H2 antihistamines and proton pump inhibitors both work to reduce gastric acid secretions but differ in their duration of action, spectrum of action, and mechanisms. H2 antihistamines work by antagonizing histamine at H2 receptors and have a shorter duration of a few hours. Proton pump inhibitors irreversibly inhibit the H+/K+ ATPase pump and have a delayed but longer lasting effect of up to 24 hours. Proton pump inhibitors also have a broader spectrum of action and can treat conditions like Zollinger-Ellison syndrome that depend more on gastrin than histamine.

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
2
Reference: Wilson and Gisvold’s Textbook of Organic Medicinal and Pharmaceutical Chemistry

3. GASTRIC ACID SECRETIONS
3

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
7
 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.
8
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.
9
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%).
11
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
12

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.
13
Reference: Wilson and Gisvold’s Textbook of Organic Medicinal and Pharmaceutical Chemistry

14. PPI vs H2 Blockers
14
 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.
15
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
17

18. MECHANISM OF ACTION
18