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Chapter 70 Antihistamines Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Histamine Endogenous compound Found in specialized cells Important role in: Allergic reaction Regulation of gastric acid secretion Histamine use limited to diagnostic procedures Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 2 Histamine Distribution Present in practically all tissues Especially high in skin, lungs, and GI tract Low content in plasma Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 3 Histamine Synthesis/storage Mast cells and basophils Produced by neurons Release Allergic Nonallergic Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 4 Fig. 70–1. Release of histamine by allergen-antibody interaction. (IgE = immunoglobulin E.) Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 5 Histamine Receptors H1 receptor Vasodilation Increased capillary permeability Bronchoconstriction CNS effects Other Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 6 H1 Receptors Vasodilation Increased capillary permeability Not the cause of asthma attack CNS effects Edema Bronchoconstriction Skin of the face and upper body Extensive: can cause hypotension Role in cognition, memory, and sleep-waking cycles Other Itching, pain, secretion of mucus Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 7 H2 Receptors Secretion of gastric acid Act directly on parietal cells to promote acid release Dominant role in acid release Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 8 Histamine Antagonists/Antihistamines Act primarily on H1 and H2 receptors Used primarily for two pathologic states 1. Allergic disorders 2. Peptic ulcer disease Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 9 Allergic Responses Mediated by histamine and other compounds Prostaglandins Leukotrienes Tryptase Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 10 Mild Allergic Responses Caused largely by histamine acting at H1 receptors Rhinitis, itching, localized edema Hay fever, mild transfusion reaction, acute urticaria Usually responsive to antihistamine therapy Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 11 Severe Allergic Responses Anaphylaxis Anaphylactic shock • Bronchoconstriction, hypotension, edema of the glottis • Histamine plays a minor role • Leukotrienes are the principal mediators • Antihistamines are of little use in treatment • Epinephrine is the drug of choice for treatment (see Chapter 17) Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 12 Two Types of Antihistamines H1 antagonists Produce selective blockade of H1 receptors Used for treatment of mild allergic disorders H2 antagonists Produce selective blockade of H2 receptors Used for treatment of gastric and duodenal ulcers Not used for treatment of allergies Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 13 H1 Antagonists H1 antagonists are divided into two major groups: First-generation H1 antagonists (highly sedating) Second-generation H1 antagonists Mechanism of action Block the actions of histamine at H1 receptors Do not block H2 receptors Some bind to muscarinic receptors Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 14 H1 Antagonists Pharmacologic effects Peripheral effects • Reduce localized flushing • Reduce itching and pain Effects on the CNS • Therapeutic dose: CNS depression Second-generation negligible CNS depression CNS stimulation Convulsions Very young children especially sensitive to CNS stimulation • Overdose Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 15 H1 Antagonists Therapeutic uses Mild allergy Severe allergy • Adjunct only, benefits may be limited Motion sickness • Promethazine, dimenhydrinate Insomnia Common cold • May decrease rhinorrhea through anticholinergic properties, not H1 blockade Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 16 H1 Antagonists Adverse effects Sedation • Less with second and third generation Nonsedative CNS effects • Dizziness, fatigue, coordination problems, confusion Gastrointestinal effects • Can cause nausea, vomiting, loss of appetite, constipation (give with food) Anticholinergic effects • Weak atropine-like effects Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 17 H1 Antagonists Adverse effects Severe respiratory depression Severe local tissue injury Cardiac dysrhythmias • Rare Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 18 H1 Antagonists Drug interactions CNS depressants Use of pregnancy and lactation Acute toxicity Large margin of safety Widespread availability of drugs CNS and anticholinergic reactions Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 19 High-Risk Patients Antihistamines contraindicated During third trimester of pregnancy Nursing mothers Newborn infants Use antihistamines with caution in: Young children Older adults Patients whose conditions may be aggravated by muscarinic blockade Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 20 H1 Antagonists: First Generation Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 21 H1 Antagonists: Second Generation Second generation (nonsedating) Fexofenadine (Allegra) Cetirizine (Zyrtec) Levocetirizine (Xyza) Loratadine (Claritin, Tavist ND, Alavert) Desloratadine (Clarinex) Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 22