乌头碱

乌头碱（aconitine）是一种生物碱毒素。是常用中药乌头属中所含有的一种化学物质，具强烈毒性,口服0.2mg左右即能使人中毒，3-5mg即可致死。民间常用草乌、川乌等植物来泡制药酒，但这种药酒可能是极端危险的，也经常因此出现中毒甚至死亡的情况。

**用途**
乌头碱以前被用作解热药和镇痛药，但在草药中的应用仍然有限。狭窄的治疗指数使计算合适的剂量很困难。

**结构和反应性**
附子属和翠雀属植物的生物活性分离物被归类为去甲二萜生物碱。根据C18碳的存在与否进一步细分。乌头碱是一种C19去甲二萜生物碱，因为它含有C18。乌头碱几乎不溶于水，但极易溶于有机溶剂，例如氯仿或乙醚。如果酒精浓度足够高，乌头碱也可溶于乙醇和水的混合物中。
像许多其他生物碱一样，乌头碱六元环的碱性氮很容易形成盐和离子，使其对极性和亲脂性结构过血脑屏障。
The acetoxyl group at the c8 position can readily be replaced by a methoxy group, by heating aconitine in methanol, to produce a 8-deacetyl-8-O-methyl derivatives. If aconitine is heated in its dry state, it undergoes a pyrolysis to form pyroaconitine ((1α,3α,6α,14α,16β)-20-ethyl-3,13-dihydroxy-1,6,16-trimethoxy-4-(methoxymethyl)-15-oxoaconitan-14-yl benzoate) with the chemical formula C32H43NO9.

**作用**
Aconitine can interact with the voltage-dependent sodium-ion channels, which are proteins in the cell membranes of excitable tissues, such as cardiac and skeletal muscles and neurons. These proteins are highly selective for sodium ions. They open very quickly to depolarize the cell membrane potential, causing the upstroke of an action potential. Normally, the sodium channels close very rapidly, but the depolarization of the membrane potential causes the opening (activation) of potassium channels and potassium efflux, which results in repolarization of the membrane potential.
Aconitine binds to the channel at the neurotoxin binding site 2 on the alpha subunit. This binding results in a sodium-ion channel that stays open longer. Aconitine suppresses the conformational change in the sodium-ion channel from the active state to the inactive state. The membrane stays depolarized due to the constant sodium influx (which is 10–1000-fold greater than the potassium efflux). As a result, the membrane cannot be repolarized. The binding of aconitine to the channel also leads to the channel to change conformation from the inactive state to the active state at a more negative voltage. In neurons, aconitine increases the permeability of the membrane for sodium ions, resulting in a huge sodium influx in the axon terminal. As a result, the membrane depolarizes rapidly. Due to the strong depolarization, the permeability of the membrane for potassium ions increases rapidly, resulting in a potassium reflux to release the positive charge out of the cell. Not only the permeability for potassium ions but also the permeability for calcium ions increases as a result of the depolarization of the membrane. A calcium influx takes place. The increase of the calcium concentration in the cell stimulates the release of the neurotransmitter acetylcholine into the synaptic cleft. Acetylcholine binds to acetylcholine receptors at the postsynaptic membrane to open the sodium-channels there, generating a new action potential.
Research with mouse nerve-hemidiaphragm muscle preparation indicate that at low concentrations (Lurida terribiles miscent aconita novercae.
Fearsome stepmothers mix lurid aconites. 
Aconitine was also made famous by its use in Oscar Wilde's 1891 story "Lord Arthur Savile's Crime".  Aconite also plays a prominent role in James Joyce's Ulysses, in which the father to protagonist Leopold Bloom used pastilles of the chemical to commit suicide.  Aconitine poisoning plays a key role in the murder mystery Breakdown by Jonathan Kellerman (2016). In Twin Peaks (season 3) Part 13, aconitine is suggested to poison the main character.
Monk's Hood is the name of the third Cadfael Novel written in 1980 by Ellis Peters. The novel was made into an episode of the well known television series Cadfael starring Derek Jacobi.

**毒性**
乌头碱的毒性作用已在多种动物身上进行了测试有效，包括哺乳动物（狗、猫、豚鼠、小鼠、大鼠和兔子）、鸽、青蛙。观察到的毒性作用有：局部麻醉、腹泻、抽搐、心律失常、死亡。
根据对人类附子中毒的不同报导的回顾，观察到以下临床特征：- 神经系统：感觉异常和脸、口周区域和四肢麻木、肌肉无力。- 心血管：低血压、心悸、胸痛、心动过缓、窦性心动过速、室性异位及其他心律失常、室性心律失常、交界性心律- 胃肠道：恶心、呕吐、腹痛、腹泻- 其他：头晕、过度换气、出汗、呼吸困难、意识模糊、头痛、流泪
乌头碱中毒的最初症状出现在口服后约20分钟至2小时，包括感觉异常、出汗、恶心。这会导致严重的呕吐、绞痛性腹泻、剧烈疼痛，然后骨骼肌麻痹。威胁生命的心律失常，包括室性心动过速、心室颤动，会因呼吸麻痹或心脏骤停而死亡。
小鼠的值为口服 1 mg/kg、静脉 0.100 mg/kg、腹膜 0.270 mg/kg 和皮下 0.270 mg/kg。小鼠的最低致死量（）为口服 1 mg/kg 和腹腔 0.100 mg/kg。小鼠的最低中毒量（）为 0.0549 mg/kg 皮下注射。大鼠静脉注射的值为 0.064 mg/kg。大鼠的为静脉注射 0.040 mg/kg和腹腔 0.250 mg/kg。大鼠的肠胃为 0.040 mg/kg。有关更多参见下表：表示平均致死量；是指最低致死量；表示最低中毒量。
对于人类，1969 年报导的最低口服致死剂量为 28 μg/kg。
乌头碱（草乌、川乌）中毒在急诊及内科中常见，多因服用自制中药及自制药膳不当所致。
它主要使迷走神经兴奋，对周围神经损害临床主要表现为口舌及四肢麻木，全身紧束感等，通过兴奋迷走神经而降低窦房结的自律性，引起异位起搏点的自律性增高而引起各心律失常，损害心肌。

**临床作用**

**参考文献**

**外部连结**
  乌头堿 Aconitinedate=20160304092838  中草药化学图像数据库 (香港浸会大学中医药学院) -  乌头碱 aconitinedate=20170514145322  化学空间 Chem-Station