Drugs in peptic ulcer disease

Dr. Y. Illangasekera
2015/16
18.02.2019
 Peptic ulcer
• Ulceration in stomach, duodenum

• Mucosa covered in hydrochloric acid and

pepsin acid-pepsin attack

• Breakdown of mucosal defence – NSAIDs/

Helicobacter pylori
 Acid production
• Gastric parietal cell
• H+ secreted into lumen by H+/K+-ATPase pump
(proton pump)

• Proton pump stimulated by

– Acetylcholine - by post-ganglionic vagal fibres
– Gastrin – by G cells of gastric antrum
– Ach + gastrin histamine by paracrine cells H2
receptors on parietal cells cAMP proton pump
 Ach
(vagus)

Histam M1
ine Paracrine
cell

G
Gastrin
 Protective mucosal barrier
• Mucous gel with HCO-3
• Neutralizes acid from
lumen, has neutral pH
• Prostaglandins E2 and I2
stimulate mucus and
bicarbonate
 Drugs used in peptic ulcer disease
• Basis of action
– Reduced HCl acid production
– Increase mucosal protection

• Inhibitors of acid secretion

– Proton pump inhibitors
– Histamine H2- receptor antagonists
• Mucosal protectants
• Antacids
• H. pylori treatment
 Proton pump inhibitors

• Irreversibly inhibit H+/K+-ATPase pump in gastric parietal cell

• Inactive at neutral pH, reactive molecules in acidic environment
• Pro-drug s activation in the acidic environment of the parietal
cell canaliculi
• Enteric coated to prevent premature activation
• More effective than H2 rec. antagonists

• Omeprazole
• Esomeprazole
• Lansoprazole
• Rabeprazole
• pantoprazole
• React with a cysteine residue on the H+/K+-ATPase to form a
covalent disulphide bond causing irreversible inhibition
 Pharmacokinetics
• Enteric coated. Absorbed from duodenum
• Should be taken 1 hour before meal
• Inhibition of HCL secretion within 1 hr.
• Maximum action in 3-4 days – 95%
suppression
• Metabolized by CYP2C19 , CYP3A4.
• Excreted in urine
 Proton pump inhibitors (PPIs)
• Well tolerated
• May cause nausea, abdominal pain, headache,
dizziness, hypergastrinaemia
• Omeprazole & esomeprazole inhibit
CYP-450
 Histamine H2 receptor antagonists

• Reversible competitive antagonists

• Block action of histamine on parietal cell
• Indirectly decrease gastrin & ACh-induced HCl
secretion
• Relieve pain, increase ulcer healing
• Cimetidine
• Ranitidine
• Famotidine
• Nizatidine
 Ach
(vagus)

Histam M1
ine Paracrine
cell

G
Gastrin
 Histamine H2 receptor antagonists

• Absorbed rapidly from the small intestine

• Not affected by food

• Peak plasma concentrations 1-3 hours

• Elimination both renal & hepatic – 2/3rd
unchanged
 H2 receptor antagonists

• Well tolerated; may cause confusion (esp. in

elderly)
• Cimetidine has antiandrogenic effects
(gynaecomastia)
• Cimetidine inhibits CYP-450 enzymes
– Reduced metabolism of phenytoin, quinidine,
theophylline, warfarin
 Mucosal protectants
• Polymerizes at pH<4
• Forms sticky gel which adheres to ulcer base
• Coats ulcer crater with polymer-glycoprotein complex
• May interact with food. Given on empty stomach
• Sucralfate
– Complex salt of sucrose sulphate and aluminum hydroxide
– May cause constipation
– May bind to quinolones, phenytoin, warfarin
• Bismuth chelate
– Colloidal compound precipitates at pH<5.
– May stimulate mucosal bicarbonate & PGE2 secretion
– Impedes growth of H. pylori
 Antacids
• Basic substances which raise luminal pH of stomach
• Acid rebound : Increased gastrin stimulates acid production,
increased amount of antacid needed
• Symptomatic relief of dyspepsia
• Tablets, liquids
• Aluminium hydroxide : Al+3 may bind to drugs i.e.
tetracyclines, cause constipation
• Magnesium hydroxide : Cause diarrhoea due to laxative effect
• Sodium biocarbonate
• Can be given in combination i.e Al + Mg hydroxides
 H. Pylori eradication
• Spiral, gram –ve rod.
• Deep in mucosal layer where pH is 7
• High urease activity, toxins and ammonia
• Prolonged gastrin secretion HCl production

• 70% of gastric ulcers, 90% of duodenal ulcers

• Treatment eradicates H.pylori in 1 week

 H. pylori eradication
• “Triple therapy” (7–14 days)
– PPI + amoxicillin + clarithromycin
– PPI + metronidazole + clarithromycin
– PPI + amoxicillin + metronidazole

• “Quadruple therapy” (10 –14 days)

– PPI + tripotassium dicitratobismuthate +
tetracycline + metronidazole
 H. pylori eradication
• Sequential therapy
– Days 1- 5 : PPI + amoxicillin
– Days 6 -10 : PPI + clarithromycin + tinidazole
 Prostaglandins
• PGE2 and PGI2
• Inhibit acid secretion, promote mucus and HCO 3-
secretion

• Misoprostol
– Long acting synthetic prostaglandin E1 analogue
– Used to prevent NSAID-induced peptic ulcers
– Often causes abdominal discomfort & diarrhoea
– Contraindicated in pregnancy