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NSAIDs GI Toxicity

Dr. N. Aletaha MD

NSAIDs

NSAIDs are popular because :AnalgesicAntipyreticAnti-inflammatory (at higher doses)

Aspirin is also used as an anti-thrombotic agent.

Epidemiology

The spectrum of NSAID-induced morbidity ranges from nausea and dyspepsia (prevalence reported as high as 50–60%) to a serious GI complication such as peptic ulceration (15–30% of individuals taking NSAIDs regularly) complicated by bleeding or perforation in as many as 1.5% of users per year.

Epidemiology

It is estimated that NSAID-induced GI bleeding accounts for 60,000 to 120,000 hospital admissions per year, and deaths related to NSAID-induced toxicity may be as high as 16,000 per year in the United States.

Epidemiology

Approximately 4–5% of patients develop symptomatic ulcers within 1 year. Unfortunately, dyspeptic symptoms do not correlate with NSAID-induced pathology. Over 80% of patients with serious NSAID-related complications did not have preceding dyspepsia.

Epidemiology

Even 75 mg/d of aspirin may lead to serious GI ulceration; thus, no dose of NSAID is completely safe.

Risk factorsEstablished risk factors include advanced age history of ulcer concomitant use of glucocorticoidshigh-dose NSAIDs multiple NSAIDs concomitant use of anticoagulants,

clopidogrel and serious or multisystem disease.

Risk factors

Possible risk factors include

concomitant infection with H. pylori, cigarette smoking, and alcohol consumption.

Risk of gastrointestinal toxicity

The risk increased by the presence of one or more of the following: Prior history of a gastrointestinal event

(ulcer, hemorrhage) Age >60High dosage of a NSAIDConcurrent use of glucocorticoids

Risk of gastrointestinal toxicity

Concurrent use of anticoagulants.Chronic as opposed to short-term (less

than one week) useUntreated Helicobacter pylori infectionUse of selective serotonin reuptake

inhibitors (SSRI)

PHARMACOLOGY

Nonsteroidal antiinflammatory drugs (NSAIDs) are competitive inhibitors of the enzyme cyclooxygenase (COX)

NSAIDs prevent COX-mediated production of prostaglandins and thromboxanes, but not leukotrienes and other eicosanoids.

PHARMACOLOGY

OVERVIEW 

 Many of the toxic effects of the NSAIDs are related to their main mode of action, the inhibition of prostaglandin synthesis.

PATHOGENESIS

TOPICAL EFFECTS

Aspirin and many other NSAIDs are not ionized at the acidic pH in the gastric lumen absorbed across the gastric mucosa.

The drug ionizes and is trapped temporarily in epithelial cells damage these cells

PATHOGENESISAspirin and many NSAIDs are weak acids that remain in a nonionized lipophilic form when found within the acid environment of the stomach. Under these conditions, NSAIDs migrate across lipid membranes of epithelial cells, leading to cell injury once trapped intracellularly in an ionized form.

PATHOGENESIS

Topical NSAIDs can also alter the surface mucous layer, permitting back diffusion of H+ and pepsin, leading to further epithelial cell damage.

Moreover, enteric-coated or buffered preparations are also associated with risk of peptic ulceration.

PATHOGENESIS

This "topical" epithelial injury by many NSAIDs does not appear to be importance

PATHOGENESIS

SYSTEMIC EFFECTS

The pathogenesis of symptomatic peptic ulcer disease caused by exposure to NSAIDs is mainly a consequence of systemic (post-absorptive) inhibition of GI mucosal cyclooxygenase (COX) activity.

PATHOGENESIS

Even intravenous or intramuscular administration of NSAIDs can cause gastric or duodenal ulcers in animals and humans

PATHOGENESIS

There are at least two forms of COX in the body, COX-1 and COX-2

Cyclooxygenase-1 (COX-1) and COX-2 are the enzymes responsible for the synthesis of prostaglandins.

PATHOGENESIS

The healthy gastric and duodenal mucosa constitutively use COX-1 to produce its mucosal-protective PGs

Conventional NSAIDs such as ibuprofen inhibit the COX-1 and the COX-2 enzymes.

PATHOGENESIS

COX-1 is an enzyme in most cells of the body.

COX-2 is expressed in many cells only in inflammatory proccess.

COX-3 in the brain may be one target of acetaminophen (paracetamol)

PATHOGENESIS

Drugs that more selectively inhibit COX-2 than COX-1 have less suppressive effects on gastric PG synthesis Examples include celecoxib .

PATHOGENESIS

However, COX-2 selective inhibitors may still block COX-1 at clinically recommended doses and thus have the potential to also block COX-1 in the stomach and duodenum and cause damage.

Cytoprotective mechanisms of PGs

Inhibit gastric acid secretion

Stimulation of glycoprotein (mucin)

Stimulation of bicarbonate secretion

Stimulation of phospholipid secretion

Cytoprotective mechanisms of PGs

Local vasodilation mucosal blood flow and oxygen delivery to epithelial cells

Increased epithelial cell migration towards the luminal surface

Epithelial cell proliferation

PATHOGENESIS

COX-1 inhibition reduces prostaglandin synthesis Reductionin mucosal blood flowHypoxiaReduction in mucosal defense.

PATHOGENESISOther mechanism of NSAIDs damage

One such mechanism is increased leukotriene production that occurs because arachidonic acid metabolism shifts to the alternative 5-lipooxygenase pathway when the COX-1 pathway is inhibited

PATHOGENESIS

GASTROINTESTINAL Side EFFECTS

Dyspepsia

Peptic ulcer disease

Bleeding

Ulcers, perforations, bleeding, obstruction, strictures enteropathy

Spectrum of NSAID-InducedGI Mucosal Injury

Upper GI• GERD • Subepithelial petechial hemorrhages Erosions Ulcers

– Stomach > duodenum

• Bleeding

– Stomach » duodenum

• Perforations/obstruction

Small Intestine

• Ulcers

• Strictures

• Diaphragms

•Enteropathy

Spectrum of NSAID-InducedGI Mucosal Injury

Colon

• Colitis

• Ulcers

• Strictures

• Diverticular bleed or perforation

• Collagenous colitis

• Relapse of IBD

adverse effects of high-dose aspirin use

nausea

vomiting

diarrhea or constipation

dyspepsia (impaired digestion)

epigastric pain

bleeding, and ulceration (primarily gastric).

Therapy of NSAID-Related Gastric or Duodenal Injury

Table 293-5 Recommendations for Treatment of NSAID-Related Mucosal Injury

Clinical Setting Recommendation

Active ulcer

NSAID discontinued

H2 receptor antagonist or PPI

NSAID continued PPI

Prophylactic therapy

Misoprostol

PPI

Selective COX-2 inhibitor

H. pylori infection Eradication if active ulcer present or there is a past history of peptic ulcer disease

Abbreviations: COX-2, isoenzyme of cyclooxygenase; PPI, proton pump inhibitor.

Patients requiring antiplatelet therapy

Those with a history of ulcer complications or a history of ulcer disease (non-bleeding) undergo testing for H. pylori and treatment if positive.

Patients requiring antiplatelet therapy

Those with a history of ulcer complications or a history of ulcer disease (non-bleeding), a history of upper gastrointestinal bleeding, those receiving dual antiplatelet therapy or concomitant anticoagulants be treated with a PPI.

patients requiring antiplatelet therapy

Patients without the above risk factors but who have other risk factors for gastrointestinal complications (including age 60 or more, use of corticosteroids, dyspepsia or GERD symptoms) should also be treated with a PPI.

Risk of gastrointestinal toxicity

ACG guidelines (2009) :

High riskHistory of complicated peptic ulcer diseaseMultiple (>2) risk factors (see below)

Moderate risk (1 to 2 risk factors)

Low riskNo risk factors

Risk of gastrointestinal toxicity

Risk:

Age >65 years

High dose NSAID therapy

A previous history of an uncomplicated ulcer

Concurrent use of aspirin (including low dose), corticosteroids, or anticoagulants

Risk of gastrointestinal toxicity

COX-2 inhibitors may be safer than conventional NSAIDs for reduction in the risk of gastrointestinal bleeding but are still associated with an increased risk.

combined GI and CV risk profile:

Patients who are at high GI/high CV risk should not receive NSAIDs, including COX-2 inhibitors.

Patients at high GI/low CV risk should receive a COX-2 inhibitor in combination with either a PPI or misoprostol.

Patients requiring antiplatelet therapy

Patients at moderate GI/low CV risk should receive a COX-2 inhibitor alone or a conventional NSAID + either a PPI or misoprostol.

patients requiring antiplatelet therapy

Patients at moderate GI/high CV risk should receive naproxen (due to its putative cardioprotective properties) and either a PPI or misoprostol.

This same strategy is endorsed for patients at low GI/high CV risk.

Patients requiring antiplatelet therapy

Patients at low GI/low CV risk can receive a conventional NSAID alone, although the "least ulcerogenic NSAID at the lowest effective dose" is recommended

Patients requiring antiplatelet therapy

All patients regardless of risk who are about to start long-term traditional NSAID therapy should be considered for testing for H. pylori and treated if positive.

primary prevention

primary prevention included

avoiding the agent

using NSAIDs that are theoretically less injurious

and/or the use of concomitant medical therapy to prevent NSAID-induced injury.

primary prevention

Several nonselective NSAIDs that are associated with a lower likelihood of GI toxicity include diclofenac, aceclofenac, and ibuprofen, although the beneficial effect may be eliminated if higher dosages of the agents are used.

prevention of NSAID-induced GI damage

Primary prevention of NSAID-induced ulceration can be accomplished by misoprostol (200 g qid) or a PPI. High-dose H2 blockers (famotidine, 40 mg bid) have also shown some promise in preventing endoscopically documented ulcers, although PPIs are superior.

Prevention of NSAID-induced GI damage

Selective COX-2 inhibitors (coxibs) a novel strategy for the prevention of NSAID-related gastroduodenal toxicity.

However, the advantage of these coxibs over nonselective NSAIDs is debatable and cardiovascular toxicity has limited the use of coxibs.

advantage of celecoxib in preventing GI complications was offset when low-dose aspirin was used simultaneously.

Guide to NSAID Therapy

Table 293-6 Guide to NSAID Therapy

No/Low NSAID GI Risk NSAID GI Risk

No CV risk (no aspirin)

Traditional NSAID Coxib or

Traditional NSAID + PPI or misoprostol

Consider non-NSAID therapy

CV risk (consider aspirin)

Traditional NSAID + PPI or misoprostol if GI risk warrants gastroprotection

A gastroprotective agent must be added if a traditional NSAID is prescribed

Consider non-NSAID therapy Consider non-NSAID therapy

Abbreviations: CV, cardiovascular; GI, gastrointestinal; NSAID, nonsteroidal anti-inflammatory drug; PPI, proton pump inhibitor.

Source: Adapted from AM Fendrick: Am J Manag Care 10:740, 2004. Reproduced with permission of INTELLISPHERE, LLC via Copyright Clearance Center.

For patients taking NSAIDs which carry a higher CV risk:

Switching to paracetamol 4g/day Will reduce cardiovascular risk Will reduce gastrointestinal risk Efficacy?

Switching to ibuprofen 1200mg/day Will reduce cardiovascular risk Will reduce gastrointestinal risk (especially if use a PPI as well) Efficacy?

Switching to naproxen 1g/day Will reduce cardiovascular risk May increase gastrointestinal risk (but what about using a PPI?) Efficacy?

THANK YOU