Effects of NSAIDs on the GIT

  • NSAIDs are popular because of their versatile effectiveness as analgesics, antipyretics, and (by definition) as anti-inflammatory agents.
  • Aspirin is also widely used as an anti-thrombotic agent.
  • Normally the stomach has three defenses against digestive juices:
  • Mucus that coats the stomach lining and shields it from stomach acid.
  • Chemical bicarbonate that neutralizes stomach acid.
  • Blood circulation to the stomach lining that aids in cell renewal and repair.
  • Another important point is therepair mechanisms include:
  • Restitution:rapid migration of deeper epithelial cells lining gastric pits to cover the damaged surface.
  • Proliferation: less rapid regeneration of new epithelial cells from progenitor cells.
  • Both require:
  • Adequate amounts of well-oxygenated blood.
  • PH close to 7.4.
  • PGs and NO.

Drug action

  • Arachidonic acid is released from membrane phospholipids as a response to inflammatory stimuli.
  • The enzyme cyclo-oxygenase catalyzes arachidonic acid to prostaglandins and leukotrienes.
  • The enzyme cyclo-oxygenase (COX) has two forms, known as COX-1 and COX-2.
  • COX-1 is involved in maintaining healthy tissue, while COX-2 is involved in the inflammation pathway.
  • Another form is COX3 found in brain (acetaminophen is the inhibitor).
  • Prostaglandins maintain an intact gastric mucosal barrier by:
  • Increasing secretion of mucus and bicarbonate.
  • Retards diffusion of acid-pepsin from the lumen into the mucosa.
  • Stimulation of phospholipid secretion by cells.
  • Enhancement of mucosal blood flow and oxygen delivery to cells via local vasodilatation.
  • Decreasing acid secretion (PGE2).
  • Enhanced epithelial cell proliferation.
  • Increased epithelial cell migration towards the luminal surface (restitution).
  • Oral and parenteral NSAIDs  inhibition of the enzyme cyclo-oxygenase, which catalyzes arachidonic acid to prostaglandins and leukotrienes.
  • NSAIDs affect both forms of cyclo-oxygenase.
  • COX-2 inhibitors are a class of drugs which selectively inhibit COX-2while sparing COX-1, thus have less suppressive effects on gastric PG synthesis e.g.:celecoxib.
  • However, COX-2 selective inhibitors can lose their specificity for COX-2 at high doses and have the potential to also block COX-1 and cause damage.

ROLE OF NITRIC OXIDE

  • Constitutive NO synthase (NOS) is important in the maintenance of an intact mucosal lining through:
  • Mediating the release of gastric mucus.
  • Stimulation of fluid secretion.
  • Maintenance of epithelial barrier function.
  • Enhancement of mucosal blood flow.

Pathogenesis of NSAID-induced gastroduodenal mucosal injury

Dual-injury hypothesis

  • Both NSAID-mediated direct acidic damage and suppression of prostaglandin synthesis are necessary to induce gastric damage.
  • When the hepatic metabolites of NSAIDs in bile are secreted into the duodenum, they cause mucosal damage to;
  • Stomach by duodeno-gastric reflux.
  • Small intestine by antegrade passage through the GI tract.
  • The antiplatelet activity of some NSAIDs in low doses may cause bleeding from preexisting ulcers.
  • When NSAIDs irritate the gastric mucosa weaken the resistance to acid gastritis, ulcers, bleeding, or perforation.
  • NSAIDs interfere with growth factors ((TGF)-beta and TGF-alpha, and other mediators responsible for restitution and adaptive protection further contributing to their toxicity.

Pathogenesis of NSAID-induced small intestinal lesions

  • Elevations in enteric bacterial numbers.
  • Occur only with NSAIDs that undergo enterohepatic recirculation.
  • Increased epithelial permeability of the small intestine more hydrogen ions to penetrate the protective mucous layer  more tissue damage over time.
  • Enterohepatic recirculation of the NSAID (some NSAIDs)
  • Repeated exposure of the intestinal mucosa to the NSAID.
  • Combination of an NSAID with bile  much more damage.
  • Influx of neutrophils into the mucosa in response to the initial tissue injury.

Aspirin

  • Not excreted in bile.
  • Potent inhibitor of COX-1 and COX-2 suppression of prostaglandin synthesis increase in gastric acidity, and a decrease in gastric and duodenal secretion of bicarbonate.
  • Effects:
  • Local toxicity through a mechanism known as ion trapping
  • Aspirin and many other NSAIDs are carboxylic acid derivatives, so they are not ionized at the acidic pH in gastric lumen  absorbed across the gastric mucosa  pH–neutral mucosa  the drug ionizes  trapped temporarily in epithelial cells where it may damage these cells.
  • Aspirin doses as low as 10 mg/day inhibit gastric PG generation.
  • After stopping low-dose aspirin therapy, the stomach requires 5 to 8 days to recover its COX-1.
  • COX-2-mediated reactions can still occur after aspirin has been given  production of 15-epi lipoxin A4  cytoprotective
  • This protective effect of 15-epi lipoxin A4 is abolishedby administering a selective COX-2 inhibitor  more gastric damage.

NSAIDs arranged in order of least injury to GI mucosa

  • IbuprofenAspirinDiclofenacSulindacNaproxenIndometacinPiroxicamKetoprofen.

ROLE OF HELICOBACTER PYLORI INFECTION

  • The role of Helicobacter pylori (H. pylori) infection in NSAID-induced gastritis or ulcer formation is complex.
  • NSAID and H. pylori infection represent independent, synergistic risk factors for uncomplicated and bleeding peptic ulcer disease
  • The risk of uncomplicated peptic ulcer disease
  • H. pylori positive H. pylori negative NSAID users.
  • H. pylori positive NSAID users (17.5 times) H. pylori negative non-users.

Major risk factors for upper GI clinical events with NSAIDs use

  • Age > 65 years.
  • History of GI ulceration.
  • History of upper GI ulcer complication.
  • Concomitant drugs (e.g.: corticosteroids, warfarin).
  • Cardiovascular disease.
  • Multiple NSAIDs:
  • Prescribed + low dose aspirin.
  • Prescribed + OTC NSAIDs.
  • Uncertain or possible risk factors
  • Duration of NSAID treatment
  • Female
  • Underlying rheumatic disease
  • Helicobacter pylori infection
  • Smoking
  • Alcohol consumption

Spectrum of NSAIDs related GIT mucosal damage and effects

  • Typical patient is one taking an NSAID for a rheumatic condition, such as osteoarthritis or rheumatoid arthritis.
  • Spectrum range from:
  • Subtle alterations through microscopic damage to surface cells:
  • Disruption of mucosal barrier function.
  • Increased mucosal permeability to hydrogen ions.
  • Increased mucosal permeability tosodium ions.
  • Gross injury if repair mechanisms are ineffective:

Upper GI

  • Edema.
  • Erythema, subepithelial petechial hemorrhages.
  • Erosions(mucosal breaks, without visible depth to the lesion).
  • Ulcers(mucosal breaks, with visible depth to the lesion).
  • Stomach > duodenum.
  • Ulcer complications:
  • Bleeding (80%).
  • Perforations.
  • Obstruction.
  • This presents clinically by dyspeptic symptoms (epigastric discomfort, upper abdominal pain, nausea, vomiting, epigastric fullness, bloatingor diarrhea).

Small intestine

  • Ulcers/erosions
  • Occult bleeding.
  • Gross bleeding.
  • Strictures.
  • Diaphragm-like stricture
  • Thin, concentric with pinhole-sized lumen
  • Mucosa in-between is normal.
  • Subacute obstruction.
  • Difficult to diagnose since they may appear as exaggerated plica circularis under x-ray.
  • Require resection of the involved intestinal segment.
  • Protein losing enteropathy. anemia, hypoalbuminemia, or malabsorption

Colon

  • Ulcers--> iron-deficiency anemia and/or frank bleeding.
  • Strictures--> complete bowel obstruction.
  • Diverticular bleeding.
  • Perforation  acute abdomen
  • Relapse of IBD.
  • There may also be an association between NSAID use and collagenous colitis.
  • Colitis.
  • Bloody diarrhea, weight loss, fatigue, and chronic iron deficiency anemia.
  • When the drug is discontinued, the NSAID-induced colitis improves.

Diagnosis

  • History + investigations of GIT bleeding.

Management of NSAIDs related GIT complications

  • If a patient develops an ulcer while on NSAIDs:
  • Identify risk factors.
  • Manage dyspepsia with acid suppression therapy.
  • Discontinue NSAID whenever possible and consider alternative analgesic e.g.: acetaminophen.
  • Lower the dose of NSAID.
  • Ulcer therapy with a proton pump inhibitor or an H2 antagonist.
  • Preventing ulcers
  • Patient's H. pylori status should also be assessed (if not done previously); if positive, appropriate therapy should be instituted.

Patients in whom NSAID therapy must be continued:

  • Proton pump inhibitor, such as omeprazole (20 mg/day) or lansoprazole (15 or 30 mg/day) for four to eight weeks followed by maintenance therapy for as long as the NSAID or aspirin is used.
  • H. pylori infection should be eradicated, if present.

Current recommendations for all patients receiving NSAIDs

1-Review treatment indications and risk factors for both GI and CV complications

  • Indications for NSAID treatment.
  • CV risk factor modification, such as tobacco cessation and blood pressure, cholesterol, glucose control.

2-Prescribe lower-risk agents.

A-For patients with risk of life-threatening GI bleeding the risk of CV events:

  • Use of NSAIDs with lower GI risk such as ibuprofen, etodolac, diclofenac.
  • COX-2 inhibitors such as celecoxib.

B- For patients in whom the risk of CV events > the risk of GI bleeding

  • COX-2 inhibitors should be avoided.

C- In patients with known CV disease or at high CV risk

  • Low doses of ASA should be prescribed.
  • GI benefits of COX-2 selectivity in the presence of low dose aspirin are lost.

3- Limit duration and dosage.

4-Ask about and avoid combination NSAID therapy.

5- Patients with a history of uncomplicated or complicated peptic ulcers (gastric, duodenal) should be tested for H. pylori prior to beginning a NSAID or low dose aspirin, if present, H. pylori should be treated with appropriate therapy.

6- Monitor patients taking both NSAIDs and coxibs for cardiovascular side effects.

8- Institute gastroprotection.

  • Misoprostol (600 mg/day), if tolerated.
  • PPIs should be considered strongly in high-risk patients.
  • H2-receptor antagonist therapy is inadequate.

Efficacy of various strategies in preventing NSAID induced ulcers and ulcer complications

Agent / GU / DU / Complications
Misoprostol / Proven / Proven / Proven
H2 RAs / Unproven / Proven / Unknown
PPIs / Proven / Proven / Likely
COX-2 / Proven / Proven / Proven

ENTERIC-COATED AND BUFFERED ASPIRIN

  • Diminishes endoscopic signs but does not protect against gastrointestinal bleeding due to systemic effect..

COX-inhibiting nitric oxide donator NSAIDs

  • NSAIDs that have the ability to donate nitric oxide.
  • Donation of nitric oxide within the gastrointestinal tract may protect the gastric mucosa from the consequences of COX inhibition.
  • AZD3582 is under trial.

Beneficial effects of NSAIDs in the gastrointestinal tract

1-Aspirin: showing promise in the chemoprevention of colorectal, and, to a lesser degree, oesophageal cancers.

  • Working during early stages of carcinogenesis.
  • Sulindac (sulindac75 or 150 mg twice daily) causes regression of adenomas in patients with FAP; however regression of polyps is incomplete.
  • Celecoxib was associated with reduction in rectal polypsin patients with FAP.
  • Low doses aspirin reduces the risk of recurrent adenomas in patients with a history of colorectal cancer or adenomas.
  • Proposed mechanisms for NSAIDs inprevention of colorectal carcinogenesis:
  • Induce apoptosis
  • Increase in arachidonic acidpromotes the conversion of sphingomyelin to ceramide, a known mediator of apoptosis.
  • Production of 13-S-HODE.
  • p21 expression, which is associated with cell-cycle arrest and apoptosis.
  • Inhibition of cyclooxygenase which is involved in colonic tumorigenesis.
  • Prostaglandin E2 is a potent stimulator of cultured colon cancer cells via a G-protein-coupled receptor leading to accumulation of beta-catenin (which stimulates cell proliferation) in the nucleus.
  • Influence epidermal growth factor receptor expression (EGFR).
  • Decreasein the number of aberrant crypt foci in the colon which may be precursors of adenomas and cancer by inhibition of pathways that activate nuclear factor kappa B.
  • Inhibit angiogenesis.
  • Modulate insulin-related neoplastic pathways.

2-Diclofenacis of value in the treatment of biliary colic.

3-Aspirin or ibuprofen for the prevention of gallstones.

4-NSAIDs may have a therapeutic potential in certain gastrointestinal motility disorders, such as aspirin in the post-irradiation syndrome.

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