Gout Drugs

Question 1

Colchicine

Answer 1

• Used to terminate acute gout attacks and prophylactically
• Mechanism
o Stabilizes tubulin to inhibit microtubule polymerization
o This impairs neutrophil chemotaxis/ingestion of crystals, thus stopping inflammation via neutrophil degranulation
• Metabolism
o Liver de-acetylation with 80% of excretion via the biliary system (20% renal)
o Decreased renal/hepatic function is a worry due to increased half-life, thus toxicity
• CBC/alkaline phosphatase should be regularly checked
• Side effects
o GI distress – a sign of overdosing, can be used to determine proper dosage
o Myelosuppression – happens in chronic treatment; occurs after GI adverse events
o Myopathy/rhabdomyolysis – can occur with overdose
o Stocking/glove neuropathy – occurs with higher doses, due to impaired neurotransmitter transport to distal neurons

Question 2

Indomethacine or (Naproxin or Glucocorticoids)

Answer 2

• Non-selective COX inhibitor (NSAID)
• Used to treat acute gout attacks through inhibiting prostaglandin production by neutrophils
• Review the lecture on NSAIDs for this guy
• Naproxin or glucocorticoids are also used to depress inflammation of gout

Question 3

Allopurinol

Answer 3

• Used to reduce plasma levels of uric acid, increase excretion of uric acid, dissolve tophi, and prevent formation of uric acid kidney stones
• Major treatment for inborn errors of metabolism that cause gout (HPRP or HGPRT)
• Mechanism
o Allopurinol is a competitive inhibitor of xanthine oxidase, a key enzyme in urate production
o Oxypurinol (a metabolite of allopurinol) is a non-competitive inhibitor of xanthine oxidase
o Decreased production of urate lowers levels in the blood
o Decreased plasma levels pull crystalline urate into soluble urate for secretion
• Side effects
o Increased incidence of acute gout attack (pulling crystalline gout into solution can trigger an acute attack in the short term)
o Hypersensitivity dermatitis or exfoliating dermatitis
• Can be prevented with desensitization upon sub-therapeutic exposure
o 6-mercaptopurine interactions
• 6-MP is metabolized by xanthine oxidase for its chemotherapeutic effects
o Ampicillin/B-lactam antibiotics contraindicated because of increased exfoliative dermatitis

Question 4

Febuxostat (Uloric)

Answer 4

• Used to reduce plasma levels of uric acid, increase excretion of uric acid, dissolve tophi, and prevent formation of uric acid kidney stones
• Potent inhibitor of xanthine oxidase (just like allopurinol)
• Not related to allopurinol structurally, so there’s less side effect risk (yay!)

Question 5

Probenecid

Answer 5

• Used to reduce plasma levels of uric acid, increase excretion of uric acid, dissolve tophi, and prevent formation of uric acid kidney stones treatment of
• Mainly used for gout cause by under-excretion
• Mechanism
o Competitive inhibitor of uric acid reabsorption in the proximal convoluted tubule, so more is excreted in urine
• Must give with adequate hydration to prevent kidney stone formation

Question 6

Pegloticase

Answer 6

• Used to treat severe gout in patients that have failed previous therapy
• Only given by IV infusion
• Mechanism
o Pegylated version of pig urate oxidase (humans do not have this enzyme naturally)
o Converts uric acid into allantoin, which can be easily excreted in the urine
o Results in rapid decline in plasma uric acid levels
• Side effects
o Acute gout flares occur in nearly all patients; prophylactic cholchicine/NSAID/or glucocorticoid should always be given before infusion
• Extremely expensive (>$30,000 a year)
• Often antibodies are developed against the PEG moiety on the enzyme