Gout_.pdf

Pharmacotherapy of Gout Arthritis Gout Gout is increase in body storage of uric acid that is the end product of purine metabolism Acute attacks : inflammation because of uric acid crystals Typical presentation : waking in night due to pain in large toe Exogenous purines: meat, fried food, alcohol 2...

Pharmacotherapy of Gout Arthritis Gout Gout is increase in body storage of uric acid that is the end product of purine metabolism Acute attacks : inflammation because of uric acid crystals Typical presentation : waking in night due to pain in large toe Exogenous purines: meat, fried food, alcohol 2 Gout therapeutics: new drugs for an old disease Christopher M Burns, Robert L Wortmann Lancet 2011; 377: 165–77 3 Gout treatment which one of the drugs below can onle ben used treat acute gout? Acute: to treat inflamation – nonsalicylate NSAIDs, esp. indomethacin, – Colchicine Chronic: to decrease uric acid levels – urocosuric agents (probenecid, sulfinpyrazone) – agents that inhibit uric acid production (allopurinol, febuxostat) – Colchicine 4 5 Colchicine which one of the drugs below can be used fro phrphlacics of gout ? Crocus plant (Colchicum autumnale), alkaloid with anti-inflamatory properties. – Can be used to relieve pain of an acute gout attack or prophylactically – Unlabeled uses: multiple sclerosis, cirrhosis Action: – Selective inhibition of microtubule assembly and prevents leucocyte migration and phagocytosis inhibits cell mitosis 6 Colchicine for prophylaxis and acute and chronic gouat colchicine is reccomended it should be taken via iv. false Effects (reduction of inflammation) and pain) occur within 12-24 hrs Dosage: In prophylaxis (the most common use), the dosage of colchicine is 0.6 mg, 1-3 times daily For terminating an attack of gout, the traditional initial dose of colchicine is usually 0.6 or 1.2 mg, followed by 0.6 mg every 2 hours until pain is relieved or nausea and diarrhea appear. – – Recently a regimen of 1.2 mg followed by a single 0.6 mg oral dose was shown to be as effective as the higher dose therapy above. Adverse events were less with the lower dose regimen. The total dose can be given intravenously if necessary, but it should be remembered that as little as 8 mg in 24 hours may be fatal. Therefore, intravenous use of colchicine is not recommended. In February 2008, the FDA requested that intravenous preparations containing colchicine be discontinued in the USA due to their potential life-threatening adverse effects. 7 Colchicine Side effects: 80% of patients – Nausea, vomiting, abdominal pain, diarrhea with oral intake – I.v. , less GI side effects, faster relief (6-12h), but increased risk of dermal side effects – Rarely liver damage and blood dyscresias – Overdose causes severe toxicity which can be fatal. Acute intoxication after overdoses is characterized by burning throat pain, bloody diarrhea, shock, hematuria, and oliguria. Multisystem failure Fatal ascending central nervous system depression has been reported -- Treatment is supportive. In February 2008, the FDA requested that intravenous preparations containing colchicine be discontinued in the USA due to their potential life-threatening adverse effects. Therefore, intravenous use of colchicine is not recommended. 8 Allopurinol final step in uric acid formation➔ allopurinol inhibits xanthine oxidase (XO) enzyme and also denovo purine synthesis Hypoxantine xantine XO Allopurinol uric acid XO alloxantine (also inhibits XO) 9 Allopurinol Used in chronic thophaceous gout, Also in patients with malignancies, calcium oxalate calculi Reduces the size of formed tophi Colchine is added in the first week of therapy Acute attacks of gout occur commonly during the early stages of therapy (possibly as a result of physicochemical changes in the surfaces of urate crystals as these start to redissolve), so treatment is never initiated during an acute attack and is usually initiated accompanied by an NSAID 10 Allopurinol which drug shouldnt be cansumeed in bm diseases or liver diseases? given orally and is well absorbed in the gastrointestinal tract. half-life is 2-3 hours; it is converted to alloxanthine (half-life: 18-30 hours) Side effects: GI disturbances, dermatitis Be cautious in liver disease and bone marrow depression 11 Febuxostat what is the recommended treatment in patients with allopurinol tolrance ? first nonpurine inhibitor of xanthine oxidase – potent and selective inhibitor of xanthine oxidase, and thereby reduces the formation of xanthine and uric acid Well absorbed orally, metabolized in liver daily dose of 80 mg or 120 mg: more effective than allopurinol at a standard 300 mg daily dose in lowering serum urate levels. Adverse Effects: liver function abnormalities, diarrhea, headache, and nausea. Febuxostat appears to be well tolerated in patients with a history of allopurinol intolerance. – As with allopurinol, prophylactic treatment with colchicine or NSAIDs should start at the beginning of treatment to avoid gout attacks. 12 which drug is recommanded to a pateint sufferinf from goat with leukemia / hperuricemia ? Rasburicase recombinant urate-oxidase : catalyzes the enzymatic oxidation of uric acid into the soluble and inactive metabolite allantoin. – it lowers urate levels more effectively than allopurinol and is indicated for the initial management of elevated plasma uric acid levels in pediatric patients with leukemia, lymphoma, and solid tumor malignancies who are receiving anticancer therapy expected to result in tumor lysis and significant hyperuricemia. Produced by a genetically modified Saccharomyces cerevisiae strain, the therapeutic efficacy may be hampered by the production of antibodies against the drug. in which case we see decrease in effecince of Rasburicase. Hemolysis in glucose-6-phosphate dehydrogenase (G6PD)-deficient in which pateints is rasburicase not recommended ? patients, methemoglobinemia, acute renal failure, and anaphylaxis all have been associated with the use of rasburicase. Other frequently observed adverse reactions include vomiting, fever, nausea, headache, abdominal pain, constipation, diarrhea, and mucositis. 13 Pegloticase The newest urate-lowering therapy; approved for the treatment of refractory chronic gout. Recombinant mammalian uricase: Urate oxidase enzyme, absent in humans and some higher primates, converts uric acid to allantoin. This product is highly soluble and can be easily eliminated by kidney. Pegloticase covalently attached to methoxy polyethylene glycol (mPEG) to prolong the circulating halflife and diminish immunogenic response. Rapidly acting iv drug, The serum half-life ranges from 6.4 to 13.8 days. Achieve a peak decline in uric acid level within 24–72 hours and maintain low urate levels for up to 21 days at doses of 4–12 mg, allowing for IV dosing every 2 weeks The recommended dose for pegloticase is 8 mg IV every 2 weeks. As noted for other urate-lowering therapy, patients should be started on prophylaxis for acute gout flares (using colchicine) while initiating pegloticase. 14 Pegloticase Adverse Effects The most common adverse events include infusion reactions and gout flare (especially during the first 3 months of treatment). Nephrolithiasis, arthralgia, muscle spasm, headache, anemia, and nausea may occur. Other less frequent side effects noted include upper respiratory tract infection, peripheral edema, urinary tract infection, and diarrhea. There is some concern for hemolytic anemia in patients with glucose-6-phosphate dehydrogenase because of the formation of hydrogen peroxide by uricase; therefore, pegloticase should be avoided in these patients. Large numbers of patients show immune responses to pegloticase. The presence of antibody is associated with shortened circulating half-life, loss of response leading to a rise in plasma urate levels, and a higher rate of infusion reactions. Monitoring of plasma uric acid level, with rising level as an indicator of antibody production, allows for safer administration and monitoring of efficacy. 15 Probenecid, Sulfinpyrazone (uricosuric agents) Organic acid Decrease urate levels: inhibits renal tubular reabsorption of uric acid, by competing for the weak-acid carrier (anionic transport) in kidneys which one of the durgs below can not be uaed during acute gouat attack ? Should not be used during an acute gout attack May precipitate an attack --- used in conjunction with cholchicine in chronic gout treatment 16 Probenecid, Sulfinpyrazone (uricosuric agents) Formation of urate stones (urolithiasis)→ fluid intake should be increased, alkalinize urine by potassiunm citrate GI disturbances, dermatitis, blood discreasiase Probenicid and Allopurinol interact – Allopurinol increases the half-life of probenecid and enhances its uricosuric effect, while – probenecid increases the clearance of alloxanthine, thereby increasing dose requirements of allopurinol 17 Probenecid, Sulfinpyrazone (uricosuric agents) Interacts with drugs actively secreted by renal tubules: penicillin, cephalosporins, NSAIDs and methotrexate – Dose reduction of these drugs may be considered. Aspirin or other salicylates are contraindicated: they will antagonize the effects of uricosuric drugs which drugs shouldnt be used with uricosuric drugs ? 18 Interleukin-1 Inhibitors Drugs targeting the IL-1 pathway, such as anakinra, canakinumab, and rilonacept, are being investigated for the treatment of gout. – Although the data are limited, these agents may provide a promising treatment option for acute gout in patients with contraindications to, or who are refractory to, traditional therapies like NSAIDs and/or colchicine. A recent study suggests that canakinumab, a fully human anti-IL-1β monoclonal antibody, can provide rapid and sustained pain relief at a dose of 150 mg subcutaneously. These medications are also being evaluated as therapies for prevention of gout flares while initiating urate-lowering therapy. 19 Gout therapeutics: new drugs for an old disease Christopher M Burns, Robert L Wortmann Lancet 2011; 377: 165–77 20 21 Am J Manag Care. 2005;11:S451-S458 Gout therapeutics: new drugs for an old disease Christopher M Burns, Robert L Wortmann Lancet 2011; 377: 165–77 22