Peptic ulcer occurs in that part of gastrointestinal tract (i.e. Stomach and duodenum) which exposed with acid pepsin mixture (APM).
In gastric ulcer acid directly fall down on to GIT mucosa wall and it damage mucosa wall that called ulcer. Gastric ulcer is commonly caused due to imbalance between aggressive and defensive factor. In the ulcer patients aggressive factor dominates defensive factor, so that mucosal digestion leading to the ulcer formation.
Aggressive Factor: (Cause ulcer) Acid, Pepsin and H. pylori.
In gastric ulcer acid directly fall down on to GIT mucosa wall and it damage mucosa wall that called ulcer. Gastric ulcer is commonly caused due to imbalance between aggressive and defensive factor. In the ulcer patients aggressive factor dominates defensive factor, so that mucosal digestion leading to the ulcer formation.
Aggressive Factor: (Cause ulcer) Acid, Pepsin and H. pylori.
Defensive factor: (Prevent ulcer) Gastric mucosa, prostaglandins,
Bicarbonate secretion, nitric oxide and innate resistance of mucosal cells.
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| Balance Between Aggressive and Defensive Factor (Image-1) |
Those agents and drugs are used to heal, cure and protect the gastric ulcer that called antiulcer drugs.
Pathogenesis of acid secretion / How to acid secretes from our body ? / Pathways Of Acid Secretion:
HCl secretes from gastric parietal cells. Histamine receptor (H2 receptor), muscarinic receptor (M3 receptor), gastrin/cholecystikinin (CCK2) receptor and prostaglandin receptor are present on basolateral membrane of parietal cells. H2, gastrin/CCK2 and M3 receptor are known as acid inducer receptors or aggressive receptors.
Prostaglandin (EP3) receptor is known as acid suppressor receptor or defensive receptor.
Mechanism of Action of Histamine Receptor:
Activated histamine (H2) receptor generate the cAMP level in gastric parietal cells that increase the calcium level and that calcium activate the terminal enzyme H+K+ATPase (Proton Pump) which secrets H+ion in the apical canaliculi of the parietal cells. |
| Mechanism of action of histamine: pathway of acid secretion through histamine receptor (Image-2) |
Mechanism of Action of Gastrin CCK2 And Muscurinic Receptor
Gastrin/CCK2 receptor and muscurinic receptor are activating phospholipase C and stimulate IP3-DAG pathway that mediates intracellular Ca+.
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| Mechanism of action of Gastrin/CCK2 and Muscurinic receptor: Pathway of gastric acid secretion through Muscurinic and gastrin/CCK2 Receptor (Image-3) |
Mechanism of Action of Prostaglandin Receptor:
Prostaglandin receptor is releasing gastric mucus and controlling excessive acidic environment in stomach. PG inhibits the acid secretion by opposing the cAMP generation. PG suppressed the cAMP in parietal cells and it have protective factor to prevent ulcer formation.
Classification of anti-ulcer Drug:
1) Neutrilization of gastric acid (Antacids)
a) Systemic:
- Sodium bicarbonate
- Sodium nitrate
b) Nonsystemic:
- Magnesium hydroxide
- Magnesium trisilicate
- Calcium carbonate
- Magaldrate
- Aluminium hydroxide gel
2) Reduction of gastric acid secretion
a) H2 antihistamines:
- Cimetidine
- Ranitidine
- Roxatidine
- Loxatidine
- Famotidine
b) Anticholinergics:
- Pirenzepine
- Propantheline
- Oxyphenonium
c) Proton pump inhibitor:
- Omeprazole
- Pantoprazole
- Rabeprazole
- Lansoprazole
- Esomeprazole
d) Prostaglandin analogues:
- Misoprostol
- Enprostil
- Rioprostil
3) Ulcer healing drugs:
- Carbenoxolone sodium
4) Anti-H. pylori drugs:
- Amoxicilline
- Clarithromycin
- Tinidazole
- Metronidazole
- Tetracycline
5) Ulcer protective:
- Colloidal bismuth subcitrate (CBS)
- Sucralfate
ANTACIDS
Antacids are weak base that raise the pH of gastric juice so that peptic ulcer activity is reduced. Antacids are pH neutralizing agents, which do not inhibit HCL secretion. During ulceration gastric pH rises between 2-3.
Antacids raises the aural pH to >5. Antacids expressed acid neutralizing capacity (ANC).
Antacids were very popular in the treatment of gastric ulcer but now-in-days antacids used in gastric ulcer has become remarkably restricted.
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| Single dose of antacids taking before meal and with meal (Image-4) |
Mechanism of Action of Systemic Antacids
1) Antacids which are weak base react with the HCl to form water and salt. The gastric acidity thus reduces the pH of gastric juices increased.
NH4OH + HCl -----------> NH4Cl + H2O
Once the pH of medium becomes less than 5 than pepsin become inactive, hence antacids ultimately inhibit the acid pepsin mixture activity.
2) Antacids increase the prostaglandin secretion in stomach and have some cytoprotective action.
3) Antacids also may have some anti-pyloric activity.
Mechanism Of Action Of Nonsystemic Antacids
1) Aluminum Hydroxide:
It should not be used in renal failure patients because small amounts of aluminum is normally absorb and excreted by kidney.
2) Magnesium salt:
It has low water solubility and low alkalinity. Magnesium salt have a laxative activity.
3) Calcium carbonate:
It is potent antacids that rapidly neutralize acid, it liberates carbon dioxide (CO2) in stomach at slower rate than sodium bicarbonate (NaHCO3). Calcium are absorbed, when long term used CaCO3 can cause hypercalcaemia, hypercalciuria and formation of calcium stone in kidney. It is not favorable antacids because calcium increases gastric secretion. Calcium ions diffuse in the gastric mucosa wall and directly promote the HCl production. It can cause loose motion.
Pharmacological Uses of antacids:
1) Gastroesophageal reflux
2) Improve Lower esophageal sphincter
2) Improve Lower esophageal sphincter
3) Gastric acidity
4) Stomach discomfort.
5) Gastric ulcer
4) Stomach discomfort.
5) Gastric ulcer
Adverse Drug Reaction (ADR) Of Antacids:
1) Aluminum hydroxide causes constipation.
2) Magnesium salt cause diarrhea.
3) Thus the combination of aluminum hydroxide and magnesium trisilicate often prescribed.
4) Calcium carbonate can cause kidney stone.
H2Antihistamines (Antagonist):
Histamine receptor are two types H1 receptor and H2 receptor, H1 receptor blocker are block the release of histamine and H2 receptor are used as anti-secretive agents because inhibit the gastric secretion (HCl). Cimetidine is the prototype drug of this category.
Mechanism of action Of Cimetidine OR H2 Antihistamine Drugs
Activated histamine (H2) receptor generate the cAMP level in gastric parietal cells that increase the calcium level and that calcium activate the terminal enzyme H+K+ATPase (Proton Pump) which secrets H+ ion in the apical canaliculi of the parietal cells. H2 antihistamines drugs are bind to the H2 receptor present on the gastric parietal cells. H2 receptor blocker have high affinity bind to the H2 receptor so they bind to the H2 receptor and completely block the binding of histamine with H2 receptor. Thus result is inhibition of the HCl production. (See image 2)
All drug of this category have same mechanism of action.
Pharmacological Action Of H2 Antihistaminic Drugs
1) H2 blockers are used in histamine induce bronchospasm, and produce bronchial relaxation.
2) H2 blockers have uterine relaxation activity in rats
3) H2 blockers have cardiac stimulation activity in specially guinea pig.
4) Gastric secretion
Pharmacokinetics Of H2 Antihistaminic Drugs
Cimetidine is absorbed orally, bioavailability 60-70% and elimination t1/2 2-3 hr due to first pass hepatic metabolism. It cross placenta and also reaches to mother milk but it poorly penetrates in brain due to hydrophilic in nature.
Pharmacological Uses Of H2 Antihistaminic Drugs:
1)Gastric Ulcer
2)Duodenum Ulcer
3)Stress ulcer and gastritis
4)Gastrointestinal reflex disease (GERD)
5)Prophylaxis of aspiration pneumonia
5)Prophylaxis of aspiration pneumonia
6)Zollinger-Ellison-Syndrome (ZES)
7)Urticaria
Adverse Drug Reaction Of H2 Antihistaminic Drugs:
1)Cimetidine:
Headaches, bowel upset, dry mouth, dizziness, confusional state, hallucination and temporary decreased in sperm count.
Headaches, bowel upset, dry mouth, dizziness, confusional state, hallucination and temporary decreased in sperm count.
2)Ranitidine:
Diarrhea/constipation, dizziness and rashes.
3)Famotidine:
Headache, bowl upset, dizziness, rash and rarely disorientation.
Proton Pump Inhibitor
Proton pump present on gastric parietal cells and it secretes the H+ ion in the apical canaliculi of the parietal cell. That release of H+ ion participated into formation of acid. Proton pump also known as terminal enzyme H+K+ATPase. Those drugs block the proton pump and block.
The secretion of H+ ions called proton pump inhibitor (PPI). PPI directly Block the acid secretion.
Mechanism of action Of Omeprazole or Proton Pump Inhibitor
Omeprazole is prototype drug of this category. The drug enters the parietal cells where the intensity of acidity is very high. Subsequently the activated drug binds with H+K+ATPase enzyme and inhibit the acid production. As the result HCl synthesis is totally stopped. After the withdrawal of drug new proton pump molecule must have to be generated for the fresh synthesis of gastric HCl. (See image 3) All drug of this category have same mechanism of action.
Pharmacokinetics Of Omeprazole Or Proton Pump Inhibitor
Omeprazole is orally absorbed, bioavailability 50-60%, plasma t1/2 ~1hr and metabolized in liver by CYP2C19. The drugs are tightly binds with proton pump so it inhibits HCl synthesis in stomach for long time.
Pharmacologically Uses Of Omeprazole OR Proton Pump Inhibitor:
1) Peptic Ulcer
2) Gastroesophageal reflux disease (GERD)
3) Zollinger-Ellison-Syndrome (ZES)
4) For the radiation of H.Pylori
5) It also used when bleeding occur due to ulcer
6) It also used in NSAIDS induce ulcer
Adverse Drug Effect Of Omeprazole OR Proton Pump Inhibitor:
1) Nausea
2) Loose stools
3) Headache
4) Abdominal Pain
Prostaglandin Analogues
Prostaglandin E2 and I2 receptor are present on gastric parietal cells. PGE2 and PGI2 are secreted gastric mucosa and they have cytoprotective action. They inhibit gastric HCl secretion by increase the secretion of gastric mucosa and bicarbonate (HCO3-), by this mechanism increase the mucosal defiance effect.
Mechanism of Action Of Misoprostol OR Prostaglandin Analogues
Prostaglandin (PG) receptor is releasing gastric mucosa and controlling excessive acidic environment in stomach. PG inhibits the acid secretion by opposing the cAMP generation. PG suppressed the cAMP in parietal cells and it have protective factor to prevent ulcer formation.
Pharmacokinetics Of Misoprostol OR Prostaglandin Analogues
Natural occurring prostaglandins have very small t1/2.
Pharmacological Uses Of Misoprostol OR Prostaglandin Analogues
1) Used in NSAIDS induce ulcer treatment
2) Used also when arthritis patients cause ulcer (due to long term used NSAIDs)
3) Gastric ulcer
Adverse Drug Effect Of Misoprostol OR Prostaglandin Analogues:
1) Diarrhoea
2) Abdominal pain
3) Cramps
4) Uterine bleeding
5) Abortion
2) Abdominal pain
3) Cramps
4) Uterine bleeding
5) Abortion
Ulcer Protective Drugs:
1) Sucralfate
It is a complex of aluminum salt {Al(OH)3} and sulfated sucrose.
Mechanism of action Of Sucralfate OR Ulcer Protective Drugs
In a strong acidic medium sucralfate devolve a sticky gel like patch. It binds with the proteins of both normal and narcotic or damage mucosa of ulcer. This patch stick to the ulcer base forming a physical barrier between the mucosa wall of stomach and acid pepsin mixture (APM) as a result digestion of mucosa wall by APM is prevented. It also increased the secretion of gastric prostaglandin, gastric mucosa and bicarbonate that secretions are defense digestion of mucosa wall. It binds with mucosal protein and prevents the digestion of mucosa wall by APM.
Pharmacokinetics Of Sucralfate OR Ulcer Protective Drugs
- Sucralfate should be taking for ulceration.
- Take 1gm of sucralfate before 20-30min of meal.
- Another dose at nocturnal acid secretion (acid secretion at night).
- 6-8 week treatment duration.
Pharmacological Uses Of Sucralfate OR Ulcer Protective Drugs
1) Gastric ulcer
2) Duodenum ulcer
3) Bile reflux
4) Gastritis
5) Phosphate stone in kidney
Adverse drug effect Of Sucralfate OR Ulcer Protective Drugs:
1) Dry mouth
2) Nausea
3) Constipation
4) Hypophosphatemia (phosphate ion binding in the intestine
Colloidal bismuth subcitrate (CBS)
CBS also called as tripotassium dicitratobimuthate. CBS is a colloidal bismuth compound and water soluble. It heal the ulcer 60-70% at 4 weeks and 80-90% at 8-9 weeks. It precipitated at <5 pH.
Mechanism of action of Colloidal Bismuth Subcitrate (CBS)
This compound is interacted with tissue to form a layer which coat the ulcer and thus prevent APM digestion of mucosa. It inhibited the secretion of pepsin and increase mucosa secretion.
Pharmacological Uses of Colloidal Bismuth Subcitrate (CBS)
1) Gastric ulcer
2) Anti-H.pylori effect
Adverse Drug Reaction of Colloidal Bismuth Subcitrate (CBS)
1) Blacking of stools and tongue.
2) Long term used can cause bismuth toxicity such as osteodystrophy and encephalopathy.
2) Long term used can cause bismuth toxicity such as osteodystrophy and encephalopathy.
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