Curare

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Curare [koo rah ree] ^[1] is a common name for various dart poisons (arrow poisons) originating from South America. The three main types or families of curare are:

• tubocurare (also known as tube or bamboo curare, because of its packing into hollow bamboo tubes; main toxin is D-tubocurarine). It is a mono-quaternary alkaloid, an isoquinoline derivative.
• calebas curare (also called "gourd curare" by older British classifications, being packed into hollow gourds; main toxins are alloferine and toxiferine)
• pot curare (packed in terra cotta pots; main toxins are protocurarine, protocurine, and protocuridine).

Of these three families, some formulas belonging to the calebas curare are the most toxic, relative to their LD₅₀ values.

Contents 1 History 2 Pharmacological properties 3 Curare and anesthesia 4 Plants from which primary components of curare can be extracted 5 Names 6 External links 7 Popular culture 8 References

[edit] History

In 1596 Sir Walter Raleigh mentioned the arrow poison in his book Discovery of the Large, Rich, and Beautiful Empire of Guiana (now Guyana). It is possible that the poison he described was not curare at all.^[2] The deadly effects of various Amazonian plant mixtures called curare were learned by early European explorers. In 1800, Alexander von Humboldt gave the first western account of how the toxin was prepared from plants by Orinoco River natives.^[3]

During 1811-1812 Sir Benjamin Collins Brody (1783-1862) experimented with curare ^[4] He was the first to show that curare does not kill the animal and the recovery is complete if the animal’s respiration is maintained artificially. In 1825 Charles Waterton (1783-1865) (who gained fame by riding a captured alligator) described a classical experiment in which he kept a curarized she-ass alive by artificial ventilation with a bellows through a tracheostomy.^[5] Waterton is also credited with bringing curare to Europe.^[6] Robert Hermann Schomburgk, who was a trained botanist, identified the vine as one of the Strychnos species and gave it the now accepted name Strychnos toxifera.^[7]

George Harley (1829-1896) showed in 1850 that curare (wourali) was effective for the treatment of tetanus and strychnine poisoning.^[8][9] From 1887 the Burroughs Wellcome catalogue listed under its 'Tabloids' brand name, tablets of curare at 1/12 grain (price 8 shillings) for use in preparing a solution for hypodermic injection. In 1914 Henry Hallett Dale (1875-1968) described the physiological actions of acetylcholine.^[10] After twenty-five years he showed that acetylcholine is responsible for neuromuscular transmission which can be blocked by curare.^[11]

The most known and historically important toxin (because of its medical applications) is d-tubocurarine. It was isolated from the crude drug (from a museum sample of curare) in 1935 by Harold King (1887-1956) of London, working in Sir Henry Dale’s laboratory. He also established its chemical structure.^[12] It was introduced into anesthesia in the early 1940s as a muscle relaxant for surgery. Curares are active (i.e. toxic or muscle relaxing, dependent on the intention of their use) only if given/applied parenterally, that is, by an injection, or direct wound contamination by poisoned dart/arrow tip. It is harmless if taken orally^{[13] [14]} because curare compounds are too large and too highly charged to pass through the lining of the digestive tract to get absorbed into the blood. This is crucial, because the native tribes use curares mainly for hunting purposes, thus the curare-poisoned prey must remain safe to eat. In medicine, curare has been superseded by a number of curare-like agents (pancuronium, an alkaloid-like substance with steroidal skeleton in its molecule), that have a similar pharmacodynamic profile but with fewer side effects. Curare has also been used historically as a paralyzing poison by South American indigenous people. The prey is killed by asphyxiation as the respiratory muscles are unable to contract resulting in apnea.

[edit] Pharmacological properties

Curare is an example of a non-depolarizing muscle relaxant (aka, competitive antagonist) which blocks the nicotinic acetylcholine receptor, one of the two types of cholinergic (acetylcholine) receptors, on the post synaptic membrane of the neuromuscular junction. Curare does not occupy the agonist position, but likely binds within the channel pore.

[edit] Curare and anesthesia

Isolated attempts to use curare during anesthesia dates back to 1912 by Arthur Lawen of Leipzig.^[15] But curare came to anesthesia via psychiatry (electroplexy). In 1939 Abram Elting and Bennett used it to modify metrazol induced convulsive therapy.^[16] Muscle relaxants are used in modern anesthesia for many reasons, such as providing optimal operating conditions and facilitating intubation of the trachea. Before muscle relaxants, anesthesiologists needed to use larger doses of the anesthetic agent, such as ether, chloroform or cyclopropane to achieve these aims. Such deep anesthesia risked killing patients that were elderly or had heart conditions. The source of curare in the Amazon was first researched by Richard Evans Schultes in 1941. Since the 1930s, it was being used in hospitals as a muscle relaxant. He discovered that different types of curare called for as many as 15 ingredients, and in time helped to identify more than 70 species that produced the drug [1].

On January 23, 1942, Dr. Harold Griffith and Dr. Enid Johnson gave a synthetic preparation of curare (Intracostin/ Intocostrin) to a patient undergoing an appendectomy (to supplement conventional anesthesia). Curare (d-tubocurarine) is now not used for anesthesia and surgery as better drugs are now available. When used with halothane d-tubocurarine can cause profound fall in blood pressure in some patients as both the drugs are ganglion blockers. ^[17]. However, it is safer to use d-tubocurarine with ether.

In 1954, a sensational article was published by Beecher and Todd suggesting that the use of muscle relaxants (drugs similar to curare) increased death due to anesthesia nearly six fold.^[18]. This has been completely disproved.

Modern anesthetists have at their disposal a variety of muscle relaxants for use in anesthesia. The ability to produce muscle relaxation independently from anesthesia has permitted anesthesiologists to adjust the two effects separately as needed to ensure that their patients are safely unconscious and sufficiently relaxed to permit surgery. However, because the muscle relaxants have no effect on consciousness, it is possible, through error or accident, that a patient may remain fully conscious and sensitive to pain during surgery, but unable to move or speak, and thus unable to alert attending staff about their pain and state of awareness. This problem is now greatly solved by BIS monitor.

[edit] Plants from which primary components of curare can be extracted

• Strychnos toxifera
• Chondrodendron tomentosum

[edit] Names

Curare is also known as Ampi, Woorari, Woorara, Woorali, Wourali, Wouralia, Ourare, Ourari, Urare, Urari, and Uirary.

d-Tubocurarine, the popular alkaloid of Curare used as a medicine, was available as Tubocurarin, Tubocurarinum, Delacurarine, Tubarine, Metubine, Jexin, HSDB 2152, Isoquinoline Alkaloid, Tubadil, Mecostrin, Intracostin and Intocostrin.

[edit] External links

• Charles Waterton's book Wanderings in South America Free version
• Neuromuscular blocking drugs: discovery and development

[edit] Popular culture

• In an episode of the TV series Heroes, Sylar is drugged with curare, when drinking a cup of chai.
  
• In an episode of the TV series M*A*S*H, "The Light That Failed" (1977) Dr. Winchester fails to read the label on a bottle of "pain medication" and inadvertently injects a patient with curare which stops the patient's breathing. Drs. Honeycutt and Pierce successfully resuscitate the patient.
• An episode of the cartoon TV series Batman Beyond is titled A Touch of Curare after an eponymous female assassin.
• In an episode of the cartoon TV series American Dad, two characters jokingly shoot each other with curare darts, temporarily paralysing them.

[edit] References

• Foldes, F.F. "Anesthesia before and after curare", Anasthesieabteilung des Albert-Einstein-College of Medicine. Anaesthesiol Reanim, 1993, 18(5):128-31. (retrieved June 20 2005)
• James, Mel. "Harold Griffith",Heirloom Series, Volume 6. (retrieved June 20 2005)
• "Curare", Blue Planet Biomes, 2000. (retrieved September 27 2005)
• Smith, Roger. "Cholernergic Transmission", (retrieved March 13, 2007)
• Strecker G J et al. "Curare binding and the curare-induced subconductance state of the acetylcholine receptor channel.", Biophysical Journal 56: 795-806 (1989). (retrieved May 12, 2007)