–4h. tic literally meaning seizing the neuron by The peak is at 2 h after intramuscular (IM) administration. Delay in 1955. The elimination half-life is 12–15 h. However, Henri Laborit’s suggestion for using chlorpromazine in premedication for anaesthesia was by 1965 outdated. It did not counteract surgi- Atropinic plants and drugs (hyoscine (scopolam- cal shock but produced arterial hypotension and its ine) and atropine from henbane and nightshades) sedative and anti-emetic properties could be had long been used for their calming effects in psy- achieved with other agents if necessary (Dripps chiatric settings but were associated with toxicity 1965). (Shorter 1997). Psychiatrists began to investigate antihistamines from 1943, and promethazine was used in sleep therapy for agitation (Guiraud 1950; Histamine and antihistamines Healy 2002). Histamine is stored predominantly in mast cell granules (Riley 1953) and in basophils. After their discovery of immunoglobin E (IgE) in 1966, Neuroleptanalgesia Kimishige Ishizaka in Denver found IgE binding Further phenothiazines were synthesised by Paul sites on basophils and mast cells and that their Charpentier of Rhône-Poulenc (now Aventis) in aggregation by anti‐IgE on basophils caused them Paris cooperating with academic laboratories to release histamine and a slow-reacting substance (Halpern 1948). In 1950 Charpentier synthesised of anaphylaxis (SRS-A), later called leukotriene chlorpromazine as a variant of promethazine, and (Tomioka 1971), during allergic reactions. his associated pharmacologist Simone Courvoisier Antihistamines were confirmed to be useful in con- recognised its more diverse range of actions in the trolling these. laboratory. Laborit described the novel effect of It became known that certain drugs lower blood adding chlorpromazine to his cocktail as ‘calm pressure by releasing histamine (Schachter 1952); without sleep’. The combination was later called these include , pethidine, atropine, certain ‘neuroleptanalgesia’. He encouraged psychiatrists muscle relaxants, antibiotics and quinine.

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The tuberomammillary nucleus (TMN) The pharmacological activity of The sedative effect of antihistamines indicated that promethazine histamine must have a role in the brain, and in Perhaps reflecting its origin from compounds block- 1957 histamine was identified within the brain. ing the actions of other biogenic amines, prometha- But it was not until much later, in 1984, that zine has broad pharmacological activity. As well as the main pathway was demonstrated, originating being a antihistamine, it has significant atropinic from approximately 64 000 histamine-producing effects (Halpern 1948). neurons in the tuberomammillary nucleus (TMN) Other actions include local anaesthetic effects near the mammillary bodies behind the hypothal- stronger than procaine (blocking sodium channels), amus (Box 2) (see Haas 2008). The TMN projects ictogenic effects (lowering the seizure threshold), to diffuse areas of the forebrain, including the prin- antiemetic effects and blocking the HERG-encoded

cipal cells in the cerebral cortex, and is part of the IKr potassium channel in heart muscle fibres, thus reticular activating system. It is activated by the prolonging the QT interval – although there is neighbouring orexin-containing neurons of the little evidence for it causing ventricular dysrhyth- lateral hypothalamus during wakefulness and not mia. In higher doses it causes delirium. This was during sleep. The TMN neurons express orexin-2 found in 31% of people reported to be taking 250 receptors. Furthermore, the histamine neurons mg daily, and in a greater proportion of those on project to other areas involved in wakefulness, higher doses. (Page 2009). Perhaps being regarded such as the noradrenergic nucleus locus coeruleus, as a safe sedative-hypnotic, it has been widely used the cholinergic nuclei of the brainstem, and the in remedies for children, but life-threatening dopamine neurons. Antihistamines block histamine adverse events of promethazine in children (respira- actions in these sites. The TMN has been described tory depression, cardiac arrest, seizures) led to a as the first violin of the orchestra of cerebral arousal Food and Drug Administration black box warning conducted by the orexin-containing neurons of the being added to the labelling in the USA in 2004. dorsolateral hypothalamus. In terms of relative potency in blocking histamine

When activated, the TMN neurons stimulate H1 H1 receptors and acetyl choline muscarinic recep- receptors in all the major parts of the brain, posterior tors, promethazine is the most potently anticholiner- pituitary and spinal cord. They increase arousal in gic of the antihistamines (Kubo 1987). It is very the sleep–wake cycle, have roles in fluid balance, much weaker in blocking dopamine receptors and feeding, control of body temperature and the cardio- is not effective in schizophrenia. vascular system, and release stress hormones from the pituitary. Conclusions In 2016 promethazine reached the pinnacle of its fame BOX 2 Subtypes of brain histamine receptors in psychiatry when it was endorsed by National and antihistamines Institute for Health and Care Excellence (NICE) guidelines as one of the best-evidenced treatments • Three types of histamine receptor are now recognised in for the management of violence, in combination with the brain: haloperidol (Cookson 2018). This apparent benefit • H , post-synaptic 1 is the result of a combination of sedative and anti- • H2, mainly post-synaptic (also involved in gastric acid Parkinsonian (anticholinergic) effects – counteracting secretion) the potential side-effects of haloperidol, which is itself • H3, largely presynaptic autoreceptors reducing the fir- very efficacious for agitation in psychosis. ing of tuberomammillary nucleus (TMN) neurons The profound importance of chlorpromazine in • Newer H1 blockers were designed to be excluded by the the history of psychiatry remains beyond dispute blood–brain barrier and are therefore non-sedative (e.g. and promethazine, despite its limitations in terms cetirizine, loratadine) of properties and its sedative side- • H blockers were developed by Sir James Black (who 2 effects, which restrict its use as an anti-allergic medi- received a Nobel Prize for his work) and treat peptic cation, still has a useful role in psychiatry. Modern ulcer (e.g. cimetidine, ranitidine) rapid tranquillisation aims to calm without sedation • H blockers have been used experimentally 3 and – ironically – uses antipsychotics as Laborit did, • Histamine receptors are all metabotropic receptors; the but usually avoids the need for an anaesthetist. second messenger for H1 is phospholipase-C, affecting inositol and calcium release • To add to the complexity, these receptors may be ‘consti- Acknowledgements tutively’ active, meaning that inverse agonism is also a I am grateful to Dr Jonathan Pimm for assistance on possibility this manuscript.

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References Kubo N, Shirakawa O, Kuno T, et al (1987) Antimuscarinic effects of anti- histamines: quantitative evaluation by receptor-binding assay. Japanese Cookson J (2018) Rapid tranquillisation: the science and advice. BJPsych Journal of Pharmacology, 43: 277–82. – Advances, 24: 346 58. Oliverio A (1994) Daniel Bovet, 23 March 1907 – 8 April 1992. Dale HH, Laidlaw PP (1910) The physiological action of β-iminazolylethy- Biographical Memoirs of Fellows of the Royal Society, 39:61–70. – lamine. British Journal of Physiology, 41: 318 44. Page CB, Duffull SB, Whyte IM, et al (2009) Promethazine overdose: clin- Dripps RD (1965) Preanesthetic medication. In The Pharmacological ical effects, predicting delirium and the effect of charcoal. Quarterly Basis of Therapeutics (3rd edn) (eds LS Goodman, A Gilman): 57–60. Journal of Medicine, 102: 123–31. Macmillan. Riley JF, West GB (1953) The presence of histamine in tissue mast cells. Guiraud P, David C (1950) Traitement de l’agitation motrice par un Journal of Physiology, 120: 528–37. antihistamininique (R3277P). Comptes Rendues du Congrès Medicale Schachter M (1952) The release of histamine by pethidine, atropine, quin- des Médecins Aliénistes et Neurologues de Langue Française, 8: ine, and other drugs. British Journal of Pharmacology and Chemotherapy, – 599 602. 7: 646–54. Haas HL, Sergeeva OA, Selbach O (2008) Histamine in the nervous sys- Shorter E (1997) A History of Psychiatry: From the Age of the Asylum to the – tem. Physiological Reviews, 88: 1183 241. Era of Prozac. John Wiley & Sons. Halpern BN, Hamburger J (1948) A new synthetic anti-histamine sub- Tomioka H, Ishizaka K (1971) Mechanisms of passive sensitization. II. stance derived from phenothiazine (phenergan, 3,277 R.P.). Canadian Presence of receptors for IgE on monkey mast cells. Journal of – Medical Association Journal, 59: 322 6. Immunology, 107: 971–8. Healy D (2002) The Creation of Psychopharmacology. Harvard University Valenstein ES (2002) Blaming the Brain: The Truth about Drugs and Press. Mental Health. Free Press.

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