Chronic Nonsteroidal Antiinflammatory Drug Use

Case Synopsis

A 60-year-old man with a history of osteoarthritis has been taking naproxen for the past 3 years without complications or side effects. He experienced sudden severe nausea and vomited frank blood. He was taken to the emergency department and underwent an urgent upper gastrointestinal (GI) endoscopy, which revealed a bleeding gastric ulcer.

Problem Analysis

Definition

Nonsteroidal antiinflammatory drugs (NSAIDs) are widely used drugs that act by inhibiting cyclooxygenase and the formation of prostaglandins. Prostaglandins are derived from arachidonic acid, formed by phospholipase A ₂ acting on cell membrane phospholipids ( Fig. 42.1 ). NSAIDs are among the most commonly used drugs worldwide and are usually well tolerated. However, like all medications, NSAIDs are not without side effects. They are known to cause the following:

GI toxicity, leading to the formation of peptic ulcers
Unwanted antiplatelet effects (nonselective inhibitors of cyclooxygenase)
Potential for increased thrombogenicity (selective cyclooxygenase-2 [COX-2] inhibitors)
Renal toxicity, with potential alterations of potassium and fluid balance, decreased renal function, nephrotic syndrome with interstitial nephritis, papillary necrosis, and rhabdomyolysis
Anaphylactic and anaphylactoid reactions in select patients

Fig. 42.1, Biosynthesis of prostaglandins from arachidonic acid via the cyclooxygenase (COX-1 and COX-2) pathways.

Recognition

Gastrointestinal Effects

NSAID use is the second most important cause of peptic ulcers after Helicobacter pylori infection. The primary mechanism of ulcer formation is from suppression of gastric prostaglandins, although decreases in nitric oxide and calcitonin gene-related peptide may also be involved. This leads to decreases in epithelial mucus, bicarbonate secretion, and mucosal resistance to injury. NSAIDs also reduce gastric mucosal blood flow, with subsequent damage to the vascular endothelium (an early effect of NSAID administration) in conjunction with an enhanced adherence of neutrophils to the vascular endothelium. The neutrophil adherence causes endothelial injury by release of oxygen-derived free radicals.

Thrombogenic Effects

Thromboxane A ₂ is a major product of COX-1 metabolism in platelets (see Fig. 42.1 ). It causes platelet aggregation, vasoconstriction, and smooth muscle proliferation. In patients with peripheral vascular disease, increased thromboxane production is associated with increased risk of major vascular events. Aspirin is a potent inhibitor of platelet cyclooxygenase (COX-1), which blocks thromboxane production for the life of the platelet. With other NSAIDs, this process lasts 24 hours or less. This effect underlies aspirin’s ability to reduce the incidence of cardiovascular death, myocardial infarction, and stroke in high-risk patients. However, high doses or toxic doses of aspirin can inhibit vitamin K–dependent coagulation factors, leading to an increase in prothrombin time and international normalized ratio.

In contrast, prostacyclin is a product of COX-2 metabolism in vascular endothelium. This is postulated from the finding that pharmacologic inhibition of COX-2 leads to the inhibition of prostacyclin formation. Prostacyclin inhibits platelet aggregation and smooth muscle proliferation and causes vasodilation. Nabumetone, etodolac, and nonacetylated salicylates (relatively COX-2–selective NSAIDs) inhibit COX-2–mediated prostacyclin biosynthesis and seem to have little or no effect on platelet aggregation. Other NSAIDs block COX-1 thromboxane biosynthesis and COX-2 prostacyclin production with less selectivity ( Table 42.1 ; Fig. 42.2 ).

TABLE 42.1

Inhibition of Prostacyclin and Thromboxane Biosynthesis and Risk of Thrombosis

From Catella-Lawson F, Crofford LJ: Cyclooxygenase inhibition and thrombogenicity. Am J Med 110:28-32, 2001.

Drug	Prostacyclin	Thromboxane	Thrombosis Risk
Low-dose aspirin	±	↓↓	↓
Conventional	↓	↓	Unclear
COX-2–specific inhibitors	↓	±	Unclear

COX, cyclooxygenase.

Fig. 42.2, Selectivity of COX-2 inhibitors.

You're Reading a Preview

Become a Clinical Tree membership for Full access and enjoy Unlimited articles

Become membership

If you are a member. Log in here