1. Pharmaceutical Chemistry II Lectures Introduction to Antihistamines &
Joseph O. Oweta | PHC 3201

2. Objectives Introduction to Antihistamines & Ethanolamines
Allergies and Histamine
2. Antihistamines and their MOA
3. Classification of Antihistamines
4. SAR's of AntiHistamines

3. Allergies and Histamine
An allergy is a response by the body to something that is ordinarily harmless.
The purpose of the immune system is to recognize harmful infection-causing invaders and to get rid of them.
However, for some people, the immune system overreacts to ordinarily harmless substances.
These people have “allergies.”
Their bodies attempt to expel these ordinarily harmless substances, causing sneezing; a runny nose; itchy, watery eyes etc

4. Allergies and Histamine
Atopy may be an inherited trait
In its sequel, there is initial exposure to an allergen.
Allergic reactions can involve most of the major components of the immune system, including:
the cellular elements,
immunoglobulin,
complement,
and cytokines.

5. Allergies and Histamine Nature
Histamine is a low-molecular-weight amine compound formed by decarboxylation of histidine and is stored in basophil and mast cell granules.
Release of histamine from these cells is triggered by antigen cross-linking IgE bound to specific receptors on the surface membranes of mast cells and basophils.

6. Allergies and Histamine Synthesis
Histamine is formed from the amino acid histidine and is stored in high concentrations in vesicles in mast cells, enterochromaffin cells in the gut, some neurons, and a few other cell types. Histamine carries its message to a large number of cells by attaching to a special receptor on the cells’ surfaces.

7. Allergies and Histamine Receptors
Four classes of histamine receptors (H1–H4) are present to varying degrees in organs and tissues. H1 receptors are most prominent in blood vessels and bronchial and intestinal smooth muscle.

8. Allergies and Histamine Receptors
H1 receptors tend to produce the symptoms of allergy.
H2 receptors tend to act as negative feedback receptors and turn the allergic off.
H2 receptors also exclusively activate the acid-producing, parietal cells of the stomach lining.
An H3 receptor, appears to exist only in the central nervous
system.

9. Allergies and Histamine

10. Allergies and Histamine Sequele
The tissue effects of histamine are evident within 1 to 2 minutes, but it is rapidly metabolized within 10 to 15 minutes.
The major effects of histamine on target tissues include increased capillary permeability, contraction of bronchial and vascular smooth muscle, and hyper secretion of mucus glands.

11. Antihistamines
Histamine has no therapeutic applications, but drugs that block its effects at H1 and at H2 receptors are very important in clinical medicine.
No antagonists of H3 or H4 receptors are currently available for clinical use.
H1 antihistamines antagonize all actions of histamine except for those mediated by H2 receptors.

12. Antihistamines
Antihistamines act as competitive inhibitors of histamine (agonist) binding.
They compete for the H1 receptors on blood vessel endothelial cells and smooth muscle cells.
Competition: [antihistamine] > [natural histamine.]

13. Antihistamines

14. Classification of Anti Histamines

15. Classification of Anti Histamines H1 Blockers (1st Generation)
Aminoalkylethers. Ex. Diphenhydramine
Ethylenediamines. Ex Tripelennamine.
Propylamine derivatives. Ex. Chlorpheniramine
Phenothiazine derivatives. Ex. Promethazine
Piperazine derivatives. Cyclizine,
Debenzocycloheptenes. Cyproheptadine
Miscellaneous drugs. Diphenyl pyraline

16. Second-Generation antihistamines.
The second-generation antihistamines bind only to peripheral H1 receptors, and reduce allergic response with little or no sedation.
Ex: Cetirizine, loratidine, fexofenadine.

17. SAR’s

18. SAR’s
The nitrogen should be 3° in nature for maximum antihistaminic activity. The ‘N’ may also form a part of heterocyclic moieties like piperidine, or piperazine or diazocine.
The group present between nitrogen atom and group X may be saturated or unsaturated or substituted.
The Ar group may be aryl or heteroaryl, which may be substituted.
The group (X) can be carbon, oxygen or nitrogen.

19. Aminoalkyl Ethers (Ethonalamines)
Derivatives of N,N-dimethyl ethanolamines
Characterised by the CHO connecting Moiety between the key diaryl and tertiary amino groups and a two or three carbon moiety.

20. Diphenhydramine
2-(diphenylmethoxy)-N,N-dimethylethanamine

21. Diphenhydramine Synthesis

22. Diphenhydramine Uses
Bittertaste from the hydrochloride salt base
Antidyskinetic
Antitussive
Sedative

23. 2-[p-chloro-α-[2-(dimethylamino)ethoxy]benzyl]pyridine bimaleate
Carbinoxamine
2-[p-chloro-α-[2-(dimethylamino)ethoxy]benzyl]pyridine bimaleate

24. Bromodiphenhydramine
2[(4-bromophenyl) phenylmethoxy)]-N, N-dimethylethanamine.

25. Bromodiphenhydramine Synthesis

26. Assignment Draw the structure of Dimenhydrinate
Highlight chemical difference between Diphenhydramine and dimenhydrinate
Draw the structures of
Doxylamine
Chlemastine

27. Phenothiazines Possess a tricyclic system
Phenothiazine derivatives possess two or three carbon chain bridge between basic phenothiazine nucleus and terminal nitrogen.
Name suggested by Dr. Loening of the Chemical Abstracts service of the IUPAC

28. 10-(2- dimethylaminopropyl) phenothiazine.
Promethazine
10-(2- dimethylaminopropyl) phenothiazine.

29. Promethazine Synthesis
2-(N-dimethylamino)-1-chloropropane

30. Promethazine Uses
Antihistaminic agent with some anti muscarinic, antiemetic and local anesthestic properties.
allergies,
anxiety prior to surgery,
as an anti-nauseant,
and for control of motion sickness.

31. Trimeprazine
10-(3-dimethylamino-2-methyl propyl)-phenothiazine.

32. Other phenothiazines Draw and Name the structures of Methdilazine
Chlorpromazine

33. Piperazines
Are derivatives of the piperazine nucleus

34. Piperazines General Structure

35. Piperazines Cyclizine
1-(diphenylmethyl)-4-methyl piperazine.

36. Cyclizine Synthesis N-methyl piperazine Urticaria Hay fever
Other allergies

37. 1-(p-chlorobenzhydryl)- 4-methylpiperazine
Chlorclyclizine
1-(p-chlorobenzhydryl)- 4-methylpiperazine
Halogen Substitution = Loss of Potency

38. Meclizine

39. Buclizine

40. Syntheses Read and Make notes on the syntheses of: Chlorcyclizine
Meclizine
Buclizine