Antihistaminic ppt

Antihistaminic ppt

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  Antihistaminic Agent
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  Histamine - Pharmacology • Histamineis an Autacoid , which are biological chemicals which act like local hormones, have a brief duration, and act near their site of synthesis. • Histamines has various function in body such as: – Mediator of inflamation and local immune responses – regulating physiological function in the gut and – acting as a neurotransmitter. • .
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  • During inflammationHistamine is produced by basophils and by mast cells, found in nearby connective tissues, which increases the permeability of the capillaries to white blood cells and some proteins, to allow them to engage pathogens in the infected tissues • In the gut it is produced by parietal cells and then promotes gastric acid secretion and thus aids in digestion. Here it acts like a local hormone • As a neurotranmitter, it effects sleeping and waking, food intake, thermal regulation, emotions and aggressive behavior, locomotion, memory, and learning
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  Histamine - Chemistry • Histamineis a Nitrogenous base. It is composed of an imidazole ring and ethylamine side chain.
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  Histamine Biosynthesis Note- There somedrugs that can block Histidine Decarboxylase such as Floromethylhistine which in theory can act as direct acting antihistamine but clinically were found to be not useful.
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  rage and ase • Storedin mast cells in Complex with Heparin (anticoagulant) • Stored in basophiles in Complex with Chondrotin • Histamine as stored in mast cells are found almost everywhere : skin and the mucosal cells of the bronchi, intestine, urinary tract, and tissues adjacent to the circulation and within neurons of CNS • It is released in response to a wide variety of immune (antigen and antibody) and nonimmune (bacterial products, xenobiotics,
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  Histamine receptors Locationand function H1, H2, H3, H4; they all are GPCR’s • H1 Location : CNS neurons, the smooth muscle of respiratory, GIT, uterine tissues, epithelial and endothelial cells, immune cells Function: vasodilation, vascular permeability, hypotension, pain, headache, tachycardia, nasal congestion, bronco-constriction, stimulation of cough receptors, allergic immune response • Therapeutic usage: H1 antihistamine are anti- allergic, and anti-emetic drugs, • H1 receptor is 40% similar to muscarinic receptors (thus some H1 antagonist shows unwanted antimuscaric side effect)
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  • H2 function- gastric acid secretion, vascular permeability, hypotension, flushing, headache, tachycardia, broncho-dilation and respiratory mucus production • Therapeutic use – H2 antihistamines are Anti-ulcer drugs • H3 Location : CNS • Function: adrenaline release and autoreceptor of Histamine in CNS • Therapeutic use – potential application against obesity • H4 function : differentiation of hematopoietic cells • Therapeutic use – none yet
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  Actions of Histamineby receptors
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  Adverse effects
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  Fig: Effects ofH1 antihistamines at histamine, adrenergic, cholinergic, and serotonin-binding receptors. Many second generation antihistamines do not enter the brain and, therefore, show minimal CNS effects.
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  H1 antihistamines • Their mainapplication is as anti-allergic, anti-emetic and • The first generation of H1 antihistamines has sedative effect due to effect on H1 receptor in brain. Structurally this effect is linked to their high lipophilicity induced BBB penetration and also they are poor substrate for brain’s endothelial P- glycoprotein efflux pumps, thus can’t exist the brain once they enter. • They also antagonize cholinergic receptors which causes dry mouth, dizziness, fatigue and are alpha adrenergic blockers which can cause cardiotoxicity by prolonging the QT interval • The second generation are more selective for H and don’t penetrate brain and thus has no sedation or cardiotoxicity • MOA: They bind and stabilize the inactive form of H1 receptors onto which Histamine is not capable of binding.
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  Therapeutic Uses:H1 blockers 1. dermatosis 2.allergic rhinitis 3. motion sickness & emesis 4. Parkinson’s disease 5. EPS 6. Insomnia
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  Classificatio n First Generation 1) Propylamines- Chlorpheniramine, Phenindamine 2) Ethanolamines - Diphenhydramine, Clemastine 3) Ethylenediamines - Pyrilamine, Tripelennamine 4) Phenothiazines - Promethazine, Trimeprazine 5) Piperazines - Cyclizine, Meclizine 6) Heptanes – Azatadine, Cyproheptadine 7) Phthalazinone – Azelastine Second Generation (Peripherally Selective) 1) Piperazine- Cetirizine/Levocetirizine 2) Piperidines - Fexofenadine, Loratadine /Desloratadine
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  Structure s Propylamine s Ethylenediamin es Ethanolamin es Piperazin es Heptane Phenothiazin es
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  SAR of H1antihistamines (1st gen only) Nsubstituent R2 C X (CH2) n R3 General framework of Anticholinergics Note the similarity in H1 antihistamines and Anticholinergics (this explains the origin of Anticholinergic side effect of H1 antihistamines) General framework of AntiHistamine (Ethanolamine based) R1
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  1. It needsa tertiary amine which is mostly di- methyl substituted or part of cyclic ring 2. The methylene (-CH2-)groups can be about 2 or 3 3. The oxygen can be removed or replaced with C 4. The terminal carbon must have two aromatic groups and R group is mostly H but can be CH3 too
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  5) Alkyl Substitutionin these aromatic rings influence selectivity • Increasing alkyl substituions at C4 increases anticholinergic activity and decreases antihistaminic activity • Increasing alkyl substituions at C2 decreases anticholinergic activity and modestly increases antihistaminic activity 6) Presence of halogen at C4 position enhances potency 7) Replacement of one of the aromatic rings with 2-pyridyl group increases histaminic selectivity 8) For max potency, the terminal carbon must have R configuration. R/S configuration at amine is less important
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  C O CH2CH2 N R1 1 2 3 4 5 6 2C 2C 2C 2C CH CH3 CH3 i-propyl C CH3 CH3 CH3 C2H5 CH3 Methyl Ethyl t-butyl Alkyl position Anticholinerg ic Antihistamini c At C2 Increases Decreases At C4 Decreases Increases Effect of increasing Alkyl group at C2 or C4
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  Halogen at C4 increases potency 2-pyridylring increases
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  Chlorpheniramin e • It isa propylamine based 1st generation H1 antihistaminic • It is chlorinated pheniramine which improves potency 10 times and changing toxicity • It’s Dextro isomer has S configuration and called DexChlorpheniramine is more potent • It also acts as serotonin-norepinephrine reuptake inhibitor or SNRI • It is combined with opiods for cough medicine because it can potentiate action of opiods • It causes drowsiness by penetrating into brain and acting on H1 receptor • Uses – Allergic rhinitis, in cough medicines • MOA (from above)
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  Zimelidine is ananti-depressent. It is a derivative of brompheniramine Note how a simple addition of double bond completely altered pharmacology of drug. But was this structural alteration randomly discovery or fully Intended? Brompheniramine H1 antihistaminic/Antiallergic Zimelidine Selective Serotonin reuptake inhibitor/ Antidepressent
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  Clemastin e • It isa ethanolamine based 1st generation H1 antihistaminic • This class has a longer duration of action (10-12 hrs) • It causes drowsiness by penetrating into brain and acting on H1 receptor • Uses – Allergic rhinitis, urticaria (itchy skin rash), anti- emetic • MOA (from above)
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  Pyrilamin e • It isa ethylenediaminebased 1st generation H1 antihistaminic • They are among the weakest antihistamines • It is combined with opiods for cough medicine because it can potentiate action of opiods • It causes drowsiness by penetrating into brain and acting on H1 receptor • Uses – Allergic rhinitis, incest bites (topically) • MOA (from above)
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  Promethazin e • It isa phenothiazine based 1st generation H1 antihistaminic • It’s sedative action is strong to be used clincally • It causes drowsiness by penetrating into brain and acting on H1 receptor • Uses – Allergic rhinitis, motion sickness, anti- emetic, sedative • MOA (from above)
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  Meclizin e • It isa Piperazine based 1st generation H1 antihistaminic • It has weak antihistaminic activity • It causes drowsiness by penetrating into brain and acting on H1 receptor • Uses – anti-emetic and motion sickness • MOA (from above)
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  Cyproheptadin e • It isa Heptane based 1st generation H1 antihistaminic • It possesses both antihistamine and anti- serotonin activity and is used as an anti-itch agent • It causes drowsiness by penetrating into brain and acting on H1 receptor • Uses – Allergic rhinitis, allergic conjunctivitis, allergic skin urticaria, hypersensitivity reactions • MOA (from above)
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  2nd generation H1 antihistamines •They don’t act on H1 receptor in brain because their lower lipophilicity doesn’t allow them to penetrate the BBB • They have low lipophilicity due to addition of hydrophilic groups OH, and COOH in the 1st gen molecules. (other hydrophilic groups can be NH2,NO2,SO4,PO4) • They have low affinity for off-targets such as muscarinic, adrenergic, and serotonergic receptors • Advantage – negligible sedation, no cardiotoxicity • Limitation – high selectivity for H1 prevents their use as anti-emetic, during motion sickness, potentiate cough medicines
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  Fexofenadin e • It isa piperadine based 2nd gen H1 antihistaminic • It produces no clinically significant Anticholinergic or α1-adrenergic blocking or sedative effect at therapeutic doses and is safe even in higher doses • It needs only single dosing daily • Uses – Allergic rhinitis, chronic urticaria • MOA (from above)
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  Cetirizine/Levocetirizi ne • It isa Piperazine based 2nd gen H1 antihistaminic • It produces no clinically significant Anticholinergic or α1-adrenergic blocking or sedative effect at therapeutic doses • It needs only single dosing daily • It’s R-enantiomer, called Levocetrizine, has 30- fold higher affinity than the S- enantiomer • Uses – Allergic rhinitis, relief from urticaria, water eyes caused by hay fever
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  Thank You