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CHAPTER 2-118: NONSTEROIDAL ANTI-INFLAMMATORY DRUGS

Craig Smollin

INTRODUCTION

The nonsteroidal anti-inflammatory drugs (NSAIDs) are a chemically diverse group of agents that have similar pharmacologic properties and are widely used for their anti-inflammatory, antipyretic, and analgesic properties (Table II–43). Overdose by most of the agents in this group usually produces only mild GI upset. However, toxicity may be more severe after overdose with oxyphenbutazone, phenylbutazone, mefenamic acid, piroxicam, or diflunisal.

TABLE II–43.NSAIDs
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TABLE II–43. NSAIDs
Drug Maximum Daily Adult Dose (mg) Half-life (h) Comments

Carboxylic acids

 Bromfenac sodium

 

150

 

1–2

 

Chronic use associated with severe liver injury.
 Carprofen 4 mg/kg (PO or SC) 4–10 (PO) 12 (IV) Approved for use in dogs only.
 Diclofenac 200 2  
 Diflunisal 1, 500 8–12 Overdose produces toxicity resembling salicylate poisoning
 Etodolac 1,000 7  
 Fenoprofen 3, 200 3 Acute renal failure.
 Ibuprofena 3, 200 2–4 Massive overdose may cause coma, renal failure, metabolic acidosis, and cardiorespiratory depression.
 Indomethacin 200 3–11  
 Ketoprofen 300 2–4 Large overdoses may cause respiratory depression, coma, and seizures.
 Ketorolac 40 (PO) 60–120 (IV) 4–6 High risk for renal failure.
 Meclofenamate 400 1–3  
 Mefenamic acid 1,000 2 Seizures, twitching.
 Naproxena 1, 500 12–17 Seizures, acidosis.
 Oxaprozin 1, 800 42–50  
 Sulindac 400 7–16 Extensive enterohepatic recirculation.
 Tolmetin 1, 800 1  

Enolic acids

 Nabumetone

 

2,000

 

24

  
 Oxyphenbutazone 600 27–64 Seizures, acidosis.
 Phenylbutazone 600 50–100 Seizures, acidosis.
 Piroxicam 20 45–50 Seizures, coma.
 Meloxicam 15 15–20  

COX-2 inhibitors

 Celecoxib

 

400

 

11

  
 Rofecoxib 50 17 Removed from US market owing to concern for increased risk for cardiovascular events.
 Valdecoxib 40 8–11 Removed from US market in 2005 owing to concern for increased risk for cardiovascular events and serious skin reactions.

aCurrently available in the United States as nonprescription formulations.

MECHANISM OF TOXICITY

  1. NSAIDs produce their pharmacologic and most toxicologic effects by inhibiting the enzyme cyclooxygenase (isoforms COX-1 and COX-2); this results in decreased production of prostaglandins and decreased pain and inflammation. Central nervous system, hemodynamic, pulmonary, and hepatic dysfunction also occurs with some agents, but the relationship to prostaglandin production remains uncertain. Prostaglandins are also involved in maintaining the integrity of the gastric mucosa and regulating renal blood flow; thus, acute or chronic intoxication may affect these organs.

  2. The newest generation of NSAIDs, known as the COX-2 inhibitors, selectively inhibit the COX-2 isoform, with no COX-1 inhibition at therapeutic doses. Because COX-1 is involved in GI mucosal protection, the likelihood of GI bleeding is less with these drugs than with conventional NSAIDs. However, COX-2 selective inhibitors have been associated with an increased risk of cardiovascular disease (both rofecoxib and valdecoxib were voluntarily withdrawn from the US market in 2004 for this reason).

  3. Pharmacokinetics. NSAIDs are generally well absorbed, and volumes of distribution are relatively small (eg, 0.15 L/kg for ibuprofen). COX-2 inhibitors have larger volumes ...

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