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Histamine and Antihistaminics Chapter 11 Histamine and Antihistaminics Chapter 11 HISTAMINE Histamine, meaning ‘tissue amine’ (histos—tissue) is almost ubiquitously present in animal tissues and in certain plants, e.g. stinging nettle. Its pharmacology was studied in detail by Dale in the beginning of the 20th century when close parallelism was noted between its actions and the manifestations of certain allergic reactions. It was implicated as a mediator of hypersensitivity Fig. 11.1: Synthesis and degradation of histamine phenomena and tissue injury reactions. It is now MAO-Monoamine oxidase known to play important physiological roles. Histamine is present mostly within storage by Asch and Schild (1966) into H1 and H2 : those granules of mast cells. Tissues rich in histamine blocked by then available antihistamines were are skin, gastric and intestinal mucosa, lungs, liver labelled H1. Sir James Black (1972) developed and placenta. Nonmast cell histamine occurs in the first H2 blocker burimamide and confirmed brain, epidermis, gastric mucosa and growing this classification. A third H3 receptor, which regions. Turnover of mast cell histamine is slow, serves primarily as an autoreceptor controlling while that of nonmast cell histamine is fast. histamine release from neurones in brain was Histamine is also present in blood, most body identified in 1983. Though some selective H3 secretions, venoms and pathological fluids. agonists and antagonists have been produced, none has found any clinical application. Features of Synthesis, storage and destruction these 3 types of histaminergic receptor are Histamine is β imidazolylethylamine. It is compared in Table 11.1. synthesized locally from the amino acid histidine Molecular cloning has revealed yet another (H4) receptor and degraded rapidly by oxidation and methylation in 2001. It has considerable homology with H3 receptor and (Fig. 11.1). In mast cells, histamine (positively binds many H3 ligands. 4-Methyl histamine, earlier considered charged) is held by an acidic protein and heparin to be a specific H2 agonist, has shown greater affinity and (negatively charged) within intracellular granules. selectivity for the H4 receptor, and is now labelled a H4 agonist. However, the H4 receptor is pharmacologically less When the granules are extruded by exocytosis, distinct. Eosinophils, mast cells and basophils are the primary + Na ions in e.c.f. exchange with histamine to cells expressing H4 receptors. Activation of H4 receptors release it free (Fig. 11.2). Increase in intracellular enhances chemotaxis of these cells. The H4 receptor may cAMP (caused by β adrenergic agonists and be playing a role in allergic inflammation: H4 antagonists are being explored as potential drugs for allergic inflammatory methylxanthines) inhibits histamine release. conditions like rhinitis and asthma. Intestines and brain are Histamine is inactive orally because liver degrades the other sites where H4 receptors have been located. all histamine that is absorbed from the intestines. PHARMACOLOGICAL ACTIONS Histamine receptors Four types of histami- nergic receptors have now been clearly delineated 1. Blood vessels Histamine causes marked and cloned. Analogous to adrenergic α and β dilatation of smaller blood vessels, including arte- receptors, histaminergic receptors were classified rioles, capillaries and venules. On s.c. injection 160 SECTION 3 TABLE 11.1 Distinctive features of three types of histaminergic receptors H1 H2 H3 1. Selective agonists 2-Methyl histamine (8:1) Dimaprit (1:2000) (R) α-Methyl histamine (relative selectivity H1: H2) 2-Pyridylethylamine(30:1) Impromidine (1:10,000) (H1: H3 1:3000) 2-Thiazolyl ethylamine (90: 1) lmetit 2. Selective antagonists Mepyramine (6000:1) Cimetidine (1: 500) Thioperamide (H1: H3 1: 23000) (relative selectivity H1: H2) Chlorpheniramine (15000:1) Ranitidine ( l : >500) Impromidine (H2 agonist) Tiprolisant DRUGS ANDRELATED AUTACOIDS 3. Receptor type Gq-protein coupled Gs-protein coupled Gi/Go-protein coupled → 2+ 4. Effector pathway PIP2 hydrolysis IP3/DAG : Adenylyl cyclase activation — a) Restricting Ca influx Release of Ca2+ from intracellular stores; cAMP ↑—phosphorylation of b) K+ channel activation Protein kinase-C activation specific proteins c) cAMP ↓ NO release→cGMP 5. Distribution in body: a) Smooth muscle (intestine, airway, a) Gastric glands—acid secretion a) Brain (presynaptically)—inhibition actions mediated uterus)—contraction b) Blood vessels (smooth of histamine release—sedation b) Blood vessels muscle)—dilatation b) Lung, spleen, skin, gastric mucosa — i) Endothelium: Release of NO and, c) Heart decrease histamine release PGI2—vasodilatation. Atria: +ive chronotropy c) Ileum—inhibition of ACh widening of gap junctions— Ventricles: +ive inotropy release from myenteric increased capillary permeability d) Uterus (rat)—relaxation plexus neurones ii) Smooth muscle of larger e) Brain—transmitter d) Certain blood vessels—inhibit NA vessels—vasoconstriction. release—vasodilatation c) Afferent nerve endings—stimulation d) Ganglionic cell—stimulation. e) Adrenal medulla—release of CAs. f) Brain—transmitter. PIP2—Phosphatidyl inositol bisphosphate; IP3—Inositol trisphosphate; DAG—Diacylglycerols; EDRF— Endothelium dependent relaxing factor; NO—Nitric oxide; PGI2—Prostacyclin; CAs—Catecholamines; cAMP —Cyclic 3', 5' adenosine monophosphate; ACh—Acetylcholine HISTAMINE AND ANTIHISTAMINICS 161 Like many other autacoids and ACh, vasodi- latation caused by histamine is partly (H1 compo- nent) indirect, mediated through ‘endothelium dependent relaxing factor’ (EDRF), i.e. NO; the receptor being located on the endothelial cells. H2 receptors mediating vasodilatation are located directly on the vascular smooth muscle. Larger arteries and veins are constricted by histamine: mediated by H1 receptor on vascular smooth muscle. Histamine also causes increased capillary permeability due to separation of endothelial cells → exudation of plasma. This is primarily a H1 response. Injected intradermally, it elicits the triple response consisting of: Red spot: due to intense capillary dilatation. CHAPTER 11 Wheal: due to exudation of fluid from capillaries and venules. Flare: i.e. redness in the surrounding area Fig. 11.2: Mechanism of antigen-antibody reaction due to arteriolar dilatation induced release of histamine from mast cell. mediated by axon reflex. In sensitized atopic individual, specific reaginic (IgE) antibody is produced and gets bound to Fc epsilon 2. Heart Direct effects of histamine on in situ receptor I (FcεRI) on the surface of mast cells. On heart are not prominent, but the isolated heart, challenge, the antigen bridges IgE molecules resulting especially of guinea pig, is stimulated—rate as in transmembrane activation of a tyrosine-protein kinase (t-Pr-K) which phosphorylates and activates phospho- well as force of contraction is increased. These γ lipaseC . Phosphatidyl inositol bisphosphate (PIP2) is are primarily H2 responses but a H1 mediated hydrolysed and inositol trisphosphate (IP3) is generated negative dromotropic (slowing of A-V conduction) 2+ 2+ which triggers intracellular release of Ca . The Ca ions effect has also been demonstrated. induce fusion of granule membrane with plasma mem- brane of the mast cell resulting in exocytotic release of 3. Visceral smooth muscle Histamine granule contents. In the granule, positively charged histamine (Hist+) is held complexed with negatively causes bronchoconstriction; guinea pigs and charged protein (Prot–) and heparin (Hep–) molecules. patients of asthma are highly sensitive. Large doses Cationic exchange with extracellular Na+ (and Ca2+) sets cause abdominal cramps and colic by increasing histamine free to act on the target cells. intestinal contractions. Guineapig uterus is contracted while that or rat is relaxed; human flushing, especially in the blush area, heat, uterus is not much affected as are most other increased heart rate and cardiac output, with little visceral smooth muscles. or no fall in BP are produced. Rapid i.v. injection Smooth muscle contraction is a H response. causes fall in BP which has an early short lasting 1 In few instances H mediated relaxation is also H and a slow but more persistent H component. 2 1 2 seen, e.g. bronchial muscle of sheep, human With low doses only the H1 component is manifest bronchi after H1 blockade. since H1 receptors have higher affinity. Fall in BP due to large doses is completely blocked only 4. Glands Histamine causes marked increase by a combination of H1 and H2 antagonists. in gastric secretion—primarily of acid but also Dilatation of cranial vessels causes pulsatile of pepsin (see Ch. 46). This is a direct action headache. exerted on parietal cells through H2 receptors and 162 AUTACOIDS AND RELATED DRUGS is mediated by increased cAMP generation, which parietal cell membrane, but through their own in turn activates the membrane proton pump (H+ receptors. K+ ATPase). 2. Allergic phenomena Mediation of hyper- Histamine can increase other secretions also, sensitivity reactions was the first role ascribed but the effect is hardly discernable. to histamine. It is an important, but only one of 5. Sensory nerve endings Itching occurs the mediators of such phenomena. Released from when histamine is injected i.v. or intracutaneously. mast cells following AG : AB reaction on their Higher concentrations injected more deeply cause surface (involving IgE type of reaginic antibodies; pain. These are reflections of the capacity of Fig. 11.2) in immediate type of hypersensitivity histamine to stimulate
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