Pharmacology of Gout

Question 1

Characteristics of Gout?

Answer 1

1. Hyperuricemia ( > 7.5 -8 mg/dL)
2. Deposits of monosodium urate crystal in joints => causing attack of acute inflammatory arthritis (intensely painful)
3. Tophi (deposits of urate crystals) around the joints with possible joint destruction; can also occur in helix of ear, parenchymal organs
4. Uric acid kidney stones
5. Gouty nephropathy

Question 2

What is the difference in Acute and Chronic Gouty Nephropathy?

Answer 2

1. Acute = oliguric or anuric renal failure due to precipitationo f uric acid in tubules
2. Chronic = deposits of monosodium urate in medullary interstitium

Question 3

Prevention of Recurrent Gout

Treatment

Answer 3

Lower urate via…

1. Life style changes:

• Diet and WL
• Avoid alcohol

2. Urate-lowering drugs:

1. Allopurinol
2. Febuxostat
3. Probenecid
4. Pegloticase

Question 4

General therapetic treatment for Acute Gout

Answer 4

Anti-inflammatory drugs

1. NSAIDS (naproxen and indomethacin) => if cant take,
2. Oral colchicine => if CI
3. Glucocorticoids: intraarticular if >2 joints are affected

Question 5

What are the 3 recommended potent NSAIDs for treating acute gout and the selectivity of each?

Answer 5

1. Naproxen (non-selective)
2. Indomethacin (COX 1 > COX 2)
3. Celecoxib (COX-2, high doses, if others not tolerated)

Question 6

Using NSAIDs for acute gout is most effective if treatment is initiated when?

Answer 6

≤48 hours of onset

Question 7

If there are more than a couple joints affected with gout or NSAIDs/ colchicine are contraindicated, which drugs can be used?

Answer 7

Glucocorticoids (betamethasone + methylprednisone + triamcinolone): systemic/intra-articular

Question 8

MOA of Colchicine used for gout

Answer 8

1. DIffuses into cells to bind to tubulin =>
2. Blocking formation of microtubules =>
3. Inhibits leukocyte migration and phagocytosis

Question 9

Colchicine for gout

1. Uses
2. Pharmocokinetics
   
   1. Best effective when?
   2. t1/2?
   3. Metabolized/excreteion?
   4. CI?

Answer 9

1. Uses
   
   1. Treats gout in patients who are NSAID intolerant or have a CI to NSAIDS
   2. Small doses, prophylactically to prevent recurrence
2. Pharmaokinetics
   
   1. Effective if given 12-24 hours after onset of symptoms
   2. t1/2 = 27 - 31 hours and metabolized by liver/excreted by kidney SO =>
   3. CI in people with advanced renal/liver impairment

Question 10

What are the common toxicities of the gout drug, Colchicine?

Answer 10

GI distress, N/V/D

Question 11

If pt with gout is an underexcreter with good GFR and no tophi or stones, which drugs can be used?

Answer 11

Urate lowering drugs + [Allopurinol, Febuxostat, Uricosuric agent]

Question 12

What is the MOA of Allopurinol?

Answer 12

• • Metabolite acts as competitive inhibitor of xanthine oxidase => cannot convert to urate
• • W/o conversion to urate, hypoxanthine and xanthine are excreted, which are both more soluble than urate/uric acid.

Question 13

Allopurinol

1. Uses
2. Pharmacokinetics

Answer 13

1. Uses
   
   1. Recurrent gout (primary or secondary)
   2. Cancer chemotherapy induced hyperuricemia (tumor lysis syndrome)
2. Pharmokinetics
   
   1. Taken orally, with 1 week to peak effect.
   2. Excreted by kidney; lower dose if renal imparirment.
   3. Lower doses of purine chemo drugs, like azathioprine

Question 14

Allopurinol toxicities

Answer 14

Commonly causes:

1. Skin rash
2. Acute attack of gout
3. N/D
4. Increased liver enzumes

Serious AE: severe hypersensitivity reaction called Stevens-Johnson Syndrome (epidermal necrolysis) –> ↑ risk if HLA-B*5801 (Chinese, Thai)

Question 15

MOA of Febuxostat used for gout

Answer 15

1. • Non-purine inhibitor of xanthine oxidase –> blocks conversion to urate
2. • Hypoxanthine and xanthine are excreted

Question 16

Febuxostat for gout

1. Use
2. Toxcities

Answer 16

1. Use: Gout, if cannot tolerate allopurinol. Thus, typically well-tolerated.
2. Toxicity: Well-tolerated, but EXPENSIVE ($384/30 tablets)

Question 17

MOA Pegloticase

Answer 17

• MOA:
  
  • Recombinant mammalian uricase, covalently attached to methoxy polyethylene glycol –> prolongs circulating 1/2-life and diminishes immunogenic response
  • Converts uric acid => allantoin, WAY more soluble

Question 18

Pegloticase

1. Uses
2. Pharmokinetics

Answer 18

1. Use: Treat chronic gout in those that don’t respond to conventional treament
2. Pharmacokinetics: _IV q 2 week_s; no need to adjust if kidney/liver are impaired.

Question 19

Toxicities with Pegloticase and how can they be managed?

Answer 19

• Infusion rxns (fever, chills, rash, angioedema, bronchospasm, hypo- or HTN)
• Thus, premedicate w/ glucocorticoids and anti-histamines

Question 20

What is Rasburicase?

Answer 20

Non-pegylated recombinant uricase used to prevent acute uric acid nephropathy due to tumor lysis syndrome in patient with high-risk lymphoma or leukemia (EXPENSIVE = ~$965 for 1.5 mg)

Question 21

MOA of Probenecid and Sulfinpyrazone used for gout

Answer 21

• Organic acid that acts at anionic transport sites in renal tubule to block resaborption of urate more than urate secretion =>
• ↑ the fractional excretion of urate –> ↓ plasma [urate]

Question 22

Uses for Probenecid for gout

Answer 22

Used in underexcreters w/ GFR >60 mL/min and no stones to ↓ body pool of urate in pt’s with:

• Hyperuricemia
• Frequent attacks
• Tophi (?)… some say OK, others say no

Question 23

Why is low-dose aspirin not a good choice for gout?

Answer 23

Aspirin promotes urate reabsorption

Question 24

Toxicities of Probenecid and Sulfinpyrazone used for gout; strategies for minimizing these effects?

Answer 24

1. Acutely ↑ risk of kidney stones (both uric acid and calcium oxalate) –> minimize by keeping well-hydrated and urine pH >6
2. Gouty arthritis flare
3. Contains sulfur, so may cause hypersensitivity