What is the most important determinant of purine synthesis?
cellular levels of PRPP
Transfers PRPP to hypoxanthine or guanine
HGPRT (salvage pathway)
Catalyzes reaction of PRPP with glutamine
amidoPRT
What is the action of xanthine oxidase?
converts xanthine to uric acid
What is lesch-nyhan syndrom and what is its cause?
absence of HGPRT– self mutilation, mental retardation, hyperuricemia
how is uric acid eliminated?
kidneys (65%) GI (35%)
where is URAT1 expressed
expressed in proximal renal tubule for reabsorption
What are the 4 stages of gout?
- asymptomatic hyperuricemia
- acute gout
- intercritical phase
- chronic gout
Gout due to increased synthesis or decreased breakdown of purines
asymptomatic hypercurcemia stage 1
acute arthritic attack of single joint (podagra)
acute gout (stage 2)
asymptomatic hyperuricemia
intercritical phase (stage 3)
hyperuricemia w/ development of tophi (UA crystals) recurrent gout attacks
chronic gout (stage 4)
Why are joints favorable to UA crystal formation?
lower temperature and more acidic
NSAID used to treat gout
indomethacin
Drugs to treat stage 2
NSAIDs, colchicine, glucocorticoids
Drugs to treat stage 4
allopurinol
probenecid
sulfinpyrazone
What does urate crystal binding in monocytes initate the assembly of?
NALP-3 inflammasome —> Activates caspase 1
Colchicine and glucocorticoids treat
acute gout
binds to tubulin to inhibit intra cellular trafficking and there fore decreases inflammatory response
cholchine
Inhibits conversion of hypoxanthine to xanthine –> UA
allopurinol
increases Urate excretion by inhibiting URAT 1 receptor
probenecid
sulfinpyrazone
More potent than probenecid but works same way
sulfinpyrazone
Main risk factor for benxbromarone
hepatotoxicity
angiotensin II receptor antagonist w/ uricosuric effects
Losartan
