ANTIHISTAMINES Asrar B Malik Ph D 312 996 7635 abmalik uic edu HISTAMINE CONTENT OF HUMAN TISSUES High in lung mucous membrane G I tract skin Histamine is stored in some organs in mast cells in granules together with heparin and proteases Histamine is stored at sites other than mast cells in epidermis gastric mucosa neurons regenerating tissues and in blood in basophils Histamine is rapidly synthesized but not taken up by cells BIOSYNTHESIS HISTIDINE IS CONVERTED INTO HISTAMINE Histidine Histidine decarboxylase O H2C H C OH C HN NH2 N Aromatic amino acid decarboxylase Histamine 2 4 imidazolyl ethylamine H2C HN N C H2 NH2 Page 1 of 10 RELEASE OF HISTAMINE By exocytosis without cell destruction By non exocytotic pathways lysis of cell membranes RELEASERS IgE antibodies causing immediate hypersensitivity Peptides which contain basic amino acids arginine and or lysine Complement derivatives anaphylatoxins e g C3a C4a C5a Substance P Bee and wasp venom constituents e g melittin polistes kinin etc CHEMICALS THERAPEUTIC AGENTS 48 80 morphine codeine d tubocurarine dextrans blood substitutes plasma expanders RELEASE INHIBITORS Mechanism receptor activation and cAMP accumulation isoproterenol epinephrine theophylline Page 2 of 10 Consequences of mediator release Antigen induced IgE dependent secretion of mediators leads to classic allergic reactions or immediate hypersensitivity Late phase reactions LPR are a later consequence initially observed at 2 8 h and are characterized pathologically by polymorphonuclear leukocyte infiltrations A second phase of cellular infiltration of mononuclear cells is apparent after 24 72 h CONSEQUENCES OF MEDIATOR RELEASE Mast Cell Mediators Classic Allergic Reaction Immediate Hypersensitivity Late Phase Reactions Hours 2 8 Minutes Infiltration with Eosinophils and Neutrophils Fibrin Deposition Smooth Muscle Contraction Pruritus Vascular Leakage Flush Hypotension Mucus Secretion Days 1 2 Infiltration with Mononuclears Macrophages Fibroblasts Tissue Destruction Page 3 of 10 HISTAMINE RECEPTORS AGONIST 2 methylhistamine RECEPTOR H1 LOCATION CNS Blood vessels endothelial cells EFFECT Cyclic GMP Increases Headache neurotransmitter Wakefulness arousal Bronchi Arterial vasodilation NO EDRF Postcapillary venules constrict Ileum Smooth muscle contraction Heart Smooth muscle contraction Adrenals Increased coronary blood flow Nose bronchi Release of catecholamines Increased exocrine secretion 4 methylhistamine methylhistamine H2 H3 cAMP Increases Heart Chronotrophy inotrophy Mast cells Negative feedback Stomach Acid production Blood vessels smooth muscles Slow drop in pressure Brain Negative feedback on histamine release sedative action Airways neurons Inhibitory action on some forms of bronchoconstriction GI tract Acetylcholine release inhibited H3 results based on laboratory animal experiments Page 4 of 10 PATHWAYS OF HISTAMINE METABOLISM IN HUMANS Page 5 of 10 ACTIONS ANTIHISTAMINES Cardiovascular H1 Blockers Substituted Ethylamines Drop in blood pressure Tachycardia Flush Headache Permeability increase X C C N Ethanolamine derivatives diphenhydramine Benadryl X 0 dimenhydrinate Dramamine X 0 Respiration Bronchoconstriction Prostaglandin release Alkylamine derivatives chlorpheniramine Chlortrimeton Glandular tissue Ethyleneamine tripelenamine PBZ Adrenals catecholamine release pheochromocytoma Stomach acid secretion Mucosa nasal secretion Piperazine cyclizine Morezine Phenothiazine promethazine Phenergan Skin Lewis triple reflex flush flare wheal Itching INVOLVEMENT IN PATHOLOGICAL PROCESSES Allergic disorders Inflammation Migraine Gastric and duodenal ulcer Myelocytic leukemia Page 6 of 10 THERAPEUTIC APPLICATIONS OF H1 BLOCKING ANTIHISTAMINES Diseases of allergy Pollinosis Urticaria Allergic rhinitis Transfusion reaction Serum sickness Hay fever Itching Atopic contact dermatitis Insect bites Ivy poisoning Motion sickness Conjunctivitis Not indicated Asthma common cold local administration on skin Cl HC O H2 C H3C H2 N H C CH3 C C H2 CH3 C H2 N N CH3 Diphenhydramine Chlorpheniramine S N HC N H3C H CH2 C H3C N N CH3 CH3 Cyclizine Promethazine HO C HO H CH N C2 C C H2 H2 H3C CH3 C CH3 Terfenadine All H1 antihistamines are competitive antagonists that is they cause a parallel shift to the right of the log dose response curve for a given histamine effect with no change in the maximal effect None of the antihistamines in therapeutic doses affect metabolism of histamine or block histamine release Page 7 of 10 ABSORPTION SIDE EFFECTS Well absorbed after oral administration Therapeutic effects 4 12 hr Metabolized in liver hydroxylation little excreted unchanged Lessened effect after chronic administration Induction of microsomal enzymes in liver increased metabolism Drowsiness additive with alcohol accidents No driving Can stimulate and depress CNS Drying salivary bronchial secretion anticholinergic antimuscarinic Local anesthesia Loss of appetite nausea vomiting Topical application use in allergic dermatitis is questionable Poisoning in children CNS effects are similar to atropine poisoning Barbiturates contraindicated Confusion delirium depression of respiration Cyclizine teratogenic in rats contraindicated in pregnancy Terfenadine Seldane Low lipid solubility does not cross blood brain barrier no atropine like effect binds to plasma proteins long half life Ineffective in motion sickness Serious side effects in case of hepatic dysfunction with concomitant administration of some drugs erythromycin or overdose Effects Ventricular arrhythmias EKG QT prolongation Page 8 of 10 H2 BLOCKERS Gastric acid secretion by parietal oxyntic cell is not blocked by antihistamines acting on H1 receptors Gastric acid secretion blocked by antihistamines acting on H2 receptors is stimulated by Histamine Acetylcholine vagus Gastrin 17 amino acids peptide hormone of antral mucosa Tumor of the pancreas Zollinger Ellison Syndrome gastrin production Commercial preparation pentagastrin H2 receptor agonist used to test gastric acid secretion James Black discovered H2 blocking antihistamines Chemically retained imidazole ring long side chain first later changes in ring structure Inhibit effect on stomach secretion in addition to some effects on blood pressure heart First drugs serious side effects myelosuppression Application gastric duodenal ulcer CIMETIDINE TAGAMET Application Inhibition of secretion caused by histamine gastrin or acetylcholine Used to treat ulcer duodenal gastric stress and in
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