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

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

3. 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

4. Chemistry and pharmacokinetics Ardabil University of Medical Sciences

5. Metabolism Ardabil University of Medical Sciences

6. 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

7. 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

8. 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

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

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

11. 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

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

13. Peripheral Nerve Endings Pain Itch Ardabil University of Medical Sciences

14. 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

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

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

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

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

20. 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

21. 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

22. 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

23. Table 24-2. 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 10-150 mgO, L, T6-24SINEQUANDoxepin hydrochloride Ethanolamines 4-8 mgO, L3-6RONDEC, d others Carbinoxamine maleate 1.34-2.68 mgO, L12TAVIST, othersClemastine fumarate 25-50 mgO, L, I, T12BENADRYL; others Diphenhydramine HCl 50-100 mgO, L, I4-6DRAMAMINE; others Dimenhydrinate Ethylenediamines 25-50 mgO, L, T4-6POLY- HISTINE-D d Pyrilamine maleate 25-50 mg, 100 mg (sustained release) O4-6PBZTripelennamine HCl Ardabil University of Medical Sciences

24. Piperazines 25-100 mgO, L, I6-24ATARAX; others Hydroxyzine HCl 25-100 mgO, L6-24VISTARILHydroxyzine pamoate 50 mgO4-6MAREZINECyclizine HCl 50 mgI4-6MAREZINECyclizine lactate 12.5-50 mgO12-24ANTIVERT; others Meclizine HCl Phenothiazines 12.5-50 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

25. Piperidines One dropT6-12LIVOSTINLevocabastine hydrochloride 10 mgO, L24CLARITINLoratadine 5 mgO24CLARINEX, AERIUS Desloratadine 10-20 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

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

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

28. Chemistry & pharmacokinetics Ardabil University of Medical Sciences

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

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

34. Table 11-4. 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

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

36. 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