Gout pharmacology

Question 1

hyperuricemia >7.5-8mg/dL

monosodium urate crystal deposition in joints causing attack of acute inflammatory arthritis (intensely painful)

tophi (deposits of urate crystals) around joints, can occur in helix of ear, parenchymal organs

uric acid kidney stones

gouty nephropathy

acute: oliguric or anuria renal failure due to precipitation of uric acid tubules

chronic: due to monosodium urate deposition in medullary interstitium

Answer 1

gout

Question 2

purine are bulit on ribose base

5-phosphoribosyl-1-pyrophosphate (PRPP) is the activated source of the ribose moiety

PRPP synthase is a regulated enzyme

recall that purine degraded to uric acid

this occur in the liver

AMP deamidated to produce IMP

IMP and GMP are dephosphorylated and ribose cleaved from the base to give hypoxanthine and guanine

xanthine formed from hypoxanthine and guanine

xanthine converted to uric acid by xanthine oxidase

Answer 2

recall that purine are salvaged

preformed nucleotide from diet or breakdown of endogenous nucleic acid is salvaged by adenine phosphoribosyl transferase (APRT)-converts free adenine to AMP

hypoxanthine-guanne phosphoribosyl transferase (HGPRT) converts hypoxanthine to AMP and guanine to GMP

absence og HGPRT results in Lesch-Nyhan syndrome

characterized by profound intellectual disability, self-mutilation and severe gout

Question 3

uric acid underexcretion (90%)

primary hyperuricemia-lower fractional excretion of filtered urate

secondary hyperuricemia-impaired renal function limiting urate excretion and drug-induced inhibition of urate excretion

Urate overproduction (10%)

primary hyperuricemia-metabolic disorder, idiopathic

seconday hyperuricemia- excessive purine intake and tumor lysis syndrome

Answer 3

urate handling in the kidneys

plasma urate concentraion increase if:

fractional excretion is < normal (e.g., 10%) ​ plasma urate conc. must increase so that the fraction excreted is amount of daily excess

or

GFR falls (kidney disease) plasma urate conc. must increase so fractional excretion of amount filtered equals amount of daily excess

treatment of gout

anti-inflammatories

acute: to promptly reduce inflammation and associated pain

prophylactic: to reduce re-occurrences

if reccurrences

increase uric acid renal excretion

-uricosuric drugs

and/or

reduce uric acid production

diet

xanthine oxidase inhibitor

recombinant uricase

Question 4

NSAID

-Naproxen (non-selective), indomethacin (COX1>COX2), celecoxib (COX2, high dose, if others not tolerated)

most effective if treatment is initiated < 48 of onset of sx

glucocorticoids – systemic / intra‐articular (discussed earlier) • option if few joints or NSAIDs and colchicine are contraindicated

Answer 4

Colchicine

MOA: diffuses into cells to bind tubulin, blocks formation of microtubules

effects: to inhibition of leukocyte migration and phagocytosis

clinical application- used in patient with NSAID intolerance, tx is effective if started within 12-24 h of symptoms onset

given orally

contraindicated in patients with advanced renal or hepatic imparment

toxicities: GI distress, diarrhea, V/N

Question 5

MOA: metabolized to alloxanthine, a competitive (pseudo-irreversible) inhibitor of xanthine oxidase

effect: hypoxanthine and xanthine are both excreted as both are more soluble than urate/uric acid

clinical application: recurrent gout primary or secondary, chemo induced hyperuricemia (tumor lysis syndrome)

orally

toxicities: skin rash, noteworthy is severe hypersensitivity reaction that can be fatal (steven-johnson-epidermal necrolysis). increase risk if HLA-B*5801 positive

Answer 5

allopurinol

Question 6

MOA-nonpurine inhibitor of xanthine oxidase

effect: hypoxanthine and xanthine are excreted

clinical application-those who cannot tolerate allopurinol

toxicities- well tolerated

orally

Answer 6

febuxostat

Question 7

MOA- recombinant mammalian uricase, attach to methoxy polyethylene glycol

effects: converts uric acid to the far more soluble allantoin (waste product of most mammalian)

clincial application- treat chronic gout in refractory to conventional therapy (biologics is last resorts)

IV

toxicities- infustion reactions-fever, chills, rash, angioedema, bronchospasm, hypotension or HTN

need to premedicate with glucocorticoid or antihistamine

Answer 7

pegloticase

rasburicase- nonpegylated recombinant uricase for the prevention of acute uric acid nephropathy due to tumor lysis syndrome inpatient with high-risk lymphoma or leukemia

Question 8

MOA- organic acid acting at anionic transport sites of renal tubule in a manner that blocks urate reabsorption more than urate secretion

note that low-dose aspirin promotes urate reabsorption (which is why aspirin is not a good choice)

effects: increases the fractional excretion of urate, decreases plasma urate concetration and urate pool in body

clincial application- reduce urate level in underexcreters with GFR > 60ml/min and no stones to decrease body pool in patients with

hyperuricemia, frequent attacks, tophi

oral

toxicities-acute increase risk of kidney stones (both uric acid and calcium oxalate) may cause gout flare

sulfur-containg

sulfinpyrazone is similar

Answer 8

probenecid

general therapeutic principles- acute gout

anti-inflammatory

-NSAIDS

• Naproxen and indomethacin
• glucocorticoids

Prevention of recurrent gout

requires urate lowering agents

-lifestyle changes, diet, weight reduction, avoidance of alcohol

drugs

-allopurinol

febuxostat

probenecid

pegloticase