Nonsteroidal anti-inflammatory drugs (NSAIDs)

Agents

• Ibuprofen
• Diclofenac
• Indomethacin
• Naproxen
• Piroxicam
• Meloxicam
• Ketorolac
• Sulindac
• Aspirin

Mechanism of action

• Reversible inhibition of the enzymes COX-1 and COX-2 → decreased prostaglandin synthesis
• Aspirin is the exception, because it leads to irreversible COX-1 and COX-2 inhibition.

Choice

• Acetaminophen
  • For mild to moderate pain
  • Safe
  • Can be used by children and pregnant women
• Ibuprofen
  • For acute, mild to moderate pain
  • Works fast
• Naproxen
  • Strong and long-lasting
  • May affect wound healing
• Aspirin
  • Only salicylate among NSAIDs
  • Commonly used as antiplatelet agents, instead of Pain management or anti-inflammatory agents
  • See Salicylate poisoning for overdose effects
• For mild to moderate pain accompanied by swelling and inflammation, non-steroidal anti-inflammatory drugs (such as ibuprofen, aspirin, and naproxen) are more effective.

Selective COX-2 inhibitors

Agent

Celecoxib

Mechanism of action

Reversible selective inhibition of COX-2 with almost no inhibition of COX-1

Effects

• Analgesic and anti-inflammatory
• Advantages in comparison to nonselective NSAIDs
  • No antiplatelet effect: platelets only possess COX-1 and are therefore not targeted by selective COX-2 inhibitors. This means that the activity of thromboxane A2 (TXA2) is not interrupted (TXA2 normally promotes platelet aggregation).
  • Gastric mucosal cells express mostly COX-1, which is involved in maintaining a healthy gastric mucosa, so there are minimal gastrointestinal side effects and a lower risk of gastric ulcers.

Indications

• Rheumatoid arthritis, osteoarthritis

Other non-opioid Pain management

Agent

Acetaminophen

Mechanism of action

• Reversibly inhibits cyclooxygenase, mainly in the CNS
• Inactivated peripherally

Effects

• Antipyretic
• Analgesic
• No anti-inflammatory effect

Side effects

• Hepatotoxicity due to acetaminophen overdose (drug-induced hepatitis)
  • Leading cause of acute hepatic failure in the US
• Pathophysiology
  • Exhaustion of hepatic metabolic pathways causes increased formation of a toxic metabolite of acetaminophen, N-acetyl-p-benzoquinoneimine (NAPQI).
    • Glutathione initially inactivates NAPQI, but its reserves are eventually depleted, leading to NAPQI build-up.
    • NAPQI → irreversible oxidative hepatocyte injury → liver cell necrosis
• Clinical features
  • Nonspecific symptoms (nausea, vomiting, pallor lethargy) or asymptomatic in the first 24 hours after ingestion
  • Progressive liver impairment (RUQ pain, liver enlargement and tenderness, abnormal liver function tests)
  • If acute liver failure does not develop, patients typically begin to recover within 2 weeks after ingestion.
  • Acute kidney failure occurs in approx. 50% of patients with acute hepatic failure.
• Antidote: PO or IV N-acetylcysteine (NAC)
  • NAC replenishes glutathione stores in the liver