cetaminophen 與 洗腎？
來源： Acetaminophen 與 洗腎？ @ 快樂小藥師 Im pharmacist nichts glücklich :: 痞客邦 PIXNET ::
今天這個謠言又捲土重來了，就是Acetaminophen與洗腎的關聯
首先，我要提醒大家一件很重要的觀念，acetaminophen不屬於NSAID
他可以解熱、鎮痛，但他不能消炎，所以藥理學上不算是NSAID
先不說藥理，你猜猜看止痛藥最大宗的生產國還有加上陳列的是那邊？
當然是歐美等國家，因為他是西藥呀！
有看過好萊塢吧，裡面的主角沒事就從櫃子裡面拿了止痛藥，直接吞下去，就算他只是演戲，最常吃西藥的人也是歐美人，結果你猜猜洗腎最多的是那邊的人？
再來，acetaminophen最著名的就是肝臟副作用，相關的藥物訊息你可以參考這邊：
N acetylcysteine對Acetaminophen的中毒治療
Acetaminophen與Acetylcysteine併用？
Acetaminophen Use in Adolescents May Double Risk for Asthma
Acetaminophen中毒與處置
Safe Use Initiative: Acetaminophen Toxicity
Over-the-counter analgesic （ibuprofen、acetaminophen）use and potential hearing loss 成藥止痛藥可能導致聽覺喪失
雖然不正確的使用acetaminophen與酒精會造成腎臟的損壞，但是這並非是acetaminophen造成的主因。
這邊有參考資料：
Acetaminophen and Alcohol May Be Nephrotoxic
另外嚴重肝臟損壞的患者，會代償性的影響腎功能
Acetaminophen-induced nephrotoxicity: Pathophysiology, clinical manifestations, and management（J Med Toxicol. 2008 Mar; 4(1): 2–6. doi: 10.1007/BF03160941）
Paracetamol-Induced Renal Tubular Injury: A Role for ER Stress（JASN February 1, 2004 vol. 15 no. 2 380-389 doi: 10.1097/01.ASN.0000111289.91206.B0）
甚至還有特地澄清acetaminophen與蛋白尿的關係：
Proteinuria is unrelated to the extent of acute acetaminophen overdose: A prospective clinical study（J Med Toxicol. 2008 Dec; 4(4): 232–237. doi: 10.1007/BF03161206）
至於acetaminophen的藥物動力學，讓我們從MicroMedex找一點證據來看看
Drug Concentration Levels
A)Therapeutic Drug Concentration
1) Analgesia, 10 mg/L [220]
a) Using a fractional sigmoid model, serum concentration at 10 mg/L achieved pain score of less than 4 of 10 in children who underwent tonsillectomy [220].
B)Peak Concentration
1) Adults
a) IV, single-dose: 28 mcg/mL (1000 mg) [53]
1) In adult subjects, the mean Cmax was 28 +/- 21 mcg/mL at the end of a 15-minute IV infusion of acetaminophen 1000 mg [53].
b) Oral, single-dose, immediate-release: 7.7 to 17.6 mcg/mL (1000 mg) [2]
1) In 24 fasting adult subjects, the Cmax ranged from 7.7 to 17.6 mcg/mL following a single 1000-mg dose of oral acetaminophen (liquid or caplet) [2].
c) Oral, multiple-dose, immediate-release, elderly patients: 23.9 mcg/mL [217]
1) In 12 very elderly patients (mean age, 89 years), the Cmax was 23.9 mcg/mL following the administration of acetaminophen 1000 mg orally 3 times daily for 5 days [217].
d) Oral, single-dose, extended-release: 6.9 to 14.1 mcg/mL (1300 mg) [2]
1) In 24 fasting male subjects, the Cmax ranged from 6.9 to 14.1 mcg/mL following a single 1300-mg dose (two 650 mg caplets) of oral extended-release acetaminophen [2].
2) Pediatrics
a) IV, single-dose: 25 to 31 mcg/mL (15 mg/kg) [53]
1) The mean Cmax values were 25 +/- 4, 29 +/- 24, 29 +/- 7, and 31 +/- 9 mcg/mL following a single 15-mg/kg dose of IV acetaminophen in neonates, infants, children, and adolescent subjects, respectively [53].
b) Oral, single-dose, immediate-release: 14.6 +/- 2.6 mcg/mL (12.5 mg/kg) [2]
1) In febrile children, the Cmax was 14.6 +/- 2.6 mcg/mL following a single 12.5-mg/kg dose of oral acetaminophen [2].
c) Rectal, single-dose: 5.5 to 14.2 mcg/mL [219]
1) In children, the mean Cmax values were 5.5, 8.8, and 14.2 mcg/mL following rectal acetaminophen doses of 10, 20, and 30 mg/kg, respectively [219].
2) The Cmax was 12.5 mg/L in 28 to 32 week old neonates and 7.5 mg/L in 32 to 36 week old neonates following a single 20-mg/kg dose (range, 16 to 26 mg/kg/dose) of acetaminophen administered rectally [218].
C)Time to Peak Concentration
1) Adults
a) Oral, immediate-release: within 1 hour [2]
1) In 24 fasting adult subjects, the Cmax of 7.7 to 17.6 mcg/mL occurred within 1 hour following a single 1000-mg dose of oral acetaminophen (liquid or caplet) [2].
2) In 12 very elderly patients (mean age, 89 years), the Cmax of 23.9 mcg/mL occurred at a Tmax of 0.9 hour following the administration of acetaminophen 1 gram orally 3 times daily for 5 days [217].
b) Oral, extended-release: 0.5 to 3 hours [2]
1) In 24 fasting male subjects, the average Cmax of 6.9 to 14.1 mcg/mL occurred at 0.5 to 3 hours following a single 1300-mg dose (two 650 mg caplets) of oral extended-release acetaminophen [2].
2) Pediatrics
a) Oral, immediate-release: within 0.5 hour [2]
1) In febrile children, the Cmax of 14.6 +/- 2.6 mcg/mL occurred within 0.55 +/- 0.09 hours following a single 12.5-mg/kg dose of oral acetaminophen [2].
b) Rectal: 107 minutes to 5.1 hours [219][218]
1) The mean Cmax and Tmax values following a single 10-, 20-, and 30-mg/kg dose of acetaminophen administered rectally to children are presented in Table 1 [219]:
Table 1
Dose Mean Cmax(mcg/mL) Tmax(minutes)
10 mg/kg 5.5 107
20 mg/kg 8.8 288
30 mg/kg 14.2 210
2) The Cmax and Tmax values following a single 20-mg/kg dose (range, 16 to 26 mg/kg/dose) of acetaminophen administered rectally are presented in Table 2 [218]:
Table 2
Gestational Age Cmax(mg/L) Median Tmax(hours)
28 to 32 weeks 12.5 3.9
32 to 36 weeks 7.5 5.1D)Area Under the Curve
1) Adults
a) IV, single-dose: 43 mcg x hr/mL (1000 mg) [53]
1) In adult subjects, the mean AUC was 43 +/- 11 mcg x hr/mL following a single 1000-mg dose of IV acetaminophen [53].
b) Oral, multiple-dose, elderly patients: 82.54 mcg x hr/mL (1000 mg 3 times daily) [217]
1) In 12 very elderly patients (mean age, 89 years), the average AUC was 82.54 mcg x hr/mL following the administration of acetaminophen 1000 mg orally 3 times daily for 5 days [217].
2) Pediatrics
a) IV, single-dose: 38 to 62 mcg x hr/mL (15 mg/kg) [53]
1) The mean AUC values were 62 +/- 11, 57 +/- 54, 38 +/- 8, and 41 +/- 7 mcg x hr/mL following a single 15-mg/kg dose of IV acetaminophen in neonates, infants, children, and adolescent subjects, respectively [53].
b) Rectal, single-dose, 20 mg/kg, neonates: 95.1 mg x hr/L (gestational age, 28 to 32 weeks); 71.7 mg x hr/L (gestational age, 32 to 36 weeks) [218]
1) The AUC was 95.1 mg x hr/L in 28 to 32 week old neonates and 71.7 mg x hr/L in 32 to 36 week old neonates following a single 20-mg/kg dose of acetaminophen administered rectally [218].
Absorption
A) Bioavailability
1) Oral: 85% to 98% [2]
a) Oral acetaminophen is rapidly absorbed from the gastrointestinal tract, mostly in the small intestine, and has a relative bioavailability of 85% to 98% [2].
B) Effects of Food
1) Delayed peak but extent of absorption not affected [2]
a) Acetaminophen may be taken with or without food. When acetaminophen is given with food, the Cmax is delayed but the extent of absorption is not affected [2].
Distribution
A) Distribution Sites
1) Protein Binding
a) 10% to 25% [53][2]
1) The protein binding of acetaminophen is low; only 10% to 25% of acetaminophen is bound to plasma proteins [53][2].
2) Tissues and Fluids
a) Spinal fluid: good [2]
1) Acetaminophen crosses the blood-brain barrier. Central diffusion to the brain and spinal fluid occurs within 15 to 45 minutes with maximum cerebrospinal fluid concentrations occurring at 2 to 4 hours [2].
b) Placenta: 7.9 mcg/mL [2]
1) After maternal ingestion, acetaminophen may cross into the fetal circulation within 30 minutes. Fetal serum concentrations are similar to maternal serum concentrations (7.9 and 5.9 mcg/mL, respectively) [2].
B) Distribution Kinetics
1) Volume of Distribution
a) Adults, 0.7 to 1 L/kg; pediatrics, 0.7 to 1.2 L/kg [53][2]
1) In adult subjects who received a single 1000-mg dose of IV acetaminophen, the mean steady-state volume of distribution was 0.8 +/- 0.2 L/kg [53].
2) In neonates, infants, children, and adolescent subjects who received a single 15-mg/kg dose of IV acetaminophen, the mean steady-state volume of distribution values were 1.1 +/- 0.2, 1.1 +/- 0.3, 1.2 +/- 0.3, and 0.8 +/- 0.2 L/kg, respectively [53].
3) Acetaminophen is distributed widely throughout most body fluids except fat and has an apparent volume of distribution of about 0.7 to 1 L/kg in adults and children [2].
Metabolism
A) Metabolism Sites and Kinetics
1) Liver: extensive [2]
a) Acetaminophen is metabolized mostly in the liver by conjugation with glucuronide, conjugation with sulfate, and oxidation via the CYP isoenzyme system, mainly via CYP2E1. The toxic reactive metabolite, N-acetyl-p-benzoquinone imine (NAPQI), is formed via the oxidative metabolism pathway, and is conjugated with glutathione to form cysteine and mercapturic acid. Additionally, minor oxidative metabolism pathways include hydroxylation to 3-hydroxy-acetaminophen and methyoxylation to form 3-methoxy-acetaminophen. These metabolites are then conjugated with glucuronide or sulfate [2].
b) High doses may induce acetaminophen glucuronidation. Steady-state plasma concentrations were lower than expected and glucuronide formation clearance was higher than expected when the acetaminophen dosage exceeded 4 grams/day in healthy adult subjects who received acetaminophen 1000 mg, 1500, mg, or 2000 mg every 6 hours for 3 days. In this study, N-acetyl-p-benzoquinone imine (NAPQI) did not accumulate with higher dosages. Additionally, glucuronidation was induced and total acetaminophen clearance was increased in patients with liver impairment and healthy older adult subjects when acetaminophen 4000 mg/day was administered daily for consecutive days [2].
c) Metabolism of acetaminophen may be slower but is similar in patients with liver impairment and in healthy subjects [2].
d) Intrapatient environmental factors such as nutrition, alcohol use, smoking, etc, do not appear to significantly affect acetaminophen metabolism. Prediction of acetaminophen half-life based on such factors is not valid [221]. Some drugs that induce cytochrome P-450 enzymes (sulfinpyrazone and anticonvulsants) may increase acetaminophen metabolism [222].
e) Following usual doses, approximately 25% of the drug is reported to be metabolized on the first pass through the liver (Clements, 1976).
B) Metabolites
1) N-acetyl-p-benzoquinone imine: major [53][2]
a) Acetaminophen is metabolized mostly in the liver by conjugation with glucuronide, conjugation with sulfate, and oxidation. The toxic reactive metabolite, N-acetyl-p-benzoquinone imine (NAPQI), is formed via the oxidative metabolism pathway, and is conjugated with glutathione to form the inactive metabolites cysteine and mercapturic acid [53][2].
2) 3-hydroxy-acetaminophen and 3-methoxy-acetaminophen: unknown [53][2]
a) Acetaminophen is metabolized mostly in the liver by conjugation with glucuronide, conjugation with sulfate, and oxidation. Minor oxidative metabolism pathways via CYP2A6 include hydroxylation to 3-hydroxy-acetaminophen and methyoxylation to form 3-methoxy-acetaminophen. These metabolites are then conjugated with glucuronide or sulfate. Glucuronide- and sulfate-derived metabolites are inactive [2].
3) cysteine, mercapturic acid, glucuronic acid and sulfate conjugates: inactive [2].
a) Acetaminophen is metabolized mostly in the liver by conjugation with glucuronide, conjugation with sulfate, and oxidation. The toxic reactive metabolite, N-acetyl-p-benzoquinone imine (NAPQI), is formed via the oxidative metabolism pathway, and is conjugated with glutathione to form the inactive metabolites cysteine and mercapturic acid. Minor oxidative metabolism pathways via CYP2A6 include hydroxylation to 3-hydroxy-acetaminophen and methyoxylation to form 3-methoxy-acetaminophen. These metabolites are then conjugated with glucuronide or sulfate. Glucuronide- and sulfate-derived metabolites are inactive [2].
Excretion
A) Kidney
1) Renal Excretion (%)
a) less than 5% unchanged [53]
1) Over 90% of the acetaminophen dose is excreted within 24 hours. Acetaminophen metabolites are excreted in the urine and less than 5% of the acetaminophen dose is excreted in the urine as unchanged drug [53].
2) In healthy subjects, approximately 3.5% of acetaminophen was excreted unchanged in the urine following doses of 8.3 to 15 mg/kg (500 to 1000 mg) of acetaminophen [2].
3) One gram of acetaminophen was administered 3 to 5 days after surgery to 6 biliary surgery patients with T tube drainage of the common bile duct. Bile and urine was collected for 8 hours after acetaminophen administration. Renal excretion (total) amounted to 35.3% of the oral dose [223].
B) Bile
1) 2.6% [223]
a) Biliary excretion is not an important elimination pathway in man. Six biliary surgery patients with T tube drainage of the common bile duct were studied for acetaminophen biliary excretion. One gram of acetaminophen was administered 3 to 5 days after surgery. Bile and urine was collected for 8 hours after acetaminophen administration. Biliary excretion of unchanged acetaminophen was 0.26%, the sulfate conjugate was 0.36%, the glucuronic acid metabolite was 0.36%, and the cysteine metabolite was 1.63%. Total biliary excretion was 2.6% of the oral dose. Renal excretion (total) amounted to 35.3% of the oral dose [223].
C) Total Body Clearance
1) Adults, 0.27 L/hr/kg [53]
a) In adult subjects who received a single 1000-mg dose of IV acetaminophen, the mean total body clearance was 0.27 +/- 0.08 L/hr/kg [53].
2) Pediatrics, 0.12 to 0.34 L/hr/kg [53]
a) In neonates, infants, children, and adolescent subjects who received a single 15-mg/kg dose of IV acetaminophen, the total body clearance values were 0.12 +/- 0.04, 0.29 +/- 0.15, 0.34 +/- 0.1, and 0.29 +/- 0.08 L/hr/kg, respectively [53].
Elimination Half-life
A) Parent Compound
1) Adults
a) 2 to 3 hours [53][2][217]
1) In adult subjects who received a single 1000-mg dose of IV acetaminophen, the mean half-life was 2.4 +/- 0.6 hours [53].
2) In healthy adults who received oral acetaminophen in the usual dosage range, the elimination half-life was about 2 to 3 hours with the immediate-release formulation and about 3 hours with the extended-release formulation [2].
3) In 12 very elderly patients (mean age, 89 years), the average half-life was 2.74 hours following the administration of acetaminophen 1000 mg orally 3 times daily for 5 days [217].
2) Pediatrics
a) 4 to 11 hours, neonates; 1.5 to 4.2 hours, children [53][2][218]
1) In neonates, infants, children, and adolescent subjects who received a single 15-mg/kg dose of IV acetaminophen, the mean half-life values were 7 +/- 2.7, 4.2 +/- 2.9, 3 +/- 1.5, and 2.9 +/- 0.7 hours, respectively [53].
2) The elimination half-life is about 1.5 to 3 hours in children receiving the immediate-release oral acetaminophen formulation; however, the elimination half-life is about 1 hour longer in neonates [2].
3) The mean elimination half-life was 11 hours for 28 to 32 week old neonates and 4 to 5 hours for 32 to 36 week old neonates [218].
Extracorporeal Elimination
A) Hemodialysis
1) Dialyzable: Yes[224]
a) It has been reported that hemodialysis removes significant amounts of acetaminophen and its glucuronide and sulfate conjugates from plasma. In patients receiving therapeutic doses of acetaminophen half-life values were noted to be reduced by 40% to 50% of intradialysis values during hemodialysis [224]. However, hemodialysis has not yet been proven to be effective in preventing or reducing the severity of liver damage associated with acetaminophen overdose [225][226].
超過90%的acetaminophen會在24小時內被排除，幾乎不到5%的Acetaminophen才會以原型排除，其他的均在肝臟代謝掉了。
說他是傷腎一族實在是言過其實。
所以跟腎臟並沒有直接的關係。
對於腎功能不佳的患者，需要調整給藥頻率
Dosage in Renal Failure 腎衰竭
A) A longer dosing interval and a reduced total daily dose of acetaminophen may be warranted in cases of severe renal impairment (CrCl 30 mL/min or less) [1].
B) It has been recommended to increase the dosing interval to every 4 hours in patients with mild renal failure (GFR greater than 50 mL/min), every 6 hours in patients with moderate renal failure (GFR 10 to 50 mL/min), and every 8 hours in patients with severe renal failure (GFR less than 10 mL/min) [39].
Dosage Adjustment During Dialysis 透析患者
A) Supplemental doses are not required following hemodialysis or peritoneal dialysis among adults [39]. A longer dosing interval and a reduced total daily dose of acetaminophen may be warranted in cases of severe renal impairment (CrCl 30 mL/min or less) [1].
只有Micromedex不夠？
專書介紹來佐證好了
ISBN-13: 978-1619423749
1.acetaminophen在正常劑量時（4g/day），不會造成肝臟及腎臟的損傷
2.高劑量的acetaminophen可能會造成腎衰竭
3.即使有些資料顯示acetaminophen與腎臟毒性的關係（請見參考資料164-166），但是在建議劑量時並沒有產生過，而且就算是長期使用也沒有發生（請見參考資料167）
再加上個醫師現身說法好了：
美國兒科醫學會對於嬰幼兒退燒之建議 by 楊為傑醫師
最後關於洗腎盛行的主因，其實這個並沒有真正的定論，歸咎於任何一種藥物都不是最正確的說法。
目前知道可能與洗腎相關的因素有：血壓還有血糖的控制不良，過度使用與腎臟有關的藥物（不管是中藥還是西藥）、還有一些個人的生活習慣或是飲食習慣，急性的疾病或是外傷，甚至你也可以懷疑台灣30年來的食安問題還有藥物賦形劑是造成的原因。
那位醫師的全文在這邊：（後來有加註acetaminophen不是NASID了）
