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6. Gout pharmacology
- 1. Gout Hussein Hallak, Ph.D. Al-Quds University
- 2. Definition A group of diseases characterized by prolonged increases in serum urate conc. recurrent attacks of acute arthritis possible renal disease
- 4. Basic Pathophysiology a disorder of purine metabolism • rate of urate production > rate of urate elimination • plasma urate conc. exceeds limit of solubility (7.0 mg/dL in plasma at 37oC)
- 5. Uric Acid waste product of purine metabolism xanthine oxidase catalyzes last two synthesis steps renal elimination governed by glomerular filtration, then passive reabsorption, then active secretion and reabsorption physicochemical properties pKa 5.5 solubility: 6-8 mg/dL at pH 5 124-160 mg/dL at pH 7
- 6. Joint Manifestations •synovial joints affected (gout attack may also occur in other joints) •deposits of calcium urate monohydrate crystals in synovial leukocytes •sudden onset of intense pain in 1 or more joints •usually remits in 2-3 days •symptom-free intervals between attacks
- 8. Systemic Manifestations fever leukocytosis elevated erythrocyte sedimentation rate (ESR) Renal Pathology deposition of urate crystals obstructive disease urate stones in pelvis
- 9. Asymptomatic Hyperuricemia gout without complications ? management is controversial: may not need to be treated nephropathy rare in absence of articular gout However, > 50% chance of gout if UA > 10 mg/dL > 50% chance of nephropathy if UA excretion > 1100 mg/day
- 10. Food to Avoid Beer and Alcoholic beverages Fish especially shell fish Legumes (Dried peas and beans) Organ meat (Liver, kidney) Meat Mushrooms Spinach Asparagus Cauliflower Artificial foods and beverages Refined flour preparations (Bakery products)
- 11. Drug-Induced Hyperuricemia thiazides nicotinic acid salicylates (< 2 g/day) ethyl alcohol L-Dopa cytotoxic agents
- 12. Management Strategies Treat the acute attack NSAIDs colchicine Prevent recurrence (lower serum UA) Inhibitor of UA formation allopurinol (Alloril®) Uricosuric agents probenecid sulfinpyrazone
- 13. Colchicine • Prevention and treatment of gout and FMF (familial Mediterranean fever). • Interferes with mobility of granulocytes in synovial space (prevent release of inflammatory mediators: Leukotrienes) • For Acute Attack: useful when taken within 24 hours of onset of a gout flare. Dose: 1 mg at first sign of gout attack, followed by 0.5 mg after 1 hour • For Prophylaxis: 0.5 mg 1 or 2 times a day • Side Effects: unacceptable nausea and diarrhea
- 14. NSAIDs many regimens indomethacin (Indovis®) 75 mg p.o. 1st dose, then 50 mg q. 6 h. for 2 days, then 50 mg q. 8 h. for 2-3 days ibuprofen (Trufen®, Nurofen®) 800 mg p.o. q. 6 h. for 2-3 days, then 800 mg q. 8 h for 2-3 days
- 15. Prevention Strategies approach based on 24-h UA urinary excretion: < 600 mg > 800 mg patient is probably an under-excreter patient is probably an over-producer uricosuric agent xanthine oxidase inhibitor
- 16. Allopurinol inhibits xanthine oxidase 100 to 300 mg p.o. once daily may increase to 600-800 mg/day adverse effects: rash GI disturbance
- 17. Allopurinol Drug Interactions: ampicillin increased frequency of penicillin rashes theophylline increased theophylline levels at allopurinol doses > 600 mg/day azathioprine increased toxicity of azathioprine
- 18. Febuxostat and Allopurinol N H N N HN O NC O S N CH3 CO2H CH3 H3C Febuxostat Allopurinol Structure Tablet Formulation 40 mg or 80 mg 100 mg or 300 mg Dosing Range 40 mg-80 mg 100 mg-800 mg Dosing Frequency Once daily Once daily for ≤300 mg Divided doses for >300 mg Drug Elimination Primarily hepatic Primarily renal Dose adjustment in None Yes patients with mild to moderate renal impairment
- 21. Sulfinpyrazone 50 mg. p.o. b.i.d. for 3-4 days, then 100 mg b.i.d. increase by 100-mg increments weekly until UA in desired range adverse effects: upper GI disturbance may reactivate peptic ulcer rash rare: anemia inhibits reabsorption of UA in proximal renal tubule
- 22. Probenecid inhibits reabsorption of UA in proximal renal tubule 250 mg p.o. b.i.d. for 1-2 weeks, then 500 mg b.i.d. for 2 weeks increase by 500 mg/day every 1-2 weeks until UA in desired range adverse effects headache GI disturbances rash, rare: anemia,
- 23. Probenecid Drug Interactions: •methotrexate enhanced methotrexate toxicity •penicillins delayed elimination of penicillin
- 24. Urinary pH Adjustment adjunctive therapy desired pH range 6.0 - 6.5 sodium bicarbonate 0.5 - 1.5 g p.o. q. 6 h.
- 25. Uric Acid Production About two-thirds of uric acid is generated endogenously by the body, while one-third comes from purines in the diet Purine Catabolism2-5 Xanthine Oxidase Xanthine Oxidase Urate Oxidase (Uricase) End product for humans, higher primates, reptiles, birds, and some mammals End product for the majority of mammals Hypoxanthine Xanthine Uric Acid Allantoin
- 26. Pegloticase (Krystexxa®) Medication for treatment of severe, treatment-refractory, chronic gout. Pegloticase is a recombinant porcine-like uricase, it metabolizes uric acid to allantoin. This reduces the risk of precipitates, since allantoin is five to ten times more soluble than uric acid. Pegloticase is pegylated to increase its elimination half-life from about eight hours to ten or twelve days, and to decrease the immunogenicity of the foreign uricase protein. This modification allows for an application just once every two to four weeks, making this drug suitable for long-term treatment Pegloticase is given as an intravenous infusion every two weeks, has been found to reduce uric acid levels
- 27. Side effects In individuals with glucose-6-phosphate dehydrogenase deficiency, pegloticase may result in severe, life-threatening hemolysis Pegloticase may also show immunogenicity, about 40% of people develop resistance to the medication over time