Hypouricemic Drugs PDF

Hypouricemic Agents And colchicine Sites of action for drugs that are used to lower serum urate levels. Goals of gout treatment 1. Safe and rapid treatment of acute gouty attacks to alleviate pain and to restore joint function. - usually done with NSAIDs, corticosteroids...

Hypouricemic Agents And colchicine Sites of action for drugs that are used to lower serum urate levels. Goals of gout treatment 1. Safe and rapid treatment of acute gouty attacks to alleviate pain and to restore joint function. - usually done with NSAIDs, corticosteroids or colchicine. 2. to prevent recurrent attacks and the future development of destructive arthropathy, tophi formation, and nephrolithiasis - done with hypouricemic therapy. Colchicine  It is an alkaloid derivative from the plant Colchicum autumnale,  It has been used in the treatment of acute gout for nearly two centuries and for joint pain since the sixth century.  It has long been believed that the clinical response of acute arthritis to colchicine was diagnostic for gout  Colchicine Mechanism of action It has antiinflammatory action by 1. Inhibiting neutrophil chemotaxis. 2. Interferes with membrane-dependent functions of neutrophils, such as phagocytosis, 3. inhibits phospholipase A2, which leads to lower levels of inflammatory prostaglandins and leukotrienes (LTB4). Colchicine Pharmacokinetics  It is not bound to plasma proteins and is highly lipid-soluble, readily passing into all tissues.  The half-life is 4 hrs following oral administration.  It can be detected in neutrophils up to 10 days after a single dose.  It is hepatically metabolized & excreted principally in the bile, with 20% excreted unchanged in urine. Colchicine Indications  Treatment of acute gouty attacks  Prophylaxis against future attacks, especially when hypouricemic therapy is initiated.  Treatment of other inflammatory arthropathies e.g., familial Mediterranean fever, pseudogout, and acute sarcoid arthritis. Colchicine  Dosages  Colchicine is available orally in 0.5-0.6-mg tablets.  Prophylactic dose: ◦ 0.6 mg once or twice daily if the patient has normal renal function (completely prevents or significantly lowers their frequency in 80% to 85% of patients). ◦ usually with minimal toxicity ◦ should be continued until the patient is without symptoms of gout for several months.  Acute attacks: 1.2 mg followed in 1 hour by 0.6 mg provides similar efficacy with less toxicity compared with higher dose regimens. Colchicine Precautions:  The dose must be reduced (or not used) in patients with ◦ severe renal insufficiency, ◦ severe hepatic disease, or ◦ medications that are CYP 3A4 inhibitors (clarithromycin, erythromycin, ketoconazole, Ca channel blockers, others).  Should be avoided (if possible) in patients on cyclosporine because of risk of neuromyopathy.  Tacrolimus is less of a problem. Colchicine Toxicity  Most adverse effects are dose and duration related.  Risk increased with chronic use and renal insufficiency.  No antidotes to overdose and hemodialysis is ineffective.  Potential side effects include: ◦ GI effects (diarrhea, nausea, vomiting, rarely malabsorption syndrome and hemorrhagic gastroenteritis). ◦ Bone marrow suppression (thrombocytopenia, leukopenia) ◦ Neuromyopathy (↑CK, proximal weakness, peripheral neuropathy, lysosomal vacuoles on biopsy) – usually seen in patients on chronic colchicine who also have renal insufficiency.  Alopecia.  Oligospermia and amenorrhea.  CNS dysfunction. Uric acid-lowering therapy (Antihyperuricemic therapy)  Uricosurics (probenecid): reduce serum urate concentration by enhancing renal excretion of uric acid.  Xanthine oxidase inhibitors (allopurinol and febuxostat): inhibit uric acid synthesis by inhibiting xanthine oxidase, the final enzyme involved in the production of uric acid.  Uricase (pegloticase): converts uric acid into allantoin. Uric acid-lowering therapy (Antihyperuricemic therapy)  Should be initiated only after an acute attack of gout has resolved entirely.  The risk of acute gouty attacks following their initiation can be minimized by gradual dose increases and by prophylaxis with colchicine, NSAIDs, or low-dose prednisone.  It is a lifelong therapy, so initiated only when they are truly indicated.  Uricosurics can be safely used concomitantly with allopurinol in some patients with severe tophaceous gout. Uricosuric therapy Mechanism of action Uricosuric drug  Inhibit URAT1 and GLUT9 resulting in less  Probenecid tubular reabsorption of urate, which leads to increased urinary excretion of uric acid  Sulfinpyrazone  Work better when there is good urine alkalinization (pH >6.0) and flow (>1500  Benzbromarone mL/day) to minimize the risk of uric acid nephropathy and nephrolithiasis.  Can be safely used in conjunction with other  Losartan urate-lowering therapies.  Fenofibrate, Atorvastatin,  Leflunomide  High-dose (>4 g/day) salicylates  PEARL: hypertension is common in patients with gout. Consider using a urate-lowering medication such as losartan to treat hypertension instead of hydrochlorothiazide, which raises uric acid levels. Uricosuric therapy  Indications of uricosuric therapy  Indications in patients with recurrent gouty arthritis include: ◦ Hyperuricemia secondary to underexcretion of uric acid (800 mg in 24- hour urine collection on a regular diet).  2. Nephrolithiasis.  3. Renal insufficiency (creatinine clearance 12.0 mg/dL or 24-hour urine uric acid >1100 mg.  Xanthine oxidase inhibitors febuxostat Allopurinol A potent and selective Inhibiting the enzyme, xanthine Mechanism of xanthine oxidase inhibitor oxidase → ↑ in the precursors, action xanthine and hypoxanthine - is metabolized by xanthine Pharmacokinetic oxidase to the active metabolite, properties oxipurinol, which has a much longer half-life (14 to 28 hours).. - 50% absorbed through - Well absorbed from the GI tract the GIT, metabolized by and has a half-life of 60 minutes. the liver, and has both - The dosage should be lowered in hepatic & renal excretion. renal insufficiency. Seen 5 to 7 days after Seen 7 to 14 days after starting Maximum anti- starting febuxostat allopurinol hyperuricemic effect - Neither allopurinol nor febuxostat should be started during an acute gout attack. Either one can be started after the attack is completely resolved. If a patient experiences a gout attack while receiving one of these drugs they should continue to take them throughout the attack. Xanthine oxidase inhibitors febuxostat Allopurinol -Available as a 40-mg and 80-mg  Available orally as 100 and 300mg Dose tablet, tablets - Given as a once-daily dose.  Usually given in once-daily dose. - It is started at 40 mg/day  To limit gout flares and toxicity, It is and subsequently increased to It is started at 100 mg/day & 80 mg/day or 120 mg/day to increased by 100 mg every month achieve a goal uric acid of 30 mL/min. if GFR is