烏頭鹼是一種生物鹼毒素。是常用中藥烏頭屬中所含有的一種化學物質，具強烈毒性，口服 02mg 左右即能使人中毒，35mg 即可致死。民間常用草烏、川烏等植物來泡製藥酒，但這種藥酒可能是極端危險的，也經常因此出現中毒甚至死亡的情況。 用途 烏頭鹼以前被用作解熱藥和鎮痛藥，但在草藥中的應用仍然有限。狹窄的治療指數使計算合適的劑量很困難。 結構和反應性 附子屬和翠雀屬植物的生物活性分離物被歸類為去甲二萜生物鹼。在生物遺傳學，烏頭鹼不是真正的生物鹼，因為並非來源於氨基酸。烏頭鹼最終來源於異戊二烯，因此它在技術上是一種萜類化合物和偽生物鹼。根據 C18 碳的存在與否進一步細分。烏頭鹼是一種 C19 去甲二萜生物鹼，因為它含有 C18。烏頭鹼幾乎不溶於水，但極易溶於有機溶劑，例如氯仿或乙醚。如果酒精濃度足夠高，烏頭鹼也可溶於乙醇和水的混合物中。 像許多其他生物鹼一樣，烏頭鹼六元環的鹼性氮很容易形成鹽和離子，使其對極性和親脂性結構過血腦屏障。 The acetoxyl group at the c8 position can readily be replaced by a methoxy group by heating aconitine in methanol to produce a 8deacetyl8Omethyl derivatives If aconitine is heated in its dry state it undergoes a pyrolysis to form pyroaconitine 1α3α6α14α16β20ethyl313dihydroxy1616trimethoxy4methoxymethyl15oxoaconitan14yl benzoate with the chemical formula C32H43NO9 作用 Aconitine can interact with the voltagedependent sodiumion 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 sodiumion channel that stays open longer Aconitine suppresses the conformational change in the sodiumion channel from the active state to the inactive state The membrane stays depolarized due to the constant sodium influx which is 101000fold 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 sodiumchannels there generating a new action potential Research with mouse nervehemidiaphragm muscle preparation indicate that at low concentrations 01 μM aconitine increases the electrically evoked acetylcholine release causing an induced muscle tension Action potentials are generated more often at this concentration At higher concentration 033 μM aconitine decreases the electrically evoked acetylcholine release resulting in a decrease in muscle tension At high concentration 033 μM the sodiumion channels are constantly activated transmission of action potentials is suppressed leading to nonexcitable target cells or paralysis 合成 Aconitine is biosynthesized by the monkshood plant via the terpenoid biosynthesis pathway MEP chloroplast pathway Approximately 700 naturally occurring C19diterpenoid alkaloids have been isolated and identified but the biosynthesis of only a few of these alkaloids are well understood Likewise only a few alkaloids of the aconitine family have been synthesized in the laboratory In particular despite over one hundred years having elapsed since its isolation the prototypical member of its family of norditerpenoid alkaloids aconitine itself represents a rare example of a wellknown natural product that has yet to succumb to efforts towards its total synthesis The challenge that aconitine poses to synthetic organic chemists is due to both the intricate interlocking hexacyclic ring system that make up its core and the elaborate collection of oxygenated functional groups at its periphery A handful of simpler members of the aconitine alkaloids however have been prepared synthetically In 1971 the Weisner group discovered the total synthesis of talatisamine a C19norditerpenoid In the subsequent years they also discovered the total syntheses of other C19norditerpenoids such as chasmanine and 13deoxydelphonine The total synthesis of napelline Scheme a begins with aldehyde 100 In a 7 step process the Aring of napelline is formed 104 It takes another 10 steps to form the lactone ring in the pentacyclic structure of napelline 106 An additional 9 steps creates the enonealdehyde 107 Heating in methanol with potassium hydroxide causes an aldol condensation to close the sixth and final ring in napelline 14 Oxidation then gives rise to diketone 108 which was converted to napelline 14 in 10 steps A similar process is demonstrated in Wiesners synthesis of 13desoxydelphinone Scheme c The first step of this synthesis is the generation of a conjugated dienone 112 from 111 in 4 steps This is followed by the addition of a benzyl vinyl ether to produce 113 In 11 steps this compound is converted to ketal 114 The addition of heat DMSO and oxylene rearranges this ketol 115 and after 5 more steps 13desoxydelphinone 15 is formed Lastly talatisamine Scheme d is synthesized from diene 116 and nitrile 117 The first step is to form tricycle 118 in 16 steps After another 6 steps this compound is converted to enone 120 Subsequently this allene is added to produce photoadduct 121 This adduct group is cleaved and rearrangement gives rise to the compound 122 In 7 steps this compound forms 123 which is then rearranged in a similar manner to compound 114 to form the aconitinelike skeleton in 124 A racemic relay synthesis is completed to produce talatisamine 13 More recently the laboratory of the late David Y Gin completed the total syntheses of the aconitine alkaloids nominine and neofinaconitine 代謝 Aconitine is metabolized by cytochrome P450 isozymes CYPs There has been research in 2011 in China to investigate indepth the CYPs involved in aconitine metabolism in human liver microsomes It has been estimated that more than 90 percent of currently available human drug metabolism can be attributed to eight main enzymes CYP 1A2 2C9 2C8 2C19 2D6 2E1 3A4 3A5 The researchers used recombinants of these eight different CYPs and incubated it with aconitine To initiate the metabolism pathway the presence of NADPH was needed Six CYPmediated metabolites M1M6 were found by liquid chromatography these six metabolites were characterized by massspectrometry The six metabolites and the involved enzymes are summarized in the following table Metabolite Name Involved CYPs M1 ODemethylaconitine CYP3A4 CYP3A5 CYP2D6 CYP2C8 M2 16ODemethylaconitine CYP3A4 CYP3A5 CYP2D6 CYP2C9 M3 Ndeethylaconitine CYP3A4 CYP3A5 CYP2D6 CYP2C9 M4 Odidemethylaconitine CYP3A5 CYP2D6 M5 3Dehydrogenaconitine CYP3A4 CYP3A5 M6 Hydroxylaconitine CYP3A5 CYP2D6 Selective inhibitors were used to determine the involved CYPs in the aconitine metabolism The results indicate that aconitine was mainly metabolized by CYP3A4 3A5 and 2D6 CYP2C8 and 2C9 had a minor role to the aconitine metabolism whereas CYP1A2 2E1 and 2C19 did not produce any aconitine metabolites at all The proposed metabolic pathways of aconitine in human liver microsomes and the CYPs involved to it are summarized in the table above 診斷和治療 For the analysis of the Aconitum alkaloids in biological specimens such as blood serum and urine several GCMS methods have been described These employ a variety of extraction procedures followed by derivatisation to their trimethylsilyl derivatives New sensitive HPLCMS methods have been developed as well usually preceded by SPE purification of the sample The antiarrhythmic drug lidocaine has been reported to be an effective treatment of aconitine poisoning of a patient Considering the fact that aconitine acts as an agonist of the sodium channel receptor antiarrhythmic agents which block the sodium channel VaughanWilliams classification I might be the first choice for the therapy of aconitine induced arrhythmias Animal experiments have shown that the mortality of aconitine is lowered by tetrodotoxin The toxic effects of aconitine were attenuated by tetrodotoxin probably due to their mutual antagonistic effect on excitable membranes Also paeoniflorin seems to have a detoxifying effect on the acute toxicity of aconitine in test animals This may result from alternations of pharmacokinetic behavior of aconitine in the animals due to the pharmacokinetic interaction between aconitine and paeoniflorin In addition in emergencies one can wash the stomach using either tannic acid or powdered charcoal Heart stimulants such as strong coffee or caffeine may also help until professional help is available 著名中毒事件 During the Indian Rebellion of 1857 a British detachment was the target of attempted poisoning with aconitine by the Indian regimental cooks The plot was thwarted by John Nicholson who having detected the plot interrupted the British officers just as they were about to consume the poisoned meal The chefs refused to taste their own preparation whereupon it was forcefed to a monkey who expired on the spot The cooks were hanged Aconitine was the poison used by George Henry Lamson in 1881 to murder his brotherinlaw in order to secure an inheritance Lamson had learned about aconitine as a medical student from professor Robert Christison who had taught that it was undetectablebut forensic science had improved since Lamsons student days Rufus T Bush American industrialist and yachtsman died on September 15 1890 after accidentally taking a fatal dose of aconite In 1953 aconitine was used by a Soviet biochemist and poison developer Grigory Mairanovsky in experiments with prisoners in the secret NKVD laboratory in Moscow He admitted killing around 10 people using the poison In 2004 Canadian actor Andre Noble died from aconitine poisoning He accidentally ate some monkshood while he was on a hike with his aunt in Newfoundland In 2009 Lakhvir Singh of Feltham west London used aconitine to poison the food of her exlover Lakhvinder Cheema who died as a result of the poisoning and his current fiancée Aunkar Singh Singh received a life sentence with a 23year minimum for the murder on February 10 2010 流行文化 烏頭鹼是古代世界最受歡迎的毒藥。普布利烏斯奧維修斯納索提到了眾所周知的繼母不喜歡繼子的問題，他寫道： Lurida terribiles miscent aconita novercaeOvid Metamorphoses 1147 Fearsome stepmothers mix lurid aconites Aconitine was also made famous by its use in Oscar Wildes 1891 story Lord Arthur Saviles Crime Aconite also plays a prominent role in James Joyces 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 Monks 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 烏頭鹼的毒性作用已在多種動物身上進行了測試有效，包括哺乳動物（狗、貓、豚鼠、小鼠、大鼠和兔子）、鴿、青蛙。觀察到的毒性作用有：區域性麻醉、腹瀉、抽搐、心律失常、死亡。 根據對人類附子中毒的不同報導的回顧，觀察到以下臨床特徵： 神經系統：感覺異常和臉、口周區域和四肢麻木、肌肉無力。 心血管：低血壓、心悸、胸痛、心動過緩、竇性心動過速、室性異位及其他心律失常、室性心律失常、交界性心律 胃腸道：噁心、嘔吐、腹痛、腹瀉 其他：頭暈、過度換氣、出汗、呼吸困難、意識模糊、頭痛、流淚 烏頭鹼中毒的最初症狀出現在口服後約 20 分鐘至 2 小時，包括感覺異常、出汗、噁心。這會導致嚴重的嘔吐、絞痛性腹瀉、劇烈疼痛，然後骨骼肌麻痺。威脅生命的心律失常，包括室性心動過速、心室顫動，會因呼吸麻痺或心臟驟停而死亡。 小鼠的值為口服 1 mgkg、靜脈 0100 mgkg、腹膜 0270 mgkg 和皮下 0270 mgkg。小鼠的最低致死量為口服 1 mgkg 和腹腔 0100 mgkg。小鼠的最低中毒量為 00549 mgkg 皮下注射。大鼠靜脈注射的值為 0064 mgkg。大鼠的為靜脈注射 0040 mgkg 和腹腔 0250 mgkg。大鼠的腸胃為 0040 mgkg。有關更多參見下表：表示平均致死量；是指最低致死量；表示最低中毒量。 物種 測試 路線 劑量（mgkg） 毒性 人類 口服 0028 行為：興奮 胃腸道：運動亢進、腹瀉、其他變化 人類 口服 0029 除致死劑量值外未報告詳情毒性作用 貓 靜脈 0080 行為：抽搐或對癲癇發作閾值的影響 貓 LDLo 皮下 0100 除致死劑量值外未報告詳情毒性作用 豚鼠 靜脈 0060 行為：抽搐或對癲癇發作閾值的影響 豚鼠 皮下 0050 除致死劑量值外未報告詳情毒性作用 豚鼠 靜脈 0025 心臟：心律失常（包括傳導改變） 小鼠 腹腔 0270 除致死劑量值外未報告詳情毒性作用 小鼠 靜脈 0100 感覺器官和特殊感覺（眼睛）：流淚 行為：抽搐或對癲癇發作閾值的影響 肺、胸：呼吸困難 小鼠 口服 1 除致死劑量值外未報告詳情毒性作用 小鼠 皮下 0270 除致死劑量值外未報告詳情毒性作用 小鼠 腹腔 0100 除致死劑量值外未報告詳情毒性作用 小鼠 口服 1 行為：抽搐或對癲癇發作閾值的影響 心臟：心律失常（包括傳導改變） 胃腸道：運動亢進、腹瀉 小鼠 皮下 00549 周圍神經和感覺：區域性麻醉 行為：鎮痛 兔子 皮下 0131 除致死劑量值外未報告詳情毒性作用 大鼠 靜脈 0080 行為：抽搐或對癲癇發作閾值的影響 大鼠 靜脈 0064 除致死劑量值外未報告詳情毒性作用 大鼠 腹腔 0250 心臟：其他變化 肺、胸：呼吸困難 大鼠 靜脈 0040 心臟：心律失常（包括傳導改變） 大鼠 腸外 0040 心臟：心律失常（包括傳導改變） 青蛙 皮下 0586 除致死劑量值外未報告詳情毒性作用 鴿子 皮下 0066 除致死劑量值外未報告詳情毒性作用 對於人類，1969 年報導的最低口服致死劑量為 28 μgkg。 烏頭鹼（草烏、川烏）中毒在急診及內科中常見，多因服用自制中藥及自制藥膳不當所致。 它主要使迷走神經興奮，對周圍神經損害臨床主要表現為口舌及四肢麻木，全身緊束感等，透過興奮迷走神經而降低竇房結的自律性，引起異位起搏點的自律性增高而引起各心律失常，損害心肌。 臨床作用 參考文獻 外部連結 烏頭堿 Aconitine 中草藥化學影像資料庫 香港浸會大學中醫藥學院 烏頭鹼 aconitine 化學空間 ChemStation Category 生物鹼 Category 缺少物質圖片的化學品條目 Category 叔醇