STRYCHNINE

Description

Strychnine, C21H22N2O2, Mr 334.4, mp 270–280 ?C (decomp.), forms colorless crystals which are slightly soluble in water, moderately in benzene, ethanol, readily soluble in chloroform [9, p. 1121].

Description

Strychnine is an extremely poisonous alkaloid produced in the seeds of trees and shrubs of the Strychnos genus; it was identified and named by C. Linnaeus in 1753. J. B. Caventou and P.-J. Pelletier discovered it in Saint Ignatius''s bean (from the Strychnos ignatii shrub) in 1818.
R. Robinson determined the structure of strychnine in 1946; and R. B. Woodward and co-workers completed a classic total synthesis in 1954. Both chemists were awarded the Nobel Prize in Chemistry for their work in 1947 and 1965, respectively.
Strychnos seeds and strychnine were used for centuries to kill animal and bird pests, but this use is no longer permitted. Strychnine has been implicated in many murders and attempted murders, possibly dating back to Alexander the Great.
Recently, J. R. Cort and A. E. Metaxas at Pacific Northwest National Laboratory developed an NMR method for distinguishing strychnine salts. If their method can be extended to other poisons and drugs, it could prove useful in forensic chemistry.

Chemical properties

Hard white crystals or powder; bitter taste. Soluble in chloroform; slightly soluble in alcohol and benzene; slightly soluble in water and ether.

Chemical properties

Strychnine is a colorless crystalline prisms or white powder. It is odorless; with a bitter taste

Physical properties

Colorless to white, odorless crystals. Bitter taste.

History

Strychnine is a white, odorless, toxic crystalline powder with a bitter taste. Strychnine is a well-known poison, but it has also been used in medications. It was one of the first alkaloids to be isolated in pure form when Joseph Bienaimé Caventou (1795 1877) and Pierre Joseph Pelletier (1788 1842) extracted it from Saint Ignatius beans (Strychnos ignatii) in 1818. Caventou and Pelletier subsequently obtained it from its main source Strychnos nux vomica; it is also found in other Strychnos species. Strychnos nux vomica is an evergreen tree native to east India, Southeast Asia, and northern Australia. The seeds of the plant are the main source of strychnine and several other alkaloids (brucine), but it is also obtained from the bark and roots. The seeds are heated and then ground to a powder that contains strychnine. The brownish-gray powder obtained from the ground seeds extracted from the nut is called nux vomica. In commercial production during the 1800s, the seeds were softened by boiling in a dilute sulfuric acid solution and then dried and ground to a powder. Strychnine was extracted from the powder using alcohol and separation techniques to remove impurities. The structure of strychnine was determined by Robert Robinson (1886 1975) in 1946; the next year Robinson received the Nobel Prize in chemistry for his work on alkaloids. Robert Burns Woodward (1917 1979) performed the first complete synthesis of strychnine in 1953.Strychnine was used in its impure powder form centuries before it was isolated. The nuts that yielded the seeds were given names such as poison nut or vomit nuts. Early workers on its properties warned about its poisonous properties and recommended against it internal use.

The Uses of STRYCHNINE

Strychnine occurs in the seeds of strychnosspecies (S. nux vomica L., S. Loganiaceae,and S. ignatii Berg). The total alkaloid con tent in these plants is 2–3%. The composition of strychnine in these species rangesbetween 1% and 3%. Strychnine is widelyknown as a poison. Its therapeutic applica tions are very limited. It is used as a rodentpoison.

The Uses of STRYCHNINE

central stimulant

The Uses of STRYCHNINE

Destroying rodents and predatory animals.

The Uses of STRYCHNINE

Strychnine as nux vomica was available in apothecaries throughoutthe 19th century, and strychnine salts such as strychnine sulfate, strychnine nitrate, andstrychnine phosphate were a popular medicine. It was sold as pills, powders, and tinctures.Small quantities of strychnine were added to tonics to serve as stimulants. Because its bittertaste stimulates saliva and gastric production, strychnine was used to counteract the lossof appetite produced by various diseases. Hypodermic injections of strychnine along withdigitalis were prescribed for treating acute heart failure in the early 20th century. Otherconditions for which strychnine was prescribed included paralysis, impotence, alcoholism,and drug addiction.
Today strychnine as nux vomica is still available as an herbal ingredient for herbal and homeopathic remedies. The action of nux vomica is attributed to strychnine and brucine. It is recommended for stomach ailments such as atonic dyspepsia, constipation, heart burn, and indigestion. It is reported to relieve nausea during pregnancy. Chinese herbalists use nux vomica externally to treat tumors, headaches, and paralysis. It is recommended for the treatment of Bell's palsy. Strychnine has some uses in modern traditional medicine. It has been used to treat the genetic disorder nonketotic hyperglycinaemia (NKH). NKH is related to glycine metabolism; it can lead to high levels of the inhibitory receptor glycine resulting in seizures. Strychnine is used in neurological research by applying it to areas of the brain or spinal column and observing how the nervous system responds. This method is called strychnine neuronography. Strychnine has been used in conjunction with antivenoms to treat poisonous snake bites. Strychnine is sometimes cut into cocaine, heroin, and other illegal substances in the production of designer drugs.
Strychnine was once used liberally as a pesticide, especially to control vertebrates.It is used as a salt in granular bait formulations. In the United States its use has been progressively limited over the years. . In the1980s, its use was curtailed for above-ground applications to reduce toxicity to nontargetspecies, especially birds; by the end of the decade, its use was limited to below ground.Currently, strychnine is only registered for use by the EPA as a below-ground bait pesticidefor use on pocket gophers.

The Uses of STRYCHNINE

Strychnine is used for the control of moles, squirrels, rabbits, gophers, mice and other small rodents and of bird pests. Rats normally avoid the bait.

Definition

ChEBI: Strychnine is a monoterpenoid indole alkaloid that is strychnidine bearing a keto substituent at the 10-position. It has a role as an avicide, a glycine receptor antagonist, a cholinergic antagonist, a rodenticide and a neurotransmitter agent. It is a monoterpenoid indole alkaloid and an organic heteroheptacyclic compound. It is a conjugate base of a strychnine(1+). It derives from a hydride of a strychnidine.

Definition

strychnine: A colourless poisonouscrystalline alkaloid found in certainplants.

Production Methods

Strychnine is extracted from Strychnos nux-vomica seeds. The very complex chemical synthesis has been achieved by WOODWARD et al. (74).

Indications

Strychnine is clinically used for the treatment of barbiturate poisoning, hemiplegia, amblyopia, blood diseases, and streptomycin toxicity. Strychnine is used to treat aplastic anemia.

World Health Organization (WHO)

Strychnine, the principal alkaloid present in nux vomica, was first used in medicine several centuries ago. However, it has no demonstrated therapeutic value and there is no current justification for its presence in any medication. It continues to be used as a rodenticide though such use is severely restricted in many countries since accidental ingestion can be lethal.

General Description

Colorless, transparent crystals or white crystalline powder. Has no odor. Used for destroying rodents and predatory animals and for trapping fur-bearing animals.

Reactivity Profile

STRYCHNINE is an alkaloid derivative. STRYCHNINE is a base and forms water soluble salts with acids. Avoid alkalis, alkali carbonates and bicarbonates, benzoates, dichromates, bromides, iodides, tannic and picric acids, salicylates, borax, gold chloride and other alkaloid precipitants, piperazine, potassium-mercuric iodide. Protect from light. [EPA, 1998]. STRYCHNINE is incompatible with the following: Strong oxidizers .

Hazard

Toxic by ingestion and inhalation. Central nervous system impairment.

Health Hazard

Super toxic; probable oral lethal dose in humans is less than 5 mg/kg, a taste (less than 7 drops) for a 70 kg (150 lb.) person. It causes violent generalized convulsions. Death results from respiratory arrest as the respiratory muscles are in sustained spasm. The lowest lethal oral dose reported for humans is 30 mg/kg.

Health Hazard

Strychnine is a highly toxic alkaloid. Itcauses hypersensitivity to sensory stimuli.It is a powerful convulsant. This results inrespiratory and metabolic acidosis (Hodgson et al. 1988). Death occurs from asphyxiaafter a few seizures. Its convulsant actionsare attributed to the antagonism of theinhibitory effects of glycine. It excites allportions of the central nervous system. Itproduces green-colored vision, which is aneffect of sensory disorders. Toxic symptomsfrom continued medication with strychnineinclude photophobia, muscular rigidity, stiff ness in joints, lassitude, and headache (vonOettingen 1952, ACGIH 1986). Ingestion of0.1 g may be fatal to humans.
LD50 value, oral (mice): 2 mg/kg
Intravenous administration of diazepamis applied for the treatment of strychninepoisoning.

Fire Hazard

When heated, emits highly toxic fumes. Fire may produce irritating or poisonous gases. Runoff from fire control or dilution water may cause pollution. Protect from light.

Agricultural Uses

Rodenticide, Avicide: Strychnine products are allowed for use only below ground where exposure to food and feed crops is not expected. It can be used in orchards, feed crop sites, pastures, range land, alfalfa fields, irrigation systems, non-agriculture rights-of-way, forests, and residential sites. Pocket gophers are primary targets. Not listed for use in EU countries. A U.S. EPA restricted Use Pesticide (RUP)

Trade name

BOOMER-RID®; CERTOX®; DOLCO MOUSE CEREAL®; GOPHER BAIT®; GOPHERGETTER®; GOPHER-GO AG BAIT®; HARE-RID®; KWIK-KIL®; MOLE DEATH®; MOUSE-NOTS®; MOUSE-RID®; MOUSE-TOX®; NUX VOMICA®; PIED PIPER MOUSE SEED® (strychnine); RO-DEX®; SANASEED®

Pharmacology

The pharmacological effect of strychnine is mainly manifested in the central nervous system, cardiovascular system, digestive system and antitumor effects.
Studies have shown that the effects of strychnine on the nervous system are mainly manifested in the following areas: (1) Strychnine can improve the excitability of the spinal cord. In the recovery period of acute myelitis patients, the nerve recovery is very slow. Strychnine can stimulate the reflex function of the spinal cord, improve the function of the sensory centers of cerebral cortex, and significantly speed up the recovery of nerve function of acute myelitis patients. (2) Strychnine can excite the medulla oblongata and improve the excitabilities of vascular movement center and respiratory center. (3) Strychnine can excite the cerebral cortex. The therapeutic dose of strychnine can excite the cerebral cortex, wake up the patients in the state of inhibition, and improve the functions of hearing, vision, taste, touch, and other receptors of patients.
The treatment effects of strychnine on the arrhythmia. Strychnine is able to block the voltage-gated sodium channel Nav1.5, which is a major subtype of the voltagegated sodium (Nav) channel. Nav1.5 exists in cardiomyocytes of mammalian species and plays an important role in maintaining excitability of cardiomyocytes and excitability conduction. Studies have shown that strychnine can inhibit the Nav1.5 current in a concentration-dependent manner; therefore, it has a potential advantage in the treatment of arrhythmias.
Strychnine can promote the digestive function through reflex. Strychnine can increase the gastric secretion through stimulation of the sensory receptors and promote digestion and appetite. In addition, 0.5?mM and 1?mM strychnine can significantly induce cell shrinkage after HepG2 exposure to strychnine for 72?h and can inhibit the proliferation of HepG2 cells and promote cell apoptosis, suggesting that strychnine may possess antitumor effects.

Clinical Use

Strychnine is commonly used in the treatment of flaccid paralysis, ENT diseases, diabetes, neurasthenia, acute myelitis, peripheral neuritis, and aplastic anemia in clinic. However, due to the relatively high toxicity of strychnine, excessive or longterm use of strychnine may lead to poison. Studies have shown that the combination of Strychnos and Glycyrrhiza or cinnamon can reduce the toxicity of strychnine. Therefore, further study of poisoning mechanism and toxicokinetics of strychnine is of great significance for the clinical safety

Safety Profile

Human poison by ingestion. Experimental poison by ingestion, intravenous, subcutaneous, and intraperitoneal routes. Experimental reproductive effects. An allergen. Lethal dose to man: 30-60 mg/kg. If ingested, the time of action depends upon the condition of the stomach, whether empty or full, and the nature of the food present. If taken by subcutaneous injection, the place of administration of the injection will affect the time of action. The first symptoms are a feeling of uneasiness with a heightened reflex of irritability, followed by muscular twitching in some parts of the body. With larger doses, this is followed by a sense of impending suffocation. Convulsive movements begin that have the effect of mechanically causing the patient to cry out or to shriek; then follow the characteristic spasms, which set in with violence. These are at first clonic and then tonic. There are successive attacks of spasms. With each successive attack, the symptoms become more violent, eventually resulting in death. A rodenticide. When heated to decomposition it emits toxic fumes of NOx.

Potential Exposure

de, requiring a certified applicator. Strychnine is an alkaloid compound that has been widely used as a rodenticide/bait to kill rodents; a medicine, respiratory stimulant. A potential danger to those involved in the extraction the seeds of the Strychnos nux vomica, Strychnos ignatii (S. sancta Ingnatius), and Strychnos tiente (Upas tree); formulation or application of this rodent poison. The sulfate is used to kill gophers and moles. A common adulterant in illicit street drugs. Listed as a potential WMD biotoxin.

Source

Strychnine silver morning glory, wood rose, and in Strychnos nusvomica L.: 15,800, 400– 12,000, 8,000, and 7,030 ppm in bark, seeds, leaves, and roots, respectively (Duke, 1992).

Environmental Fate

Chemical/Physical. Reacts with acids forming water-soluble salts (Worthing and Hance, 1991). Emits toxic nitrogen oxides when heated to decomposition (Lewis, 1990).

Metabolic pathway

Strychnine is used for the control of rodents in field situations and experiments on its sorption and degradation in soil have been reported but with very little information specifically on metabolic pathways. Metabolism in rats has been conducted and this has been supported by studies in vitro using liver microsomes from several species. A picture of its metabolism has been established but further work on minor pathways and conjugation may be necessary.

Solubility in water

(g/L):
Alcohol (6.67 g/L), amyl alcohol (4.55 g/L), benzene (5.56 g/L), chloroform (200 g/L), glycerol (3.13 g/L), methanol (3.85 g/L), toluene (≈ 5 g/L) (Windholz et al., 1983), pyridine (>12.3 g/kg at 20–25 °C) (Dehn, 1917)

Shipping

UN1692 Strychnine or strychnine salts, Hazard Class: 6.1; Labels: 6.1-Poisonous material.

Purification Methods

It crystallises from CHCl3/Et2O and sublimes at 125o/0.01mm. It can also be purified by conversion to the hydrochloride [m 275-295o (dec), []D -44o (0.03N HCl)] with aqueous HCl, then neutralisation with ammonia. [Beilstein 27 II 723, 27 III/IV 7530.] It is POISONOUS.

Degradation

Strychnine is a base which forms stable salts with inorganic acids, e.g. the hydrochloride and sulfate. It is hydrolytically stable at 25 °C with DT₅₀ values >31 days at pH 5,7 and 9 (PM).

Incompatibilities

Incompatible with oxidizers (chlorates, nitrates, peroxides, permanganates, perchlorates, chlorine, bromine, fluorine, etc.); contact may cause fires or explosions. Keep away from alkaline materials, strong bases, strong acids, oxoacids, epoxides. Dangerous when heated; forms toxic fumes, including nitrogen oxides. In the body, caffeine may increase the strychnine effect.

Waste Disposal

Consult with environmental regulatory agencies for guidance on acceptable disposal practices. Generators of waste containing this contaminant (≥100 kg/mo) must conform to EPA regulations governing storage, transportation, treatment, and waste disposal. In accordance with 40CFR165, follow recommendations for the disposal of pesticides and pesticide containers. Must be disposed properly by following package label directions or by contacting your local or federal environmental control agency, or by contacting your regional EPA office. Careful incineration has been recommended for disposal. Two procedures are suggested. Pour or sift onto a thick layer of sand and soda ash mixture (90-10). Mix and shovel into a heavy paper box with much paper packing Burn in incinerator. Fire may be augmented by adding excelsior and scrap wood. Stay on the upwind side. Waste may be dissolved in flammable solvent (alcohols, benzene, etc.) and sprayed into fire box of an incinerator with afterburner and scrubber.

References

Regnault., Annalen, 26, 17 (1838)
Watson, Sen.,!. Ind. Chem. Soc., 3,397 (1926)
Schwyzer., Die Fabrikation der Alkaloide, (Berlin, 1927)
Leuchs, Beyer., Ber., 68, 290 (1935)
Clemo., J. Chem. Soc., 1695 (1936)
Briggs, Openshaw, Robinson., ibid, 903 (1946)
Chakravarti, Robinson., Nature, 160, 18 (1947)
Woodward., ibid, 162, 155 (1948)
Woodward., Tetrahedron, 19,247 (1963)
Nagarajan etal., Helv. Chim. Acta, 46, 1212 (1963)
Sandberg et al., Tetrahedron Lett., 6217 (1968)
Absolute configuration: Peerdemann., Acta Cryst., 9,824 (1956)
Pharmacology: Lambruschini., Rev. Soc. argent. biol., 14, 353 (1938)
Travell., J. Pharm. expo Ther., 69,21 (1940)
Weigmann., Arch. expo Path. Pharm., 196, 521 (1940)
Raymond-Hamet., Bull. sci. pharmacol., 48, 306 (I 941)
Coppee, Coppee-Bolly., Arch. intern. physiol., 51,97 (1941)
Abreu, Woodbury., J. Pharm. expo Ther., 78, 321 (1943)