Pharmacological effects of Histamine PDF

Part 1 1: Auttacoids Inflamm mation is the comp plex biolo gical resp ponse of vascular v tisssues to harmful oduces locally-acting stimuli.. Injur...

Part 1 1: Auttacoids Inflamm mation is the comp plex biolo gical resp ponse of vascular v tisssues to harmful oduces locally-acting stimuli.. Injury pro g substancces that inittiate inflam mmatory re esponse and acttivate the repair r proc cess. Thesse substances are terrmed 'auta acoids'. Examp ples of auttacoids:  Amino acid derivatives d s: e.g. hista amine and d 5-HT (serrotonin).  Vas soactive peptides: p e.g. e angiote ensin, kininns and enddothelins.  erivatives: e.g. prost aglandins, thrombox Fattty acid de xanes, leukkotrienes, etc. e  e family of cytokines:: e.g. interle The eukins, inte erferones, TNF, T growthh factors, etc. e █ Histtamine  Hisstamine is formed frrom the a amino acid d histidine by the aaction of histidine h dec carboxylase and storred mainly in mast ce ells. Non-m mast cell hhistamine is found in sseveral tisssues includ ding the brrain.  No clinically useful dru ugs affect the synthe esis or meetabolism of histamiine, but cerrtain drugs can cause e release o of histamin ne from maast cells ass a side efffect. Histam se: can oc mine releas ccur throug gh 2 proce esses:  Ca22+ dependent mech hanism: byy fixation of o IgE to th he surfacee of mast cell c with 2+ sub bsequent activation of the complem ment, this causes Ca influ ux and deg granulation n of mast cells. c Manyy drugs can induce th his type e. g. penicillin.  Ca22+ indepen ndent mec chanism: – Displacem ment of hisstamine fro om storag ge granules s by drug gs: e.g. mo orphine, tubocurarrine, vanco omycin, an nd amine antibiotics. – Mast cell damage: by b venomss, or mechanical trauma. 111  Pharmacological effects of histamine Histamine acts on at least 4 types of receptors: R Postreceptor Site Effect mechanism H1 Gq CNS Functions related to appetite and satiety ↑ IP3 & DAG Nonvascular Spasm (→ bronchoconstriction, GIT spasm). smooth ms Blood vessels – VD of microcirculation (arterioles and precapillary sphincters) → ↑ capillary permeability (edema) and fall of BP. – This VD is due to release of NO from vascular endothelium. Exocrine glds ↑ exocrine secretions (bronchial, lacrimal, etc) Sensory nerves Pain and itching H2 Gs Gastric parietal ↑ HCl secretion. ↑ cAMP cells Heart ↑ cardiac contractility and HR. Mast cells ↓ histamine release (-ve feed back effect). H3 Gi CNS and Wakefulness and modulation of other ↓ cAMP presynaptic neurotransmitters release. nerve endings H4 Gi Inflammatory Regulation of the inflammatory response ↓ cAMP cells Clinical uses of histamine  Histamine itself has no clinical applications.  Some selective agonists are available for diagnostic purposes only e.g. test for gastric secretion. Histamine antagonists Physiological antagonists (adrenaline): adrenaline reverses all the effects of histamine by action on different receptors (see ANS). Histamine receptor antagonists: – H1-blockers: e.g. diphenhydramine, loratidine, etc. (see below) – H2-blockers: e.g. cimetidine, ranitidine, famotidine, etc. (see GIT) – H3 and H4 -blockers: are not yet available for clinical use. Histamine release inhibitors (mast cell stabilizers): ketotifen and cromoglycate They inhibit Ca2+ influx into mast cells and prevent mast cell degranulation. 112  Desensitization therapy (immunotherapy): Immunotherapy is a process in which an allergic patient can become desensitized to antigens that trigger allergic responses. Small doses of the allergic substance are injected weekly. Each week the dose is increased. Gradually a protective antibody (IgG) is formed to block the allergic reaction. Many patients notice an improvement within 6 months. █ H1-receptor antagonists 1st generation H1 blockers 2nd generation H1 blockers Examples Diphenhydramine Loratidine Dimenhydrinate Azelastine Clemastine Cetirizine Antazoline Fexofenadine Cyclizine - Meclizine Chlorpheniramine Ketotifen is a 2nd gen H1 blocker Promethazine and mast cell stabilizer (see Cyproheptadine respiratory pharmacology). CNS They can cross BBB (more Cannot cross BBB (less lipophilic) effects lipophilic) and exert significant and have little or no CNS actions CNS actions Potency Less potent H1 blockers More potent H1 blockers Effects – Relief of itching, pain and allergic response. related to – ↓ capillary permeability and inflammatory edema induced by H1 histamine blocking – ↓ bronchoconstriction, bronchial secretions, lacrimation, etc. Other Sedation: but excitation or even effects convulsions may occur in some cases (especially in children or with high doses). Atropine-like actions: most of the first generation drugs can block peripheral muscarinic Not present receptors leading to urine retention and blurred vision. Antiemetic action: useful in preventing motion sickness. α-receptor blocking action: 113  leading to orthostatic (postural) hypotension in susceptible individuals. 5-HT receptor blocking action (especially cyproheptadine): so it is useful drug for treating carcinoid syndrome. Duration of 3-8 h 3-24 h action Therapeutic Allergic conditions: uses – The use of H1-blockers is effective in allergic conditions in which histamine is the primary mediator (e.g. allergic rhinitis and urticaria). – N.B. In bronchial asthma, which involves several mediators, the use of H1-blockers is generally ineffective. Motion sickness and vestibular disturbances: – The first-generation H1-blockers (especially diphenhydramine and promethazine) are effective in preventing motion sickness, but their efficacy in Ménièrs's disease is not established. – They act by blocking H1 and muscarinic receptors in the vestibulocerebellar pathway. – N.B. Scopolamine remains the most effective treatment for motion sickness. Carcinoid syndrome: – Carcinoid syndrome is caused by a serotonin-secreting neoplasm of the enterochromaffin cells of the GIT. – When the tumor is not operable, cyproheptadine and other 5-HT blockers can be used to block 5-HT receptors. Adverse – Sedation with impaired The second-generation drugs effects concentration, but rarely are metabolized by the hepatic excitation and convulsions CYP450 enzymes. Some of the may occur in children after early drugs in this group toxic doses. prolonged the QT interval and caused serious arrhythmia – Anticholinergic (atropine- (torsade de pointes) when given like) actions: this may cause with other drugs that inhibit urine retention, dry mouth and CYP450 system (e.g. blurred vision. ketoconazole), and in patients 114