Clinical pharmacology

1. Mucosal protective agents
Domina Petric, MD

2. • Both mucus and epithelial cell-cell
tight junctions restrict back
diffusion of acid and pepsin.
• Epithelial bicarbonate secretion
establishes a pH gradient within
the mucous layer: pH 7 at the
mucosal surface, pH 1-2 in the
gastric lumen.
Introduction

3. Introduction
Blood flow carries bicarbonate and vital nutrients to
surface cells.
Areas of injured epithelium are quickly repaired by
restitution: migration of cells from gland neck cells seals
small erosions to reestablish intact epithelium.
Mucosal prostaglandins are important in stimulating
secretion of mucus and bicarbonate.
Mucosal prostaglandins also stimulate mucosal blood flow.

4. Mucosal protective agents
Sucralfate
Prostaglandin analogs
Bismuth compounds

5. Sucralfate
• Sucralfate is a salt of sucrose
complexed to sulfated
aluminium hydroxide.
• In water or acidic solutions it
forms a viscous, tenacious
paste that binds selectively to
ulcers or erosions for up to 6
hours.

6. Sucralfate
• Sucralfate has limited solubility.
• It breaks down into sucrose sulfate
(strongly negatively charged) and
an aluminium salt.
• Less than 3% of intact drug and
aluminium is absorbed from the
intestinal tract.
• The remainder is excreted in the
feces.

7. Pharmacodynamics
• Negatively charged sucrose
sulfate binds to positively charged
proteins in the base of ulcers or
erosions.
• A physical barrier is formed.
• Barrier restricts further caustic
damage and stimulates mucosal
prostaglandin and bicarbonate
secretion.

8. Clinical use
• Sucralfate is administered in a
dose of 1 g 4 times daily on an
empty stomach (at least 1 hour
before meal).
• Sucralfate, administered as a
slurry through a nasogastric tube,
reduces the incidence of clinically
significant upper gastrointestinal
bleeding in critically ill patients.

9. Clinical use
• Sucralfate is still used for
prevention of stress-related
bleeding.
• There is concern that acid
inhibitory therapies (antacids,
H2 antagonists, PPIs) may
increase the risk of nosocomial
pneumonia.

10. Adverse effects
• Constipation occurs in 2% of
patients due to the aluminium salt.
• Small amount of aluminium is
absorbed.
• Sucralfate should not be used for
prolonged periods in patients with
renal insufficiency.
• Sucralfate may bind to other
medicinations, impairing their
absorption.

11. Prostaglandin analogs
• The human gastrointestinal
mucosa synthesizes a number
of prostaglandins.
• The primary ones are
prostaglandins E and F.
• Misoprostol (methyl analog of
PGE1) is approved for
gastrointestinal conditions.

12. Prostaglandin analogs
• After oral administration, misoprostol
is rapidly absorbed and metabolized
to a metabolically active free acid.
• The serum half-life is less than 30
minutes.
• It must be administered 3-4 times
daily.
• It is excreted in the urine, but dose
reduction is not needed in patients
with renal insufficiency.

13. Pharmacodynamics
• Misoprostol has both acid inhibitory
and mucosal protective properties.
• It stimulates mucus and bicarbonate
secretion, and enhances mucosal
blood flow.
• It binds to a prostaglandin receptor
on parietal cells, reducing
histamine-stimulated cAMP
production with modest acid
inhibition.

14. Clinical use
• Peptic ulcers develop in
approximately 10-20% of
patients who receive long-term
NSAID therapy.
• Misoprostol reduces the
incidence of NSAID-induced
ulcers to less than 3% and the
incidence of ulcer
complications by 50%.

15. Adverse effects
• Diarrhea and cramping abdominal
pain occur in 10-20% of patients.
• Misoprostol stimulates uterine
contractions.
• It should not be used during
pregnancy or in women of
childbearing potential that do not
use contraception.
• No significant drug interactions.

16. Bismuth compounds
• Bismuth subsalicylate and
bismuth subcitrate potassium!
• Bismuth subsalicylate
undergoes rapid dissociation
within the stomach, allowing
absorption of salicylate.
• Over 99% of the bismuth
appears in the stool.

17. Bismuth compounds
• Minimal bismuth is absorbed (1%),
but it is stored in many tissues and
has slow renal excretion.
• Salicylate is readily absorbed and
excreted in the urine.
• Bismuth subcitrate potassium is
usually used in combination with
metronidazole, tetracycline and IPP
as quadruple therapy for H. pylori.

18. Pharmacodynamics
• Bismuth coats ulcers and
erosions.
• It creates protective layer
against acid and pepsin.
• It may also stimulate
prostaglandin, mucus and
bicarbonate secretion.

19. Pharmacodynamics
Bismuth subsalicylate
reduces stool frequency
and liquidity in acute
infectious diarrhea due
to salicylate inhibition of
intestinal prostaglandin
and chloride secretion.

20. Pharmacodynamics
Bismuth has direct
antimicrobial effects and
binds enterotoxins.
Bismuth compounds
have direct antimicrobial
activity against H. pylori.

21. Clinical use
• Nonprescription bismuth
compounds are widely used by
patients for the nonspecific
treatment of dyspepsia and acute
diarrhea.
• Bismuth subsalicylate is used for
the prevention of traveler´s
diarrhea: 30 mL or 2 tablets 4
times daily.

22. Clinical use
Bismuth compounds are used in four
drug regimen for the eradication of
H. pylori infection during 10-14 days:
• PPI twice daily
• bismuth subsalicylate 2 tablets
(262 mg each) 4 times daily
• tetracycline 250-500 mg 4 times
daily
• metronidazole 500 mg 4 times daily

23. Clinical use
Another regime for H. pylori during
10 days:
• PPI twice daily
• bismuth subcitrate 140 mg 4 times
daily
• metronidazole 125 mg 4 times
daily
• tetracycline 125 mg 4 times daily

24. Adverse effects
• Bismuth causes harmless
blackening of the stool which may
be confused with gastrointestinal
bleeding.
• Liquid formulations may cause
harmless darkening of the tongue.
• Bismuth agents should be used for
short periods only and should be
avoided in patients with renal
insufficiency.

25. Adverse effects
• Prolonged usage of some bismuth
compounds, but not bismuth
subsalicylate and citrate, may
rarely lead to bismuth toxicity.
• Toxicity results in encephalopathy:
ataxia, headaches, confusion,
seizures.
• High dosages of bismuth
subsalicylate may lead to
salicylate toxicity.

26. Literature
• Katzung, Masters, Trevor.
Basic and clinical
pharmacology.