Gout and Pharm for Gout Flashcards
colchicine
depolimerization of microtubules, inhibits the function of polymorphonuclear lymphocytes
Tx: gout (ACUTE, PROPHYLAXIS of attack, FAMIAL MEDITERRANEAN FEVER)
SE: GI (acute), Blood dyscrasia (chronic), MYOPATHY (proximal weakness and elevated CPK), peripheral neuropathy, rhabdomyolysis
does NOT reduce uric acid
CI: renal disease
monitor: CBC, ALK PHOS
metab: hepatic de-acetylation
not removed by dialysis, no antidote
indomethacin
with ANTACID
COX inhibitor: analgesic, antipyretic
inhibits leukocyte motility
Tx: ACUTE gout
SE: GI, CNS (severe frontal headache), hematopoietic
CI: antagonize furosemide and HCTZ (antagonize diuretics)
allopurinol
xanthine oxidase inhibitor (competitive)
metabolite (oxypurinol) inhibits xanthine oxidase (non-competitive: irreversible: suicide inhibitor)
effect: reduces uric acid levels in plasma and urine: increases xanthine and hypoxanthine, dissolves crystals, prevent kidney stones
Tx: gout in primary and secondary hyperuricemia
AE: FLARE UPs (acute gout), hypersensitivity: DERMATITIS
monitor: LFTs
CI: 6-MP, ampicillin (and related antibiotics)
can use in RENAL IMPAIRMENT (adjust dose for insufficiency)
probenecid
interferes with uric acid reabsorption by BRUSH BORDER transporter (more UA in urine)
Tx: gout in patients that excrete less than 1 g of UA/day (dissolves uric acid in joints)
DRINK LOTS of WATER
CI: renal impairment, salicylates and other NSAIDs (inhibit uricosuric action of probenecid)
SWITCH to acetaminophen
HYDROCHLOROTHIAZIDE diminishes availability: effects transport across tubule
febuxostat
xanthine oxidase inhibitor
Tx: gout in people allergic to allopurinol
AE: FLARE UP (must give PROPHYLACTIC)
CAN USE in RENAL IMPAIRMENT
pegloticase
IV (expensive)
LONG acting: 2 weeks
urate oxidase: uric acid to allantoin (easily excreted in urine)
lowers uric acid in serum and urinary excretion
AE: acute gout (need PROPHYLAXIS)
Tx: SEVERE gout in those that conventional therapy is CI or has been ineffective
can develop Ab against PEG (most patients)
6-mercaptopurine
metabolized by xanthine oxidase
ALLOPURINOL inhibits metabolization and increases its blood levels
MUST REDUCE DOSE
uricosuric agents
increase renal excretion of uric acid
PROXIMAL CONVOLUTED TUBULE: filtered uric acid is completely reabsorbed early, next segment secretes, next segment partially reabsorbs (brush border transporter)
gout
monoarticular arthritis: DISTAL LOWER EXTREMITY (1st MTP)
late stage: asymmetric polyarticular
Dx: urate crystals neg. birefringence (yellow parallel)
Sx: PAIN, tophi, multiple attacks, mx inflammation in 1 day, REDNESS, hyperuricemia
MONOSODIUM URATE crystals
risks: alcohol (BEER), seafood, red meat, genetics
protective: milk, yogurt
hyperuricemia
plasma rate greater than 6.8-7 mg/dL
tophi
monosodium urate accumulation
locations; extensor surface of extremities
urolithiasis
5-10% of urinary stones in US
40% in hot, arid climates with low urine volumes and acidic pH
20% of un-Tx’ed gout patients have them
80% of stones in gout patients are completely uric acid, rest just have nidus of uric acid
urinary stone of uric acid
risk factors: increased uric acid excretion, reduced urine volume, low urine pH
Where in the kidney can monosodium rate deposit?
interstitium
leads to renal impairment
podagra
gout in big toes
Does rate precipitate at high or low pH?
low: acidotic conditions precipitate urate
xanthine oxidase
converts xanthine to uric acid
uricase
in animals not humans
converts uric acid to allantoic acid
hypoxanthine guanine phosphoribosyl transferase (HGPRT)
purine salvage pathway
hypoxanthine and guanine to IMP and GMP
How does the kidney deal with uric acid?
- glomeruli: freely filtered
- PROXIMAL tubule: completely reabsorbed
- PROXIMAL tubule: half secreted, largely reabsorbed
overall: 8-12% excreted
lots of transporters: URAT, OAT, ABCG, MRP, NPT1
In what ways does hyperuricemia develop? Which is more common?
90%: decreased efficiency of uric acid excretion
10%: increased uric acid production (typically inherited defects)
Do underexcretors of uric acid have a normal rate of urinary uric acid excretion?
YES, production and clearance are relatively equal
REDUCED EFFICIENCY of urate excretion that obligates a higher serum rate concentration to achieve the necessary rate of uric acid excretion
Who has more total body urate: men or women?
men have twice as much (1200mg)
women may have increased excretion due to estrogen
Do the intestines play a role in urate metabolism?
bacteria degrade uric acid
1/3 of total urate metabolism
high uric acid may cause rate to deposit occutly
When does primary hyperuricemia begin in men?
puberty
When do women get hyperuricemia?
post menopause
When is the highest incidence of gout in men? women?
men: 30 - 45 yrs
women: 55 - 70 yrs
two decades later than initial physiologic increase in serum urate
inflammatory cycle of gout attack
complement (C5a), macrophages, fibroblasts, mast cells,
- IL-1B: activate neutrophils and endothelial cells in blood
- NEUTROPHILS move into tissue and phagocytose urate crystals
- crystals coated with Ig: IL-1B, IL-8, TNF, proteases, ROS; uncoated crystals: lyse phagolysosome
- local tissue damage lease to additional neutrophil recruitment
Lesch-Nyhan syndrome
X-linked
HPRT deficiency
overproduction of uric acid, self-mutilation
systemic conditions promoting hyperuricemia: overproduction
hemolytic anemia, sickle cell disease, polycythemia vera, megaloblastic anemia, thalassemia, myelodysplastic syndrome, leukemia, lymphoma, multiple myeloma, Waldenstrom’s macroglobulinemia, essential thrombocytosis, tumors, tumor less syndrome, psoriasis, sarcoidosis, metabolic myopathies, mitochondrial myopathies
systemic conditions promoting hyperuricemia: underproduction
renal insufficiency, dehydration, lactic acidosis, ketoacidosis
systemic conditions promoting hyperuricemia: over and underproduction
MI, CHF, sepsis
systemic conditions promoting hyperuricemia: metabolic states
hyper/hypothyroidism, hyper/hypoparathyroidism, obesity
drugs that cause hyperuricemia
CYCLOSPORINE, ALCOHOL, LEAD POISONING
other: CSFs, ethambutol, thiazide and loop diuretics
salicylates, nicotinic acid, pyrazinamide
drugs that increase uric acid excretion
clycopyrrolate, iopanoic acid, Ca ipodate, probenecid, salicylates, calcitonin, citrate, estrogens, fenofibrate, acetohexamide, amflutizole, ascorbic acid, azapropazone, azauridine, benzbromarone, dicumarol, difluisal, glycerol guaiacolate, glycine, iodopyracte, losartan, meclofenamic acid, orotic acid, outdated tetracyclines, phenolsulfonphthalein, sulfinpyrazone
Tx for acute gout
NSAIDs, colchicine, steroids, adrenocorticotropic hormone
Tx for chronic gout
give acute gout Tx first to prevent flare
lowest dose to maintain serum rate below 6.8 mg/dL- preferably below 6
allopurinol, febuxostat, pegloticase
DON’T use these for just hyperuricemia
What should hyperuricemic people be screened for?
HTN, CAD, DM, obesity, alcoholism
Diseases gout is associated with
obesity, hypertriglyceridemia, glucose intolerance, metabolic syndrome, HTN, atherosclerosis, hypothyroidism
renal insufficiency
What situations may lead to uric acid nephropathy?
chronic hyperuricemia
acute hyperuricemia in tumor lysis syndrome
Do you treat asymptomatic hyperuricemia?
NO
try to identify cause
pseudogout
old people (70-75 yrs)
CALCIUM PYROPHOSPHATE DIHYDRATE
recurrent/chronic inflammatory monoarticular/oligoarticular arthritis: joints not affected by osteoarthritis: wrist, knee, ankle, MCP, elbow; hemarthrosis
Sx: pseudo-polymyalgia rheumatica, FEVER, carpal tunnel, CNS disease complicating ligamentum flavum or transverse ligament of atlas
incidental finding
blue and rhomboid on parallel, BIREFRINGENCE
familial: ANKH, chromosome 5p
dysregulated chondrocyte differentiation
NLRP3
Dx: ultrasound (can’t always see chonedrocalcinosis on X-ray)
Dx before 55: consider underlying disease, familial
Dx older than 55: consider HYPERPARATHYROIDISM
pseudogout associations
osteoarthritis, trauma, familial
metabolic: hyperparathyroidism, hemochromatosis, hypophosphatasia, hypomagnesemia, ochronosis
NOT renal disease or diuretic use (unless dialysis dependent)
ANKH
AD
chromosome 5p
encodes transmembrane protein with functions including PPi transport
FAMILIAL PSEUDOGOUT
calcium hydroxyapatite (HA) deposition disease
chronic renal failure, hyperphosphatemia enhances HA deposits both in and around joints
elderly: HA released from bone causing acute synovitis in osteoarthritis knee, shoulder (Milwaukee shoulder)
joint destruction: attenuation/ rupture of supporting structures
subacromial bursitis, pseudopodagra (found female)
Tx: NSAIDs, selective COX-2 inhibitors, local steroid injection, local irrigation, high freq. ultrasound
association: severe OSTEOARTHRITIS
no biofringence
calcium hydroxyapatite
primary mineral of bone and teeth
abnormal accumulations in areas of its damage
NLRP3 (cryopyrin)
CPPD
activates inflammasome leading to activation of capsize-1 and IL-1B
