藥物---202303091224Acetaminophen Toxicity

 Acetaminophen 乙醯胺酚, 對乙醯胺基酚（英語：Acetaminophen、Paracetamol、簡稱：APAP）、撲熱息痛，在台灣, 以前普拿疼的廣告打很兇, 所以一般民眾比較知道的名稱是普拿疼. 但普拿疼以前是商品名, 現在已經成品牌(普拿疼是Haleon消費保健用品公司旗下知名的全球品牌之一). 醫師與民眾如果說到普拿疼, 通常是指 acetaminophen, 至於普拿疼肌立裡面成分是 Diclofenac sodium(屬於 NSAID). 與乙醯胺酚完全不同. 我的文章若提到普拿疼, 一般都是指 acetaminophen (台灣食藥署的藥物食品安全周報有止痛藥介紹)

PUBLISHED MARCH 19, 2014 PAIN MANAGEMENT
Acetaminophen Toxicity: What Pharmacists Need to Know


google中文翻譯
攝入後，對乙酰氨基酚會迅速從胃腸道 (GI) 吸收並迅速分佈到全身。在 30 到 60 分鐘內達到血漿峰濃度4；食物可能會延遲達到峰值濃度的時間，但吸收的程度不受影響。 12 過量服用時，血漿峰值濃度通常在 4 小時內達到。 13 對乙酰氨基酚的半衰期約為治療劑量後的 2 至 3 小時，但可以肝損傷患者增加到 4 小時以上。 4,12,14
對乙酰氨基酚通過三個主要肝臟途徑在肝臟中廣泛代謝：葡萄醣醛酸化、硫酸化和 CYP450 2E1 氧化。12 大約 90% 的對乙酰氨基酚與經腎臟消除的硫酸化和葡萄醣醛酸化代謝物結合。14 在剩餘的對乙酰氨基酚中，約 2% 是在尿液中以原形排泄，其餘經過 CYP450 介導的氧化形成活性代謝物 N-乙酰基-對苯醌亞胺 (NAPQI)。 15​​-18 在正常情況下，這種有毒代謝物與穀胱甘肽中的巰基反應，將其轉化為在尿液中排出前轉化為無害的代謝物。4
毒性
由於各種原因，藥物可能會產生毒性作用。某些藥物的毒性與不良代謝物的形成有關；因此，對乙酰氨基酚的毒性與 NAPQI 的產生有關。急性大劑量或長期使用時，主要的代謝途徑——葡萄醣醛酸和硫酸鹽結合系統——變得飽和，更多的對乙酰氨基酚被 CYP450 系統代謝。這導致 NAPQI 的產量增加。當穀胱甘肽耗盡約 70% 時，NAPQI 開始在肝細胞中積聚，導致肝損傷。 15,16,18 因此，用類似穀胱甘肽的化合物（如 N-乙酰半胱氨酸）替代穀胱甘肽可作為對乙酰氨基酚毒性的有用解毒劑.
對乙酰氨基酚中毒可由急性過量或慢性過度使用引起。急性過量被定義為在 8 小時內消耗了中毒量的藥物，而慢性過量是由於重複劑量達到或超過推薦限度而發生的。 12 意外過量也可能是由於多次攝入含有對乙酰氨基酚的產品。成人對乙酰氨基酚的推薦劑量為每 4 至 6 小時 650 至 1,000 毫克，24 小時內不超過 4,000 毫克；在兒童中，推薦劑量為每 4 至 6 小時 10 至 15 mg/kg，24 小時內不超過 50 至 70 mg/kg。 12 成人單劑量超過 150 mg/kg 或 7.5 g 已被考慮可能有毒，儘管與肝損傷相關的最小劑量範圍為 4 至 10 g。6,12,14,19 在兒童中，單劑量 120 mg/kg 至 150 mg/kg 與肝毒性有關；然而，<200 mg/kg 的劑量不太可能導致毒性。 14,20
雖然確切的最大劑量尚未明確定義，但美國毒物控制中心協會 (AAPCC) 建議無論攝入多少藥物，如果患者出現與毒性。 21 AAPCC 為急性、單次、無意攝入對乙酰氨基酚和反复超治療攝入對乙酰氨基酚提供了醫院轉診指南（表 1）。 21

Pharmacokinetics
Upon ingestion, acetaminophen is rapidly absorbed from the gastrointestinal (GI) tract and quickly distributed throughout the body. Peak plasma concentrations are achieved within 30 to 60 minutes4; food may delay time to peak concentration, but the extent of absorption is not affected.12 With overdoses, peak plasma concentrations are usually achieved within 4 hours.13 The half-life of acetaminophen is approximately 2 to 3 hours after therapeutic doses, yet can be increased to more than 4 hours in patients with hepatic injury.4,12,14
Acetaminophen is extensively metabolized by the liver via three main hepatic pathways: glucuronidation, sulfation, and CYP450 2E1 oxidation.12 Approximately 90% of acetaminophen is conjugated to sulfated and glucuronidated metabolites that are renally eliminated.14 Of the remaining acetaminophen, approximately 2% is excreted unchanged in the urine and the rest undergoes CYP450-mediated oxidation to form a reactive metabolite, N-acetyl-p-benzoquinone imine (NAPQI).15-18 Under normal circumstances, this toxic metabolite reacts with sulfhydryl groups in glutathione, converting it to harmless metabolites before being excreted in the urine.4
Toxicity
Drugs may have toxic effects due to various reasons. Toxicity of some drugs is related to the formation of an undesirable metabolite; consequently, toxicity of acetaminophen is related to the production of NAPQI. With large acute doses or with chronic use, the major metabolic pathways—the glucuronide and sulfate conjugation systems—become saturated, and more acetaminophen is metabolized by the CYP450 system. This results in increased production of NAPQI. When glutathione is approximately 70% depleted, NAPQI begins to accumulate in the hepatocytes, resulting in hepatic damage.15,16,18 Therefore, the replacement of glutathione with glutathione-mimicking compounds such as N-acetylcysteine serves as a useful antidote to acetaminophen toxicity.
Acetaminophen toxicity can result from either an acute overdose or from chronic overuse. Acute overdose is defined as consumption of a toxic amount of a drug within an 8-hour period, whereas chronic overdose occurs as a result of repeated doses at or above the recommended limit.12 Unintentional overdoses may also occur as a result of ingestion of multiple products containing acetaminophen. The recommended dose of acetaminophen in adults is 650 to 1,000 mg every 4 to 6 hours, not to exceed 4,000 mg in a 24-hour period; in children, the recommended dose is 10 to 15 mg/kg every 4 to 6 hours, not to exceed 50 to 70 mg/kg in 24 hours.12 Single doses of more than 150 mg/kg or 7.5 g in adults have been considered potentially toxic, although the minimal dose associated with liver injury can range anywhere from 4 to 10 g.6,12,14,19 In children, single doses of 120 mg/kg to 150 mg/kg have been associated with hepatotoxicity; however, doses <200 mg/kg are unlikely to result in toxicity.14,20
While the exact maximum dose has not been well defined, the American Association of Poison Control Centers (AAPCC) has recommended that regardless of the amount of drug ingested, a patient should be brought for medical evaluation if he or she displays signs or symptoms consistent with toxicity.21 The AAPCC has provided guidelines for hospital referral both for acute, single, unintentional ingestion of acetaminophen and for repeated supratherapeutic ingestion of acetaminophen (TABLE 1).21