1. Davis MDCH 5210 - Antihistamines, 2006 1 Histamine receptors – H 1 - Allergic responses. Watery eyes, congestion, etc. from allergies. Anaphylaxis – bronchial larynx constriction. Skin allergic response – reddening, rashes, welts. Edema from injury. H 2 –Gastric secretion. Important for ulcer treatment and acid reflux H 3 – ? CNS receptors. There are also H 1 receptors in the CNS. Antihistamines are also used for motion sickness. In general their antimuscarinic effects are similar to that of scopolamine, although weaker. Antihistamines

2. Davis MDCH 5210 - Antihistamines, 2006 2 Histamine Agonists

3. Davis MDCH 5210 - Antihistamines, 2006 3 Ethylenediamines Antihistamines – H 1 Blockers

4. Davis MDCH 5210 - Antihistamines, 2006 4 Aminoalkylethers Piperazine/N-heterocycle Series Antihistamine SAR

5. Davis MDCH 5210 - Antihistamines, 2006 5 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. Stereo- and regioisomers

6. Davis MDCH 5210 - Antihistamines, 2006 6 Alkyl Amines Long Duration, less sedation than ethylenediamines, ethanolamines. The “next best thing” until the “2nd generation” were developed.

7. Davis MDCH 5210 - Antihistamines, 2006 7 A Cl at the 2-position weakens H 1 activity relative to antimuscarinic activity and D 2 antagonist activity Rigid Analogs (I)

8. Davis MDCH 5210 - Antihistamines, 2006 8 PrimethixeneLoratadine (Claritin)Desloratadine (Clarinex) Rigid Analogs (II)

9. Davis MDCH 5210 - Antihistamines, 2006 9 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. Astemizole

10. Davis MDCH 5210 - Antihistamines, 2006 10 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! Antihistamines “related” to butyrophenones

11. Davis MDCH 5210 - Antihistamines, 2006 11 Butyrophenone-like structures

12. Davis MDCH 5210 - Antihistamines, 2006 12 Allegra Propaganda - www.allegra.com

13. Davis MDCH 5210 - Antihistamines, 2006 13 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. www.zyrtec.com

14. Davis MDCH 5210 - Antihistamines, 2006 14 Linking the first generation with Non-sedative Antihistamines. Big Picture - Bottom Line Structural Summary

15. Davis MDCH 5210 - Antihistamines, 2006 15 Anti-emetics

16. Davis MDCH 5210 - Antihistamines, 2006 16 Synthetic Tropane Alkaloids Anti-emetic Table

17. Davis MDCH 5210 - Antihistamines, 2006 17 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” 2005 Nobel Prize

18. Davis MDCH 5210 - Antihistamines, 2006 18 Gastric Secretions Cell Biology

19. Davis MDCH 5210 - Antihistamines, 2006 19 Gastric receptors are pharmacologically distinct. The classic H 1 antagonists don’t interact with H 2 receptors. Antihistamines are an important treatment for gastric disorders; antacids, ulcer treatment, acid-reflux disease. H 2 Histamine antagonists.

20. Davis MDCH 5210 - Antihistamines, 2006 20 H 2 Histamine antagonists. - Structures