Hyperuricemia and Gout

Question 1

MOA of colchicine?

Answer 1

depolimerization of microtubules by binding tubuilin. This inhibits mitosis, causing a wide array of toxicites, but more importantly, inhibits neutrophil motility and activity, giving it an anti-inflammatory effect.

Question 2

ADE of colchicine?

Answer 2

GI disturbances

blood dyscrasias

Question 3

MOA of indomethacin?

Answer 3

NSAID –> Non-selective COX inhibitor
analgesic and antipyretic
inhibits leukocyte motility

Use only for acute attacks

Question 4

ADE of indomethacin?

Answer 4

GI ulcers
CNS - severe frontal headaches
Hematopoietic disorders
Antagonizes furosemide and HCTZ

Question 5

MOA of probenicid?

Answer 5

Urocosuric drug.
inhibits transport of organic anions across epithelial barriers. Interferes with uric acid reabsorption by the organic acid transporter in the brush border of the proximal tubule.

Question 6

ADE of probenicid?

Answer 6

Must give with adequate hydration to prevent kidney stones.

Salicylates inhibit uricosuric action.

Question 7

MOA of febuxostat?

Answer 7

potent xanthine oxidase inhibitor

structurally UNrelated to allopurinol but more potent than it with fewer side effects

Question 8

ADE of febuxostat?

Answer 8

almost none. rare elevation of transaminase.

Can be used in renal failure (as opposed to allopurinol)

Question 9

MOA of pegloticase?

Answer 9

PEGylated formulation of pig urate oxidase. Lowers uric acid levels by converting uric acid into allantoin, which is excreted in urine.
Rapidly lowers serum uric acid and dissolves tophi

Question 10

ADE of pegloticase?

Answer 10

Gout flares.
89% of subjects develop antibodies against the PEG moiety of pegloticase. PEGylating it makes it last 10-12 days instead of 8 hours though.
It also costs ~ $30k/year so not feasible.

Question 11

What is the definition of hyperuricemia?

Answer 11

plasma concentration of uric acid > 7 mg/dL

Question 12

What is most common cause of hyperuricemia?

Answer 12

90% due to renal dysfunction (under-excretion).

Question 13

What is the cause of primary renal hyperuricemia? Secondary?

Answer 13

primary renal: kidney disease

secondary renal: long-term diuretic therapy or toxemia of pregnancy

Question 14

What is cause of primary metabolic hyperuricemia? secondary?

Answer 14

primary metabolic: enzyme abnormalities
secondary metabolic: increased purine biosynthesis caused either by certain blood disorders or chemotherapies/ratdiation

Question 15

What is the precursor of uric acid?

Answer 15

xanthine

Question 16

What are the goals of gout treatment?

Answer 16

terminate acute attack
prevent recurrence
reverse deposited ureate cyrstals
prevent kidney stones

Question 17

When should colchicine be used?

Answer 17

effective only for gouty arthritis. Is also a prophylactic against such attacks.

Question 18

MOA of allopurinol?

Answer 18

competitive inhibition of xanthine oxidase (XO)

after being metabolized to oxypurinol, it noncompetitively inhibits XO.

reduces plasma levels and urinary excretion of UA.
Increases plasma levels and urinary excretion of xanthine and hypoxanthine.

Question 19

ADE of allopurinol?

Answer 19

increase of acute gout attacks
hypersensitivity reactions
Liver function disruption
Interaction with 6-mercaptopurine and ampicillin

Question 20

What should be given with pegloticase?

Answer 20

colchicine, NSAID and glucocorticoids to prevent gout flares

Question 21

What is urate oxidase?

Answer 21

enzyme present in almost all mammals except humans. It convers uric acid to allantoin, a benign metabolite which is easily excreted in urine.