Pharmaceutical Chemistry II Lectures 10 & 11 Introduction to Antihistamines & Ethanolamines Joseph O. Oweta | PHC 3201

Objectives Introduction to Antihistamines & Ethanolamines 1.Allergies and Histamine 2. Antihistamines and their MOA 3. Classification of Antihistamines 4. SAR's of AntiHistamines

Allergies and Histamine An allergy is a response by the body to something that is ordinarily harmless. The purpose of the immune system is to recognize harmful infection-causing invaders and to get rid of them. However, for some people, the immune system overreacts to ordinarily harmless substances. These people have “allergies.” Their bodies attempt to expel these ordinarily harmless substances, causing sneezing; a runny nose; itchy, watery eyes etc

Allergies and Histamine Atopy may be an inherited trait In its sequel, there is initial exposure to an allergen. Allergic reactions can involve most of the major components of the immune system, including: – the cellular elements, – immunoglobulin, – complement, – and cytokines.

Allergies and Histamine Nature Histamine is a low-molecular-weight amine compound formed by decarboxylation of histidine and is stored in basophil and mast cell granules. Release of histamine from these cells is triggered by antigen cross-linking IgE bound to specific receptors on the surface membranes of mast cells and basophils.

Allergies and Histamine Synthesis Histamine is formed from the amino acid histidine and is stored in high concentrations in vesicles in mast cells, enterochromaffin cells in the gut, some neurons, and a few other cell types. Histamine carries its message to a large number of cells by attaching to a special receptor on the cells’ surfaces.

Allergies and Histamine Receptors Four classes of histamine receptors (H1–H4) are present to varying degrees in organs and tissues. H1 receptors are most prominent in blood vessels and bronchial and intestinal smooth muscle.

Allergies and Histamine Receptors H 1 receptors tend to produce the symptoms of allergy. H 2 receptors tend to act as negative feedback receptors and turn the allergic off. H 2 receptors also exclusively activate the acid- producing, parietal cells of the stomach lining. An H 3 receptor, appears to exist only in the central nervous system.

Allergies and Histamine

Allergies and Histamine Sequele The tissue effects of histamine are evident within 1 to 2 minutes, but it is rapidly metabolized within 10 to 15 minutes. The major effects of histamine on target tissues include increased capillary permeability, contraction of bronchial and vascular smooth muscle, and hyper secretion of mucus glands.

Antihistamines Histamine has no therapeutic applications, but drugs that block its effects at H 1 and at H 2 receptors are very important in clinical medicine. No antagonists of H 3 or H 4 receptors are currently available for clinical use. H 1 antihistamines antagonize all actions of histamine except for those mediated by H 2 receptors.

Antihistamines Antihistamines act as competitive inhibitors of histamine (agonist) binding. They compete for the H1 receptors on blood vessel endothelial cells and smooth muscle cells. Competition: [antihistamine] > [natural histamine.]

Antihistamines

Classification of Anti Histamines

Classification of Anti Histamines H1 Blockers (1 st Generation) Aminoalkylethers. Ex. Diphenhydramine Ethylenediamines. Ex Tripelennamine. Propylamine derivatives. Ex. Chlorpheniramine Phenothiazine derivatives. Ex. Promethazine Piperazine derivatives. Cyclizine, Debenzocycloheptenes. Cyproheptadine Miscellaneous drugs. Diphenyl pyraline

Second-Generation antihistamines. The second-generation antihistamines bind only to peripheral H1 receptors, and reduce allergic response with little or no sedation. Ex: Cetirizine, loratidine, fexofenadine.

SAR’s

1.The nitrogen should be 3° in nature for maximum antihistaminic activity. The ‘N’ may also form a part of heterocyclic moieties like piperidine, or piperazine or diazocine. 2.The group present between nitrogen atom and group X may be saturated or unsaturated or substituted. 3.The Ar group may be aryl or heteroaryl, which may be substituted. 4.The group (X) can be carbon, oxygen or nitrogen.

Aminoalkyl Ethers (Ethonalamines) Derivatives of N,N-dimethyl ethanolamines Characterised by the CHO connecting Moiety between the key diaryl and tertiary amino groups and a two or three carbon moiety.

Diphenhydramine 2-(diphenylmethoxy)-N,N-dimethylethanamine

Dimenhydramine Synthesis

Dimenhydramine Uses Bittertaste from the hydrochloride salt base – Antidyskinetic – Antitussive – Sedative

Carbinoxamine 2-[-p-chloro-(-(2-(dimethylamino) ethoxy] benzyl] pyridine maleate.

Bromodiphenhydramine 2[(4-bromophenyl) phenylmethoxy)]-N, N-dimethylethanamine.

Bromodiphenhydramine Synthesis

Assignment Draw the structure of Dimenhydrinate Highlight chemical difference between Diphenhydramine and dimenhydrinate Draw the structures of – Doxylamine – Chlemastine