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Anti histaminic agent part-1.pptx

The document provides information about antihistaminic agents. It discusses autocoids and lists histamine as a classical amine autacoid. Histamine is synthesized from the amino acid histidine and acts as a mediator in allergic reactions, gastric acid secretion, inflammation and other physiological processes. The pathophysiological roles of histamine are described. There are four types of histamine receptors, H1-H4, with the H1 receptor increasing gastric acid secretion. First and second generation antihistamines are classified based on their structure and mechanisms of action. Specific examples of antihistamines from different classes are provided along with their uses.

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School of Pharmaceuticals and Population Health Informatics, Faculty of Pharmacy, DIT University, Dehradun, Uttarakhand-248009, India SUBJECT CODE - BP501T COURSE & YEAR - B. Pharm. & 3rd FACULTY NAME - Dr. Shashank Shekher Mishra Medicinal Chemistry-II 1
Anti HistaminicAgents PART- 1 2
Autocoids 3  Autos- Self, Akos- healing substance or remedy  Diverse substance produced by variety of cells in the body having intense biological activity, but act locally.  Local hormones  Classical autocoids-  Amine autocoids- Histamine, 5-hydroxytryptamine  Lipid derived autocoids- Prostaglandins, Leukotrienes, Platelet activating factor  Peptide autocoids- Plasma kinins, Angiotensin
4 Histamine 4  Tissue amine, Histos- Tissue  Present within storage granules of mast cell.  Histamine rich tissues = Skin, Gastric and intestinal mucosa, Lungs, Liver, Placenta.  Major mediator of allergy and inflammatory process.  Significant role in the regulation of gastric acid secretion, neurotransmission and immune modulation.  Histamine is also present in blood, most body secretions, venoms and pathological fluids.
5 Histamine Synthesis,storageanddegradation 5  β imidazolylethylamine  Synthesized locally from the amino acid histidine and degraded rapidly by oxidation and methylation.  Release = Histamine contain positive charge held by acidic protein and heparin (negative charge).  When granules are broken by exocytosis = Na+ is exchanged by Histamine. Decarboxylation of the amino acid L-Histidine yields Histamine
6 6 Pathophysiologicalroles 6  Gastric secretion:  Allergic phenomena: Exposure of an antigen to a previously sensitized(exposed) subject can immediately trigger allergic reactions ¨If sensitized by IgE antibodies attached to their surface membranes, mast cells will degranulate when exposed to the appropriate antigen & release histamine, ATP and other mediators  As transmitter: believed to be the afferent transmitter which initiates the sensation of itch and pain at sensory nerve endings.  Inflammation: mediator of vasodilatation
7 Histamine receptors
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15 Drugs that block the histamine release
16 Drugs having dual action
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18 1. Which class of antibody is associated with an allergic reaction? a) IgE b) IgA c) IgM d) IgG
19 2. Which of the following enzyme is essential for the conversion of histidine to histamine? (a)Histidine amylase (b)Histidine hydrolase (c)Histidine decarboxylase (d)Histidine phosphorylase
20 3. Which of the following histamine receptor increases the release of gastric acid? (a)H1 receptor (b)H2 receptor (c)H3 receptor (d)H4 receptor
21 1. First-Generation Antihistamine Classes A. AMINOALKYL ETHERS (ETHANOLAMINES) B. ETHYLENEDIAMINES C. PIPERAZINES (CYCLIZINES) D. PROPYLAMINES (MONOAMINOPROPYL OR ALKYLAMINE DERIVATIVES) E. PHENOTHIAZINES F. DIBENZOCYCLOHEPTENES AND DIBENZOCYCLOHEPTANES 2. Second-Generation Antihistamine Classes
22 A. AMINOALKYL ETHERS (ETHANOLAMINES) Diphenhydramine Hydrochloride 2-(diphenylmethoxy)-N,N- dimethylethanamine hydrochloride (Benadryl) Dimenhydrinate The 8-chlorotheophyllinate (theoclate) salt of diphenhydramine, 8- chlorotheophylline 2-(diphenylmethoxy)-N,N- dimethylethylamine (Dramamine) Recommended for nausea of motion sickness and for hyperemesis gravidarum (nausea of pregnancy) Other therapeutically useful derivatives of diphenthydramine have been obtained by para substitution of methyl (methyldiphenhydramine), methoxy (medrylamine), chloro (chlorodiphenhydramine), or bromo (bromodiphenhydramine) on one of the phenyl rings. N, N-dimethylethanolamine derivatives
23 23 A. AMINOALKYL ETHERS (ETHANOLAMINES) Bromodiphenhydramine Hydrochloride 2-[(4-bromophenyl)-phenylmethoxy]-N, N- dimethylethanamine hydrochloride (Ambodryl Hydrochloride) Doxylamine Succinate The acid succinate salt (bisuccinate) of doxylamine, 2-[-[2-(dimethylamino)ethoxy]- -methylbenzyl]pyridine bisuccinate (Decapryn Succinate)
24 24 24 A. AMINOALKYL ETHERS (ETHANOLAMINES) Carbinoxamine Maleate bimaleate salt, (d, l)-2-[p-chloro--[2- (dimethylamino)ethoxy]benzyl]pyridinebimalea te (Clistin) Clemastine Fumarate Dextrorotatory clemastine, R,R-2[2[1-(4-chlorophenyl)-1- phenylethoxy]ethyl]-1- methylpyrrolidine hydrogen furnarate
25 25 B. ETHYLENEDIAMINES Thonzylamine Methapyrilene Pyrilamine Maleate Tripelennamine Hydrochloride
26 26 26 C. PIPERAZINES (CYCLIZINES) Cyclizine Hydrochloride Chlorcyclizine Hydrochloride Meclizine Hydrochloride Buclizine Hydrochloride
27 D. PROPYLAMINES (MONOAMINOPROPYL OR ALKYLAMINE DERIVATIVES) Pheniramine Maleate Chlorpheniramine Maleate Brompheniramine Maleate
28 Pyrrobutamine Phosphate Triprolidine Hydrochloride
29 E. PHENOTHIAZINES Promethazine Hydrochloride Trimeprazine Tartrate
30 F. DIBENZOCYCLOHEPTENES AND DIBENZOCYCLOHEPTANES The dibenzocycloheptene and dibenzocycloheptane antihistamines may be regarded as phenothiazine analogs in which the sulfur atom has been replaced by an isosteric vinyl group or a saturated ethyl bridge. Azatadine Maleate Cyproheptadine Hydrochloride
31 Miscellaneous - Diphenylpyraline Hydrochloride 4-(diphenylmethoxy)-1-methylpiperidine Hydrochloride - Antazoline Phosphate N-(4,5-Dihydro-1H-imidazol-2-ylmethyl)-N- (phenylmethyl)aniline - Phenindamine Tartrate 2-methyl-9-phenyl-2,3,4,9-tetrahydro-1H- indeno[2,1-c]pyridine
32 2. Second-Generation Antihistamine Classes -lower sedation potential and reduced binding affinities for nontarget proteins including muscarinic, adrenergic, and serotonergic receptors. Terfenadine Astemizole - Astemizole and terfenadine proved to be “nonsedating” and target-receptor selective. - Serious cardiovascular toxicities (QT prolongation and arrhythmias). Both astemizole and terfenadine have been withdrawn from the U.S. market.
33 Further drug design efforts resulted in the discovery of new second- generation agents, which retained the nonsedating and receptor- selectivity properties, but lacked the cardiotoxicity of astemizole and terfenadine. Acrivastine, an alkene-acid derivative of triprolidine (E)-3-{6-[(E)-1-(4-methylphenyl)-3- pyrrolidin-1-yl- prop-1-enyl]pyridin-2-yl}prop-2-enoic acid
34 Cetirizine and Levocetirizine, oxidation metabolites of hydroxyzine Hydroxyzine - Does not penetrate or accumulate in the CNS. - R-enantiomer is has a 30-fold higher affinity than the S- enantiomer, and dissociates more slowly from H1-receptors. - Pharmacologically, it displays the same receptor and CNS selectivity profile as the racemate, cetirizine.
35 Fexofenadine Hydrochloride 2-[4-[1-hydroxy-4-[4 [hydroxy(diphenyl)methyl]piperidin-1- yl]butyl]phenyl]-2-methylpropanoic acid Fexofenadine is a primary oxidative metabolite of terfenadine. No sedative or other CNS effects Does not cross the BBB
36 Loratadine Loratadine is structurally related to the antihistamines azatadine and cyproheptadine, and to some tricyclic antidepressants. It differs from azatadine, in that a neutral carbamate group has replaced the basic tertiary amino moiety, and a phenyl ring has been substituted with a chlorine atom. Ethyl 4-(8-chloro-5,6-dihydro-11H- benzo[5,6]cyclohepta[1,2-b]pyridin- 11-ylidene)piperidine-1-carboxylate
37 INHIBITION OF HISTAMINE RELEASE: MAST CELL STABILIZERS Stabilize mast cells and inhibit the release of histamine and other mediators of inflammation. Cromolyn Sodium - Nedocromil Sodium - Lodoxamide Tromethamine
38 Structure activity relationship (general structure of the H1 receptor antagonist) Where , Ar1 = Phenyl group Ar2 Phenyl, benzyl, pyridyl or thenyl group 38 Substitution on aryl group Replacement of aliphatic N group With small basic heterocyclic ring Increased branching on Substitution between X and N Modify the potency, metabolism, ability to reach the site of action & toxicity in vivo.
39 Ar1 and Ar2 substituents These provide bulk producing antagonistic activity Generally two aromatic rings - phenyl, benzyl, or an isostere such as pyridyl; Pyridyl generally results in more potent compounds than phenyl If fused must be non–coplanar as in the three ringed structures related to TCA’s and phenothiazines Para substitution with small lipophilic groups increases potency and decreases metabolism due to decreased ring hydroxylation. Ortho or meta substitution reduces antihistaminic activity 39
40 This diaryl pattern is present in both first- and second-generation antihistamines. X Atom X can be an oxygen, nitrogen, or carbon, which links the side chain to an “aromatic tail.” The nature of atom X is the basis for the structural classification of H1 antagonists. The classical H1 antagonists are divided into six classes based on what X equals: X =C–O: (Aminoalkyl Ethers) 1. Ethanolamines 2. Propanolamines (clemastine, diphenylpyraline) X = C 3. Propylamines (Saturated and Unsaturated)
41 X = N: 4. Ethylenediamines 5. Piperazines (Cyclizines) and Tricyclics 6. Miscellaneous: This forms the sixth class of traditional antihistamines and would include many of the newer antihistamines since they do not fall into one of the older, traditional, classes. 41
42 Mechanismof Actionof H1 antihistamines
Uses Drugs Uses Diphenhydramine New widely used for the nausea of motion sickness and for nausea of pregnancy Tripelennamine 1. Used for euphoriant 2. Tranquillising effect Pheniramine Used as antihistamanic Chlorpheniramine 1. Adjunct therapy in anaphylatic shock 2. Allergic and basomotor stimuli, allergic conjunctivitis 3. Allergic rhinitis, in cough medicines Dexchlorphenirami ne Used to treat allergic condition such as hay fever or urticaria Promethazine 1. 1st generation H1 receptor antagonist and anti-emetic 2. Strong anticholinergic and sedative/hypnotic effect 3. Previously used as antipsychotic Cyproheptadine Both antihistamanic and used in hypersensitivity reactions 43
Uses Drugs Uses Antazoine 1. It is used to releive nasal congestion and in eye drops Antazoline+nephazoline Relieve symptoms of allergic conjunctivitis Clemastine 1. Allergic rhinitis, urticaria (itchy skin rash),anti-emetic Pyrilamine Allergic rhinitis, incest bites(topically) Meclizine Anti-emetic and motion sickness Cetrizine Allergic rhinitis Astimazole It gives protection against asthma, hay fever, chronic utricaria Dimenhydramine+ chlortheophylline 1. Nausea and motion sickness 2. Antiemetic and sedative in housepets 44
Diphenhydramine hydrochloride 45
Triprolidine 46
Promethazine 47
Thank You 48