Non-Steroidal Anti-Inflammatory Drugs

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Non-Steroidal Anti-Inflammatory Drugs (NSAIDS) are very commonly used analgesics. Many drugs, such as ibuprofen and naproxen, are available over the counter. Others are only accessible by prescription.

While NSAIDs have significant benefits, there are also risks with these drugs, including gastric irritation and/or ulceration, renal impairment, and cardiovascular events.

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The indications for NSAIDs are as follows:


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Common Medications

  • ASA
  • ibuprofen
  • naproxen
  • COX-2 inhibitors
  • others

Acetylsalicylic Acid

Acetylsalicylic acid (ASA), or aspirin, is an NSAID that is one of the best-known drugs in the world. It is also one of the oldest - people have known since the time of Hippocrates that willow bark, from which ASA is derived, was effective at treating fevers and pains.


Salicylates are rapidly absorbed through the stomach and small intestine, with peak plasma levels within 1-2 hours. Aspirin is rapidly hydrolyzed to acetic acid and salicylate by esterases in the tissue and blood.

As doses increase, elimination half-life increases from 3-5 hours for 600 mg/day to 12-16 hours for dosages greater than 3.6g/day.


Standard dosing is as follows.

Usual dose may be repeated every 4 hours, or small doses (0.3g) every three hours. Because of long half-lives, frequent dosing is not required when daily doses of 4 g or more are taken, and total dose can be divided by three and taken following meals.



Ingested salicylate may be excreted unchanged, but metabolic pathways become overwhelmed when total body load exceeds 600 mg.

Alkalinization of the urine increases rate of excretion.




  • NSAID with long half-life (14 hours)
  • preferentially inhibits COX2 as opposed to COX1


Cox2 inhibitors (COXIBs)

  • less short term GI effects, but increased CV events
  • concern over long term renal damage


Other NSAIDs



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Mechanism of Action

ASA is a irreversible, nonselective inhibitor of cyclooxygenases COX1 and COX2, preventing eicosanoid synthesis. It also intereferes with chemical mediators of the kallikrein system, inhibiting granulocyte adherence to damage vasculature, stabilizing lysozomes, and inhibiting migration of PMNs and macrophages.


ASA acts at peripheral sites of inflammation, as well, most likely, at subcortical regions, to reduce pain.


ASA reduces fever, likely by direct inhibition of COX and secondary prevention of IL-1 release from macrophages during inflammation. Superficial vasodilation, and accompanying sweating, assists in lowering body temperature.


ASA prolongs bleeding time, doubling it if given for one week. This is due to inhibition of platelet synthesis of thromboxane (TX) A2. TXA2 causes platelets to change shape, degranulate, and aggregate during hemostasis. ASA's period of action is 8-10 days - similar to the life span of a platelet - due to its irreversible action.



Cox1 vs Cox2

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


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Adverse Effects


GI bleeding

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.

Risk is dose- and time-dependent. Endoscopic studies show a prevalence of gastric ulcers in 10-25% of people taking chronic NSAIDs for arthritis - 5-15 times the expected levels (ref).

Increased risk is seen with previous bleeding history, and concomittant steroid, anti-coagulant, or ASA use.

Proton pump inhibitors and misoprostol can be used to help prevent GI toxicity.



Renal Toxicity

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 prostaglandin inhibition on ADH.

Hyperkalemia can result from decreased K secretion due to decreased GFR.

Acute interstitial nephritis can result from allergy. Membranous glomerulopathy can follow NSAID toxicity 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.



Other side effects include:

Gastrointestinal effects, such nausea are among the most common side effects, but can be mitigated by taking with meals followed by a glass of water or antacids.


Chronic toxicity is possible, especially in the elderly. Salicylism can occur at higher doses, and is characterized by vomiting, tinnitus, decreased hearing, and vertigo.


Reye's syndrome can occur in children with influenza. While the effect of ASA is in doubt (Hurwitz, 1987, 1989), acetominophen is a safter choice.

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ASA Overdose

Overdose, which is often accidental, can be life-threatening. It is potentially toxic at >150 mg/kg, with serious toxicity occurring with doses of 300-500 mg/kg.


Early after toxic dosing, direct stimulation of the respiratory centre in the medulla leads to hyperventilation, acute respiratory alkalosis and increased O2 consumption. Later, increasing anion gap metabolic acidosis occurs first as a mixed disorder, then pure as respiratory depression begins. Toxic doses can also cause glucose intolerance and cardiotoxicity.


Findings can include:

Ventilatory assistance may be required, with sodium bicarbonate infusions to alkanize the urine and increase the amount of salicylate excretion.




Guidance on Use


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Resources and References


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