A34. Drugs used in peptic ulcer diseases. Pharmacotherapy of peptic ulcer diseases.

Question 1

What is the Antibiotic therapy for H. pylori infection?

Answer 1

Chronic H pylori infection is present in most cases of recurrent non-NSAID peptic ulcers.

1. Triple therapy: metronidazole, bismuth salts, tetracycline for 14 days. Add omeprazole to reduce it to 7 days. Has greater side effects than the other two.
2. Modified triple therapy: PPI + clarithromycin + metronidazole for 1 week. (lowest side effect profile, best if there’s a penicillin allergy, no amoxicillin).
3. Alternative triple therapy: PPI + clarithromycin and amoxicillin for 1 week

Question 2

What are the risk factors of NSAID induced gastric mucosal damage?

Answer 2

1. GI ulcer
2. Age
3. Smoking
4. Parallel steroids
5. Anticoagulants

Question 3

What is the physiological MOA of prostaglandins and how can they help prevent or heal Peptic ulcers?

Answer 3

1. Prostaglandins increases mucosal protection (enhances cell replication) and inhibits acid secretion. It also prevents H+ back-diffusion. 2. Stimulates mucus and bicarbonate secretion 3. Causes vasodilation allowing more blood flow to the area promoting new epithelial cell growth and again inhibits the acid secretion.

Question 4

What is sucralfate and it’s MOA?

Answer 4

Sucralfate is a basic albumin salt of sucrose octasulphate. MOA: 1. sucralfate polymerizes in active environment → polymer binds to injured tissue and forms protective coating over ulcer beds. (the (-) sucrose octasulphate bind to (+)protein molecules: gel) 2. Stimulates PG synthesis 3. Decreases back-diffusion of H+. 3. Accelerates the healing of peptic ulcers and reduces their recurrence.

Question 5

Bismuth Chelate **

Answer 5

Bismuth Chelate (De-nol)/Pepto-Bismol (Bismuth Subsalicylate) used for the enhancement of gastric mucosal defense and has antipeptic activity. Bismuth chelate has many protective effects. Its MOA is that it starts chelating with protein forming a coating and therefore coats the surface of the ulcer. Other effects includes stimulation of mucosal protective enzymes, antimicrobial effects and sequestration of enterotoxins.

Question 6

What are Antacids and it’s MOA?

Answer 6

Antacids are weak bases that react w/ gastric acid to form water and some form of salt. It diminishes gastric acidity by reducing pepsin activity (requires pH of less than 4 to be active). It can be used for symptomatic relief of peptic ulcers and GERD, and may promote healing of duodenal ulcers.

Question 7

Name the M1 receptor antagonists.

Answer 7

1. Pirenzepine 2. Telenzepine

Question 8

Name some proton pump inhibitor (PPIs).

Answer 8

1. Omeprazole (pro-drug) 2. Pantoprazole 3. (Dex)lansoprazole 4. Esomeprazole 5. Rabeprazole (practically no difference between these drugs only some minor pharmacokinetic differences, that’s it) - half-lives only about 1-2 hours

Question 9

Name the Histamine 2R antagonists.

Answer 9

Histamine 2R antagonists: [mostly supplanted by PPIs] 1. Cimetidine 2. Nizatidine: has highest bioavailability of H2 antag 3. Ranitidine** 4. Famotidine: has lowest bioavailability of H2 antag

Question 10

Name the factors that influence the integrity of the gastric mucosa.

Answer 10

Aggressive factors: 1. HCL 2. Pepsin 3. H pylori Protective factors: 1. Mucosal layer 2. Microcirculation (NO)

Question 11

Name the different ulcer types.

Answer 11

Ulcer types: - Type I: distal, antral, duodenal ulcers. Mechanism: hypersecretion (dominant aggressive factors) - Type II: upper gastric ulcers. Secretion is normal or decreased, but defensive mechanisms are lessened. Tends to undergo malignant transformation (decreased defensive mechanism)

Question 12

Pharmacokinetics of Sucralfate?

Answer 12

Pharmacokinetics: 1. Dose: must take 4x/day (not ideal, poor pt compliance) 2. Very low toxicity, too insoluble to absorb from oral route 3. Don’t take antacids or H2 antagonists simultaneously!! needs acidic environment to be activated.

Question 13

What are the side effects of administering M1 receptor antagonists?

Answer 13

Side effects: similar to atropine 1. Blurred vision 2. Dry mouth 3. Constipation-diarrhea 4. Headache 5. Atropine-like CNS effects

Question 14

What are the adverse effects of Bismuth chelate?

Answer 14

Adverse effects: 1. Darkening of oral cavity 2. Encephalopathy if absorbed, osteodystrophy (only if renal damage)

Question 15

Pharmacokinetics of M1 receptor antagonists

Answer 15

Low therapeutic value. rarely used

Question 16

What are the effects of Histamine 2R antagonists?

Answer 16

Histamine 2R anatagonists are Antisecretory agent. Responsible for: 1. Inhibition of gastric secretion: basal gastric acid secretion, stimulated (muscarin agonist, gastrin)gastric acid secretion (histamine final common mediator?), pepsin, intrinsic factor secr. 2. other: enhanced immune response (?), antagonism of certain effects of histamine on heart and vessels.

Question 17

What is the MOA of PPIs?

Answer 17

MOA: irreversibly blockage of the final step of acid secretion (H/K ATPase). Usually very effective.

Question 18

What kinds of interaction can PPIs have in the body?

Answer 18

1. Omeprazole inhibits clopidogrel-induced anti-aggregation (compete for CYP2C19). if patient can’t take aspirin, they can be prescribed clopidogrel. remember this reaction - pts lose the cardioprotective effect. clopidogrel also can cause gastric damage. this is a good reason to choose a different PPI besides omeprazole. 2. May decrease absorption of drugs that need acidity for absorption (e.g. ketoconazole, digoxin)

Question 19

What is the MOA of PPIs?

Answer 19

MOA: irreversibly block final step of acid secretion (H/K ATPase). usually very effective.

Question 20

What are the indication for PPI therapy?

Answer 20

1. ZES: first-line. high dose 2. peptic ulcer: 20-30 mg/day 3. Reflux esophagitis (depending on severity). also 20-30 mg/day. better than H2 blockers, but may switch to those if PPIs are ineffective. 4. often given as prophylaxis for patients on daily aspirin

Question 21

Name the prophylactic agents for NSAID-induced gastric damage.

Answer 21

Drugs: 1. Selective COX-2 inhibitors 2. Misoprostol 3. PPIs for gastric but not intestinal mucosal injury 4. H2-R blockers

Question 22

What are the indications and dose of Bismuth Chelate therapy?

Answer 22

Indicated in gastric and duodenal ulcers. (= with H2 blocking drugs, less relapse) Dose: 4x120 mg (30’ min before meals 2h after last meal)

Question 23

physiology duodenum

Answer 23

brunner glands (mucus rich in bicarbonate to reduce acidity. The stomach and the duodenum would be digested if it wasnt for the mucus and bicarbonate ions., neutralizing the acid. The stomach wall is thicker than that of the duodenum due to the increase and constant acid exposure. The duodenum is only momentarily exposed to acid. Blood also brings bicarbonate to help neutralize acid.

Question 24

What are the causes of peptic ulcers

Answer 24

H.Pylori bacteria, gram negative bacteria, common in low income countries and settings, colonize in the gastric mucosa, release adhesions –> foveolar cells.proteases damage the mucosal cells. usually starts in the antrum and spreads into the stomach and eventually into the duodenum…eventually causes ulcers another cause is NSAID use, ex ibuprofen inhibiting COX which is involved in the production/synthesis of inflammatory prostaglandins. leaves gastric mucosa susceptible to damage. rare (zollinger- ellison syndrome- tumor- gastrinoma- neuroendocrine tumor)in the duodenal wall or pancreas. secretes abnormal amounts of gastrin. excess gastrin promotes parital cells to secrete excess HCL. ulcers develops in the first portion of the duodenum or distal duodenum, or jejunum. ulcers look small round pounched out parts/holes in the mucosa, has a clean base (hcl and constant churning getting the debris out of the ulcer)beneath the base is a scar tissue + blood vessels …occationally the ulcer can bleed if the erosion goes deep. gastric ulcers for in the lesser curveture of the stomach , duodenal -right after the pyloric sphincter. duodenal ulcers…brunner gland hypertrophy. Deep ulcers can cause bleeding into the GI tract ?…dangerous when there is a nearby artery. bleeding/rapid loss of blood can lead to shock. lesser curvature of the stomach left gastric artery or duodenal- gastroduodenal artery. other complications can be perforations…. where gastrointestinal contents to spill out to the peritoneal cavity which is usually sterile. ….complication of duodenal ulcers…when there is a perforation air starts to collect under the diaphragm irretating the phrenic nerve sending up referred pain to the shoulder. long standing duodenal ulcers near the pyloric sphincter can cause so much edema and scarring that it can obstuct normal passage of gastric contents…gastric outlet obstruction can lead to nausea and vomiting

Question 25

symptoms of gastric ulcers

Answer 25

epigastric pain: aching or burning pain in upper abdomen bloating belching vomiting gastric ulcer pain increases while eating due to the physical presence of the food + hcl production stimulate in the process of eating. (weight loss) duodenal ulcers: pain when the stomach is empty??? associated with weight gain

Question 26

diagnosis

Answer 26

upper endoscopy/gastroscopy biopsy is done to check for malignancy + h.pylori infection

Question 27

treatment options

Answer 27

depends on the underlying cause h.pylori….combo of antibiotics and acid lowering medication extreme cases: surgery is needed (vagotomy, antrectomy , pyloroplasty) (perforations bleedings or scar tissue obstructing passage of food.)

Question 28

substances that can worsen peptic ulcers?

Answer 28

NSAIDs alcohol tobacco caffeine

Question 29

What are the indications for histamine 2R antagonists?

Answer 29

1. Peptic Ulceration: 1000 mg cimetidine/day: 50% reduction of secretion. 300 mg ranitidine/day: 70% reduction of secretion. 2. Duodenal ulcer: 85-90% are healed after 8 weeks treatment 3. Gastric ulcer: 50-70% are healed after 8 weeks. 4. Zollinger-Ellison syndrome: high doses are needed, second line choice 5. Other condition: reflux oesophagitis, stress ulcers, preanesthetic use in emergency, non ulcer dyspepsia

Question 30

What are the side effects of histamine 2R antagonists?

Answer 30

1. CNS: headache, dizziness, CNS disturbance in elderly people. 2. GI: nausea, diarrhea, constipation 3. Muscle: Myalgia 3. Skin: skin rashes, pruritus 4. Only cimetidine: loss of libido, gynecomastia, impotentia (binds to androgen receptors), binds to cytochrome P-450; inhibit the activity of hepatic microsomal 7. Rare effects: thrombo-leukocytopenia, hepato-renal toxicity, i.v. inj can cause bradycardia 8. Hypochlorohydria: favours the survival of bacteria–> candidal peritonitis. Growth of bacteria that form from ingested nitrates, carcinogen nitrosamines (??) 9. Diagnosis of gastric cancer can be retarded in the presence of H2 blockers.

Question 31

Name the doses of histamine 2R antagonists.

Answer 31

1. Cimetidine: 800 mg at bedtime - 4 x 200 mg - 2 x 400 mg 2. Ranitidine: 300 mg at bedtime - 2 x 150 mg 3. Famotidine: 40 mg at bedtime - 2 x 20 mg 4. Nizatidine: 300 mg at bedtime - 2 x 150 mg

Question 32

PPI

Answer 32

MECHANISM: H+ -K+ -ATP-ase: final step in gastric acid secretion inhibited by substituted benzimdazole: Omeprazole and derivatives INDICATION: Zollinger-Ellison syndroma 60-80-120 mg/day Peptic ulcer (like H2 blocking drugs) 20-30 mg/day Reflux esophagitis (better than H2 blocking drugs) 20-30mg/day

Question 33

ppi

Answer 33

INTERACTION Omeprazol inhibits the clopidogrel-induced antiaggregation Mechanism: the active metabolite of clopidogrel and omeprazol is produced by the enzym CYP2C19. Competition for the metabolizing enzyme CYP2C19

Question 34

m1 muscarin receptor antagonist

Answer 34

gastric secretion is blocked in lower doses than other cholinergic functions Absorbtion: poorly absorbed Indication: duodenal ulcer: 2x 50 mg/day gastric ulcer: 3x 50 mg/day Side effects: blurred vision less frequently dry mouth constipation-diarrhoea frequently headache frequently CNS frequently

Question 35

What is the mortality rate of bleeding from the upper GI?

Answer 35

Bleeding from upper gastrointestinal tract is life-threating; the mortality is 5–20%.

Question 36

What is the frequency of GI bleedings in western europe and USA?

Answer 36

The frequency of acute gastrointestinal bleeding in Western Europe and USA is 60-100/100 000 person/year (In Hungary: 140/100 000 person/year).

Question 37

Who can get stress ulcers and it’s mortalilty rate?

Answer 37

A stress ulcer can develop in patients in intensive care units. Mortality due to gastric bleeding associated with stress ulcer can reach, even exceed 50%.

Question 38

Name the agents of ulcer therapy which inhibits the agressive factors.

Answer 38

1. Anti-secretory agents a)Histamine H2 blocking drugs b) Proton pump inhibitors c) Anticholinergic drugs 2. Antacids

Question 39

What is the therapy for eradication of helicobacter pylori?

Answer 39

…

Question 40

Name the agents that increase mucosal resistance when it comes to ulcer therapy.

Answer 40

1. Sucralfate 2. Prostaglandins 3. Bismuth salts

Question 41

What are the indications of sucralfate?

Answer 41

Indication: gastric and duodenal ulcer

Question 42

what is the dosage of sucralfate?

Answer 42

Dose: 4x1 g 1 h before a meal

Question 43

What interactions does sucralfate have?

Answer 43

Interaction: antacids, H2 antagonist should not be taken simultaneously (sucralfate is effective only in acidic einviroment)

Question 44

What are the adverse effects of sucralfate?

Answer 44

Obstipation

Question 45

Name the prostaglandin drugs?

Answer 45

1. Misoprostol (PGE1 analog)

Question 46

Why aren’t prostaglandins used so much anymore?

Answer 46

Prostaglandins are effective in reducing risk of ulcers from NSAID use, but not widely used due to multiple daily dosing and poorly-tolerated adverse effects (GI upset, diarrhea, uterine contractions). It is also expensive and (presumably) not allowed during pregnancy.

Question 47

Antacids

Answer 47

• administered after meals for max effectiveness • Sodium compounds o sodium bicarb, sodium citrate o cause systemic alkalosis - this is something that is taught but not actually common clinically. not recommended for long-term use. o fluid retention (Na) • Magnesium hydroxide: poor solubility, can cause unpleasant feeling. mild systemic alkalosis risk too o “cathartic effect” but can cause diarrhea • aluminum compounds: o aluminum hydroxide, basic Al carbonate gel, Al phosphate gel o may cause constipation. slow action o binds to tetracyclines etc o not really absorbed, but if absorbed: encephalopathy, possibly even related to Alzheimers risk? • Calcium carbonate: o risk of hypercalcemia, milk-alkali syndrome o only for short tx • combo: magaldrate - Mg(OH2) + Al(OH)3

Question 48

List the mucosal protective agents.

Answer 48

1. Sucralfate
2. Misoprostol
3. Bismuth salts

Question 49

How is the absorption of Histamine 2R antagonists?

Answer 49

Absorption: good absorption from the stomach but can be altered by food or antacids.

Question 50

When is histamine 2R antagonists administered?

Answer 50

They are given more before sleep: cholinergic tone is higher at night /early morning (also true for asthmatic attacks). Less acid needed during the night than during the day when digesting food.

Question 51

What are the side effects of PPIs?

Answer 51

1. Hypergastrinaemia: (hyperplasia, carcinoid tumor?) 2. GI: Potential risk of bacterial overgrowth. Diarrhea induced by clostridium difficile and additional bacteria (Salmonella, Shigella, E coli, Campylobacter). However there is rarely gastrointestinal disturbance. 3. CNS: headache, dizziness 4. Skin rash 5. Leukopenia 6. Community aquired and nosocomial pneumonia 8. Long term use: osteoporosis, increased risk of hip fracture

Question 52

ppis

Answer 52

• indications: o ZES: first-line. high dose o peptic ulcer: 20-30 mg/day o reflux esophagitis (depending on severity). also 20-30 mg/day. better than H2 blockers, but may switch to those if PPIs are ineffective. o often given as prophylaxis for patients on daily aspirin • interactions: o **omeprazole inhibits clopidogrel-induced anti-aggregation (compete for CYP2C19). if patient can’t take aspirin, they can be prescribed clopidogrel. remember this reaction - pts lose the cardioprotective effect • clopidogrel also can cause gastric damage • this is a good reason to choose a different PPI besides omeprazole o may decrease absorption of drugs that need acidity for absorption (e.g. ketoconazole, digoxin) Proton pump inhibitors (PPIs): standard treatment. more effective than H2 ATGs for GERD, peptic ulcer, non-ulcer dyspepsia, and prevention of stress-related mucosal bleeding