Gastroenterology: Pharmacology - Anti-ulcer medications

Question 1

What % of peptic ulcers are caused by H. pylori infection or NSAID use?

Answer 1

> 90%

Question 2

Two classes of agents used in treatment of acid-peptic disorders

Answer 2

1. Agents that reduce intragastric acidity
2. Agents that promote mucosal defence

Question 3

Explain how acid is secreted in the stomach

Answer 3

Gastrin is secreted by antral G cells in response to intraluminal dietary peptides, and via direct stimulation by gastrin-releasing peptide (GRP) from vagal postganglionic neurons
Vagal postganglionic neurons also indirectly increase gastrin secretion from antral G cells by inhibiting somatostatin release from antral D cells
Gastrin travels through the bloodstream and binds to gastrin / CCK-B receptors on parietal and enterochromaffin-like cells in the fundic glands
Enterochromaffin-like cells are then stimulated to secrete histamine by gastrin; they also release histamine in response to ACh from vagal postganglionic neurons acting on M3 receptors
Parietal cells secrete acid across canalicular membrane via H+/K+-ATPase in response to gastrin* (acting on CCK-B receptor), ACh (M3 receptor), and histamine (H2 receptor)

*in humans it’s believed that gastrin stimulates acid secretion indirectly via histamine release from ECL cells, wheras ACh (from vagal postganglionic nerves) provides direct parietal cell stimulation

Question 4

What cells in the stomach release gastrin? Where are they located?

Answer 4

G cells in the antrum

Question 5

What is the effect of gastrin and ACh receptor activation on enterochromaffin-like cells?

Answer 5

Stimulate histamine release

Question 6

Explain how acid secretion is regulated in the stomach

Answer 6

Antral D cells are stimulated to release somatostatin by increased intraluminal H+ and by CCK (which is released into the bloodstream by duodenal I cells in response to proteins and fats)
Binding of somatostatin to receptors on adjacent antral G cells inhibits further gastrin release

Question 7

Describe the difference in intracellular signaling pathways produced by the binding of gastrin, ACh and histamine to their respective parietal cell receptors

Answer 7

Gastrin and ACh bind to CCK-B and M3 receptors respectively on parietal cells and cause an increase in cytosolic Ca2+, stimulating an intracellular signaling cascade that culminates in acid secretion from H+/K+ ATPase pump on the canalicular surface
Histamine binds to H2 receptor on parietal cell, resulting in adenylyl cyclase activation -> increased cAMP, intracellular signaling cascade that culminates in acid secretion from H+/K+ ATPase pump on the canalicular surface

Question 8

How much gastric HCl is released after a meal? How much antacid is required to neutralise this and what is the duration of action?

Answer 8

45mEq/hr gastric HCl released postprandially
156mEq antacid given 1hr after a meal effectively neutralises gastric acid for up to 2hrs

Question 9

Four factors determining the acid-neutralisation capacity of an antacid

Answer 9

1. Rate of dissolution (liquid vs tablet)
2. Water solubility
3. Rate of reaction with acid
4. Rate of gastric emptying

Question 10

Pharmacodynamics of antacids

Answer 10

Weak bases which react with gastric hydrochloric acid to form a salt and water

Question 11

Four examples of antacid and products formed by each

Answer 11

1. Sodium bicarbonate -> CO2 and NaCl
2. Calcium carbonate -> CO2 + CaCl2
3. Magnesium hydroxide -> MgCl2 + H2O
4. Aluminium hydroxide -> AlCl3 + H2O

Question 12

Adverse effects of sodium bicarbonate as an antacid

Answer 12

1. CO2 causes gastric distension and belching
2. Unreacted alkali is easily absorbed and may cause metabolic alkalosis in high doses or in renal insufficiency
3. NaCl absorption may exacerbate fluid retention in the setting of HF, HTN, renal insufficiency
4. Excessive use with calcium-containing dairy products may cause milk-alkali syndrome (hypercalcaemia, metabolic alkalosis, and AKI)

Question 13

Adverse effects of calcium carbonate as an antacid

Answer 13

1. CO2 causes gastric distension and belching
2. Unreacted alkali is easily absorbed and may cause metabolic alkalosis in high doses or in renal insufficiency
3. Excessive use with calcium-containing dairy products may cause milk-alkali syndrome (hypercalcaemia, metabolic alkalosis, and AKI)

Question 14

Advantages of magnesium/aluminium hydroxide vs sodium bicarbonate/calcium carbonate

Answer 14

Less belching as no CO2 generated
Less likely to cause metabolic alkalosis due to efficiency of neutralisation reaction

Question 15

Why are magnesium and aluminium hydroxide commonly administered in combination?

Answer 15

Unabsorbed Mg2+ causes osmotic diarrhoea
Aluminium salts cause constipation
Giving together minimises impact on bowel function

Question 16

How might antacids change absorption of other medications?

Answer 16

1. Binding drug to reduce its absorption
2. Increasing intragastric pH to change drug’s solubility (especially weakly acidic or basic drugs)

Question 17

Antacids should not be administered within 2hrs of which 4 drugs/drug classes

Answer 17

1. Tetracyclines
2. Fluoroquinolones
3. Itraconazole
4. Iron

Question 18

Describe the pharmacokinetics of H2-receptor antagonists

Answer 18

Absorption: rapidly absorbed from intestine
Distribution: all except nizatidine undergo first pass metabolism resulting in bioavailability of ~50%
Metabolism: t1/2 1.1-4hrs
Elimination: hepatic and renal

Question 19

Are H2 receptor antagonists selective?

Answer 19

Yes: highly selective and do not affect H1 or H3 receptors

Question 20

Pharmacodynamics of H2-receptor antagonists

Answer 20

Histamine released from ECL cells by gastrin or vagal stimulation is blocked from binding to parietal cell -> acid secretion reduced
Direct stimulation of parietal cell by gastrin or ACh also has a diminished effect on acid secretion when H2-receptor blockade is present

Question 21

What are H2-receptor antagonists better at inhibiting and why: nocturnal acid secretion of meal-stimulated acid secretion?

Answer 21

Nocturnal acid secretion, as this is mostly dependent on histamine
Less effective at inhibiting meal-stimulated acid secretion as this is stimulated by gastrin and ACh in addition to histamine

Question 22

What is the impact of H2-receptor antagonists on gastric pH?

Answer 22

Raises nocturnal and fasting gastric pH to 4-5

Question 23

What is the magnitude and duration of acid inhibition achieved by prescription doses of H2-receptor antagonists?

Answer 23

Maintains >50% acid inhibition for 10hrs (so needs twice-daily dosing)
OTC doses achieve acid inhibition for 6-10hrs

Question 24

Indications for H2-receptor antagonists

Answer 24

1. GERD with infrequent symptoms (<3x per week)
2. PUD (for nocturnal healing of uncomplicated gastric or duodenal ulcers; healing rates >80-90% after 6-8 weeks)
3. Nonulcer dyspepsia
4. Prevent of bleeding from stress-related gastritis

Question 25

Why are continuous infusions of H2-receptor antagonists preferred over bolus in the setting of prevention of bleeding from stress-related gastritis?

Answer 25

Continuous infusion achieves more consistent, sustained elevation of intragastric pH

Question 26

What % of critically ill patients will have clinically important upper GI bleeding? What is the aetiology?

Answer 26

1-5% Due to impaired mucosal defence mechanisms as a result of poor perfusion (even in setting of normal or decreased acid secretion)

Question 27

Adverse effects of H2-receptor antagonists

Answer 27

1. Diarrhoea/constipation 2. Headache 3. Fatigue 4. Myalgias 5. Confusion and hallucinations 6. Cimetidine may cause hyperprolactinaemia: gynaecomastia and impotence in men, and galactorrhoea in women 7. Contraindicated in pregnancy and breastfeeding as they cross the placenta and are secreted in breastmilk (but no known harmful effects) 8. Blood dyscrasias 9. Bradycardia and hypotension with rapid IV infusion 10. Reversible LFT derangement 11. CYP450 inhibition (cimetidine)

Question 28

List the six PPIs available for clinical use. Which are available in IV form?

Answer 28

Omeprazole Esomeprazole* Pantoprazole* Rabeprazole Lansoprazole Dexlansoprazole *available IV

Question 29

Specific adverse effects of cimetidine

Answer 29

Gynaecomastia, impotence, galactorrhoea CYP450 inhibitor

Question 30

How does cimetidine cause gynaecomastia/galactorrhoea?

Answer 30

Inhibits binding of dihydrotestosterone to androgen receptor Inhibits metabolism of oestradiol Increases serum prolactin

Question 31

Pharmacokinetics of PPIs

Answer 31

Absorption: administered as prodrug in acid-resistant enteric-coated capsules, coatings dissolve in alkaline intestinal lumen and prodrug is absorbed Distribution: lipophilic weak bases, bioavailability decreased by food but acid inhibition most effective during maximal activity of proton-pump secretion (so should be given 1hr prior to meal so that peak serum concentration coincides with this) Metabolism: rapid first-pass and systemic hepatic metabolism, t1/2 ~1.5hrs but acid inhibition lasts up to 24hrs due to irreversible binding to H+/K+ ATPase (at least 18hrs is needed to synthesise new pumps) - however not all pumps are inactivated with first dose of medication so up to 3-4 days of medication are required (similarly after stopping drug it takes 3-4 days for full acid secretion to return) Elimination: primarily hepatic, negligible renal clearance (no dose reduction required except with severe liver disease)

Question 32

Pharmacodynamics of PPIs

Answer 32

Lipophilic weak bases which diffuse readily across lipid membranes into acidified compartments (i.e. parietal cell canaliculus) where they become activated and irreversibly bind to inactivate H+/K+ ATPase

Question 33

Why do IV PPIs need to be administered as a continuous infusion or as repeated bolus injections?

Answer 33

PPIs have no effect on pumps in intracellular vesicles Half-life is short: when drug is metabolised, previously quiescent pumps are moved to the canalicular membrane and start secreting acid Therefore to provide maximal inhibition in first 24-48hrs, must be given as continuous infusion or repeat boluses

Question 34

What % of acid secretion is inhibited by PPIs? What is the intragastric pH and mean numbers of hours this pH is maintained?

Answer 34

90-98% pH 3.3-4 pH >4 maintained for 10-14hrs

Question 35

Five clinical uses of PPIs

Answer 35

1. GERD 2. PUD 3. Non-ulcer dyspepsia 4. Prevention of bleeding from stress-related gastritis 5. Gastrinoma and other hypersecretory conditions

Question 36

4 extraoesophageal complications of GERD

Answer 36

1. Asthma 2. Chronic cough 3. Laryngitis 4. Non-cardiac chest pain

Question 37

Describe triple and quadruple therapy for H. pylori associated PUD

Answer 37

All 14 days' duration Triple therapy: 1. PPI BD 2. Clarithromycin 500mg BD 3. Either amoxicillin 1g BD or metronidazole 500mg BD Quadruple therapy (due to rising clarithromycin resistance): PPI BD and EITHER: - Bismuth subsalicylate 524mg, metronidazole 500mg, and tetracycline 500mg all QID; OR - Amoxicillin 1g, clarithromycin 500mg, metronidazole 500mg all BD

Question 38

Asymptomatic peptic ulceration develops in what % of people taking frequent NSAIDs? In what % of people taking frequent NSAIDs do ulcer-related complications develop?

Answer 38

10-20% develop asymptomatic peptic ulceration 1-2% develop ulcer-related complications

Question 39

IV PPI dosing for prevention of gastric ulcer rebleeding in the acute setting

Answer 39

Initial bolus 80mg Followed by continuous infusion 8mg/hr

Question 40

Adverse effects of PPIs

Answer 40

1. Diarrhoea 2. Headache 3. Abdominal pain 4. May reduced B12, Ca2+ and Mg2+ absorption 5. Increased risk of C. diff and other enteric infections 6. Increased risk of nosocomial pneumonia 7. Transient rebound acid hypersecretion (due to hyperplastic effects of elevated gastrin levels on ECL and parietal cells) 8. May reduce clopidogrel activation (requires CYP450)

Question 41

Five mucosal defense mechanisms

Answer 41

1. Mucus and epithelial cell-cell tight junctions 2. Epithelial bicarbonate secretion (pH 7 at mucosal surface) 3. Blood flow carrying bicarbonate and nutrients to surface cells 4. Restitution of injured epithelium (process in which migration of cells from gland neck cells seal small erosions) 5. Mucosal prostaglandins stimulate mucus and bicarbonate secretion and mucosal blood flow

Question 42

Pharmacodynamics and pharmacokinetics of sulcralfate

Answer 42

Sucrose complexed to sulfated aluminium hydroxide Forms viscous paste in acidic conditions which binds selectively to ulcers or erosions for up to 6hrs Excreted in faeces (only 3% absorbed)

Question 43

Sucralfate dosage

Answer 43

1g QID on empty stomach

Question 44

Clinical uses of sucralfate

Answer 44

Administered to critically ill patients to reduce risk of stress-induced UGIB Less effect than H2 antagonists and PPIs but sometimes preferred due to concerns that acid inhibitory therapies may increase risk of nosocomial pneumonia

Question 45

Adverse effects of sucralfate

Answer 45

1. Constipation due to aluminium salts 2. May bind other medications, reducing their absorption

Question 46

Pharmacokinetics of misoprostol for GI conditions

Answer 46

PGE1 analogue Rapidly absorbed and metabolised to active metabolite t1/2 <30mins (must be administered 3-4x daily) Urinary excretion but dose reduction not needed in renal insufficiency

Question 47

Pharmacodynamics of misoprostol for GI conditions

Answer 47

Inhibits acid Stimulates mucus and bicarbonate secretion Increases mucosal blood flow

Question 48

Clinical uses of misoprostol in GI conditions

Answer 48

NSAID-induced ulcers (highly effective but not commonly used due to its high adverse-effect profile and multiple daily dosing)

Question 49

Pharmacodynamics of bismuth compounds

Answer 49

Unclear: - Coats ulcers and erosions - May stimulate prostaglandin, mucus and bicarbonate secretion - Direct antimicrobial activity and binds enterotoxins

Question 50

Clinical uses of bismuth compounds

Answer 50

1. Nonspecific dyspepsia 2. Acute diarrhoea 3. Prevention of traveler's diarrhoea 4. H. pylori quadruple eradication therapy

Question 51

Adverse effects of bismuth compounds

Answer 51

1. Black stools 2. Bismuth toxicity with prolonged use or in renal insufficiency: encephalopathy 3. Salicylate toxicity with high doses of bismuth subsalicylate