1. H2 ANTIHISTAMINES
H2 BLOCKERS vs PPIs
By
Sumbal Ilyas
18551507-084
Submitted To
Dr. Ghulam Mustafa

2. GASTRIC ACID SECRETIONS
 The presence of acid and proteolytic pepsin enzymes are generally assumed
to be required for the hydrolysis of proteins and other food constituents.
 The acid secretory unit of the gastric mucosa is the parietal cell. Parietal
cells contain an H+, K+-ATPase or proton pump that secretes proton (H+) in
exchange for the uptake of K+ ion.
 Secretion of acid by gastric parietal cells is stimulated by various mediators
at receptors located on the basolateral membrane.
 They include
1. Histamine agonist of H2-receptors
2. Gastrin activity at G receptors
3. Acetylcholine (ACh) receptors
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Reference: Wilson and Gisvold’s Textbook of Organic Medicinal and Pharmaceutical Chemistry

3. GASTRIC ACID SECRETIONS
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4.  Drugs whose pharmacological action primarily involves antagonism of the
action of histamine at its H2-receptors find therapeutic application in the
treatment of acid-peptic disorders including
 Heartburn
 Gastroesophageal reflux disease (GERD)
 Gastric and duodenal ulcers
 Hypersecretory diseases such as Zollinger-Ellison syndrome.
 They are also useful in combination with H1-antihistamines for the
treatment of chronic urticaria and for the itching of pruritus.
4 H2 ANTIHISTAMINES
Reference: Wilson and Gisvold’s Textbook of Organic Medicinal and Pharmaceutical Chemistry

5.  H2 antihistamines have following parts.
 Mainly an imidazole ring is present.
 Replacement of the imidazole ring with a furan (raniditine) or a thiazole
(famotidine, nizatidine) heterocycle with a basic ring substitutent enhances
both the potency and selectivity of H2-antagonism.
5 SAR FOR H2 ANTAGONIST
Reference: Wilson and Gisvold’s Textbook of Organic Medicinal and Pharmaceutical Chemistry

6.  1972:
 At the beginning of the 1970s sir
James Black developed the drug
Cimetidine that suppresses the
formation of gastric acid and is used
to fight ulcers.
 He first discovered H2 receptors and
then characterized its antagonist.
 He was awarded a Nobel prize in
1988
6 History
Reference: https://www.nobelprize.org/prizes/medicine/1988/black/facts/

7. CIMETIDINE
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 Cimetidine (Tagamet) is a colorless crystalline
solid.
 It reduces basal and nocturnal gastric acid
secretions.
 It is used to treat gastrointestinal disorders
such as gastric or duodenal ulcer, GERD and
hypersecretory conditions.
 Cimetidine inhibits many of the isoenzymes of
the hepatic CYP450 enzyme system.
 Other actions of Cimetidine include an
increase in gastric bacterial flora.
 Its half-life is around 2 hours and is excreted
through urine.
Reference: Wilson and Gisvold’s Textbook of Organic Medicinal and Pharmaceutical Chemistry

8. FAMOTIDINE
 Famotidine (Pepcid), is a white to pale-
yellow crystalline compound.
 It is a thiazole bioisotere of cimetidine that
contains a guanidine substituent that may
mimic the imizadole of cimetidine.
 A bioisostere is a molecule resulting from
the exchange of an atom or of a group of
atoms with an alternative atom or group of
atoms.
 Famotidine is a competitive inhibitor of
histamine H2- receptors with a potency
significantly greater than cimetidine.
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Reference: Wilson and Gisvold’s Textbook of Organic Medicinal and Pharmaceutical Chemistry

9. FAMOTIDINE
 It inhibits basal and nocturnal gastric secretion as well as secretion
stimulated by food and pentagastrin.
 It can be used for the short-term treatment of duodenal and benign gastric
ulcers, GERD, pathological hypersecretory conditions (e.g., Zollinger-
Ellison syndrome), and heartburn.
 Famotidine is absorbed (37%–45% bioavailability).
 In intravenous administration, about 70% of the drug is eliminated in the
urine as an unchanged drug.
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Reference: Wilson and Gisvold’s Textbook of Organic Medicinal and Pharmaceutical Chemistry

10. RANITIDINE
 Ranitidine (Zantac), is a white solid.
 It is an aminoalkyl furan derivative
with pKa values of 2.7 (side chain) and
8.2 (dimethylamino).
 Ranitidine is more potent than
cimetidine, but less potent than
famotidine.
 Bioavailability of its oral dose is about
50.
 Half-life of the drug is 2 to 3 hours, and
it is excreted along with its metabolites
in the urine.
10
Reference: Wilson and Gisvold’s Textbook of Organic Medicinal and Pharmaceutical Chemistry

11. NIZATIDINE
 Nizatidine (Megagastro) is an off-white
to buff crystalline solid that is soluble
in water
 It is a thaizole derivative of raniditine
and has pKas of 2.1 (sidechain) and 6.8
(dimethylamino).
 It is more potent than cimetidine.
 Nizatidine has excellent oral
bioavailability (90%).
 The half-life is 1 to 2 hours. It is
excreted primarily in the urine (90%)
and mostly as unchanged drug (60%).
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Reference: Wilson and Gisvold’s Textbook of Organic Medicinal and Pharmaceutical Chemistry

12. Other Anti Ulcer And Gastric Acid
Hypersecretory Diseases Therapy:
“PROTON PUMP INHIBITORS”
 Working
 H2 blockers vs PPIs
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13. “PROTON PUMP INHIBITORS”
 The final step in acid secretion in the parietal cell is the extrusion or
“pumping” of protons into the lumen of stomach by the membrane H, K-
ATPase
 Thus, inhibition of this proton pump acts beyond the site of action of second
messengers (e.g., calcium and cAMP)
 It is independent of the action of histamine, gastrin, and acetylcholine.
 Thus, acid pump inhibitors block both basal and stimulated acid secretion.
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Reference: Wilson and Gisvold’s Textbook of Organic Medicinal and Pharmaceutical Chemistry

14. PPI vs H2 Blockers
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 Both work by reducing acid secretions.
 PPI work by inhibiting H+/K+ ATPase, therefore decreasing Gastric Acid
Secretions.
 But the control of gastric acid secretions depend on 3 basis
1. Duration of Action
2. Spectrum of Action
3. Mechanism of Action
Reference: Wilson and Gisvold’s Textbook of Organic Medicinal and Pharmaceutical Chemistry

15. DURATION OF ACTION
 Tells which will show long lasting effect.
 PPI took advantage in duration of time as their effect is delayed as it inhibit
proton pump irreversibly.
 H2 blockers have short time duration period i.e., about few hours and they
show immediate effect which is lost after some time.
 H2 blockers begin working within an hour, and last for up to 12 hours.
 PPIs are also used for this purpose, but they have a delayed onset of action
and work for a longer period of time, most up to 24 hours and the effects
may last up to three days.
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Reference: Wilson and Gisvold’s Textbook of Organic Medicinal and Pharmaceutical Chemistry

16. SPECTRUM OF ACTION
 Both PPIs and H2 blockers can be used to treat diseases like GERD, peptic
ulcers by reducing secretions.
 By diseases like ZE syndrome and H pylori infection can only be treated
by Proton Pump Inhibitors.
 This is because they are due to the secretions from gastrin receptor rather
than activation of histamine receptor.
16
Reference: Wilson and Gisvold’s Textbook of Organic Medicinal and Pharmaceutical Chemistry

17. MECHANISM OF ACTION
Reference: Wilson and Gisvold’s Textbook of Organic Medicinal and Pharmaceutical Chemistry
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18. MECHANISM OF ACTION
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