Lesson 29 - Pharmacology of Histamine (PDF)

Lesson 29 Pharmacology of Histamine 3° Medicine Professor: Vittoria Carrabs PhD Academic year: 2024/25  INDEX 1. Introduction 2. Histamine receptors 3. Actions of Histamine 4. Agonists and Antagonists 5. Clinical uses 6. Adverse effects  1. Introduction Histamin...

Lesson 29 Pharmacology of Histamine 3° Medicine Professor: Vittoria Carrabs PhD Academic year: 2024/25  INDEX 1. Introduction 2. Histamine receptors 3. Actions of Histamine 4. Agonists and Antagonists 5. Clinical uses 6. Adverse effects  1. Introduction Histamine is a basic amine It is found in most tissues but is present in high concentrations in tissues exposed to the outside enviroment (lungs, skin and gastrointestinal tract). Histamine is released from mast cells by exocytosis during inflammatory or allergic reactions. Histamine is metabolized by histaminase and/or by a methylating enzyme. Synthesis: L-histidine decarboxylase L-histidine histamine 2. Histamine receptors Four types of histamine receptor, termed H 1–4 , have been identified All are G protein–coupled receptors (GPCRs) but their downstream signalling systems differ. H1 receptor [Ca2+] H2 receptor [AMPc] in parietal cells(acid secretion) The four are implicated in the inflammatory response  3. Physiological actions of histamine 1. Mediated through H1 receptor Contraction of most smooth muscle, except blood vessels Vasodilatation Bronchoconstriction Increased vascular permeability Promoting waking (H1 ) or sleep (H3 ) Stimulation of sensory nerve fibres: itching in the skin 2. Mediated through H2 receptor Stimulation of gastric secretion Cardiac stimulation 3. Physiological actions of histamine GASTRIC SECRETION H2 receptor: Histamine stimulates the secretion of gastric acid Implicated in the pathogenesis of peptic ulcer. 3. Physiological actions of histamine EFFECTS ON SKIN (H1 receptor) Injected intradermally, histamine causes the ‘triple response’: Reddening (local vasodilatation), weal (increased permeability of postcapillary venules) flare (from an ‘axon’ reflex in sensory nerves releasing a peptide mediator) H1 antagonists are used to control itch caused by allergic reactions, insect bites Histamine is important in type I hypersensitivity reactions such as allergic rhinitis and urticaria, modulating both the innate and acquired immune response 3. Physiological actions of histamine SLEEP/WAKE HOMEOSTASIS Antagonists of H3 receptor can be used to treat narcolepsy. * First-generation antihistamines (antagonists of H1 receptor, e.g. chlorphenamine ) can cross the blood–brain barrier and induce drowsiness  4. Antihistamines They are H1-receptor antagonists and H1-receptor inverse agonist (II generation) Antihistamines are used for treating various inflammatory and allergic conditions Antagonist vs Inverse Agonist Antagonists: simply block the H1 receptor, preventing histamine from binding. Inverse Agonists: not only block histamine from binding but also reduce the basal activity of the H1 receptor. This can lead to a more potent antiallergic effect. *Basal activity : natural activity level of a receptor in the absence of any ligand.  4. Antihistamines These are divided into: First-generation which cross the blood–brain barrier: sedating actions CHLORPHENAMINE, CINNARIZINE, CYCLIZINE, CYPROHEPTADINE, HYDROXYZINE, KETOTIFEN, PROMETHAZINE Second generation: no sedation BILASTINE, CETIRIZINE, DESLORATADINE, FEXOFENADINE, LEVOCETIRIZINE, LORATADINE INVERSE AGONIST 4. Antihistamines  4. Antihistamines Most orally active antagonists are well absorbed The duration of the action of many antihistamines is 24 hours facilitating once daily dosing Many of them are extensively metabolized in the liver by cytochrome P450 enzymes 1st generation antihistamins have peripheral anticholinergic effects Anticholinergic syndrome is the principal manifestation of an overdose of first-generation antihistamines. Which drug would you administer to reverse anticholinergic toxicity? inhibitor of ach E increase Ach decrease anticholinergic syndrome effect  5. Clinical uses H1 –RECEPTOR ANTAGONISTS ALLERGIC REACTIONS Non-sedating drugs (e.g. 2nd generation: fexofenadine , cetirizine ) are used for allergic rhinitis and urticaria Formulations in drops for allergic conjunctivitis Topical preparations may be used for insect bites Injectable formulations are useful as an adjunct to adrenaline ( epinephrine ) for severe drug hypersensitivity reactions and emergency treatment of anaphylaxis. Azelastine (nasal) to treat symptoms of allergic rhinitis, including sneezing, nasal itching, and nasal discharge. ANTIEMETICS Prevention of motion sickness (e.g. promethazine, doxylamine ) Other causes of nausea, especially labyrinthin disorders 5. Clinical uses H3 –RECEPTOR ANTAGONISTS NARCOLEPSY TREATMENT PITOLISANT It is a first-in-class histamine receptor (H 3 ) antagonist /inverse agonist indicated for the treatment of excessive daytime sleepiness (EDS) in adult patients with narcolepsy Blocking H 3 receptors increases the synthesis and release of histamine , a wake promoting neurotransmitter in the brain maria 2023-10-31 19:00:06 -------------------------------------------- EXAMEEEEN. in allergic asthma, avoidshistamine!!!!!!!! 6. Adverse effects They are mainly metabolized in the liver and excreted in the urine. To treat allergies, the sedative CNS effects are generally unwanted. Contraindications 1st and 2nd generation Alcohol Anticholinergics Digestive obstruction Glaucoma atropine 2nd generation Arrhytmia Inhibitors of CYP3A4 (interaction) 6. Adverse effects ADRs: Sedation Anticholinergic effects The most common is dryness of the mouth, but blurred vision, constipation and retention of urine can also occur Digestive disturbances SECOND-GENERATION DRUGS Cardiac toxicity, arrhythmia Increased when the drug was taken with grapefruit juice or with agents that inhibit cytochrome P450 in the liver Drug-induced photosensitivity!