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Antihistamines Histamine receptors – H1- Allergic responses. Watery eyes, congestion, etc. from allergies. Anaphylaxis – bronchial larynx constriction. Skin allergic response – reddening, rashes, welts. Edema from injury. H2 – Gastric secretion. Important for ulcer treatment and acid reflux H3 – ? CNS receptors. There are also H1 receptors in the CNS. Antihistamines are also used for motion sickness. In general their antimuscarinic effects are similar to that of scopolamine, although weaker. 1 Davis MDCH 5210 - Antihistamines, 2006 H HN NH 2 HN Histamine N H Histamine Agonists NH 2 N 2-methyl histamine H1 Agonist CH3 H3 C HN NH 2 N H HN NH 2 N H3 C H 4-methylhistamine H2 Agonist (R)-methyl histamine H3 Agonist 2 Davis MDCH 5210 - Antihistamines, 2006 Antihistamines – H1 Blockers Ethylenediamines Ar1 X (CH 2 )n N Ar2 CH 3 CH 3 SAR Prototype CH 3 Phenbenzamine N CH 3 N HN Antazoline N N 3 Davis MDCH 5210 - Antihistamines, 2006 R1 CH 3 H N O O CH 3 CH 3 N Antihistamine SAR CH 3 SAR Prototype R1 is a small group like H, CH 3,OCH3 Aminoalkylethers Diphenhydramine (Benadryl) Cl O NCH 3 Cl Diphenylpyraline N Meclizine Good H1 antagonist, but also good antimuscarinic N Piperazine/N-heterocycle Series CH 3 Cl CH 3 O Clemastine (Tavist) N CH 3 4 Davis MDCH 5210 - Antihistamines, 2006 Stereo- and regioisomers Antihistamines are stereospecific. A number of new, single isomer drugs are being developed. Antihistamines are structurally similar To SSRIs and to antipsychotics. Notice The subtle difference between fluoxetine And several antihistamines. 5 Davis MDCH 5210 - Antihistamines, 2006 Alkyl Amines N CH3 N CH3 N R Cl R = H Pheniramine R = Cl Chlorpheniramine (Chlortrimeton) R = Br Brompheniramine (Dimetane) Pyrrobutamine (Pyronil) N N H3 C N CH3 N CH3 N CH 3 CH3 Triprolidine (Actidil) Dimethindene (Forhistal) Phenindamine (Nolahist) Long Duration, less sedation than ethylenediamines, ethanolamines. The “next best thing” until the “2nd generation” were developed. 6 Davis MDCH 5210 - Antihistamines, 2006 Rigid Analogs (I) A Cl at the 2-position weakens H1 activity relative to antimuscarinic activity and D2 antagonist activity S N N Mebhydrolin Cl CH2 CH2 CH2 N(CH 3 )2 NCH 3 Chlorpromazine S N Fenthazine N CH2 CH2 N(CH 3 )2 N N N S OCH 3 H Promethazine (Pheregan) N CH2 CHN(CH 3 )2 CH3 F Astemizole (Hismanal) 7 Davis MDCH 5210 - Antihistamines, 2006 Rigid Analogs (II) S Cl Cl N N N N CH3 Primethixene N O OCH2CH 3 Loratadine (Claritin) H Desloratadine (Clarinex) 8 Davis MDCH 5210 - Antihistamines, 2006 Astemizole N N N N F OCH 3 H Astemizole (Hismanal) Hismanal was FDA approved in 1988 as an antihistamine for allergy and hay fever symptom relief. The FDA first warned consumers and healthcare providers of new safety information regarding Hismanal February 9, 1998 due to the risk of death, cardiovascular adverse events, anaphylaxis, and serious drug interactions. In addition, Hismanal labeling was changed to stress avoiding the use of Hismanal in combination with certain other medications and for liver disorder patients to completely avoid its' use. After a series of labeling changes and warnings Hismanal was recalled on June 21, 1999. 9 Davis MDCH 5210 - Antihistamines, 2006 Antihistamines “related” to butyrophenones Terfenadine was discontinued when it became apparent that there was a high frequency of heart arrythmia associated with the drug. Fexofenadine is a metabolite and is the activated form responsible for antihistamine activity. In patients with compromised liver metabolism, or when the presence of other drugs limited the metabolism of terfenadine, persistent levels resulted in the observed arrythmias. Therefore, the fexofenadine replaced terfenadine (1997). Ventricular Arrythmias are not good! F OH N Haloperidol (Haldol) Prototype butyrophenone antipsychotic 10x Chlorpromazine O Cl 10 Davis MDCH 5210 - Antihistamines, 2006 Butyrophenone-like structures OH Terfenadine (Seldane) N OH [OX] COOH OH Fexofenadine (Allegra) N OH H Cl N N OH O Cetirizine (Zyrtec) O 11 Davis MDCH 5210 - Antihistamines, 2006 Allegra Propaganda - www.allegra.com 12 Davis MDCH 5210 - Antihistamines, 2006 www.zyrtec.com If you haven't gotten the relief you want from Claritinィ (loratadine), Clarinexィ (desloratadine), or Allegraィ (fexofenadine HCl), ask your doctor if ZYRTEC is right for you. 13 Davis MDCH 5210 - Antihistamines, 2006 Structural Summary Linking the first generation with Non-sedative Antihistamines. Big Picture - Bottom Line Cl O N N CH3 N CH3 CH3 Diphenhydramine Meclizine Cl O NH Cl N O OH N N Desloratadine Cetirizine 14 Davis MDCH 5210 - Antihistamines, 2006 Anti-emetics 15 Davis MDCH 5210 - Antihistamines, 2006 Anti-emetic Table Synthetic Tropane Alkaloids 16 Davis MDCH 5210 - Antihistamines, 2006 2005 Nobel Prize Press Release: The 2005 Nobel Prize in Physiology or Medicine 3 October 2005 The Nobel Assembly at Karolinska Institutet has today decided to award The Nobel Prize in Physiology or Medicine for 2005 jointly to Barry J. Marshall and J. Robin Warren for their discovery of "the bacterium Helicobacter pylori and its role in gastritis and peptic ulcer disease” 17 Davis MDCH 5210 - Antihistamines, 2006 Gastric Secretions Cell Biology 18 Davis MDCH 5210 - Antihistamines, 2006 H2 Histamine antagonists. Gastric receptors are pharmacologically distinct. The classic H1 antagonists don’t interact with H2 receptors. Antihistamines are an important treatment for gastric disorders; antacids, ulcer treatment, acid-reflux disease. 19 Davis MDCH 5210 - Antihistamines, 2006 H2 Histamine antagonists. - Structures H H H N N H3 C N H N N H N N O CH3 CHNO2 N CN CH2 N(CH3) 2 Cimetidine (Tagamet) S N N H S CH3 N S S H S HN N Metiamide (H2 Selective) Burimamide (Non-selective) H3 C N CH3 N HN S H S CH3 HN H Ranitidine (Xantac) NH2 NSO2 NH2 Famotidine (Pepcid) C(NH2)2 20 Davis MDCH 5210 - Antihistamines, 2006