4/19 Gout Drugs - Pilch Flashcards
what is gout?
associated with ______
causes of _____
acute infl responses to formation of monosodium urate cyrstals in joints/cartilage
- painful distal arthritis
- also joint destruction, subcutaneous deposits (tophi), renal calculi/damage
associated with hyperuricemia
- uric acid is major end pdt of purine metabolism
- predisposition based on:
- genetics: variants in urate transporter genes SLC2A9, ABCG2
- overproduction of uric acid (10%)
- decr renal elimination of urate salts (90%)
- diet: incr intake of purine-rich/fatty foods (12%) - poultry, red meat, fish, alcohol, soda
Western countries
M > F (3-4x)
gout dx
needle aspiration of joint during acute attack
polarized microscopy? uric acid crystals!
pathophys of gouty joint
urate crystals present in joints → phagocytosed by synoviocytes → infl mediators released!
- PG
- IL1
- lysosomal enzymes
mediators…
- attract polymorphonuclear leukocytes
- amplify infl response via LTB4, PGs
later on, mononuclear phagocytes join in and release more infl mediators
end result: MASSIVE INFL RESPONSE
pharmacotx of gout
3 goals
how? 4 mechs w exampls
goals:
- decrease infl associated with acute attack
- lower serum urate levels
- prevent recurrent flares
how? mechanisms to target
- disable leukocyte/phagocyte (PMN, MNP) migration and phagocytosis [1]
- colchicine
- NSAIDs
-
inhibit COX-mediated PG production [1]
- NSAIDs (ex. indomethacin)
-
incr uric acid excretion and breakdown [2, 3]
- excretion: uricosuric agents (prebenecid, sulfinpyrazone)
- breakdown: pegloticase
-
decr uric acid synthesis [2, 3]
- allopurinol
- febuxostat
acute gout tx:
NSAIDs
indomethacin and others like ibuprofen, naproxen, suldinac, ketoprofen (all except aspirin, salicylates, tolmetin): frontline agents for acute gout
- inhibit COX-mediated PG synthesis, phagocytosis of uric acid crustals
start tx ASAP after sx onset, take regularly until resolved
celecoxib (COX2 specific) is potentially better tolerated in pt with GI issues (ex. peptic ulcers)
acute gout tx
colchicine
- inhibits tubulin polymerization into mts
- interferes w leukocyte (PMN) and phagocyte (MNP) migration, phagocytosis
adverse effects
- n/v, abd pain
- acute tox: burning throat pain, bloody diarrhea, shock, hematuria, oliguria, neutropenia, axonal neuromyopathy
- soooo NSAIDs are used more often, but useful for pts with contraindications for NSAIDs
acute gout tx:
corticosteroids
reserved for acute gout flares if contraindicates to other tx
oral (systemic) or intraarticular inj (if no more than 2 jts)
- oral: prednisone, prednisolone
- intraarticular: triamcinolone, acetonide
lowering serum urate:
XO inhibitor
mech/ex x2
when? how?
indications
adverse effects (general)
goal: want to get under 6 mg/dL (ideally under 5)
initial tx for hyperuricemia: xanthine oxidase inhibitors
- mech: inhibit xanthine oxidase to reduce biosynth of xanthine and uric acid
- allopurinol: purine analog acting as irrev/suicide XO inhibitor
- febuxostat: non purine irrev inhibitor of XO
do not initiate tx during an attack
- can precipitate attack initially! bc urate crystals are being withdrawn from tissues!
- ONLY going to give during intercricital pd, with expectation of continuing for yrs/life
- initiate w colchicine or NSAID until steady state urate normalized to < 6
indications:
- chronic tophaceous gout (dissolves tophi quicker than uricosurics)
- 24hr urinary uric acid on purine-free diet > 1.1g
- recurrent renal stones
- renal impairment
adverse effects
- GI intolerance: diarrhea, n/v
allopurinol vs febuxostat
adv effects
XO inhibitors
allopurinol has potential for other side effects (beyond GI):
- allergic skin rxn (can be as severe as toxic epidernal necrolysis)
- peripheral neuritis, necrotizing vasculitis
- bone marrow depletion
- hepatic tox, interstitial nephritis
- aplastic anemia, cataracts (rare)
allopurinol also interacts with other drugs: mercaptopurines (ex. azathioprine), probenecid, oral anticoags
febuxostat has better safety profile, is well-tolerated in pt with history of allopurinol intolerance
lowering serum urate:
uricosuric agent
mech
what to expect
fun fact about aspirin
when? indications/contraindications
adverse effects
if XO inhibitor fails to lower urate to target levels…consider adding a uricosuric!
probenecid (only one available in US)
-
mech: organic acid that acts at anion transport site of proximal renal tubule → increase secretion AND decrease reabs of uric acid
- good rxn? tophaceous deposits reabs → arthritis relief, bone remineralization
*at analgesic dose, ASA inhibits secretory urate transporter!
- dont use it w for analgesia in gout pt
indications/contraindications:
- gouty urate underexcretion when allopurinol/febuxostat fail or are contraindicated
- tophaceous gout or incr frequent gout attack → decr body pool of uric acid
- start: 2-3wk after acute attack
- NOT FOR USE IN PTS EXCRETING LOTS OF URIC ACID → want to avoid renal calculi
adverse effects/cautions
- GI irritation (divided doses w food is the way to go)
- predisposition to form renal stones
- need to maintain high urine volume, and pH kept above 6
lowering serum urate:
pegloticase
mech
indications
adverse effects
pegylated, recombinant mammalian uricase
mech: hydrolyzes uric acid → allantoin
indications: when everything else fails
- IV dose can maintain low urate levels for 21days → 2wk dosing
- need adequate renal fx for good response
adverse effects
- IV infusion reactions and gout flares (usually first 3mo)
- start with colchicine or NSAID before pegloticase
- often pre-tx with antihistamines or corticosteroids to avoid rxns
- hi cost, no real idea about duration of tx
