H2 Antagonist - Department of Pharmaceutical Chemistry

1. Presented By:
Kankan Roy
( M.Pharmacy 1st Semester)
H₂ ANTAGONIST
Submitted To :
Dr. Vikram Deep Monga
(Department of P’Chemistry)
2019-20
1

2. AUTACOID
• ‘Auto’ means self and ‘Akos’ means remedy or healing .
• Site of action - locally ( act as a Local Hormone) .
• Release during – Allergy, Hypersensitivity, Inflammation .
• Classification :
i. Amine Autacoids – Histamine, 5- Hydroxytriptamine .
ii. Lipid derivative Autacoids – Prostaglandins, Leukotrienes, Platelet
activating factor .
iii. Peptide Autacoids – Plasma kinins ( Bradykinin, kallidin ), angiotensin.
iv. Miscellaneous Autacoids – 1.Cytokinin – Interleukin, TNF-alpha .
2.Peptides – Gastrin, Somatostatin,
Endothelin .

3. HISTAMINE
Histamine

4. INTRODUCTION
• Histamine = Tissue Amine ( Histos = Tissue) .
• Imidazole ethylamine .
• Present within storage granules of mast cell .
• Histamine rich tissues are Skin, Gastric & Intestinal mucosa, Lungs, Liver, Placenta.
• Histamine receptors are basically four types H1, H2, H3, H4 .
• Histamine synthesized by Histidine(amino acid) and degraded by Oxidation and
Methylation .
• Histamine is involved in the inflammatory response and has a central role as a
mediator of itching. As part of an immune response to foreign pathogens, histamine is
produced by basophils and by mast cells found in nearby connective tissues.

5. Synthesis and metabolism
• Histamine is derived from the decarboxylation of the amino acid
histidine, a reaction catalyzed by the enzyme L-histidine decarboxylase.
It is a hydrophilic vasoactive amine.
• Once formed, histamine is either stored or rapidly inactivated by its
primary degradative enzymes, histamine-N-methyltransferase or diamine
oxidase. In the central nervous system, histamine released into the
synapses is primarily broken down by histamine-N-methyltransferase,
while in other tissues both enzymes may play a role.

6. Histidine Histamine

7. Physiological Roles

8. HISTAMINE AND IT’S RECEPTORS
• H1 – They are present in Smooth muscle, endothelium, CNS and cause
Bronchoconstriction, vasodilation, separation of endothelial cells, pain and itching,
motion sickness.
• H2 – They are present in gastric parietal cell, basophils. And helps in regulating
gastric acid secretion, inhibition of IgE-dependent degranulation.
• H3 - They are present in CNS cells, and some in peripheral NS. And helps in
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..

9. N-guanylhistamine as a lead
Partial Agonist
Poor Antagonist
1. Partial Agonist .
2. Poor Antagonist .
3. This means that both terminal
amines are essential for activity.
Antagonist activity
increased

11.  Guanylhistamine provided the lead.
 Extension of the side chain increased anti H2 potency but some agonist activity
remained.
 Replacing the basic guanidino group with the neutral
thiourea yielded effective H2 antagonists.
 Burimamide lacked agonist action but was not orally absorbed
 In Metiamide (1) reduce the pKa of the ring N, reduced ionization, increased
membrane permeability and absorption and 10X more potent than Burimamide,
 (2) cause the tautomer to predominate which interact with H2 But caused kidney
damage and granulocytopenia, possibly due to the thiourea so was replaced by the
isosteric guanidine.
 This compound being highly basic was 20 times less potent Replacement of this group
with strong electron withdrawer but more lipophilic cyano derivative yielded
Cimetidine.

12. Selective H2 Agonist :
 Dimaprit
 Impromidine
H2-Antihistamines :
 Cimetidine
 Ranitidine
 Famotidine
 Roxatidine
 Nizatidine
 Oxmetidine
 Etintidine
 Lupitidine
 Tiotidine

18. H2 antagonists
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.
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

20. SAR of H2 Antagonists
• Imidazole ring is required ring for competitive antagonism of histamine
H2-receptors.
• Other heterocyclic ring ( Furan, Thiophene, Thiazole etc) that enhance the
potency .
• The ring and terminal nitrogen should be separated by four carbon
atoms for optimum antagonist activity.
• The terminal nitrogen group should be polar, non basic substituents for
maximum antagonist activity .

21. SYNTHESIS AND DRUG PROFILE
CIMETIDINE :
Mol. Formula – C₁₀H₁₆N₆S
Brand name – Tegamet .
Onset of action – 30 mins .
Duration of action – 4-8 hours .
Half life – 123(~2 hours) .
Metabolism – Liver .
Nature – Crystalline Powder .
Solubility – Soluble in Water but sparingly soluble in Ethanol.
Use - Peptic Ulcer .
Adverse effect – Gynaecomastia .

22. Synthesis :

23. Famotidine
Mol. Formula - C₈H₁₅N₇O₂S₃ .
Brand name –Pepcid, Famocid , Famtac .
Nature – White or Yellowish White
crystalline powder.
Solubility – Soluble in Water , Ethanol ,
glacial acetic acid but insoluble in
Ethyl acetate .
Metabolism – Hepatic .
Half life – 2.5- 3.5 hours .
Route of Administration – Oral, IV .
Use – Duodenal and gastric ulcers , heart burn .

24. Synthesis :

25. Nizatidine (New Drug)
Mol. Formula - C₁₂H₂₁N₅O₂S₂ .
Brand Name – axid , Tazac .
Nature – White or slightly brownish crystalline
powder .
Soluble – Soluble in Water and Methanol .
Half life – 1- 2 hours .
Route of Administration – Oral .
Metabolism – Liver .
Use – Peptic ulcer .

26. Synthesis :

27. Roxatidine (New DRUG)
Mol. Formula - C₁₉H₂₈N₂O₄ .
Brand name – Rotane , Zorpex .
Half life – 5 – 7 hours.
Route of administration – Oral .
Metabolism – Hepatic diacetylation .
Minor involvement of CYP2D6 and
CYP2A6 .
Use – oesophagitis , ulceration .

28. Synthesis :

29. ADVERSE EFFECT