Non-opioid analgesics

NSAIDs - The COX Blockers

• Mechanism: Inhibit cyclooxygenase (COX) enzymes, blocking prostaglandin (PG) and thromboxane (TXA₂) synthesis from arachidonic acid.
  • COX-1 (Constitutive): Protects gastric mucosa, supports renal function, promotes platelet aggregation.
  • COX-2 (Inducible): Mediates inflammation, pain, and fever.

• Classes & Agents:

  • Non-selective (COX-1 & COX-2): Ibuprofen, Naproxen, Indomethacin, Ketorolac.
  • COX-2 Selective: Celecoxib (less GI toxicity, ↑ CV risk).
  • Irreversible (Aspirin): Unique cardioprotective antiplatelet effect.

• Key Adverse Effects:

  • GI: Gastritis, ulcers, bleeding (due to ↓ protective PGs).
  • Renal: ↓ GFR, acute kidney injury, interstitial nephritis.
  • CV: ↑ BP, edema, ↑ thrombosis risk (especially COX-2 selective).

⭐ Aspirin toxicity classically presents with a mixed respiratory alkalosis (early stimulation of medullary respiratory center) and a high anion gap metabolic acidosis (late). Tinnitus is a common early sign.

Acetaminophen - The Liver's Nemesis

• Mechanism: Reversibly inhibits cyclooxygenase (COX), mostly in the CNS. Inactivated peripherally, so it lacks significant anti-inflammatory effects compared to NSAIDs.
• Use: Antipyretic and analgesic. Used when NSAIDs are contraindicated (e.g., peptic ulcer disease, renal disease, bleeding risk).
• Toxicity: Overdose causes severe hepatotoxicity. The toxic metabolite, N-acetyl-p-benzoquinone imine (NAPQI), depletes glutathione stores, leading to hepatocellular necrosis.

  ⭐ The Rumack-Matthew nomogram is used to assess hepatotoxicity risk post-ingestion and guide the need for N-acetylcysteine therapy.

• Antidote: N-acetylcysteine (NAC) regenerates glutathione, which detoxifies NAPQI. Most effective when given within 8-10 hours of ingestion.

Aspirin - The Platelet Poison

• MOA: Irreversibly inhibits cyclooxygenase (COX-1 and COX-2) via acetylation.
  • Blocks synthesis of prostaglandins & thromboxane A₂ (TXA₂).
• Dose-Dependent Effects:
  • Low (<300 mg/day): ↓ platelet aggregation.
  • Intermediate (300-2400 mg/day): Antipyretic & analgesic.
  • High (2400-4000 mg/day): Anti-inflammatory.
• Kinetics: Follows zero-order elimination at high, toxic doses.
• Adverse Effects:
  • GI bleeding/ulcers, tinnitus (salicylism).
  • ⚠️ Reye's syndrome in children with viral illness.

⭐ Clinical Pearl: Due to irreversible inhibition, the antiplatelet effect lasts for the lifespan of the platelet (~7-10 days).

High‑Yield Points - ⚡ Biggest Takeaways

• Acetaminophen acts centrally; its overdose, causing hepatotoxicity, is treated with N-acetylcysteine.
• NSAIDs non-selectively block COX-1 and COX-2, risking GI ulcers, nephrotoxicity, and cardiovascular events.
• Aspirin is an irreversible COX inhibitor with antiplatelet effects; it can cause Reye's syndrome in children.
• Celecoxib, a selective COX-2 inhibitor, spares the GI tract but increases thrombotic risk and carries a sulfa allergy warning.
• Ketamine, an NMDA receptor antagonist, provides potent analgesia and dissociative anesthesia.