L7-Treatment of Peptic Ulcer Diseases

Goals & Strategy of PUD Treatment

Treatment Goals

•Rapid relief of symptoms

•Healing of ulcer

•Preventing ulcer recurrences

•Reducing ulcer-related complications

•Reduce the morbidity (including the need for endoscopic therapy or surgery)

•Reduce the mortality

General Strategy

•Treat complications aggressively if present

•Determine the etiology of ulcer

•Discontinue NSAID use if possible

•Eradicate H. pylori infection if present or strongly suspected, even if other risk factors (e.g., NSAID use) are also present;

•Use antisecretory therapy to heal the ulcer if H. pylori infection is not present

•Smoking cessation should be encouraged

•If  DU is diagnosed by endoscopy, RU testing of endoscopically obtained gastric biopsy sample, with or without histologic examination should establish presence or absence of H. pylori

•If  DU is diagnosed by x-ray , then a serologic , UBT, or fecal antigen test to diagnose H. pylori infection is recommended before treating the patient for H. pylori


Management of  NSAIDs Ulcers

This can be considered under two headings:

  1. The healing of an ulcer that has developed during NSAID or COX-2 inhibitor treatment
  2. Strategies for preventing NSAID ulcers in patients who currently are ulcer free

1-Healing the Established NSAIDs-Associated Ulcer

-If possible, NSAID should be stopped, as healing with a histamine H2-receptor antagonist (H2-RA) will be faster than if the NSAID is continued

-PPI have been shown in 3 randomized controlled trials to be more effective than ranitidine or misoprostol for healing NSAID ulcers when the NSAID is continued

2-Best Prevention & Treatment for Upper GI Lesions Induced by NSAIDs

•There is conclusive evidence that PPIs decrease the incidence of ulcers & erosions, & heal them when they have occurred, even when NSAIDs administration is continued

The Astronaut Study

•Ranitidine 150 mg twice daily Vs. Omeprazole 20 or 40 mg daily

•Gastroduodenal ulcer healing rates at 8weeks

Ranitidine 87% & Omeprazole 20 mg 71%

•The healing rate of H.pylori eradication, peptic ulcer healing, or the extent of mucosal damage induced by NSAIDs are clearly related to the acid inhibition level achieved with the corresponding treatment

Reducing Risk of NSAIDs Ulcers by Choice of Agent

•Choose, where possible, an NSAID from the less damaging end of the spectrum

•Use it in the lowest dose that is effective

•Use highly selective COX-2 inhibitors (whether to use them instead of a largely non-selective NSAID such as diclofenac or ibuprofen requires judgments about cost vs. benefit for the individual patient

•In low-risk patients such as young – middle age individuals without past history of ulcer & with no hazard-increasing cotherapies (e.g warfarin or steroids), the risk of using a non-selective NSAID is very small

Preventing NSAIDs Ulcers with Co-Prescribed Gastric Protectants

•Patients who continue to require NSAIDs should receive either a PPI or misoprostol to prevent ulcer recurrence

Drugs Therapy for Treatment of PUD

Degree of Acid Inhibition to Heal an Ulcer

•It has been reported that a sustained increase in pH > 3 would be sufficient to heal an ulcer •However, one of the risk factors for refractory gastric ulcer appears to be the impossibility of maintaining gastric pH > 4 for a minimum daily period of 16 hr

The Purpose of Inhibiting Gastric Acid Secretion in cases of Upper GI Bleeding

•In upper GI bleeding, the aim is to achieve the least acid gastric pH possible in order to prevent acid degradation of the clot & accelerate healing as much as possible

• Both clinical & experimental studies suggest that extremely potent inhibition is required to achieve the intended efficacy

The Ideal Drug to Achieve Potent Acid inhibition

•Ideal drug should be able to maintain pH > 4 for ≥ 16 hr/day •Such level guarantee a consistent response to treatment, & sufficient for most refractory cases of peptic acid disease •Efficacy of the drug would also have to be consistent, so that such potent acid inhibition levels might be achieved in all patients, regardless of their basal acid secretion, metabolic capacity, or the presence or absence of H. pylori infection

Drugs Therapy for Treatment of PUD

  1. H2-Receptors antagonists
  2. H+, K+ ATPase: Proton pump inhibitors (PPIs)
  3. Cyto-protective agent (Sucalfate)
  4. Prostaglandin agonists
  5. Antacids
  6. Antibiotics for H. pylori eradication

1- H2-Receptors Antagonists

•These  agents are capable of 90% reduction in basal & food-stimulated secretion of gastric acid after single dose. they are somewhat less effective in reducing nocturnal secretion

•Studies have demonstrated their effectiveness in promoting the healing of DU & GU, & preventing their recurrence

• These meds are equally effective in treating these conditions

•Previous recommendations were to administer these agents at least twice a day, a single bedtime dose may be just as effective & may elicit better compliance

•If administered for 6-8 weeks, can heal DU 75% & 90% respectively

Agents

•Cimetidine 800mg OD or 400mg BID

•Ranitidine 300mg OD or 150mg BID

•Famotidine 40mg OD or 20mg BID

•Nizatidine 300mg OD or 150mg BID

*Should by taken for 6-8 weeks*

Pharmacokinetics

•Rapidly absorbed 1-3 hrs to peak

•Ranitidine & Cimetidine hepatically metabolized whereas Famotidine & Nizatidine are renally excreted

•Dose adjustment is needed in some renal & hepatic failure patients

Side Effects

•Usually minor; include headache, dizziness, diarrhea, & muscular pain

•Hallucinations & confusion in elderly patients

•Hepatotoxicity with Ranitidine

•Cimetidine elevates serum prolactin & alters estrogen metabolism in men

•Gynecomastia, Galactorrhea and reduced sperm count

Drug Interactions

•Cimetidine slows microsomal metabolism of some drugs

•Cimetidine causes these in a dose-dependent but reversible manner

•Inhibits the metabolism of warfarin, theophylline, diazepam & phenytoin

•Ranitidine has less effect on hepatic enzymes

•Famotidine & Nizatidine has no effect on hepatic drug metabolism

•Combining H2 inhibitor with antacid has little rationale although is done.  H2 antagonist + PPI inhibits efficacy of PPI

•Over the counter H2 blockers now available, labeled for short-term use in heartburn & dyspepsia

2- Proton Pump Inhibitors (PPIs)

Same Acid Inhibition as Anti-H2??

•No

•Among anti-secretory drugs, PPIs can inhibit gastric acid secretion with a greater efficacy than anti-H2

•They are potent acid inhibitors

•Potent acid inhibition is arbitrarily defined as inhibition that achieves maintenance of an intragastric pH > 4 for ≥ 16 hr out of 24 hr

Agents

1st Generation

•Omeprazole

•Lansoprazole

•Pantoprazole

2nd Generation

•Rabeprazole

•Esomeprazole

Pharmacological Effect

•PPIs dose-dependently inhibit basal & food acid secretion

•Decreases pepsinogen secretion &, due to the increase in intragastric pH, inhibit the proteolytic activity of pepsin

Comparative Anti-secretory Efficacy of the Different PPIs

•Among different PPIs administered at standard doses, esomeprazole 40 mg/day has a greater anti-secretory potency

•Rabeprazole 20 mg/day & lansoprazole 30 mg/day show a faster action, & slightly greater acid inhibition capacity than omeprazole 20 mg/day & pantoprazole 40 mg/day

Side Effects

•No evidence that they cause direct toxic effects.

•Most common adverse reactions include episodes of diarrhea, nausea, abdominal pain, dizziness, headache, or skin rash

•These manifestations are most often transient & moderate in severity, not requiring reductions in compound dosage

PPIs & Vitamin B12 Deficiency

•In some patients continuously taking PPIs, a mild vitamin B12 deficiency has been seen as the result of decreased vitamin absorption

•This is due to impaired release of the vitamin from food, because this is a process enhanced by the presence of an intragastric acid environment

Time of Administration

•Should by administered while fasting & before a meal so that at the time the peak plasma concentration is reached, there is also a maximum of proton pumps activated (i.e. secreting acid)

•For treatment of DU & GU should be used for 4-6 weeks

Pharmacokinetics

How can PPIs have a Short Half-life & a Long-lasting Effect?

•Despite their short plasma half-life, PPIs exert a persistent pharmacological action because by irreversibly binding to the proton pump they render necessary the synthesis of new enzymes to re-establish gastric acid secretion

Metabolism

•PPIs undergo extensive first-pass metabolism in the liver, resulting in various inactive metabolites that are excreted in the urine or bile

•Metabolized by the cytochrome P450 system (mainly by isoenzymes CYP2C19 & CYP3A4)

Esomeprazoie?

•It is the S isomer of omeprazole

•Pharmacokinetic & pharmacodynamic studies suggest that this isomer undergoes less first-pass metabolism in the liver & has a lower plasma clearance as compared with omeprazole

Dose Adjustment in Liver Failure

•In patients with severe liver failure, the area under the plasma curve for PPIs increases 7-9 fold, & their half-life is prolonged to 4-8 hr. A decrease in the usual dose of these drugs is recommended in this group of patients

Drug Interactions

•Theoretically, their influence on phenytoin, carbamazepine, warfarin, & diazepam should be monitored

•However, as confirmed by a recent analysis of cases recorded by (FDA), the clinical impact of these interactions is very low (rates lower than 0.1 -0.2 per 1,000,000 prescriptions), with no differences between the different PPIs

Presence of H. Pylori influence Degree of Acid inhibition ??

•PPIs show a decreased efficacy in patients not infected by H. pylori. This often requires the use of higher doses of the PPI

Do PPIs Have Direct Action on H.Pylori??

•Yes, PPIs inhibit the urease protecting H. pylori from acid & are effective on this microorganism in vitro, although in vivo they only achieve eradication in 10-15% of cases

Do PPI Promote Actions of Antibiotics in H. Pylori Eradication?

•In vitro, PPIs have additive even synergistic effect with several antimicrobial agents

•Studies suggest that high dose omeprazole increase amoxycillin level in gastric juice, & high dose of PPIs improve H.pylori cure rate when given with amoxycillin

•Clarithromycin activity against H. pylori is enhanced as gastric pH increases

3- Cyto-Protective Agent ( Sucalfate)

Sucralfate = complex of Aluminum Hydroxide & Sulfated Sucrose

•Binds to positively charged groups in proteins, glycoproteins of necrotic tissue (coat ulcerated mucosa)

•Not absorbed systemically

•Require acidic media to dissolve & coates the ulcerative tissue so, it can not be given with H2-antagonist, PPIs, & antacids

Administration

•Should not be given with food, give 1hr before or 3hr after meal

•Dose: 1gm/ 4times daily or 2 gm/ 2times daily

•Must be given for 6-8 weeks

•Large tablet & difficult to swallow

Side Effects

•Constipation; black stool & dry mouth

•It is very safe in pregnancy

4- Prostaglandin Agonists (PGE1) Misoprostol

•Inhibits secretion of HCl & stimulates secretion of mucus & bicarbonatemis

•It is a methyl analog of PGE1

•It is approved for prevention of ulcer induced by NSAIDs

•Optimal role in ulcer treatment is difficult to define

•PPIs may be as effective as misoprostol for this indication

•Routine clinical prophylaxis of NSAIDs-induced ulcers may not be justified

•However, in patients with rheumatoid arthritis requiring NSAIDs therapy, prophylaxis with Misoprostol or a PPI may be cost-effective

Administration

•Should be given 4 time/ day ( inconvenient)

Side effects

•Up to 20% develop diarrhea & cramps •Category X

5- Antacids

•Weak bases that react with gastric acid to form water & salt (Neutralize acid)

•Studies indicate mucosal protection either through stimulation of prostaglandin production or binding of unidentified injurious substance

•Antacids vary in palatability & price

•Antacids contain either Sodium-bicarbonate, Aluminum-hydroxide, magnesium-hydroxide & calcium carbonate

•Require large neutralizing capacity (a single dose of 156 meq antacid given 1 hr after meal effectively neutralize gastric acid for 2 hr, a second dose given 3 hr after eating maintains the effect for over 4 hr after the meal)

•Very inconvenient to administer

•Tablet antacids are generally weak in their neutralizing capability, & a large number of tablets would be required for this high-dose regimen

Side Effects

•Cation absorption (sodium, magnesium, aluminum, calcium) leads to systemic alkalosis (concern with renal impairment)

•Sodium content an issue with congestive heart failure

•Aluminum hydroxide may be constipating, Magnesium hydroxide may produce diarrhea so, they used in combination

•Calcium-carbonate containing antacids work rapidly & very effective but large dose may cause calciuria

The Mechanism & Side Effects of Various Acid Suppressive Medications

6- Antibiotics for H. Pylori Eradication

•H. pylori eradication significantly reduce the risk of ulcer recurrence & re-bleeding & less expensive than chronic antisecretory therapy

•Continuing antisecretory therapy for > 2 weeks following antibiotic treatment is unnecessary after  H.pylori eradication

Duration of treatment & adverse effects should be considered

Duration of H. Pylori Eradication Therapy

•Until recently, the recommended duration of therapy for H.pylori eradication was 10 -14 days

•There are number of recent studies evaluated one-, five-, & seven-day regimens

•Although not proven, potential benefits of shorter regimens include better compliance, fewer adverse drug effects, & reduced cost to the patient

Adverse Effects

•The most commonly reported adverse events were nausea, vomiting, & diarrhea

•A bitter or metallic taste in the mouth is associated with eradication regimens containing clarithromycin

•Bismuth subsalicylate may cause a temporary grayish-black discoloration of the stool

Selected Long-Duration Regimens for H. pylori Eradication

Short-Course Therapy for Eradication of Helicobacter pylori

Resistance

•Resistant H. pylori has been documented in cases of failed eradication therapy based on biopsy & culture results & is of great concern in patients at high risk for complications of  H.pylori infection

•Resistance rate to clarithromycin is currently 2-30% & to metronidazole 15-66%

•Primary resistance to clarithromycin is a strong predictive risk factor for treatment failure, whereas primary resistance to metronidazole does not always lead to treatment failure

•70 % of patients failing one or more regimens responded well to triple-drug therapy that included:

Pantoprazole, amoxicillin, & levofloxacin  for 10 days

•A meta-analysis of current literature on treatment of resistant H. pylori showed benefit in using quadruple drug therapy, including:

  • Clarithromycin + ranitidine + bismuth + amoxicillin (1 g twice daily) therapy, as well as a combination of
  • PPIs (standard dosage for 10 days) + bismuth + metronidazole + tetracycline

Recurrence

•Recurrence of H. pylori infection is defined by:

  • A positive result on urea breath or stool antigen testing six or more months after documented successful

Risk factors for recurrence include:

  • Non-ulcer dyspepsia
  • Persistence of chronic gastritis after eradication therapy
  • Female gender
  • Intellectual disability
  • Younger age
  • High rates of primary infection
  • Higher urea breath test values

•Recurrence rates worldwide vary but lower in developed countries

•In the primary care setting, physicians may choose to treat recurrences with an alternative eradication regimen, depending on symptoms & risk factors for complications of infection

•It is too early to know whether shorter courses of eradication therapy will be associated with a higher resistance rate

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