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药物中毒

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丙戊酸中毒
原作者: Hong Kim;郑辛甜翻译,肖锋校对 发布日期:2015-01-05

 Title: Valproic acid toxicity
题目:丙戊酸中毒
Author作者: Hong Kim
翻译:郑辛甜 校对:肖锋

Valproic acid (VPA) is often used to treat seizure disorder and mania as a mood stabilizer. The mechanism of action involves enhancing GABA effect by preventing its degradation and slows the recovery from inactivation of neuronal Na+ channels (blockade effect).
丙戊酸(VPA)常被用于治疗癫痫和躁狂症,是一种情绪稳定药物。作用机制包括通过抑制GABA(γ-氨基丁酸)降解来增强其效应以及减缓神经元Na+通道失活的恢复(阻塞效应)。

VPA normally undergoes beta-oxidation (same as fatty acid metabolism) in the liver mitochondria, where VPA is transported into the mitochondria by carnitine shuttle pathway.
VAP通常在肝微粒体中经历β-氧化(与脂肪酸代谢相同)并通过肉碱穿梭通路转运到线粒体中。

In setting of an overdose, carnitine is depleted and VPA undergoes omega-oxidation in the cytosol, resulting in a toxic metabolite.
当VPA过量时,肉毒碱耗尽,VPA将在细胞液中进行ω-氧化,产生有毒代谢物。

Elevation NH3 occurs as the toxic metabolite inhibits the carbomyl phosphate synthase I, preventing the incorporation of NH3 into the urea cycle.
增多的氨作为毒性代谢物抑制了氨甲酰磷酸合成酶,并阻止氨进入尿素循环。

Signs and symptoms of acute toxicity include:
急性VPA中毒的症状和体征:

•GI: nausea/vomiting, hepatitis
•消化系统:恶心呕吐、肝炎;
•CNS: sedation, respiratory depression, ataxia, seizure and coma/encephalopathy (with serum concentration VPA: > 500 mg/mL)
•中枢神经系统:镇静,呼吸抑制,共济失调,惊厥和昏迷/脑病(当VPA血浆浓度> 500 mg/mL)

Laboratory abnormalities
实验室检查指标异常:

•Serum VPA level: signs of symptoms of toxicity does not correlate well with serum level.
•血浆VPA水平:中毒症状体征与血浆浓度没有很好的相关性。
•NH3: elevated
•氨水平升高。
•Liver function test: elevated AST/ALT
•肝功能检查:AST/ALT升高。
•Basic metabolic panel: hypernatremia, metabolic acidosis
•基础代谢层面:高钠血症、代谢性酸中毒。
•Complete blood count: pancytopenia
•全血细胞计数:全血细胞减少。

Treatment: L-carnitine
治疗:左旋肉碱
Indication: hyperammonemia or hepatotoxicity
适应证:高钠血症或肝毒性
•Symptomatic patients: 100 mg/kg (max 6 gm) IV (over 30 min) followed by 15 mg/kg IV Q 4 hours until normalization of NH3 or improving LFT
•有症状的患者:100 mg/kg(最多 6 g)静注(超过30 min)之后每4 h15 mg/kg 静注直至氨水平正常或肝功能检查结果改善。
•Asymptomatic patients: 100 mg/kg/day (max 3 mg) divided Q 6 hours.
•无症状的患者:每天100 mg/kg (最多3 mg),分成每6小时一次。

References 参考文献:
Goldfrank's Toxicologic Emergencies  9th ed. P 705