Anti histamines-1.pptx

Anti histamines

1. ADVANCED MEDICINAL CHEMISTRY ANTI-HISTAMINES Presented to: Dr . Huma Rao Presented by : Abdul Rauf M.Phil pharmaceutical Chemistry 1

2. Topics Introduction Histamine Receptors- Types & Role H1 Anti-Histamines Mechanism of Action Classification Structure Activity Relationship in General Structure Activity Relationship with respect to each Functional Class Pharmacokinetics of H1 Anti-Histamines H2 Antihistamines Mode of Action Drugs & SAR H3 & H4 Antihistamines 2

3. Introduction Histamine, chemically known as 4(5)-(2-aminoethyl) imidazole , is an endogenous biologically active substance act as an important chemical transmitter Histamine is formed by the decarboxylation of histidine catalyzed by Histidine decarboxylase It is released in response to endogenous or exogenous responses 3

4. Histamine Receptors Histamine receptors are hepta -helical trans membrane molecules that transduce extracellular signals by way of G-proteins, to intracellular second messenger systems. H 1  receptors couple to G q  which regulates Ca ++  mobilization, H 2  receptors couple to G s  to stimulate cyclic AMP, H 3  and H 4  receptors both couple to G i /o  to inhibit cyclic AMP accumulation.  The active and inactive states of these receptors exist in equilibrium; at rest, the inactive state isomerizes with the active state and vice versa 4

5. Histamine Receptors 5 H1 Receptors H2 Receptors H3 Receptors H4 receptors Receptor Expression Nerve cells, airways, smooth muscles, epithelial cells , eosinophils, neutrophils, monocytes , T & B lymphocites cells, hepatocytes , Chondrocytes Nerve cells, airways, vascular smooth muscle, endothelial cells, epithelial cells High expression in histaminergic neurons, monocytes , low expression in peripheral tissues High expression on bone marrow , hematopoietic cells, eosinophils, neutrophils, T cells , mast Cells Histamine function in general Increase Pruritis , pain , vasodilatation, vascular permeability , flushing , headache, tachycardia, bronco-constriction, cough Increase gastric acid secretion Tachycardia, hypotension Increase pruritis , nasal congestion , prevent excessive bronco-constriction No involvement of Mast cells Increase Pruritis , differentiation of myeloblasts , no involvement of mast cells Histamine function in the CNS Sleep/wakefulness, food intake, thermal regulation, emotions/aggressive behavior, locomotion, memory, learning Neuroendocrine Presynaptic heteroreceptor ; ↓ histamine, dopamine, serotonin, noradrenaline , and acetylcholine release To be defined

6. 6 H1 Receptors H2 Receptors H3 Receptors H4 receptors Histamine function in allergic inflammation and immune modulation ↑ Release of histamine and other mediators; ↑ cellular adhesion molecule expression and chemotaxis of eosinophils and neutrophils; ↑ antigen-presenting cell capacity, co-stimulatory activity on B cells; ↑ cellular immunity (Th1), ↑ autoimmunity; ↓ humoral immunity and IgE production ↑ Eosinophil and neutrophil chemotaxis ;↓ IL-12 by dendritic cells; ↑ IL-10 and development of Th2 or tolerance-inducing dendritic cells; ↑ humoral immunity;↓ cellular immunity; suppresses Th2 cells and cytokines; indirect role in allergy, autoimmunity, malignancy, graft rejection Probably involved in control of neurogenic inflammation through local neuron-mast cell feedback loops; ↑ proinflammatory activity and APC capacity ↑ Calcium flux in human eosinophils; ↑ eosinophil chemotaxis ; ↑ IL-16 production (H 2  receptor also involved)

7. H1 Anti-Histamines- Mode of Action H 1  antihistamines act as inverse agonists They combine with and stabilize the inactive conformation of the H 1  receptor, shifting the equilibrium toward the inactive state. H 1  antihistamines down-regulate allergic inflammation directly through the H 1  receptor indirectly through nuclear factor-κB, an ubiquitous transcription factor, through which they down-regulate antigen presentation, expression of pro-inflammatory cytokines and cell adhesion molecules, and chemo taxis. 7

8. H1 Anti-Histamines- Classification Based Upon Chemical Groups (06 Groups) Alkyl amines, Ethanolamine, Ethylene diamine , Phenothiazines , Piperazines, Piperidines . Based Upon Pharmacological Action (More important) First-generation Readily cross the blood brain barrier and Sedate and impair cognitive and psychomotor function Some of these antihistamines have been modified into antidepressants ( tricyclic antidepressants ) Second-generation Do not cross the blood-brain barrier to a significant extent Relatively non-sedating and non-impairing. Highly Specific & Selective for H1 Receptors 8

9. Sr. no Name of Group 1 st Generation 2 nd Generation 1 Alkylamines Brompheniramine , chlorpheniramine , dimethindene ,**, ‡  pheniramine , ‡  triprolidine Acrivastine 2 Ethanolamine s Carbinoxamine , clemastine , dimenhydrinate , diphenhydramine , doxylamine , phenyltoloxamine * 3 Ethylenediamine Antazoline , pyrilamine , tripelennamine 4 Phenothiazides Methdilazine , promethazine 5 Piperazine Buclizine , cyclizine , hydroxyzine ,* meclizine , oxatomide * Cetirizine ,* levocetirizine 6 Piperidine Azatadine , cyproheptadine , diphenylpyraline , ketotifen Astemizole ,** bilastine ,** desloratadine ,* ebastine ,** fexofenadine ,* levocabastine , ‡  loratadine ,* mizolastine ,** olopatadine , ‡  rupatadine ,** terfenadine 9

10. Structure Activity Relationship General structure of H1 antagonists 10

11. I Two aromatic rings are essential Ar ’ : It may be aryl or heteroaryl Ar ’’ : it may be aryl or heteroaryl Or methyl aryl II it may be O, N, C is essential for activity III most antihistamines have ethylene chain Extension & branching of chain decreases activity Homologation : increase neuroleptic &anti –depressant activity IV Tertiary amine group is essential for activity This N may be present in the form of heterocyclic ring 11

12. Drugs and Structure (Aryl Groups) 1.Diphenhydramine 2.Pyrilamine 3.Doxylamine 4.Bromodiphenhydramine Substitution at Para-position with electron withdrawing group can enhance the activity Bromo group – antimicrobial activity 12

13. Drugs and Structure (X Group) It is one of the most important group and chemical classification is based on this group 13

14. III ethylene chain is present in most of the antihistamines Homologation of the chain result in the enhance Neuroleptic and antidepressant activity IV Tertiary amine is important for activity Generally di -amine group is present But the Nitrogen atom might be in the ring structure Drugs and Structure 14

15. Structure Activity Relationship of H1-Antihistamines with their Chemical Classification 15

16. 16 Alkyl amines Chlorphineramine 20-40times more potent than Phineramine S enantiomer is more potent (200-1000 times) Used as Gold standard Tripolidine (1 st Gen) Alkene side chain enhance the potentcy E isomer is 1000 times more potent than Z isomer Acarvistine (2 nd Gen) Carboxyethylene derivative of tripolidine less muscarinic side effects Used as tablets 8-60mg These are one of the most potent H1 antihistamines , having relatively longer half lives .

17. 17 Ethanol amines( Amino Alkyl Ethers) Diphenhydramine : (1 st Gen) Bromo & Chloro Derivatives are more potent Significant anti- cholenergic activity Effects : motion sickness , anti- Parkinsonism Sleeping Aid Dimenhydrinate (1 st Gen) Salt of diphenhydramine ( theoclate /8, Chlorotheophynilate ) Act on Histamine receptors in CTZ , centrally acting antihistamine

18. 18 Ethanol amines( Amino Alkyl Ethers) Doxylamine (1 st Gen) Antihistamine potency is equivalent to diphenhydramine But it is used as night time sedative in mild sleep disorders Clemastine : (1 st Gen) Nitrogen is present in the form of ring structure Dextrorotatory is active isomer Used in allergies , lesser CNS effects

19. 19 Ethylene diamines Triplennamine (1 st Gen) Potency equal to diphenhydramine Anti chlonergic effects are lesser Moderately effective Pyrilamine (1 st Gen) Methoxy derivative of triplennamine As they are moderately effective

20. 20 Phenothiazides Methadilazine (1 st Gen) have local anesthetic properties Lead to the development of antipsychotic drugs It is not currently used Promethazine (1 st Gen) Used in allergies as elixir in children Phenergan

21. 21 Piperazines ( Cyclizines ) Also called as cyclic diamines These are moderately potent antihistamine activity High potential to cause psychomotor dysfunction Slow onset of action -Long Duration of action Cyclizine Hydrochloride(1 st gen) : Prophylactic use in motion sickness As IM injection

22. 22 Piperazines ( Cyclizines ) Hydroxyzine is 1 st generation drug Cetrizine (2 nd Gen) is its metabolite Relatively more polar Donot cross BBB More potent antihistamine as compared to others Levocetrizine : levo -isomer of Cetrizine more active

23. 23 Piperidine Derivatives Diphenylpyraline (1 st Gen) 1 st generation drug Strong antichlenergic properties Not used as antihistamine It has further two types 1- Simple Piperidine Derivatives 2- Dibezocycloheptenes (contain seven membered fused ring)

24. 24 Piperidine Derivatives Terfinadine (2 nd gen) Selective long acting H1 antihistamine It lacks anticholenergic properties But it blocks Potassium channels in cardiocytes Prolong QT interval Fexofenadine (2 nd Gen) Active metabolite of Terfinadine , now developed as a drug No effect on cardiocytes

25. 25 Piperidine Derivatives( Dibenzocycloheptenes ) Cyroheptadine antihistamine & anti-Serotonin Activity Appetite Stimulant Used in mild depression Loratadine (2 nd Gen) Potency is greater then terfinadine Selective peripheral H1 antagonist No substantial Side effects Desloratadine (2 nd Gen) Active metabolite of loratadine Used widely in different form of allergies

26. Pharmacokinetics Generation Drug Onset of action Half life Metabolism Excretion 1 st Chlorpheniramine 3 28 In GIT Kidneys 1 st Diphenhydramine 2 9.2 Liver & conjucated with Glycine and glucuronidase Kidneys 1 st Hydroxyzine 2 20 Liver (95% converted into cetrizine ) Kidneys 2 nd Cetrizine 1 6.5 Not metabolized Unchanged through kidneys 2 nd loratidine 2 24 Liver( descarbodexoyloratidine ) Kidneys and GIT 2 nd Desloratidine 1 27 Liver(3-hydroxydesloratidine) Kidneys and GIT 2 nd Terfinadine 2 12 Liver ( fexofenadine 30% ) GIT & Kidneys 2 nd Fexofenadine 2 14 Not metabolized GIT 2 nd Ebastine 2 10 Liver ( cerebastine ) Kidneys 26

27. H2 Anti-Histamines- Mode of Action H 2  antihistamines act as competitive antagonist Gastrin stimulates histamine release from enterochromaffin -like cells H2 receptor activation result in activation of adenylate cyclase , which raises intracellular cAMP levels. cAMP then activates protein kinase A (PKA) PKA stimulate H+/K+ ATPase transporters at the plasma membrane allows for the secretion of more acid from parietal cells 27

28. H2 Anti-Histamines- Structure These are structurally related to histamine molecule 28 Cimetidine 60-70% oral bioavailability Stable Inhibit CYP isozymes Interaction with other drugs Famotidine 65-70% oral bioavailability Extent to inhibit CYP is lesser More potent than Cimetidine Used in benign gastric & Duodenal ulcers,

29. 29 Ranitidine 50% oral bioavailability Potent than Cimetidine Used in active Ulcers Currently its license is under suspension NDMA impurities Nizatidine > 90% oral bioavailability Don’t interfere with CYP isozymes Used in active Ulcers

30. H3 & H4 Anti-Histamines These Receptors are widely distributed in CNS Research is being conducted in their role in pathology of CNS disorders(Alzheimer Disease & Parkinson's Disease) Only One H3 Blocker i.e. Betahistine is available in the market Used for the treatment of Ménière’s disease Role of these receptors in other inflamatory conditions is also under investigation 30 Structure of Betahistine

31. References: Text Book of Organic Medicinal and Pharmaceutical Chemistry by Wilson & Gisvold H 1  Antihistamines:  Current Status and Future Directions. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3650962/ https://www.youtube.com/watch?v=2cA8X1TClkg&ab_channel=Dr.ParjanyaShukla%26Dr.M.P.SinghClasses https://en.wikipedia.org/wiki/H1_antagonist New antihistamines – perspectives in the treatment of some allergic and inflammatory disorders. https://www.archivesofmedicalscience.com/New-antihistamines-perspectives-in-the-treatment-of-some-allergic-and-inflammatory,69448,0,2.html 31