Their mechanism of action is predominantly by inhibition of prostaglandin synthesis by the enzyme cyclo-oxygenase which catalyses the conversion of arachidonic acid to the various prostaglandins that are the chief mediators of inflammation.
Annual incidence of gastrointestinal bleeding 50-150 cases per 100,000.
Responsible for an estimated 16,500 deaths and 76,000 hospitalizations per year in the U.S.
Traditional NSAIDs inhibit COX-1 AND COX-2 to varying degrees.
Act by inhibiting both isoforms of cyclooxygenase enzyme COX-1 and COX-2.
Many side effects of NSAIDs are due to COX-1 suppression-gastrointestinal ulceration, bleeding and platelet dysfunction. Inhibition of COX-2 facilitates anti-inflammatory, analgesic and antipyretic effects of NSAIDs.
Long-term use associated with adverse effects including upper and lower gastrointestinal tract bleeding, and increased adverse cardiovascular events.
PRECISION trial indicated that among patients with symptomatic arthritis who had moderate to high risk of cardiovascular events approximately one in 20 experience major toxicity over 1-2 years, and patients using naproxen or ibuprofen experience significantly higher risk of major toxicity than those using celecoxib .
Associated with chronic kidney injury, heart failure, hypertension and death.
Generate mucosal lesions in every part of the G.I. tract, but most commonly in the stomach and the small intestine.
Even low doses of NSAID’s can lead to the generation of erosions and ulcerations in the small intestine.
Courses of NSAID’s for as little as two weeks can lead to mucosal lesions.
Small intestine mucosal lesions tend to persist if therapy is continued or discontinued.
Meta-analysis including 31 trials and 116,429 patients revealed in association with increased rates of myocardial infarction, stroke, and cardiovascular death in patients taking either selective or nonselective NSAIDs (Trelle S et al ).
Increased risk of heart attack or stroke can occur with NSAID use at early as 2 weeks and increases with duration of treatment.
Increased CV risks associated with increased doses of NSAIDs.
Risks for CV disease similar for all NSAIDs.
Can increase heart attack and stroke in patients with no cardiovascular risk factors, although those with risk factors have higher risk with NSAIDs.
Patients treated with NSAIDs after first MI have a higher mortality rate in the first year than those not treated with NSAIDs.
Among patients receiving anti-thrombotic treatment following a MI use of nonsteroidal anti-inflammatory drugs was associated with an increased risk of bleeding and excess thrombotic events: physicians should use caution when prescribing NSAID’s for patients who have recently experienced an MI (Schjerning AM et al).
Nonsteroidal anti-inflammatory drugs block prostaglandin and prostacyclin biosynthesis by their inhibiton of cyclooxygenase (COX) enzymes.
Aspirin inhibits COX-1 reducing thromboxane production leading to it antiplatelet effect.
COX-2 NSAID’s have relatively greater anti-inflammatory, antipyretic, and analgesic effects.
COX -2 inhibitors have a high rate of ischemic cardiovascular events and it is recommended that these drugs be avoided in the setting of ischemic heart disease.
NSAIDs increase risk of heart failure.
COX-1 is expressed within most tissues generating prostaglandins which protect gastrointestinal mucosa and maintains vascular homeostasis.
Risk factors for associated gastrointestinal ulcers include advanced age, history of ulcers, concomitant use of corticosteroids, higher dosage of NSAIDs, concomitant and use of anticoagulants.
1-3% have gastrointestinal bleeding.
Can increase the risk of hemorrhage of patients on warfarin by raising the INR and inhibit platelet function.
Reversibly inhibit platelet cyclooxygenase.
Should stop short-acting NSAIDs 1 day in advance and long-acting NSAIDs 2 to 3 days in advance of surgery.
May be reintroduced after surgery when the patient is hemodynamically stable and the risk of bleeding is acceptable.
Accounts for almost one-fourth of all reported adverse drug events.
Approximately 15% of users have gastrointestinal symptoms such as dyspepsia, heartburn, nausea and vomiting.
Clinical and endoscopic observations indicate that even the short-term ministration of NDAIDs, even in low doses, frequently can induce adverse affects in the small intestine as increased gut permeability, gut inflammation, mucosal erosions, and ulcerations.
Raise systemic vascular resistance and reduce renal perfusion in susceptible individuals.
Mediates inhibition of cyclooxygenases inhibition vasodilatory prostanoid production, reducing the diameter of the efferent arteriole and contributes to decrease in GFR.
In patients with underlying volume depletion the risk of acute renal failure with NSAIDs use increases.
Increases the risk for CHF.
Patients at risk for NSAID induced nephrotoxicity include those with severe cardiac, liver or renal disease, as well as the elderly.
Newer cyclooxygenase-2 inhibitors celecoxib and rofexicob have mush less effect on platelet function than aspirin or nonselective NSAIDs.
Can reduce the incidence rate and mortality from digestive tract carcinomas including esophageal, gastric, colon, and rectal lesions.
Meta-analyses reveal associated reduction of 36% reduction in the risk of lung cancer with daily use of NSAIDs.
For patients using NSAID’s from 4-10 years have significant increase in risk of renal cell carcinoma.
Patients exposed to non-aspirin NSAIDs for over 10 years should be counseled to discontinue these meds because of strong association between the use and the risk of developing renal cancer.
Can induce regression of existing colorectal adenomas in patients with FAP.
There is a risk of cross-sensitivity in treating patients with allergic reactions to aspirin.
Decrease renal function by inhibiting prostaglandin production.
Regular use can be an effective agent in breast cancer chemoprevention.
Nonselective NSAIDs inhibit both COX-1 and COX-2.
Long-term use decreases risk of developing oral cancer among smokers.
Observational studies suggest that some traditional agents such as diclofenac and ibuprofen increase cardiovascular risk compared with no NSAID therapy.
Danish study of 107,092 patients surviving first hospitalization for CHF: found that heart failure was associated with frequent use of NSAIDs with increased risk of death and cardiovascular morbidity (Gislason).
Frequently prescribed with PPI’s to minimize adverse effects on the G.I. tract.
PPI’s suppress gastric acid excretion secretion and are effective in reducing NSAID induced damage in the stomach, but are without benefits in preventing other G.I. tract damage.
PPI’s alter the small intestine microbiome augmenting the toxic effects of NSAIDs on the intestinal mucosal and maybe responsible for significant complications such as anemia.
NSAIDs are available in a variety of formulations: tablet, injection, topical cream and suppository.