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PHYSIOLOGICAL EFFECTS OF ENDOGENOUS HISTAMINE • Mediator of hypersensitivity • Regulation of gastric acid secretion • Neurotransmitter in the CNS • HISTAMINE H1-ANTAGONISTS • Antihistamines historically refer to antagonists at H1 receptors. • First generation or Classical H1-antagonists include: – – – – – • • • • Aminoalkyl ethers Piperazines Propylamines Phenothiazines Dibenzocycloheptenes/heptanes Second or Non-sedating generation Some structural similarities to first generation. More specific in action –lesser side effects. Limited in distribution profiles STRUCTURE ACTIVITY RELATIONSHIPS • • • • • • • • • • • • General Antihistamine Structure Ar = Aryl (phenyl, substituted phenyl, heteroaryl) Ar’ = Second aryl or arylmethyl; X = O, C or N; (CH2)n = carbon chain; NRR’ = Terminal amine group Subclassification of 1st generation antihistamines is based on nature of the connecting atom; diaryl substitution pattern; and the terminal amine function Diaryl substitution: is essential for significant H1 binding; present in 1st and 2nd generation antihistamines; must not be co-planar; may be tricyclic e.g. Phenothiazines, Dibenzocycloheptanes Amine Moiety: may be: simple dimethyl amino or part of heterocycle e.g. some Phenothiazines, Dibenzocycloheptenes, 2nd generation antihistamines, etc. (CH2)n , n = 2 or 3 Diaryl causes 1st and 2nd generation antihistamines to be more hydrophobic than histamine. Atihistamine Metabolism Oral administration results in 1st pass metabolism N-dealkylation; deamination Amino acid/glucuronide conjugation; aromatic hydroxylation to form phenols which can then be conjugated. Ar' R X Ar (CH2)n N R' AMINOALKYL ETHERS (ETHANOLAMINES) • • General structure: Diaryl tertiary aminoalkyl ether moiety is a shared pharmacophore for muscarinic receptors. Aminoalkyl ethers display anticholinergic activity. R'' Ar' O Ar • • • R CH2 CH2 N R' Diphenhydramine Hydrochloride (Benadryl): Displays anticholinergic and sedative properties Oral, IM and IV administration. CHOCH2CH2N(CH3)2 HCl Diphenhydramine Hydrochloride …AMINOALKYL ETHERS (ETHANOLAMINES) • Dimenhydrinate (Dramamine) • • • Used against motion sickness (30 min before trip) and Hyperemesis gravidarum (nausea of pregnancy). Oral, IM and IV administration. H CHOCH2CH2N(CH3)2 O Cl Dimenhydrinate N N N N CH3 CH3 O …AMINOALKYL ETHERS (ETHANOLAMINES) • • • • • • Doxylamine Succinate (Decapryn Succinate) Potent like diphendydramine Has sedating action Carbinoxamine Maleate (Clistin) Potent antihistamine Is a racemic mixture Cl CH3 CHCOOH CH2COOH CHCOOH CH2COOH OCH2CH2N(CH3)2 OCH2CH2N(CH3)2 N Doxylamine Succinate Carbinoxamine Maleate N …AMINOALKYL ETHERS (ETHANOLAMINES) • • • • Clemastine Fumarate (Tavist) Dextro clemastine has 2 chiral centers. Long duration of action Also has antimuscarinic activity …AMINOALKYL ETHERS (ETHANOLAMINES) • • Phenyltoloxamine Aromatic rings located differently from diphenhydramine yet produces potent antihistamine activity CHOCH2CH2N(CH3)2 HCl Diphenhydramine Hydrochloride PROPYLAMINES (MONOAMINOPROPYL DERIVATIVES) • General Structure: Ar' R CH • • • • C H2 C H2 N Pheniramines Ar R' Propylamines with saturated connecting carbon; consist of phenyl and 2pyridyl aryl group and terminal dimethylamino. All pheniramines are chiral. Antihistaminic activity almost exclusively on S-stereomers. Pheniramines differ in phenyl substitution at para position: H, Cl and Br. Halogenation yields 20-50-fold more potency. Poor oral availability – Firstpass metabolism. Metabolism by mono- & di-N-dealkylation and NOxidation & amino acid conjugation. …PROPYLAMINES (MONOAMINOPROPYL DERIVATIVES) • • • Chlorpheniramine Maleate (ChlorTrimeton). Dextro enantromorph is most active. Half-life of 12-15 hrs. Chlorpheniramine or Dexchlorpheniramine maleate HC CH2CH2N(CH3)2 N CHCOOH CHCOOH Cl …PROPYLAMINES (MONOAMINOPROPYL DERIVATIVES) • • • Triprolidine Hydrochloride Geometric isomerism important for activity. Trans isomers (pyrrolidinomethyl group is trans to the 2-pyridyl group) possess activity. (E)- isomers are superior to (Z)- isomers as H1 antagonists. Triprolidine HCl N C C H C N H2 HCl CH3 PIPERAZINES (CYCLIZINES) • General Structure: CH • • • • • • • • • N N R Considered cyclic ethylenediamines X Connecting moiety is CHN Terminal amine and connecting N are part of piperazine ring. The 2 N are aliphatic with comparable pKas. Piperazines are characterized by slow onset and long duration of action. Peripheral and central antimuscarinic activity. Cyclizine Hydrochloride (Marezine) Light-sensitive crystalline powder with bitter taste. Cyclizine HCl or Treatment and prophylaxis of motion sickness. Lactate HC N N CH3 HCl or Lactate …PIPERAZINES (CYCLIZINES) • Meclizine HCl (Bonine, Antivert). • Used mainly against nausea and vomiting associated with vertigo and motion sickness. Meclizine HCl CH3 HC N N HCl Cl CH2 PHENOTHIAZINES • General Structure: R S N CH2CH(CH2)N R'' • • • • • • R' Ethylenediamines with bridged aryl units 2 or 3 carbons between ring system and terminal N. Branched alkyl chain is required for the antihistaminic phenothiazines but not the antipsychotic phenothiazines. Chirality close to alkyl N has less effect on antihistaminic activity. Metabolism by mono- & di-N-dealkylation, aromatic oxidation and Noxidation. Promethazine Hydrochloride (Phenergan) Promethazine HCl S N CH2CHN(CH3)2 CH3 HCl DIBENZOCYCLOHEPTENES/HEPTANES • General Structure: X N CH3 • • • • Related to the phenothiazines except that the S and N atoms are replaced by 2 and 1 carbons, respectively. Cyproheptadine Hydrochloride (Periactin) Possesses both antihistamine and antiserotonin. Antipruritic agent. Sedation as principal side effect. SECOND GENERATION H1-ANTAGONISTS • • • • • Structurally dissimilar; similar physiological profiles; high potency H1-antagonists Prolonged antihistaminic effects due to slow receptor dissociation and active antihistaminic metabolites. Less affinity for muscarinic, adrenergic and serotonergic receptors. Therefore less sedating side effects. Serious arrhythmias when co-administered with drugs that inhibit their metabolism such as imidazole antifungals. …SECOND GENERATION H1-ANTAGONISTS • • • • Fexofenadine (Allegra) Oxidized metabolite of Terfenadine Less cardiotoxic than Terfenadine. Marketed as a racemate. • • • • Selective for H1 with no sedative other CNS effects. Experimental evidence shows it does not cross the BBB. 60-70% protein-bound, 5% is metabolized. Remainder is eliminated in bile and urine. OH C CH3 HO N COOH CH3 HCl Fexofenadine Terfenadine …SECOND GENERATION H1-ANTAGONISTS • • • • • • • • Loratadine Structurally related to dibenzocycloheptenes/heptanes. Selective peripheral H1-antagonist. No CNS or autonomic side-effects. Half-life of 8-15 hr. Desloratadine (Clarinex) Metabolite of Loratadine More potent inhibitor of histamine release Cl N Loratadine N COOCH2CH3 Desloratadine (Clarinex) …SECOND GENERATION H1-ANTAGONISTS • • • • • • • Cetirizine (Zyrtec) Does not readily penetrate BBB. Minimal CNS side effects and cardiac rhythm. Levocetirizine (Xyzal) Developed from Cetirizine Active enantiomer Higher affinity than S enantiomer Cl Cetirizine HC N N CH2CH2OCH2COOH Levocetirizine (Xyzal) TOPICAL HISTAMINE H1-RECEPTOR ANTAGONISTS • • • • • • Azelastine (Astelin) Nasal spray for allergic rhinitis N-dealkylated metabolite is active Eyedrops for allergic conjunctivitis Emedastine (Emadine) Topically for conjunctivitis Azelastine Emedastine TOPICAL HISTAMINE H1-RECEPTOR ANTAGONISTS • • • • • • • Levocabastine (Livostin) Conjunctivitis Olopatadine (Patanol) Structurally related to tricyclic antihistamines Long duration of action Rapid onset Nasal and eyedrops Levocabastine Olopatadine …HISTAMINE H2-RECEPTOR ANTAGONISTS • Histamine H2 antagonist are structurally related to histamine General Structure of H2 Receptor Antihistamines H N R NHCH 3 X HN N Y …HISTAMINE H2-RECEPTOR ANTAGONISTS • • • • • • • Cimetidine (Tagamet) Relatively hydrophilic. Affects Cytochrome P-450 metabolism of drugs. 60-70% oral bioavailability. Plasma half-life of ~2 hrs. Famotidine (Pepcid) Treatment of duodenal and benign gastric ulcers, gastroesophageal reflux disease, pathologic hypersecretory conditions and heartburn. H3C CH2SCH2CH2CNH2 CH2SHCH2CH2NHCNH2CH3 N NSO2NH2 NCN HN N Cimetidine (H2N)2C N S Famotidine …HISTAMINE H2-RECEPTOR ANTAGONISTS • • • • • • • Ranitidine (Zantac) HCl salt is highly water-soluble. Plasma half-life of 2-3 hr. Used to treat active duodenal ulcers associated with H. pylori infections. Nizatidine (Axid) Soluble in water, chloroform and alcohol. Half-life of 1-2 hr. CH2SCH2CH2NHCNHCH3 CHNO2 (H3C)2N Ranitidine O CH2SCH2CH2NHCNHCH3 CHNO2 S N Nizatidine (H3C)2N