Define autacoids. Describe histamine, its receptors and actions, and classify the antihistamines with their uses.

Definition and Synthesis

• Histamine is formed from histidine by histidine decarboxylase, and destroyed by histaminase (diamine oxidase) and by methylation
• Stored in — mast cell and basophil granules (bound to heparin), enterochromaffin-like (ECL) cells of the gastric mucosa, and histaminergic neurons of the posterior hypothalamus

Histamine Receptors

Actions of Histamine

• Cardiovascular — arteriolar vasodilatation (H1 and H2) with a fall in blood pressure; increased capillary permeability causing oedema; direct cardiac stimulation (H2)
• The triple response OF LEWIS after intradermal injection — (1) a red spot from local capillary dilatation; (2) a bright red flare spreading outward, from arteriolar dilatation mediated by an axon reflex; (3) a wheal from increased permeability and oedema
• Respiratory — bronchoconstriction, marked in asthmatics; increased bronchial secretion
• Gastric — powerful stimulation of acid secretion through H2 receptors; histamine is the final common mediator of acid secretion, which is why H2 blockers work whatever the stimulus
• Nerve endings — itching and pain
• Histamine releasers — morphine, tubocurarine, vancomycin (causing "red man" syndrome if infused rapidly), radiocontrast media, polymyxin B, and the anaphylatoxins C3a and C5a

Antihistamines — Classification

Uses of H1 Antihistamines

• Allergic disorders — allergic rhinitis, urticaria, angio-oedema, atopic dermatitis, drug and insect-bite reactions, conjunctivitis
• They relieve itch, sneezing and rhinorrhoea well, but nasal blockage poorly, since congestion is largely mediated by leukotrienes
• Motion sickness and vertigo — promethazine, cinnarizine, dimenhydrinate; effective through their antimuscarinic and central actions, so only first-generation drugs work
• Nausea and vomiting, including of pregnancy (doxylamine with pyridoxine) and of vestibular origin
• Sedation and insomnia — promethazine, diphenhydramine; a short-term measure only
• Common cold — symptomatic relief comes from the antimuscarinic drying effect, not from any antihistamine action
• As an adjunct in anaphylaxis — but never as the primary treatment, which is adrenaline

Anaphylaxis — the Clinical Consequence of Mass Histamine Release

• Adrenaline is the only drug that reverses every feature, and it must be given intramuscularly into the anterolateral thigh without waiting for intravenous access — 0.5 mg of 1:1000 in an adult, repeated after 5 minutes if needed
• Antihistamines and steroids are adjuncts, never the primary treatment; deaths continue to occur because an antihistamine was given while adrenaline was delayed
• Anaphylactoid reactions — clinically identical but caused by direct mast cell degranulation without IgE, so they can occur on first exposure; caused by radiocontrast, vancomycin, opioids and NSAIDs
• Patients on beta-blockers may respond poorly to adrenaline; glucagon is used, as it raises cardiac cAMP by a route that bypasses the blocked receptor

Adverse Effects and Applied Aspects

• First generation — sedation and impaired psychomotor performance (dangerous when driving or operating machinery, and additive with alcohol), dry mouth, blurred vision, urinary retention, constipation, and confusion in the elderly
• Contraindicated or used with care in glaucoma and prostatic enlargement, because of the antimuscarinic action
• Avoid first-generation drugs in the elderly, in whom they contribute substantially to anticholinergic burden, falls and delirium
• Antihistamines do not prevent anaphylaxis and must never delay adrenaline — a recurring and lethal error
• H2 blockers — ranitidine, famotidine, cimetidine; used for peptic ulcer and reflux. Cimetidine is a potent enzyme inhibitor and has antiandrogen effects (gynaecomastia, impotence); famotidine and ranitidine do not
• Widely sold over the counter in India in cold and cough preparations, often combined irrationally; sedation in a driver or a student is a real and unrecognised harm
• Antihistamines do not work well for nasal blockage, which is leukotriene-mediated; an intranasal corticosteroid is the more effective treatment for allergic rhinitis
• Cetirizine causes more sedation than loratadine or fexofenadine in a minority of patients, so "non-sedating" should not be taken as absolute
• Every patient who has had anaphylaxis needs an adrenaline auto-injector, training in its use, a written plan, and referral for allergy assessment to identify the trigger
• Chlorpheniramine remains widely used and useful in India because it is cheap and available parenterally, but its sedative and antimuscarinic effects must be weighed, particularly in the elderly
• H2 blockers have largely been displaced by proton pump inhibitors for acid suppression, though famotidine retains a place where a proton pump inhibitor is unsuitable
• Ranitidine was withdrawn worldwide after nitrosamine contamination was found, and famotidine is now the usual alternative
• Warn patients about driving and machinery when prescribing any first-generation antihistamine, and about the additive effect of alcohol