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HISTAMINES & ANTIHISTAMINES, 1ST & 2ND GENERATION, H1 & H2 ANTAGONIST

This document discusses antihistamines and histamine. It describes how histamine is synthesized from the amino acid histidine and plays important roles in various physiological processes. Histamine exerts its effects through four receptor types. The involvement of histamine in immune/allergic reactions and gastric acid secretion led to the development of antihistamines. Antihistamines are classified as first generation H1 antagonists, second generation H1 antagonists, and H2 antagonists. The document outlines the structures, classifications, and mechanisms of various types of antihistamines.

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ANTIHISTAMINES AY-2019-20 Purushotham K N Assistant professor Dept. of Ph. Chemistry SACCP. 1
HISTAMINE AND ANTIHISTAMINES 2
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 Histamine (β-Aminoethyl imidazole or [2-(imidazol- 4-yl)ethylamine]) is a hydrophilic molecule consisting of an imidazole ring with amino group connected by two methylene groups.  Analogs of histamine activated the four classes of histamine receptors (H1, H2, H3 and H4).  2-Methylhistamine and 4(5)-Methyl histamine have a preferential effect on H1 and H2 receptors respectively. HISTAMINE4
 Histamine or B-imidazolylethylamine is synthesized from L-histidine by histidine decarboxylase, an enzyme that is expressed in many mammalian tissues including gastricmucosa parietal cells, mast cells, and basophils and the central nervous system (CNS).  As a result, histamine plays an important role in human physiology including regulation of the cardiovascular system, smooth muscle, exocrine glands, the immune system, and central nerve function.  It is also involved in embryonic development, the proliferation and differentiation of cells, hematopoiesis, inflammation, and wound healing.  Histamine exerts its diverse biologic effects through four types of receptors. 5
 The involvement of histamine in the mediation of immune and hypersensitivity reactions and the regulation of gastric acid secretion has led to the development of important drug classes useful in the treatment of symptoms associated with allergic and gastric hypersecretory disorders. 6
H1-Receptors Mediate effects on smooth muscle leading to vasodilation, increased vascular permeability, and contraction of nonvascular smooth muscle. H2-Receptors Mediate histamine stimulation of gastric acid secretion and may be involved in cardiac stimulation. H3-Receptors Feedback inhibitors in CNS, gastrointestinal tract, lung, heart. Types7
DISTRIBUTION  Widely distributed in animal kingdom and is presented in venoms, bacteria and plants.  Particularly tissues having high concentration of histamine and that contain large number of mast cells such as skin, bronchial tree mucosa and intestinal mucosa. 8
SYNTHESIS, STORAGE AND METABOLISM OF HISTAMINE Histamine is a dibasic vasoactive substance formed from the decarboxylation of the amino acid histidine by the enzyme L- histidine decarboxylase. SSM9
The main site of histamine storage in most tissues is the mast cells and basophil in the blood. In these cells, histamine is synthesized and stored in secretory granules that are then carried through the axons and stored in nerve terminals located in the median eminence or posterior pituitary gland. Histamine is positively charged with the pH of approximately 5.5, and ionically complexed with negatively charged acidic groups on other c o n s t i t u e n t s o f t h e s e c r e t o r y g r a n u l e . Non-mast cell sites of histamine formation or storage include the epidermis, gastric mucosa, neurons within the CNS and cells in r e g e n e r a t i n g o r r a p i d l y g r o w i n g t i s s u e s . Histamine is released continuously rather than stored because of rapid turnover at non-mast cell sites. Non-mast cell sites of histamine production contribute significantly to the daily excretion of h i s t a m i n e m e t a b o l i t e s i n t h e u r i n e . 10
Metabolism of histamineALD-DH- aldehyde dehydrogenase, DAO- Diamino-oxidase, MAO-Monoamino-oxidase, SAM- S-Adenosylmethionine, SAH- S-Adenosylhomocysteine, HMT- Histonemethyl Transferases. 11
Antihistamines H1 Antagonists *First Generation *Second Generation H2 Antagonists CLASSIFICATION12
First Generation Antihistamines (Sedative Type)  Alkylamines- Diphenhydramine HCL, Bromo Diphenhydramine HCL, DimenHydrinate, Doxylaminesuccinate.  Ethylenediamines- Tripelennamine Citrate, Tripelennamine HCl, Pyrilamine Maleate.  Piperazines (Cyclizines)-Cyclizines HCl, Cyclizines Lactate, ChloroCyclizines HCl, Meclizine HCl.  Propylamines- Pheniramine Malete, Chlorpheniramine Malete, DexChlorpheniramine Malete, BromoPheniramine Malete, DexbromoPheniramine Malete,  Phenothiazines- Promethazine HCl, Trimeprazine Tartaret.  Dibenzocycloheptenes & Dibenzocycloheptanes- Cyproheptidine HCl, Azatadine Maleate, H-1 1st Gen.13
Second Generation Antihistamines (Non- Sedative Type)  Fexofenadine HCl,  Terfenadine  Loratadine  Cetirizine  Acrivastine H-1 2nd Gen.14
Like histamine, most of the classic antihistamines may be described by a substituted ethylamine moiety i.e., GAS.  Aryl group: In the above structure, 1. Ar is aryl(including phenyl & heteroaryl group like 2-pyridyl). 2. Ar’ is aryl or aryl methylgroup. Some times the two aromatic rings are bridged, which constitutes tricyclic ring derivatives. General Antihistamine Structure[GAS] SAR15
 Nature of X: The nature of X provides the basis of chemical classification of classical anti-histamines e.g., 1. When X = O i.e., GAS = Aminoalkylether’s 2. When X = N i.e., GAS = Ethylene-diamine’s 3. When X = C i.e., GAS = Monoaminopropyl’s General Antihistamine Structure[GAS] SAR16
 Nature of Alkylchain: Most of the structures of classical antihistamines contain an ethylene chain. Extension or Branching of this chain results in a less active compound (promethazine is an exception). Homologation plays an important role in the development of Neuroleptics & tricyclic antidepressants from anti-histamines. General Antihistamine Structure[GAS] SAR17
 Nature of Terminal ‘N’ atom: Terminal ‘N’ atom should be a 3º amine for the maximum activity. The terminal ‘N’ may be a part of heterocyclic ring as in Chlorocyclizine, and still retains high antihistaminic activity. General Antihistamine Structure[GAS] SAR18
AMINOALKYL ETHERS (ETHANOLAMINES) General structure The aminoalkyl ether antihistamines are characterized by the presence of a CHO connecting moiety (X) and a two- or three-carbon atom chain as the linking moiety between the key diaryl and tertiary amino groups 19
General structure 20 8-chlorotheophylline
Ethylenediamines The Ethylenediamine antihistamines are characterized by the presence of a nitrogen-connecting atom (X) and a two-carbon atom chain as the linking moiety between the key diaryl and tertiary amino moieties General structure 21
General structure 22
PIPERAZINES (CYCLIZINES) The piperazines or cyclizines can also be considered ethylenediamine derivatives or cyclic ethylenediamines; in this series, however, the connecting moiety (X) is a CHN group, and the carbon chain, terminal amine functionality, and the nitrogen atom of the connecting group are all part of a piperazine moiety. GENERAL STRUCTURE 23
GENERAL STRUCTURE 24 4-methylpiperazine
PROPYLAMINES The propylamine antihistamines are characterized structurally by an sp3 or sp2 carbon-connecting atom with a carbon chain of two additional carbons linking the key tertiary amino and diaryl pharmacophore moieties GENERAL STRUCTURE 25
GENERAL STRUCTURE 26 2,3,4,9-tetrahydro-2-methyl-9-phenyl-1H-indeno[2, 1-c] pyridine bitartrate
(E)-2-[3-(1-pyrrolidinyl)-1-p-tolylpropenyl]pyridine monohydrochloride monohydrate 27
PHENOTHIAZINES The phenothiazine derivatives that display therapeutically useful antihistaminic actions contain a two- or three-carbon, branched alkyl chain between the ring system and terminal nitrogen atom GENERAL STRUCTURE 28 Phenothiazine ring
GENERAL STRUCTURE 29
DIBENZOCYCLOHEPTENES & DIBENZOCYCLOHEPTANES- GENERAL STRUCTURE The dibenzocycloheptene and dibenzocycloheptane antihistamines may be regarded as phenothiazine analogs in which the sulfur atom has been replaced by an isosteric vinyl group (cyproheptadine) or a saturated ethyl bridge (azatadine), and the ring nitrogen has been replaced by an sp2 carbon atom. 30
GENERAL STRUCTURE 31 1-methylpiperidine
 The first generation antihistamines penetrate blood brain barrier and also possess anticholinergic properties.  This has lead to the development of second generation antagonists known as non sedating antihistamines. i.e. the second generation antihistamines do not penetrate the Blood Brain Barrier and as such do not cause drowsiness. SECOND GENERATION32
SECOND GENERATION33
Drugs whose pharmacological action primarily involves antagonism of the action of histamine at its H2-receptors find therapeutic application in the treatment of acid-peptic disorders including heartburn, gastroesophageal reflux disease (GERD), erosive esophagitis, gastric and duodenal ulcers, and gastric acid pathologic hypersecretory diseases such as Zollinger-Ellison syndrome. They are also useful in combination with H1-antihistamines for the treatment of chronic urticaria and for the itching of anaphylaxis and pruritis. H2-RECEPTORS ANTAGONIST34
HORMONAL REGULATION OF ACID SECRETION BY PARIETAL CELLS. 35
H2 Receptor Antagonists 36
37 REFERENCES  Wilson and Gisvold’s Textbook of Organic medicinal & pharmaceutical chemistry edition -12, pg.no :733- 755  https://en.wikipedia.org/wiki/Antihistamine  https://en.wikipedia.org/wiki/Histamine
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