Nathan P. Samsa, Pharm.D., R.Ph. Antihistamines Nathan P. Samsa, Pharm.D., R.Ph.

My Objectives Answer the objectives they refuse to teach us Design this lecture in a logical manor to facilitate understanding

Histamine Brief overview: Derived from amino acid histidine “Antihistamine” is old terminology Politically correct term: “H1-Receptor Antagonist” N H O 3 + Histidine decarboxylase Histamine

Objectives 930 931 2937 2938 2939 2943 2946 2947

Antihistamines: 2937 Objective 2937: List three important sites where histamine is stored in the body, and describe/identify the types of cells which store histamine at these sites

Antihistamines: 2937 cont. Storage sites: Cellular production: Gastrointestinal mucosa Epidermis Bronchial mucosa Cerebrospinal fluid Cellular production: Mast cells-tissues (predominant) Basophils-blood

Antihistamines: 2938 Objective 2938: Based on analog binding and resulting physiological changes distinguish among histamine receptor subtypes H1, H2, and H3

Antihistamines: 2938 cont. H1 Couples to Gq–protein to activate phospholipase C Found throughout the CNS and densely concentrated in hypothalamus Stimulates wakefulness

Antihistamines: 2938 cont. H2 Couples to Gs-protein to activate adenylyl cyclase Found predominatly in the GI tract Increases secretion of gastric acid from parietal cells in the stomach Antagonists block acid secretion Cimetadine (Tagamet®) Famotidine (Pepcid®) Nizatidine (Axid®) Ranitadine (Zantac®

Antihistamines: 2938 cont. H3 Couples with Gi-protein to inhibit adenylyl cyclase Proposed as a neural presynaptic auto-receptor serving to modulate histamine synthesis and release in the CNS, as well as neurotransmitters (e.g. acetylcholine, dopamine, GABA, norepinephrine, serotonin) Peripheral tissue, including the gastric mucosa, where it may negatively control gastric acid secretion

Antihistamines: 2938 cont. H4 Couples with Gi-protein to inhibit adenylyl cyclase Just recently discovered The H4 receptor is highly expressed in peripheral blood leukocytes and intestinal tissue, making this receptor a potentially interesting target in allergic and inflammatory diseases

Antihistamines: 2943 Objective 2943: Describe the effects of histamine on: Bronchiolar smooth muscle The cardiovascular system Nerve endings Secretory tissues

Antihistamines: 2943 cont. Bronchiolar smooth muscle: Contraction due to H1 activation Dilitation due to H2 activation Humans have less bronchoconstriction from histamine than other species Leukotrienes and platelet activating factor are the major contributors of bronchoconstriction

Antihistamines: 2943 cont. The cardiovascular system: “Triple Response” Localized red spot-maximum diameter Due to direct vasodilator effect of histamine Brighter red flush (flare) extending around original spot Due to indirect histamine stimulation of axons that cause vasodilation Wheal that occupies original localized red spot Due to direct vasoconstriction and edema formation

Antihistamines: 2943 cont. The cardiovascular system cont.: Vasodilation: H1 response is relatively rapid and short lived On endothelial cells-secrete local vasodilatory substances which eventually stimulate NO production H2 response is slower and more sustained On vascular smooth muscle cells Therefore H1 antagonists effectively counter small dilator responses to low concentrations of histamine, but only blunt the initial phase

Antihistamines: 2943 cont. The cardiovascular system cont.: Vasoconstriction: H1 stimulation causes postcapillary venules to contract, separating the cells, exposing freely permeable basement membranes Edema Permits passage of mast cells recruited to tissues

Antihistamines: 2943 cont. The cardiovascular system cont.:

Antihistamines: 2943 cont. The cardiovascular system cont.: Heart: H1 effects: Acts directly to slow AV conduction H2 effects: Promotes influx of Ca2+ Increases heart rate by hastening diastolic depolarization in the SA node Baroreceptor reflexes typically stimulate to counteract the decreased heart rate

Antihistamines: 2943 cont. Nerve endings: Histamine stimulates various nerve endings Epidermis: Itch Dermis: Pain Thought to be associated with the “flare” component of the triple response Typically H1 receptor mediated

Antihistamines: 2943 cont. Secretory tissues: Exocrine glands: potent stimulator of gastric secretion (HCl & pepsin) Enhances salivary and lacrimal gland secretion (minimal unless large doses are given) Stimulates chromaffin cells in adrenal medulla to secrete catecholamines

Antihistamines: 2939 Objective 2939: Explain how histamine may limit the intensity of allergic reactions in skin and blood

Antihistamines: 2939 cont. In allergic response, IgE is generated and binds to mast cells and basophils IgE binding causes eventual release of histamine from vesicles The vasoconstrictive properties of histamine help to prevent spread of mediators from the immediate areas

Antihistamines: 2947 Objective 2947: Explain how first generation antihistamines produce sedation, urinary retention and even blurred vision

Antihistamines: 2947 cont. Antihistamines exhibit effects other than H1-mediated M1: Antimuscarinic activity Atropine-like properties/“anti-SLUD” Anti-parkisonism Ethanolamines, ethylenediamines α1: Alpha antagonism Orthostatic hypotension Phenothiazines

Antihistamines: 2947 cont. 5-HT2 IKr Anti-emetic Antivertigo Relaxes gastric smooth muscle Cyproheptadine, azatadine, phenothiazines IKr Prolong phase 3 of action potential by inhibiting potassium rectifier channels Ethanolamines, piperidines Anti-emetic Medullary chemoreceptor trigger zone Antivertigo Diminishes vestibular stimulation

Antihistamines: 2947 cont. First generation antihistamines: All have properties beyond peripheral H1 antagonism Knowing the intricacies of the side effects help to tailor the drug to the patient Many side effects are marketed a Diphenhydramine As Anti-allergy: Benadryl® As Sleep aid: Unisom®

Antihistamines: 2947 cont. Second generation antihistamines: Astemizole (off-market) Desloratidine Loratidine Fexofenidine Terfenadine (off-market)

Antihistamines: 2947 cont. Second generation antihistamines: Second generation antihistamines do not cross the blood brain barrier well, thus they do not inhibit hypothalamic wakefulness They bind much more selectively to peripheral H1 receptors and have a lower binding affinity for the cholinergic and alpha-adrenergic receptor sites than other antihistamines

Antihistamines: 2947 cont. First-&-a-half generation antihistamines: Cetirizine Still has higher incidence of drowsiness than true second generation agents FDA does not allow cetirizine to be marketed as a second generation Summary statement between generations: 1st generations bind non-selectively to central and peripheral H1-receptors while 2nd generations bind H1-receptors selectively

Antihistamines: 2946 Objective 2946: Describe the mechanism of potential drug-drug interactions which may lead to lethal ventricular arrhythmias in patients taking terfenadine and antibiotics such as erythromycin

Antihistamines: 2946 cont. Erythromycin blocks the metabolism of either drug by inhibiting CYP3A4 Increased astemizole and terfenadine concentrations inhibit the potassium rectifier currents (IKr) in cardiac myocytes, therefore slowing repolarization

Antihistamines: 2946 cont. Clinically manifested as prolongation of the QT interval, possibly leading to torsade de pointes Ethanolamines and loratidine possibly

Antihistamines: 931 Objective 931: Discuss the pharmacology (mechanisms of action, pharmacodynamics, indications, and contra-indications) of the following antihistamines: Ethanolamines: Dimenhydrinate, Diphenhydramine Ethylaminediamines: Pyrilamine Piperazine derivatives: Hydoxyzine, Cyclizine, Meclizine Alkylamines: Brompheniramine, Chlorpheniramine Phenothiazine derivatives: Promethazine Piperidines: Fexofenadine Others: Loratadine, Cetirizine

Antihistamines: 931 cont. Ethanolamines: Carbinoxamine (Cardec®) Clemastine (Tavist®) Dimenhydrinate (Dramamine®) Diphenhydramine (Benadryl®) Doxylamine (Unisom®)

Antihistamines: 931 cont. Ethanolamines: Highly anticholinergic Structure mimics anti-muscarinics Highly sedative Crosses blood brain barrier readily Low incidence of GI side effects Diphenhydramine is metabolized into dimenhydrinate

Antihistamines: 931 cont. Ethylaminediamines (Ethylenediamines): Pyrilamine (Triaminic®) Tripelennamine (PBZ®)

Antihistamines: 931 cont. Ethylaminediamines (Ethylenediamines): Very specific for H1 receptors Moderate incidence of somnolence Common GI side effects Lower incidence of anticholinergic and anti-emetic properties than other classes

Antihistamines: 931 cont. Piperazines (Cylizines): : Cetirizine (Zyrtec®) Cyclizine (Marezine®) Hydoxyzine (Atarax®, Vistaril®) Meclizine (Antivert®)

Antihistamines: 931 cont. Piperazines (Cylizines): Moderately potent antihistaminics with a lower incidence of drowsiness Slow onset and long duration of action Some piperazines exhibited a strong teratogenic potential, inducing a numberof malformations in rats Cetirizine is a metabolite of hydroxyzine Does not cross the blood brain barrier as well as hydroxyzine

Antihistamines: 931 cont. Alkylamines: Brompheniramine (Dimatapp®) Chlorpheniramine (Chlor-Trimeton®) Dexchlorpheniramine (Polaramine®) Pheniramine (Poly-Histine®) Tripolidine (Actidil®) Pyrrolidines: Acrivastine (Semprex-D®)

Antihistamines: 931 cont. Alkylamines: Most potent H1 antagonists Generally regarded as one of the better daytime-use 1st generation H1 antagonists Only moderate incidence of somnolence Has some anticholinergic activity CNS stimulation more common than other classe Acrivastine does not display significant anticholinergic activity at therapeutic concentrations, and does not cross the blood brain barrier readily

Antihistamines: 931 cont. Phenothiazines: Methdilazine (Tacaryl®) Promethazine (Phenergan®) Trimeprazine (Temaril ®)

Antihistamines: 931 cont. Phenothiazines: Have relatively high anticholinerc effects Has some 5-H2 antagonistic effect Major use is for anti-emetic properties

Antihistamines: 931 cont. Piperidines: Dibenzocycloheptenes/heptanes: Azatadine (Optimine®) Cyproheptadine (Periactin®) Phenindamine (Nolahist®) Second generationn piperidines: Astemizole (Hismanal®) Desloratidine (Clarinex®) Fexofenadine (Allegra®) Loratidine (Claritin®) Terfenadine (Seldane®)

Antihistamines: 931 cont. Piperidines: Highly selective for peripheral H1 Have no significant anticholinergic effects Well tolerated Astemazole and terfenadine were pulled from the U.S. market due to drug interactions Desloratidine is a metabolite of loratidine Fexofenadine is a metabolite of terfenadine The heptanes have 5-HT2 & H1 antagonism

Antihistamines: 931 cont. Others: Loratadine, Cetirizine If they researched better, they’d know these drugs fit in the classes already listed Phthalazinones: Azelastine (Astelin®) Selective antagonism of H1-receptors versus other neurotransmitter receptors (low antimuscarinic activity)

Antihistamines: 930 Objective 930: explain why H1-antihistamines are clinically useful in treatment of allergic rhinitis and urticaria but not in management of bronchial asthma

Antihistamines: 930 cont. Allergic bronchoconstriction is caused primarily by leukotrienes and platelet activating factor This is why leukotriene receptor antagonists are a treatment in asthma management In other animals, histamine causes allergic bronchoconstriction

References Basic & Clinical Pharmacology-Katzung Goodman & Gilman’s The Pharmacological Basis of Therapeutics-Hardman Principles of Medicinal Chemistry-Foye http://web6.duc.auburn.edu/~deruija/hist_antihis.pdf http://www.courses.vcu.edu/ptxed/m2/powerpoint/download/Lichtman%20Antihistamine.PDF http://www.duc.auburn.edu/~deruija/hist_intro.pdf http://www.sigmaaldrich.com/sigma/rbi-handbook/sg_ls_cs_rbibook_histamine.pdf