Pharm of Gout & Hyperuricemia (Fitz) Flashcards
a decrease in pH has what effect on Urate?
shifts rxn to left and precipitates uric acid crystals
determinant of acute gout (inflamm)
list factors contributing to gout attacks in the first MTP joint:
- temp: lower temp in the joint which favors crystallization
- pH: trauma can cause acidosis, low pH favors uric acid crystallization
- joint hydration: nocturnal intra-articular dehydration may cause nocturnal crystallization, and nocturnal onset of pain
- presence of altered matrix proteins, exposed cartilage fragments and nucleating debris: enhanced by joint trauma and/or pre-existing osteoarthrtitic damage in ellderly
symptoms of hyperuricemia?
none
symtpoms of acute gout flare?
joint inflammation
symptoms of advanced/chronic gout?
CONSTANT joint pain, inflamm, tophi
this drug class can be used for prompt termination of acute gout attack, prevention of recurrences of acute gout
Anti-inflamm drugs
this drug class is used for prevention & reversal or urate crystal deposits in joints, urinary tract, renal interstitium, and tissues and parenchymal organs
anti-hyperuricemic (urate-lowering) drugs
this anti-inflammatory binds to tubulin & depolymerizes microtubules. It disrupts granulocyte function and inhibits LTB4 formation
Colchicine
__ are the mainstay of tx of acute attacks of gout in pts who have no contraindication to them.
NSAIDs
caution with NSAIDs for tx of acute attacks of gout in pts with what?
ulcers
HTN
coronary disease
fluid retention
what type of gout is colchicine good for? therapeutic index? adverse effects?
specific tx for ACUTE gout
NARROW therapeutic index: doses should be decreased in renal and hepatic dysfunction
GI toxicity (diarrhea, ab pain); Risk for BM suppression
analgesic properties of colchicine? effect on uric acid levels?
NOT an analgesic: but indirectly relieves pain by blocking degranulation
does NOT modify uric acid levels
corticosteroids for gout attacks? risks?
prednisone and methylprednisolone
long-term risks such as osteoporosis and infx, BUT risk for short-term tx in gout relatively LOW
allopurinol and febuxostat are what type of hyperuricemic drugs?
XO inhibitors–> INHIBIT urate biosynthesis
Probenecid (USA), sulfinpyrazone, and benzbromarone are what type of hyperuricemic drugs?
URAT1 inhibitors –> enhance urate excretion
pegloticase and rasburicase are what tyype of hyperuricemic drugs?
Recombinant urate oxidase enzyme –> enhance urate metabolism
1st line ULT drugs in gout?
XO inhibitors –> allopurinol and febuxostat
what combo is appropriate in some pts to achieve serum urate target (<6 mg/dl)?
Combo of ORAL ULT with an oral URICOSURIC agent
what drug combo is appropriate for severe disease, failure, or intolerance to appropriately dosed XO inhibitors?
ULT with a Urate oxidase recombinant enzyme (pegloticase)
allopurinol acts by inhibiting what enzyme?
Xanthine oxidase
Blocks conversion of BOTH Hypoxanthine to Xanthine and Xanthine to Uric acid
t1/2 of allopurinol and oxypurinol (active metabolite)? dosing interval for both
t1/2 allpurinol=2 hrs
t1/2 oxypurinol=16 hrs
Once daily, PO
febuxostat acts by inhibiting what enzyme?
XO
this drug is NOT a purine analog, has a better and different adverse effect profile (liver function) vs allopurinol, and can be used in pts with RENAL DISEASE
febuxostat
paradox for initial phase of ULT?
early increase in acute gout attacks
this may contribute to non-compliance in long-term gout tx
Explain the NSAIDs and ULT paradox:
recommended to administer oral colchicine or a NSAID in pts who are beginning ULT to decrease acute gout associated with initiation of ULT
risk associated with use of allopurinol/febuxostat alongside xanthine drugs (i.e., 6-MP, azathioprine, theophylline)?
allopurinol and febuxostat inhibit metabolism of xanthine drugs used in cancer chemo, immunosuppression, asthma conferring RISKS of overexposure and requiring DOSE ADJUSTMENTS
black box warning of allopurinol?
not recommended for tx of ASYMPTOMATIC hyperuricemia
should be discontinued at 1st apearance of skin rash or other signs of allergic rxn
pts with this HLA genotype should avoid allopurinol d/t severe hypersensitivity
HLA-B*5801
populations with high allele frequency include Han chinese and Thai descent
probenecid effects in kidney?
Probenecid=URAT1 inhibitor (blocks URAT on APICAL side)
BLOCKS tubular re-absorption > tubular secretion –> NET EFFECT=ENHANCE urate excretion
normal urate excretion=10% of filtered load
urate excretion with Probenecid=20% of filtered load
uricosuric agents (2nd line agents in pts with tophaceous gout or hyperuricemia) should be avoid in who?
pts with risk/hx of nephrolithiasis or uric acid nephropathy
urate-lowering tx are of no benefit for __
acute gout –> should generally not be initiated during acute attack
paradox of aspirin use during acute gout attack?
do not use standard dose ASA as anti-inflamm agent for acute gout attacks
ASA blocks tubular secretion > tubular absorption and thereby AGGRAVATES HYPERURICEMIA
what effect do thiazides and loops have on urate clearance?
interfere with urate clearance by effects on multiple transporters in PCT –> uric acid retention
what drugs augment metabolic degradation of uric acid into allantoin?
Recombo enzyme uric acid oxidase:
Pegloticase
Rasburicase
indication for pegloticase?
hyperuricemia associated with MALIGNANCY (TUMOR LYSIS syndrome)
IV q 2 wks
indication for Rasburicase?
gout-associated hyperuricemia
IV qdx5 days
Boxed warning for both pegloticase and rasburicase?
severe hypersensitivty rxns (including anaphylaxis) have been reported
Rasburicase: contraindicated in G6PD deficiency d/t risk for hemolysis
