W5 Antihistamine Drugs (Mayers-Aymes).pdf

Antihistamine Drugs Dr. Mayers-Aymes, PharmD [email protected] 1 Reading List for Antihistamines Access Medicine supplemental reading: Chapter 16, Histamine, Serotonin, & the Ergot Alkaloids. In: Basic & Clinical Pharmacology, 14th Edition, by Bertram Katzung Histamine section: https://accessm...

Antihistamine Drugs Dr. Mayers-Aymes, PharmD [email protected] 1 Reading List for Antihistamines Access Medicine supplemental reading: Chapter 16, Histamine, Serotonin, & the Ergot Alkaloids. In: Basic & Clinical Pharmacology, 14th Edition, by Bertram Katzung Histamine section: https://accessmedicine.mhmedical.com/content.aspx?bookid=2249&secti onid=175217811#1148434807 Histamine receptor antagonists section: https://accessmedicine.mhmedical.com/content.aspx?bookid=2249&secti onid=175217811#1148434808 Practice questions in Canvas 2 Learning Objectives Antihistamines 1. 2. 3. 4. 5. 6. 7. Outline the major of roles of histamine in the body. List one first generation drug and 3 second generation drugs that act at H 1receptors. Explain the meaning of “prototype drug.” Explain the molecular mechanism of actions of H 1-receptor antagonists. Explain the pharmacological effects of H 1-receptor antagonists. Describe the therapeutic uses of each of the H 1-receptor antagonists in the drug list. Describe the important pharmacokinetic properties of the H 1-receptor antagonists in the drug list 8. Describe the main adverse effects, drug interactions, and contraindications of the H1-receptor antagonists in the drug list. 3 Drug List (Prototype) Histamine H1and H2 receptor subtypes are of the most interest clinically. Histamine H1 receptor antagonists will be discussed here. Histamine H2 receptor drugs will be covered in the Digestive -1 module. 4 Histamine Formed from histidine. Most histamine found in mast cells and basophils. Mediates a wide range of cellular responses. Histamine receptors: H1, H2, H3, H4 Whalen, K. (2018). Lippincott Illustrated Reviews: Pharmacology. [VitalSource Bookshelf]. Retrieved from https://bookshelf.vitalsource.com/#/books/9781496386113/ 5 Effects of Histamine 1. 2. 3. 4. 5. 6. 7. Sensory nerve endings: pain and itching Cardiovascular system: decrease in BP & Increase in HR Skin: flushing Bronchiole smooth muscle: bronchoconstriction Intestinal smooth muscle: contraction of intestinal smooth muscle Exocrine excretion: production of nasal and bronchial mucus Stomach: gastric acid secretion 6 Have you seen any of these branded drugs? 7 Case Study A healthy 45-year-old physician attending a reunion in a vacation hotel developed dizziness, redness of the skin over the head and chest, and tachycardia while eating. A short time later, another physician at the table developed similar signs and symptoms with marked orthostatic hypotension. The menu included a green salad, sautéed fish with rice, and apple pie. 8 Case Study A healthy 45-year-old physician attending a reunion in a vacation hotel developed dizziness, redness of the skin over the head and chest, and tachycardia while eating. A short time later, another physician at the table developed similar signs and symptoms with marked orthostatic hypotension. The menu included a green salad, sautéed fish with rice, and apple pie. ❖Compare the patient’s symptoms to the effects of histamine outlined on Slide 6 – treatment with an antihistamine drug. ❖Certain types of fish contain large quantities of histamine. ❖This syndrome is called scombroid poisoning (FYI). 9 Mechanism of Action: Antihistamines competitively block histamine or act as inverse agonist at H1 receptors. N.B. the presence of the H-1 antihistamines (in diagram C) prevent histamine from activating the histamine 1 receptor. Reference: (Golan, 03/2016)Golan, D. E. (2016). Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy, 4th Edition. [[VitalSource Bookshelf version]]. Retrieved from vbk://9781496327062 10 Mechanism of Action Are all antihistamines selective for the H1 receptor……? N.B. α adrenergic effects are mediated by blocking the α-1 receptor. Whalen, K. (2018). Lippincott Illustrated Reviews: Pharmacology. [VitalSource Bookshelf]. Retrieved from https://bookshelf.vitalsource.com/#/books/9781496386113/ 11 Mechanism of Action So, to review, which neurotransmitter(s) bind to: cholinergic receptors adrenergic receptors? Whalen, K. (2018). Lippincott Illustrated Reviews: Pharmacology. [VitalSource Bookshelf]. Retrieved from https://bookshelf.vitalsource.com/#/books/9781496386113/ 12 Adverse Effects of Antihistamines (Primarily 1st Generation) Whalen, K. (2018). Lippincott Illustrated Reviews: Pharmacology. [VitalSource Bookshelf]. Retrieved from https://bookshelf.vitalsource.com/#/books/9781496386113/ 13 Pharmacological Effects of Antihistamines Sedation via antagonism of muscarinic receptors Reduction in symptoms of nasal and dermatological allergies caused by histamine release Inhibition of nausea, vomiting, and vertigo via antagonism of histaminergic and cholinergic signals from the vestibular system Anti-parkinsonism effects due to via antagonism of CNS muscarinic receptors (in the brain) Analgesia (providing pain relief locally) **N.B paradoxical stimulation ranging from excitation through to tremors, hallucinations and convulsions may occur especially in children. Therapeutic Uses General: Sneezing, rhinorrhea, itchy/watery eyes, itching of nose or throat, pruritis, urticaria, insect bites/stings, allergic rashes Diphenhydramine (additional uses): nausea, motion sickness. Relief of pain and itching (topical administration) associated with insect bites, poison ivy, and other topical allergens 15 1st versus 2nd Generation 1st Generation 2nd Generation Block cholinergic, serotonin and alpha-adrenergic receptors More selective for H1 receptors (less autonomic effects) Easily cross the blood brain barrier (BBB) Less likely to cross the blood brain barrier (BBB) Sedation Little or no sedative actions 16 Principles of Pharmacology Lecture Application Second generation drugs are less likely to cross the blood brain barrier (BBB) and thus have low CNS penetration. Due to the following characteristics: ❖Ionization in physiological fluid ❖Low lipid solubility ❖High binding affinity to albumin The drowsiness/sedation caused by 1st generation antihistamines may be a therapeutic effect OR an adverse effect…..it depends….WHY?!?!? 17 General Pharmacokinetics of Antihistamines Absorbed well after oral administration (good bioavailability). Onset of action occurs in 1–3 hours. Diphenhydramine has a plasma half-life of 3–9 hours whereas the second-generation drugs have a half-life of 12–24 hours. 18 Diphenhydramine Therapeutic uses: analgesic, allergic reactions, sleep aid Pregnancy: crosses placenta; not known to cause birth defects; FDA category B) Precautions: ❑Asthma (due to thickening of bronchiole secretions) ❑Due to possible anti-muscarinic effects: cardiovascular disease, glaucoma, urinary obstruction ❑Anti-muscarinic effects and alpha-adrenergic effects are especially bad for the elderly. (Additional detail will be provided in upcoming lectures.) ❑Not recommended for daytime use due to sedative effects. ❑Lactation (Enters breast milk; may make baby drowsy or irritable.) 19 Diphenhydramine Pharmacokinetics Availability: Oral, IV, IM, topical Distributed in all tissues including the CNS About 50% to 60% of an oral dose of diphenhydramine is metabolized by the liver before reaching the systemic circulation (first-pass effect) Adverse Effects Sedation, urinary retention, tachycardia, hypotension, vertigo, dry mouth, increased appetite 20 Cetirizine, Fexofenadine, Loratadine Dosing: once to twice daily Less sedation (and adverse effects) than diphenhydramine – WHY? Loratadine and cetirizine are pregnancy category B and fexofenadine is category C. 21 Specific Pharmacokinetics Cetirizine Oral and IV High bioavailability (~70%) No P450 metabolism; minor hepatic glucuronidation and oxidation Excretion: urine (70% - 50% as unchanged drug); feces (10%) Levocetirizine is the isomer of cetirizine. Fexofenadine Oral Should not be taken with fruit juices as they inhibit absorption Metabolism: minimal (hepatic: ~5%) Bioavailability: ~33% Excretion: feces (80%) and urine (12%) as unchanged drug 22 Loratadine Oral only Metabolism: Extensively hepatic via CYP2D6 and 3A4 to active metabolite (prodrug). Excretion: Excreted about equally in urine and feces. 23 Learning Objectives - Antihistamines Outline the major of roles of histamine in the body. List one first generation drug and 3 second generation drugs that act at H1receptors. Explain the meaning of “prototype drug.” Explain the molecular mechanism of actions of H 1-receptor antagonists. Explain the pharmacological effects of H 1-receptor antagonists. Describe the therapeutic uses of each of the H 1-receptor antagonists in the drug list. Describe the important pharmacokinetic properties of the H 1-receptor antagonists in the drug list. Describe the main adverse effects, drug interactions and contraindications of the H1-receptor antagonists in the drug list. 24 Case Study A 50-year-old woman who suffers from allergic rhinitis and experiences itchy eyes, sneezing, and rhinorrhea. To relieve her symptoms, she purchases diphenhydramine over-the-counter from the grocery store. She, however, dislikes the unpleasant effects she experiences when she takes the drug. She complains that drowsiness and dry mouth are the most annoying effects. 1. Based on the patient’s complaints, suggest another antihistamine that could be used to manage her allergic rhinitis symptoms. 2. How does the mechanism of action of drug you listed in Question 1 differ from that of diphenhydramine? 3. Would the drug listed in Question 1 cause the drowsiness and dry mouth? Provide a reason for your answer. 25 Based on the patient’s complaints, suggest another antihistamine that could be used to manage her allergic rhinitis symptoms. 26 How does the mechanism of action of drug you listed in Question 1 differ from that of diphenhydramine? 27 Antihistamines may be given as adjunctive therapies for use with epinephrine in the treatment of anaphylaxis. Fexofenadine is likely to be a suitable antihistamine for this indication. A. True B. False 28 Which of the following drugs should be avoided with fruit juices? A. B. C. D. Diphenhydramine Fexofenadine Cetirizine Loratadine 29 Some antihistamine drugs cause dry mouth and constipation due to block of which receptor? A. B. C. D. Serotonin Muscarinic Alpha adrenergic Histamine 30 Which pharmacokinetic properties most likely leads to a drug’s ability to cross the blood brain barrier? A. High protein binding B. Ionization in physiological fluid C. Lipophilic 31