H1 & H2 receptor antagonist

H1-antihistamines are used to treat allergy symptoms. Within this group are two generations called the first generation and second generation antihistamines. H2-antihistamines are used to treat gastrointestinal conditions.
The H2 receptor antagonists are reversible competitive blockers of histamine at the H2 receptors, particularly those in the gastric parietal cells, where they inhibit acid secretion. They are highly selective, do not affect the H1 receptors, and are not anticholinergic agents.
The key difference between H1 and H2 receptors is that the H1 receptor couples with Gq/11 stimulating phospholipase C while the H2 receptor interacts with Gs to activate adenylyl cyclase. Histamine is an organic nitrogenous compound that involves local immune responses.

1. H1 & H2 Receptor Antagonist Ashok Mpharm . 1 st Year 210121210013 GUIDED BY :- Dr. MANOJ MEDAL Dept . of Pharmaceutical Sciences GJUS&T Hisar

2. Histamine Histamine :- Histamine: A  substance that plays a major role in many allergic reactions , dilating blood vessels and making the vessel walls abnormally permeable. Histamine is part of the body's natural allergic response to substances such as pollens. Functions of Histamines:- Histamine is a signaling molecule, sending messages between cells.  It tells stomach cells to make stomach acid a nd it helps our brain stay awake. Some antihistamines can make us sleepy and other antihistamines are used to treat acid reflux.

3. Histamine

4. Formation of Histamine in Body

5. Histamine English scientists George Barger and Henry H.  Dale first isolated histamine from the plant fungus ergot in 1910 , and in 1911 they isolated the substance from animal tissues. It is formed by the decarboxylation (the removal of a carboxyl group) of the amino acid histidine .

6. Histamine Receptors and Their Distribution Almost all mammalian tissues contains histamine. Widely distributed in skin, GIT, mucosa, lungs, brain and bone- merrow . It is also component of some venoms, Sting secreation , bacteria and plants . The mast cell is predominant storage site for histamine in most tissues. The concentration of histamine is particularly high in tissue that contain large members of most cells such as skin , bronchial tree mucosa and intestinal mucosa.

7. HISTAMINE AND ITS RECEPTORS H1 – Smooth muscle, endothelium, CNS.- Bronchoconstriction , vasodilation , separation of endothelial cells, pain and itching, allergic rhinitis, motion sickness. H2 – gastric parietal cell, basophils . Regulate gastric acid secretion, inhibition of IgE -dependent degranulation . H3 - CNS cells, and some in peripheral NS. Presynaptic , feedback inhibition of histamine synthesis and release. They also control release of DA, GABA, ACh , 5-HT & NE. H4 - Highly expressed in bone morrow and white blood cells. Mediate mast cell chemotaxis ..

8. Classification of Hisatamine

9. H1 RECEPTOR BLOCKERS 1 st generation h1 blockers: Aminoalkylethers ( ethanolamines ): Ex. Diphenhydramine , dimenhydrinate , doxylamine succinate Ethylenediamines : Ex Tripelennamine , pyrilamine maleate , antazoline phosphate Propylamine derivatives: Ex. Chlorpheniramine , pheniramin e maleate . Phenothiazine derivatives: Ex. Promethazine , trimeprazine tartrate . Piperazine derivatives: Cyclizine , chlorocyclizine , meclizine Debenzocycloheptenes : Cyproheptadine , azatadine Miscellaneous drug: Diphenyl pyraline

10. Second-Generation antihistamines The second-generation antihistamines bind only to peripheral H1 receptors, and reduce allergic response with little or no sedation. These newer agents are structurally divers, but are derivatives of first generation drugs. The new second generation drugs currently on the market include: Acrivastine Cetrizine and levocetrizine Desloratadine and loratidine Fexofenadine terfenadine

11. SAR of Histamine A protonatable amine A connecting atom X which can be O, C or N A carbon chain, usually ethyl Variations in the diaryl groups, connecting moiety, substituentson the connecting moiety, and substituents on the terminalnitrogen account for the differences observed in potency as well as pharmacologic, metabolic, and adverse reaction profiles

12. SAR OF 1ST GENERATION H1 BLOCKERS 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 . Generally two aromatic rings - phenyl, benzyl, or an isostere such as pyridyl ; Pyridyl generally results in more potent compounds than phenyl. 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.

13. SAR OF 1ST GENERATION H1 BLOCKERS 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 X = C: 2. Propanolamines ( clemastine , diphenylpyraline ) 3. Propylamines (Saturated and Unsaturated) X = N: 4. Ethylenediamines 5. Piperazines ( Cyclizines ) and Tricyclics .

14. Some Structures of Drugs chlorpheniramine dhiphenhydramine pyrilamine

15. AMINOALKYL ETHERS 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. The simple diphenyl derivative diphenhydramine was the firt clinically useful member of the ethanolamines series and serves as a prototype.

16. AMINOALKY ETHERS Replacement of one of the phenyl rings of the diphenhydramine with a 2-pyridyl group, as in doxylamine enhances the antihistaminic activity. The diaryl tertiary aminoalkyl ether structure serves as a pharmacophore for the muscarinic receptors. Drowsiness ,as well as other CNS effects, is a common side-effects of tertiary amino alkyl ethers because of the ability of these compounds to penetrate BBB and bind to the central H1 receptors. Conversion to a quaternary ammonium salt does not alter the antihistaminic activity but does increases in anticholinergic action.

17. AMINOALKYL ETHERS Diphenhydramine HCL Doxylamine carbinoxamine bromodiphenhydramine

18. Bromodiphenhydramine synthesis

19. ETHELENDIAMINES R1 and R2 should be small (CH3) for maximum H1-antagonist activity. Ar1 and Ar2 can be benzene ring or any other isosteric rings such asheterocycles . One of the aromatic should be benzyl for better activity which has Psubstitution

20. H1 Receptor Antagonists Tripelennamine   HCl Chlorpheniramine Maleate

21. Synthesis of Triprolidine HCl

22. Promethazine HCl Promethazine is used to  prevent and treat nausea and vomiting  related to certain conditions (such as before/after surgery, motion sickness). It is also used to treat allergy symptoms such as rash, itching, and runny nose.

23. Cyproheptadine HCl Cyproheptadine is an antihistamine used  to relieve allergy symptoms  such as watery eyes, runny nose, itching eyes/nose, sneezing, hives, and itching. It works by blocking a certain natural substance (histamine) that your body makes during an allergic reaction

24. 2nd generation h1 blockers Uses Piperazine derivative CETIRIZINE and levocetrizine Piperidine derivative FEXOFENADINE TERFENADINE dibenzepines LORATADINE DESLORATADINE AZELASTIN ALLERGY URTICARIA COMMON COLD

25. 2 nd Generation h1 blockers Desloratadine

26. H2 Receptor Antagonists

27. H2 Receptor Antagonists :- are a group of medicines that reduce the amount of acid produced by the cells in the lining of the stomach are commonly called H2 blockers. Cimetidine ( Tagamet ) Ranitidine ( Zantac) Famotidine ( Pepcid , Pepcid AC) - Nizatidine ( Axid ) These products have been approved for the relief of “heartburn associated with acid indigestion, and sour stomach.” They should not be taken for longer than 2 weeks and are not recommended for children < 12 years of age.

28. MOA of H2 blockers The H2 antagonists are competitive antagonists of histamine at parietal cell H2 receptor .They suppress the normal secretion of acid by parietal cells and the meal –stimulated secretion of acid . They accomplish this by two mechanism : Histamine released by ECL( enterochromaffin – like) cells in the stomach is blocked from binding on parietal cell H2 receptor , which stimulate acid secretion : therefore other substances that promote acid secretion ( such as gastrin and acetylcholine ) have a reduce effect on parietal cell when the H2 receptors are blocked

29. Side effects of H2 blockers Some of the side effects that may occur with H2 receptor blockers include: constipation diarrhea difficulty sleeping dry mouth dry skin headaches ringing in the ears a runny nose trouble urinating

30. SAR of H2-receptor Antagonists The H 2 -receptor antagonists were the result of the international modification of the histamine structure and deliberate search for a chemically related substance that would act as competitive inhibitor of the H 2 -receptors.

31. SAR Of H2 Antagonists Imidazole ring is not the only required ring for competitive antagonism of histamine H 2  -receptors. Other heterocyclic rings (furan, thiophene , thiazole , etc) that enhance the potency and selectivity of H2-receptor antagonism can be used. The ring and terminal nitrogen should be separated by four carbon atoms for optimum antagonistic activity. The isosteric thioether link is also present in certain drugs. The terminal nitrogen group should be polar, nonbasic substituents for maximal antagonist activity. In general, antagonistic activity varies inversely with the hydrophilic character of the nitrogen group (exception ranitidine and nizatidine )

32. Drugs of H2 Receptor Antagonists

33. When to Use H2 Receptor Antagonists To reduce acid reflux which may cause heartburn or inflammation of the gullet ( esophagitis ). These conditions are sometimes called gastroesophageal reflux disease (GERD). To treat ulcers in the stomach and in part of the gut (the duodenum). To help heal ulcers associated with anti-inflammatory agents (NSAIDs). In other conditions where it is helpful to reduce acid in the stomach. Also :Damage to the stomach and/or intestines due to stress or trauma, -Pancreatic problems Stomach or intestinal ulcers (sores) resulting from damage caused by medication used to treat rheumatoid arthritis.

34. References :- https://en.wikipedia.org/wiki/H2_antagonist https://www.slideshare.net/arzoodharasandiya/h1-h2-receptor-blockers

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