All NSAIDs are weak organic acids and produce, to some extent, anti-inflammatory, analgesic, and anti-pyretic effects.

The standard, prototypical NSAID is aspirin or acetylsalicylic acid (ASA).

ASA is well absorbed from the stomach and small intestine.  In addition to the decrease in PGs, which may be detrimental to the gastric mucosa, ASA (and other NSAIDs) will directly harm the epithelial lining of the stomach and small intestine by their acidic nature.  Generally, the higher the concentration of acid, the greater the degree of damage.  Raising the gastric pH to 3.5 will decrease the extent of damage.  Therefore antacids are often administered concomitantly with large doses of aspirin.

Following absorption, ASA is hydrolysed by plasma esterases to acetic acid (HOAc) and salicylic acid (SA).  Due to the acidic nature of the drug, alkaline conditions will hasten its elimination (by ionisation and increased water solubility) from the blood and renal systems.  For this reason, IV administration of sodium bicarbonate is standard therapy in ASA toxicity.

At low (analgesic) doses, ASA exhibits 1st order elimination kinetics with a half-life of 3.5 to 5 hours.  However, as plasma levels of ASA increase, conjugation and secretory pathways become saturated.  Therefore at high doses (chronic anti-inflammatory or overdose) the elimination of ASA demonstrates 0 order kinetics, with a half-life of 12 hours or longer.

Mechanism of Action -- ASA nonselectively and irreversibly inhibits both isozymes of cyclooxygenase (COX I and COX II) thereby inhibiting the synthesis of prostaglandins and thromboxanes.  The irreversible nature of ASA's activity is related to its acetylation of the enzyme.  The acetyl group from ASA covalently binds to the enzyme, permanently inhibiting its activity.

PHARMACODYNAMICS

Anti-inflammatory -- This action of ASA is primarily due to the decrease in production of PGs.  Since, in most inflammatory conditions, this is mediated by COX II, it is presumed that this effect is mainly the result of COX II inhibition.  It has been hypothesised that ASA may also interfere with the kallikrein system, thus inhibiting the production of additional inflammatory mediators such as bradykinin and kallidin.  The support for this theory is not as strong as the PG inhibition.  Secondary to the decrease in PG, ASA will demonstrate decreased granulocyte adherence, stabilisation of lysosomes, decreased migration of polymorphonuclear leukocytes, macrophages, and other cell mediators of inflammation.

Analgesic -- Also due to the decreased production of PGs, ASA is most effective in the treatment of mild to moderate pain.  It probably works both peripherally at the site of injury and also centrally to inhibit PG-dependent pain pathways.

Anti-pyretic -- ASA will lower an abnormally elevated body temperature but produces little change in the normal body temperature.  Again, this effect is primarily due to a decrease in the production of PG.  Secondarily, vasodilatation in the absence of PG will also aid in the dissipation of excess heat and contribute to the anti-pyretic activity.

Anti-platelet -- Recall that TXA₂ acts to promote platelet aggregation while PGI₂ (prostacyclin) acts to inhibit platelet aggregation.  ASA slightly prolongs bleeding time by decreasing platelet aggregation.  This is due to the decreased synthesis of TXs.  Since the mechanism of ASA is irreversible, the ability of platelets to aggregate (and consequently the ability of  blood to clot) is inhibited at least 8 days, the time required for the formation of new platelets, assuming that 100% of platelets were inhibited.  Many clinicians now believe that the antiplatelet effects of aspirin are more pronounced at lower doses while high dose, chronic administration of ASA will not further inhibit platelet aggregation and may in fact have the opposite effect.  The reasoning behind this theory is that at lower doses, inhibition of platelets per se is complete and irreverisible.  Platelets, having no nuclei, are unable to synthesise new COX I and therefore cannot synthesise new thromboxane.  However, endothelial cells, a major sight of prostacyclin synthesis,  do have nuclei and may express the gene for COX I and synthesise further prostacyclin.  However, at progressively  higher doses of ASA, each new COX I synthesised by the endothelial cell is immediately inhibited, thus no prostacyclin is synthesised -- an effect which may off-set the inhibition of TXA₂ synthesis.

Uricosuric -- ASA may produce a uricosuric effect, although this is a dose-dependent mechanism.  Lower doses of aspirin typically cause the retention of urate while higher doses promote urate excretion.  This will be discussed more in depth in the section on gout.

Analgesia/Anti-inflammation -- ASA is NOT effective in the treatment of visceral pain (arising from the abdomen, kidney, heart).  NOTE that caffeine will increase the efficacy of ASA by about 30% (it will also increase the analgesic activity of  other NSAIDs).  However, the ability of caffeine to increase the secretion of gastric acid will contribute to potential GI damage.  ASA is effective in mild to moderate headache and sports injuries such as sprains, strains, and minor joint damage.  The anti-inflammatory actions of ASA make it useful in the treatment of rheumatoid and osteo-arthritis (RA, OA).  All of the anti-inflammatory and most of the analgesic effects are presumed to be mediated through COX II activity.

Anti-pyresis-- ASA is the most effect agent in lowering elevated temperatures.  There is much debate over the value of treating fever.  However, the potential for serious (even lethal) damage with profound hyperpyrexia necessitates the value of anti-pyretic therapy.  ASA is effective in inhibiting the production of PGE₂ , which is produced by interleukin 1 in response to a pyrogen (agent that increases temperature).  NOTE, in the schematic below, that IL-1 also mediates fever.  Therefore, ASA may lower, but not totally abolish, a fever.

Anti-platelet -- This action of ASA is primarily dependent upon inhibition of COX I, decreasing TXA₂ and therefore the ability of platelets to aggregate.  It is used prophylactically to decrease thrombosis and the risk of cardiovascular injury in those patients at risk and following a history of transient ischaemic attacks, unstable angina, myocardial infarction, and coronary artery bypass grafts.  Following MI, ASA has been associated with a 40% reduction in the occurrence of a second MI.

Antiplatelet -- effective at doses as low as 80 mg twice weekly
Analgesic -- 300 - 600 mg every four hours, p.r.n.
Anti-inflammatory -- 3200 - 3600 - 4000 mg, in divided doses, t.i.d.
Uricosuric -- 5000 mg daily

GI upset with nausea, pain -- probably a direct effect but may also reflect decrease PG
Hepatic -- mild asymptomatic hepatitis if the patient is predisposed.
Renal -- decrease in GFR, again if the patient is predisposed.
Hypersensitivity -- usually manifests as bronchoconstriction.  This is especially true with asthmatics and is probably LT mediated.
 
Reye's Syndrome -- There is a strong (yet unproven) correlation between aspirin use and the development of Reye's Syndrome in children and young adolescents.  There must be some viral infection present (most notably varicella or chicken pox and influenza viruses) to precipitate the Syndrome.  It is presumed to arise from mitochondrial damage (among its effects, ASA is know to uncouple mitochondrial oxidative phosphorylation reactions) which lead to severe hepatic injury, encephalopathy, and death.  ASA use is CONTRAINDICATED in any child who may have a viral infection.

ASA is also CONTRAINDICATED in patients with haemophilia.

Treatment -- The clinician should:
1) limit further absorption of salicylates with activated charcoal,

2) hasten its elimination with intravenous sodium bicarbonate which may also help correct any acid/base imbalances or, if ineffective, haemodialysis, and

3) provide supportive care in the form of IV fluids, cold baths for pyrexia.

Another chronic toxicity that has been observed with some NSAIDs and saliclyates in particular is male reproductive toxicity.  Chronic administration may decrease sperm cell count and motility, thus decreasing the fertility of the male.  This is an apparently reversible effect, although the time required for full recovery of spermatogenesis may comprise months to years.  The salicylates that are more prone to cause this reproductive toxicity include sulphasalazine and mesalamine.  These effects are presumed to be mediated by the reduction in prostaglandin synthesis.

Methyl salicylate -- Oil of Wintergreen is present in locally applied ointments and creams.  Of note is the extreme toxicity of this compound.  Due to its high lipophilicity, as little as 4 ml of the oil may be fatal to children

Salsalate (salicylsalicylic acid) is metabolised to SA.

Na Thiosalicylate -- is an injectable form of SA.

Choline salicylate -- is an oral liquid dosage form of SA.

Mesalamine (5-aminosalicylic acid) -- used primarily for inflammatory bowel disease (IBD).  One formulation of this drug is available as a rectal suppository and retention enema.  Since it is inactivated before reaching the lower colon, the oral preparation requires formulation in polymer-coated spheres.

Olsalazine -- a dimer of 5-aminosalicylic acid, this agent is used primarily for IBD and Crohn's disease.

Sulphasalazine -- a covalently linked complex of mesalamine and sulphapyridine.  Used in IBD and Crohn's disease.

Diflunisal -- This drug is not converted to SA, but is, rather, a derivative of SA.  It exhibits greater anti-inflammatory effects than ASA but has little anti-pyretic effects (presumably through its relative inability to cross the blood brain barrier).  It is used for RA, OA, and sports injuries.  It produces less gastrointestinal and antiplatelet effects that ASA, probably by less direct acidity in the stomach and lack of acetylation binding to COX I, respectively.

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