MSK & Anti-inflammatory Pharmacology

The arachidonic acid pathway and corticosteroids

One cascade, several targets. Phospholipase A2 releases arachidonic acid from membrane phospholipids. Cyclooxygenase (COX) converts it to prostaglandins, prostacyclin, and thromboxane, which mediate pain, fever, inflammation, and platelet aggregation. COX-1 is constitutive: it protects the gastric mucosa, supports renal blood flow, and makes platelet thromboxane A2. COX-2 is induced at sites of inflammation, is also constitutive in the kidney, and makes endothelial prostacyclin.

Corticosteroids act furthest upstream. They induce lipocortin (annexin A1), which inhibits phospholipase A2 and shuts down the entire arachidonic acid cascade; they also suppress NF-κB and COX-2 expression, broadly reducing inflammatory gene transcription. Chronic use causes iatrogenic Cushing syndrome: osteoporosis, hyperglycemia, immunosuppression, and adrenal suppression.

Taper glucocorticoids after prolonged use; abrupt withdrawal of a suppressed adrenal axis can precipitate adrenal crisis.

NSAIDs, aspirin, celecoxib, and acetaminophen

Nonselective NSAIDs. Ibuprofen, naproxen, indomethacin, and ketorolac reversibly inhibit COX-1 and COX-2, blocking prostaglandin synthesis for analgesic, antipyretic, and anti-inflammatory effect. Blocking COX-1 removes protective gastric prostaglandins, causing peptic ulcers and bleeding. Renal prostaglandins dilate the afferent arteriole; NSAIDs let it constrict, dropping GFR and causing acute kidney injury, especially when renal perfusion is already prostaglandin-dependent (volume depletion, heart failure, CKD). Acute interstitial nephritis and fluid retention also occur.

Aspirin. Unlike other NSAIDs, aspirin irreversibly acetylates COX-1 and COX-2. Anucleate platelets cannot resynthesize COX, so the antiplatelet effect lasts their 7–10 day lifespan. Toxicity includes tinnitus, chronic interstitial nephritis, and Reye syndrome (hepatic failure plus encephalopathy) in children with a viral illness. Overdose causes an early respiratory alkalosis from direct respiratory center stimulation, then an anion-gap metabolic acidosis; urine alkalinization with sodium bicarbonate speeds salicylate excretion.

Celecoxib. Selectively inhibits COX-2 and spares COX-1, so there is less GI ulceration and no antiplatelet effect. But it lowers endothelial prostacyclin while platelet thromboxane persists, raising cardiovascular and thrombotic risk. It contains a sulfonamide group, so sulfonamide allergy is a caution.

Acetaminophen. Reversibly inhibits COX mostly in the CNS (it is inactivated peripherally), giving analgesia and antipyresis but little anti-inflammatory or antiplatelet effect. In overdose, the saturated normal pathways shunt drug to cytochrome P450, forming NAPQI, which depletes glutathione and causes centrilobular hepatic necrosis; chronic alcohol use raises the risk. The antidote is N-acetylcysteine, which regenerates glutathione.

Gout pharmacology

Treating the flare. Acute gout is treated with NSAIDs (indomethacin), colchicine, or glucocorticoids. Colchicine binds tubulin and blocks microtubule polymerization, impairing neutrophil chemotaxis and phagocytosis; it is used for acute attacks and for prophylaxis (and in familial Mediterranean fever), is dose-limited by GI toxicity (diarrhea, nausea), and does not lower urate.

Xanthine oxidase inhibitors. Allopurinol and febuxostat block xanthine oxidase, cutting uric acid production; they are used for chronic gout and tumor lysis prophylaxis. Azathioprine and 6-mercaptopurine are also degraded by xanthine oxidase, so allopurinol raises their levels and their doses must be reduced to avoid marrow toxicity such as pancytopenia.

Uricosurics and uricases. Probenecid blocks urate reabsorption in the proximal tubule and also inhibits penicillin secretion; avoid it in urate overproducers and stone formers, whose urine is already urate-rich. Pegloticase (refractory gout) and rasburicase (tumor lysis) are recombinant uricase enzymes that convert uric acid to soluble allantoin; both can cause hemolysis in G6PD deficiency.

Timing rule. Do not start or stop urate-lowering therapy (allopurinol, febuxostat, probenecid) during an attack, because shifting urate levels can prolong or trigger flares. Start it later under colchicine cover, and continue established therapy through any flare.

DMARDs and biologics

Methotrexate. Inhibits dihydrofolate reductase, lowering tetrahydrofolate and therefore purine and thymidine synthesis; it is the anchor DMARD for rheumatoid arthritis. Toxicity includes myelosuppression, hepatotoxicity, mucositis, and pulmonary fibrosis, and it is teratogenic. Folic acid supplementation reduces toxicity, and leucovorin (folinic acid) rescue bypasses the enzyme block in normal cells.

TNF-α inhibitors. Etanercept is a TNF-α decoy receptor (a receptor–Fc fusion protein); infliximab and adalimumab are anti-TNF-α monoclonal antibodies. All treat RA, IBD, and psoriasis but can reactivate latent tuberculosis, because TNF maintains granulomas, so screen with a PPD or IGRA before starting.

Etanercept ends in -cept (a receptor decoy); the -mab drugs are monoclonal antibodies.

Other DMARDs. Leflunomide inhibits dihydroorotate dehydrogenase (pyrimidine synthesis) and is hepatotoxic and teratogenic; hydroxychloroquine requires eye monitoring for retinopathy.

Bone agents

Bisphosphonates. Alendronate and zoledronate are pyrophosphate analogs that bind hydroxyapatite; osteoclasts ingest them during resorption and undergo apoptosis. They reduce bone resorption in osteoporosis, Paget disease of bone, and hypercalcemia of malignancy.

• Pill esophagitis: take oral forms upright with a full glass of water.
• Osteonecrosis of the jaw, classically after a dental procedure.
• Atypical femoral fractures with long-term use.

Other bone drugs. Denosumab, a monoclonal antibody against RANKL, blocks osteoclast formation. Teriparatide, a recombinant PTH analog given intermittently, stimulates osteoblasts and builds new bone.