DOTT Notes: NSAIDs (Nonsteroidal Anti-inflammatory Drugs)

D - Drug Name & Classification

Chemical Classes (Katzung classifies them as):

Almost all NSAIDs are weak organic acids - the exception is nabumetone (a ketone prodrug).

O - Other Info (Mechanism & Pharmacokinetics)

Mechanism of Action

• Primary: Inhibition of cyclooxygenase (COX) enzymes → blocks conversion of arachidonic acid → prostaglandin G2 (PGG2) → prostaglandin H2 (PGH2) → downstream prostaglandins/thromboxane/prostacyclin
• Result: Antipyretic + Analgesic + Anti-inflammatory effects
• Additional mechanisms: Inhibition of chemotaxis, ↓ IL-1 production, ↓ free radical/superoxide production, interference with calcium-mediated intracellular events

COX Isoforms - Key Distinction:

Why COX-2 Selective Inhibitors are Prothrombotic:

• Platelets use COX-1 only → produce TXA2 (pro-aggregation, vasoconstriction)
• Vascular endothelium uses COX-2 → produce PGI2/prostacyclin (anti-aggregation, vasodilation)
• Coxibs block vascular PGI2 WITHOUT blocking platelet TXA2 → net prothrombotic state → ↑ MI/stroke risk

Aspirin is Unique:

• Irreversibly acetylates and blocks COX (both COX-1 and COX-2)
• All other NSAIDs are reversible inhibitors
• Low-dose aspirin (75-325 mg) → irreversible platelet COX-1 inhibition → antiplatelet effect lasting platelet lifespan (~7-10 days)

Pharmacokinetics (General):

• Well absorbed orally; food does not significantly reduce bioavailability
• Highly protein-bound (~98%) - usually to albumin
• Most are racemic mixtures (exception: naproxen is a single enantiomer; diclofenac has no chiral center)
• Metabolism: mainly by CYP3A or CYP2C families in the liver
• Elimination: mainly renal (urine) with some biliary excretion and enterohepatic circulation
• GI tract irritation correlates with degree of enterohepatic circulation
• All accumulate in synovial fluid with repeated dosing

Key Half-Lives:

T - Toxicity / Adverse Effects

GI Toxicity (most common):

• Peptic ulcers, GI bleeding, GI perforation
• Mechanism: ↓ COX-1 → ↓ prostaglandins (PGE2, PGI2) → ↓ mucosal protection (↓ mucus, ↓ bicarbonate, ↓ blood flow)
• Risk ↑ with: higher dose, longer duration, concurrent steroids or anticoagulants, H. pylori, elderly
• Coxibs (celecoxib) have ↓ GI risk but not zero
• Prevention: co-prescribe PPIs (omeprazole) or misoprostol

Renal Toxicity:

• Prostaglandins normally maintain renal afferent arteriole dilation (esp. in volume-depleted states)
• NSAIDs → ↓ renal PGs → ↓ GFR, sodium/water retention, edema, hypertension, AKI
• Coxibs have equal renal toxicity to non-selective NSAIDs
• Avoid in: CKD, volume depletion, heart failure, cirrhosis

Cardiovascular:

• All NSAIDs (including coxibs) → ↑ risk of MI, stroke, hypertension
• Coxibs particularly prothrombotic (↓ PGI2 without ↓ TXA2 - see mechanism above)
• Rofecoxib (Vioxx) and valdecoxib were withdrawn due to ↑ CV events
• Naproxen appears to have the most favorable CV profile among NSAIDs
• FDA black box warning: strengthened 2015 - all non-aspirin NSAIDs ↑ risk of serious CV events

Hematological:

• All non-selective NSAIDs → reversible ↓ platelet aggregation
• Aspirin → irreversible platelet inhibition (stop 7-10 days before surgery)
• Coxibs do NOT affect platelet function at therapeutic doses

Hepatotoxicity:

• Elevated liver enzymes (aminotransferases)
• Diclofenac and sulindac have highest incidence of liver enzyme elevations
• Rare but serious hepatotoxicity possible

Respiratory:

• Aspirin-exacerbated respiratory disease (AERD): aspirin/NSAID-induced bronchoconstriction in susceptible asthmatic patients
• Mechanism: COX inhibition → ↑ arachidonic acid shunted to lipoxygenase (LOX) pathway → ↑ leukotrienes → bronchoconstriction
• Nonacetylated salicylates (sodium salicylate, salsalate) are safer in these patients

CNS:

• Headache, dizziness, tinnitus (salicylism/toxicity)
• Indomethacin: highest CNS toxicity (headache, dizziness, depression)
• Flurbiprofen: rarely causes cogwheel rigidity, ataxia, tremor, myoclonus

Reproductive / Obstetric:

• COX-2 is required for ovulation and implantation → NSAIDs may → reversible infertility
• Avoid in pregnancy (especially ≥30 weeks): risk of premature closure of ductus arteriosus
• Indomethacin is used off-label as a tocolytic but with caution
• Aspirin: low dose is safe and used in pregnancy (e.g., pre-eclampsia prevention)

Hypersensitivity / Allergy:

• Cross-reactivity between aspirin and other NSAIDs common in AERD
• Celecoxib: sulfonamide allergy caution (benzenesulfonamide structure)

Salicylate Toxicity (Salicylism):

• Mild: tinnitus, hearing loss, nausea, vomiting
• Severe: respiratory alkalosis → metabolic acidosis, hyperthermia, delirium, coma
• Treatment: urine alkalinization (↑ ionization → ↓ reabsorption), hemodialysis in severe cases

T - Therapeutic Uses

Indications:

Contraindications:

• Active peptic ulcer disease
• Renal impairment / AKI risk states (volume depletion, HF, CKD)
• AERD / aspirin-sensitive asthma (for most NSAIDs)
• Third trimester of pregnancy
• Prior CABG surgery (celecoxib CI)
• Known CVD (caution/avoid coxibs)
• Sulfonamide allergy (celecoxib)

Drug Interactions:

High-Yield Exam Points

1. Aspirin is the only NSAID that irreversibly inhibits COX - all others are reversible.
2. Coxibs spare COX-1 → ↓ GI toxicity, no antiplatelet effect, but ↑ CV risk (↓ PGI2).
3. Renal toxicity is equal for coxibs and non-selective NSAIDs.
4. Indomethacin = most potent anti-inflammatory NSAID; most CNS toxicity; drug of choice in acute gout and ankylosing spondylitis; used for PDA closure.
5. Tolmetin does NOT work for gout (unique exception).
6. Naproxen = best cardiovascular safety profile among non-selective NSAIDs.
7. Diclofenac/sulindac = highest hepatotoxicity risk.
8. Piroxicam = longest half-life (57h) among non-selective NSAIDs → once daily but ↑ GI risk.
9. AERD = aspirin-exacerbated respiratory disease: COX inhibition → ↑ leukotrienes → bronchospasm.
10. NSAIDs in pregnancy ≥30 weeks → premature closure of ductus arteriosus (CI).
11. Nabumetone = only NSAID that is NOT a weak acid (it's a ketone prodrug).
12. Celecoxib = sulfonamide-containing → caution in sulfa allergy; metabolized by CYP2C9.
13. Low-dose aspirin + NSAIDs = ibuprofen can competitively block aspirin's antiplatelet effect (give aspirin first, wait 30 min before ibuprofen).
14. Nonacetylated salicylates (salsalate, sodium salicylate) = do NOT inhibit platelets; safer in AERD and renal dysfunction.

• D - Drug name, chemical classification, and individual agents
• O - Other info: mechanism of action (COX-1 vs COX-2), pharmacokinetics, half-lives, protein binding
• T (first) - Toxicity and adverse effects, organ by organ
• T (second) - Therapeutic uses, indications, contraindications, and drug interactions

• Aspirin's irreversible COX inhibition (unique among NSAIDs)
• Coxibs reduce GI risk but NOT renal risk
• The prothrombotic mechanism of coxibs (↓ PGI2 without ↓ TXA2)
• Indomethacin for gout/AS/PDA, but tolmetin fails in gout
• Ibuprofen blocking aspirin's antiplatelet effect if given first