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. Ashok
Mpharm. 1st Year
210121210013
GUIDED BY :-
Dr. MANOJ MEDAL
Dept. of Pharmaceutical Sciences
GJUS&THisar

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 and 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
 1st generation h1 blockers:
 Aminoalkylethers ( ethanolamines ): Ex. Diphenhydramine,
dimenhydrinate, doxylamine succinate
 Ethylenediamines : Ex Tripelennamine, pyrilamine maleate,
antazoline phosphate
 Propylamine derivatives: Ex. Chlorpheniramine,
pheniraminemaleate.
 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. 2nd Generation h1 blockers
Desloratadine

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.  The H2-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 H2-receptors.

31. SAR Of H2 Antagonists
 Imidazole ring is not the only required ring for competitive
antagonism of histamine H2 -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 :-
1. https://en.wikipedia.org/wiki/H2_antagonist
2. https://www.slideshare.net/arzoodharasandiya/h1-
h2-receptor-blockers

35. For Listening