Celecoxib & Thrombosis
Selective COX-2 inhibitor spares gastric mucosa (COX-1), but inhibits endothelial PGI2 (prostacyclin) without inhibiting platelet TXA2 -> increases cardiovascular thrombotic risk.
Acetaminophen Antidote
Toxic metabolite NAPQI depletes glutathione; N-acetylcysteine (NAC) restores hepatic glutathione reserves. Rumack-Matthew nomogram guides 4-hour levels.
Acute vs Chronic Gout
Acute flare: Indomethacin (NSAIDs), Colchicine (inhibits tubulin polymerization), or intra-articular steroids. Chronic prevention: Allopurinol (xanthine oxidase inhibitor).
Opioid Non-Tolerant Effects
Tolerance develops to all opioid effects EXCEPT Miosis (pinpoint pupils) and Constipation. ALWAYS prescribe bowel regimen (stimulant laxative) with chronic opioids.
NSAIDs, Acetaminophen & COX-2 Inhibitors
Inhibition of cyclooxygenase enzymes alters prostaglandin and prostacyclin balance:
| Analgesic Class | Representative Agents | Mechanism of Action | Adverse Reactions & Key Board Pearls |
|---|---|---|---|
| Non-Selective NSAIDs | Ibuprofen, Naproxen, Indomethacin, Ketorolac | Reversibly inhibit both COX-1 and COX-2 → ↓ prostaglandin synthesis | Gastric ulcers, acute interstitial nephritis, afferent arteriolar vasoconstriction → acute kidney injury; Indomethacin closes PDA |
| Selective COX-2 Inhibitor | Celecoxib | Selectively inhibits inducible COX-2; spares constitutive COX-1 in gastric mucosa and platelets | Reduced ulcer risk; increased cardiovascular thrombotic risk; contains sulfonamide moiety (sulfa allergy) |
| Acetaminophen (APAP) | Paracetamol / Tylenol | Central COX inhibitor; weak peripheral anti-inflammatory activity; antipyretic and analgesic | Overdose metabolizes via CYP2E1 to toxic NAPQI → centrilobular hepatic necrosis; Antidote: N-acetylcysteine (NAC) within 8–10 hours |
| Aspirin (Salicylate) | Acetylsalicylic acid | Irreversible COX-1 > COX-2 acetylation; at high doses causes uncoupling of oxidative phosphorylation | Overdose: Mixed respiratory alkalosis and high anion gap metabolic acidosis; Reye syndrome in viral illnesses in children (avoid aspirin) |
Gout Therapeutics & Opioid Receptor Pharmacology
Managing inflammatory crystal arthropathies and acute severe pain involves targeted molecular mechanisms:
| Therapeutic Agent | Clinical Role | Mechanism of Action | High-Yield Clinical Pearls |
|---|---|---|---|
| Colchicine | Acute Gout flare (< 36 hrs onset) and Pericarditis | Binds tubulin → inhibits microtubule polymerization; impairs leukocyte chemotaxis and phagocytosis | Diarrhea, abdominal cramps, myelosuppression, neuromyopathy; narrow therapeutic window |
| Allopurinol / Febuxostat | Chronic Gout urate-lowering therapy | Competitively inhibits xanthine oxidase → blocks conversion of hypoxanthine → xanthine → uric acid | Do NOT start during acute flare (fluctuating levels worsen flare); Allopurinol: SJS/TEN in HLA-B*5801; severe drug interaction with 6-MP / Azathioprine |
| Morphine / Hydromorphone / Fentanyl | Severe acute pain, palliative care | Full agonists at mu-opioid receptors (coupled to Gi → closes presynaptic Ca2+ channels, opens postsynaptic K+ channels) | Respiratory depression, sedation, constipation, miosis; Reversal: Naloxone (Narcan) |
| Methadone | Opioid use disorder maintenance, neuropathic pain | Long-acting mu-opioid agonist + NMDA receptor antagonist + SNRI activity | Long, variable half-life (24–36 hrs); suppresses cravings without euphoria; high risk of QT prolongation and Torsades de Pointes |
| Buprenorphine | Opioid use disorder | Partial mu-opioid agonist with very high binding affinity; combined with naloxone (Suboxone) | Precipitates acute withdrawal if administered to patient with active full-agonist opioids in system; ceiling effect on respiratory depression |
Board Traps & Common Distractors
- Never initiate or adjust urate-lowering therapy (Allopurinol) during an acute gout flare; sudden drops in serum uric acid promote crystal dissolution and destabilization, severely exacerbating and prolonging the acute synovitis. Wait 2–4 weeks after resolution of flare.
- Co-administration of NSAIDs with ACE inhibitors and diuretics constitutes the lethal 'triple whammy' on the glomerulus (NSAIDs constrict afferent arteriole, ACEi dilates efferent arteriole, diuretics reduce renal perfusion), triggering acute renal shutdown.
- Allopurinol must be used with extreme caution in patients of Asian descent (screen for HLA-B*5801) due to severe hypersensitivity syndrome (DRESS, SJS/TEN) with high mortality.