GIT Flashcards
What are the causes for peptic ulcer
- infection with gram-negative Helicobacter pylori and 2. the use of NSAIDs.
↑ HCl secretion and ↓ mucosal defence against gastric acid
What is the treatment approach for peptic ulcer
1) eradicating the H. pylori infection
2) reducing secretion of gastric acid
3) providing agents that protect the gastric mucosa from damage
How do we diagnose h pylori
1.
endoscopic biopsy of the gastric mucosa or
2.
serology and urea breath tests (13CO2 LVL)
✓ Eradication of H. pylori results in rapid healing of active ulcers and low
recurrence rates (less than 15% compared with 60% to 100% per year
for initial ulcers healed with acid-reducing therapy alone).
✓ Successful eradication of H. pylori (80% to 90%) is possible with various
combinations of antimicrobial drugs.
What is the triple and quadruple therapy for peptic ulcer
✓ Triple therapy: PPI+ amoxicillin+ clarithromycin
(metronidazole may be used in penicillin-allergic patients).
✓ This is preferred when rates of clarithromycin resistance are low & the patient
has no prior exposure to macrolide antibiotics
✓ Quadruple therapy:
✓ bismuth subsalicylate+ metronidazole+ tetracycline+ PPI.
✓ This is currently first line therapy and leads to 90% greater eradication rate
✓ Quadruple therapy should be considered in areas with high resistance to
clarithromycin.
✓ Treatment with a SINGLE antimicrobial drug is much LESS effective, results in
antimicrobial resistance, and is NOT recommended.
✓ Substitution of antibiotics is also NOT recommended.
Gastric acid secretion is stimulated by acetylcholine, histamine, and
gastrin
What are H2 blockers
Cimetidine, ranitidine, famotidine, and nizatidine potently inhibit (greater
than 90%) basal, food-stimulated, and nocturnal secretion of gastric acid.
✓ Cimetidine was the first histamine H2-receptor antagonist. However, its
utility is limited by its adverse effect profile and drug–drug interactions
✓ Ranitidine was removed from the market
1.
Actions:
✓ The histamine H2-receptor antagonists act selectively on H2 receptors
in the stomach, but they have NO effect on H1 receptors.
3. Pharmacokinetics:
✓ After oral administration, the H2 antagonists distribute widely
throughout the body (including into breast milk and across the
placenta) and are excreted mainly in urine.
✓ famotidine is also available in I.V. formulations.
✓ The t 1/2 of all of these agents may be ↑ in patients with renal
dysfunction, and dosage adjustments are needed.
4. Adverse effects:
✓ In general, the H2 antagonists are well tolerated.
✓ Cimetidine can have endocrine effects because it acts as a nonsteroida
✓ The other agents do not produce the anti-androgenic and prolactinstimulating effects of cimetidine.
✓ Other CNS effects (such as confusion and altered mentation) occur
primarily in elderly patients and after IV administration.
✓ Cimetidine ↓ several CYTP450 isoenzymes and can interfere with the
metabolism of many other drugs, such as warfarin, phenytoin, and
clopidogrel
✓ All H2 antagonists may reduce the efficacy of drugs that require an
acidic environment for absorption, such as itraconazole and
ketoconazole.
What are the uses for H2 blockers
a.
Peptic ulcers:
✓ All four agents are equally effective in promoting the healing of
duodenal and gastric ulcers.
✓ Recurrence is common if H. pylori is present and the patient is treated
with these agents alone.
✓ Patients with NSAID-induced ulcers should be treated with PPIs,
because these agents heal and prevent future ulcers more effectively
than H2 antagonists do.
b. Acute stress ulcers:
✓ These drugs are given as an I.V. infusion to prevent and manage acute
stress ulcers associated with high-risk patients in ICU.
✓ PPIs have gained favour for this indication.
c. Gastroesophageal reflux disease (GERD):
✓ Low doses of H2 antagonists, currently available for OTC sale, are
effective for the treatment of heartburn (GERD) in only about 50% of
patients.
✓ H2-receptor antagonists act by stopping acid secretion. Therefore, they
may not relieve symptoms for at least 45 min.
✓ Antacids more quickly and efficiently neutralize stomach acid, but their
action is ONLY temporary.
✓ PPIs are now used preferentially in the treatment of GERD.
What are PPIs
: Inhibitors of the H+/K+-ATPase proton pump
✓ The PPIs bind to the H+
/K+-ATPase enzyme system (proton pump) and
suppress the secretion of hydrogen ions into the gastric lumen which is
the final step in gastric acid secretion
✓ The available PPIs include dexlansoprazole, esomeprazole, lansoprazole,
omeprazole, pantoprazole, and rabeprazole.
✓ Omeprazole, esomeprazole, and lansoprazole are available OTC for
short-term treatment of GERD.
- Actions:
✓ These agents are prodrugs with an acid-resistant enteric coating to
protect them from premature degradation by gastric acid.
✓ The coating is removed in the alkaline duodenum, and the prodrug, a
weak base, is absorbed and transported to the parietal cell.
✓ There, it is converted to the active drug and forms a stable covalent
bond with the H+/K+-ATPase enzyme.
✓ It takes about 18 hours for the enzyme to be resynthesized, and acid
secretion is inhibited during this time.
✓ At standard doses, PPIs inhibit both basal and stimulated gastric acid
secretion by more than 90%.
✓ An oral product containing omeprazole combined with sodium
bicarbonate for faster absorption is also available over the counter and
by prescription.
Pharmacokinetics:
✓ All these agents are effective orally.
✓ For maximum effect, PPIs should be taken 30 to 60 minutes before
breakfast or the largest meal of the day.
✓ dexlansoprazole has a dual delayed release formulation and can be
taken without regard to food.
✓ Esomeprazole, lansoprazole, and pantoprazole are also available in IV
formulations.
✓ T1/2 is only a few hours with long duration of action, why?
✓ Metabolites of these agents are excreted in urine and feces.
What is the therapeutic use for PPIs
✓ The PPIs are superior to the H2 antagonists in suppressing acid
production and healing ulcers.
✓ They are the preferred drugs for:
✓ stress ulcer treatment and prophylaxis
✓ treatment of GERD,
✓ erosive esophagitis,
✓ active duodenal ulcer,
✓ pathologic hyper-secretory conditions (for example, Zollinger-Ellison
syndrome, in which a gastrin-producing tumor causes hypersecretion of
HCl).
✓ If a once-daily PPI is only partially effective for GERD symptoms,
increasing dosing to twice daily or administering the PPI in the morning
and adding an H2 antagonist in the evening may improve symptom
control.
✓ H2 antagonists reduce the activity of the proton pump, and PPIs require
active pumps to be effective. That’s why if an H2-receptor antagonist is
needed, it should be taken well after the PPI.
✓ PPIs also reduce the risk of bleeding from ulcers caused by aspirin and
other NSAIDs and may be used for prevention or treatment of NSAIDinduced ulcers.
✓ They are used + antimicrobial regimens to eradicate H. pylori.
What are the side effects for PPIs
✓ Omeprazole and esomeprazole may ↓effectiveness of clopidogrel
because they ↓ CYP2C19 and prevent the conversion of clopidogrel to
its active metabolite.
✓ PPIs+ clopidogrel use is NOT recommended because of ↑ risk of
cardiovascular events. What is the alternatives for patients using
clopidogrel?
✓ PPIs may ↑ the risk of fractures, particularly if the duration of use is 1
year or greater (Figure 42.6).
✓ Prolonged acid suppression with PPIs (and H2 antagonists) may result in
low vitamin B12 because acid is required for its absorption in a
complex with intrinsic factor. (give B12 I.M.)
✓ Elevated gastric pH may also impair the absorption of calcium
carbonate.
✓ Calcium citrate is an effective option for calcium supplementation in
patients on acid suppressive therapy, since absorption of the citrate salt
is not affected by gastric pH.
✓ Diarrhea and Clostridium difficile colitis may occur in patients receiving
PPIs.
✓ Patients must be counselled to discontinue PPI therapy and contact
their physician if they have diarrhea for several days.
✓ Additional adverse effects may include hypomagnesemia and an ↑
incidence of pneumonia.
What’s the use of prostaglandins agonists in GIT problems
Prostaglandin E, produced by the gastric mucosa, inhibits secretion of
acid and stimulates secretion of mucus and bicarbonate (cytoprotective
effect).
✓ A deficiency of prostaglandins is thought to be involved in the
pathogenesis of peptic ulcers.
✓ Misoprostol, an analog of prostaglandin E1, is approved for the
prevention of NSAID-induced gastric ulcers (Figure 42.7).
✓ Prophylactic use of misoprostol should be considered in patients who
are taking NSAIDs and are at moderate to high risk of NSAID-induced
ulcers, such as elderly patients and those with previous ulcers.
✓ Misoprostol is contraindicated in pregnancy,?
✓ since it can stimulate uterine contractions and cause miscarriage.
✓ Dose-related diarrhea and nausea are the most common adverse
effects and limit the use of this agent.
✓ Thus, PPIs are preferred agents for the prevention of NSAID-induced
ulcers.
What are antacids
Antacids are weak bases that react with gastric acid to form water and a
salt to diminish gastric acidity. Because pepsin (a proteolytic enzyme) is
inactive at a pH greater than 4, antacids also reduce pepsin activity.
1.
Chemistry:
✓ Antacid products vary widely in their chemical composition, acidneutralizing capacity, sodium content, palatability, and price.
✓ The efficacy of an antacid depends on its capacity to neutralize gastric
HCl and on whether the stomach is full or empty (food delays stomach
emptying allowing more time for the antacid to react).
✓ Commonly used antacids are combinations of salts of aluminum and
magnesium, such as aluminum hydroxide and magnesium hydroxide
[Mg(OH)2].
✓ Calcium carbonate [CaCO3] reacts with HCl to form CO2
and CaCl2
and
is also a commonly used preparation.
✓ Systemic absorption of sodium bicarbonate [NaHCO3] can produce
transient metabolic alkalosis and a significant sodium load. Therefore,
this antacid is not recommended for long-term use.
2. Therapeutic uses:
✓ Antacids are used for symptomatic relief of peptic ulcer disease and
GERD, and they may also promote healing of duodenal ulcers.
✓ They should be administered after meals for maximum effectiveness.
✓ [Note: Calcium carbonate preparations are also used as calcium
supplements for the treatment of osteoporosis.]
3.
Adverse effects:
✓ Aluminum hydroxide tends to cause constipation, whereas magnesium
hydroxide tends to produce diarrhea.
✓ Preparations that combine these agents aid in normalizing bowel
function.
✓ Absorption of the cations from antacids (Mg2+ , Al3+ , Ca2+ ) is usually not
a problem in patients with normal renal function; however,
accumulation and adverse effects may occur in patients with renal
impairment
What are the mucosal protective agents
✓ Also known as cytoprotective compounds, these agents have several
actions that enhance mucosal protection mechanisms, thereby preventing
mucosal injury, reducing inflammation, and healing existing ulcers.
1.
Sucralfate:
✓ This complex of aluminum hydroxide and sulfated sucrose binds to
positively charged groups in proteins of both normal and necrotic mucosa.
✓ By forming complex gels with epithelial cells, sucralfate creates a physical
barrier that protects the ulcer from pepsin and acid, allowing the ulcer to
heal.
✓ Although sucralfate is effective for the treatment of duodenal ulcers and
prevention of stress ulcers, its use is limited due to the need for multiple
daily dosing and drug–drug interactions
✓ Because it requires an acidic pH for activation, sucralfate should not be
administered with PPIs, H2 antagonists, or antacids.
✓ Sucralfate is well tolerated, but it can interfere with the absorption of
other drugs by binding to them.
✓ This agent does not prevent NSAID-induced ulcers, and it does not heal
gastric ulcers.
2. Bismuth subsalicylate:
✓ This agent is used as a component of quadruple therapy to heal peptic
ulcers.
✓ In addition to its antimicrobial actions,
✓ it inhibits the activity of pepsin,
✓ increases secretion of mucus,
✓ and interacts with glycoproteins in necrotic mucosal tissue to coat and
protect the ulcer.
