Cox1 is constitutively active and is responsible for producing physiological prostaglandins. This has GI-protective effects and is also involved in kidney and platelet function.
Cox2 is inducible and is primarily involved in pathological events such as inflammation
20,000 GI bleeds and 1000-2000 deaths per year in Canada.
Although generally well-tolerated, NSAIDs can cause GI bleeds via subepithelial hemorrhages, erosions, and ulcerations. The dual-injury hypothesis suggests NSAIDs have direct toxic effects on the mucosa and indirect effects through hepatic metabolites and decreased synthesis of mucosal prostaglandins, altered mucus and bicarbonate secretion, and reduced blood flow. The stomach antrum is most frequently and severely affected. Endoscopic studies show a prevalence of gastric ulcers in 10-25% of people taking chronic NSAIDs for arthritis 5-15 times the expected levels.
NSAIDs inhibit prostaglandin formation, reducing afferent arteriole vasodilation in the nephron. This leads to a drop in GFR and can contribute to acute renal failure in some settings. Resulting sodium retention can lead to hypertension and CHF.
Hyponatremia can also follow due to loss of PG's inhibitory effect on ADH.
Hyperkalemia can result from decreased K secretion due to decreased GFR and decreased renin production (how?)
Acute interstitial nephritis can result from allergy. Membranous glomerulopathy as well.
Analgesic nephropathy, due to many years of regular analgesic use, can lead to slowly progressive renal failure. This can involve oxidative damage by free radicals and lead to decreased kidney size, bumpy contours, and papillary calcifications.
Renal
There are dose-dependent and time-dependent increases in risk. There is a 1% chance of bleeds for someone taking advil for 6 months and a 3-4% chance for people taking it for more than a year.
In increasing risk, ibuprofen, diclofenac, naproxen.
Increased risk are people with prevoius bleeding history, concomittant steroid, anti-coagulant, ASA use.
PPIs and misoprostol can be used to help prevent GI toxicity.
Other side effects include: