Curare
Curare
Curare (pronounced cue-rah’-ree) is a general term for certain chemical substances found in different plants throughout the world’s rainforests. These plants produce a harmless sap which for centuries the natives of the rainforests have refined into a deadly poison. The way of refining and delivering the poison from certain types of plants is similar for natives occupying equatorial regions from South America, Africa, and Southeast Asia. Animals are hunted with blow-guns loaded with darts that have been prepared with lethal doses of the curare preparations.
The word curare is derived from woorari, a word of native American origin from the Amazon and Orinoco basins meaning”poison.“There are different plants used to produce the poisons for the tips of the darts used in hunting. The blowgun is particularly effective against arboreal animals, such as monkeys and birds. The hunters’ final curare preparation is composed of”curares“or poisons from various plants. Curares from these plants share the same chemical composition. They are all alkaloids. An alkaloid is an organic compound containing nitrogen and usually oxygen. They are found in seed plants and are usually colorless and bitter, like codeine or morphine.
The plant Strychnos toxifera produces the strongest type of curare for the hunters of the rainforests. Other curare type plants, however, have been used in western medicine as anesthetics after it was discovered that curares can have nonlethal effects such as skeletal muscle relaxants. Tubocurarine, an anesthetic muscle relaxant introduced into medical practice in the early 1940s contains a curare alkaloid from the chondrodendron plant family.
History
Early eighteenth- and nineteenth-century researchers studied the effects of curare. In 1780 Abbe´ Felix Fontana found that its action was not on the nerves and heart but on the ability of the voluntary muscles to respond to stimuli. In British experiments, several English researchers showed that animals injected with curare would recover if their respiration was artificially continued. Laboratory experiments were continued throughout the nineteenth century using curare to find out more about the relationship between the nervous and skeletal muscle systems. In 1850 Claude Bernard using curare identified the neuromuscular junction where the curare interferes with the acceptance of the neural impulse. Earlier in that century Squire Waterton had conjectured that curare could be used in the treatment of tetanus.
The first use of curare in surgery was in 1912. A German physician and physiologist, Arthur Lawen, wrote about his use of curare in surgery on a patient. He was able to relax the patient’s abdominal muscles with a small amount of regular anesthesia after administering curare. In order to control the curare he also learned how to intubate (insert a tube into the patient’s trachea) and then ventilate the lungs, that is add air through the tube to control breathing. His reports, which were published only in German, were ignored largely because anesthesiologists at that time had not learned the techniques of intubation and ventilation.
In 1938 Richard and Ruth Gill returned from a trip to South America to New York with a large stock of crude curare. They collected these plants from their Ecuadorian ranch for the Merck Company. At that time there was some interest in using curare for the treatment of a friend who had multiple sclerosis. Merck lost interest in the project, but some of the Gill’s curare stock passed on to Squibb & Co. Early use of the drug for anesthetic purposes, however, were not successful, and interest was dropped at that time for further clinical experimentation.
Interest in curare resumed in 1939 when psychiatrists from the American Midwest began to use it to treat certain categories of patients. Children with spastic disorders were injected with curare but when no long-range improvement was observed, these psychiatric researchers passed it on to those who were using Metrazol, a drug that was a precursor to
KEY TERMS
Electroconvulsive therapy (ECT)— Formerly known as”shock treatment.“The administration of a low dose electric current to the head in conjunction with muscle relaxants to produce convulsions. A treatment method whose underlying action is still not fully understood, it has proven effective in relieving symptoms of some severe psychiatric disorders for which no other treatment has been effective, for example, severe depression.
Intubation— The insertion of a tube through the throat and trachea as part of the anesthetic procedure using a muscle relaxant. Muscle relaxant—A drug used to relax the voluntary muscles during an operation.
Tubocarine— One of the many muscle relaxants used with curarelike effects.
Ventilation— Keeping air flowing through the lungs after the breathing muscles have been relaxed during an operation.
electro-convulsive therapy (ECT), formerly referred to as shock treatment. The curare appeared to absorb some of the intense muscle responses or seizures, thus helping to avoid seizure-induced fractures to the bones. Other psychiatrists began to experiment with the drug after its successful application to ECT.
Shortly afterwards a Canadian physician, Harold Griffith, began to prepare to use curare for surgery after he saw the positive results of its use in psychiatric patients. He first utilized curare in an operation on January 23, 1942. Then he reported on the successful use of curare as a muscle relaxant for this operation, which was an appendectomy. He administered the curare after the patient’s trachea was anesthetized and intubated early in the operation. The muscles of the abdominal wall became relaxed by the curare to help in the performance of the operation. Twenty-five other patients received similar treatment. After Griffith’s report of his work, the use of curare and other synthetic type curare muscle relaxants became the standard practice for surgical procedures requiring muscle relaxation.
Tubocurarine
Since 1942 there have been about 50 different relaxants used in clinical anesthesia. Tubocurarine, whose chemical structure was determined 1935, is the prototype of a muscle relaxant that still contains the alkaloid constituent of curare and produces a similar physiological effect. Another semisynthetic derivative of tubocurarine is even more potent. It is given intravenously since it is not active when taken orally.
Anesthetic muscle relaxants block nerve impulses between the junctions of the nerve and muscle. It is believed they accomplish this task preventing the acceptance of acetylcholine, which is a chemical neurotransmitter, by the muscle fiber. In addition to the main clinical use of curare is as an accessory drug in surgical anesthesia to obtain relaxation of skeletal muscle, it is also used to facilitate diagnostic procedures, such as laryngoscopy and endoscopy. It is also used in cases of tetanus and myasthenia gravis, an autoimmune disorder.
Resources
BOOKS
Barash, Paul G., Bruce F. Cullen, and Robert K. Stoelting. Clinical Anesthesia. Philadelphia, Lippincott, 1992.
Dripps, Robert D., James E. Eckenhoff, and Leroy D. Vandam. Introduction to Anesthesia. Philadelphia: Saunders, 1988.
Gold, Mark and Michael Boyette. Wonder Drugs: How They Work. New York: Simon & Schuster, 1987.
OTHER
University of California, Los Angeles—Mildred E. Mathias Botanical Garden. ”Curare, a South American Arrow Poison“<http://www.botgard.ucla.edu/html/botanytextbooks/economicbotany/Curare> (accessed November 17, 2006).
Jordan P. Richman
Curare
Curare
Curare (pronounced cue-rah'-ree) is a general term for certain chemical substances found in different plants throughout the world's rainforests. These plants produce a harmless sap which for centuries the natives of the rainforests have refined into a deadly poison. The way of refining and delivering the poison from certain types of plants is similar for natives occupying equatorial regions from South America , Africa , and Southeast Asia . Animals are hunted with blowguns loaded with darts that have been prepared with lethal doses of the curare preparations.
The word curare is derived from woorari, a word of native American origin from the Amazon and Orinoco basins meaning poison. There are different plants used to produce the poisons for the tips of the darts used in hunting. The blowgun is particularly effective against arboreal animals, such as monkeys and birds . The hunters final curare preparation is composed of "curares" or poisons from various plants. Curares from these plants share the same chemical composition. They are all alkaloids. An alkaloid is an organic compound containing nitrogen and usually oxygen . They are found in seed plants and are usually colorless and bitter like codeine or morphine .
The plant Strychnos toxifera produces the strongest type of curare for the hunters of the rainforests. Other curare type plants, however, have been used in western medicine as anesthetics after it was discovered that curares can have non-lethal effects such as skeletal muscle relaxants . Tubocurarine, an anesthetic muscle relaxant introduced into medical practice in the early 1940s contains a curare alkaloid from the chondrodendron plant family.
History
Early eighteenth and nineteenth century researchers studied the effects of curare. In 1780 Abbe Felix Fontana found that its action was not on the nerves and heart but on the ability of the voluntary muscles to respond to stimuli. In British experiments, several English researchers showed that animals injected with curare would recover if their respiration was artificially continued. Laboratory experiments were continued throughout the nineteenth century using curare to find out more about the relationship between the nervous and skeletal muscle system. In 1850 Claude Bernard using curare identified the neuromuscular junction where the curare interferes with the acceptance of the neural impulse. Earlier in that century Squire Waterton had conjectured that curare could be used in the treatment of tetanus .
The first use of curare in surgery was in 1912. A German physician and physiologist, Arthur Lawen, wrote about his use of curare in surgery on a patient. He was able to relax the patients abdominal muscles with a small amount of regular anesthesia after administering curare. In order to control the curare he also learned how to intubate (insert a tube into the patient's trachea) and then ventilate the lungs, that is add air through the tube to control breathing. His reports, which were published only in German, were ignored largely because anesthesiologists at that time had not learned the techniques of intubation and ventilation.
In 1938 Richard and Ruth Gill returned from a trip to South America to New York with a large stock of crude curare. They collected these plants from their Ecuadorian ranch for the Merck Company. At that time there was some interest in using curare for the treatment of a friend who had multiple sclerosis. Merck lost interest in the project, but some of the Gill's curare stock passed on to Squibb & Co. Early use of the drug for anesthetic purposes, however, were not successful, and interest was dropped at that time for further clinical experimentation.
Interest in curare resumed in 1939 when psychiatrists from the American midwest began to use it to treat certain categories of patients. Children with spastic disorders were injected with curare but when no long range improvement was observed, these psychiatric researchers passed it on to those who were using Metrazol, a drug that was a precursor to electroconvulsive therapy (ECT), formerly referred to as shock treatment. The curare appeared to absorb some of the intense muscle responses or seizures, thus helping to avoid seizure induced fractures to the bones. Other psychiatrists began to experiment with the drug after its successful application to ECT.
Shortly afterwards a Canadian physician, Harold Griffith, began to prepare to use curare for surgery after he saw the positive results of its use in psychiatric patients. He first utilized curare in an operation on January 23, 1942. Then he reported on the successful use of curare as a muscle relaxant for this operation, which was an appendectomy. He administered the curare after the patient's trachea was anesthetized and intubated early in the operation. The muscles of the abdominal wall became relaxed by the curare to help in the performance of the operation. Twenty-five other patients received similar treatment. After Griffith's report of his work, the use of curare and other synthetic type curare muscle relaxants became the standard practice for surgical procedures requiring muscle relaxation.
Tubocurarine
Since 1942 there have been about 50 different relaxants used in clinical anesthesia. Tubocurarine, whose chemical structure was determined 1935, is the prototype of a muscle relaxant that still contains the alkaloid constituent of curare and produces a similar physiological effect. Another semisynthetic derivative of tubocurarine is even more potent. It is given intravenously since it is not active when taken orally.
Anesthetic muscle relaxants block nerve impulses between the junctions of the nerve and muscle. It is believed they accomplish this task preventing the acceptance of acetylcholine , which is a chemical neurotransmitter , by the muscle fiber. In addition to the main clinical use of curare is as an accessory drug in surgical anesthesia to obtain relaxation of skeletal muscle, it is also used to facilitate diagnostic procedures, such as laryngoscopy and endoscopy . It is also used in cases of tetanus and myasthenia gravis, an autoimmune disorder.
Resources
books
Barash, Paul G., Bruce F. Cullen, and Robert K. Stoelting. Clinical Anesthesia. Philadelphia, Lippincott, 1992.
Dripps, Robert D., James E. Eckenhoff, and Leroy D. Vandam. Introduction to Anesthesia. Philadelphia: Saunders, 1988.
Gold, Mark, and Michael Boyette. Wonder Drugs: How TheyWork. New York: Simon & Schuster, 1987.
Jordan P. Richman
KEY TERMS
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .- Electroconvulsive therapy (ECT)
—Formerly known as "shock treatment." The administration of a low dose electric current to the head in conjunction with muscle relaxants to produce convulsions. A treatment method whose underlying action is still not fully understood, it has proven effective in relieving symptoms of some severe psychiatric disorders for which no other treatment has been effective, for example, severe depression.
- Intubation
—The insertion of a tube through the throat and trachea as part of the anesthetic procedure using a muscle relaxant.
- Muscle relaxant
—A drug used to relax the voluntary muscles during an operation.
- Tubocarine
—One of the many muscle relaxants used with curarelike effects.
- Ventilation
—Keeping air flowing through the lungs after the breathing muscles have been relaxed during an operation.
Curare
Curare
Curare is a name used to identify a variety of highly toxic (poisonous) extracts from some types of woody vines that grow in South America. European scientists began studying curare in the late sixteenth century after explorers learned that Indians living along the Amazon and Orinoco Rivers in South America had been using it for centuries to make poison-tipped hunting arrows. The poison in the arrows killed animals by paralyzing (numbing) their muscles. When the muscles used for breathing became paralyzed, the animals died of suffocation. These deadly arrows were sometimes used against the European explorers and soldiers. Natives called the poisonous plant ourari (or "woorari"), which became "curare" to the Europeans.
In 1735 a scientific expedition sponsored by the French Academy of Sciences was sent to the area of South America that is now Ecuador. Heading the expedition was the Frenchman Charles Marie de la Condamine, who spent part of ten years in South America scientifically exploring the region. La Condamine collected samples of curare and took them back to France.
During the nineteenth century, doctors tried to use curare as a muscle relaxant in the treatment of rabies, tetanus (an infectious disease that usually enters the body through a wound), and epilepsy (a chronic, or lasting, disease of the nervous system characterized by convulsions), but these trials were unsuccessful because available curare extracts were not of equal quality and potency (strength). In the 1870s curare was used to keep conscious animals from moving during experimental surgery. This practice angered many people in Great Britain and led to the passage of anti-vivisection laws (laws against using animals for scientific experimentation).
The first breakthrough leading to successful medical use of curare came in 1935, when Harold King isolated its active principle, which he called tubocurarine. A chemically pure alkaloid (an organic base of a plant, containing nitrogen and usually oxygen) of curare was introduced in 1942 by Thomas Cullen. This purified alkaloid is called d-tubocurarine. Curare contains two alkaloids: curine, which paralyzes the muscle fibers of the heart, and curarine, which paralyzes the motor nerve endings in voluntary muscles.
That same year, a country doctor and part-time anesthetist named Harold Griffith of Montreal, Quebec, tested the use of curare in surgery. He used it as a muscle relaxant that let him use lower, safer doses of anesthesia. Over the next ten years, many doctors began using curare to relax their patients' muscles during abdominal surgery or during tracheal intubation (the inserting of a tube into the trachea to allow a patient to breathe).
Artificial Curare
Because the effects of natural curare were still unpredictable, Swiss-Italian pharmacologist Daniele Bovet (1907-1992; winner of the 1957 Nobel Prize in medicine) of the Pasteur Institute in Paris, France, set out to make a synthetic (artificially produced) uniform curare. He succeeded in 1947 with the medicine gallamine, and then went on to make more than 400 compounds that had the same effects as curare. One of these compounds, succinylcholine, became a widely used and effective curare substitute that could be given in precise dosages with predictable effects. Succinylcholine allows complete muscle relaxation during surgery without deep anesthesia.
While d-tubocurarine and similar compounds totally paralyze the muscles, they do not affect the central nervous system. A patient who receives an injection (shot) of this drug into a muscle quickly begins to feel dizzy and warm. The muscles of the jaw, neck, and head are the first to become weak and relaxed. The person can hear low tones better because small muscles in the middle ear relax. Then the arms and legs begin to feel heavy and difficult to move. Breathing becomes harder, and the patient experiences "shortness of breath," even with artificial respiration. He cannot swallow and feels like he is choking because saliva accumulates in the throat. Soon it is impossible to move at all. During this time the patient is fully conscious of everything around him and can sense pain. For this reason anesthesia is still needed during medical procedures, though in smaller amounts.
The effects of curare do not last long, and a person or animal who has been poisoned by this substance can fully recover if given artificial respiration until the poison wears off. The action of d-tubocurarine or its related compounds like succinylcholine begins to wear off after about 20 minutes if a single moderate dose is injected into a vein, the usual method of giving the drug. During surgery the patient may have to be given additional small doses of d-tubocurarine. The drug has little or no effect if taken by mouth, unless swallowed in very large doses.
Curare-like drugs are sometimes used to relax muscles when doctors are correcting dislocations or setting bone fractures, and in the control of muscle spasms during convulsions like those seen with tetanus, epilepsy, drug overdose, and following the bite of the black widow spider. These drugs are also used during tracheal intubation, and to help make examinations of the larynx, bronchial tubes, and esophagus easier.
curare
Tubocurarine blocks the effects of the neurotransmitter acetylcholine in sites where it acts on the type of post-synaptic membrane receptors which are known as nicotinic. Quite the most important sites of these receptors are the junctions between motor nerves and voluntary skeletal muscle. When injected — and this includes injection by poisoned arrow — control of voluntary muscles is lost and flight or escape is not possible. Long before King had investigated the structure of tubocurarine, Claude Bernard had shown in 1856 that curare blocked neuromuscular transmission, without affecting conduction in the nerve or the contractility of the muscle. We now know that curare competes with acetylcholine for combination with the receptors on the muscle membrane — causing neuromuscular block.
In surgery, access to body cavities is hampered by tension in the voluntary muscles. These can be relaxed using anaesthetics, but only if dangerous dosage levels are used. Another, rather awkward solution is for assistants to hold open the incision with retractor. Motor paralysis by tubocurarine offered a surer and less cumbersome alternative. Use of such muscle relaxants became widespread for major surgery from the mid twentieth century. Not all voluntary muscles are equally sensitive to tubocurarine, and fortunately the respiratory muscles are the most spared. Thus by careful control of the dosage respiration can be maintained, although it is usual for anaesthetists to control the ventilation of the lungs mechanically.
For many years the commercial supply of tubocurarine was by extraction from crude curare extracts. New synthetic drugs, such as atracurium, have now largely replaced tubocurarine in medical practice. Nevertheless, for a while, surgery owed a debt to the experimentation of primitive peoples with their need for an arrow poison.
Alan W. Cuthbert
Bibliography
Sneader, W. (1985). Drug discovery — the evolution of modern medicines. Wiley, Chichester.
See also acetylcholine; anaesthesia, general; neuromuscular junction; paralysis; membrane receptors.
curare
curare
cu·ra·re / k(y)oŏˈrärē/ • n. a bitter, resinous substance obtained from the bark and stems of certain South American plants (families Menispermaceae and Loganiaceae). It is traditionally used by some Indian peoples to poison their arrows and darts.