adverse events, SAMAV) (myalgia) (myopathy) (myonecrosis) (clinical rhabdomyolysis) [7] CK CK CK (asymptomatic raised CK [4] statin Intervention Trial

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statins 李燕鳴 Hydroxy-3-methyglutaryl coenzyme A reductase inhibitors ( statins [] [,3] [-5] 005~008 statins 434 50 (8.%) (5.5%) 88.% (57.%) (30.%) (3%) 3 (0.8%) 4 (0.9%) 53 (.

1 statins 李燕鳴 Hydroxy-3-methyglutaryl coenzyme A reductase inhibitors ( statins [] [,3] [-5] 005~008 statins (8.%) (5.5%) 88.% (57.%) (30.%) (3%) 3 (0.8%) 4 (0.9%) 53 (.%) 8 6 (atorvastatin rosuvastatin) 花蓮慈濟醫院家庭醫學科 adverse event, muscle, statins [6] (National Lipid Association, NLA) the statin muscle safety task force) 04 statins [7] statin 不良反應的類型及臨床表徵 Statins HMG-CoA (sarcolemmic membrane) ubiquinone (myositis) creatine kinase, CK) [4,5,7-9] statins NLA statin (statin-associated muscle 4 家庭醫學與基層醫療第五期

adverse events, SAMAV) (myalgia) (myopathy) (myonecrosis) (clinical rhabdomyolysis) [7] CK CK CK (asymptomatic raised CK [4] statin Intervention Trial Evaluating Rosuvastatin ) 7 (6% vs 5.4%) [0] 0.

2 adverse events, SAMAV) (myalgia) (myopathy) (myonecrosis) (clinical rhabdomyolysis) [7] CK CK CK (asymptomatic raised CK [4] statin Intervention Trial Evaluating Rosuvastatin ) 7 (6% vs 5.4%) [0] 0.% [] statin fluvastatin(5.%) pravastatin(0.9%) atorvastatin (4.9%) simvasatin(8.%) [] 0%~5% [3] /000 [4] ( European Atherosclerosis Society) 表 statins 相關肌肉不良反應的類型類型 / 機構 National Lipid Association American College of Cardiology/ American Heart Association 肌肉疼痛 (myalgia) (CK 無上升 ) 肌病變肌疼痛肌疼僵硬肌觸痛運動後肌痙攣肌力弱 ( 非因肌疼痛所致及 CK 不需有上升 ) 肌疼痛或無力肌不適肌炎肌壞疽橫紋肌溶解症 CK 上升無症狀註 :CK: creatine kinase 資料來源 : 參考資料 4, 6 肌發炎 ( 經切片或磁振影像檢查有發炎反應 ) 肌酵素上升或 CK 較治療前明顯上升 (hyperckemia) - 輕度 :CK 值上升 3 倍以上 - 中度 :CK 值上升 0 倍或以上 - 嚴重 :CK 值上升 50 倍或以上肌壞死合併有尿液肌球蛋白 (myoglobinuria) 陽性或急性腎臟衰竭 ( 血清 creatinine 上升 0.5mg/dL) 肌不適併有 CK 值上升 (< 0 倍 ) 肌不適合併 CK 值明顯上升 (>0 倍 ); 尿液肌球蛋白陽性或血清 creatinine 上升 CK 值上升但無肌症狀家庭醫學與基層醫療第五期 5

3 05 statins CK /000~/0000 [5] 診療 statin 相關肌病變的流程建議 SAMAV statin 圖 statins 相關肌病變症狀的評估和處置 statins 用藥病患出現肌肉不適症狀詳細病史 ( 相關病徵及其他可能發生交互作用的藥品和食物 ) 理學檢查檢驗 CK 值, CRP, vitamin D, 甲狀腺激素 CK 值低於參考值上限 0 倍 CK 值正常 CK 值高 ( 等 ) 於參考值 0 倍肌發炎肌疼痛檢驗腎功能尿肌蛋白評估症狀嚴重性異常可耐受難耐橫紋肌溶解症嚴密監控臨床徵狀及 CK 複檢繼續 statin 用藥 statin 停藥 statin 停藥用及轉介轉介腎臟科專科症狀減退及 CK 值恢復後正常再次評估 statin 用藥的利與弊肌病變症狀或 CK 值未下降再次 statin 用藥或用另類降血脂藥註 :CK: 血清肌酸激酶 (creatine kinase) CRP: c-reactive protein 資料來源 : 參考資料, 6 6 家庭醫學與基層醫療第五期

4 表 statins 相關肌疼痛臨床指標計分 (proposed statin myalgia clinical index score) 臨床症狀 ( 新或不明原因的肌症狀 ) 計分部位對稱髖部收縮肌 / 大腿背部疼痛對稱性小腿肌疼痛對稱性上肢近端肌疼痛不非對性非特異性間隔性時序 (statins 藥物治療後出現症狀 ) < 4 週 4- 週 > 週停藥後多久症狀緩和 < 週 -4 週 >4 週再次用藥後多久出現相同症狀 < 4 週 4- 週 statins 相關肌不良反應的可能性很可能有可能不大可能資料來源 : 參考資料總分 <7 4 statin (proposed statin myalgia clinical index score) SAMAV ( ) [7] CK [, 7, 5] CK 50, C reactive protein D D CK 3 4 CK statin ( rosuvastatin pravastatin ( 3 家庭醫學與基層醫療第五期 7

5 表 3 常用 Hydroxy-3-methyglutaryl coenzyme A reductase inhibitors (statins) 藥動學參數比較學品名 Atorvastatin Fluvastatin Lovastatin Pravastatin Simvastatin Rosuvastatin 商品名 Lipitor R Lescol R Mevacor R Mevalotin R Zocor R Crestor R 吸收比例 (%) >= Tmax(hr) Cmax (mg/ml) 7-66 a Bioavailability (%) 食物影響降低降低 / 增加增加降低 0 降低分佈血漿蛋白質結合率 (%) 98 >99 > 脂溶性 b.0.5 NA 代謝肝臟代謝 CYP 3A4, 3A5 CYPC9 CYP3A4 sulfation CYP3A4 CYPC9 代謝物活性活性非活性活性非活性活性低活性排除清除率 (L/hr/kg) 半衰期 t/(hr) 尿排泄 (%) 註 Tmax : 血中濃度最高量時間,Cmax: 最大血中濃度, Bioavailability 生物可用率 NA 無資料 a 劑量為 40mg 的最大濃度,b log P 在 ph 7.4 的藥物脂溶度資料來源 : 參考資料 4 statin 4 statin ezetimibe bile acid sequestrants [, 7, 5] 危險因素及預防策略 SAMAV atorvastatin, lovastatin, simvastatin cytochrome P450 erythromycin, fibrates, diltiazem, verapamil, amiodarone, colchcine [, 6] SAMAV [6] statins 8 家庭醫學與基層醫療第五期

6 7% [7] CYP3A4 macrolide ( erythromycin, clarithromycin) Azoles ketoconazole diltiazem, verapamil) digoxin Fibrates (gemfibrozil) C statins [5,8,9] cycloporins statins statins (rosuvastatin 5mg, simvastatin 0mg, lovastatin 0mg) amiodarone lovastatin 40 mg/ simvastatin 0 mg/ [6] statin CK CK NLA CK CK [7] 結語 Statins statins ( ) [0] 參考資料. Stone NJ, Robinson JG, Lichtenstein AH, et al: Treatment of blood cholesterol to reduce atherosclerotic cardiovascular disease risk in adults: synopsis of the 03 American College of Cardiology/American Heart Association Cholesterol Guideline. Ann Intern Med 04; 60: Gillett RC, Norrell A: Considerations for safe use of statins: liver enzyme abnormalities and muscle toxicity. Am Fam Physician 0; 83: Thompson PD, Panza G, Zaleski A, Talyor B: Statin-associated side effects. J Am Coll Cardiol 06; 67: MoBhammer D, Schaeffeler E, Schwab M Morike K: Mechanisms and assessment of statin-related muscular adverse effects. Br Clin Pharmacol 04; 78: Sathasivam S: Statin induced myotoxicity. Euro J Int Med 0; 3: Statins 009; 7: Rosenson RS, Baker SK, Jacobson TA, Kopecky SL, Guyton JR, Parker BA: An assessment by the Statin Muscle Safety Task Force. J Clin Lipidol 04; 8: S Mörike K: Mechanisms and assessment of statinrelated muscular adverse effects. Br J Clin Pharmaco 04; 78: 家庭醫學與基層醫療第五期 9

7 9. MoBhammer D, Schaeffeler E, Schwab M Morike K: Mechanisms and assessment of statin-related muscular adverse effects. Br Clin Pharmacol 04; 78: Ridker PM, Danielson e, Fonseca FA, et al: Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 008; 359: Farmer JA, Torre-Amione G: Comparative tolerability of HMG-CoA reductase inhibitors. Drug Saf 000; 3: Joy TR, Hegele RA: Narrative review: statinrelated myopathy. Ann Intern Med 009; 50: Abd TT, Jacobson TA: Statin-induced myopathy: a review and update. Expert Opin Drug Saf 0; 0: Chang CH, Kusama M, Ono S, Sugiyama Y, Orii T, Akazaw M: Assessment of statin-associated muscle toxicity in Japan: a cohort study conducted using claims database and laboratory information. BMJ Open 03; 3: e doi: 0. 36/bmjopen Stroes ES, Thompson PD, Corsini A, et al: Statin-associated muscle symptoms: impact on statin therapy European Atherosclerosis Society Consensus Panel Statement on assessment, aetiology and management. Europ Heart J doi: /eurheartj/ehv Meador BM, Huey KA: Statin-associated myopathy and its exacerbation with exercise. Muscle Nerve 00; 4: Roberts WC: The rule of 5 and the rule of 7 in lipid-lowering by statin. Am J Cardiol 997; 80: Talbert R: Safety issue with statin therapy. J Am Pharm Assoc 006; 46: Bellosta S, Paoletti R, Corsini A: Safety of statins-focus on clinical pharmacokinetics and drug interactions. Circulation 004; 09[suppl III]: Jacobson TA, Ito MK, Maki KC, et al: National Lipid Association Recommendations for patient centered management of dyslipidemia: Part -Full report. J Clin Lipidol 05; 9: 家庭醫學與基層醫療第五期

社區醫學陳俊佑 1 陳榮福 2 黃志芳 3 黃偉城 3 王培銘 3 黃致達 3 前言 % 17.9% 7.6% [1] (EBM, Evidence-Based Medicine) hypercholesterolemia Hypertriglyceridemia (mixed hy

社區醫學陳俊佑 1 陳榮福 2 黃志芳 3 黃偉城 3 王培銘 3 黃致達 3 前言 % 17.9% 7.6% [1] (EBM, Evidence-Based Medicine) hypercholesterolemia Hypertriglyceridemia (mixed hy 陳俊佑 1 陳榮福 2 黃志芳黃偉城王培銘黃致達前言 2007 2% 17.9% 7.6% [1] (EBM, Evidence-Based Medicine) hypercholesterolemia Hypertriglyceridemia (mixed hyperlipidemia) metabolic syndrome EBM 1 高雄長庚家醫科住院醫師 2 高雄長庚新陳代謝科主任