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Antihistamines

Antihistamines. Topic 9 : . Dr. Korawuth Punareewattana Dept. of Vet Phar & Tox Khon Kaen University. Topics. Histamine Sources of histamines Histamine receptors Histamine effects Antihistamines H 1 receptor antagonists (H 1 blockers) First generation Second generation

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Antihistamines

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  1. Antihistamines Topic 9 : Dr. Korawuth Punareewattana Dept. of Vet Phar & Tox Khon Kaen University

  2. Topics • Histamine • Sources of histamines • Histamine receptors • Histamine effects • Antihistamines • H1 receptor antagonists (H1 blockers) • First generation • Second generation • Third generation • H2 receptor antagonists (H2 blockers)

  3. Histamine Histamine is an organic nitrogen compound involved in local immune responses as well as regulating physiological function in the gut and acting as a neurotransmitter Sources of histamine in nature • plants • venoms and stings • synthesized by bacteria and certain fungi • found in human or animal tissues

  4. Histamine in Human and Animals • unevenly distributed throughout the body • found in various cell types • mast cells • basophils - circulating counterpart of the mast cell • neurons – eg. CNS • enterochromaffin-like cells (ELC’s) in the stomach • tissues • skin • lung • gastrointestinal tract

  5. Histamine Release Mechanisms of histamine release • Immunologic • usually a component of an immediate hypersensitivity reaction (IgE) • Pharmacologic (direct release) Some agents can directly stimulate histamine release • Morphine • Tubocurarine • Succinylcholine • Radiocontrast media • Vancomycin (red-man syndrome) • Physical stimuli • scratching the skin

  6. Immunological mechanism of Histamine Release

  7. Histamine Receptors • Types of histamine receptors • H1 receptor • H2 receptor • H3 receptor • H4 receptor • Histamine can interact to all of these receptors • Also, somedrugs can interact selectively to these receptors

  8. Histamine Effects • H1: GI smooth muscle contraction Bronchial smooth muscle contraction • H2: Cardiac stimulation, Gastric secretion • H1 & H2: Dilation of arterioles and veins • H3: • Mainly in the CNS • Preterminal and autoreceptors • Not considered further • H4: • Differentiation of myeloblasts

  9. Intradermal Injection of Histamine 1. Rednessat immediate injection site: direct vasodilation 2. Larger red area- called a flare: due to local axon reflex 3. Wheal: due to increased vessel permeability 4. Pain, itching: effects on nerves

  10. Other Effects of Histamine • extravascular smooth muscle • contraction of bronchial smooth muscle: • H1 mediated • contraction of GI smooth muscle: • H1 mediated • increased gastric secretion: • H2 mediated

  11. Summary of Histamine Effects • Bronchial contraction H1 • GI contraction H1 • Heart H2, H1 (AV node) • Large artery contraction H1 • Microvessel dilation H1 & H2 • Venule permeability H1 & H2 (?) • Gastric acid secretion H2 • CNS arousal H1

  12. Antihistamines • H1 receptor antagonists (H1 blockers) • 1st generation or classical (older) • 2nd generation or non-sedating (newer) • 3rd generation • H2 receptor antagonists (H2 blockers) • gastric acid blockers

  13. H1 receptor antagonists • 1st generation antihistamines are more likely to • cause sedation in therapeutic doses • affect autonomic receptors (cholinergic and adrenergic) • 2nd generation antihistamines • are sometimes called “non-sedating” antihistamines • But better call it low-sedating • 3rd generation antihistamines • are the active metabolites of 2nd generation agents

  14. H1 receptor antagonists • block H1 receptors competitively • reduce local response to intradermal histamine • antagonize the vasoconstrictor, • and to a lesser extent, the vasodilator effects of histamine • antagonize histamine-induced bronchospasm • inhibit GI smooth muscle contractions

  15. H1 receptor antagonists (cont) • 1st generation antihistamines have some important central effects • sedation • antimotion sickness • excitation – rare in adults; more common in children • other pharmacological actions (1st generation) • anticholinergic properties - e.g. like atropine • alpha adrenergic blockade • 5-HT (serotonin) receptor blockade

  16. Major Classes ofH1 receptor antagonists • 1st generation • 2nd generation • 3rd generation

  17. 1st GenerationH1 receptor antagonists • developed in France pre-WWII • more sedating • penetrate the CNS and generally have CNS effects • significant anticholinergic effects

  18. 1st GenerationH1 receptor antagonists • Diphenhydramine (Benadryl) • highly sedating, available OTC • Chlorpheniramine • lower sedating • Cyproheptadine (also anti-serotonin)

  19. 1st GenerationH1 receptor antagonists • Clemastine (Tavist ) • Pyrilamine • Tripelennamine (Pyribenzamine) • one of the oldest • Hydroxyzine (Atarax) • used frequently for urticaria

  20. 1st GenerationH1 receptor antagonists Drugs that used principally as antiemetics • Dimenhydrinate • Meclizine (Antivert ) • Promethazine (Phenergan) • good antimotion sickness activity (antiemetic) • used by NASA for space motion sickness • Belong to Phenothiazine drugs (acepromazine) • Antiemetic, antihistminic, anticholinergic • Sedative, local anesthetic action

  21. 2nd GenerationH1 receptor antagonists General properties • Greater affinity for H1 receptor • less sedating - less CNS penetration • almost no anticholinergic effects • some can produce cardiac toxicity in certain circumstances

  22. 2nd GenerationH1 receptor antagonists • Cardiotoxic H1 antihistamines • Terfenadine (Seldane) • Astemizole (Hismanal) • These 2 drugs delay action potential repolarization by blocking K+ channels

  23. 2nd GenerationH1 receptor antagonists • Non-cardiotoxic H1 antihistamines • Loratadine (Claritin) • Cetirizine (Zyrtec)

  24. 3rd GenerationH1 receptor antagonists • Active metabolites of 2nd generation • No cardiotoxicity • Not metabolized by the liver, and excreted unchanged in either urine or feces • Specific drugs • Fexofenadine (allegra) • Metabolite of Terfenadine • Norastemizole • Metabolite of Astemizole • Descarboethoxyloratadine • Metabolite of Loratadine

  25. H1 receptor antagonists: Veterinary Uses • Decongestants for sinusitis of allergic or viral etiologies • Respiratory inflammatory disease • (cyproheptidine, particularly useful in cat) • Pruritus (skin disease) in dog and cat • (drug of choice – clemastine, chlorpheniramine) • Sedative (hydroxyzine) or Hypnotic (diphenhydramine) • to modify animal behavior • Motion sickness in dog and cat • (meclizine, diphenhydramine)

  26. H2 Receptor Antagonists Old drug • Cimetidine (Tagamet) • Prototype H2 blocker Newer drugs - More effective and longer duration • Ranitidine (Zantac) • Famotidine (Pepcid) • Nizatidine (Axid)

  27. H2 Receptor Antagonists Mechanism of action • Competitively inhibits H2 receptors of the parietal cells Pharmacological effects • inhibition of gastric acid secretion • decrease the amount of pepsin secretion • antiulcer effects - heals gastric and duodenal ulcers; • Incidence of serious side-effects is very low

  28. H2 Receptor Antagonists Therapeutic uses • Rx and prevention of gastric, abomasal and duodenal ulcers • Uremic gastritis • Esophagitis • Esophageal reflux • Hypersecretory conditions associated with gastrinoma • All drugs are therapeutically equivalent in treating gastric ulcer in human when used in appropriate doses • Cimetidine is the first line agent • Most familiar and low cost

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