Page 1 of 10NNHCH2CHCOHONH2Histidine decarboxylaseAromatic amino acid decarboxylaseNNHCH2CH2NH2 ! High in: lung, mucous membrane, G.I. tract, skin! Histamine is stored in some organs in mast cells, in granules together with heparin andproteases.! 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.Histidine Histamine (2-[4-imidazolyl] ethylamine)HISTAMINE CONTENT OF HUMAN TISSUESANTIHISTAMINESAsrar B. Malik, Ph.D.312-996-7635 [email protected]: HISTIDINE IS CONVERTED INTO HISTAMINEPage 2 of 10! By exocytosis without cell destruction! By non-exocytotic pathways, lysis of cell membranesRELEASERS ! 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 expandersRELEASE INHIBITORS Mechanism: $-receptor activation and cAMP accumulation! isoproterenol! epinephrine! theophyllineRELEASE OF HISTAMINEPage 3 of 10Consequences of mediator release. Antigen-induced IgE-dependent secretion of mediators leadsto classic allergic reactions or immediate hypersensitivity. Late phase reactions (LPR) are a laterconsequence initially observed at 2-8 h. and are characterized pathologically bypolymorphonuclear leukocyte infiltrations. A second phase of cellular infiltration of mononuclearcells is apparent after 24-72 h.CONSEQUENCES OF MEDIATOR RELEASEMast CellMediators__________________________________________ “Classic” Allergic Reaction Late Phase Reactions(Immediate Hypersensitivity Hours (2-8) Minutes Infiltration with Eosinophils and Neutrophils Fibrin DepositionSmooth Muscle Contraction Days (1-2)Pruritus Vascular Leakage Flush Hypotension Infiltration with MononuclearsMucus Secretion (Macrophages, Fibroblasts) Tissue DestructionPage 4 of 10AGONIST RECEPTOR LOCATION EFFECT2-methylhistamine H1CNSBlood vessels, endothelial cellsBronchiIleumHeartAdrenalsNose, bronchi Cyclic GMP IncreasesHeadache; neurotransmitter?Wakefulness, arousalArterial vasodilation (NO, EDRF)Postcapillary venules constrictSmooth muscle contractionSmooth muscle contractionIncreased coronary blood flowRelease of catecholaminesIncreased exocrine secretion4-methylhistamine H2HeartMast cellsStomachBlood vessels, smooth musclescAMP IncreasesChronotrophy, inotrophyNegative feedbackAcid production!Slow drop in pressure" -methylhistamine H3*BrainAirways, neuronsGI tractNegative feedback on histaminerelease (sedative action?)Inhibitory action on some forms ofbronchoconstrictionAcetylcholine release inhibited*H3 results based on laboratory animal experimentsHISTAMINE RECEPTORSPage 5 of 10PATHWAYS OF HISTAMINE METABOLISM IN HUMANSPage 6 of 10! ACTIONS:CardiovascularDrop in blood pressure TachycardiaFlushHeadachePermeability increaseRespirationBronchoconstrictionProstaglandin releaseGlandular tissueAdrenals - catecholamine release(pheochromocytoma)Stomach - acid secretionMucosa, nasal secretionSkinLewis triple reflex (flush, flare, wheal)Itching! ANTIHISTAMINES:H1 Blockers: Substituted Ethylamines X-C-C-NEthanolamine derivativesdiphenhydramine (Benadryl; X = 0)dimenhydrinate (Dramamine;X = 0)Alkylamine derivativeschlorpheniramine (Chlortrimeton)Ethyleneaminetripelenamine (PBZ)Piperazinecyclizine (Morezine)Phenothiazinepromethazine (Phenergan)!! INVOLVEMENT IN PATHOLOGICAL PROCESSES:Allergic disordersInflammationMigraineGastric and duodenal ulcerMyelocytic leukemiaPage 7 of 10CHOCH2CH2NCH3CH3CHCH2CH2NCH3CH3NClNSCH2CHCH3NCH3CH3CHN NCH3CN CH2OHCH2CH2CHOHCCH3CH3CH3DiphenhydramineChlorpheniraminePromethazineCyclizineTerfenadine! 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 All H1-antihistamines are competitive antagonists; that is, they cause a parallel shift to the right of the log dose-responsecurve for a given histamine effect with no change in the maximal effect. None of the antihistamines in therapeutic dosesaffect metabolism of histamine or block histamine release.THERAPEUTIC APPLICATIONS OF H1 BLOCKING ANTIHISTAMINESPage 8 of 10! 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 pregnancyTerfenadine (Seldane)! Low lipid solubility, does not cross blood-brain barrier, no atropine-like effect, binds to plasmaproteins, 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 ABSORPTION, SIDE EFFECTSPage 9 of 10! 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 mucosaTumor of the pancreas: Zollinger-Ellison Syndrome, gastrin production! Commercial preparation: pentagastrinH2-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.!
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