Other NSAIDs share the same mechanism of action as ASA with the exception that all other NSAIDs are reversible inhibitors of COX.  Additional actions that may contribute to their anti-inflammatory effects include decreased chemotaxis of inflammatory cells, down-regulation of interleukin-1, and decreased calcium-mediated cellular effects.

The individual agents may vary in the specificity of their effects, but all, in general, will exhibit anti-inflammatory, anti-pyretic, and analgesic activity.  Typically, they are not as effective as ASA in inhibition of platelet aggression.  Many, along with ASA, are uricosuric (enhance the excretion of uric acid).

General indications for all NSAIDS include rheumatoid arthritis (RA), osteoarthritis (OA), and ankylosing spondylitis (AS), although the specific approved indications may vary from drug to drug.

All NSAIDs are relatively well absorbed, highly plasma protein bound, metabolised, and eliminated renally.  They share with ASA the side effects of GI upset, a tendency to prolong bleeding time, blood dyscrasias (that range from haemolytic anaemia, aplastic anaemia, and agranulocytosis to thrombocytopaenia and leukopaenia and will vary from drug to drug).  All NSAIDs have the potential to cause nephrotoxicity (although the specific nephropathy may range from acute renal failure to interstitial nephritis to nephrotic syndrome) and elevated liver enzymes and hepatoxicity.  Co-administration of different NSAIDs will often result in decreased efficacy by either compound.

Ibuprofen -- less GI and platelet effects than ASA -- rarely will produce agranulocytosis and aplastic anaemia
Naproxen -- slightly prolongs bleeding time, longer half-life
Fenoprofen -- slightly greater risk of interstitial nephritis
Flurbiprofen -- available for ophthalmology -- lower intraoperative miosis and inflammation
Ketoprofen -- inhibits both COX and lipoxygenase (LOX)
Oxaprozin -- long half-life, once daily dosing, uricosuric
Diclofenac -- potent, greater COX inhibition that some NSAIDs, may inhibit LOX, may increase liver enzymes
Sulindac -- prodrug, may produce a Stevens-Johnson type reaction, blood dyscrasias, nephrotic syndrome, and hepatotoxicity
Tolmetin -- short half-life
Etodolac -- less GI effects than many NSAIDs, uricosuric
Nabumetone -- prodrug, long half-life, once daily dosing, less GI side effects, relatively selective for COX II
Meclofenamate -- may prolong bleeding times, cause haemolytic anaemia, contraindicated in pregnancy
Mefenamic acid -- less anti-inflammatory effects than ASA, more GI effects
Piroxicam -- long half-life (up to 76 hours), once daily or every other or third day dosing
Carprofen -- another me-too, widely used in veterinary medicine
Phenylbutazone -- strongly uricosuric, agranulocytosis, aplastic anaemia, nephrotoxic, rash
Azapropazone -- fewer blood dyscrasias that PBZ
Ketorolac -- strongly analgesic (equipotent with morphine), used primarily for analgesia, especially good both IV and PO for post-operative pain.
Indomethacin -- very potent, also decreases leukocyte migration, and inhibits LOX, especially effect in acute gout, used IV to close a patent ductus arteriosus, high incidence of GI side effects, blood dyscrasias, and nephrotoxicity

Cyclo-oxygenase II Specific Inhibitors -- Celecoxib (Celebrex®) and rofecoxib (Vioxx®) are new agents that have greater specificity for the COX II isozyme of cyclo-oxygenase.  Recall that it is this isozyme that is expressed during and primarily responsible for prostaglandin-mediated inflammatory reactions.  Clinical trials have indicated an efficacy equal to that of other NSAIDs in reducing joint pain and swelling.  These agents are approved for the treatment of both osteo- and rheumatoid-arthritis, however they are also being investigated for the treatment of other types of pain.  The early side effect profiles of these agents indicated a significantly reduced incidence of gastric ulceration relative to non-selective COX inhibitors, however since the release of celecoxib, several patients have presented with severe GI bleeding.  This could reflect an inappropriately high dose or it could be acting in a manner similar to the non-selective COX inhibitors.  There appears to be no alteration in platelet aggregation or prothrombin time.  Celecoxib and rofecoxib may possess the same potential for nephrotoxicity as other NSAIDs, therefore the patient should be monitored for renal disease or damage.  The dose for celecoxib is 100 to 200 mg once a day to twice daily.

Derivatives of coal tar (acetanilide, phenacetin, antipyrine) all inhibit COX to produce analgesic and antipyretic effects.  However, their nephrotoxicity caused their removal from the market.  Paracetamol (acetaminophen, APAP), an active metabolite of acetanilide and phenacetin) is the only drug of the class currently on the market.

APAP is well absorbed orally.  It is not as highly plasma protein bound as the NSAIDs.  It is metabolised extensively in the liver by conjugation reactions.  The metabolism of APAP will be covered in more depth below.

APAP presumably works through inhibition of COX.  It produces analgesia and antipyresis at levels comparable to ASA in some individuals.  However, there is a variable response depending upon the individual and some patients may not respond to either effect of APAP.  APAP does not affect platelet aggregation nor does it possess uricosuric effects.  Its anti-inflammatory effects are negligible.  The exact reason for this lack is not known, but theories suggest that it does not inhibit COX in the presence of peroxides (which are present in chronic inflammation as with arthritis) or that it does not decrease neutrophil activation as other NSAIDs do at least minimally.

APAP is the preferred analgesic/antipyretic in patients who are hypersensitive or allergic to ASA, are haemophilic, have peptic ulcer disease, are taking NSAIDs for chronic inflammatory diseases, or children with viral infections.
 

Paracetamol Toxicity
The fatal adult dose of paracetamol is stated at 140 mg/Kg which corresponds to 9.8 G of drug for a 70 Kg person or approximately 30 325 mg tablets.  However as little as 3 G of drug per day for one (1) year may produce hepatic damage.  Therefore, standard, therapeutic doses of APAP may produce transient, reversible increases in hepatic enzymes and chronic ingestion may cause irreversible hepatotoxicity.  Higher doses may produce dizziness, excitement, and disorientation.  The primary toxic response is hepatic in nature and may first manifest as nausea, vomiting, diarrhoea, and abdominal pain followed by severe hepatotoxicity, hepatic necrosis, and renal tubular necrosis.  The toxicity is due to the accumulation of a toxic intermediary metabolite when normal metabolic pathways have become saturated due to the high levels of APAP.  The intermediary is normally conjugated to an inactive form by glutathione.  When GSH becomes depleted, the reactive intermediate accumulates.
 

Treatment of APAP Toxicity
N-Acetylcysteine -- This compound may either scavenge the toxic intermediate directly and/or regenerate additional GSH.  It is given IV (Europe) or PO (USA) as a 5% solution within 36 hours of ingestion.  NOTE that it is most effective if given within 10 hours of ingestion.  The loading dose is 140 mg/Kg, then 70 mg/Kg q4h for 17 doses or until the risk of hepatoxicity has passed.  NOTE that this is based upon the blood level of APAP.  The liver is at risk for irreversable damage if the plasma level of APAP is approximately 200 mcg/ml 4 hours post ingestion.  The risk for damage continues linearly over time (as a function of the log plasma concentration) such that 24 hours post ingestion, the risk for hepatotoxicity is still present when plasma APAP is over 5 mcg/ml.  The side effects of N-acetylcysteine are nausea/vomiting/diarrhoea and skin rash.  It also has a strong odour.  It should be made fresh from a stock solution for each dose and should not be used if discolouration has occurred.   Investigative use of parenteral N-acetylcysteine has been performed in the U.S.A. and this route of administration is becoming more popular in this country.

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