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Aconite (Aconitum napellus)


Aconitum napellus
Synonyms / Common Names / Related Terms
Acetylbenzoylaconin, aconite root, aconiti frus, aconiti herba, aconiti lateralis preparata, aconiti tuber, aconitine, aconitknollen, aconito, Aconitum angustius, Aconitum anthoroideum, Aconitum artemisiifolium, Aconitum austroyunnanense, Aconitum balfourii, Aconitum barbatum, Aconitum brachypodum, Aconitum brunneum, Aconitum carmichaelii, Aconitum chasmanthum, Aconitum chilienshanicum, Aconitum columbianum, Aconitum coreanum, Aconitum episcopale, Aconitum< ferox, Aconitum flavum, Aconitum gymnandrum, Aconitum hemsleyanum, Aconitum japonicum, Aconitum karakolicum, Aconitum kongboense, Aconitum kusnezoffii, Aconitum longilobum, Aconitum moldavicum, Aconitum nagarum, Aconitum napellus, Aconitum naviculare, Aconitum ouvrardianum, Aconitum paniculigerum, Aconitum pendulum, Aconitum polyschistum, Aconitum pomeense, Aconitum pterocaule, Aconitum racemulosum, Aconitum richardsonianum, Aconitum rotundifolium, Aconitum scaposum, Aconitum sczukinii, Aconitum sessiliflorum, Aconitum sinomantanum Nakai, Aconitum soongaricum, Aconitum spicatum, Aconitum stylosum, Aconitum sungpanense, Aconitum taipeicum, Aconitum tanguticum, Aconitum transectum, Aconitum uncinatum, Aconitum vilmorinianum, Aconitum vulparia, autumn monkshood, bachnag, bear's foot, bikh, bikhroot, bish, bishma, blauer eisenhut, blue monkshood, blue monkshood herb, blue monkshood root, blue rocket, brute killer, bushi, cao wu (Chinese), chan-wu (Chinese), ch'uan wu (Chinese), cuanwu (Chinese), dudhia bish (German), eisenhutknollen (German), friar's cap, friar's cowl, fuchswurz (German), fu-tzu (Chinese), fu zi (Chinese), garden monkshood, garden wolfsbane (German), giftwurzel (German), helmet flower, higenamine, house bane, hsüeh shang i chih hao (Chinese), Indian aconite, kako-bushi (Japanese), kuan pai fu (Chinese), lang tu (Chinese), leopard killer, mithazahar (Indian), moenchswurz (German), monkshood, monkshood herb, monkshood root, monkshood tuber, monnikskap, monsebane, mouse-bane, mousebane, old wife's hood, pao-fuzi (Japanese), racine d'aconit (French), soldier's cap, storkjelm (German), sturmhutknollen (German), teufelswurz (German), Turk's cap, ts'ao wu (Chinese), venusvogn (Danish), visha, wolfbane, wolf's bane, wolfsbane, wolfshbone, wolfswurzel (German), wu hui (Chinese), wu t'ou (Chinese).

Mechanism of Action

Pharmacology:

  • Constituents: There are approximately 350 species of aconite. Generally, the alkaloids aconitine, hypaconitine, mesaconitine, and jesaconitine have the strongest pharmacologic and toxic effects while their derivatives are weaker and less toxic. Many reports support aconite's cardiovascular effects of tachycardia and arrhythmias.
  • Anabolic effects: Aconite alkaloids, in particular mesaconitine, accelerate liver RNA synthesis mainly by the increase of RNA polymerase in mouse livers suggesting that aconite has anabolic activity.5
  • Analgesic effects: Based on animal experiments, mesaconitine's analgesic activity is mediated by central noradrenergic pathways.5,6
  • Anti-inflammatory effects: Alkaloids from methanol extracts of crude Aconitum carmichaeli roots inhibited acute inflammation but were not effective against chronic inflammation in animal models. Inhibitory effects of aconitines when induced by histamine appears in decreasing order, aconitine > hypaconitine > mesaconitine. Their benzoylaconine analogs were effective in acute inflammation at higher doses. Their anti-inflammatory effects appears in decreasing order, benzoylmesaconine > benzoylaconine > benzoyhypaconine.7 Based on studies of inflammation models in animals, mesaconitine has CNS-mediated anti-inflammatory effects. It appears to inhibit inflammation at early stages. Mesaconitine did not inhibit prostaglandin synthesis and the adrenal system was not involved in anti-inflammatory effects.8
  • Antipyretic effects: Mesaconitine and ignavine demonstrated hypothermic effects; ignavine being effective only at high doses.9
  • Cardiovascular effects: Aconite administered intraperitoneally produced bradycardia in mice.10 Results of this experiment suggest that the anterior hypothalamus and surrounding muscarinic receptors are involved in the transmission of aconite-induced bradycardia. It was also found that aconitine increased cortical acetylcholine release, but this effect was not mediated by central muscarinic receptors. Acetylcholine is not involved in aconitine induced bradycardia. The action was inhibited by propranolol signifying that higenamine has calcium agnoistic effects.
  • Intracerebroventricular injection of aconitine produced tachycardia and hypertension in cats.11 Pretreatment with practolol or propranolol inhibited the tachycardia. Reserpine decreased tachycardia but not hypertension. These results suggest that aconitine's tachycardic effects are mediated by central beta-adrenergic receptors, and its hypertensive effects are because of central stimulation that causes peripheral vasoconstriction.
  • Higenamine, a component of the aconite root, had concentration-dependent positive inotropic effects in the papillary muscles of guinea pigs.12
  • Aconitine injections (0.03-10mcg) in the locus coeruleus in rats resulted bradycardia or tachycardia, arrhythmias, and hypertension.13 High doses had positive chronotropic effects. Low doses variously had positive or negative chronotropic effects. These effects were blocked by phentolamine and 2-bromo-lysergic acid diethylamide, a serotonin antagonist; atropine had no effect. Aconitine's cardiovascular effects may be mediated by alpha-adrenergic and/or serotonergic pathways.
  • Aconitine accelerates its spontaneous slow depolarization, and produces extremely rapid tachycardia, flutter and fibrillation in animals.14 Aconitine-induced fibrillation might be contributed to the formation of local blocks and ectopic pacemakers.15
  • Central nervous system (CNS) effects: Mesaconitine inhibited motor coordination and motor activity and demonstrated weak sedative effects in animal models. Ignavine displayed no sedative effects.9
  • Endocrine effects: Based on animal study, various root-derived aconitans reduced plasma glucose levels in a dose-dependent manner.16
  • Immunological effects: Aconitine stimulates the response of IFN-gamma-activated expression of Ia antigen by macrophages by increasing plasma corticosterone levels.17 Aconitum carmichaeli increases the secretion of interleukin-1b, interleukin-6, and tumor necrosis factor-alpha in human mononuclear cells (secondary source).
  • Neuomuscular blockade effects: Various alkaloids in processed aconite displayed neuromuscular blocking effects in isolated mouse phrenic nerve-diaphragm muscle preparations. Hypaconitine effects were four times stronger than aconitine and mesaconitine and were one-third to one-sixth as toxic. Coryneine, lipodeoxyaconitine, and lipohypaconitine had weaker effects; and lipoaconitine, higenamine, kobusine, benzoylmesaconine, and chasamine were not effective. It is suggested that aconitine's mechanism of action is blocking sodium channels in nerve membranes. Hypaconitine's mechanism of action was not determined.18

Pharmacodynamics/Kinetics:

  • Absorption: Aconitine is absorbed by the esophagus and stomach of a rat with the ability of the esophagus to absorb aconitine being stronger than that of the stomach.3
  • Distribution: Autopsy results after homicidal aconite poisoning detected jesacontine in the vomitus, stomach contents, plasma, and urine at concentrations of 32.2mcg/mL, 5.48mcg/mL, 0.433mcg/mL, and 1.07mcg/mL, respectively.4
  • Metabolism: Aconite is metabolized in the liver. The metabolism of aconite and its alkaloids has not been concluded in humans. De-esterification at C-8 and C-14 by esterase and N or O dealklyation by cytochrome P450 enzymes suggests possible pathways for the diesterditerpene-type alkaloids such as aconitine, mesaconitine, and hypaconitine.2 Aconitine is hydrolyzed at the C-8 group to benzoylaconine and at the C-8 and C-14 groups into aconine. Mesaconitine is hydrolyzed at the C-8 group to benzoylmesaconine and at the C-8 and C-14 groups to mesaconine. Hypaconitine is hydrolyzed at the C-8 group to benzoylhypaconine and at the C-8 and C-14 groups to hypaconine. These hydrolysis products are less toxic.
  • Elimination: Aconitum alkaloids aconitine, mesaconitine, and hypaconitine and their metabolites were detected in the urine 6 days after ingestion. It is suggested these alkaloids are excreted in a time-dependent manner.2
  • Because of aconite's lipid solubility and molecular size of 645.7 kilodaltons, hemodialysis, peritoneal dialysis, hemoperfusion and hemofiltration are unlikely to be effective in enhancing elimination.1

References
  1. Tai, Y. T., Lau, C. P., But, P. P., Fong, P. C., and Li, J. P. Bidirectional tachycardia induced by herbal aconite poisoning. Pacing Clin Electrophysiol  1992;15(5):831-839. 1382285
  2. Mizugaki, M., Ito, K., Ohyama, Y., Konishi, Y., Tanaka, S., and Kurasawa, K. Quantitative analysis of Aconitum alkaloids in the urine and serum of a male attempting suicide by oral intake of aconite extract. J Anal Toxicol  1998;22(4):336-340. 9681338
  3. Feldkamp, A., Koster, B., and Weber, H. P. [Fatal poisoning caused by aconite monk's hood (Aconitum napellus)]. Monatsschr Kinderheilkd  1991;139(6):366-367. 1896051
  4. Mori, A., Mukaida, M., Ishiyama, I., Hori, J., Okada, Y., Sasaki, M., Mii, K., and Mizugaki, M. [Homicidal poisoning by aconite: report of a case from the viewpoint of clinical forensic medicine]. Nippon Hoigaku Zasshi 1990;44(4):352-357. 2266613
  5. Murayama, M. and Hikino, H. Stimulating actions on ribonucleic acid biosynthesis of aconitines, diterpenic alkaloids of Aconitum roots. J Ethnopharmacol 1984;12(1):25-33. 6084153
  6. Zheng, P. and Yang, Y. R. [Site of analgesic action of aconitine and the relation between its action and the central noradrenergic system]. Zhongguo Yao Li Xue Bao  1988;9(6):481-485. 3256209
  7. Hikino, H., Konno, C., Takata, H., Yamada, Y., Yamada, C., Ohizumi, Y., Sugio, K., and Fujimura, H. Antiinflammatory principles of Aconitum roots. J Pharmacobiodyn  1980;3(10):514-525. 7205533
  8. Hikino, H., Takata, H., Fujiwara, M., Konno, C., and Ohuchi, K. Mechanism of inhibitory action of mesaconitine in acute inflammations. Eur J Pharmacol  8-13-1982;82(1-2):65-71. 6127222
  9. Saito, H., Ueyama, T., Naka, N., Yagi, J., and Okamoto, T. Pharmacological studies of ignavine, an aconitum alkaloid. Chem.Pharm Bull.(Tokyo) 1982;30(5):1844-1850. 7116516
  10. Kimura, I., Takada, M., and Nojima, H. Aconitine induces bradycardia through a transmission pathway including the anterior hypothalamus in conscious mice. Biol Pharm Bull  1997;20(8):856-860. 9300130
  11. Telang, B. V. and Ng'ang'a, J. N. Involvement of Central adrenergic mechanisms in the induction of cardiac arrhythmias by aconitine nitrate administered intraventricularly. Indian J Physiol Pharmacol  1975;19(1):1-10. 1158425
  12. Kimura, I., Chui, L. H., Fujitani, K., Kikuchi, T., and Kimura, M. Inotropic effects of (+/-)-higenamine and its chemically related components, (+)-R-coclaurine and (+)-S-reticuline, contained in the traditional sino-Japanese medicines "bushi" and "shin-i" in isolated guinea pig papillary muscle. Jpn J Pharmacol 1989;50(1):75-78. 2724702
  13. Perlman, R. and Guideri, G. Cardiovascular changes produced by the injection of aconitine at the area of the locus coeruleus in unanesthetized rats. Arch Int Pharmacodyn Ther  1984;268(2):202-215. 6145396
  14. Matsuda K, Hoshi T, and Kameyama S. Effects of aconitine on the cardiac membrane potential of the dog. Japan J Physiol 1959;9:419-429.
  15. GOTO, M., TAMAI, T., and YANAGA, T. Studies on the appearance and termination of aconitine-induced atrial fibrillation with microelectrodes. Jpn J Physiol 4-15-1963;13:196-207. 13949441
  16. Konno, C., Murayama, M., Sugiyama, K., Arai, M., Murakami, M., Takahashi, M., and Hikino, H. Isolation and hypoglycemic activity of aconitans A, B, C and D, glycans of Aconitum carmichaeli roots. Planta Med 1985;(2):160-161. 4034735
  17. Kimura, I., Makino, M., Honda, R., Ma, J., and Kimura, M. Expression of major histocompatibility complex in mouse peritoneal macrophages increasingly depends on plasma corticosterone levels: stimulation by aconitine. Biol Pharm Bull  1995;18(11):1504-1508. 8593467
  18. Kimura, M., Muroi, M., Kimura, I., Sakai, S., and Kitagawa, I. Hypaconitine, the dominant constituent responsible for the neuromuscular blocking action of the Japanese-sino medicine "bushi" (aconite root). Jpn J Pharmacol  1988;48(2):290-293. 3210453




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