H2 RECEPTOR ANTAGONISTS The H2 receptor antagonists (H2RA) are a class of drugs used to block the action of histamine on parietal cells (specifically the histamine H2 receptors) in the stomach, decreasing the production of acid by these cells. PROTON - PUMP INHIBITORS Proton-pump inhibitors (PPIs): are a group of drugs whose main action is a pronounced and long-lasting reduction of gastric acid production. They are the most potent inhibitors of acid secretion available. These drugs are among the most widely sold drugs in the world, and are generally considered effective. The vast majority of these drugs are benzimidazole derivatives, but promising new research indicates the imidazopyridine derivatives may be a more effective means of treatment.

1. H2 - ANTAGONIST AND PROTON PUMP INHIBITORS
BY: A.M. NASEEFA
AZEEZ. MYMOONA.NASEEFA

2. H2 RECEPTOR ANTAGONISTS
The H2 receptor antagonists (H2RA) are a
class of drugs used to block the action of
histamine on parietal cells (specifically the
histamine H2 receptors) in the stomach,
decreasing the production of acid by these
cells.
H2 antagonists are used in the treatment of
dyspepsia, although they have been
surpassed in popularity by the more effective
proton pump inhibitors.
AZEEZ. MYMOONA.NASEEFA

3. The prototypical H2 antagonist was cimetidine,
developed by Smith, Kline & French (now
GlaxoSmithKline) in the mid-to-late 1960s and first
marketed in 1976; sold under the trade name
Tagamet, cimetidine would later become the first
ever blockbuster drug. The use of quantitative
structure-activity relationships (QSAR) led to the
development of other agents—starting with
Ranitidine, first sold as Zantac—which has fewer
adverse effects and drug interactions and is more
potent.
AZEEZ. MYMOONA.NASEEFA

4. Eg for H2 receptor blockers:
* Cimetidine (Imidazole ring)
* Ranitidine (Furan ring)
Famotidine (Thiazole ring)
Nizatidine (Thiazole ring)
AZEEZ. MYMOONA.NASEEFA

5. STRUCTURAL ACTIVITY RELATIONSHIP OF H2 ANTAGONIST:
Imidazole ring
1) Methylation at 5 position leads to arterial histamine selective agonistic action R=CH3.
2) N-Guanylhistamine weak antagonist.
5
2
3
4
1
AZEEZ. MYMOONA.NASEEFA

6. 3) Increasing the of side length of side chain from 2 to 4 carbon couple with
replacement of guanidine group by the neutral methyl thiourea function
Burimamide.:
4) N Imidazo tautomer has prominent activity.
5) Thiourea structural feature is eliminated by replacing the thiourea sulphur with
cyano-imino function to produce cimetidine which is effective gastric antisecretory
agent that promotes the healing of duodenal ulcer.
AZEEZ. MYMOONA.NASEEFA

7. Mechanism of action :
The H2 antagonists are competitive antagonists of histamine at the 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 mechanisms: Histamine released by ECL
( enterochromaffin-like) cells in the stomach is blocked from binding on
parietal cell H2 receptors, which stimulate acid secretion; therefore, other
substances that promote acid secretion (such as gastrin and acetylcholine)
have a reduced effect on parietal cells when the H2 receptors are blocked.
AZEEZ. MYMOONA.NASEEFA

8. Clinical use
• H2-antagonists are used by clinicians in the treatment of
acid-related gastrointestinal conditions.
• Peptic ulcer disease (PUD)
• Gastroesophageal reflux disease (GERD/GORD)
• Dyspepsia
• Prevention of stress ulcer (a specific indication of
ranitidine)
AZEEZ. MYMOONA.NASEEFA

9. Adverse effects
H2 antagonists are, in general, well tolerated, except for
cimetidine, wherein all of the following adverse drug
reactions (ADRs) are common.
Infrequent ADRs include hypotension.
Rare ADRs include: headache, tiredness, dizziness,
confusion, diarrhea, constipation, and rash.In addition,
gynecomastia may also occur in fewer men.
cimetidine may also cause loss of libido, and impotence,
all of which are reversible upon discontinuation.
AZEEZ. MYMOONA.NASEEFA

10. PR
O
TO
N
PU
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P
IN
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SAZEEZ. MYMOONA.NASEEFA

11. PROTON - PUMP INHIBITORS
Proton-pump inhibitors (PPIs): are a group of drugs whose main action
is a pronounced and long-lasting reduction of gastric acid production.
•They are the most potent inhibitors of acid secretion available.
•These drugs are among the most widely sold drugs in the world, and
are generally considered effective.
•The vast majority of these drugs are benzimidazole derivatives, but
promising new research indicates the imidazopyridine derivatives may
be a more effective means of treatment.
•High dose or long-term use of PPIs carries a possible increased risk of
bone fractures
AZEEZ. MYMOONA.NASEEFA

12. Examples: Clinically used proton pump inhibitors:
Omeprazole
Lansoprazole
Pantoprazole
Rabeprazole
AZEEZ. MYMOONA.NASEEFA

13. SAR
1) The Substituted pyridine ring, substituted benzimidazole moiety & methyl sulfinyl chain connecting these two
is essential for the biological effect.
2) Biological activity & chemical stability largely depends on their substitution pattern.
Pyridine substitution compared to timoprazole 4-methoxy group in the pyridine ring increases the
biological activity by enhancing nucleophilicity of pyridine nitrogen atom. A 4-fluro alkoxy substitution combining
lipophilicity & electron demanding properties results strong inhibitory activity.
Eg: Lansoprazole SAVIPRAZOLE
AZEEZ. MYMOONA.NASEEFA

14. 3) Benzimidazole substitution, Unsaturated benzimidazole moiety shows
irreversible gastric proton pump inhibition.
Benzimidazole substitution by electron demanding group leads to strong activity.
Benzimidazole substitution by electron accepting group leads to less activity.
AZEEZ. MYMOONA.NASEEFA

15. Mechanism of action:
Proton pump inhibitors act by irreversibly blocking the H+/K+ ATPase, or, more
commonly, the gastric proton pump of the gastric parietal cells.
The proton pump is the terminal stage in gastric acid secretion, being directly
responsible for secreting H+ ions into the gastric lumen, making it an ideal
target for inhibiting acid secretion.
Targeting the terminal step in acid production, as well as the irreversible nature
of the inhibition, results in a class of drugs that are significantly more effective
than H2 antagonists and reduce gastric acid secretion by up to 99%.
The PPIs are given in an inactive form, which is neutrally charged (lipophilic)
and readily crosses cell membranes into intracellular compartments (like the
parietal cell canaliculus) with acidic environments. In an acid environment, the
inactive drug is protonated and rearranges into its active form
AZEEZ. MYMOONA.NASEEFA

16. Medical uses:
These drugs are used in the treatment of many conditions, such
as:
 Dyspepsia
 Peptic ulcer disease
 Gastroesophageal reflux disease (GERD or GORD)
 Laryngopharyngeal reflux
 Barrett's esophagus
 Eosinophilic esophagitis
 Stress gastritis prevention
 Gastrinomas and other conditions that cause hypersecretion
of acid
 Zollinger–Ellison syndrome (often 2–3x the regular dose is
required as compared to the other indications)
AZEEZ. MYMOONA.NASEEFA

17. Adverse effects
Common adverse effects include: headache, nausea, diarrhea, abdominal
pain, fatigue, and dizziness.
Infrequent adverse effects include: rash, itch, flatulence, constipation,
anxiety, and depression. Also infrequently, PPI use may be associated with
occurrence of myopathies, including the serious reaction rhabdomyolysis.
Long-term use of PPIs has been less studied than short-term use, and the
lack of data makes it difficult to make definitive statements.
AZEEZ. MYMOONA.NASEEFA

18. Reference:
Medical pharmacology by K.D.Tripathi
Principles of pharmacology by David. E. Golan.
AZEEZ. MYMOONA.NASEEFA

19. THANK
YOU
AZEEZ. MYMOONA.NASEEFA