Colchicine in Gout Treatment

Hypouricemic Agents and Colchicine

• Hypouricemic agents are drugs used to lower serum urate levels.
• Colchicine comes from the Colchicum autumnale plant.
• Colchicine has been used for centuries to treat acute gout and joint pain.
• The clinical response to colchicine was initially a diagnostic tool for gout.

Sites of Action for Drugs

• Drugs used to lower serum urate levels work at various points in the purine metabolism pathway.
• Purines are metabolized to hypoxanthine and xanthine, then further to uric acid.
• Xanthine oxidase inhibitors prevent uric acid production.
• Uricosurics increase renal excretion of uric acid.
• Uricase converts uric acid to allantoin, which is more readily excreted.
• Tissue deposition and inflammation (tophi formation) from uric acid are also targeted.
• Drugs can also inhibit processes such as phagocytosis of uric acid crystals.

Goals of Gout Treatment

• Acute gout attacks require rapid pain relief and restoration of joint function (NSAIDS, corticosteroids, colchicine are often used).
• Long-term prevention of recurrent attacks and prevention of destructive arthropathy, tophi formation, and nephrolithiasis is achieved with hypouricemic therapy.

Colchicine Mechanism of Action

• Colchicine acts as an anti-inflammatory agent.
• It interferes with neutrophil functions, including chemotaxis and phagocytosis.
• Colchicine inhibits phospholipase A2, which lowers inflammatory prostaglandins and leukotrienes.

Colchicine Pharmacokinetics

• Colchicine is not protein-bound.
• It's highly lipid-soluble and readily crosses tissues.
• The half-life is about 4 hours after oral administration.
• Colchicine can be detected in neutrophils for up to 10 days after a single dose.
• It's primarily metabolized in the liver and excreted in bile with about 20% excreted unchanged in urine.

Colchicine Indications

• Treatment of acute gouty attacks.
• Prophylaxis against future attacks, especially when initiating hypouricemic therapy.
• Treatment of other inflammatory arthropathies (e.g., familial Mediterranean fever, pseudogout, acute sarcoid arthritis).

Colchicine Dosages

• Colchicine is available as 0.5-0.6 mg tablets.
• Prophylactic dose: 0.6 mg once or twice daily (reduces frequency in up to 85% of patients with normal renal function), usually until symptoms are resolved.
• Acute attacks: 1.2 mg initial dose, followed by 0.6 mg one hour later; provides similar efficacy to higher dose regimens with less toxicity.

Colchicine Precautions

• Reduce dose or avoid in patients with severe renal or hepatic insufficiency.
• Avoid in patients taking CYP3A4 inhibitors.
• Cautious use in patients on cyclosporine (risk of neuromyopathy). Tacrolimus is less problematic.

Colchicine Toxicity

• Most side effects are dose and duration-related and worsen with chronic use and renal insufficiency.
• No antidotes for overdose, and hemodialysis is ineffective.
• Potential side effects include GI effects, bone marrow suppression, neuromyopathy, alopecia, and reproductive issues.

Uric Acid-Lowering Therapy (Antihyperuricemic)

• Uricosurics (probenecid): enhance renal excretion of uric acid.
• Xanthine oxidase inhibitors (allopurinol, febuxostat): inhibit uric acid synthesis.
• Uricase (pegloticase): converts uric acid to allantoin.

Uric Acid-Lowering Therapy (Initiation)

• Should be initiated only after an acute gout attack has resolved.
• The risk of recurrence is minimized by gradual increases and prophylaxis using colchicine, NSAIDs, or low-dose prednisone.

Uricosuric Therapy (Mechanism)

• Inhibit URAT1 and GLUT9 to decrease tubular reabsorption of uric acid.
• Works best with increased urine alkalinity (pH >6.0) and flow (>1500 mL/day).

Uricosuric Therapy (Probenecid)

• Generally well-tolerated (>90% of patients).
• Should not be stopped during an acute gout attack.
• Half-life: 6-12 hours, hepatically metabolized.
• Forms: 500 mg tablets, sometimes combined with 0.5 mg colchicine.
• Dosage: Initial dose 500 mg twice daily, gradually increased to 3 g daily (average 1 g/day in divided doses).

Uricosuric Therapy (Drug Interactions)

• Probenecid prolongs the half-life of penicillin, dapsone, methotrexate, indomethacin, and others by decreasing their renal excretion.
• It also prolongs heparin metabolism.

Xanthine Oxidase Inhibitors (Indications)

• Urate overproduction (uric acid >800 mg/24 hr urine).
• Nephrolithiasis
• Renal insufficiency (CrCl < 50 mL/min).
• Tophi (may take months to resolve).
• Failure or intolerance of uricosuric agents.
• Other indications include hyperuricemia with nephrolithiasis, tumor lysis syndrome prophylaxis, HPRT deficiency (Lesch-Nyhan syndrome), myeloproliferative disorders, serum urate >12.0 mg/dL, or 24-hour urine uric acid >1100 mg.

Xanthine Oxidase Inhibitors (Febuxostat/Allopurinol - Mechanism/PK)

• Febuxostat/Allopurinol mechanism of action involves inhibiting xanthine oxidase which leads to more xanthine and hypoxanthine.
• Febuxostat is absorbed in the GIT at 50%, metabolized by the liver, and excreted through the liver and kidneys.
• Allopurinol is metabolized to oxipurinol by xanthine oxidase and has a long half-life (14-28 hrs.).

Xanthine Oxidase Inhibitors (Febuxostat/Allopurinol- Dosages/Toxicity)

• Febuxostat is given at 40-mg/80-mg once daily and can be increased to 80-120mg/day.
• Allopurinol is given at 100-mg/300-mg daily and can be increased to 4 mg/kg.
• Allopurinol side effects include a maculopapular rash (3% risk), diarrhea, abnormal liver function enzymes.
• Allopurinol hypersensitivity syndrome (AHS) is less common but can be severe, presenting with skin rash, fever, eosinophilia, hepatic necrosis, leukocytosis, and worsening renal function within 2-4 weeks of starting treatment. AHS occurs in 0.1% to 0.4% of patients. Use of desensitization protocols is no longer recommended.

Pegloticase Mechanism/Administration/Precautions

• Pegloticase is a recombinant mammalian uricase attached to polyethylene glycol (PEG).
• It's used for severe or refractory gout when other treatments fail to lower serum uric acid to <6 mg/dL.
• Given as a 2-hour IV infusion of 8 mg every 2 weeks
• All patients must be screened for G6PD deficiency before use. Avoid in patients with low G6PD activity.
• Monitor serum uric acid levels before each infusion to assess efficacy and to avoid antibody-mediated reactions, including anaphylaxis.
• Initiate prophylaxis (colchicine, NSAIDs, or prednisone) one week before pegloticase initiation.

Renal Handling of Uric Acid

• Uric acid is excreted primarily (66%) through the kidneys via glomerular filtration, proximal tubule reabsorption, and tubular secretion and reabsorption.
• In renal failure, GI excretion increases.

Test your knowledge on colchicine's role in treating gout, including its anti-inflammatory effects, recommended dosages, and potential drug interactions. This quiz covers essential information about the use of colchicine in clinical practice and its effects on patient care.