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Anti histamines-1.pptx

This document discusses anti-histamines, including H1, H2, H3, and H4 receptor types and their roles. It focuses on H1 anti-histamines, covering their mechanism of action as inverse agonists, classifications as first or second generation, and structure-activity relationships. First generation drugs readily cross the blood-brain barrier and can cause sedation, while second generation are less sedating. The document discusses various chemical groups of H1 anti-histamines and provides examples of drugs for each group along with notes on their potency and usage.

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ADVANCED MEDICINAL CHEMISTRY ANTI-HISTAMINES Presented to: Dr. Huma Rao Presented by : Abdul Rauf M.Phil pharmaceutical Chemistry 1
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
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
Histamine Receptors Histamine receptors are hepta-helical trans membrane molecules that transduce extracellular signals by way of G-proteins, to intracellular second messenger systems. H1 receptors couple to Gq which regulates Ca++ mobilization,  H2 receptors couple to Gs to stimulate cyclic AMP, H3 and H4 receptors both couple to Gi/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
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 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 (H2 receptor also involved)
H1 Anti-Histamines- Mode of Action H1 antihistamines act as inverse agonists They combine with and stabilize the inactive conformation of the H1 receptor, shifting the equilibrium toward the inactive state. H1 antihistamines down-regulate allergic inflammation directly through the H1 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
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
Sr. no Name of Group 1st Generation 2nd Generation 1 Alkylamines Brompheniramine, chlorpheniramine, dimethindene,**,‡ pheniramine,‡ triprolid ine Acrivastine 2 Ethanolamines 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
Structure Activity Relationship General structure of H1 antagonists 10
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
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
Drugs and Structure (X Group) It is one of the most important group and chemical classification is based on this group 13
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
Structure Activity Relationship of H1-Antihistamines with their Chemical Classification 15
16 Alkyl amines Chlorphineramine 20-40times more potent than Phineramine S enantiomer is more potent (200-1000 times) Used as Gold standard Tripolidine (1st Gen) Alkene side chain enhance the potentcy E isomer is 1000 times more potent than Z isomer Acarvistine (2nd 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 Ethanol amines( Amino Alkyl Ethers) Diphenhydramine : (1st Gen) Bromo & Chloro Derivatives are more potent Significant anti-cholenergic activity Effects : motion sickness , anti- Parkinsonism Sleeping Aid Dimenhydrinate (1st Gen) Salt of diphenhydramine (theoclate/8, Chlorotheophynilate ) Act on Histamine receptors in CTZ , centrally acting antihistamine
18 Ethanol amines( Amino Alkyl Ethers) Doxylamine (1st Gen) Antihistamine potency is equivalent to diphenhydramine But it is used as night time sedative in mild sleep disorders Clemastine : (1st Gen) Nitrogen is present in the form of ring structure Dextrorotatory is active isomer Used in allergies , lesser CNS effects
19 Ethylene diamines Triplennamine (1st Gen) Potency equal to diphenhydramine Anti chlonergic effects are lesser Moderately effective Pyrilamine (1st Gen) Methoxy derivative of triplennamine As they are moderately effective
20 Phenothiazides Methadilazine(1st Gen)  have local anesthetic properties Lead to the development of antipsychotic drugs It is not currently used Promethazine(1st Gen) Used in allergies as elixir in children Phenergan
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(1st gen) : Prophylactic use in motion sickness As IM injection
22 Piperazines (Cyclizines) Hydroxyzine is 1st generation drug Cetrizine (2nd 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 Piperidine Derivatives Diphenylpyraline (1st Gen) 1st 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 Piperidine Derivatives Terfinadine (2nd gen) Selective long acting H1 antihistamine It lacks anticholenergic properties But it blocks Potassium channels in cardiocytes Prolong QT interval Fexofenadine(2nd Gen) Active metabolite of Terfinadine, now developed as a drug No effect on cardiocytes
25 Piperidine Derivatives(Dibenzocycloheptenes) Cyroheptadine  antihistamine & anti- Serotonin Activity  Appetite Stimulant Used in mild depression Loratadine (2nd Gen) Potency is greater then terfinadine Selective peripheral H1 antagonist No substantial Side effects Desloratadine (2nd Gen) Active metabolite of loratadine Used widely in different form of allergies
Pharmacokinetics Genera tion Drug Onset of action Half life Metabolism Excretion 1st Chlorpheniramine 3 28 In GIT Kidneys 1st Diphenhydramine 2 9.2 Liver & conjucated with Glycine and glucuronidase Kidneys 1st Hydroxyzine 2 20 Liver (95% converted into cetrizine) Kidneys 2nd Cetrizine 1 6.5 Not metabolized Unchanged through kidneys 2nd loratidine 2 24 Liver(descarbodexoyloratidine) Kidneys and GIT 2nd Desloratidine 1 27 Liver(3-hydroxydesloratidine) Kidneys and GIT 2nd Terfinadine 2 12 Liver (fexofenadine 30%) GIT & Kidneys 2nd Fexofenadine 2 14 Not metabolized GIT 2nd Ebastine 2 10 Liver (cerebastine) Kidneys 26
H2 Anti-Histamines- Mode of Action H2 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
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 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
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
References: Text Book of Organic Medicinal and Pharmaceutical Chemistry by Wilson & Gisvold H1 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.Parjanya Shukla%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