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Hyperuricemia & Gout
台中榮民總醫院臨床藥學科鄭鴻基主任
前言 -1 痛風為現代人常見的文明病之一，根據估
計約有 5﹪的國人（約 100 萬人）血中的尿酸值偏高，但絕大多數沒有任何徵狀，只是抽血時偶然發現血中的尿酸濃度偏高。
一般而言，尿酸值越高或持續越久越容易得到痛風，尤其是每 100 ㏄血中尿酸超過9 毫克者，約有 70-90﹪機會得到痛風。
前言 -2 早期痛風被視為一種富貴人家才會得到的帝
王病，因為歷史上許多名人，君王如牛頓、亞歷山大大帝、英王喬治亞四世、路易十四、富蘭克林、達爾文等均罹患過此病
近年來患者年齡層也有逐漸下降的趨勢，原本好發於 30-50 歲以上的痛風疾病，近年來20 多歲的患者也大有人在。
尿酸的形成和排泄 尿酸是由嘌呤 (Purine) 代謝所產生的最終產物，而嘌呤則存在於食物中或體內的細胞。一般而言，體內尿酸約 20﹪來自飲食， 80﹪來自身體的新陳代謝。正常人約有三分之二的尿酸由腎臟經尿液排出，約三分之一由腸內細菌分解代謝，另約有小於百分之一由汗腺排泄。
但腎臟功能異常的病人則由腎臟排泄的量減少，相對地由腸道排泄的量會增加。
正常人血中尿酸濃度受性別、年齡影響，女性在停經前尿酸值較男性低，但停經後則尿酸會慢慢增高。
青春期前血中尿酸濃度較低，但青春期後則會逐漸增加接近成年人。因此，若尿酸產生過多或排泄減少，均會造成血中尿酸過高。
They add color to your life
Uric acid
QUESTIONS 人體內正常貯存量尿酸約多少 mg? 人體正常每天應排除多少尿酸 ? XANTHINE 分解成尿酸是藉何物完成 ? 尿酸需要何物可以分解為 ALLANTION 在酸性溶液中 :URIC ACID &
ALLANTOIN 何者溶解度大 ?
Uric acid Excretion by
kidney GFR(95%) Proximal tube:
1.reabsoption(98%) 2.resecretion(50%)
Distal tube,colleting tube:reabsorption(40%)
They wipe your tears
何謂高尿酸血症 是指血中尿酸濃度約大於 7 mg/dl 以上，但一般在實驗室中常用的化學自動分析儀，則以超過8mg/dl 為高，實際上尿酸在體液中之飽和溶解度是 6.4mg/dl ，因此如果血清尿酸值超過6.4mg/dl 以上即為過飽和狀態，就開始有尿酸鹽結晶會析出。
流行病學的定義中，所謂的「正常人」事實上包含一些無症狀的高尿酸血症的病人。 但高尿酸血症並不ㄧ定等於痛風，它需要經過一段很長的時間才會有第一次痛風關節炎的發作，這時候才開始稱為「痛風」，在從未有過關節炎發作者，只能稱為無症狀的高尿酸血症。
Asymptomatic hyperuricemia High level of serum uric acid
concentration No clinical syndrome
Serum uric acid level (mg/dl) Incidence of gout
>9.0 7.0-8.9%
7.0–8.9 0.37-0.5%
<7.0 0.1%
高尿酸血症的原因 -1A. 尿酸生成過多： 1. 原發性生成過多： i. 遺傳：家族中若有痛風或尿酸過高者，其子女發生
痛風的機率為一般人的 10 倍 。 ii. 肥胖：肥胖的人較易流汗，也因此經腎臟、膀胱排
出之尿量會減少，如此經腎臟排出之尿酸量也相對的減少而造成高尿酸血症，此外肥胖的人如果減肥或飢餓時，體內脂肪會燃燒而產生酮體，此酮體由尿中排泄，排泄時會阻礙尿酸之排泄，因此會使血中尿酸值增高而造成高尿酸血症。
高尿酸血症的原因 -2A. 尿酸生成過多： 1. 原發性生成過多： iii. 年齡 iv. 性別：一般男性較女性容易罹患痛風，但女性
停經後痛風之發生率增加。 v. 飲食：飲酒、高嘌呤飲食 vi. 運動過度：劇烈運動會使出汗量增加，尿酸由
尿液中排出減少，運動後所產生的過多的乳酸，亦會阻礙其排泄，運動時肌肉收縮的關係，使肌肉中ATP 下降，造成 AMP 上升，結果 adenosin degradation 增加，而引起血液中尿酸值增加。
高尿酸血症的原因 -3A. 尿酸生成過多： 2. 續發性高尿酸血症 i. 核蛋白產生過多：如白血病、 Hodge king病，紅血球增多症等血液疾病，主要是因細胞破壞太快， 而使細胞內之主要成份核蛋白新陳代謝加速，而產生太多尿酸存積在體內來不及排出所引起之高尿酸血症。
ii. 酵素缺損或增加：如 HGPRT 的先天性欠損所引起之一種病叫 Lesch-Nyhan syndrome ， PRPP Synthetase 的活性過高，糖尿病 type I 等，這類疾病的主要特徵是家族性遺傳因素。
高尿酸血症的原因 -3A. 尿酸生成過多： 2. 續發性高尿酸血症 iii. 腎障礙：主要是因腎障礙，或某些藥物會
抑制尿酸經腎臟之排泄，例如抗結核病藥(PZA) ，降壓利尿劑，少量之Aspirin(<2g/day) 等。此外副甲狀腺機能亢進症及 Sarcoidosis 等也會使血中鈣增加而影響尿酸在腎之代謝，結果造成尿酸之上升。
高尿酸血症的原因 -4
B. 尿酸排泄量減少 1. 尿酸排泄機能降低 2. 腎臟功能障礙：如慢性腎炎等 3. 服用藥物影響尿酸排泄：如利尿劑等 4. 酸中毒如：糖尿病、乳酸血症、飲酒過
多
會造成高尿酸血症的疾病1. 酒精成隱症2. 糖尿病酮酸中毒3. 高血脂症4. 副甲狀腺機能亢進5. 肥胖6. 急慢性腎衰竭7. 牛皮癬8. glucose-6-phosphatase 缺陷
會造成高尿酸血症的藥物1. 酒精2. 抗癌藥，如： cytotoxic drug3. 利尿劑，但 Spironolactone 不會引起高尿酸血
症4. 抗結核病藥物，如： PZA5. Levodopa6. Nicotinic acid7. Salicylates (<2g/day)
容易與痛風混淆的疾病
1. Pseudogut ：乃 CCPD(calcium pyrophosphate dihydrate) 沉積於關節形成。
2. Palindromic Rheumastism ：急性發生時常伴隨紅血球沉降速率 (ESR) 的升高。
3. Trauma/Haemarthrosis ：4. Infected joint/cellulitis ：5. Secondary gout/unreclated hyperuricemia ：
如高血壓、三酸甘油脂過高、乾癬、肥胖、甲狀腺機能低下、腎衰竭等造成尿酸過高而引發續發性痛風。
痛風的臨床症狀
無症狀症高尿酸血症 急性痛風 中間緩解期 (INTERCRITICAL GOUT)
慢性痛風
痛風所引起的相關疾病 痛風性腎病變 尿路結石 其它相關疾病：痛風病人常合併有高血壓、糖尿病、血管硬化和高脂血症。目前痛風已被美國心臟病協會列為缺血性心臟病的危險因素之一，即痛風是動脈硬化的促進因子，因為痛風如未好好治療的話，則由長期間持續的高尿酸血症會使過多的尿酸鹽結晶沈積在冠狀動脈內，加上高尿酸血症也會使血小板的凝集亢進，這些原因加速了動脈硬化的進展。
Gout complications(1)
Oh my God!!
Mommy..Help!!
Gout complications(2) Renal function impairment1.urate nephropathy2.uric acid calculi3.acute uric acid obstructive nephropathy Cardiovascular disease-Ischemic heart disease-arteriosclerosis risk factor Hyperlipemia,diabetes,hypertension —obesity,(UA,CH,TG) 腦血管病變
尿酸腎結石 (Uric acid nephrolithiasis)
尿酸是尿路結石常見的成份。 在美國尿酸結石的盛行率約為 5~10
% ，而在原發性痛風的患者，尿酸結石的發生率高達 10~20% 。
部份病人其尿酸結石的發生早於痛風性關節炎的發作。
尿酸腎結石之致病機轉 尿酸屬於一種弱酸，且具有兩個解離係數 (dissociation Constants) 。
尿酸的溶解度決定於兩個主要因素 :1) 尿酸的濃度 , 2) 尿液的酸鹼值 (pH) 。
當尿液 pH 值小於 5.5 時，其尿酸呈現過度飽和而易形成尿酸結石。
但在 pH 大於 6.5 時，大部份的尿酸皆會以離子型尿酸鹽存在。
尿酸結石的形成三因素 酸性尿 (pH 值小於 5.5)
尿液之尿酸濃度過高(hyperuricuria) (亦即 24 小時尿液尿酸量大於 600mg)
每日尿液量過少。
尿酸結石診斷評估 詳細的病史 ( 高尿酸血症之原因及其相關疾病 ) 尿液的 pH 值 24 小時尿液尿酸含量 腹部平面 X-光 : 由於尿酸結石不含鈣或含鈣量較少，不易顯示
超音波或逆流性腎盂攝影 無顯影劑的電腦斷層 : 最佳的顯影方法，它可用來偵測與定位尿酸結石、與其他結石做區分、且可排除腫瘤或其他病因 ( 如乳突狀壞死 ) 。
無顯影劑的電腦斷層攝影
痛風的診斷美國風濕病協會 (1977) 診斷標準
以下三大項出現一大項 ( 含 ) 以上即可診斷為痛風 : 一、關節液 : 特徵性的尿酸鹽晶體 二、痛風石 : 含有尿酸鹽晶體 三、以下 12 小項中包括臨床生化及 X 光檢查中出現六項以上 :
1. 一天即可達最嚴重的發炎， 2. 發作一次以上， 3.單一關節的關節炎， 4. 發作處有紅腫熱痛， 5. 第一蹠趾關節痛腫， 6.單側大腳趾侵犯， 7.單一跗骨侵犯， 8. 痛風石， 9. 高尿酸血症， 10. 不對稱性腫脹， 11.X 光 -皮質下囊腫沒有糜爛， 12. 關節液培養不出細菌。
病人呈現急性關節腫痛
臨床懷疑痛風性關節炎
鑑別診斷1.假痛風 2.反覆性風濕症3. 血清陰性關節病變 4.感染性關節炎5.外傷性 / 關節血腫 6. 第 II型血高脂症
確立診斷1.詢問高尿酸血症 / 痛風病史2.儘可能抽取關節液及分析結晶體且 排除感染及其他關節炎之可能性3. 關節超音波及 X 光之特徵
They spread fragrance
Hyperuricemia is a risk factor for gout, but some patients with normal serum uric acid levels develop acute gouty arthritis.
Overproduction of urate• Primary idiopathic hyperuricemia • Hypoxanthine-guanine phosphoribosyl-transferase deficiency • Phosphoribosylpyrophosphate synthetase overactivity • Hemolytic processes • Lymphoproliferative disease • Myeloproliferative disease • Polycythemia vera • Psoriasis (severe) • Paget's disease • Rhabdomyolysis • Exercise • Alcohol • Obesity • Purine-rich diet
Decreased excretion of uric acid
• Primary idiopathic hyperuricemia • Renal insufficiency • Polycystic kidney disease • Diabetes insipidus • Hypertension • Acidosis
--Lactic acidosis --Diabetic ketoacidosis
• Down syndrome • Starvation ketosis • Berylliosis • Sarcoidosis • Lead intoxication • Hyperparathyroidism • Hypothyroidism • Toxemia of pregnancy • Bartter's syndrome
Decreased excretion & Overproduction of uric
acid
Combined mechanism • Glucose-6-phosphate dehydrogenase
deficiency • Fructose-1-phosphate aldolase deficiency • Alcohol • Shock
Decreased excretion of uric acid
• Drug ingestion --Salicylates (less than 2 g per day) --Diuretics --Alcohol --Levodopa-carbidopa (Sinemet) --Ethambutol (Myambutol) --Pyrazinamide --Nicotinic acid (niacin; Nicolar) --Cyclosporine (Sandimmune)
痛風的治療( 一 ) 飲食控制 ( 二 ) 藥物治療 無症狀高尿酸血症 急性痛風 慢性痛風
Most acute gout attacks occur in a lower extremity joint, often the first metatarsophalangeal joint.
Because an acute gout attack may be associated with edema, erythema, warmth and tenderness, the differential diagnosis includes septic arthritis and cellulitis.
TREATMENT Serum uric acid concentrations may be
reduced with nonpharmacologic therapy. Useful dietary and lifestyle changes include weight reduction, decreased alcohol ingestion, decreased consumption of foods with a high purine content, and control of hyperlipidemia and hypertension. Used alone, however, these measures will probably not reduce serum uric acid levels to normal, which is the treatment goal for the prevention of acute gout attacks. Symptomatic hyperuricemia usually requires medication.
They make you laugh
Acute Gouty Arthritis
Three treatments currently available for acute gouty arthritis attacks are nonsteroidal anti-inflammatory drugs (NSAIDs), colchicine and corticosteroids.
Prevention of Recurrent Attacks
Hyperuricemic therapy should be initiated in patients with frequent gout attacks, tophi or urate nephropathy. A low dosage of an NSAID or colchicine is effective in preventing acute gouty attacks. Hyperuricemic drug therapy should not be started until an acute attack of gouty arthritis has ended, because of the risk of increased mobilization of uric acid stores. A reasonable goal is to reduce the serum uric acid concentration to less than 6 mg per dL (360 µmol per L).
Acute gouty arthritis Rapid onset,
swelling, inflammation mildnight ,peak:24-
48hr,3-14 days spontaneous recovery
Monoarticular,MTP joint
A number of condition may precipitate an attack
Signs
Radiographic Findings
Treatment1. Goals: relieve pain and inflammation
not aimed at lower serum UA conc with hypouricemic agents.
1. Rest2. Adequate fluid status assessment
correct dehydration if no contraindication
3. Evaluation of prediposing factors DC offending drug
4. Medications
Medication for Acute GA NSAID Colchicine Steroid or ACTH 1.all highly effective 2.selection depend on co-existent condition: (renal dysfunction, physician or p’t
preference)
NSAIDs most important for acute attack
IV/IM form is not superior to oral form in GI toxicity, in Nephrotoxicity or
any other aspects Ketolac injection is the only injected
NSAID proved by FDA
NSAIDs 優先選 short-acting, short duration, potent antiinfl
ammatory effect Indomethacin( indocin ):50mg tid-qid Diclofenic acid: Cataflam, Voren Naproxen:750mg st250mg tid
Special NSIADs: Specific COX-2 inhibitors: celecoxib, rofecoxib Meloxicam: preferential COX-2 inhibitor, least GI side
effect Sulindac: least nephrotoxicity Cinopal: least GI toxicity
NSAIDsClinical Contraindications History of peptic ulcer with active bleeding
or GI intoerance Age >65 y/o (relative) Renal insufficiency or CCr <50 ml/min
(relative) Poor compensated CHF Hepatic dysfunction Anticoagulation therapy History of allergic or rash to NSAIDs
QUESTIONS 血中尿酸濃度大於 9mg/dl 時 , 其發生痛
風的機率 ? 請列舉三種易引起高尿酸血症之葯物 ? 請列舉三種易引起高尿酸血症之疾病 ? 易引起尿酸結石形成的三個因素 :? 急性痛風之首選藥物 ? 高尿酸血症不是引起痛風的必要條
件 ,why?
受影響者 影響者 作用 備註
降血糖藥 Sulfonylureas如glyburide 、 tolbutamide 、 chlorpropamide
PhenylbutazoneOxyphenbutazone
抑 制 sulfonylureas 的 代 謝 ，延長其半衰期，增加發生低血糖的危險性。
應監測血糖，宜避免併用。
口服抗凝血劑 所有非類固醇類消炎藥
損害腸胃道黏膜並抑制血小板凝集，增加腸胃道出血的可能性。
避免併用，若需併用應監測prothrombin time 。
ACEI
Captopril
IndomethacinIbuprofen其他非類固醇類消炎藥 (sulindac 除外 )
降壓效果減弱 避 免 併 用 ， 必 要 時 使 用sulindac ， 並 監 測 血壓 。 Enalapril 及 lisinopril與 indomethacin 間的交互作用很小。
- 交感神經阻斷劑 非類固醇類消炎藥 降壓效果減弱 避免使用非類固醇類消炎
利尿劑，包括 Loop 、保鉀與 thiazides 類
Indomethacin其他非類固醇類消炎藥 (sulindac 除外 )
降壓及排鈉效果減弱，可能惡化充血性心衰竭。
避免使用非類固醇類消炎藥，必要時使用 sulindac ，並監測體液滯留的徵兆。
Methotrexate ( 高劑量
)
Ketoprofen其他非類固醇類消炎藥
Methotrexate 排出減少，血中濃度上升，毒性增加，可能致死。
不可同時給藥。 完成高劑量療法後 12 小時再服用ketoprofen 較安全。
PhenytoinSulfonamides
非類固醇類消炎藥 競爭蛋白質結合部位 監測藥品血中濃度
Aminoglycosides 非類固醇類消炎藥 腎 功 能 減 弱 ， amino-glycosides 廓清率降低，血中濃度增高。
應監測 aminoglycosides 的血中濃度，並適當調整劑量。
出血時間 (Bleeding time )
Ketoprofen, ASA 延長出血時間約 3-4 分鐘
they see only the good in you
COX II INHIBITORS
COX II INHIBITORS
COX II INHIBITORS
老年人需要服用 NSAIDs 時 , 最佳的選擇順序是 ?
1. INDOMETACIN2. CELEBREX(COX II INHIBITERS)3. SULINDAC4. PIROXICAM5. CATAFLAM
老年人需要服用 NSAIDs 時 , 最佳的選擇順序是 ?
1. INDOMETACIN---42. CELEBREX(COX II INHIBITERS)---13. SULINDAC---24. PIROXICAM---45. CATAFLAM---3
?
急性痛風避免使用那些藥物 ?
1. ALLOPURINOL2. BENZBROMARONE3. CORTICOSTEROIDS4. NSAIDS5. COLCHICINE
They give you support
老年人是否選擇 COX II INHIBITORS ?
Becoz they are your true friends
Allopurinol
100mg/tab
Indications Oral: Prevention of attack of gouty arthritis and
nephropathy; treatment of secondary hyperuricemia which may occur during treatment of tumors or leukemia; prevention of recurrent calcium oxalate calculi
Pregnancy Risk Factor C Lactation Enters breast milk/compatible Contraindications Hypersensitivity to allopurinol
or any component of the formulation
Warnings/Precautions-1
Do not use to treat asymptomatic hyperuricemia. Discontinue at first signs of rash;
Reduce dosage in renal insufficiency, reinstate with caution in patients who have had a previous mild allergic reaction,
Use with caution in children; monitor liver function and complete blood counts before initiating therapy and periodically during therapy,
Warnings/Precautions-2
Use with caution in patients taking diuretics concurrently.
Risk of skin rash may be increased in patients receiving amoxicillin or ampicillin. The risk of hypersensitivity may be increased in patients receiving thiazides, and possibly ACE inhibitors.
Adverse Reactions The most common adverse reaction to
allopurinol is a skin rash (usually maculopapular; however, more severe reactions, including Stevens-Johnson syndrome, have also been reported). While some studies cite an incidence of these reactions as high as >10% of cases (often in association with ampicillin or amoxicillin), the product labeling cites a much lower incidence, reflected below. Allopurinol should be discontinued at the first appearance of a rash or other sign of hypersensitivity.
Steven johnson syndrome 嚴重的過敏反應通常由藥物引起會出現紅疹情形於手掌腳底是一種多型性紅斑疾病(erythema multiforma) 會產生泡狀病兆也有可能經病毒或黴漿菌(mycoplasma)感染
Steven johnson syndrome
Steven johnson syndrome
Allopurinol 藥害救濟 藥害救濟是衛生署為使民眾在正當使用合法藥物卻發生藥物不良反應，而導致死亡、障礙或是嚴重疾病時，能獲得迅速救濟之服務。
AHS( 數天 - 數月出現 ),SJS,TEN
Discontinute drug, supportive therapy
個案詳細資料
They never blame you
Drug Interactions-1
Hepatic enzyme inhibitor; isoenzyme profile not defined
Decreased effect: Ethanol decreases effectiveness, uricosurics Increased toxicity: Inhibits metabolism of azathioprine and
mercaptopurine (reduce to 1/3 or 1/4 of usual dose)
Use with ampicillin or amoxicillin may increase the incidence of skin rash
Drug Interactions-2
Increased toxicity: Urinary acidification with large amounts of
vitamin C may increase kidney stone formation
Thiazide diuretics enhance toxicity, monitor renal function; thiazide diuretics and captopril (possibly other ACE inhibitors) may increase risk of hypersensitivity
Vidarabine neurotoxicity may be enhanced Cyclosporine levels may be increased
Table 1. Standard allopurinol desensitization protocol
Curr Opin Rheumatol 2002 May;14(3):281-286 Copyright © 2002 Lippincott Williams & Wilkins
All rights reserved
Drug Interactions-3Increased toxicity: Hepatic iron uptake may be increased with
iron supplements Allopurinol prolongs half-life of oral
anticoagulants; allopurinol increases serum half-life of theophylline; allopurinol may compete for excretion in renal tubule with chlorpropamide and increases chlorpropamide's serum half-life
Ethanol/Nutrition/Herb Interactions Ethanol: Avoid ethanol (may decrease effectiveness).
Mechanism of Action Allopurinol inhibits xanthine oxidase,
the enzyme responsible for the conversion of hypoxanthine to xanthine to uric acid. Allopurinol is metabolized to oxypurinol which is also an inhibitor of xanthine oxidase; allopurinol acts on purine catabolism, reducing the production of uric acid without disrupting the biosynthesis of vital purines
Pharmacodynamics/Kinetics
Onset of action: Peak effect: 1-2 weeks Absorption: Oral: ~80%; Rectal: Poor and erratic
Distribution: Vd: ~1.6 L/kg; Vss: 0.84-0.87 L/kg; Protein binding: <1% Metabolism: ~75% to active metabolites, chiefly
oxypurinol Bioavailability: 49% to 53% Half-life T1/2: Parent drug: 1-3 hrs; Oxypurinol: 18-30 hours End-stage renal disease: Prolonged Time to peak, Oral: 30-120 minutes Excretion: Urine (76% as oxypurinol, 12% as unchange
ALLOPURINOL 主要活性代謝物是 ?
OXIPURINOL ALLANTOIN ALLOPURINE
QUESTIONS ALLOPURINOL T1/2=? OXIPURINOL T1/2=? ALLOPURINOL INTERACTION: CYCLOPHOSPHAMIDE---? BONE MARROW
SUPPRESSION
VIDRARBINE-------? CYCLOSPORINE-----? WARFARIN----?
Usual Dosage(Oral)
Children 10 years: 10 mg/kg/day in 2-3 divided doses or 200-300 mg/m2/day in 2-4 divided doses, maximum: 800 mg/24 hours
Alternative: <6 years: 150 mg/day in 3 divided doses; 6-10 years: 300 mg/day in 2-3 divided doses
Children >10 years and Adults: Daily doses >300 mg should be administered in divided doses uric acid level is obtained
Usual Dosage(Oral)-2
Myeloproliferative neoplastic disorders: 600-800 mg/day in 2-3 divided doses for prevention of acute uric acid nephropathy for 2-3 days starting 1-2 days before chemotherapy
Gout: Mild: 200-300 mg/day; Severe: 400-600 mg/day
Elderly: Initial: 100 mg/day, increase until desired uric acid level is obtained
Dosing adjustment in renal impairment: Must be adjusted due to accumulation of allopurinol and metabolites:
Oral: Removed by hemodialysis; adult maintenance doses of allopurinol* (mg) based on creatinine clearance (mL/minute): See table.
Adult Maintenance Doses of Allopurinol*
Creatinine Clearance (mL/min) Maintenance Dose of Allopurinol (mg)
140 400 qd
120 350 qd
100 300 qd
80 250 qd
60 200 qd
40 150 qd
20 100 qd
10 100 q2d
0 100 q3d
*This table is based on a standard maintenance dose of 300 mg of allopurinol per day for a patient with a creatinine clearance of 100 mL/min.Hemodialysis: Administer dose posthemodialysis or administer 50% supplemental dose
Monitoring Parameters CBC, serum uric acid levels, I & O, hepatic and renal function, especially at start of therapy
Reference Range Uric acid, serum: An increase occurs during childhood Adults:
Male: 3.4-7 mg/dL or slightly more Female: 2.4-6 mg/dL or slightly more Values >7 mg/dL are sometimes arbitrarily regarded as
hyperuricemia, but there is no sharp line between normals on the one hand, and the serum uric acid of those with clinical gout. Normal ranges cannot be adjusted for purine ingestion, but high purine diet increases uric acid. Uric acid may be increased with body size, exercise, and stress.
Dietary Considerations Should administer oral forms after meals with plenty of fluid.
Patient Information-1 Maintain adequate hydration (2-3 L/day of
fluids unless instructed to restrict fluid intake) to avoid possible adverse renal problems.
While using this medication, do not use alcohol, other prescription or OTC medications, or vitamins without consulting prescriber.
You may experience drowsiness (use caution when driving or engaging in tasks requiring alertness until response to drug is known);
nausea, vomiting, or heartburn
Patient Information-2
hair loss (reversible). Report skin rash or lesions; painful urination or blood in urine or stool; unresolved nausea or vomiting; numbness of extremities; pain or irritation of the eyes; swelling of lips, mouth, or tongue; unusual fatigue; easy bruising or bleeding; yellowing of skin or eyes; or any change in color of urine or stool.
Pregnancy precautions: Inform prescriber if you are or intend to be pregnant.
They give you support
Colchicine 0.5mg/tab
秋水仙素
COLCHICINE
Colchicine mechanism
PMN: Polymorphonuclear neutrophil
Use Treatment of acute gouty
arthritis attacks prevention of recurrences of
such attacks; management of familial
Mediterranean fever Unlabeled/Investigational
Primary biliary cirrhosis
Precaution Pregnancy Risk Factor C (oral); D
(parenteral) Lactation Enters breast milk/use
caution (AAP rates "compatible") Contraindications Hypersensitivity to
colchicine or any component of the formulation; serious renal, gastrointestinal, hepatic, or cardiac disorders; blood dyscrasias; pregnancy (parenteral)
Warnings/Precautions
Severe local irritation can occur following S.C. or I.M. administration;
Use with caution in debilitated patients or elderly patients; use caution in patients with mild to moderate GI, renal, or liver disease
Adverse Reactions
>10%: Gastrointestinal: Nausea, vomiting,
diarrhea, abdominal pain 1% to 10%: Dermatologic: Alopecia Gastrointestinal: Anorexia <1%: Rash, azoospermia,
agranulocytosis, aplastic anemia, bone marrow suppression, hepatotoxicity, myopathy, peripheral neuritis
Overdosage/ToxicologySymptoms of overdose include acute
nausea, vomiting, abdominal pain, shock, kidney damage, muscle weakness, burning in throat, watery to bloody diarrhea, hypotension, anuria, cardiovascular collapse, delirium, convulsions, and respiratory paralysis. Treatment includes gastric lavage and measures to prevent shock, hemodialysis or peritoneal dialysis. Atropine and morphine may relieve abdominal pain.
Drug InteractionsDecreased effect: Vitamin B12 absorption may be decreased Increased toxicity: Sympathomimetic agents CNS depressant effects are enhancedEthanol: Avoid ethanol.
Food: Cyanocobalamin (vitamin B12): Malabsorption of the substrate. May result in macrocytic anemia or neurologic dysfunction.
They rejoice with joy
Mechanism of ActionDecreases leukocyte motility,
decreases phagocytosis in joints and lactic acid production, thereby reducing the deposition of urate crystals that perpetuates the inflammatory response
長期服用 COLCHICINE 需要補充 ?
VITAMINE A VITAMINE E VITAMINE B2 VITAMINE B12 VITAMINE C FOLIC ACID VITAMINE K
服用 COLCHICINE 常見的副作用 ?
Nausea, vomiting, diarrhea, abdominal pain Alopecia Anorexia
Pharmacodynamics/Kinetics
Onset of action: Oral: Pain relief: ~12 hr if adequately dosed
Distribution: Concentrates in leukocytes, kidney, spleen, and liver; does not distribute in heart, muscle, and brain
Protein binding: 10% to 31% Metabolism: Partially deacetylated hepatically Half-life elimination: 12-30 minutes; ESRD: 45minsTime to peak, serum: Oral: 0.5-2 hours, Excretion: Primarily feces; urine (10% to 20%)
Usual DosageGouty arthritis, acute attacks: Adults: Oral: Initial: 0.5-1.2 mg, then 0.5-0.6 mg every
1-2 hours or 1-1.2 mg every 2 hours until relief or GI side effects (nausea, vomiting, or diarrhea) occur to a maximum total dose of 8 mg; wait 3 days before initiating another course of therapy
Gouty arthritis, prophylaxis of recurrent attacks: Adults: Oral: 0.5-0.6 mg/day or every other day; patients who are to undergo surgical procedures may receive 0.5-0.6 mg 3 times/day for 3 days before and 3 days after surgery
Dosing adjustment in renal impairment
Clcr<50 mL/minute: Avoid chronic use or administration
Clcr<10 mL/minute: Decrease dose by 75% for treatment of acute attacks
Hemodialysis: Not dialyzable (0% to 5%); supplemental dose is not necessary
Peritoneal dialysis: Supplemental dose is not necessary
Colchicine
Most effective drug for prevention of recurrence
Ever the drug of choice for acute gout attacks.
Advantage: provide 1.symptomatic relief to 95% p’ts in early course 2.diagnostic confirmation
Colchicine Traditional acute gout attack: 1mg st0.5mg q1-2hr to symptom relief or GI
side effects or total dose 6mg Current trend: low dose: 1# BID-1# TID For prophylasix: 1# po bid In renal insufficiency: 1# po qd-qod GFR< ml/min------50% dose GFR< ml/min------DC Prophylatic dose of colchicine induce GI
adverse effects in 4% p’ts.
藥品 作用
Cyclosporine 升高 cyclosporine血中濃度及腎毒性，包括胃腸、肝、腎、及肌神經毒性。應監測血中濃度，適時調整劑量
Erythromycin 使 colchicine代謝受抑制，升高血中濃度，加強作用
Vitamin B12 可能改變迴腸黏膜功能而引起可逆性 vitamin B12吸收不良。
中樞神經抑制劑 中樞神經抑制劑敏感性增加
擬交感神經作用劑
加強擬交感神經作用劑的反應
檢驗值 使 alkaline phosphatase 及 AST值升高，血小板數目減少。尿中紅血球或血紅素試驗可能呈偽陽性。
Patient Information-1 Do not exceed recommended dosage. Consult prescriber
about a low-purine diet. Maintain adequate hydration (2-3 L/day of fluids unless instructed to restrict fluid intake). Do not use alcohol or aspirin-containing medication without consulting prescriber. You may experience nausea, vomiting, or anorexia ; hair loss (reversible).
Stop medication and report to prescriber if severe vomiting, watery or bloody diarrhea, or abdominal pain occurs. Report muscle tremors or weakness; fatigue; easy bruising or bleeding; yellowing of eyes or skin; or pale stool or dark urine.
Patient Information-2 Pregnancy/breast-feeding precautions: Inform
prescriber if you are or intend to be pregnant. Consult prescriber if breast-feeding.
Dietary Considerations May need to supplement with vitamin B12.
Becoz they are your true friends
BENZBROMARONE100MG/TAB
•A. Benzbromarone is a benzofuran derivative used as a uricosuric for the treatment of hyperuricemia and gout. •B. DOSING INFORMATION: Oral doses of 50 to 200 mg once a day have been effective for hyperuricemia.
•C. PHARMACOKINETICS: Benzbromarone is variably absorbed; oral bioavailability is dependent on particle size, and has been estimated as 50 to 55%. Peak serum levels occur 2 to 3 hours after oral administration; peak effects occur in 8 to 12 hours. BENZBROMARONE is greater than 99% protein bound. Its half-life is approximately 3 hours; it is mainly eliminated via the bile, with small amounts appearing in the urine.
.
•D. CAUTIONS: The main adverse reactions associated with benzbromarone are gastrointestinal (ie, diarrhea). Hypersensitivity reactions with dermatologic manifestations have occurred. Benzbromarone should be used with caution in the presence of renal failure. Benzbromarone may precipitate an acute attack of gout and/or uric acid nephropathy.
•E. CLINICAL APPLICATIONS: Benzbromarone is effective for reducing serum uric acid levels in the treatment of asymptomatic and symptomatic hyperuricemia and gout.
IMPORTANT NOTE Benzbromarone should not be used to treat acute
gouty attacks since it may cause an exacerbation if given during an attack. Benzbromarone should be initiated only after an acute attack has subsided.
During treatment initiation with benzbromarone for gout, a NSAIDS or colchicine should be administered to reduce the risk of precipitating an acute gouty attack. In general, an adequate fluid intake should be maintained and the pH of the urine should be adjusted to neutral or slightly alkaline to reduce the risk of renal stones.
DOSAGE IN RENAL FAILURE
The efficacy of BENZBROMARONE is decreased in the presence of renal dysfunction, and the drug is not recommended if glomerular filtration rate is less than 20 mL/minute (Heel et al, 1977).
One study reported a marked decrease in efficacy of BENZBROMARONE in patients with renal insufficiency, and the drug was ineffective in patients undergoing hemodialysis (Masbernard & Giudicelli; 1981).
BENZBROMARONE使用時注意病人腎功能 ?
The efficacy of BENZBROMARONE is decreased in the presence of renal dysfunction, and the drug is not recommended if glomerular filtration rate is less than 20 mL/minute (Heel et al, 1977).
CONTRAINDICATIONS A. Acute gout attack
PRECAUTIONS A. BENZBROMARONE may precipitate
an acute gout attack and/or uric acid nephropathy
B. Hepatic disease C. Maintain adequate fluid intake and
maintenance of a relatively high urine pH to reduce the risk of nephrolithiasis
D. Renal failure
PLACE IN THERAPY
BENZBROMARONE is a useful uricosuric with potent serum urate lowering properties. Like SULFINPYRAZONE and PROBENECID, BENZBROMARONE increases urinary excretion of uric acid. However, BENZBROMARONE is more potent than either of these 2 agents, and may have a more favorable side effect profile than existing drugs. It also has a more favorable pharmacokinetic profile than existing uricosurics, and is suitable for once-daily dosing.
MECHANISM OF ACTION
BENZBROMARONE lowers serum uric acid concentrations and increases urinary urate excretion, probably by inhibition of proximal renal tubular urate reabsorption with no effect on uric acid synthesis (Sinclair & Fox, 1975; Gilman et al, 1990).
It increases urinary uric acid excretion shortly after an oral dose, and reduces serum urate levels by 33% to 59% in a dose-dependent manner after single or repeated dosing.
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And let you up
病患衛教1. 從未有過痛風關節炎發作的高尿酸血症患者通常不需要藥物治療，但如果尿酸持續過高，就要找出原因及開始注意飲食，如有相關疾病如：肥胖、高血壓、高血脂症等也應加以一起治療。
2. 約一半的痛風患者在急性痛風發作前有誘因存在，其中以啤酒為最重要原因（佔 60﹪），其次為海產( 佔 18﹪)，內臟食物（佔 14﹪）而豆類製品則幾乎很少引起發作，根據台灣、日本、及美國學者測量，各種嘌呤含量也不太高，因此可以推翻民間誤傳痛風不可以吃豆類的說法。另一個間接證據就是常吃豆類食品的出家人也很少得到痛風。
病患衛教 -飲食調整建議1. 維持標準的體重：若體重過重應慢慢減胖，不宜快速減肥或斷食，
以免因細胞大量崩解產生尿酸而導致痛風發作。減重應以每月減輕一公斤為宜。
2.在醣類方面：所有五穀根莖類皆可食用，蔬菜類除曬乾的香菇、紫菜不宜大量食用外，如豆芽、豆苗皆可食用。水果則無禁忌。
3. 在蛋白質方面：含有高嘌呤的食物如內臟、魚類（海參、海哲皮例外）宜減少攝取。
4. 在油脂方面：由於高脂肪食物會抑制尿酸排泄，在急性痛風期應避免大量食用。
5.酒精：酒精在體內會代謝成乳酸影響尿酸排泄，並且本身會加速尿酸形成，故患者須禁酒，尤其是啤酒最容易導致痛風發作，應絕對禁止。
6. 水分：每天至少 3000㏄的水，多喝水份可以促進尿酸排泄及預防尿路結石。
Even if you dont
When you need them and doesnt
PATIENT EDUCATIONSWhat is gout? Gout is a kind of arthritis caused by too much uric acid in the
joints. The acid causes joint pain. Who can get gout? If you eat a lot of foods that are rich in purines, you may get
gout. Some of these foods are salmon, sardines, liver and herring.
You may get gout if you're overweight, drink alcohol or have high cholesterol. Men have gout more often than women.
Some medicines may cause gout, such as certain diuretics ("water pills"), niacin (a B-complex vitamin), aspirin (taken in low doses), cyclosporine and some drugs used to treat cancer.
PATIENT EDUCATIONS-2
What is a gout attack like? It may be sudden. It usually starts at night, often in the big toe.
The joint becomes red, feels hot and hurts. The joint hurts more when you touch it. Other joints may also be affected.
What should I do if I have a gout attack? The sooner you get treatment, the sooner the pain will go
away. Your doctor can prescribe medicine to stop the joint swelling and pain.
You should rest in bed. Putting a hot pad or an ice pack on the joint may ease the pain. Keeping the weight of clothes or bed covers off the joint can also help.
With treatment, your gout attack should go away in a few days. You may never have another attack.
PATIENT EDUCATIONS-3
What if I don't get treatment?
If you don't get treatment, a gout attack can last for days or even weeks. If you keep having more attacks, more joints will be affected, and the attacks will last longer.
If you have gout attacks for many years, you may develop tophi (say: toe-fee). These are soft tissue swellings caused by uric acid crystals. Tophi usually form on the toes, fingers, hands and elbows. You may also get kidney disease or kidney stones. Over time, the bone around a joint may be destroyed.
PATIENT EDUCATIONS-3
What can I do to avoid gout attacks?
Your doctor can prescribe medicines to prevent future gout attacks. These medicines wash the uric acid from your joints, reduce the swelling or keep uric acid from forming.
You should lose weight if you need to. If you have high blood pressure or high cholesterol, get treatment and follow a low-salt, low-fat diet.
Stay away from alcohol and foods that are high in purines.
Drinking lots of water can help flush uric acid from your body.
When they need you
FIGURE 1. Acute gout. Note erythema and swelling
of the first metatarsophalangeal joint.
TABLE The Purine Content of Foods and Beverages
High Best to avoid:
Liver, kidney, anchovies, sardines, herring, mussels, bacon, codfish, scallops, trout, haddock, veal, venison, turkey, alcoholic beverages
Moderate May eat occasionally:
Asparagus, beef, bouillon, chicken, crab, duck, ham, kidney beans, lentils, lima beans, mushrooms, lobster, oysters, pork, shrimp, spinach
Low No limitation:
Carbonated beverages, coffee, fruits, breads, grains, macaroni, cheese, eggs, milk products, sugar, tomatoes and green vegetables (including lettuce and excluding vegetables listed above)
FIGURE 2. Gouty tophi involving the proximal interphalangeal joint with erythema of the overlying skin.
CorticosteroidsOral Prednisone, 0.5 mg per kg
on day 1, taper by 5.0 mg each day thereafter
Fluid retention; impaired wound healing
Intramuscular Triamcinolone acetonide (Kenalog), 60 mg intramuscularly, repeat in 24 hours if necessary
May require repeat injections; risk of soft tissue atrophy
Intra-articular Large joints: 10 to 40 mg* Small joints: 5 to 20 mg*
Preferable route for monoarticular involvement
ACTH† 40 to 80 IU intramuscularly; repeat every 8 hours as necessary
Repeat injections are commonly needed; requires intact pituitary-adrenal axis; stimulation of mineralocorticoid release may cause volume overload
ACTH=adrenocorticotropic hormone
Guideline of acute gout
Do you act along
Case presentation 1. 陳 X 鏗 , 男性 ,60歲,165 公分. 入院日期 : 91-10-07 出院日期 : 91-10-12 主訴: nausea, vomiting, diarrhea, general
malaise in recent 3 weeks. PI: HTN, DM, & hyperlipidemia for 7 yrs without
regular control. About 3 weeks ago, gout attack of R’t knee & he took colchicine 1# q2hr x 10’s by himself. Diarrhea , dry mouth, polydipsia, polyuria, general malaise were noted. BW loss about 7-8 kg/3wks. Check one touch sugar: 920mg/dl on 7/10,osmolarity:343. Under the impression of HHNK he is admitted for further evaluation.
Case presentation 1. Past history: 1.Hx of type II DM for 3-4 yrs with
diamicron 2# bid + glucophage 2# bid keep BS:150-200mg/dl
2.Hypertension: Rx: amlodipine 2# qd + Lisinopril 10mg
bid 3.Hyperlipidemia:Rx simvastatin 1# qn 4.GB stone S/p op at 85-01-24 5.Gouty arthritis without regular control.
Case presentation 1.Progression note:91-10-07 S:dry mouth & tongue mucosa, general
weakness, O: osmolarity:343, blood sugar: 981mg/dl,
blood keton (-), BUN/Cr:51/2.0, Clcr: 81ml/min, DUP: 3.6g, Na:127, K: 6.1
WBC:10170 Impression: HHNK 1 NPO. 2 Hydration.6L N/S –G/S in 24hr 3. Insulin pump(100U in 500ml N/S keep infusion
rate5U/hr adjust by BS ), keep BS:150-200mg/dl 4. KCL supplement: 10meq in 500ml iv fluid. 5.After blood sugar was stable, N7/R3: sc bid was
prescribed.
Case presentation 1.91-10-08:S: general malaise, but improved.O: BUN/Cr: 35/1.3, Bp:130/75, PR:100 BS: 389-293-310-414-260-102-232- 279-high-448 Chol: 257, TG:845mg/dl---156 (12/10), HDL:48, T.C/HDL-C:5.4, WBC:10170P:1.P’t education with diet control 2.Shift Insulin to N7/R3 SC, monitor BS 3.Shift Simvastatin----Gemfibrozil 2# bidac 4.F/U: electrolyte, BS, renal function.
Case presentation 1. 91-10-10:S: Acute onset of painful erythematous swelling
change over of R’tlateral mid-tasal area with local heat since 9/10 night, UA:8.1, consult IMRH & sono showed: multiple microtophi & swelling in soft tissue over middle tarsal bones..
Imp: Acute gouty arthritis & cellulitis Rx: cortrosyn inj 0.5mg im stat colchicine1# stat & bid celecoxib 2# stat & bid
Case presentation 1.Date Na K Cl Ca BUN Cr TG UA
7/10 133 5.0 95 10.9 8.88/22
7/10 127 6.1 91 51 2.07/10 141 4.27/10 140 4.2 35 1.38/10 139 3.7 9.2 1.2 845 8.19/10 138 3.7112/10
147 4.1 1.1 156
CRP 2.5 HbA1c
15.1 GHb 22.7
HHNK 與 DKA 的診斷HHNK DKA
Typically people Type II Type IPlasma glucose(mg/dl)
>600 >250
Arterial pH >7.3 <7.3Serum bicarbonate(mEq/l)
>15 <15
Serum and urine ketones
Small Positive
Effective serum osmolality(mOsm/kg)
>320 Variable
Alteration in sensoria or mental obtundation
Stupor, coma
Alert/drowsy/
stupor,coma
When you are up
Case presentation 2. 林 X 夫 ,男性 ,63歲 ,病歷號 :588254C 入院日期 : 91-07-22 出院日期 : 91-07-26 主訴 :acute onset of painful sensation ,
erythematous change over bil. medial aspect of ankle & MCPs of feet, Bil wrists &MCPs of hands, L’t elbow & shoulder.
Case presentation 2. Present illness: quite well before except arthritis over L’t
medial ankle & L’t 1st MCP initially 4 yrs ago. Intermittent acute attack of poly arthritis after that time ( add R’t ankle & 1st MCP of R’t foot)---MCPs & wrist of bil. Hands. The duration about 1 week/ time.Take black pills by himself. LMD: hyperuremia was told & with irregular treatment . Acute onset of chief complain symptoms in recent 2 days, came to Er at 91-07-22: BUN:20, Cr: 2.2, K: 5.3, UA: 10.7mg/dl, CRP: 22.5, WBC: 17200 80.6/9, vial ER for admission to ward for evaluation.
Case presentation 2. Progression note:
After admission, SF of R’t ankle was aspirated, the result show: MSU: (+++), intracellular. SF/C: (-), CPPD( - ),
SF: WBC: 49300/cumm, N:95%, 24hrs UA excretion: 673.38mg, Clcr:70 Treatment: colchicine 1# bid, meloxicam: 1# bid, Prednisolone: 5mg bid----qd. Fina: 2#
bid.
Think of them
Case presentation 3 王 X 惠 ,女性 ,35歲 ,病歷號 :1195949C 入院日期 : 91-04-17 出院日期 : 91-04-26 主訴 :General malaise, poor appetite,
impaired LFT. P.I:35 yrs female initial presented with skin rash,photosensitivity since 1987/7. In 1989/11 she developed general edema, SLE was Dx at CGMH.because severe proteinuria,19 courses of Endoxan pulse Tx were given at VGHTP from 1991-1993.Due to poor Endoxan response, CsA had ever used.
Case presentation 3 1997/7:Renal Bx: Class IV A/C:2/6. 1998/4:Cellcept 2# bid was added . 1999-03-13.renal Bx class III & V A/C: 2/9. 2001/1: Rhabdomyolysis due to bezalip 2002/1: GA attack over R’t knee & recurred. Rx: allopurinol 2# qd + colchicine 1# bid. 2002/2:Persistent proteinuria & impaired renal function, repeat renal Bx: class VI A/C:0/9---add immuran 1# qd
Poor appetite, general malaise, fatigue for 3-4 wks. Check GPT:741---DC immuran
From OPD transfer to ward for further evaluation.
Case presentation 3 Impression: 1.Acute hepatitis R/O drug induce 2.SLE with lupus nephritis class IV 3.Gouty arthritis , R’t Knee 4.HTN Progression note: HbsAg: (-), anti-HCV (-), Abd sono(-) finding,
PCR of CMV DNA (-). 24hr UA: 4.1mg/dl, total vol: 3350ml/24hr 24hr UA excretion: 137.35<700mg----
undercxcretion.
Case presentation 3Date
ALKP
AST ALT LDH Bil-T
Bil-D
TG UA Cr
90-5/16
17 25 180 0.2 0 423
90-5/30
251 13.7
90-6/27
339
90-9/26
32 8.1
90-11/21
61 201 6.7 2.1
91-03/05
218 11.2 2.1
91-4/10
138 741 2.5
91-4/17
133 271 706 561 2.9
91-4/22
154 83 430 487 2.4
When you are down
問題 . 請問其診斷為何 ? (1) 細菌性關節炎 (2) 痛風關節炎 (3)假痛風 一位 60 歲已停經女性，因胃潰瘍穿孔而接受緊急手術治療，開刀後第三天，右側大腳趾之蹠趾關節突然紅腫疼痛且有發燒
隔日測其血清尿酸為 4.2mg/dl ( 正常值 )
血尿酸值正常者併發痛風之臨床分析 (Ann Rheum Dis 2003; 62:90-92)1.血尿酸值正常者發生痛風的機率可達 39-43%
(Ann Rheum Dis 1997; J Rheumatol 1997)2.韓國痛風發作的病人 226位，有 27位 (12%)之血尿酸值是正常 =>21 位追踪 3年，有 17位 (81%)事後會有高尿酸血症 (中間 值為 3 個月，範圍 1週 ~2 年 )，其餘 4 位之血尿酸值仍為正常， 也未再痛風發作3. 若與高尿酸血症併發痛風者比較，血尿酸值正常者發生痛風者 痛風發作年齡較大 (60.613.9 歲 ) 痛風首次徵狀到確定診斷之間隔較短 (32.2個月 ) 發生痛風石的機會較少 血清肌酸酐值較低
問題 . 請問最佳的治療為何 ?(1) 靜脈注射秋水仙素 (2)注射消炎藥 Ketorolac (3) 關節抽液併關節內類固醇注射 (4) 給予Allopurinol
一位 64 歲男性，以前常因痛風發作而服用消炎止痛藥。這次因多處胃潰瘍併大量出血而住院治療
第二天，右側膝關節突然紅腫疼痛而且有發燒 其血清尿酸為 9.8 mg/dl ( 正常值 < 7.2) NPO 中
And let you up
問題 . 試問該病人如何治療高尿酸血症 ?
1) 改用促進尿酸排泄的藥物 , 2) Allopurinol 之減敏治療
一位 52 歲體型稍胖的男性，最近三年來常有急性下肢 1-2個關節腫痛，大多一週內完全消退 (平均一年至少發作三次 ) 。理學檢查發現左大腳趾關節處紅腫熱痛，而且周圍已有痛風石沈積，血清尿酸值為 12.8mg/dl
， 血清肌酸酐為 4.2 mg/dl, 且有腎結石以前曾用過 Allopurinol ，但因發生皮膚紅疹而停用。
分解尿酸的藥物 (Uricase)Rasburicase
此類藥物屬於分生合成的尿酸鹽氧化酶(Urate oxidase) ，可將尿酸分解成具高溶解度的代謝產物 Allantoin (其溶解度為尿酸之 10~100 倍 ) 。
可迅速降低尿酸濃度，對於血液腫瘤疾病與將接受化學藥物治療的患者，其治療及預防高尿酸血症產生的併發症效益很高 ( 實証醫學 B 級 ) 。
RASBURICASE
PROPRIETARY NAME: ELITEKTM (Sanofi-Synthelabo)
INDICATIONS: Rasburicase is indicated for the initial management of plasma uric acid levels in pediatric patients with leukemia, lymphoma, and solid tumor malignancies who are receiving anti-cancer therapy expected to result in tumor lysis and subsequent elevation of plasma uric acid. Decreasing the hyperuricemia is done in order to prevent acute renal failure in these patients.
CLINICAL PHARMACOLOGY:
Rasburicase is a recombinant urate-oxidase enzyme. It is produced by a genetically modified Saccharomyces cerevisiae strain cloned with cDNA from a strain of Aspergillus flavus. This recombinant enzyme is a tetrameric protein similar to native A. flavus urate oxidase. Urate oxidase is an endogenous enzyme in most mammals, but not in humans. Rasburicase catalyzes enzymatic oxidation of uric acid into allantoin, a water soluble product that is easily excreted by the kidneys.
PHARMACOKINETICS: Steady state is achieved within 2 to 3
days following infusion of rasburicase 0.2 mg/kg/day as a 30-minute infusion daily. The volume of distribution of rasburicase is 110 to 127 mL/kg. Its elimination half-life is 18 hours. Total body clearance is increased about 35% in children and adolescents compared to adults.1,5 Rasburicase is expected to undergo peptide hydrolysis like other proteins. Impaired hepatic function should not alter the elimination of rasburicase. The pharmacokinetics of rasburicase have not been evaluated in patients with impaired renal function, but renal elimination is expected to be a minor pathway. Allantoin is eliminated renally, but appears to be nontoxic.
ADVERSE REACTIONS: The most common adverse effects observed
during rasburicase therapy have included vomiting (50%), fever (46%), nausea (27%),
headache (26%), abdominal pain (20%), constipation (20%), diarrhea (20%), mucositis (15%), and rash (13%).
Serious adverse reactions caused by rasburicase have included anaphylaxis (less than 1%), rash (1%), hemolysis (less than 1%), and methemoglobinemia (less than 1%).
Other serious adverse events commonly observed during rasburicase therapy included fever (5%), neutropenia with fever (4%), respiratory distress (3%), sepsis (3%), neutropenia (2%), and mucositis (2%).1
DOSING: Rasburicase is administered immediately prior to
and during chemotherapy initiation. Chemotherapy should be initiated 4 to 24 hours after the first rasburicase dose.
The recommended dose of rasburicase is 0.15 or 0.2 mg/kg as a single daily dose for 5 days. Rasburicase should be administered as a 30-minute intravenous infusion.
Dosage adjustments are not necessary in patients with renal or hepatic impairment. The required quantity of solution is diluted with 0.9% sodium chloride solution to make a total volume of 50 mL. The final solution should be infused over 30 minutes. No filters should be used for the infusion. Glucose solutions should not be used for dilution due to potential incompatibility.
治療高尿酸血症促進尿酸排泄的藥物 (Uricosuric drugs)
這類藥物包括probenecid(Benemid) 、 Sulfinpyrazone 、 Benzbromarone (Narcaricid) 、 抗血脂藥物(fenofibrate) 、及降血壓藥 (Losartan) 。
由於 probenecid 及 Sulfanpyrazone 在腎功能不佳的病人 ( 腎絲球瀘過率≦ 50 毫升 / 分鐘 ) 療效減低，易致尿酸鹽沈積在腎臟，而且具較高的毒性 ( 如出血或骨髓抑制 ) ，因此目前很少被使用。
Benzbromarone 在腎功能不佳的病人，仍可有效促進尿酸由腎臟排泄 ( 實証醫學 C 級 ) ，但須注意防範尿酸鹽在腎臟的沈積，以及其少見的肝臟副作用。在歐洲醫療體系，甚至與 Allopurinol 合併使用，具有降尿酸加乘的效果。
高尿酸血症患者使用 Allopurinol或Benzbromarone治療之效果比較 (Med Assoc Thai 2002; 85:s40-7)
一交叉臨床試驗(Allopurinol 4週—藥物清除 4週—Benzbromarone 100mg/日，為期 4週 )
降低尿酸的效果， Benzbromarone優於Allopurinol
實証醫學等級 C
促進尿酸排泄的藥物降血脂藥物 Fenofibrate (Lipansyl)
最近的研究發現降血脂藥物 Fenofibrate (Lipansyl)可有效促進尿酸排泄，而且可合併其他降尿酸藥物 ( 實証醫學 C 級 ) 。由於高尿酸血症患者若合併有高血脂症，則可考慮使用此藥物。
促進尿酸排泄的藥物降血壓藥物 Losartan (Cozaar)
在降血壓藥物中，有一種血管張力素轉化酶抑制劑 Losartan (Cozaar) ，被發現有促進尿酸排泄的功效，因此也可用來降低血尿酸值。當高尿酸血症患者，若同時併有高血壓，則可優先使用此降壓藥。
降尿酸藥與降血脂藥 Fenofibrate 或降血壓藥Loasrtan 之合併療法對於尿酸的作用
1. 這是隨機但非雙盲的臨床藥物試驗
2.結果顯示合併降血脂藥物 (fenofibrate)或合併 降血壓藥物 (losartan)，皆能促進尿酸由尿液排泄 而降低血尿酸值
Ann Rheum Dis 2003; 62(6): 497-8
實証醫學等級 C
使用促進尿酸排泄藥物的問題1. 併發症 造成尿酸塩沉積在腎臟組織及腎結石 可能增加痛風的發作 (初期使用 ) 過敏 (Sulfinpyrazone)
骨膸的抑制 (Probenecid)
肝炎 (Benzbromarone)
2.預防之道 須足夠飲水及尿液鹼性化 同時口服秋水仙素 以低劑量開始使用，且緩慢增量
痛風的治療
血尿酸值須控制到多少？
預防痛風復發 6.0mg/dl促進痛風石吸收 5.0mg/dl
器官移植合併高尿酸血症1.高尿酸血症的原因 腎功能異常 使用環孢靈 (Ciclosporine)
2.解決方法 儘量矯正高尿酸血症的原因 使用 Allopurinol 或 尿酸分解酶 (uricase)
若有高血壓 => 優先考慮 Losartan (Cozarr)
若有高血脂 => 優先考慮 Fenofibrate
難以控制的高尿酸血症 (5-10%)
1.原因• 高尿酸血症的原因持續存在
(利尿劑的使用、照常喝酒、肥胖 )
2.處理方法
矯正及排除高尿酸血症的原因
可考慮使用尿酸分解酶 (uricase)
痛風石合併腎功能不好的高尿酸血症1.困難處 無法使用高劑量的 Allopurinol (易發生副作用 ) 促進尿酸排泄藥效果不佳且易致腎結石 這類病人之血尿酸值須控制在 5.0mg/dl2.解決方法 儘量矯正高尿酸血症的原因 使用尿酸分解酶 (uricase)
若有高血壓 => 優先考慮 Losartan (Cozarr)
若有高血脂 => 優先考慮 Fenofibrate 徵狀治療痛風發作 (不得己 )
611942C
UA(mg/dl) Scr(mg/dl)
890622 8.4 1.8
891116 5.3 2.0
They may not tell you
1164830J
UA(mg/dl) Scr(mg/dl)
910319 12.1
910510 10.8
910927 6.7
They are always there
234981H
UA(mg/dl) Scr(mg/dl)
910512 12.3 3.0
910513 2.2
910516 2.1
9011290112CCCAD - S/P PTCA Valvular heart disease - AR Hyperlipidemia HCVD 藥 名 使用劑量及用法 25mg Dithiazid tab 0.5 TAB PO BID Tapal tab 1 TAB PO QD Isordil tab 10mg 1 TAB PO TIDAC Doxazosin tab 2mg 1 MG PO BID Herbesser tab 30mg 1 TAB PO TID Perindopril-4 tab 1 TAB PO QD Benzbromarone-100 100 MG PO QD Fenofibrate-200cap 1 CAP PO QDCC
Chol TG HDL UA 213 244 11.7215 289 5.2250 124 71
結論 ( 一 ) 痛風是一臨床常見的醫療問題，若未適當的治療，會
產生痛風石、關節及內臟的傷害 老年發作之痛風常呈現非典型徵狀 痛風的關節炎的診斷須在受犯關節的關節液有尿酸鹽
結晶，才可確立 高尿酸血症是痛風的主因，但非必要條件 治療主在 1)終止急性痛風 (NSAIDs及低劑量秋水仙素為主 ) 2)治療高尿酸血症 (去除其原因、口服降尿酸 藥物及調整生活飲食 )
3) 評估且治療痛風相關之疾病
結論 ( 二 )臨床藥師對痛風應認識的重點
痛風與高尿酸血症之病態生理學 急性期與慢性期痛風葯物治療有何不同? 高尿酸血症葯物治療的時機? 痛風與高尿酸血症最新葯物 (Allopurinol;
Benzbromarrone;Rasburicase etc.) 之葯動學 (pk)及葯理學臨床應用?
痛風治療葯物之副作用與葯物交互作用 飲食的控制(低普林食物?高普林食物 ?)
Thanks for your attention !
