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History
3 BIOSYNTHESIS
small animals.[11] In the United States, most baits containing strychnine have been replaced with zinc phosphide
baits since 1990. In the Netherlands, rodenticides with
strychnine are forbidden. Some animals are immune to
strychnine, usually these are species such as fruit bats that
have evolved resistance to poisonous alkaloids in the fruit
they eat. The drugstore beetle has a symbiotic gut yeast
that allows it to digest pure strychnine.
Strychnine toxicity in rats is dependent on sex. It is more
toxic to females than to males when administered via
subcutaneous injection or intraperitoneal injection. Differences are due to higher rates of metabolism by male
rat liver microsomes. Dogs and cats are more susceptible
among domestic animals, pigs are believed to be as susceptible as dogs, and horses are able to tolerate relatively
large amounts of strychnine. Birds aected by strychnine
poisoning exhibit wing droop, salivation, tremors, muscle tenseness, and convulsions. Death occurs as a result
of respiratory arrest. The clinical signs of strychnine poisoning relate to its eects on the central nervous system.
The rst clinical signs of poisoning include nervousness,
restlessness, twitching of the muscles, and stiness of the
neck. As the poisoning progresses, the muscular twitching becomes more pronounced and convulsions suddenly
appear in all the skeletal muscles. The limbs are extended and the neck is curved to opisthotonus. The pupils
are widely dilated. As death approaches, the convulsions
follow one another with increased rapidity, severity, and
duration. Death results from asphyxia due to prolonged
paralysis of the respiratory muscles. Following the ingestion of strychnine, symptoms of poisoning usually appear
within 15 to 60 min. The LD50 -values for strychnine in
animals are listed below in table 1.
2.2
Human toxicity
After injection, inhalation, or ingestion, the rst symptoms to appear are generalized muscle spasms. They appear very quickly after inhalation or injection within
as few as ve minutes and take somewhat longer to
manifest after ingestion, typically approximately 15 minutes. With a very high dose, the onset of respiratory failure and brain death can occur in 15 to 30 minutes. If a
lower dose is ingested, other symptoms begin to develop,
including seizures, cramping, stiness, hypervigilance,
and agitation. Seizures caused by strychnine poisoning can start as early as 15 minutes after exposure and
last 12 - 24 hours. They are often triggered by sights,
sounds, or touch and can cause other adverse symptoms,
including hyperthermia, rhabdomyolysis, myoglobinuric
kidney failure, metabolic acidosis, and respiratory acidosis. During seizures, mydriasis (abnormal dilation),
exophthalmos (protrusion of the eyes), and nystagmus
(involuntary eye movements) may occur.[11]
As strychnine poisoning progresses, tachycardia
(rapid heart beat), hypertension (high blood pressure),
tachypnea (rapid breathing), cyanosis (blue discoloration), diaphoresis (sweating), water-electrolyte
imbalance, leukocytosis (high number of white blood
cells), trismus (lockjaw), risus sardonicus (spasm of the
facial muscles), and opisthotonus (dramatic spasm of the
back muscles, causing arching of the back and neck) can
occur. In rare cases, the aected person may experience
nausea or vomiting.[11]
The proximate cause of death in strychnine poisoning can
be cardiac arrest, respiratory failure, multiple organ failure, or brain damage.[11]
The LD50 -values estimated from dierent cases of
strychnine poisoning are listed below in table 2.
For occupational exposures to strychnine, the
Occupational Safety and Health Administration and
the National Institute for Occupational Safety and Health
have set exposure limits at 0.15 mg/m3 over an 8-hour
work day.[31]
Because strychnine produces some of the most dramatic and painful symptoms of any known toxic reaction,
strychnine poisoning is often portrayed in literature and
lm including authors Agatha Christie and Arthur Conan
Doyle.[32]
3 Biosynthesis
An 1809 painting depicting opisthotonus
The symptoms of poisoning in humans are generally similar to those as in animals, because the mechanism of action is apparently similar across species. The toxicity of
strychnine in humans is not ethically studied, so most information known comes from cases of strychnine poisoning, both unintentional and deliberate.
3
molecular size it is the most complex [organic] substance
known (attributed to Sir Robert Robinson).[39]
The rst total synthesis of strychnine was reported by the
research group of R. B. Woodward in 1954, and is considered a classic in this eld.[40][41] The Woodward account
published in 1954 was very brief (3 pp.),[42] but was followed by a 42-page report in 1963.[43] The molecule has
since received continuing wide attention in the years since
for the challenges to synthetic organic strategy and tactics
presented by its complexity; its synthesis has been targeted and its stereocontrolled preparation independently
achieved by more than a dozen research groups since the
rst success (see main strychnine total synthesis article).
5 Pharmacokinetics
strychnine biosynthesis
5.1 Absorption
step is hydrolysis of the acetal, which opens the ring by
elimination of glucose (O-Glu) and provides a reactive
aldehyde. The nascent aldehyde is then attacked by a
secondary amine to aord geissoschizine, a common intermediate of many related compounds in the Strychnos
family.[33]
A reverse Pictet-Spengler reaction cleaves the C2C3
bond, while a subsequent Mannich reaction forms the
C3C7 bond, and a Michael addition forms the C2
C16 bond to provide dehydropreakuammicine. Hydrolysis of the methyl ester and decarboxylation leads to
noruorocurarine. Stereospecic reduction of the endocyclic double bond by NADPH and hydroxylation
provides the Wieland-Gumlich aldehyde, which was
rst isolated by Heimberger and Scott in 1973, although previously synthesized by Wieland and Gumlich
in 1932.[36][37] To elongate the appendage by 2 carbons,
acetyl-CoA is added to the aldehyde in an aldol reaction
to aord prestrychnine. Strychnine is then formed by a
facile addition of the amine with the carboxylic acid or
its activated CoA thioester, followed by ring-closure via
displacement of an activated alcohol.
Chemical synthesis
Strychnine may be introduced into the body orally, by inhalation, or by injection. It is a potently bitter substance,
and in humans has been shown to activate bitter taste receptors TAS2R10 and TAS2R46.[44][45][46] Strychnine is
rapidly absorbed from the gastrointestinal tract.
5.2 Distribution
Strychnine is transported by plasma and erythrocytes.
Due to slight protein binding, strychnine leaves the bloodstream quickly and distributes to the tissues. Approximately 50% of the ingested dose can enter the tissues in
5 minutes. Also within a few minutes of ingestion, strychnine can be detected in the urine. Little dierence was
noted between oral and intramuscular administration of
strychnine. In persons killed by strychnine, the highest
concentrations are found in the blood, liver, kidney and
stomach wall. The usual fatal dose is 60100 mg strychnine and is fatal after a period of 12 hours, though lethal
doses vary depending on the individual.
5.3 Metabolism
Strychnine is rapidly metabolized by the liver microsomal
enzyme system requiring NADPH and O2 . Strychnine
competes with the inhibitory neurotransmitter glycine resulting in an excitatory state. However, the toxicokinetics
after overdose have not been well described. In most severe cases of strychnine poisoning, the patient dies before
reaching the hospital. The biological half-life of strychnine is about 10 hours. This half-life suggests that normal
hepatic function can eciently degrade strychnine even
when the quantity ingested is high enough to cause severe
poisoning.
5.4
Excretion
A few minutes after ingestion, strychnine is excreted unchanged in the urine, and accounts for about 5 to 15% of
a sublethal dose given over 6 hours. Approximately 10 to
20% of the dose will be excreted unchanged in the urine
in the rst 24 hours. The percentage excreted decreases
with the increasing dose. Of the amount excreted by the
kidneys, about 70% is excreted in the rst 6 hours, and
almost 90% in the rst 24 hours. Excretion is virtually
complete in 48 to 72 hours.[6]
Mechanism of action
REFERENCES
lavage with tannic acid or potassium permanganate solutions to oxidize strychnine. Seizures are controlled by
anticonvulsants, such as phenobarbital or diazepam,[11]
along with muscle relaxants such as dantrolene to combat
muscle rigidity. Chloroform or heavy doses of chloral,
bromide, urethane or amyl nitrate can also be used to restrain the convulsions. Because diazepam, as the anticonvulsant of choice, is not eective in all cases, a combination with midazolam, fentanyl, or pancuronium is recommended for controlling the convulsions. Strychnine
poisoning demands an aggressive management with early
intubation, control of muscle tremors, and prevention of
rhabdomyolysis and renal failure with dialysis. If a poisoned person is able to survive for 6 to 12 hours, they have
a good prognosis.[11]
Strychnine is a neurotoxin which acts as an antagonist of Also, George Harley (18291896) showed in 1850 that
glycine and acetylcholine receptors. It primarily aects Curare (wourali) was eective for the treatment of tetanus
the motor nerves in the spinal cord which control muscle and strychnine poisoning.
contraction. An impulse is triggered at one end of a nerve
by the binding of neurotransmitters to the receptors. In
the presence of a neuroinhibitor, such as glycine, a greater 8 See also
quantity of excitatory neurotransmitters must bind to receptors before there will be an action potential generated.
Avicide
Glycine acts primarily as an agonist of the glycine recep Denatonium
tor, which is a ligand-gated chloride channel in neurons
located in the spinal cord and in the brain. This chlo "Poisoning Pigeons in the Park"
ride channel will allow the negatively charged chloride
ions into the neuron, causing a hyperpolarization which
The Mysterious Aair at Styles
pushes the membrane potential further from threshold.
Strychnine is an antagonist of glycine, which means it
binds to the same receptor, preventing the inhibitory ef- 9 References
fects of glycine on the postsynaptic neuron. Therefore,
action potentials are triggered with lower levels of exci- [1] NIOSH Pocket Guide to Chemical Hazards #0570.
tatory neurotransmitters. When the inhibitory signals are
National Institute for Occupational Safety and Health
prevented, the motor neurons are more easily activated
(NIOSH).
and the victim will have spastic muscle contractions, resulting in death by asphyxiation.[4][47] Structure of strych- [2] Everett, A. J.; Openshaw, H. T.; Smith, G. F. (1957).
221. The constitution of aspidospermine. Part III. Renine in complex with ACh binding protein (AChBP).[48]
Treatment
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doi:10.1039/JR9570001120.
[7] Inglis-Arkell, Esther (11 June 2013). Rat poison strychnine was an early performance-enhancing drug. io9.
Gawker Media. Retrieved 23 Nov 2015.
[23] Zenz, C.; Dickerson, O. B.; Horvath, E. P. (1994). Occupational Medicine, 3rd edition, p. 640. St Louis.
[24]
[8] http://www.spectroscopynow.com/
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[25]
[9] H. G. Wells, The Invisible Man
[10] INCHEM: Chemical Safety Information from Intergovernmental Organizations:Strychnine. http://www.
inchem.org/documents/pims/chemical/pim507.htm
[11] CDC - The Emergency Response Safety and Health
Database: Biotoxin: STRYCHNINE - NIOSH. www.
cdc.gov. Retrieved 2016-01-02.
[12] Tucker, RK; Haegele, MA (1971). Comparative acute
oral toxicity of pesticides to six species of birds.
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doi:10.1016/0041-008X(71)90088-3. PMID 5110827.
[13] RTECS (1935)
[14] Moraillon, R.; Pinoult, L. (1978). Diagnostic et traitement d'intoxications courantes des carnivores. Rec Med
Vet (in French). 174 (12): 3643.
[15] Longo, V. G.; Silvestrini, B.; Bovet, D. (1959). An investigation of convulsant properties of the 5,7-diphenyl1,3-diazadamantan- 6-ol (IS 1757)". J. Pharmacol. Exp.
Ther. 126 (1): 419. PMID 13642285.
[16] Setnikar, I; Murmann, W; Magistretti, MJ; Da Re, P
(1960). Amino-methylchromones, brain stem stimulants
and pentobarbital antagonists. The Journal of Pharmacology and Experimental Therapeutics. 128: 17681.
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[17] Haas, H (1960).
On 3-piperidino-1-phenyl-1bicycloheptenyl-1-propanol (Akineton). 2. Archives
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20438. PMID 13710192.
[18] Prasad, CR; Patnaik, GK; Gupta, RC; Anand, N; Dhawan,
BN (1981). Central nervous system stimulant activity of
n-(delta 3-chromene-3-carbonyl)4 iminopyridine (compound 69/224)". Indian journal of experimental biology.
19 (11): 10756. PMID 7338366.
[19] Zapata-Ortiz, V; Castro de la Mata, R; Barantes-Campos,
R (1961). The anticonvulsive action of cocaine.
Arzneimittel-Forschung. 11: 65762. PMID 13787891.
[20] Sandberg, F; Kristianson, K (1970). A comparative
study of the convulsant eects of strychnos alkaloids.
Acta pharmaceutica Suecica. 7 (4): 32936. PMID
5480076.
[21] Spector, W. S. (1956). Handbook of Toxicology, Vol. 1,
p. 286. W. B. Saunders Company, Philadelphia.
[22] Ward, Justus C.; Crabtree, D. Glen (2006). Strychnine
X. Comparative accuracies of stomach tube and intraperitoneal injection methods of bioassay. Journal of the
American Pharmaceutical Association. 31 (4): 113115.
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[26] Goodman, L. S.; Gilman, A. G.; Gilman, A. The pharmalogical basis of therapeutics, 1985, New York Macmillan
Publishing & Co., Inc.
[27] Bennett, S. M. http://www.the-piedpiper.co.uk/th15\
char"005C\relax{}%28f\char"005C\relax{}%29.htm
[28] Gossel, T. A., Bricker J. D. (1994). Principles of Clinical
Toxicology, 3rd edition, p. 351. Raven Press, New York.
[29] Migliaccio, E; Celentano, R; Viglietti, A; Viglietti, G
(1990). Strychnine poisoning. A clinical case. Minerva
anestesiologica. 56 (12): 412. PMID 2215981.
[30] Ellenhorn, M.J.; Schonwald, S.; Ordog, G. (1997). J.
Wasserberger. Ellenhorns Medical Toxicology: Diagnosis
and Treatment of Human Poisoning, 2nd edition, p. 1660.
Williams and Wilkins, Baltimore.
[31] CDC - NIOSH Pocket Guide to Chemical Hazards
[32] Chemistry in its element - strychnine. Royal Society of
Chemistry. Retrieved 18 May 2016.
[33] Bonjoch, Josep; Sol, Daniel (1 September 2000). Synthesis of Strychnine. Chemical Reviews. 100 (9): 3455
3482. doi:10.1021/cr9902547.
[34] Dewick, Paul M. (2009). Medicinal natural products: a
biosynthetic approach (3rd ed.). Chichester: A John Wiley & Sons. pp. 377378. ISBN 978-0-470-74167-2.
[35] Treimer, Johannes F.; Zenk, Meinhart H. (1 November 1979). Purication and Properties of Strictosidine
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[36] Heimberger, Stanley I.; Scott, A. Ian (1 January
1973). Biosynthesis of strychnine. Journal of the
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[37] Wieland, Heinrich; Gumlich, Walter (1 January 1932).
"ber einige neue Reaktionen der Strychnos - Alkaloide.
XI. Justus Liebigs Annalen der Chemie. 494 (1): 191
200. doi:10.1002/jlac.19324940116.
[38] K. C. Nicolaou, Dionisios Vourloumis, Nicolas
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Total Synthesis at the Dawn of the Twenty-First Century,
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[39] R. Robinson, 1952, Molecular structure of Strychnine,
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REFERENCES
10
10.1
10.2
Images
File:Opisthotonus_in_a_patient_suffering_from_tetanus_-_Painting_by_Sir_Charles_Bell_-_1809.jpg
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10.3
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