A-34. Drugs used in peptic ulcer diseases. Pharmacotherapy of peptic ulcer diseases.

Question 1

The 4 main groups of agents in the treatment of peptic ulcer?

Answer 1

Antisecretory agents
Antacids
Mucosal defense enhancers
Drugs used for eradication of H. pylori

Question 2

Characteristics of type 1 ulcers?

Answer 2

Distal, antral + duodenal ulcers due to hypersecretion of gastric acid

Question 3

Characteristics of type 2 ulcers?

Answer 3

Upper gastric ulcers; normal / decreased gastric acid with decreased defense mechanisms

Type II ulcers tend to undergo malignant transformation

Question 4

Pathomechanism of ulcer formation?

Answer 4

“Back diffusion” of gastric acid from the lumen to the gastric mucosa occurs when mucosal integrity is compromised, resulting in further mucosal injury.

Question 5

What does the mucosal integrity depend on?

Answer 5

Mucosal integrity depends on mucus secreted from gastric epithelial cells and on mucosal microcirculation, which is NO dependent. Prostaglandins, specifically PGE2 and PGI2 also protect the gastric mucosa by inhibiting HCl secretion and relaxing mucosal vessels, improving blood flow.

Question 6

What are the 3 groups of Anti-secretory agents used?

Answer 6

H2 antagonists
Proton pump inhibitors
M1 antagonists

Question 7

H2 antagonists. Drugs?

Answer 7

Famotidine, ranitidine, nizatidine and cimetidine (longest to shortest half-life)

Question 8

H2 antagonists. MOA?

Answer 8

Inhibit H2 on parietal cells → ↓ cAMP → ↓ H/K-ATPase activity

Inhibit both basal + stimulated (via food / pH increase) gastric acid secretion, as well as pepsin and intrinsic factor secretion

They also antagonize effects of histamine on heart + vessels; may enhance immune responses

Question 9

H2 antagonists. Dosage and indications?

Answer 9

Famotidine 2 x 20 mg/day or 1 x 40 mg/day (on doses list)

○ Peptic ulcer - both gastric and duodenal; effective for both, but more effective for duodenal
○ Zollinger-Ellison syndrome - gastrinoma; high doses needed
○ Reflux esophagitis, stress ulcers and pre-anesthetic in emergency procedures

Question 10

H2 antagonists. Side effects?

Answer 10

○ HA, dizziness, nausea, diarrhea, constipation, myalgia, rashes and pruritus
○ CNS disturbances - mainly in elderly
○ Hypochlorhydria - low gastric HCl; ↑ bacterial survival; candidal peritonitis; can favor growth of bacteria which produce carcinogenic nitrosamines
○ Rarely - thrombo-/leukocytopenia, hepatorenal toxicity and bradycardia (if given i.v.)
○ May slow the detection of gastric cancer

Question 11

Unique side effects for Cimetidine?

Answer 11

■ Anti-androgenic effects - binds androgen R → ↓ libido, gynecomastia, impotence
■ CYP450 inhibition

Question 12

PPIs. Drugs?

Answer 12

Rabeprazole, Pantoprazole, Lansoprazole, Esomeprazole, and Omeprazole (long to short T1/2)

Question 13

PPIs. MOA?

Answer 13

They inhibit the H+/K+-ATPase proton pump on the luminal surface of parietal cells

Question 14

PPIs. Dosage and Indications?

Answer 14

Pantoprazole 20-40 mg 1-2x/day (on doses list)

Same as H2 atgs (except stress ulcer + pre-anesthesia); better than H2 atgs for reflux esophagitis

Question 15

PPIs. Side effects?

Answer 15

○ Hypergastrinemia - may cause hyperplasia of G cells or carcinoid tumors
○ Pneumonia - ↑ risk of nosocomial + community-acquired respiratory infections
○ Diarrhea - ↑ risk of C. diff and others (Salmonella, Shigella, E. coli, Campylobacter) or overgrowth of normal flora
○ Osteoporosis - with long-term use, ↑ hip fracture risk
○ HA, dizziness, skin rash, leukopenia

Question 16

Omeprazol interaction?

Answer 16

Omeprazole inhibits anti-aggregation effect of clopidogrel because both are pro-drugs activated by CYP2C19 + thus compete with each other for activation

Question 17

M1 antagonists. Drugs?

Answer 17

Pirenzepine and Telenzepine

Question 18

M1 antagonists. MOA?

Answer 18

Selective M1 muscarinic atgs → block cholinergic vagal stimulation of gastric secretions at the level of the parasympathetic ganglia

Block gastric secretion at lower doses than those which block other cholinergic functions → ↓ sfx

Question 19

M1 antagonists. Kinetics and Indications?

Answer 19

Poor oral absorption

Duodenal or gastric ulcers (higher dose for gastric)

Question 20

M1 antagonists. Side effects?

Answer 20

Frequent - constipation / diarrhea, dry mouth, HA, CNS effects
Less frequent - blurred vision

Question 21

Antacids. Sodium compounds?

Answer 21

Sodium bicarbonate and sodium citrate

● Sodium bicarb + HCl forms NaCl, water and CO2
● Can cause systemic alkalosis and fluid retention (via ↑ Na+)

Question 22

Antacids. Magnesium compounds?

Answer 22

Magnesium hydroxide

It forms MgCl2 and water; poorly soluble, long DOA and cathartic effect (diarrhea)

Question 23

Antacids. Aluminum compounds?

Answer 23

Aluminum hydroxide, basic Al carbonate gel and Al phosphate gel

AlCl3 formed from Al-OH and HCl; Al-OH has slow action and AlCl3 is poorly soluble → constipation, binding of tetracyclines + phosphate; can cause encephalopathy in kidney dysfunction

Question 24

Antacids. Calcium compounds?

Answer 24

Calcium carbonate

10% of formed CaCl2 is absorbed and can cause hypercalcemia and milk-alkali syndrome; only given short-term

Question 25

3 mucosal defense enhancers?

Answer 25

Bismuth chelate, Sucralfate, Misoprostol

Question 26

Bismuth chelate

MOA, indications and side effects?

Answer 26

MOA: chelates with proteins to form a protective coating over ulcers; also acts weakly as an antacid
○ taken 30 mins before or 2 hours after last meal

Indication: gastric and duodenal ulcers; combined with H2 atgs → less relapse

Side Effects:
○ Darkening of oral cavity
○ In renal impairment - encephalopathy and osteodystrophy

Question 27

Sucralafate

MOA, indications, side effects and interaction?

Answer 27

Basic aluminum salt of sucrose octasulfate

MOA: negatively charged sucrose octasulfate binds (+) charges on proteins, forming a gel; decreases back-diffusion of H+ into mucosa; stimulates PG synthesis; taken before meals

Indications: gastric and duodenal ulcers

Side Effects: obstipation - severe or complete constipation

Interaction: only effective in acidic environment → not given with antacids / H2 blockers!

Question 28

Misoprostol

MOA, indications, side effects and contraindication?

Answer 28

Synthetic PGE1

MOA: stimulates mucus secretion; enhances mucosal blood flow; prevents back diffusion; enhances cell replication; inhibits acid secretion (via ↓ cAMP)

Indication: NSAID-induced gastric mucosa damage
(Prophylaxis of NSAID ulcers can also be via COX2-selective NSAIDs, PPIs and H2 atgs)

Side Effects: diarrhea

Contraindication: pregnancy - stimulates uterine contractions!

Question 29

H. pylori classic triple therapy consists of?

Answer 29

Metronidazole + bismuth citrate + tetracycline or amoxicillin

Given for 14 days, or 7 days with omeprazole added; highest sfx risk

Question 30

H. pylori modified triple therapy consists of?

Answer 30

PPI + clarithromycin + metronidazole

Given for 7 days; lowest sfx risk

Question 31

H. pylori alternative triple therapy consists of?

Answer 31

PPI + clarithromycin + amoxicillin

Given for 7 days; middle sfx risk

Question 32

3 virulent mechanisms of H. pylori

Answer 32

H. pylori infects the gastric mucosa by neutralization of gastric acid with urease, breaking down urea to NH3 and CO2 which neutralizes gastric acid, forming NH4Cl.

Other factors in H. pylori pathogenicity are cytotoxins, PLA2 / PLAC, induction of leukotriene + PAF release, and endotoxin-induced endothelial damage.

H. pylori infection increases risk of gastric carcinoma.