Antiulcer drugs
Peptic ulcer disease (PUD)
Ulcers are localized erosions of the mucous membranes of the stomach or
duodenum. It is not known how these ulcers arise but the presence of gastric acid
aggravates the problem and delays recovery.
Mechanism of gastric acid secretion:
Secretion of acid (HCl) is regulated by the action of various mediators at
the receptors including:
1- Histamine at H2 receptor (cellular).
2- Gastrin at the G receptor (blood).
3- Acetylcholine at the M2 receptor (neuronal).
Treatment:
Medications that are used for treatment of peptic are:
1- Antacids.
2- Anticholinergic or antimuscarinic agents.
3- H2 receptor antagonists.
4- Proton pump inhibitors (inhibitors of H+ / K+ ATPase).
5- Chemical compelexation.
6- Prostaglandins (PGs).
H2 antagonists: Burimamide, metiamide, cimetidine, ranitidine, famotidine,
nizatidine.
They act as blockers for H2 receptors that are present in stomach and uterus.
The first drug that block H2 receptors is burimamide that is upon molecular
modification leads to metiamide which is 10 times more active as burimamide.
H
N
H
N
N
NH
Burimamide
CH3
CH3
S
HN
H
N
H
N
S
N
CH3
S
Metiamide
cimetidine
N-cyano-N--methyl-N =- -[( - methylimidazol- -yl)methylthio]ethyl
guanidine
}
* Administered
mg per day.
* disadvantages: ) not completely absorbed if administered with antacids
or sucralfate. ) inhibit the liver microsomal enzyme system CYP
,
what leads to decrease metabolism of phenytoin, theophylline, diazepins.
) affect potency in male.
ranitidine
N- -[ -(dimethylaminomethyl)furfurylthio]ethyl-N
- -nitro- , -ethendiamine.
- -methyl
* administered
mg per day
* weak inhibitor of liver microsomal enzyme system so it can be
administered with drugs comntraindicated in case of cimetidine.
famotidine
-[ -(diaminomethyleneamino)thiazol- -yl]methylthio
-N-sulfamoylproionamidine
* administered mg once or mg twice daily.
SAR of H2-antagonists.
1-immidazole ring is not required for competitive antagonism at the
H2-receptor, other heterocyclic rings can be used like furan and
thiazole.
2-Separation between the nitrogen atom and heterocyclic ring by 4
carbon atoms gives optimum activity
.
3-The terminal nitrogen atom should be polar and non basic for
maximal 4-antagonistic activity, while groups that are positively
charged at physiologic ph have agonistic activity.
4-Antagonistic activity is inversely proportional to hydrophilicity of
the nitrogen atom, but the hydrophilic nitrogen group in
ranitidine is an exception.
proton pump inhibitors
Mechanism of action
These agents work by irreversibly inhibiting an enzyme complex called the
proton pump (H+/k+ ATPase). This enzymic pump is present in the membranes
of parietal cells and is responsible for releasing HCl into the stomach as a final
step in acid secretion.
Y
N
S CH2
N
X
O
N
H
X
Y
Omeprazole
5-OCH3
3- CH3 , 4-OCH3 , 5-CH3
Lansoprazole
H
3- CH3 , 4-OCH2 CF3
Pantoprazole
b-OCHF2
3- OCH3 , 4-OCH3
Rabeprazole
H
3- CH3 , 4-OCH2 CH2CH2 OCH3
omeprazole
-methoxy- -([( -methoxy- , -dimethyl- -pyridinyl)methyl]sulfinyl
H-benzimidazole.
}
**omeprazole that can block H+ / K+ pump in the stomach,
Used if the other strategies are useless…