Antihistaminic agents for B Pharm Fifth semester students

Antihistaminic agents for B Pharm Fifth semester students

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  Antihistaminic agents Dr. D.P. Kawade Associate Professor Priyadarshini J L College of Pharmacy
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  HISTAMINE Histamine is aβ-imidazolylethylamine derivative present in all mammalian tissues. It was first discovered by SIR HENRY DALE. Its synthesis occurs in mast cells, parietal cells of gastric mucosa, CNS, periphery. It functions as an autocoid & one of the mediator involved in the allergic inflammatory responses. It has an important role in the regulation of gastric acid secretion.
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  BIOSYNTHESIS OF HISTAMINE
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  BIOSYNTHESIS OF HISTAMINE •Histamine is synthesized in cytoplasmic granules of its storage cells, mast cells & basophils. • It is formed from naturally occurring amino acid, S-histidine, via the catalysis of the pyridoxal phosphate – dependent enzyme histidine decarboxylase/ aromatic decarboxylase.
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  METABOLISM OF HISTAMINE •Metabolism of histamine takes by the enzymatic inactivation. • Enzymes that involve in the metabolism are: 1. Histamine N-methyl transferase(HMT) 2. Diamine oxidase. •Histamine is metabolized as N- methylimidazole acetic acid , imidazole acetic acid riboside. Both are excreted through urine.
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  IMPORTANCE OF HISTAMINE •It is not used therapeutically but in the past it has been used to test acid secreting capacity of stomach. To test bronchial hyperactivity in asthmatics. For diagnosis of pheochromocytoma , but these pharmacological tests are risky. In pulmonary laboratories, histamine aerosol has been used as a provocative test of bronchial hyperactivity. To distinguish between real & pseudoanesthesia
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  RECEPTORS • Histamine receptorsare belonging to the family of G-Protein coupled receptors. • The sub types of histamine receptors are: •  H1 H2 H3 H4   
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  HISTAMINE ANTAGONISTS • Drugsthat block the action of histamine at H1 ,H2 ,H3 ,H4 receptors • The development of antihistamines began by the discovery of PIPEROXAM. 1. Drugs that inhibits the histamine release. 2. Drugs that inhibits the action of released histamine a. H1 antagonists(first,second&third generations) b. H2 antagonists c. H3 antagonists 3.Drugs having dual action
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  GENERAL STRUCTURE OFANTIHISTAMINES STRUCTURAL REQUIREMENTS: Ar is aryl: Phenyl, substituted phenyl,hetero aryl groups like 2- pyridyl. Ar1 : Second aryl (or) aryl methyl group. X: Connecting atom of O, C, (or) N. (CH2 )n: Carbon chain usually ethyl. NRR1 : Basic, terminal amine functional group
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  DRUGS THAT BLOCKTHE RELEASED HISTAMINE H1 ANTAGONISTS(FIRST GENERATION DRUGS): • These are classical antihistamines. These are clinically used in the treatment of histamine mediated allergic conditions like allergic rhinitis, allergic conjuctivitis etc
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  Allergies and Histamine Receptors •H1 receptors tend to produce the symptoms of allergy. • H2 receptors tend to act as negative feedback receptors and turn the allergic off. • H2 receptors also exclusively activate the acid- producing, parietal cells of the stomach lining. • An H3 receptor, appears to exist only in the central nervous • system.
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  Antihistaminic agents • Antihistaminesact 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.]
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  Antihistamines
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  Classification of AntiHistamines
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  Classification of AntiHistamines H1 Blockers (1st Generation) • Aminoalkylethers Ex. *Diphenhydramine hydrochloride, Dimenhydramine, Doxylamine succinate,Clemastine fumarate • Ethylenediamines Ex Tripelenamine hydrochloride • Propylamine derivatives  Saturated: Chlorpheniramine maleate  Unsatureted: *Triprolidine hydrochloride • Phenothiazine derivatives Ex. *Promethazine hydrochloride, Trimeprazine tartrate • Piperazine derivatives. Cyclizine, chlorcyclizine,Meclizine, Buclizine • Debenzocycloheptenes Ex: Cyproheptadine hydrochloride, Azatidine • Miscellaneous drugs Ex: Diphenyl pyraline
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  H1 Blockers (1st Generation) •H1 Antagonist with non classical structures Ex: Astemizole • Nonsedative H1 antagonist Piperazine derivative: Cetrizine Pyridine and piperidine derivatives Ex: Loratidine, • Inhibition of Histamine Release (mast cell stabilizers) Ex: Cromolyn sodium
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  Second-Generation antihistamines. The second-generationantihistamines bind only to peripheral H1 receptors, and reduce allergic response with little or no sedation. Ex: Cetirizine, Loratidine, Fexofenadine.
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  SAR of H1 Antagonist
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  SAR’s 1. The nitrogenshould 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.
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  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.
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  Diphenhydramine • 2-(diphenylmethoxy)-N,N-dimethylethanamine Uses: Diphenhydramineis used to relieve red, irritated, itchy, watery eyes; sneezing; and runny nose caused by hay fever, allergies, or the common cold. Diphenhydramine is also used to relieve cough caused by minor throat or airway irritation
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  Diphenhydramine Synthesis
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  Aminoalkylethers Uses: It isa relatively selective histamine H1 -receptor antagonist. In vivo studies have shown that concentrations dependent upon the inhibition of histamine stimulated vascular permeability in the conjunctiva following topical ocular administration. It appears to be devoid of effects on adrenergic, dopaminergic, and serotonin receptors. It is used with antitussives and decongestants for the relief of cough and cold.
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  Dimenhydrinate Dimenhydrinate (Mixture ofDiphenhydramine and 8-chlorotheophylline) Used as histamine H1 -receptor antagonist, antinauseant, in motion sickness, radiation sickness, and also in the case of nausea during pregnancy. Aminoalkylethers
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  Aminoalkylethers Uses: A comparisonof the activities of the antipodes indicates that the asymmetric centre close to the side chain of nitrogen is of lesser importance to antihistaminic activity. It is a long-acting ethanolamine antihistamine with sedative and anticholinergic side eff
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  Aminoalkylethers Uses: It isstructurally related to diphenhydramine with the aminoalkyl side chain incorporated in a piperidine ring. It is a potent antihistaminic agent.
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  Uses: The activityis mainly confined to the geometric isomer in which the pyrrolidino-methyl group is trans to the 2-pyridyl group. Pharmacological studies confirm the high activity of triprolidine and the superiority of (E) over corresponding (Z) isomers as H1 -antagonists. In guinea pig ileum sites, the affi nity of triprolidine (E) for H1 -receptors was more than 1000 times the affinity of its (Z) partner. Propylamine derivatives Unsaturated
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  Tripelenamine IUPAC: N'-benzyl-N,N-dimethyl-N'-pyridin-2-ylethane-1,2-diamine Ethylenediamines Uses: Tripelennamineis a histamine H1 antagonist used to treat hypersensitivity reactions, coughs, and the common cold. A histamine H1 antagonist with low sedative action but frequent gastrointestinal irritation. It is used to treat asthma; HAY fever; urticaria; and rhinitis; and also in veterinary applications
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  Chlorclyclizine IUPAC: 1-[(4-chlorophenyl)-phenylmethyl]-4-methylpiperazine Uses: Substitutionof halogen in the 2nd or 3rd position of either of the benzhydryl rings results in a much less potent activity. Chlorcyclizine is indicated in the symptomatic relief of utricaria, hay fever, and certain other allergic conditions. Piperazine derivatives
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  Meclizine IUPAC: 1-(p-Chlorophenyl benzyl)-4-(3-methylbenzyl)piperazine Uses: It is a moderately potent antihistaminic agent. It is used primarily as an antinauseant in the prevention and treatment of motion sickness; in the treatment of nausea and vomiting associated with vertigo and radiation sickness. Piperazine derivatives
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  Buclizine IUPAC: 1-[(4-tert-butylphenyl)methyl]-4-[(4-chlorophenyl)- phenylmethyl]piperazine Piperazine derivatives
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  Propylamine derivatives Saturated Uses: Chlorpheniraminerelieves red, itchy, watery eyes; sneezing; itchy nose or throat; and runny nose caused by allergies, hay fever, and the common cold. Chlorpheniramine helps control the symptoms of cold or allergies but will not treat the cause of the symptoms or speed recovery
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  Phenedamine tartrate IUPAC: 2-methyl-9-phenyl-1,3,4,9-tetrahydroindeno[2,1-c]pyridine Uses:It is used to treat sneezing, runny nose, itching, watery eyes, hives, rashes, itching, and other symptoms of allergies and the common cold.
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  Phenothiazines • Possess atricyclic system • Phenothiazine derivatives possess two or three carbon chain bridge between basic phenothiazine nucleus and terminal nitrogen.
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  Promethazine 10-(2- dimethylaminopropyl) phenothiazine. IUPAC:N,N-dimethyl-1-phenothiazin-10-ylpropan-2-amine Uses: It may be used effectively in perennial and seasonal allergic rhinitis, vasomotor rhinitis, allergic conjunctivitis due to inhalant allergens and foods, and certain milder type of skin manifestations of urtricaria. It also possesses some anticholinergic, antiserotonergic, and marked local anaesthetic properties
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  Promethazine Synthesis 2-(N-dimethylamino)-1-chloropropane
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  Promethazine Uses • Antihistaminicagent with some anti muscarinic, antiemetic and local anesthestic properties. – allergies, – anxiety prior to surgery, – as an anti-nauseant, – and for control of motion sickness.
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  Trimeprazine IUPAC: 10-(3-dimethylamino-2-methyl propyl)-phenothiazine Uses:It is used as histamine H1 -receptor antagonist.
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  1-methyl-4-(2- tricyclo[9.4.0.03,8 ]pentadeca- 1(15),3,5,7,9,11,13- heptaenylidene)piperidine;hydrochlorid e 2-(1-methylpiperidin-4-ylidene)-4- azatricyclo[9.4.0.03,8 ]pentadeca- 1(15),3(8),4,6,11,13-hexaene
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  • Uses ofCiproheptadine: This dibenzocycloheptene may be regarded as a phenothiazine analogue in which the sulphur atom has been replaced by an isosteric vinyl group and the ring nitrogen replaced by a sp2 carbon atom. • It also possesses antiserotonin activity and is used as an antipruritic agent associated with skin disorders (utricaria, allergic dermatitis, neurodermatitis). It is used to stimulate the appetite in under-weight patients and those suffering from anorexia nervosa. Uses of Azatadine: It is a potent, long-acting antihistaminic with antiserotonin activity. In early testing, azatadine exhibited more than three times the potency of chlorpheniramine in the isolated guinea pig ileum screening and more than seven times the oral potency of chlorpheniramine in the protection of guinea pig against a double lethal dose of intravenously administered histamine
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  IUPAC: 1-[(4-fluorophenyl)methyl]-N-[1-[2-(4-methoxyphenyl)ethyl]piperidin-4- yl]benzimidazol-2-amine Uses: Itis indicated for seasonal allergic rhinitis and chronic utricaria. It is an effective antiallergic agent giving protection against asthma, hay fever, and chronic urticaria. It does not exhibit any noticeable CNS activity
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  IUPAC: 4-(8-Chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2- b]pyridin-11-ylidene)-1-piperidinecarboxylic acidethyl ester Nonsedative H1 -antihistamines Pyridine and piperidine derivative
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  IUPAC: 2-[2-[4-[(4-chlorophenyl)-phenylmethyl]piperazin-1- yl]ethoxy]acetic acid
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  IUPAC: 2-[2-[4-[(R)-(4-chlorophenyl)-phenylmethyl]piperazin-1- yl]ethoxy]acetic acid Levocetrazine
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  IUPAC: Disodium;5-[3-(2-carboxylato-4-oxochromen-5-yl)oxy-2- hydroxypropoxy]-4-oxochromene-2-carboxylate Inhibition ofhistamine release (mast cells stabilizers)
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  Piperazines • Are derivativesof the piperazine nucleus
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  Piperazines General Structure
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  Piperazines Cyclizine 1-(diphenylmethyl)-4-methyl piperazine.
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  Cyclizine Synthesis N-methyl piperazine Urticaria Hayfever Other allergies
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  Chlorclyclizine 1-(p-chlorobenzhydryl)- 4-methylpiperazine Halogen Substitution= Loss of Potency
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  H2-antagonists: Cimetidine*, Famotidine,Ranitidin. Cimetidine IUPAC: 1-cyano-2-methyl-3-[2-[(5-methyl-1H- imidazol-4-yl)methylsulfanyl]ethyl]guanidine
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  Uses: It isa H2 -receptor antagonist that not only inhibits gastric acid secretion, but also prevents other actions of histamine mediated by H2 - receptors. It is used in the treatment of peptic ulceration. Cimetidine has a weak antiandrogenic effect. Gynaecomastia may occur in patients treated for a month or more
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  Famotidine Uses: It actsas a competitive, reversible H2 -antagonist with a slow onset of equilibrium. This type of blockade is called nonequilibrium antagonism. It is used in the treatment of duodenal and gastric ulcers, Zollinger–Ellison syndrome, and heart burn IUPAC: 3-[[2-(diaminomethylideneamino)-1,3-thiazol-4- yl]methylsulfanyl]-N'-sulfamoylpropanimidamide;hydrochloride
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  Ranitidin Uses: In Ranitidine,the imidazole ring of cimitidine was replaced by furan in conjugation with some rearrangement of the terminal functionality; the 128 Drugs Acting on Digestive System substituted guanidine group has been isosterically modifi ed by utilizing a nitromethenyl moiety to basicity. It is used in the treatment of duodenal ulcer, gastric ulcer, and pathological hypersecretory conditions. IUPAC: (E)-1-N'-[2-[[5-[(dimethylamino)methyl]furan-2- yl]methylsulfanyl]ethyl]-1-N-methyl-2-nitroethene-1,1-diamine
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  After absorption, theactive metabolite diffuses into the parietal cells and accumulates in the acidic secretory canaliculi
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  Gastric Proton pumpinhibitors: Omeprazole, Lansoprazole, Rabeprazole, Pantoprazole Uses: It is used in the treatment of duodenal ulcer, gastric ulcer, and pathological hypersecretory conditions
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  Uses: It isused in the treatment and prevention of NSAIDs-induced gastric ulcers as well as Zollinger–Ellison syndrome
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  Uses: There isno evidence that any of the pantoprazole metabolites have signifi cant pharmacological activity.
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  Uses: It isused in gastric hypersecretory disorders.