PRINCIPLES OF DRUG THERAPY
IN GASTROINTESTINAL DISEASES
Mohammad Minakari,MD,IUMS
Dyspepsia
• 25% ORGANIC
• 75% FUNCTIONAL
Organic Dyspepsia
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Peptic ulcer disease
Gastroesophageal reflux
Gastroesophageal malignancy
Biliary pain
Drug-induced dyspepsia
Other causes
Dyspepsia
Indications for Testing and Treatment
of Helicobacter pylori Infection
Helicobacter pylori Eradication
• Initial therapy:
– Triple therapy:
• proton pump inhibitor (PPI), amoxicillin (1 g twice
daily), and clarithromycin (500 mg twice daily) for 7 to
14 days.
• Metronidazole instead of amoxicillin
• Increased ppi duration can increase eradication rate
minimally
• No ppi is better than the others for eradication
Quadruple therapy
• A PPI, combined with bismuth (525 mg four
times daily) and two antibiotics (eg,
metronidazole 250 mg four times daily and
tetracycline 500 mg four times daily) given for
10 to 14 days.
• In IRAN , quadruple therapy is preferred for
initial therapy.
Sequential therapy
• Clarithromycin sequential therapy :Omeprazole (20 mg twice daily)
and amoxicillin (1 g twice daily) for five days, followed by
omeprazole (20 mg twice daily), clarithromycin (500 mg twice
daily), and tinidazole (500 mg twice daily) for five or more days
• Levofloxacin -250 sequential therapy :Omeprazole (20 mg twice
daily) plus amoxicillin (1 g twice daily) for five days, followed by
omeprazole (20 mg twice daily), levofloxacin (250 mg twice daily),
and tinidazole (500 mg twice daily) for five or more days
• Levofloxacin -500 sequential therapy :Omeprazole (20 mg twice
daily) plus amoxicillin (1 g twice daily) for five days, followed by
omeprazole (20 mg twice daily), levofloxacin (500 mg twice daily),
and tinidazole (500 mg twice daily) for five or more days
ERADICATION CONFIRMATION
• Patients who have persistent symptoms after
H. pylori treatment for dyspepsia
• Patients who had an H. pylori associated ulcer
• Patients who had gastric mucosa associated
lymphoid tissue (MALT) lymphoma
• Patients who had resection for early gastric
cancer
TREATMENT FAILURES
• Clarithromycin should not be used unless resistance testing
confirms the H. pylori strain is susceptible to the drug .
• Antibiotics previously taken should generally be avoided.
• Tetracycline may be more effective in this setting than
metronidazole
• A simpler treatment regimen could improve compliance and,
as a result, efficacy.
• levofloxacin or rifabutin or furazolidone can be considered
Testing for resistance
• Routine culture and testing for antibiotic
susceptibility and resistance for H. pylori is not
currently recommended.
• Patients with refractory disease may require
culture and sensitivity testing.
SIDE EFFECTS
• Are reported in up to 50 % of patients taking
one of the triple therapy regimens .
• The adverse effects are usually mild
• Fewer than 10 % of patients stop treatment
due to side effects.
SIDE EFFECTS
• Metronidazole :can cause a peripheral neuropathy,
seizures, and a disulfiram-like reaction when taken with
alcohol.
• Clarithromycin can cause taste alteration, nausea,
vomiting, abdominal pain, and rarely QT prolongation.
• Tetracycline can induce a photosensitivity reaction in
some cases. It should also not be administered to
pregnant women or young children.
• Amoxicillin can cause diarrhea or an allergic reaction
with skin rash.
FUNCTIONAL DYSPEPSIA
• Presence of one or more of the following:
postprandial fullness, early satiation,
epigastric pain or burning and no evidence of
structural disease (including at upper
endoscopy) to explain the symptoms.
• The criteria should be fulfilled for the last
three months with symptom onset at least six
months before diagnosis.
TREATMENTS OTHER THAN
ANTISECRETORY
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Antidepressants
Prokinetic agents
Fundic relaxant drugs
Antinociceptive agents
Psychological therapy
Complementary and alternative medicine
GERD
ACID SUPPRESSIVE MEDICATIONS
Over-the-counter antacids and/or H2 receptor
blockers
Prescription H2-blockers (twice daily)
Intermittent (2 weeks) use of a PPI
Omeprazole (20 mg daily) or equivalent dose of the
other PPIs
Omeprazole (20 mg twice daily or 40 mg daily) or
equivalent doses of the other PPIs
METHODS OF TREATMENT
• STEP DOWN THERAPY:
Rapid symptom removal
Higher cost
• STEP UP THERAPY:
Slower symptom removal
Lower cost
ACID SUPPRESSIVE MEDICATIONS
• The H2 receptor antagonists offer a therapeutic
gain of 10 to 24 % relative to the placebo for
healing esophagitis.
• The PPIs are more effective in healing esophagitis
than the H2 receptor antagonists.
• PPIs lead to more rapid healing and symptom
relief than H2 receptor antagonists
• PPIs exhibit a dose-response curve for healing
high-grade esophagitis as evidenced by higher
healing rates with higher doses and/or more
potent compounds unlike H2RA.
Nonerosive gastroesophageal reflux
disease
• Esophageal hypersensitivity
• Abnormal acid exposure but have not
developed overt mucosal injury
• Functional heartburn
– The first two groups, but not the third group of
patients, may respond to antisecretory therapy.
– PH metry can help for differentiation
WHAT PPI?
• The difference between various PPIs is small
and clinically non-significant
• Esomeprazole is the most potent
• Pantoprazole is the least interactive
• Interaction with clopidogrel is an unresolved
issue
PPI DOSE
SAFETY
• Prolonged hypochlorhydria and
hypergastrinemia
• Possible association of PPIs with gastric
atrophy
SAFETY
• a 2008 guideline on gastroesophageal reflux disease
(GERD) management developed by the AGA found
insufficient evidence to recommend for or against bone
density studies, calcium supplementation, H. pylori
screening, or any other routine precaution in patients
taking proton pump inhibitors .
• However, studies subsequent to that guideline
continue to raise concerns about possible infectious
complications, electrolyte disturbances, and metabolic
bone disease associated with PPI use.
Infections
• Clostridium difficile and other enteric
infections
• Pneumonia : both community acquired
pneumonia (CAP) and health care associated
pneumonia (HCAP)
Malabsorption
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Magnesium absorption
Hip fracture and calcium malabsorption
Vitamin B12 malabsorption
Iron malabsorption
Hypergastrinemia
• Gastric carcinoid tumors in rats.
• No dysplasia or neoplastic changes in patients
treated with omeprazole for up to 11 years.
• The clinical significance of other theoretical
risks related to hypergastrinemia (such as
colon cancer) has not been established.
Atrophic gastritis/Gastric cancer
• Not proven
• Controversy about eradication of H.pylori
• Most experts believe that it is unnecessary
ADJUNCTIVE THERAPY
• Prokinetic agents
• Reflux inhibitors
MAINTENANCE THERAPY
• Maintenance acid suppressive therapy is often
necessary
• A trial off medications should be considered in
all patients with gastroesophageal reflux
disease (GERD) who have a good clinical
response to acid suppression with the
exception of those with severe esophagitis on
upper endoscopy (Los Angeles classification
Grade C and D) and Barrett’s esophagus
MAINTENANCE THERAPY
• Rapidity of recurrence :
– less than three months: continuous therapy
– more than three months : on demand therapy
MAINTENANCE THERAPY
• PPIs at a standard dose or a lower dose (usually
one-half of the standard dose) were more
effective than H2RAs in resolving GERD symptoms
at four weeks and promoting healing esophagitis
at eight weeks.
• PPIs at a standard dose were more effective than
a lower dose in preventing relapse of symptoms.
• PPIs at a standard dose were more effective than
PPIs at a lower dose in maintaining healing of
esophagitis.
ULCERATIVE COLITIS
METHODS OF TREATMNT
• Step-up
• Step-down
• Severity based
Severity of UC
GOALS OF MEDICAL Tx IN UC
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To induce remission
To maintain remission
To maintain adequate nutrition
To minimize disease- and treatment-related
complications
• To improve the patient’s quality of life
Induction of remission in UC
CHOOSING MEDICATION
5-ASA
ORAL 5-ASA
5-ASA
• Are effective in remission induction in mild to
moderate UC
• Are effective in maintaining remission
• Are usually safe and well tolerated
• Are not effective in doses < 2 g/day
• Have dose dependent response
Side effects of sulfasalazine
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Side effects of sulfasalazine
• 15% of patients stop sulfasalazine intake due
to adverse effects
• 90% of them can tolerate other 5-ASAs
Glucocorticoids
• At doses equivalent to 40 to 60 mg/day of oral
prednisone,glucocorticoids are effective first-line
therapy for moderateor severe flares of UC.
• The use of doses higher than60 mg/day is
associated with increased side effects without
appreciable clinical benefit and thus should be
avoided.
• The addition of sulfasalazine to corticosteroids in
moderately to severely active UC does not offer
any incremental benefit.
Side Effects of Glucocorticoids
Glucocorticoids
• Should not be used for maintenance therapy
• Should be tapered and discontinued in a few
months
Immunomodulators:Azathioprine and
6-Mercaptopurine
• Probably effective in induction of remission
• Need 2-3 months for appearance of benefits
• Effective in maintaining remission
AZA/6MP METABOLISM
AZA/6MP
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AZA:2-3 mg/kg/day
6MP:1-1.5 mg/kg/day
Leukopenia is not necessary for effectiveness
Checking 6TG/6MMP is useful in nonresponders
Cyclosporine
• Cyclosporine A is a potent inhibitor of cellmediated immunity.
• Its use in UC is primarily in patients with
severe,steroid-refractory disease.
• Intravenous cyclosporine 2-4 mg/kg
• The addition of azathioprine or 6-MP in
patients who have responded to intravenous
cyclosporine reduces the rate of relapse or
colectomy.
SIDE EFFECTS OF CYCLOSPORINE
SIDE EFFECTS OF CYCLOSPORINE
• During intravenous therapy,cyclosporine levels
should be monitored daily, and the dose should
be adjusted to achieve a trough concentration
(measured one hour before dosing) between 200
and 400 ng/mL,determined by high-pressure
liquid chromatography.
• Serum electrolytes and serum creatinine levels
should be monitored daily or every other day.
OTHER THERAPIES
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Methotrexate
Tacrolymus
Probiotics/prebiotics/synbiotics
Nicotine
Heparin
Anti-Tumor Necrosis Factor
Antibodies
INFLIXIMAB INDICATION
• Patients with moderately to severely active UC
who have had an inadequate response to
conventional therapy.
• Infliximab is now accepted as part of the
standardtreatment options in patients with
UC.
DOSAGE
• 5mg/kg IV infusion
• 0,2,6 weeks ,then continue if there is clinical
response,every 8 weeks
MANAGEMENT OF MILD TO
MODERATE UC
MANAGEMENT OF MILD TO
MODERATE UC
Management of severely active
ulcerative colitis.
IMPORTANT POINTS
• Empiric therapy(WITHOUT COLONOSCOPY) is
not acceptable in patients who might have
IBD.
• Maintenance therapy is almost always needed
in UC patients
• IBS is not colitis!
• IBD treatment is usually long term/lifetime,the
patients must know it
THANK YOU