Aspirin - mechanism & use
Irreversible COX inhibitor. Decreases thromboxane / prostaglandin (PGE2) synthesis. No-nucleus platelets can't resynthesize COX-1 (TXA2 incr. plt agg); endothelial cells can resynthesize COX-2 (prostacyclin = PGI2 decr plt agg); net effect anticoagulant.
Use: Low dose (<300mg/day) = decr. plt agg. Intermediate (300-2400) = antipyretic, analgesic. High (2400-4000) anti-inflamm.
Aspirin - toxicity
GI upset. Chronic use: can lead to ARF (PGE inhibition = decr. dilation of afferent arteriole), interstitial nephritis, upper GI bleeding. Reye's syndrome in kids with viral infection (fatty liver, encephalopathy). (Irreversible COX inhibitor)
Ibuprofen, naproxen, indomethacin, ketorolac - mechanism & use
NSAIDs. Reversible COX inhibitors (-1 and -2); block prostaglandin synthesis. Antipyretics, analgesics, anti-inflammatory. Indomethacin - close PDAs, also for acute gout
Ibuprofen, naproxen, indomethacin, ketorolac - toxicity
Renal damage (PGE inhibition = decr dilation of aff. arteriole), fluid retention, aplastic anemia, GI distress, ulcers. (Reversible COX inhibitors)
Celecoxib - mechanism & use
COX-2 selective inhibitor. Blocks inducible COX-2 in inflammatory cells, vascular endothelium, which mediates inflammation & pain (mostly promotes PGE2 pathway). Spares constitutive COX-1 (helps maintain gastric mucosa - prostaglandins). Less GI toxic effects. Used for rheumatoid arthritis & arthritis.
Celecoxib - toxicity
Increases risk of thrombosis, sulfa allergy. Less bleeding / lower incidence of ulcers (COX-1 prostaglandins preserve GI mucosa) (COX-2 inhibitor. Mech: COX-2 in vascular endothelium blocked, decreasing prostacyclin, which normally inhibits plt agg - but doesn't block TXA2 from COX-1 in platelets, like aspirin, so pro-thrombotic)
Acetaminophen - mechanism & use
Reversible COX inhibitor, mostly in CNS (inactivated peripherally). Antipyretic, analgesic, but lacks anti-inflammatory properties. Used instead of aspirin in kids with viral infection (prevent Reye's syndrome)
Acetaminophen - toxicity
Overdose = hepatic necrosis (NAPQI = metabolite; depletes glutathione & forms toxic adducts in liver. EtOH makes it worse - processed by same CYP450 (2E1) & induces, incr. NAPQI production.) N-acetylcysteine is antidote (regenerate glutathione). (Reversible COX inhibitor mostly in CNS)
Etidronate, pamidronate, alendronate, risedronate - mechanism & use
Bisphosphonates. Inhibit osteoclastic activity, reducing both formation & resorption of hydroxyapetite. For malignancy-associated hyperCa, Paget's dz of bone, post-menopausal osteoporosis.
Etidronate - incorporates into ATP, cytotoxic compound formed, rarely used (can cause osteomalacia). Risedronate, alendronate - block osteoclast mevalonate pathway (farnesyl-PP synthase - prenylation of regulatory proteins for ruffled border).
Etidronate, pamidronate, alendronate, risedronate - toxicity
Corrosive esophagitis, nausea, diarrhea. Rare osteonecrosis of jaw. Hard to absorb (1st thing in morning, lots of water, can't lay back down until after breakfast). MSK pain too (at any time in treatment). (Bisphosphonates - inhibit osteoclast activity)
Colchicine - mechanism & use
For ACUTE gout. Binds, stabilizes tubulin, inhibiting polymerization & impairing WBC chemotaxis / degranulation.
Colchicine - toxicity
GI side effects, esp. if given orally (indomethacin less toxic in acute gout). (anti-gout drug, binds / stabilizes tubulin, inhibits WBC fxn)
Probenecid - mechanism & use
For CHRONIC (not acute) gout. Inhibits reabsorption of uric acid in PCT. Also inhibits secretion of penicillin (historicla wartime use).
Allopurinol - mechanism & use
For CHRONIC (not acute) gout. Inhibits xanthine oxidase, so less conversino of xanthine to uric acid. Also used in lymphoma, leukemia to prevent tumor lysis syndrome.
Allopurinol - toxicity
Increases toxicity of azathioprine, 6-MP (both normally metabolized by xanthine oxidase).
Salicylates in gout
DON'T GIVE THEM - all but highest doses depress uric acid clearance; even 5-6 g/day have only minor uricosuric activity.
Etanercept - mechanism, use, toxicity
Recombinant human TNF receptor that binds TNF (TNF decoy reCEPTor). For RA, psoriasis, ankylosing spondylitis. No major toxicity.
Infliximab - mechanism, use, toxicity
Anti-TNF antibody. Used for Crohn's, RA, ankylosing spondylitis. Predisposes to infections (e.g. reactivation of latent TB)
Adalimumab - mechanism, use, toxicity
Directly binds TNF-alpha; used for RA, psoriasis, ankylosing spondylitis. No major toxicity