Gout and Pharm for Gout

Question 1

colchicine

Answer 1

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

Question 2

indomethacin

Answer 2

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)

Question 3

allopurinol

Answer 3

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)

Question 4

probenecid

Answer 4

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

Question 5

febuxostat

Answer 5

xanthine oxidase inhibitor
Tx: gout in people allergic to allopurinol
AE: FLARE UP (must give PROPHYLACTIC)
CAN USE in RENAL IMPAIRMENT

Question 6

pegloticase

Answer 6

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)

Question 7

6-mercaptopurine

Answer 7

metabolized by xanthine oxidase
ALLOPURINOL inhibits metabolization and increases its blood levels
MUST REDUCE DOSE

Question 8

uricosuric agents

Answer 8

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)

Question 9

gout

Answer 9

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

Question 10

hyperuricemia

Answer 10

plasma rate greater than 6.8-7 mg/dL

Question 11

tophi

Answer 11

monosodium urate accumulation

locations; extensor surface of extremities

Question 12

urolithiasis

Answer 12

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

Question 13

Where in the kidney can monosodium rate deposit?

Answer 13

interstitium

leads to renal impairment

Question 14

podagra

Answer 14

gout in big toes

Question 15

Does rate precipitate at high or low pH?

Answer 15

low: acidotic conditions precipitate urate

Question 16

xanthine oxidase

Answer 16

converts xanthine to uric acid

Question 17

uricase

Answer 17

in animals not humans

converts uric acid to allantoic acid

Question 18

hypoxanthine guanine phosphoribosyl transferase (HGPRT)

Answer 18

purine salvage pathway

hypoxanthine and guanine to IMP and GMP

Question 19

How does the kidney deal with uric acid?

Answer 19

1. glomeruli: freely filtered
2. PROXIMAL tubule: completely reabsorbed
3. PROXIMAL tubule: half secreted, largely reabsorbed
   overall: 8-12% excreted
   lots of transporters: URAT, OAT, ABCG, MRP, NPT1

Question 20

In what ways does hyperuricemia develop? Which is more common?

Answer 20

90%: decreased efficiency of uric acid excretion

10%: increased uric acid production (typically inherited defects)

Question 21

Do underexcretors of uric acid have a normal rate of urinary uric acid excretion?

Answer 21

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

Question 22

Who has more total body urate: men or women?

Answer 22

men have twice as much (1200mg)

women may have increased excretion due to estrogen

Question 23

Do the intestines play a role in urate metabolism?

Answer 23

bacteria degrade uric acid
1/3 of total urate metabolism
high uric acid may cause rate to deposit occutly

Question 24

When does primary hyperuricemia begin in men?

Answer 24

puberty

Question 25

When do women get hyperuricemia?

Answer 25

post menopause

Question 26

When is the highest incidence of gout in men? women?

Answer 26

men: 30 - 45 yrs
women: 55 - 70 yrs
two decades later than initial physiologic increase in serum urate

Question 27

inflammatory cycle of gout attack

Answer 27

complement (C5a), macrophages, fibroblasts, mast cells,

1. IL-1B: activate neutrophils and endothelial cells in blood
2. NEUTROPHILS move into tissue and phagocytose urate crystals
3. crystals coated with Ig: IL-1B, IL-8, TNF, proteases, ROS; uncoated crystals: lyse phagolysosome
4. local tissue damage lease to additional neutrophil recruitment

Question 28

Lesch-Nyhan syndrome

Answer 28

X-linked
HPRT deficiency
overproduction of uric acid, self-mutilation

Question 29

systemic conditions promoting hyperuricemia: overproduction

Answer 29

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

Question 30

systemic conditions promoting hyperuricemia: underproduction

Answer 30

renal insufficiency, dehydration, lactic acidosis, ketoacidosis

Question 31

systemic conditions promoting hyperuricemia: over and underproduction

Answer 31

MI, CHF, sepsis

Question 32

systemic conditions promoting hyperuricemia: metabolic states

Answer 32

hyper/hypothyroidism, hyper/hypoparathyroidism, obesity

Question 33

drugs that cause hyperuricemia

Answer 33

CYCLOSPORINE, ALCOHOL, LEAD POISONING
other: CSFs, ethambutol, thiazide and loop diuretics
salicylates, nicotinic acid, pyrazinamide

Question 34

drugs that increase uric acid excretion

Answer 34

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

Question 35

Tx for acute gout

Answer 35

NSAIDs, colchicine, steroids, adrenocorticotropic hormone

Question 36

Tx for chronic gout

Answer 36

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

Question 37

What should hyperuricemic people be screened for?

Answer 37

HTN, CAD, DM, obesity, alcoholism

Question 38

Diseases gout is associated with

Answer 38

obesity, hypertriglyceridemia, glucose intolerance, metabolic syndrome, HTN, atherosclerosis, hypothyroidism
renal insufficiency

Question 39

What situations may lead to uric acid nephropathy?

Answer 39

chronic hyperuricemia

acute hyperuricemia in tumor lysis syndrome

Question 40

Do you treat asymptomatic hyperuricemia?

Answer 40

NO

try to identify cause

Question 41

pseudogout

Answer 41

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

Question 42

pseudogout associations

Answer 42

osteoarthritis, trauma, familial
metabolic: hyperparathyroidism, hemochromatosis, hypophosphatasia, hypomagnesemia, ochronosis
NOT renal disease or diuretic use (unless dialysis dependent)

Question 43

ANKH

Answer 43

AD
chromosome 5p
encodes transmembrane protein with functions including PPi transport
FAMILIAL PSEUDOGOUT

Question 44

calcium hydroxyapatite (HA) deposition disease

Answer 44

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

Question 45

calcium hydroxyapatite

Answer 45

primary mineral of bone and teeth

abnormal accumulations in areas of its damage

Question 46

NLRP3 (cryopyrin)

Answer 46

CPPD

activates inflammasome leading to activation of capsize-1 and IL-1B