Page 1 of 7HISTAMINE AND ANTI-HISTAMINE DRUGSThomas M. Guenthner, Ph.D.Department of PharmacologyUIC College of MedicineE418 [email protected] [2-(4-imidazolyl)ethylamine]First Synthesized in 1907Pharmacological properties demonstrated in 1911Extracted from tissues and named 1927 (Histo- = tissue + amine)First antihistamine drugs 1943-44Receptor subtypes characterized 1966-presentHistamine is an Autacoid (aut- = self, akos = cure); a molecule biosynthesized orsecreted by a cell that exerts a pharmacological effect on neighboring cells; a “localhormone” It is also a neurotransmitter.Histamine is found throughout the body, but in high concentrations in the brain, gut,skin, and lungs. It is concentrated in 3 main cell types; mast cells, enterochromaffin-like(ECL) cells and a variety of neurons.Page 2 of 7Histamine receptors are found in tissues where histamine acts pharmacologically. There are currently 4 known types of histamine receptors.The pharmacological activity of histamine depends on the tissue and type ofreceptor that it activatesPage 3 of 7Mast cell histamine is a major mediator of the “immediate hypersensitivity response”,along with cytokines, prostaglandins, leukotrienes, heparin, and proteases.Page 4 of 7Degranulation and histamine release can be triggered by antigen-IgE interaction, or bydirect chemical stimulation of mast cells. Result of release of Mast cell histamine: Vasodilation, Increased vascular permeability,stimulation of local pain-sensing neurons = redness, swelling, stinging or itching Beneficial consequences of histamine release: increased local circulation, increasedcapillary permeability, increased leukocyte mobilization and chemotaxis, sensation offoreign object (all help fight infection)Harmful consequences of histamine release: pain, itching, swelling, drop in bloodpressure (shock), bronchoconstriction, tracheal swelling.ALL PHARMACOLOGICAL MODULATION OF HISTAMINE ACTIVITY IS AIMEDAT BLOCKING IT (ANTIHISTAMINE DRUGS)Indirect anithistamine activity:Cromolyn (blocks degranulation)Epinephrine (counteracts its physiological activity)VasoconstrictionBronchodilationIncreased cardiac output(Little or no effect on vascular permeability)Direct antihistamine activity (Histamine antagonists)Page 5 of 7The first antihistamine drugs were used as “anti-allergy” drugs to block histaminemediation of the immediate hypersensitivity response. These act primarily at H1receptors, and are known as the “First Generation” antihistaminesPage 6 of 7Major side effects: Sedation, Anticholinergic (antimuscarinic) activityDry mouthAbility to block H1 receptors in the CNS makes these drugs useful as mild sedativesand mild antinausea drugs (e.g motion sickness) – their second major therapeuticapplication.“Second generation” antihistamines also act at H1 receptors, but have much lessantimuscarinic and sedative side effects. “Third generation” antihistamines: Second generation drugs with decreased cardiac sideeffectsH2 antagonists:Major use of H2 antagonists is to block the stimulation by histamine of H2 receptor-mediated acid secretion in the stomach. H2 histamine antagonists are very effective intreatment of gastric hyperacidity and peptic ulcer disease.Page 7 of 7Histamine antagonists that selectively target H3 and H4 receptors have potentialtherapeutic applications, but these have no current defined clinical use.MAJOR DRUGS TO KNOW:First Generation H1 antagonists:Chlorpheniramine (Benadryl, etc. OTC) Diphenhydramine (Chlor-trimetron, etc. OTC)Promethazine (Phenergan, etc. OTC)Antiemetic and Motion Sickness:PromethazineMeclizine (Bonine OTC)Dimenhydrinate (Dramamine OTC) (salt of diphenhydramine andchlorotheophylline)Second Generation H1 antagonists:Loratadine (OTC)Fexofenadine (Rx) H2 antagonists:Cimetidine (OTC)Famotidine (OTC)Ranitidine (OTC)Not Histamine Receptor
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