drugs used in peptic ulcer and dyspepsia

Question 1

Peptic ulcer by Use of Nonsteroidal anti-inflammatory drug (NSAID)
Treatment Approaches?

Answer 1

Avoidance of NSAIDs/ prevention of ulcer

Question 2

Inadequate mucosal defense against gastric acid

Treatment Approaches?

Answer 2

Protecting the gastric mucosa from damage

Question 3

3 Drugs Classification

Answer 3

1. Agents that reduce intragastric secretion/acidity
2. Agents that enhance mucosal resistance/cytoprotective agents
3. Drugs for treatment of Helicobacter Pylori infection

Question 4

Agents that reduce intragastric secretion/acidity

Answer 4

1.Proton pump inhibitors(PPIs):
Omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, pantoprazole
2. H2-receptor antagonists:
Cimetidine, ranitidine, famotidine
3. Antacids:
Aluminum hydroxide, calcium carbonate, Mg(OH)2, NaHCO3
Muscarinic antagonists (pirenzepine, telenzepine, propantheline, etc.)

Question 5

Agents that enhance mucosal resistance/cytoprotective agents

Answer 5

Prostaglandin analogs:
Misoprostol, Sucralfate
Miscellaneous: carbenoxolone, bismuth compounds

Question 6

Drugs for treatment of Helicobacter Pylori infection

Answer 6

Antibiotics:
Amoxicillin, Bismuth compounds, Clarithromycin, Metronidazole, Tetracycline

Triple therapy :(PPI + clarithromycin + amoxicillin or metronidazole)

Quadruple therapy: (PPI + metronidazole + Bismuth subnitrate + tetracycline)

Question 7

Effects of Drugs on Acid Secretion

• H2 receptor antagonist
• Proton pump inhibitor

Answer 7

H2-receptor antagonist has a marked effect upon nocturnal acid secretion

Proton pump inhibitor suppresses meal-stimulated and nocturnal acid secretion

Question 8

Proton pump inhibitors (PPI)

1. examples
2. What else does this drug require?
3. 2 MOAs
4. ROA
5. Therapeutic Uses

Answer 8

1.PROLED:Pantoprazole,Rabeprazole,Omeprazole, Lansoprazole,Esomeprazole, Dexlansoprazole,

2. Prodrugs - given 30min before meal
   - After absorption into systemic circulation, the prodrug diffuses into parietal cells and activated in the acidic secretory canaliculi
3. MOA:
   - Irreversibly binds covalently with H+ K+-ATPase ( require18 hours to resynthesize new enzyme)

• Inhibit both basal and stimulated gastric acid secretion
  4. enteric coated capsule / tablet / powder for suspension to protect them from premature degradation by gastric acid; intravenous :pantoprazole / lansoprazole

5.For short-term treatment 4-8 weeks for GU and DU
Zollinger-Ellison Syndrome (pathologic hypersecretion)
Treatment and prevention of NSAID-associated GU, Prevention of stress related mucosal bleeding(critical illness)
Multiple endocrine hyperplasia

Question 9

PPI PHARMACOKINETICS

1. ABSORPTION
2. METABOLISM- what enzyme?
   - excretion
   - how many days therapy?
3. PROTEIN BINDING
4. GIVEN HOW MANY TIMES DAILY?
5. WHEN IS DOSE REDUCTION REQUIRED?

Answer 9

1.Rapid absorption from small intestine
2. Extensively metabolised by CYP2C19 (slow metabolizer)
-Metabolites excreted in urine and faeces
-Takes ~5 days of therapy to get 70% inhibition of acid secretion at once daily dose.
3Highly protein bound.
4.Usually given twice daily.
5.Dose reduction needed in liver disease, but not in chronic renal failure.

Question 10

PPI 8 ADVERSE EFFECTS

Answer 10

1. Headache,
2. Abdominal pain, diarrhoea, constipation,
3. Myopathy
4. Arthralgia, rash
5. Vitamin B12 /Fe deficiency
6. Prolonged hypochlorhydria
7. Secondary hypergastrinemia/acid rebound,
8. Use of these drugs can “mask” the symptoms of gastric cancer

Question 11

PPI Drug Interaction

Answer 11

1. Omeprazole inhibits the metabolism of warfarin, phenytoin, diazepam, and cyclosporine.
2. PPIs + Clopidogrel → ↑ risk of major cardiovascular events OR acute coronary syndrome(↓ CYP2C19/3A4)
3. ↑Fracture risk (↓ Ca2+ absorption, impaired activity of osteoclasts)
4. Hypomagnesemia
5. ↑ Enteric infections
6. ↑ Community Acquired Pneumonia
7. ↑ Neoplasia (gastric polyps/gastric cancer/gastric carcinoids/colon cancer)

Question 12

PPI Drug administration- when?
- what should be taken after for
best effect?
- Regimen for GERD symptoms?

Answer 12

1. PPIs should be taken 30 minutes before breakfast or the largest meal of the day.
2. H2-receptor antagonist (if also needed) should be taken well after the PPI for best effect.
3. In patients with GERD, PPI twice-daily regimen or PPI in the morning and adding an H2 antagonist in the evening may improve symptom control.

Question 13

Agents Reduce Intragastric Secretion :
H2 receptor antagonists

1. 5 EXAMPLES
2. 2 MOA

Answer 13

1. EXAMPLE: Cimetidine, Ranitidine, Famotidine, Nizatidine, Roxatidine
   Cimetidinewas the prototypical histamine H2-receptor antagonist from which later drugs were developed.
2. MOA:
   -Inhibit acid production by reversible inhibition of H2-receptors on basolateral membrane of parietal cell.
   -Mainly inhibit nocturnal acid secretion

Question 14

H2 receptor antagonists PHARMACOKINETICS

1. ABSORPTION
2. HOW MANY TIMES DAILY
3. PROTEIN BINDING
4. METABOLISM - in liver
   - excretion
5. DOSE REDUCTION

Answer 14

PHARMACOKINETICS:

1. Rapid absorption, peak 1-3 hr.
2. Can be given twice daily in doses of 400-600 mg or 800mg at bedtime
3. Minimal protein binding.
4. Metabolized <30% in liver. Excreted in urine (reduce dose in renal impairment).
5. dose reduction in renal disease

Question 15

H2 receptor antagonists SIDE EFFECTS

Answer 15

1. In general, well tolerated, except forcimetidine
2. Few S/E reported: Diarrhoea, headache, drowsiness, fatigue, muscle pain, confusion, hallucination, slurred speech, blood dyscrasias
3. Crosses placenta, and Secreted in breast milk

Question 16

3 Uses of H2 Blockers

Answer 16

DU/GU by mainly inhibit nocturnal acid secretion -The most determinant of the rate of healing of DU

treatment of GERD,

prevent occurrence of stress ulcer

Question 17

1. DRUG INTERACTIONS OF H2 BLOCKERS 
(cimetidine and ranitidine)
2. Tolerance
3. CNS penetration
4. Excretion

Answer 17

Cimetidine –

1. decrease testosterone binding to androgen receptor gynaecomastia (reversible),
   - Inhibits CYPs :CYP1A2, CYP2C9, CYP2D6 that metabolize estradiol and many other drugs( warfarin,phenytoin,quinidine,carbamazepine,theophyline,imipramine) —> increase drug serum level
2. Tolerance occurs With Chronic use of H2 blockers (but not with PPIs.)
3. Penetration of cerebrospinal fluid occurs at high dose
4. unchanged drug and metabolites appear in urine and bile

Ranitidine
inhibits CYPs minimally. Famotidine has no significant effect.

Question 18

Agents Reduce Intragastric Acidity: Antacids

1. 4 examples
2. what are they?
3. ROA
4. Constituents
5. Why are Mg and Al used in combinations?

Answer 18

1.Aluminum hydroxide Al(OH)3, Calcium carbonate, Mg(OH)2, NaHCO3

2. They are weak bases that react with gastric hydrochloric
3. Antacids are used in combination (liquid/tablet) to neutralize acid.
4. Most antacids have principal constituent Magnesium or Aluminum alone or combination:
   -Aluminium hydroxide (usually a mixture of Al(OH)3 and aluminium oxide) and/or magnesium hydroxide [Mg(OH)2].
   - Occasionally combined with Sodium carbonate [NaCO3] or Calcium salt
5. Mg has laxative effects (Used prior to endoscopy) and
   Al causes constipation so using both gives neither constipation or diarrhoea

Question 19

Antacids-MOA-

1. How?
2. Can we heal ulcer using antacids alone?
3. Used for?

Answer 19

1. -Ability to reduce gastric acidity
   - NaHCO3 + H ions—> H2CO3—>H20 + CO2

• NaHCO3—> Na ions + HCO3 that are absorbed into circulation In intestine
• Pepsin is inactive in solution above pH 4.0
  2. Ulcer healing effectiveness by antacids alone is inadequate
  3. It is for symptomatic relief and only justified for minor symptoms

Question 20

ANTACIDS: HOW LONG AFTER MEALS? WHY

DOSAGE

Answer 20

Normally given 1 hour after a meal effectively neutralizes gastric acid for 2 hours.

A second dose given 3 hours after eating – will then maintain the effect for 4 hours after meals

Question 21

Adverse effects of the 4 Antacids

Answer 21

1. Aluminium hydroxide :hypophosphatemia, constipation,
2. Magnesium hydroxide :diarrhoea,
3. Calcium carbonate :hypercalcaemia and causes rebound acid secretion, chelation of drugs given together
4. Sodium bicarbonate: sodium overload, metabolic alkalosis

Question 22

Prostaglandin analogs: Misoprostol

MOA

Answer 22

Misoprostol:

PGE2 & PGI2 synthesized by gastric mucosa & bind to EP3 receptor
Stimulate the Gi pathway decrease cAMP and gastric acid secretion.
2. Cytoprotective effect(high dose) = stimulate mucus and bicarbonate secretion & increase mucosal blood flow
Misoprostol (analog of PGE1) inhibit basal acid secretion ~90% and food-stimulated secretion ~80%.

Question 23

Adverse effects of misoprostol

Answer 23

Diarrhoea, abdominal pain & cramps

Question 24

CONTRAINDICATION of misoprostol

Answer 24

1. Contraindicated during pregnancy
   (stimulate uterine contraction,
   2.used for therapeutic abortion

Question 25

CLINICAL USE of misoprostol effectiveness for peptic ulcer compared to H2 antagonists and PPIs

Answer 25

To prevent or reduce NSAID induced mucosal injury(e.g. in patients with rheumatoid arthritis); less effective than H2 antagonists and the PPIs in acute treatment of peptic ulcers)

Question 26

What is Sucralfate ?

Answer 26

Complex of aluminium hydroxide and sucrose-octasulfate

Question 27

1. MOA of Sucralfate | 2. Does it prevent NSAID-induced ulcers?

Answer 27

In acid pH, sucralfate forms viscous sticky polymer that form complex gels with mucus and adheres to epithelial cells and ulcer crater for 6 hr Thus creates a physical barrier which prevents destruction of mucosa by pepsin, acid and bile. Stimulates prostaglandin release as well as mucus and bicarbonate output, and it inhibits peptic digestion. Does not prevent NSAID-induced ulcers, nor does it heal gastric ulcers. Sucralfate effectively heals duodenal ulcers and is used in long-term maintenance therapy to prevent their recurrence.

Question 28

1. Drug Interaction of Sucralfate | 2. Sytemic Side effects?

Answer 28

1.As it requires an acidic pH for activation, sucralfate should not be administered with H2 antagonists or antacids or PPI. Interfere with the absorption of other drugs by binding to them (quinolones, digoxin, theophylline, amitriptyline etc.) 2.Some of the drug is absorbed systemically, no systemic side effects.

Question 29

3 Therapeutic Uses of sucralfate

Answer 29

1. Prophylaxis of bleeding from stress ulcer 2. Oral mucositis (radiation, aphthous ulcer) 3. As enema for radiation proctitis

Question 30

3 Therapeutic Uses of sucralfate

Answer 30

1. Prophylaxis of bleeding from stress ulcer 2. Oral mucositis (radiation, aphthous ulcer) 3. As enema for radiation proctitis

Question 31

4 Adverse effects of sucralfate - which patient to avoid in?

Answer 31

1 .Constipation 2. Inhibit absorption of other drugs in GIT 3. Formation of bezoars in stomach -Avoid in patient with renal failure

Question 32

name 2 Bismuth compounds 2 MOA

Answer 32

1. subcitrate, subsalicylate 2-Bind to base of ulcer, coating it and protecting it from acid & pepsin -Promote mucin and bicarbonate secretion

Question 33

Uses of Bismuth Compounds

Answer 33

1. Have significant antibacterial effects | 2. Used to eradicate H pylori infection and prevent ulcer recurrence

Question 34

4 Side effects of Bismuth compounds

Answer 34

Side effects: black stool, constipation, darkening of tongue, neurotoxicity with long term use

Question 35

Therapy of Helicobacter pylori Infection

Answer 35

Triple therapy x 10-14 days:  PPI healing dose twice/d (see lower pane) +  Clarithromycin 500 mg + (Amoxicillin 1 g or Metronidazole 500 mg ) twice a day. (Tetracycline 500 mg can be substituted for amoxicillin or metronidazole.) Quadruple therapy x 7-14 days:  Proton pump inhibitor twice a day +  Metronidazole 500 mg three times daily + Bismuth subsalicylate 525 mg four times daily +  Tetracycline 500 mg four times daily or   H2 receptor antagonist twice a day + Bismuth subsalicylate 525 mg  four times daily + Metronidazole 250 mg four times daily +  Tetracycline 500 mg four times daily

Question 36

1. Normal control of acid secretion | 2. How does H pylori increase gastric acid?

Answer 36

1.Normal control of acid secretion: A low antral pH stimulates release of somatostatin from D cells in the antral glands. Somatostatin inhibits gastrin release from adjacent G cells and acid secretion reduced. 2. -H. pylori produces alkaline ammonia to protect itself against acidity in the stomach - Production of NH3 on the surface of gastric epithelium and antral gland, prevents ‘D’ cells from sensing the true level of luminal acidity - Somatostatin release is reduced and gastrin release is increased leading to excess acid secretion

Question 37

Synthesis of prostaglandin and function

Answer 37

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