Gout + Drugs B&B Flashcards
what occurs in gout?
monosodium uric acid deposits in joints, crystals are phagocytosed by macrophages/neutrophils —> inflammatory response triggered, recurrent attacks of acute arthritis
what are the 3 conditions needed to allow gout to develop?
- hyperuricemia
- cool temperatures (feet)
- genetic disposition
podagra
gout occurring in the base of the great toe (1st metatarsophalangeal joint), most common location
what causes chronic tophaceous gout?
tophi = uric acid collections in connective tissue (due to repetitive gouty arthritis)
occur in ears, tendons, bursa - not painful, but form small bumps
seen with long-standing hyperuricemia
what causes urate nephropathy?
renal conditions caused by gout —> uric acid crystals in urine, uric acid kidney stones, chronic renal failure
what are common triggers of primary gout attacks?
primary gout - overproduction of uric acid
attacks triggered by diet (red meat, seafood) and alcohol, also trauma/surgery (due to tissue breakdown)
how do purines become uric acid, as occurs in gout?
purines —> hypoxanthine —> uric acid via xanthine oxidase
this is why red meat and seafood can trigger gout attacks, due to the high purine content!
explain how alcohol can trigger gout attacks?
alcohol metabolism consumes ATP… adenosine is a purine, which is broken down to uric acid
alcohol metabolism also produces lactic acid, which activates the urate transporter 1 (URAT1) in the kidneys, increasing reabsorption of uric acid
Pt is a 45yo M with a BMI of 37 presenting with joint pain in the knee, which occurred shortly after a steak dinner in which the patient consumed several alcoholic drinks. What is the most likely cause of their symptoms?
gout attack - triggered by red meat/seafood (high purine content) and alcohol (induces purine metabolism via ATP consumption)
explain why diuretics could cause secondary gouty arthritis?
uric acid is excreted in kidneys - therefore, anything causing a reduction in GFR would decrease uric acid excretion —> hyperuricemia
ex - renal failure, volume depletion, diuretics
explain why myeloproliferative disorders (chronic myeloid leukemia, essential thrombocytopenia, polycythemia vera) can cause secondary gouty arthritis
associated with high cell turnover —> increased purine metabolism —> hyperuricemia —> gout
Lesch-Nyhan syndrome
X-linked absence of HGPRT enzyme in purine salvage pathway (hypoxanthine-guanine phosphoribosyltransferase) —> excess uric acid production, causing juvenile gout
presents with neurological impairment + hypotonia/chorea + self-mutilating behavior
male child with hypotonia/chorea + self-mutilating behaviors + gout =
Lesch-Nyhan syndrome: X-linked absence of HGPRT enzyme in purine salvage pathway (hypoxanthine-guanine phosphoribosyltransferase) —> excess uric acid production, causing juvenile gout
explain how Von Gierke’s Disease can cause secondary gout?
aka glycogen storage disease type 1, glucose-6-phosphate deficiency presenting in infancy
—> severe hypoglycemia, causing seizures and lactic acidosis (Cori cycle)
lactate and urate are linked via URAT1 (urate transporter 1) in kidney —> high lactic acid causes increased uric acid reabsorption —> gout
how do gout crystals appear in polarized light microscopy (used for diagnosis)?
gout crystals (needle-shaped) are birefringent - reflect polarized light (waves vibrate in only 1 direction) in 2 ways based on orientation
yeLLow when paraLLel, while blue when perpendicular (think b and p are opposite)
how are acute attacks of gout treated? (3)
- NSAIDs
- glucocorticoids
- colchicine
what is the mechanism and clinical use of colchicine?
microtubule inhibitor used to treat acute attacks of gout (and also pericarditis, familial mediterranean fever)
binds tubulin and prevents polymerization, inhibiting WBC migration into joints and phagocytosis
what kind of drugs are allopurinol and febuxostat, and what is their clinical use?
xanthine oxidase inhibitors (converts hypoxanthine from purines into uric acid) used to prevent gout (also tumor lysis syndrome)
allopurinol - competitive inhibitor
febuxostat - noncompetitive inhibitor
why must NSAIDs or colchicine be administered with allopurinol or febuxostat?
these are xanthine oxidase inhibitors that abruptly lower serum uric acid levels (used to treat gout) - this can actually cause precipitation of urate crystals in joints, triggering acute gout attack
NSAIDs/colchicine treat acute gout attacks
what is the limiting factor of allopurinol as a first-line drug for gout prevention?
xanthine oxidase inhibitor, but causes severe side effects - GI upset, hepatic toxicity, skin rash (hypersensitivity), rarely bone marrow suppression
[febuxostat can be tried in intolerant patients]
which 2 immunosuppressants interact with xanthine oxidase inhibitors (allopurinol, febuxostat)?
azathioprine and 6-MP (mercaptopurine) - both metabolized by xanthine oxidase
if xanthine oxidase is inhibited, effects of these immunosuppressants are boosted, increasing toxicity
what is the clinical use of pegloticase?
recombinant porcine uricase (uric acid oxidase, degrades urate) - used to treat severe, refractory gout
given via IV every 2 weeks (attached to PEG/polyethylene glycol, prolongs half life)
[PEGlotICASE = PEG-attached urICASE]
what is the mechanism of pegloticase?
recombinant porcine uricase (uric acid oxidase, degrades urate) - used to treat severe, refractory gout
converts uric acid to allantoin, which is more water soluble and can be excreted by the kidneys
[PEGlotICASE = PEG-attached urICASE]
what is the clinical use of rasburicase?
Recombinant URICASE (RasbURICASE) - converts uric acid to allantoin (water soluble, excretable)
NOT used to treat gout due to rapid on/off action (more immunogenic) - only used in tumor lysis syndrome when uric acid must be lowered quickly (to prevent acute renal failure due to uric acid nephropathy)
