HISTAMINE Histamine is widely distributed in the body and is derived from the decarboxylation of histidine.

It is concentrated in mast-cell and basophil granules. The highest concentrations are found in the lung, nasal mucous membrane, skin, stomach and duodenum (i.e. at interfaces between the body and the outside environment). Histamine is liberated by several basic drugs (usually when these are given in large quantities intravenously), including tubocurarine, morphine, codeine, vancomycin and suramin. Histamine controls some local vascular responses, is a neurotransmitter in the brain, releases gastric acid (Chapter 34) and contributes to allergic responses. There are two main types of histamine receptors, H1 and H2. H1-RECEPTORS In humans, stimulation of H1-receptors causes dilatation of small arteries and capillaries, together with increased permeability, which leads to formation of oedema. Histamine induces vascular endothelium to release nitric oxide, which causes vasodilatation and lowers systemic blood pressure. Inhaled histamine induces bronchospasm. In fetal vessels (e.g. the umbilical artery), histamine causes vasoconstriction. Histamine contributes to the triple response to mechanical stimulation of the skin which consists of localized pallor, which gives way to a wheal (localized oedema caused by increased vessel permeability and attributable to histamine) surrounded by a more distant and slowly developing flare (due to arteriolar

dilatation via an axon-reflex mechanism and involving tachykinins such as substance P, rather than histamine). Local injection of histamine causes itching and sometimes pain due to stimulation of peripheral nerves. Inhaled histamine is used as a challenge to determine bronchial hyperreactivity and assist in the diagnosis of asthma. H2- AND H3-RECEPTORS H2-receptors are principally concerned with the stimulation of gastric acid release (Chapter 34). Their contribution to most vascular responses is minor, but some (e.g. in the pulmonary vasculature) are H2-receptor mediated. H3-receptors are involved in neurotransmission. HYPERSENSITIVITY REACTIONS INVOLVING HISTAMINE RELEASE Anaphylactic shock (acute anaphylaxis) In certain circumstances, injection of an antigen is followed by the production of reaginic IgE antibodies. These coat mast cells and basophils, and further exposure to the antigen results in rapid degranulation with release of histamine and other mediators, including tachykinins, prostaglandin D2 and leukotrienes. Clinically, the patient presents a picture of shock and collapse with hypotension, bronchospasm and oropharyngeal-laryngeal oedema, often accompanied by urticaria and flushing. Asimilar so-called anaphylactoid reaction may occur after the non-IgE-mediated release of mediators by x-ray contrast media.

404 CLINICAL IMMUNOPHARMACOLOGY Key points Anaphylaxis and anaphylactoid reactions Anaphylaxis: is IgE-mediated hypersensitivity (type-1) that occurs in a previously sensitized individual; its pathophysiology is major cardiovascular and respiratory dysfunction due to vasoactive mediator release from mast cells; common causes are penicillins, cephalosporins and many other drugs, insect stings and food allergies (e.g. strawberries, fish, peanuts). Anaphylactoid reactions: are due to drug dose-related pharmacologically induced mediator release from mast cells and basophils; common causes include aspirin, NSAIDs and radiographic contrast media. Atopy Some individuals with a hereditary atopic diathesis have a propensity to develop local allergic reactions if exposed to appropriate antigens, causing hay fever, allergic asthma or urticaria. This is due to antigen combining with mast-cell-associated IgE in the mucosa of the respiratory tract or the skin. Key points Treatment of anaphylactic shock

Anaphylactic shock is a medical emergency and its treatment is as follows: Stop the offending drug or blood/blood product infusion. Check the patients blood pressure (lie them flat) and check for the presence of stridor/bronchospasm. Administer oxygen (FiO2 4060%). Administer adrenaline (epinephrine) 0.51mg intramuscularly, and repeat after ten minutes if necessary. Give intravenous colloids (0.9% NaCl) for refractory hypotension. Administer hydrocortisone, 100200 mg i.v. Administer chlorpheniramine, 12.5 mg i.v. Give nebulized salbutamol, 2.55 mg for refractory bronchospasm. DRUGS THAT BLOCK THE EFFECTS OF MEDIATORS OF ALLERGY Therapeutic approaches to the management of allergic disease produced by mediators include the following: inhibition of their biosynthesis; blockade of their release; antagonism of their effects. INHIBITION OF BIOSYNTHESIS OF PRO-INFLAMMATORY MEDIATORS INTRANASAL AND TOPICAL GLUCOCORTICOSTEROIDS

These are covered in Chapters 33 and 40. Uses These preparations are used in the therapy of allergic rhinitis and they are very effective in reducing the symptoms of nasal itching, sneezing, rhinorrhoea and nasal obstruction (they are more effective than cromoglicate). Common agents used to treat hay fever include beclometasone, budesonide and fluticasone. Adverse effects The adverse effects of all these preparations are similar, namely sneezing, and dryness and irritation of the nose and throat. Occasionally, epistaxis is a problem. BLOCKADE OF RELEASE OF PRO-INFLAMMATORY MEDIATORS SODIUM CROMOGLICATE AND NEDOCROMIL See also Chapter 33. Uses Sodium cromoglicate and nedocromil are effective in preventing exercise-induced and allergic asthma (but less effective than inhaled glucocorticosteroids for the latter). They are also effective in preventing hay fever and its symptoms. Cromoglicate is used as nasal or eye drops for allergic rhinitis and conjunctivitis. Local adverse effects include occasional nasal irritation or transient stinging in the eye. ANTAGONISM OF THE EFFECTS OF PRO-INFLAMMATORY MEDIATORS ANTIHISTAMINES

There are a large number of antihistamines (H1-receptor antagonists) available, several of which are available without prescription.

Their antihistaminic actions are similar when used in clinically appropriate dosage, but their major differences are in duration of effect, degree of sedation and anti-emetic potential. Uses These include the following: hypersensitivity reactions; urticaria and hay fever; bee and wasp stings; anti-emetic (e.g. cyclizine). Mechanism of action Antihistamines are competitive antagonists of histamine at H1-receptors. Pharmacokinetics Antihistamines are rapidly absorbed from the intestine and

are effective within about 30 minutes. They generally undergo hepatic metabolism. Newer agents, such as fexofenadine, cetirizine and loratadine have half-lives that permit once or twice daily dosing. They do not penetrate the bloodbrain barrier and cause less psychomotor impairment than firstgeneration antihistamines. Adverse effects These include the following: sedation and psychomotor impairment, especially with older (first-generation) agents; photosensitivity rashes; antimuscarinic effects: dry mouth, blurred vision, etc. (first-generation agents); prolongation of the QTc and torsades de pointes. Contraindications Antihistamines should be avoided in porphyria and in the WardRomano syndrome (congenital long-QT syndrome). ADRENALINE (EPINEPHRINE) Adrenaline (epinephrine) is uniquely valuable therapeutically in anaphylactic shock. Its rapid action may be life-saving in general anaphylaxis due to insect venom allergy and reaction to drugs. The usual dose is 0.51.0 mg, repeated after ten minutes if necessary, given intramuscularly or if necessary intravenously. It is effective by virtue of its -agonist activity which reverses vascular dilatation and oedema, and its 2-agonist activity which produces cardiac stimulation and

bronchodilatation. It also reduces the release of pro-inflammatory mediators and cytokines. TREATMENT OF ANAPHYLACTIC SHOCK 1. Stop any drug or blood/blood product that is being administered intravenously. 2. Adrenaline 0.51 mg i.m. or 0.250.5 mg i.v. 3. Intravenous fluid (e.g. 0.9% NaCl, normal saline). 4. Oxygen (high concentration FiO2 2840% ). 5. Hydrocortisone 100200 mg intravenously. 6. Antihistamine intravenously (e.g. chlorpheniramine, 12.5 mg). 7. Consider nebulized salbutamol (2.55 mg) for residual bronchospasm. THERAPY OF ALLERGIC RHINITIS (HAY FEVER) The patient who presents with symptoms of allergic rhinitis should be assessed to ensure that infection is not the primary problem. If infection is the cause, the presence of a foreign body should be excluded and appropriate antibacterial therapy prescribed. If the symptoms are due to allergy, the first step in therapy is allergen avoidance and minimization of exposure (e.g. to ragweed pollen). However, complete avoidance is difficult to achieve. For patients with mild intermittent symptoms, either intranasal antihistamine (e.g. olopatadine or azelastine) or intranasal cromoglicate or a shorter-acting non-sedating systemic antihistamine (e.g. acrivastine or fexofenadine) is effective. Short-term use of a nasal decongestant such as

pseudoephedrine is effective, but if used for longer periods causes rebound vasomotor rhinitis. Ipratropium bromide administered intra-nasally may be added if rhinorrhoea is the predominant symptom. If symptoms are more chronic, the firstline therapy is intranasal glucocorticosteroids because these are effective against all symptoms, and are more effective than antihistamines or cromoglicate. In children, topical cromoglicate given by insufflator or nasal spray is useful. If rhinorrhoea is the main problem, ipratropium bromide may be added with or without a long-acting antihistamine (e.g. cetirizine). If these measures are ineffective, consider low-dose intranasal steroids, or immunotherapy or surgery if there is evidence of sinusitis. 406 CLINICAL IMMUNOPHARMACOLOGY Key points Antihistamines and therapy of allergic disorders Antagonists at H1-receptors; widely available agents, often without prescription (e.g. chlorpheniramine). Used to treat hay fever and urticaria, and also used as therapy for motion sickness. Should not be applied topically for skin irritation, as they may cause dermatitis. Hepatically metabolized (CYP3A long- and shorteracting drugs. Duration of effects often outlasts their presence in the blood. First-generation agents are shorter acting (e.g.

chlorpheniramine), sedating and anticholinergic, better anti-emetics, and have some 5HT and -adrenoceptor antagonist activity. Second-generation agents have few or no sedative or ancilliary properties, and are longer acting (e.g. cetirizine). Second generation agents (e.g. cetirizine, loratadine) are safe (i.e. ventricular tachycardia is not a risk) if co-prescribed with macrolides or azoles.