STEPTRACKERPHARMACOLOGY | INFLAMMATION & MSK | HIGH-YIELD REVIEW

NSAIDs, Acetaminophen & Aspirin

COX inhibitors relieve pain, fever and inflammation by cutting prostaglandin synthesis — which also explains their gut, kidney, platelet and pregnancy toxicities.

FOCUS ON
COX-1 (constitutive): gastric mucus, renal afferent dilation, platelet TXA₂. COX-2 (inducible): inflammation, pain, fever; endothelial PGI₂. Nonselective NSAIDs (ibuprofen, naproxen, indomethacin, ketorolac, diclofenac): reversible; adverse — peptic ulcer/GI bleed, AKI (afferent constriction), interstitial nephritis, papillary necrosis, ↑ K⁺, Na⁺/fluid retention (↑ BP, HF), ↑ CV events, AERD, premature ductus closure (avoid after 20 weeks: oligohydramnios). Indomethacin: closes PDA, gout, pericarditis. Celecoxib (COX-2): less GI bleed, ↑ MI/stroke risk, sulfa. Aspirin: irreversible acetylation; low dose antiplatelet, high dose anti-inflammatory; salicylate toxicity — tinnitus, respiratory alkalosis then anion-gap metabolic acidosis, hyperthermia, AMS → bicarbonate (urine alkalinization), dialysis; Reye syndrome in children. Acetaminophen: central COX inhibition, no anti-inflammatory/antiplatelet effect; overdose → NAPQI depletes glutathione → centrilobular necrosis → N-acetylcysteine (Rumack-Matthew nomogram at 4 h).
DRUG
MECHANISM
USE
ADVERSE · NOTES
Ibuprofen · naproxen
Reversible COX-1 and COX-2 inhibition
Pain, fever, inflammation, dysmenorrhea, gout
GI bleeding, AKI, ↑ BP, HF exacerbation; ibuprofen blocks aspirin's antiplatelet effect
Indomethacin
Potent nonselective COX inhibitor
PDA closure, acute gout, pericarditis, hemicrania, preterm labor
GI, renal toxicity, headache
Ketorolac
Parenteral NSAID
Short-term severe pain (≤ 5 days), renal colic
High GI/renal risk
Celecoxib
Selective COX-2 inhibitor
Arthritis in GI-bleed-risk patients
↑ MI/stroke (↓ PGI₂, TXA₂ intact), sulfa allergy, renal effects
Aspirin (low dose)
Irreversible COX-1 acetylation in platelets
ACS, secondary prevention, preeclampsia prevention
GI bleed; Reye syndrome in children
Aspirin (high dose)
COX-1/2 inhibition; uricosuric at very high dose, retains urate at low dose
Rheumatic fever, Kawasaki (with IVIG)
Tinnitus, hearing loss, metabolic acidosis
Salicylate overdose
Stimulates respiratory center; uncouples oxidative phosphorylation
Early respiratory alkalosis → mixed AG acidosis; hyperthermia, tinnitus, AMS
Sodium bicarbonate (alkalinize urine), glucose, hemodialysis
Acetaminophen
Central COX inhibition (weak peripherally)
Pain and fever; children (no Reye risk); pregnancy
Hepatotoxicity > 4 g/day or less with alcohol, malnutrition
Acetaminophen overdose
CYP2E1 → NAPQI; glutathione depleted
Nausea day 1, ↑ LFTs day 2–3, liver failure day 3–5
N-acetylcysteine (best < 8 h); nomogram uses 4-h level
NSAID renal effects
↓ PGE₂/PGI₂ → afferent constriction; ↓ renin
AKI in volume-depleted, CKD, HF, cirrhosis, ACEi users
Hyperkalemia, type 4 RTA-like state, AIN, papillary necrosis
NSAIDs in pregnancy
Fetal prostaglandins keep ductus open, support fetal kidney
Avoid after 20 weeks (oligohydramnios), after 30 weeks (ductus closure)
Acetaminophen preferred
Aspirin-exacerbated respiratory disease
COX block shunts arachidonic acid to leukotrienes
Asthma + nasal polyps + NSAID sensitivity
Montelukast, aspirin desensitization

Mechanism — acetaminophen overdose

Glucuronidation, sulfation saturated
→
More goes through CYP2E1 → NAPQI(↑ with alcohol, isoniazid)
→
Glutathione used up
→
Zone 3 (centrilobular) necrosisNAC restores glutathione

COX-1 vs COX-2 effects

ACTION
COX-1
COX-2
Stomach protection
Yes
Minor
Platelet TXA₂
Yes
No
Inflammation, pain
Some
Yes
Endothelial PGI₂
Some
Yes

How it's tested

COMMON CONFUSIONSalicylate toxicity gives a mixed picture: early respiratory alkalosis (central stimulation), then anion-gap metabolic acidosis.
THE TRAPA normal LFT panel early after acetaminophen overdose doesn't exclude toxicity — use the timed level on the nomogram and give NAC if in doubt.
YOUR APPROACHNeed anti-inflammatory? NSAID (check GI, renal, CV, pregnancy). Need only pain/fever relief? Acetaminophen (check liver).

If you see… think…

Tinnitus, tachypnea, fever, AG acidosis → salicylate toxicity
Liver failure days after an overdose, centrilobular necrosis → acetaminophen
Antidote that regenerates glutathione → N-acetylcysteine
Fever in a child with influenza — which antipyretic → acetaminophen (avoid aspirin)
Closing a PDA in a preterm infant → indomethacin (or ibuprofen)
AKI after NSAID in a patient on ACEi and diuretic → afferent constriction
NSAID with less GI bleeding but ↑ MI risk → celecoxib
Asthma, nasal polyps, NSAID reaction → AERD
Oligohydramnios after mid-pregnancy NSAID use → fetal renal effect
Irreversible COX inhibitor → aspirin