Question 10

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Outline the mechanism of action of drugs commonly used to prevent stress ulceration in intensive care.

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College Answer

For a good answer candidates were expected to mention the following key broad points, being there are drugs that act by decreasing acid production in the stomach, drugs that act as mucosal protectors and drugs that reduce intra gastric acidity. Based upon that candidates would be expected to mention and outline the 
mechanism of action of H2 receptor antagonists, H+K/=ATPase (proton pump) inhibitors, sucralfate’s mechanism of action and antacids. Candidates who structured  their answer tended to provide more complete answers and score better. Candidates  who failed did so because of a lack of sufficient knowledge of the mechanism of action of the drugs.
Syllabus: Q2, 2a. b,c
References: Basic and Clinical Pharmacology Katzung 10th Ed pg 1009.
Pharmacology Rang & Dale 6th Ed p 526-7, 255, 497, 587

Discussion

Drug classes

Available classes are:

  • antacids such as aluminium hydroxide,
  • anticholinergic drugs such as atropine, 
  • H2 antagonists such as ranitidine
  • Proton pump inhibitors such as pantoprazole
  • PGE2 agonists such as misoprostol
Administration
  • All of these drugs can be administered as oral or IV formulations, except for sucralfate and antacids
Absorption
  • Apart from antacids and sucralfate, all are are well absorbed by the oral route. 
  • Antacids and sucralfate are minimally absorbed
Distribution
  • Atropine, H2As and PPIs have small volumes of distribution (0.2-2.0 L/kg)
  • Misoprostol is widely distributed
Elimination
  • H2 antagonists are mainly renally cleared
  • PPIs and misoprostol are mainly metabolised by the liver
  • Atropine is 50% metabolised and 50% excreted unchanged
Mechanism of action
  • Antacids combine with hydrochloric acid to produce a chloride salt and water, neutralising the acid.
  • Sucralfate converts into a polymer anionic gel which coats the mucosa as a protective barrier, and also releases aluminium hydroxide (an antacid)
  • Anticholinergic drugs, H2 antagonists and misoprostol all decrease cAMP, which results in decreased apical availability of proton pumps (H+/K+ ATPase proteins). These are all reversible competitive inhibitor effects.
  • PPIs bind covalently and irreversibly to H+/K+ ATPase proteins, disabling them
Side effects
  • Antacids can cause constipation, alkalosis, and occasionally contain toxic ingredients (aluminium, bismuth). They can also bind other drugs, decreasing their availability.
  • Anticholinergic drugs cause tachycardia, mydriasis, urinary retention, and constipation
  • Sucralfate can cause constipation
  • H2 antagonists can interfere with CYP450 enzymes
  • PPIs cause hypomagnesemia, interstitial nephritis, and increase the risk of hospital-acquired pneumonia and C.difficile infection 
  • Misoprostol causes diarrhoea and uterine contractions

References

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