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ACEM Primary Written > Gastroenterology: Pharmacology - Anti-ulcer medications > Flashcards

Gastroenterology: Pharmacology - Anti-ulcer medications Flashcards

1
Q

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

A

> 90%

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2
Q

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

A
  1. Agents that reduce intragastric acidity
  2. Agents that promote mucosal defence
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3
Q

Explain how acid is secreted in the stomach

A

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

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4
Q

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

A

G cells in the antrum

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5
Q

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

A

Stimulate histamine release

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6
Q

Explain how acid secretion is regulated in the stomach

A

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

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7
Q

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

A

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

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8
Q

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

A

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

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9
Q

Four factors determining the acid-neutralisation capacity of an antacid

A
  1. Rate of dissolution (liquid vs tablet)
  2. Water solubility
  3. Rate of reaction with acid
  4. Rate of gastric emptying
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10
Q

Pharmacodynamics of antacids

A

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

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11
Q

Four examples of antacid and products formed by each

A
  1. Sodium bicarbonate -> CO2 and NaCl
  2. Calcium carbonate -> CO2 + CaCl2
  3. Magnesium hydroxide -> MgCl2 + H2O
  4. Aluminium hydroxide -> AlCl3 + H2O
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12
Q

Adverse effects of sodium bicarbonate as an antacid

A
  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)
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13
Q

Adverse effects of calcium carbonate as an antacid

A
  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)
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14
Q

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

A

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

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15
Q

Why are magnesium and aluminium hydroxide commonly administered in combination?

A

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

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16
Q

How might antacids change absorption of other medications?

A
  1. Binding drug to reduce its absorption
  2. Increasing intragastric pH to change drug’s solubility (especially weakly acidic or basic drugs)
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17
Q

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

A
  1. Tetracyclines
  2. Fluoroquinolones
  3. Itraconazole
  4. Iron
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18
Q

Describe the pharmacokinetics of H2-receptor antagonists

A

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

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19
Q

Are H2 receptor antagonists selective?

A

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

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20
Q

Pharmacodynamics of H2-receptor antagonists

A

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

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21
Q

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

A

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

22
Q

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

A

Raises nocturnal and fasting gastric pH to 4-5

23
Q

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

A

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

24
Q

Indications for H2-receptor antagonists

A
  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
25
Q

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

A

Continuous infusion achieves more consistent, sustained elevation of intragastric pH

26
Q

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

A

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

27
Q

Adverse effects of H2-receptor antagonists

A
  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)
28
Q

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

A

Omeprazole
Esomeprazole*
Pantoprazole*
Rabeprazole
Lansoprazole
Dexlansoprazole

*available IV

29
Q

Specific adverse effects of cimetidine

A

Gynaecomastia, impotence, galactorrhoea
CYP450 inhibitor

30
Q

How does cimetidine cause gynaecomastia/galactorrhoea?

A

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

31
Q

Pharmacokinetics of PPIs

A

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)

32
Q

Pharmacodynamics of PPIs

A

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

33
Q

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

A

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

34
Q

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

A

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

35
Q

Five clinical uses of PPIs

A
  1. GERD
  2. PUD
  3. Non-ulcer dyspepsia
  4. Prevention of bleeding from stress-related gastritis
  5. Gastrinoma and other hypersecretory conditions
36
Q

4 extraoesophageal complications of GERD

A
  1. Asthma
  2. Chronic cough
  3. Laryngitis
  4. Non-cardiac chest pain
37
Q

Describe triple and quadruple therapy for H. pylori associated PUD

A

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

38
Q

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

A

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

39
Q

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

A

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

40
Q

Adverse effects of PPIs

A
  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)
41
Q

Five mucosal defense mechanisms

A
  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
42
Q

Pharmacodynamics and pharmacokinetics of sulcralfate

A

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)

43
Q

Sucralfate dosage

A

1g QID on empty stomach

44
Q

Clinical uses of sucralfate

A

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

45
Q

Adverse effects of sucralfate

A
  1. Constipation due to aluminium salts
  2. May bind other medications, reducing their absorption
46
Q

Pharmacokinetics of misoprostol for GI conditions

A

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

47
Q

Pharmacodynamics of misoprostol for GI conditions

A

Inhibits acid
Stimulates mucus and bicarbonate secretion
Increases mucosal blood flow

48
Q

Clinical uses of misoprostol in GI conditions

A

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

49
Q

Pharmacodynamics of bismuth compounds

A

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

50
Q

Clinical uses of bismuth compounds

A
  1. Nonspecific dyspepsia
  2. Acute diarrhoea
  3. Prevention of traveler’s diarrhoea
  4. H. pylori quadruple eradication therapy
51
Q

Adverse effects of bismuth compounds

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

ACEM Primary Written (150 decks)

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