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Antihistamine Presentation by Manisha Sonawane
- 1. ANTI-HISTAMINICS DRUG Mrs.Sonawane Manisha Dhondiram Assist.Professor PRAVARA RURAL COLLEGE OF PHARMACY,LONI
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- 3. HISTAMINE ā¢ Histamine isan important chemical messenger communicating information from one cell to another and is involved in a variety of complex biologic actions. It is mainly stored in an inactive bound form, from which it is released as a result of an antigenāantibody reaction initiated by different stimuli such as venoms, toxins, proteolytic enzymes, detergents, food materials, and numerous chemicals. ā¢ Histamine exerts its biologic function by interacting with at least three distinctly specific receptors H1, H2, and H3. It was the mediator associated with allergic manifestations. It binds to and activates specific receptors in the nose, eyes, respiratory tract, and skin, causing characteristic allergic signs and symptoms. ā¢ It also causes contraction of smooth muscles, relaxation of capillaries, and gastric acid secretion.
- 4. HISTAMINE Histamine is Ī²-Imidazolylethylamine. It is synthesized locally from amino acid histidine. It is stored in mast cell, along with acidic protein heparin. ā¢ Histamine is comprised of an imidazole ring connected to an amino group through ethylene bridge. ā¢ It is called as tissue amine & is involved in diversified physiological processes.
- 5. Physiological actions ofHistamine Vasodilation Broncho-constriction Allergic reaction (itching) Gastric Secretion Vascular permeability H1 receptor causes H2
- 6. Location: The tissue fixedmast cells & blood basophiles are principle cells where histamine is stored in secretary granules Mast cell: Skin: Basophile Cell: Lungs: GIT Parietal Cell ECC Bone marrow
- 7. CO2 Biosynthesis HISTIDINE HISTAMINE Amino Acid Histamine issynthesis in cytoplasmic granual of its strorage cell,Mast cell,Basophils.It is biosynthesized from basic amino acids hostidie by decarboxylation process,in the presence of HDC
- 8. Histamine-N-methyl transferase HISTAMINE N-Methyl histamine MAO 1-Methylimidazole-4-acetaldehyde Aldehyde Dehydrogenase 1-Methylimidazole-4-acetic acid Diamine Oxidase Aldehyde Dehydrogenase Imidazole-4-Acetaldehyde Imidazole-4-AcetIcAcid Imidazole-Acetic Acid Phosphoribosyl transferase I-Ribosyl-Imidazole-4-AcetIc Acid Metabolism
- 9. Release of Histamine: ā¢Histamine is released in response to tissue injury, inflammation & allergic reaction. ā¢ An allergen (antigen) interacts with Ab on mast cells. ā¢ Once the mast cell Ab-Ag Complex is formed, a series of events occurs. ā¢ That series of events leads to cell granulation & release of histamine from mast cell. ā¢ The released histamine bound with histamine receptor.
- 10. Receptors Type Location Function H1Smooth muscle of intestine, bronchi & BV, endothelium & CNS Allergic reaction itching, Inflammation GI smooth muscle contraction, Bronchial smooth muscle contraction Blood Vessels dilation H2 Parietal Cells Gastric secretion H3 CNS, mainly in the striatum, substantia nigra, and the cortex Presynaptically present and controls the release of histamine. H4 Thymus, small intestine, spleen, colon, basophils, Located at eosinophiles, basophiles and other mast cells which also promote chemotaxis.
- 11. ANTI-HISTAMINICS These are thedrugs act against the action of histamine either competively or non competitively. H1 Antagonist (Antiallergens): These are the agents which inhibit binding of histamine at H1 receptor. H2 Antagonist (Anti-secretary drugs): These are the agents which is used in peptic ulcer, gastric ulcer, Zollinger-Ellison Syndrome, as antacid
- 12. ā¢ 1st generationantihistamines are more likely to cause sedation in therapeutic doses affect autonomic receptors (cholinergic and adrenergic) these are classical/(older) ā¢ 2nd generation antihistamines are sometimes called ānon-sedatingā antihistamines. But better call it low-sedating & newer. ā¢ 3rd generation antihistamines are the active metabolites of 2nd generation agents H1 Antagonists
- 13. H1 Antagonists First GenerationH1 receptor antagonists (Classical Anti-Histamine) General Structure of 1st Generation Drugs
- 14. First Generation H1receptor antagonists Classical Anti-Histamine Amino alkyl ethers ethers Diphenhydramine hydrochloride Doxylamine Succinate
- 15. First Generation H1receptor antagonists Classical Anti-Histamine Propylamine Derivatives Chlorpheniramine maleate Triprolidine hydrochloride
- 16. First Generation H1receptor antagonists Classical Anti-Histamine Ethylenediamine Derivatives Tripelennamine hydrochloride
- 17. First Generation H1receptor antagonists Classical Anti-Histamine Piperazine Derivatives Chlorcyclizine hydrochloride Buclizine hydrochloride Meclizine hydrochloride
- 18. First Generation H1receptor antagonists Classical Anti-Histamine Phenothiazine Derivatives Promethazine hydrochloride Trimeprazine tartarate
- 19. First Generation H1receptor antagonists Classical Anti-Histamine Dibenzo-cycloheptanes Azatadine Loratadine Cyproheptadine hydrochloride
- 20. Second Generation H1receptor antagonists Classical Anti-Histamine Cetrizine Acrivastine
- 21. Third Generation H1receptor antagonists Classical Anti-Histamine Levocetrizine
- 22. SAR of 1stGeneration Anti- histamine General Structure of 1st Generation Drugs
- 23. SAR of Arylgroup Aryl group can be Phenyl ring or heteroatom ring Diphenhydramine hydrochloride Doxylamine
- 24. SAR of Arylgroup Ar I can be aryl (phenyl) or aryl methyl Diphenhydramine hydrochloride Triprolidine hydrochloride
- 25. Nature of X WhenX = CHO (Amino alkyl ether) N (Ethylene Diamine) C
- 26. Alkyl Chain Ethylene Chainis essential for activity Diphenhydramine hydrochloride
- 27. Alkyl Chain Extension orbranching of this chain results in less active compounds
- 28. Terminal Nitrogen The terminalNitrogen atom should be tertiary amine for maximum activity. Diphenhydramine hydrochloride Doxylamine
- 29. Terminal Nitrogen Diethyl amine(-N-(C2H5)2) derivatives are found to possess better activity.
- 30. Terminal Nitrogen The terminalNitrogen can be cyclized into the ring Triprolidine hydrochloride
- 31. Terminal Nitrogen Since theantihistamine have a close resemblance with anticholinergic agent, most of antihistamine do exhibit anticholinergic action & vice versa.
- 32. Pharmacophore X ray crystallographypredicts that two phenyl & protonated Nitrogen mainly interact with H1 receptor. For proper binding the distance between two aromatic ring should be 4.90 Ao & between second aromatic ring & protonated nitrogen should be 5.3 Ao.
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- 34. Antihistamin e MOA: H1 Antagonist Histaminebinding to H1 receptor can cause allergic and hypersensitivity reactions s/a fever, itching, dermatitis etc. Antihistamine are used to treat these symptoms by inhibiting the binding of histamine to it`s receptor by blocking it by competitive antagonism.
- 35. Synthesis : Diphenhydramine Hydrochloride K2CO3 HCl Diphenylbromo methane Dimethyl amino ethanol Diphenhydramine Diphenhydramine hydrochloride
- 36. Synthesis : Promethazine Hydrochloride S I2 AlCl3 HCl Diphenylamine Sulphur Phenothiazine 1-Chloro-2-(dimethylamino)Propane -HCl Promethazine
- 37. H2 Receptor Blocker TheH2 receptor antagonist are competitive inhibitors of histamine at the parietal cell H2 receptor. They supress the normal secretion of acid by parietal cells & meal stimulated secretion of acid. Histamine released by ECL cells in the stomach is blocked from binding on parietal cell H2 receptors that stimulate acid secretion.
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- 42. SAR of H2Receptor antagonist Basic Heterocyclic ring R Flexible Chain N Polar Group
- 43. MOA of H2Receptor antagonist Basic Heterocyclic ring Originally imidazole ring was found to be active, example cimetidine. Cimetidine
- 44. SAR of H2Receptor antagonist Other heterocyclic ring like furan, thiazole enhance the potency Ranitidine Famotidine
- 45. SAR of H2Receptor antagonist Introduction of basic moieties like dimethyl amino, methyl guanidine on heterocyclic ring improves activity. Ranitidine Famotidine
- 46. SAR of H2Receptor antagonist 2,5 di substitution is best for furan Ranitidine
- 47. SAR of H2Receptor antagonist Flexible Chain Chain comprises of either 4 or 3 Carbon long chain containing sulphur atom. Ranitidine
- 48. SAR of H2Receptor antagonist Flexible Chain Sulphur atom should be present between heterocyclic ring & Polar group ( N atom) Cimetidine
- 49. SAR of H2Receptor antagonist Flexible Chain Replacement of Sulphur (S) by methylene group (-CH2-) drops activity Cimetidine
- 50. SAR of H2Receptor antagonist Polar Group The terminal nitrogen group should be polar Ranitidine
- 51. SAR of H2Receptor antagonist Polar Group Cyanoguanidine substituent results in potent compound Cimetidine
- 52. H2 MOA Receptor antagonist Histamine actionon gastric acid: H2 Receptor antagonist ā¢ These drugs inhibit the acid production by reversibly competing with histamine for the binding with H2-receptor on the basolateral membrane of parietal cells. ā¢ The most predominant effect of H2-receptor antagonist is on acid secretion. ā¢ Histamine on H2-receptors produces cAMP- dependent protein kinase to elicit the response in the gastrointestinal tract (GIT). ā¢ The H2-antagonists reversibly bind the H2-receptors and reduce the cAMP formation, which is responsible for the activation of proton pump and subsequently reduces the gastric acid formation in the GIT.
- 53. Therapeutic Application Duodenal Ulcers GastricUlcers Pathological Hypersensitivity Upper GI Bleeding Gastroesophageal reflux disease Zollinger-Ellison Syndrome
- 54. Proton Pump Inhibitors Drugswhich are used to reduce or inhibit gastric acid production & secretion, are known as Proton Pump Inhibitors (PPI`s). These are more potent & longer duration of action than H2 antagonist. They act by irreversibly blocking H+/K+ ATPase enzyme of gastric parietal cells.
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- 59. SAR of ProtonPump Inhibitors Basic structure for PPI`s
- 60. SAR of ProtonPump Inhibitors Benzimidazole ring should be substituted since non substituted benzimidazole derivatives causes thyroid enlargement.
- 61. SAR of ProtonPump Inhibitors Replacement of the -SOCH2-, linking chain by variety of other groups like -SCH2-, -SO2CH2-, leads to loss of activity.
- 62. SAR of ProtonPump Inhibitors Extending -SOCH2- chain give rise to inactive compounds
- 63. SAR of ProtonPump Inhibitors The substituent which increases nucleophilicity of Pyridine Nitrogen makes compound more stable s/a āOCH3 & easily convertible to active form sulfenamide.
- 64. SAR of ProtonPump Inhibitors Presence of āOCH3 (electron withdrawing) at C-6 on benzimidazole make compound more stable & easily convertible to active form sulfenamide.
- 65. SAR of ProtonPump Inhibitors Pantoprazole Replacement of -OCH3 (methoxy group) by fluoromethyl (-CH3F) group decreases the activity.
- 66. SAR of ProtonPump Inhibitors Omeprazole Replacement of -OCH3 (methoxy group) by trimethyl group (-CH3) groups decreases the activity
- 67. SAR of ProtonPump Inhibitors Omeprazole Addition of difluoroaldehyde (-FCHO-F) group at 6th position increases the activity
- 68. MOA of Proton Pump Inhibitors ā¢ These drugssuppress gastric acid secretion through H+ K+ ATPase pump, the two major signaling pathways that are present with the parietal cells, that is, cAMP dependent and Ca2+. ā¢ The respective receptors for the actions are M3 and H2. ā¢ These receptors are modulated through the respective ionic mechanism and elicited by the acetylcholine from M3 and histamine from H2 receptor for release of the gastric acid mediated through H+ K+ ATPase pump. The proton pump inhibitors act on these receptors and inhibit H+ K+ ATPase and reduce the activation of parietal cells to release the gastric acid.
- 69. MOA of ProtonPump Inhibitors The ultimate mediator of acid secretion is the H+ - K+ ATPase ( Proton pump) of the parietal cell. All the PPI`s contain a sulphinyl (-SO-) group in a bridge between substituted benzimidazole & pyridine ring. At neutral pH these agents are chemically stable, lipid-soluble, weak-bases that are devoid of inhibitory activity. These drugs reach parietal cells from the blood gets protonated & thereby trapped. The protonated agent rearranges to form a sulphenic acid (-SOH) & Sulphenamide (-SN-). The sulphenamide interacts covalently with Sulfhydryl (-SH) group of cysteine of the H+/K+ ATPase enzyme i.e Proton Pump, & inhibit irreversibly & thereby blocks gastric acid secretion.
- 70. PPI`s Sulphenic acidSulphenamide Enzyme-Inhibitor Complex
- 71. Mast Cell Stabilizers ā¢ Itinhibits the release of histamine, leukotrienes & other substances that cause hypersensitivity reactions from the mast cells. ā¢ It is a mast cell stabilizer & it have anti-inflammatory activity. Cromolyn Sodium
- 72. Mast Cell Stabilizers MOAā¢ It inhibit degranulation of mast cells thus preventing the release of histamine. ā¢ It stabilizes the membranes of mast cells, stopping the release of allergy mediators (histamine, leukotrienes & others) & supressing activation of eosinophiles, neutrophiles, thrombocytes, & macrophages which takes part in the formation of bronchospasm.
- 73. Mast Cell Stabilizers ā¢Uses ā¢Bronchial Asthma ā¢ Used in Nasal Solution for allergic rhinitis ā¢ Eye drop to treat allergic conjuctivitis