Histamine and Serotonin By S.Bohlooli, PhD Ardabil University of Medical Sciences

Basic pharmacology of histamine Chemistry Pharmacokinetics Pharmacodynamics Ardabil University of Medical Sciences

Distribution Histamine is widely, if unevenly, distributed throughout the animal kingdom and is present in many venoms, bacteria, and plants. Ardabil University of Medical Sciences

Chemistry and pharmacokinetics Ardabil University of Medical Sciences

Metabolism Ardabil University of Medical Sciences

Storage and release Immunologic release histamine plays a central role in immediate hypersensitivity and allergic responses The release of histamine only partially explains the biological effects that ensue from immediate hypersensitivity reactions Chemical and mechanical release Tubocurarine, succinylcholine, morphine Ardabil University of Medical Sciences

Pharmacodynamics Mechanism of action Tissue and organ system effect Nervous system Cardiovascular system Bronchial smooth muscle Gastrointestinal tract smooth muscle Other smooth muscle organs Secretary tissue Metabolic effects The triple response Other effects possibly mediated by histamine Ardabil University of Medical Sciences

Receptor Subtype DistributionPostreceptor Mechanism Partially Selective Agonists Partially Selective Antagonists H1 H1 Smooth muscle, endothelium, brain G q, IP 3, DAG HistaprodifenMepyramine, triprolidine, cetirizine H2 H2 Gastric mucosa, cardiac muscle, mast cells, brain G s, cAMP AmthamineCimetidine, 1 ran itidine, 1 tiotidine H3 H3 Presynaptic: brain, myenteric plexus, other neurons G i, cAMP R--Methylhistamine, imetit, immepip Thioperamide, iodophenpropit, clobenpropit, 1 tiprolisant 1 H4 H4 Eosinophils, neutrophils, CD4 T cells G i, cAMP Clobenpropit, imetit, clozapine Thioperamide

Nervous system regulation of drinking body temperature secretion of antidiuretic hormone control of blood pressure perception of pain wakefulness Ardabil University of Medical Sciences

Cardiovascular System Vasodilation Increased "Capillary" Permeability Triple Response of Lewis Heart Histamine Shock Ardabil University of Medical Sciences

Extravascular Smooth Muscle Contraction is due to activation of H1 receptors relaxation (for the most part) is due to activation of H2 receptors Ardabil University of Medical Sciences

Exocrine Glands regulator of gastric acid secretion Ardabil University of Medical Sciences

Peripheral Nerve Endings Pain Itch Ardabil University of Medical Sciences

Clinical pharmacology of histamine Clinical use a diagnostic agent to assess nonspecific bronchial hyperreactivity in asthmatics as a positive control injection during allergy skin testing Toxicity and contraindications Flushing, hypotension,tachycardia, headache wheals, brochoconstriction, gastrointestinal upset Ardabil University of Medical Sciences

Histamine antagonists H 1 receptor antagonists H 2 receptor antagonists Ardabil University of Medical Sciences

Basic Pharmacology of H 1 Receptor Antagonists Chemistry Pharmacokinetics Pharmacodynamics Ardabil University of Medical Sciences

Chemistry Structure-activity Relationship reversible competitive inhibitors contain a substituted ethylamine moiety Ardabil University of Medical Sciences

Pharmacokinetics Absorption, distribution Metabolism: Astemizole and Terfenadine Ardabil University of Medical Sciences

Pharmacological Properties Smooth Muscle Capillary Permeability Flare and Itch Immediate Hypersensitivity Reactions Central Nervous System Can both stimulate and depress the CNS Ardabil University of Medical Sciences

Pharmacodynamics Histamine receptor blockade Other actions Sedation Antinausea and antiemetic actions Antiparkinsonism effects Antichlinoceptor effect: Promethazine Adrenoceptor blocking action Serotonin blocking action Local anesthesia: Promethazine Ardabil University of Medical Sciences

Clinical pharmacology of H 1 receptor antagonists Clinical use Allergic reaction Motion sickness and vestibular disturbance Nausea and vomiting of pregnancy? Toxicity Sedation, antimuscarninc action, Drug allergy Drug interaction Teratogenic effects Ardabil University of Medical Sciences

Table Preparations and Dosage of Representative H 1 -Receptor Antagonists* SINGLE DOSE (ADULT) PREPARATI ONS a DURATI ON OF ACTION, HOURS TRADE NAMECLASS AND NONPROPRIETARY NAME First-Generation Agents Tricyclic Dibenzoxepins mgO, L, T6-24SINEQUANDoxepin hydrochloride Ethanolamines 4-8 mgO, L3-6RONDEC, d others Carbinoxamine maleate mgO, L12TAVIST, othersClemastine fumarate mgO, L, I, T12BENADRYL; others Diphenhydramine HCl mgO, L, I4-6DRAMAMINE; others Dimenhydrinate Ethylenediamines mgO, L, T4-6POLY- HISTINE-D d Pyrilamine maleate mg, 100 mg (sustained release) O4-6PBZTripelennamine HCl Ardabil University of Medical Sciences

Piperazines mgO, L, I6-24ATARAX; others Hydroxyzine HCl mgO, L6-24VISTARILHydroxyzine pamoate 50 mgO4-6MAREZINECyclizine HCl 50 mgI4-6MAREZINECyclizine lactate mgO12-24ANTIVERT; others Meclizine HCl Phenothiazines mgO, L, I, S4-6PHENERGAN; others Promethazine HCl Piperidines 4 mgO, L4-6PERIACTINCyproheptadine HCl c 25 mgO4-6NOLAHISTPhenindamine tartrate Second-Generation Agents Alkylamines 8 mgO6-8SEMPREX-D d Acrivastine b Piperazines 5-10 mgO12-24ZYRTECCetirizine hydrochloride b Phthalazinones 2 sprays per nostril T12-24ASTELINAzelastine hydrochloride b Ardabil University of Medical Sciences

Piperidines One dropT6-12LIVOSTINLevocabastine hydrochloride 10 mgO, L24CLARITINLoratadine 5 mgO24CLARINEX, AERIUS Desloratadine mgO24EBASTELEbastine 10 mgO24MIZOLLENMizolastine 60 mgO12-24ALLEGRA, TELFAST Fexofenadine HCl, hydrochloride. * For a discussion of phenothiazines, see Chapter 18. a Preparations are designated as follows: O, oral solids; L, oral liquids; I, Injection; S, suppository; T, topical. Many H 1 -receptor antagonists also are available in preparations that contain multiple drugs. b Has mild sedating effects. c Also has antiserotonin properties. d Trade name drug also contains other medications. Ardabil University of Medical Sciences

Application:Common Cold? Despite persistent popular belief, H1 antagonists are without value in combating the common cold. Ardabil University of Medical Sciences

Basic pharmacology of serotonin Chemistry Pharmacokinetics Pharmacodynamics Ardabil University of Medical Sciences

Chemistry & pharmacokinetics Ardabil University of Medical Sciences

Pharmacodynamics Mechanism of action Tissue and organ system effect Nervous system Airways Cardiovascular system Gastrointestinal tract Skeletal muscle Ardabil University of Medical Sciences

Clinical pharmacology of Serotonin Serotonin agonists Serotonin antagonists Ardabil University of Medical Sciences

Table Serotonergic Drugs: Primary Actions and Clinical Uses CLINICAL DISORDERDRUG EXAMPLES ACTIONRECEPTOR Anxiety, depressionBuspirone, ipsaperone Partial agonist 5-HT 1A MigraineSumatriptanAgonist5-HT 1D Migraine, depression, schizophrenia Methysergide, trazodone, risperidone, ketanserin Antagonist5-HT 2A/2C Chemotherapy-induced emesisOndansetronAntagonist5-HT 3 Gastrointestinal disordersCisaprideAgonist5-HT 4 Depression, obsessive-compulsive disorder, panic disorder, social phobia, posttraumatic stress disorder Fluoxetine, sertraline Inhibitor5-HT transporter Ardabil University of Medical Sciences

Serotonin antagonists Phenoxybenzamine (5HT 2 ) Cyproheptadine (5HT 2 ) Ketanserin (5HT 1C ) Odansetrone (5HT 3 ) Ardabil University of Medical Sciences

Appetite control through serotonin? Sertonin related to sleep, emotion, sex, and appetite Could reduce food intake Fenfluramine, dexfenfluramine Cause serotonin release and inhibition of food uptake Toxicity: fatal and nonfatal pulmonary hypertension Valvular lesions Ardabil University of Medical Sciences