Confessions of a Knit-Wit Gout Drugs

3.2 – “Confe “Confessions ssions of a knit knit--wit”: Gout drugs (allopurinol, febuxostat, probenecid, peglotica pegloticase) se) Physiology • Purine metabolism: Nucleic acids broken down to nucleotides (purine-shaped collection plate). Purine is broken down into hypoxanthine by Xanthine oxidase (XO letter from hypo kid) → Xanthine (larger kid). Xanthine is broken down into uric acid by Xanthine oxidase, sent to kidney for excretion. • Uric acid is a poorly soluble product of purine metabolism that is generally excreted in the urine (yellow aisle = tubular lumen). Overproduction or underexcretion will result in hyperuricemia; underexcretion is more common. o Causes of increased urate production: idiopathic primary gout; myeloproliferative & lymphoproliferative disorders; tumor lysis syndrome; Lynch syndrome (HGPRT deficiency) o Causes of decreased clearance: CKD; thiazide & loop diuretics. • Gout is a metabolic disease characterized by deposits of uric acid. o Most often an initial attack of gout will occur in a single joint, classically a knee or the big toe (priest with flaming toe). Crystal precipitate induces local activation of prostaglandins & lysosomal enzymes, attracting neutrophils & increasing inflammation. o Over time, uric acid crystals can precipitate in the joints and skin, resulting in formation of tophi. o Uricemia can precipitate uric acid renal calculi, or even interstitial nephritis o Uric acid crystals are needle shaped & negatively birefringent under polarized light (knitting needles) • CPPD disease aka pseudo-gout o Calcium pyrophosphate crystal deposition disease o Presents like uric acid induced gout, but results from deposition of calcium pyrophosphate (it’s lying in looking like gout – hence “thou shall not lie”). Differentiated by microscopy: calcium pyrophosphate crystals are rhomboid-shaped & positively birefringent (blue rhomboid censor). o Deposition triggers an inflammatory response much like that seen in gout o Acute treatment is very similar to gout • Uric acid crystals can form in tumor lysis syndrome (cancer crab stained glass shattered into crystals); o most commonly occurs in treatment of aggressive lymphomas & acute lymphoblastic leukemia (white T-cell crusaders). o Allopurinol used preventatively. • Lesch-Nyhan syndrome o Deficiency of HGPRT results in excess uric acid production. o Skin and lips are common sites of deposition for uric acid crystals → pain (may be the stimulus for the self-injurious behavior) (kid poked in flesh with knitting needle) Treatment of ac acute ute gout (tr (tripping ipping over yarn) • All also suitable for CPPD • NSAIDs are first response; mediate inflammation (kid with fire extinguisher) • Glucocorticoids can be used in Tx of severe, systematic gout, depending on the level of pain (moon face). • Colchicine (chorus) o First line for acute gout. o Administered orally to relieve gout within 12-24 h o Binds intracellular tubulin, preventing polymerization into tubulin ( palm fronds; kid binding fronds in hands). Disrupts cytoskeletal function, including phagocytosis, degranulation, and neutrophil migration (blocked first responders) o Brush border cells in GI tract are sensitive → diarrhea (muddy shoes) o N/V, Abd pain Manageme Management nt of chronic gout • Goal is to prevent recurrent of episodes and to minimize risk of urate nephrolithiasis • Allopurinol (pure nun) o First line for chronic management o Inhibits XO, ↓uric acid in the body (nun grabbing XO notes) o Adverse effects ▪ May precipitate acute attack after initiating therapy. Often started with concurrent NSAID or colchicine therapy. ▪ Can interfere with breakdown of purine analogs (e.g. 6-MP, azathioprine) → increased risk of toxicity (purine rosaries) ▪ Rashes. Risk of SJS/TEN (tengu mask) ▪ DRESS syndrome, with eosinophilia (eo-slingshot, eosinophilic dress) • Febuxostat (XO -stopped) o Inhibits XO, ↓uric acid in the body (nun grabbing XO notes) o Adverse effects ▪ May precipitate acute attack after initiating therapy. Often started with concurrent NSAID or colchicine therapy. ▪ Can interfere with breakdown of purine analogs (e.g. 6-MP, azathioprine) → increased risk of toxicity (purine rosaries) ▪ Rashes. Risk of SJS/TEN (tengu mask) ▪ DRESS syndrome, with eosinophilia (eo-slingshot, eosinophilic dress) • Probenecid (Cid the probation officer) o Uricosuric agent used to manage underexcretion. Second line agents for underexcretion o Inhibits organic anion transporter, site of active transport sites of reabsorption & secretion in the PCT (preventing punk kid grabbing yarn) o Adverse effects: ▪ Increase in uric acid in urine increases risk of uric acid stones (lots of yellow yarn balls) ▪ Can inhibit the excretion of many drugs (e.g. penicillin, anionic agents, antibiotics) (penicillin pencil) ▪ Can precipitate an acute attack. Must be started 2-3 weeks after resolution of an acute attack ▪ Sulfa drug (kid throwing stinky eggs) • Aspirin (ASA umpire) o At high doses prevents reabsorption of uric acid (ump blocking yarn collector); at low doses, can block urinary excretion (kid catching yarn) o d/t need for high dosing, should never be used as treatment for hyperuricemia. • Pegloticase o Urate oxidase enzyme that converts uric acid to more water soluble allantoin (holy water – just in case) o Used in refractory gout. o Used to prevent gout symptoms in patients at high risk for tumor lysis syndrome. o Adverse effects: ▪ Can cause hemolysis in G6PD deficiency (G6PD watermelon with bite) o Can cause anaphylaxis (kid suffocating). Seen in 6-15% of patients. Must be administered IV in an inpatient setting by a qualified provider d/t high risk of severe Adverse effects (ivy around door)