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The role of histamine in pharmacology Dr.

Nelson Brown
Textbook: “Basic & Clinical Pharmacology” Katzung, Masters and Trevor, 11th or 12th edition


• Biologically active amine (autacoid, like serotonin) found in plant and animal tissues; active component of some venoms and stinging secretions • Nervous tissues • Also found in non-neural tissues (mast cells, basophils) • Released locally

Gastric acid secretion .Neurotransmitter or neuromudulator .Histamine • Multiple receptors in multiple tissues • Complex physiologic / pathologic effects: .Mediator of immediate allergic reactions (urticaria. allergies) and inflammatory reactions .

oxidation) • In tissues granules in mast cells and basophils Mast cell . upon release.Basic pharmacology of histamine • Formed by de-carboxylation of L-Histidine • Stored in intracellular granules. histamine is metabolically inactivated (methylation.

systemic mastocytosis) are associated with increased number of mast cells or basophils secretion of histamine or histamine metabolites • Brain (neurotransmitter) Neuro-endocrine control Cardio-vascular regulation Thermal / body weight regulation .Basic pharmacology of histamine • Enterochromaffin-like (ECL) cells of the stomach (fundus): activate the acid-producing parietal cells of the gastric mucosa • Some tumors (gastric carcinoid.

Storage and release of histamine • Immunologic release: Part of type I hypersensitivity (immediate) response (urticarial. allergic reactions) • Chemical and mechanical release: Displacement secondary to other amines (morphine). chemical mast cell injury .

brain. brain (cAMP production) H3: pre-synaptic. DAG. mast cells. Ca++) H2: gastric mucosa.Pharmacodynamics • Four different cell surface receptors (H1-H4) • Belong to the 7-transmembrane spanning G protein coupled receptors • Variable post-receptor mechanisms (depending on type of G protein) H1: smooth muscle. brain. cardiac muscle. lymphocytes . nerves (IP3. endothelium. neutrophils. myenteric plexus H4: eosinophils.

Separation of endothelial cells Edema (transudation of fluids and proteins) 3. Direct cardiac effects Increased contractility and heart rate . Direct vasodilator action (arterioles and pre-capillary sphincters) 2. H2) Flushing.Tissue / organ effects • Cardiovascular system: decreases systolic / diastolic pressure and increases heart rate (H1. headache 1.

Tissue / organ effects • Bronchiolar smooth muscle: Bronchoconstriction (H1-mediated) • Patients with asthma (or cystic fibrosis) are very sensitive to histamine .

Tissue / organ effects • Gastrointestinal tract smooth muscle: Contraction of intestines (H1-mediated) * Large doses of histamine may cause diarrhea .

Tissue / organ effects • Secretory tissues: . increased Calcium) * Stimulates secretion in the small and large intestine .Powerful stimulant of gastric acid secretion .Activation of H2 receptors on gastric “parietal” cells (increased cAMP.

Control of the appetite (H1. H3) .Stimulates sensory nerve endings (pain.Tissue / organ effects • Nervous system . itching) during urticarial response and reactions to insect stings (H1-mediated) .Sleep (central effect) • Metabolic effects: H3 receptor knockout mice > food intake < energy expenditure obesity insulin resistance .

Mechanism of action unclear 3. Physiologic antagonists: Epinephrine: smooth muscle actions opposite to histamine. nedocromil). Injection of epinephrine can save your life in systemic anaphylaxis! 2.Histamine antagonists 1. Histamine receptor antagonists: The most commonly used are H1 and H2 antagonists (antihistamines) . Release inhibitors: Reduce degranulation of mast cells (cromolyn.

Pharmacokinetics • • • • • Stable amines Rapid absorption after oral administration Metabolized in microsomal system (liver) Effective duration of action of 4-6 hours Used to treat allergic conditions . block autonomic receptors (Diphenhydramine. Some are metabolized by a P450 type that is inhibited by drugs such as the antifungal ketoconazole. less sedating (Cetirizine.H1 receptor antagonists 1.Second generation H1 antagonists: less complete distribution into the CNS. sedating. . Chlorpheniramine) .First generation H1 antagonists: enter the CNS. Loratidine. Desloratidine).

Adrenoceptor-blocking actions (promethazine) .Local anesthesia (block Na channels similar to procaine or lidocaine) .Anti-nausea. anti-emetic (prevent motion sickness) .Serotonin-blocking actions (cyproheptadine) .H1 receptor antagonists 1. Pharmacodynamics • Reversible competitive binding to H1 receptors • Many “inverse agonists” • Low potency at the H2 receptor • First generation H1 antagonists have many actions in addition to blocking the actions of histamine (cross reactivity with muscarinic cholinoceptors.Sedation (variable between drugs and patients) .Anti-parkinsonism effects . alpha-adrenoceptors. serotonin and local anesthetic receptors): .Atropine-like effects (anti-cholinoceptor) .

Clinical use of H1 receptor antagonists 1. promethazine (sedating) cyclizine. chronic urticaria 2.Possible teratogenic effects .In atopic dermatitis. Motion sickness and vestibular disturbances: . Allergic reactions: .First generation (prevention): diphenhydramine.First choice to treat “symptoms” of allergic reactions and urticaria . meclizine (less sedating) 3. used mainly as sedative .Second generation: allergic rhinitis.Not effective in asthma . Nausea and vomiting of pregnancy (morning sickness): .

Important drug-drug interactions: Macrolides (erythromicin. . First generation H1 antihistamines: Sedation Visual disturbance Urinary retention Arrhytmias 2. Second generation H1 antihistamines: . ketoconazol. clarithromicin).Adverse effects 1.

H2 receptor antagonists • Inhibit histamine-induced acid secretion .

Effects: • • Reduction of acid gastric secretion Other (non-related to H2 blocking): inhibition of P450 system (cimetidine). Selective competitive antagonism at H2 receptors: • Cimetidine • Ranitidine • Famotidine 2. anti-androgen effects (binding to androgen receptors. cimetidine) .H2 receptor antagonists 1.

Clinical uses of H2 receptor antagonists • • • Peptic ulcer disease Gastric ulcer Gastro-esophageal reflux disorder • - Hypersecretory disease: Zollinger-Ellison syndrome (acid hypersecretion associated with gastrin-secreting tumor) - Systemic mastocytosis and multiple endocrine adenomas .

delirium (the elderly) Gynecomastia (men) and galactorrhea (women). somnolence. rash Confusion. dizziness. headache.H2 receptor antagonists Adverse effects: These agents are generally well tolerated Diarrhea. anti- androgenic effect (cimetidine) .