Hyperuricemia/Gout

Question 1

Define: hyperuricemia

Answer 1

Uric acid: product of purine metabolism 
Converted to: xanthine, hypoxanthine
Xanthine oxidase 
Normal: ~5 mg/dL 
> 7 mg/dL (men); > 6 mg/dL (women)
\+/- 2 S.D above mean

Question 2

Define: gout

Answer 2

Recurrent attacks of painful inflammatory monoarthritis
Most common form of inflammatory arthritis (elderly)
Ask with hyperuricemia
Precipitation of monosodium rate crystals
–activate monosites/macrophages via TLR
–Innate immune response
–Cytokines (IL-1beta); endothelial activation, neutrophil attraction
Lower pH –> more crystallization

Question 3

Major causes of hyperuricemia and gout

Answer 3

Under-excretion (90%): renal impairment, HTN, drugs
Over-production (10%): purine-rich diet, lympho-myeloproliferative d/o, cytotoxic antineoplastic agents (tumor lysis syndrome)
Beer, organ meat, sugar/fructose

Question 4

Drugs that cause hyperuricemia

Answer 4

Low dose aspirin
Thiazide diuretics
Pyrazinamide (anti-TB)
Cyclosporine (CsA)

Question 5

General approach to treat hyperuricemia

Answer 5

Asymptomatic:
--Diet modification, weight loss
Symptomatic:
--diet modification
--drug tx to lower risk of attacks, relieve sx of acute attack, reduce serum rate levels

Question 6

Drugs to treat acute attacks of gout

Answer 6

Anti-inflammatory agents

Don’t (newly) treat with uricostatic or uricosuric agents during an acute attack. Wait until flare is done.

Question 7

Allopurinol

Answer 7

Uricostatic agent
Xanthine oxidase inhibitor (competitive)
analog of hypoxanthine
–oxypurinol = active metabolite (non-competitive inhibitor)
1. Dissolution of tophi, prevents progression of gouty arthritis (lowers serum rate)
2. Decreases risk of nephropathy
3. Increase incidence of acute attacks during early stage (tissue mobilization of rate) (suppressed by colchicine)
Oral admin
t1/2: 1-2h. (for oxypurinol: 18-30h)
Use: reduce serum urate to <6 mg/dL
–Give colchicine before starting
–Prevent tumor-lysis syndrome
–Combo with uricosurics
Interactions: probenecid (increased clearance)
–MERCAPTOPURINE, AZATHIOPRINE (dose reduction)
–Warfarin (incr risk of bleeding)
Adverse: hypersensitivity (give oxypurinal instead)

Question 8

Febuxostat

Answer 8

Uricostatic agent
Non-purine, non-competitive inhibitor of oxidized and reduced forms of XO
Alternative to allopurinol
Not more efficacious overall
Adverse: abnormal liver function (monitor)

Question 9

Uricostatic agents

Answer 9

Prevent formation of uric acid
Inhibit Xanthine oxidase
Allopurinol
Febuxostat

Question 10

Probenecid

Answer 10

Uricosuric agent
Inhibits transport of organic acids by URAT-1 (proximal tubule); increases urinary urate levels
Combined with liberal fluid intake (prevent renal stones)
Maintain urinary pH > 6 (give bicarb)
Should not be used with NEPHROLITHIASIS or over-production of rate
Ineffective if renal insufficiency
Combined with NSAIDs or colchicine
Interactions: GI, reduced efficacy by salicylates, block excretion of other drugs (penicillin)

Question 11

Salicylate

Answer 11

Uricosuric agent
Low dose: blocks proximal tubular secretion of rate, produces hyperuricemia
High dose: blocks secretion of rate, BLOCKS REABSORPTION, uricosuric effect (increased risk of renal calculi, aspirin toxicity)

Question 12

Losartan

Answer 12

Uricosuric agent (ARB) 
Moderate uricosuric
Use: intolerance to probenecid and HTN

Question 13

Uricosuric agents

Answer 13

Probenecid
Salicylate
Losartan

Question 14

Pegloticase, rasburicase

Answer 14

Uricase (enzyme)
Recombinant urate oxidase
Hyperuricemia from tumor lysis syndrome (pediatric patients)
NOT for chronic gout
Adverse: severe anaphylaxis, hemolytic anemia, methemoglobinemia

Question 15

Colchicine

Answer 15

Anti-inflammatory
Anti-mitotic effects: interferes microtubule formation (beta-tubulin polymerization)
Prevents activation, degranulation, and migration of neutrophils
Oral. ENTEROHEPATIC RECIRCULATION.
CYP 3A4
Reduced dose in hepatic/renal insufficiency, elderly, and pts taking 3A4 and P-glycoprotein inhibitors
2nd line therapy (dt toxicity)
–acute gout: 2 doses 1h apart
–gout prevention
–Fixed dose combo with probenecid
Adverse: GI, myelosuppresion, leucopenia, granulocytopenia, thrombopenia, aplastic anemia, rhabdomyelosis
LIFE THREATENING if combined with 3A4 and P-glycoprotein inhibitors
7-14 days elapse b/w courses of tx

Question 16

Indomethacin

Answer 16

Anti-inflammatory (NSAID)
Non-selective inhibitor of COX 1/2 (20x more potent than ASA)
Use: gout (sulindac is safer but less potent); closure of PDA
Narrow therapeutic indx
–30-50% experience adverse effects (20% must stop use)
–GI effects, diarrhea, acute pancreatitis, hepatitis (potentially fatal)
–Severe frontal HA (most common) (25-50%)

Question 17

Prednisone

Answer 17

Anti-inflammatory (GC)

Question 18

Anti-inflammatory agents

Answer 18

First line agents to relieve pain of acute gouty arthritis: NSAIDs, GC
NSAIDs: used within 24h of sx onset, high doses for 3-4 days, tapered for 7-10 days, indomethacin, sulindac, naproxen
ASA is contraindicated!
Glucocorticoids: if NSAIDs are ineffective/not tolerated, high doses rapidly tapered over 10-14 days, intra-articular admin useful if only 1-2 joints affected