Gout Treatment

Question 1

Gout

Pathophysiology

Answer 1

Deposition of uric acid crystals in connective tissue and/or the joint space.

• Excess uric acid
• Sodium ureate precipitates (low water solubility)
• MΦ take up noxious crystals
• Lysosomal enzymes fail to metabolize precipitate
• Mechanical stress ⇒ lysosomal rupture ⇒ release of cytotoxic enzymes and inflammatory mediators
• Recurrent joint inflammation and tissue damage
  
  • Joint pain ⇒ big toe, foot, ankles, knees

Question 2

Hyperurecemia

Risk Factors

Answer 2

• Foods rich in purines
  
  • Anchovies, sardines, fish roes, herring
  • Yeast
  • Organ meat (liver, kidney, sweetbreads)
  • Legumes (dried beans, peas)
  • Meat extracts, consomme, gravies
  • Mushroom, spinach, asparagus, cauliflower
• Alcoholic beverages
• Certain drugs ⇒ induce gout in susceptible pts
  
  • Diuretics, aspirin, niacin, cyclosporine, L-Dopa
• Genetics, gender, obesity
• Defect in the enzyme that breaks down purines
• Exposure to lead

Question 3

Ethanol Effects

Answer 3

• Ethanol metabolism ⇒ production of NADH
  
  • Excess NADH converts pyruvic acid → lactic acid
  • Lactic acid serves as an exchange anion ⇒ ⊕ uric acid reabsorption
• EtOH admin shown to ↑ uric acid production via net ATP → AMP
• ↓ Urinary excretion 2/2 dehydration and metabolic acidosis contributes
• Non-alcoholic components may play a role
  
  • Ingested purines in beer (e.g. absorbable guanosine)

Question 4

Acute Attack

Treatment

Answer 4

• NSAIDS
  
  • Indomethacin or naproxen
  • Avoid aspirin
• Corticosteroids (prednisone) or ACTH
  
  • Usually intra-articular
• Colchicine ⇒ when NSAIDS or corticosteroids cannot control sx
  
  • Given PO every hour until sx improve or until side effects become intolerable

Question 5

Aspirin

Effects

Answer 5

Urate ⇆ across tubular lumen ⇒ opposing effects on urate transport by different doses of aspirin:

• Large doses of aspirin (an acid) ⇒ uricosuric
  
  • Compete with uric acid ⇒ net ↓ in uric acid reabsorption
• Low doses of aspirin ⇒ net uric acid retention
  
  • ⊗ secretory transporters

Aspirin should not be used for analgesia in patients with gout.

Question 6

Colchicine

Uses

Answer 6

• Acute attacks refractory to NSAIDS/steroids
  
  • Not used as frequently as NSAIDS d/t adverse effects
• Lower doses also used for prophylaxis of recurring gouty arthritis

Question 7

Colchicine

MOA and Effects

Answer 7

• Binds to tubulin ⇒ ⊗ tubulin polymerization to form microtubules:
  
  • ⊗ leukocyte migration/phagocytosis
  • ⊗ leukotriene B4 formation
• ↓ Inflammation and pain associated with acute gouty arthritis
• More specific for gout than NSAIDS

Question 8

Colchicine

Adverse Effects

Answer 8

• Major side effects are GI distress ⇒ diarrhea and vomiting
  
  • Drug undergoes enterohepatic circulation ⇒ ↑ T_½ ⇒ ↑ exposure of the GI tract
• Acute high doses:
  
  • Renal failure
  • Bloody diarrhea
• Chronic use:
  
  • Bone marrow suppression
  • Aplastic anemia
  • Thrombocytopenia
  • Alopecia

Question 9

Colchicine

Contraindications

Answer 9

Renal disease, hepatic dysfunction, or GI disease

Question 10

Attack Prevention

Answer 10

• Small daily doses of colchicine or NSAIDS
• Maintain a healthy weight, eat the right foods, and drink fluids

Question 11

Hyperuricemia

Treatment

Answer 11

Urate crystals form @ point of saturation (6.8 mg/dL)

Goal of tx to lower serum urate concentration to < 6 mg/dL

Allopurinol ⇒ ↓ uric acid production

Probenecid ⇒ ↑ uric acid elimination

Question 12

Probenecid

MOA and Effects

Answer 12

Uricosuric agent

• Secreted and reabsorbed from the proximal tubule
• Competes with uric acid for renal tubule anionic transport sites ⇒ net ↓ in uric acid reabsorption
  
  • Also ⊗ secretion of other weak acids such penicillin
• Probenecid ↓ total body urate pool in patients with gout
• Should not be used in pts already secreting large amounts of uric acid
  
  • Will precipitate uric acid calculi in the kidney
  • Encourage patient to drink water, give sodium carbonate to prevent

Question 13

Probenecid

Adverse Effects

Answer 13

• Major adverse effects:
  
  • GI irritation
    
    • Take with food or antacids
  • Rash
• May aggravate gout at first
  
  • Tx concurrently with low dose colchicine
  • Introduce drug slowly,
  • Keep patient well hydrated

Question 14

Probenecid

Limitations

Answer 14

Use of probenecid has limitations because:

• Many patients have reduced kidney function
• Uricosuric agents may cause crystallization of uric acid if hydration is not maintained
• Potential for many drug interactions d/t ⊗ of secretion of weak acids ⇒ ∆ clearance
  
  • Methotrexate, oral hypoglycemic agents, zidovudine (HIV antiviral)

Question 15

Allopurinol

MOA and Effects

Answer 15

↓ uric acid production:

• Purines → hypoxanthine and xanthine → uric acid by xanthine oxidase
• Allopurinol is an isomer of hypoxanthine
  
  • Allopurinol → alloxanthin [oxypurinol]
    
    • Active metabolite
    • Much more effective inhibitor
    • Longer half-life than the parent drug
• Allopurinol ⇒ irreversible ⊗ of xanthine oxidase
  
  • ↓ Plasma urate levels
  • ↑ Hypoxanthine and xanthine levels which are more soluble

Question 16

Allopurinol

Adverse Effects

Answer 16

• ↑ Risk of gout early in therapy
  
  • Urate crystals move from tissue to plasma
  • ↑ Dose slowly to prevent acute attacks
• Major adverse effects:
  
  • Skin-rash or other allergic reactions
  • GI disturbances
• Rare adverse effects:
  
  • Peripheral neuropathy
  • Bone marrow suppression
  • Hepatic toxicity
  • Interstial nephritis
• Monitor liver and kidney function
• Drug interactions w/ other drugs metabolized by xanthine oxidase
  
  • Azathioprine or mercaptopurine

Question 17

Allopurinol

Indications

Answer 17

• More widely used than uricosuric agents to prevent acute attacks:
  
  • Lowers serum uric acid in both overproduction and impaired excretion
  • Can be used in pts with renal dysfunction (with caution)
  • Administered once a day
• Can also be used for pts with:
  
  • Recurring renal stones
  • Excessively high serum urate levels
  • Secondary hyperuricemia associated with malignancies

Question 18

Uricase Enzymes

Answer 18

Enzymes that metabolize uric acid to allantoin

• Various forms to tx ⟰ uric acid release after cancer chemotherapy
• Pegylated form to tx gout refractory to other treatments
• Allergic rxn in a small but significant number of pts
  
  • Pts will also develop antibodies to the drug ⇒ ∆ therapeutic efficacy

Question 19

Febuxostat

Answer 19

Non-purine selective inhibitor of xanthine oxidase

• Hepatic metabolism ⇒ can be used in renal insufficiency
  
  • Causes ↑ liver enzymes
• Chemically different from allopurinol ⇒ tolerated by pts w/ allopurinol allergy
• More effective vs allopurinol at ↓ uric acid levels
• At present clinical effect does not appear to be superior

Question 20

Drug Summary

Answer 20