![R](https://upload.wikimedia.org/wikipedia/commons/f/f0/R._Bentley_%26_H._Trimen%2C_Medicinal_Plants_Wellcome_L0019166.jpg)
Curare (
/kʊˈrɑːri/ or
/kjʊˈrɑːri/;
''koo-rah-ree'' or
''kyoo-rah-ree'') is a common name for various
alkaloid
Alkaloids are a class of basic, naturally occurring organic compounds that contain at least one nitrogen atom. This group also includes some related compounds with neutral and even weakly acidic properties. Some synthetic compounds of similar ...
arrow poison
Arrow poisons are used to poison arrow heads or darts for the purposes of hunting and warfare. They have been used by indigenous peoples worldwide and are still in use in areas of South America, Africa and Asia. Notable examples are the poisons se ...
s originating from plant extracts. Used as a
paralyzing agent by indigenous peoples in
Central
Central is an adjective usually referring to being in the center of some place or (mathematical) object.
Central may also refer to:
Directions and generalised locations
* Central Africa, a region in the centre of Africa continent, also known as ...
and
South America
South America is a continent entirely in the Western Hemisphere and mostly in the Southern Hemisphere, with a relatively small portion in the Northern Hemisphere at the northern tip of the continent. It can also be described as the southe ...
for hunting and for therapeutic purposes, curare only becomes active when it contaminates a wound. These poisons cause weakness of the
skeletal muscles
Skeletal muscles (commonly referred to as muscles) are organs of the vertebrate muscular system and typically are attached by tendons to bones of a skeleton. The muscle cells of skeletal muscles are much longer than in the other types of muscle ...
and, when administered in a sufficient dose, eventual death by
asphyxia
Asphyxia or asphyxiation is a condition of deficient supply of oxygen to the body which arises from abnormal breathing. Asphyxia causes generalized hypoxia, which affects primarily the tissues and organs. There are many circumstances that can i ...
tion due to
paralysis
Paralysis (also known as plegia) is a loss of motor function in one or more muscles. Paralysis can also be accompanied by a loss of feeling (sensory loss) in the affected area if there is sensory damage. In the United States, roughly 1 in 50 ...
of the
diaphragm. Curare is prepared by boiling the bark of one of the dozens of plant sources, leaving a dark, heavy paste that can be applied to arrow or dart heads. In medicine, curare has been used as a treatment for
tetanus
Tetanus, also known as lockjaw, is a bacterial infection caused by ''Clostridium tetani'', and is characterized by muscle spasms. In the most common type, the spasms begin in the jaw and then progress to the rest of the body. Each spasm usually ...
or
strychnine poisoning
Strychnine poisoning can be fatal to humans and other animals and can occur by inhalation, swallowing or absorption through eyes or mouth. It produces some of the most dramatic and painful symptoms of any known toxic reaction, making it quite notic ...
and as a paralyzing agent for surgical procedures.
History
The word 'curare' is derived from ''wurari'', from the Carib language of the
Macusi of Guyana. It has its origins in the Carib phrase "mawa cure" meaning of the Mawa vine, scientifically known as ''
Strychnos toxifera
''Strychnos toxifera'', called bush rope and devil doer, is a species of flowering plant in the genus ''Strychnos'', native to Costa Rica, Panama, Colombia, Ecuador, Venezuela, the Guianas, Brazil, Peru and Bolivia. It is the principal source of ...
''. Curare is also known among indigenous peoples as Ampi, Woorari, Woorara, Woorali, Wourali, Wouralia, Ourare, Ourari, Urare, Urari, and Uirary. The noun 'curare' is not to be confused with the Latin verb 'curare' ('to heal, cure, take care of').
Classification
In 1895 pharmacologist
Rudolf Boehm sought to classify the various alkaloid poisons based on the containers used for their preparation. He believed curare could be categorized into three main types as seen below. However useful it appeared, it became rapidly outmoded. Richard Gill, a plant collector, found that the indigenous peoples began to use a variety of containers for their curare preparations, henceforth invalidating Boehm's basis of classification.
* Tube or bamboo curare: Mainly composed of the toxin
D-tubocurarine
Tubocurarine (also known as ''d''-tubocurarine or DTC) is a toxic alkaloid historically known for its use as an arrow poison. In the mid-1900s, it was used in conjunction with an anesthetic to provide skeletal muscle relaxation during surgery o ...
, this poison is found packed into hollow bamboo tubes derived from
Chondrodendron and other genera in the
Menispermaceae
Menispermaceae (botanical Latin: 'moonseed family' from Greek ''mene'' 'crescent moon' and ''sperma'' 'seed') is a family of flowering plants. The alkaloid tubocurarine, a neuromuscular blocker and the active ingredient in the 'tube curare' form ...
. According to their
LD50 values, tube curare is thought to be the most toxic.
* Pot curare: Mainly composed of alkaloid components protocurarine (the active ingredient), protocurine (a weak toxicity), and protocuridine (non-toxic) from both Menispermaceae and
Loganiaceae
The Loganiaceae are a family of flowering plants classified in order Gentianales. The family includes up to 13 genera, distributed around the world's tropics. There are not any great morphological characteristics to distinguish these taxa from ot ...
/Strychnaceae. This subtype is found originally packed in
terra cotta
Terracotta, terra cotta, or terra-cotta (; ; ), in its material sense as an earthenware substrate, is a clay-based unglazed or glazed ceramic where the fired body is porous.
In applied art, craft, construction, and architecture, terracotta ...
pots.
*
Calabash
Calabash (; ''Lagenaria siceraria''), also known as bottle gourd, white-flowered gourd, long melon, birdhouse gourd, New Guinea bean, Tasmania bean, and opo squash, is a vine grown for its fruit. It can be either harvested young to be consumed ...
or
gourd
Gourds include the fruits of some flowering plant species in the family Cucurbitaceae, particularly ''Cucurbita'' and ''Lagenaria''. The term refers to a number of species and subspecies, many with hard shells, and some without. One of the earli ...
curare: Mainly composed of
C toxiferine I, this poison was originally packed into hollow gourds from Loganiaceae/Strychnaceae alone.
Manske also observed in his 1955 ''The Alkaloids'':
The results of the early re-1900work were very inaccurate because of the complexity and variation of the composition of the mixtures of alkaloids involved ... these were impure, non-crystalline alkaloids ... Almost all curare preparations were and are complex mixtures, and many of the physiological actions attributed to the early curarizing preparations were undoubtedly due to impurities, particularly to other alkaloids present. The curare preparations are now considered to be of two main types, those from Chondrodendron or other members of the Menispermaceae family and those from Strychnos, a genus of the Loganiaceae now Strychnaceae family. Some preparations may contain alkaloids from both ... and the majority have other secondary ingredients.
Hunting uses
Curare was used as a paralyzing poison by many South American indigenous people. Since it was too expensive to be used in warfare, curare was mainly used for hunting.
The prey was shot by arrows or
blowgun
A blowgun (also called a blowpipe or blow tube) is a simple ranged weapon consisting of a long narrow tube for shooting light projectiles such as darts. It operates by having the projectile placed inside the pipe and using the force created by ...
darts dipped in curare, leading to asphyxiation owing to the inability of the victim's respiratory muscles to contract. In particular, the poison was used by the
Island Caribs
The Kalinago, also known as the Island Caribs or simply Caribs, are an indigenous people of the Lesser Antilles in the Caribbean. They may have been related to the Mainland Caribs (Kalina) of South America, but they spoke an unrelated languag ...
, indigenous people of the
Lesser Antilles
The Lesser Antilles ( es, link=no, Antillas Menores; french: link=no, Petites Antilles; pap, Antias Menor; nl, Kleine Antillen) are a group of islands in the Caribbean Sea. Most of them are part of a long, partially volcanic island arc betwe ...
in the
Caribbean
The Caribbean (, ) ( es, El Caribe; french: la Caraïbe; ht, Karayib; nl, De Caraïben) is a region of the Americas that consists of the Caribbean Sea, its islands (some surrounded by the Caribbean Sea and some bordering both the Caribbean Se ...
, on the tips of their arrows.
In addition, the
Yagua people
Yagua are an indigenous people in Colombia and northeastern Peru, numbering approximately 6,000. Currently, they live near the Amazon, Napo, Putumayo and Yavari rivers and their tributaries. As of 2005, some Yagua have migrated northward to ...
, indigenous to Colombia and northeastern Peru, commonly used these toxins via
blowpipes to target prey 30 to 40
paces
A pace is a unit of length consisting either of one normal walking step (approximately ), or of a double step, returning to the same foot (approximately ). The normal pace length decreases with age and some health conditions. The word "pace" is al ...
distant.
Due to its popularity among the indigenous people as means of paralyzing prey, certain tribes would create
monopolies
A monopoly (from Greek el, μόνος, mónos, single, alone, label=none and el, πωλεῖν, pōleîn, to sell, label=none), as described by Irving Fisher, is a market with the "absence of competition", creating a situation where a speci ...
from curare production.
Thus, curare became a symbol of wealth among the indigenous populations.
In 1596, Sir
Walter Raleigh
Sir Walter Raleigh (; – 29 October 1618) was an English statesman, soldier, writer and explorer. One of the most notable figures of the Elizabethan era, he played a leading part in English colonisation of North America, suppressed rebellion ...
mentioned the
arrow poison
Arrow poisons are used to poison arrow heads or darts for the purposes of hunting and warfare. They have been used by indigenous peoples worldwide and are still in use in areas of South America, Africa and Asia. Notable examples are the poisons se ...
in his book ''
Discovery of the Large, Rich, and Beautiful Empire of Guiana'' (which relates to his travels in
Trinidad
Trinidad is the larger and more populous of the two major islands of Trinidad and Tobago. The island lies off the northeastern coast of Venezuela and sits on the continental shelf of South America. It is often referred to as the southernmos ...
and
Guayana), though the poison he described was possibly not curare. In 1780, Abbe Felix Fontana discovered that it acted on the voluntary muscles rather than the nerves and the heart.
In 1832,
Alexander von Humboldt
Friedrich Wilhelm Heinrich Alexander von Humboldt (14 September 17696 May 1859) was a German polymath, geographer, naturalist, explorer, and proponent of Romantic philosophy and science. He was the younger brother of the Prussian minister, p ...
gave the first western account of how the toxin was prepared from plants by
Orinoco
The Orinoco () is one of the longest rivers in South America at . Its drainage basin, sometimes known as the Orinoquia, covers , with 76.3 percent of it in Venezuela and the remainder in Colombia. It is the fourth largest river in the wor ...
River natives.
![Curare darts and quiver-ETHAM 007525-IMG 9972-gradient](https://upload.wikimedia.org/wikipedia/commons/9/94/Curare_darts_and_quiver-ETHAM_007525-IMG_9972-gradient.jpg)
During 1811–1812,
Sir Benjamin Collins Brody experimented with curare (''woorara''). He was the first to show that curare does not kill the animal and the recovery is complete if the animal's
respiration
Respiration may refer to:
Biology
* Cellular respiration, the process in which nutrients are converted into useful energy in a cell
** Anaerobic respiration, cellular respiration without oxygen
** Maintenance respiration, the amount of cellul ...
is maintained artificially. In 1825,
Charles Waterton
Charles Waterton (3 June 1782 – 27 May 1865) was an English naturalist, plantation overseer and explorer best known for his pioneering work regarding conservation.
Family and religion
Waterton was of a Roman Catholic landed gentry family de ...
described a classical experiment in which he kept a curarized
female
Female (Venus symbol, symbol: ♀) is the sex of an organism that produces the large non-motile ovum, ova (egg cells), the type of gamete (sex cell) that fuses with the Sperm, male gamete during sexual reproduction.
A female has larger gamet ...
donkey
The domestic donkey is a hoofed mammal in the family Equidae, the same family as the horse. It derives from the African wild ass, ''Equus africanus'', and may be classified either as a subspecies thereof, ''Equus africanus asinus'', or as a ...
alive by
artificial respiration with a bellows through a
tracheostomy
Tracheotomy (, ), or tracheostomy, is a surgical airway management procedure which consists of making an incision (cut) on the anterior aspect (front) of the neck and opening a direct airway through an incision in the trachea (windpipe). The r ...
.
Waterton is also credited with bringing curare to Europe.
Robert Hermann Schomburgk
Sir Robert Hermann Schomburgk (5 June 1804 – 11 March 1865) was a German-born explorer for Great Britain who carried out geographical, ethnological and botanical studies in South America and the West Indies, and also fulfilled diplomatic missi ...
, who was a trained botanist, identified the vine as one of the genus ''
Strychnos
''Strychnos'' is a genus of flowering plants, belonging to the family Loganiaceae (sometimes Strychnaceae). The genus includes about 100 accepted species of trees and lianas, and more than 200 that are as yet unresolved. The genus is widely dis ...
'' and gave it the now accepted name ''Strychnos toxifera''.
Medical use
George Harley (1829–1896) showed in 1850 that curare (''wourali'') was effective for the treatment of
tetanus
Tetanus, also known as lockjaw, is a bacterial infection caused by ''Clostridium tetani'', and is characterized by muscle spasms. In the most common type, the spasms begin in the jaw and then progress to the rest of the body. Each spasm usually ...
and
strychnine
Strychnine (, , US chiefly ) is a highly toxic, colorless, bitter, crystalline alkaloid used as a pesticide, particularly for killing small vertebrates such as birds and rodents. Strychnine, when inhaled, swallowed, or absorbed through the eye ...
poisoning. In 1857,
Claude Bernard
Claude Bernard (; 12 July 1813 – 10 February 1878) was a French physiologist. Historian I. Bernard Cohen of Harvard University called Bernard "one of the greatest of all men of science". He originated the term '' milieu intérieur'', and the ...
(1813–1878) published the results of his experiments in which he demonstrated that the mechanism of action of curare was a result of interference in the conduction of
nerve impulses
An action potential occurs when the membrane potential of a specific cell location rapidly rises and falls. This depolarization then causes adjacent locations to similarly depolarize. Action potentials occur in several types of animal cells, ...
from the
motor nerve
A motor nerve is a nerve that transmits motor signals from the central nervous system (CNS) to the muscles of the body. This is different from the motor neuron, which includes a cell body and branching of dendrites, while the nerve is made up of ...
to the
skeletal muscle
Skeletal muscles (commonly referred to as muscles) are organs of the vertebrate muscular system and typically are attached by tendons to bones of a skeleton. The muscle cells of skeletal muscles are much longer than in the other types of muscl ...
, and that this interference occurred at the
neuromuscular junction
A neuromuscular junction (or myoneural junction) is a chemical synapse between a motor neuron and a muscle fiber.
It allows the motor neuron to transmit a signal to the muscle fiber, causing muscle contraction.
Muscles require innervation to ...
.
From 1887, the Burroughs Wellcome catalogue listed under its 'Tabloids' brand name,
grain
A grain is a small, hard, dry fruit (caryopsis) – with or without an attached hull layer – harvested for human or animal consumption. A grain crop is a grain-producing plant. The two main types of commercial grain crops are cereals and legum ...
(5.4mg) tablets of curare (price: 8shillings) for use in preparing a solution for hypodermic injection. In 1914,
Henry Hallett Dale
Sir Henry Hallett Dale (9 June 1875 – 23 July 1968) was an English pharmacologist and physiologist. For his study of acetylcholine as agent in the chemical transmission of nerve pulses (neurotransmission) he shared the 1936 Nobel Prize in Ph ...
(1875–1968) described the physiological actions of
acetylcholine
Acetylcholine (ACh) is an organic chemical that functions in the brain and body of many types of animals (including humans) as a neurotransmitter. Its name is derived from its chemical structure: it is an ester of acetic acid and choline. Part ...
. After 25 years, he showed that acetylcholine is responsible for
neuromuscular transmission, which can be blocked by curare.The best known and historically most important toxin (because of its medical applications) is d-
tubocurarine
Tubocurarine (also known as ''d''-tubocurarine or DTC) is a toxic alkaloid historically known for its use as an arrow poison. In the mid-1900s, it was used in conjunction with an anesthetic to provide skeletal muscle relaxation during surgery or ...
. It was isolated from the crude drug – from a museum sample of curare – in 1935 by Harold King of London, working in
Sir Henry Dale's laboratory. King also established its chemical structure. Pascual Scannone, a Venezuelan anesthesiologist
who trained and specialized in New York City, did extensive research on curare as a possible paralyzing agent for patients during surgical procedures. In 1942, he became the first person in Latin America to use curare during a medical procedure when he successfully performed a tracheal intubation in a patient to whom he administered curare for muscle paralysis at the El Algodonal Hospital in Caracas, Venezuela.
After its introduction in 1942, curare/curare-derivatives became a widely used paralyzing agent during medical and surgical procedures. In medicine, curare has been superseded by a number of curare-like agents, such as
pancuronium
Pancuronium (trademarked as Pavulon) is an aminosteroid muscle relaxant with various medical uses. It is used in euthanasia and is used in some states as the second of three drugs administered during lethal injections in the United States.
Mec ...
, which have a similar pharmacodynamic profile, but fewer side effects.
Chemical structure
The various components of curare are organic compounds classified as either
isoquinoline
Isoquinoline is a heterocyclic aromatic organic compound. It is a structural isomer of quinoline. Isoquinoline and quinoline are benzopyridines, which are composed of a benzene ring fused to a pyridine ring. In a broader sense, the term isoquin ...
or
indole
Indole is an aromatic heterocyclic organic compound with the formula C8 H7 N. It has a bicyclic structure, consisting of a six-membered benzene ring fused to a five-membered pyrrole ring. Indole is widely distributed in the natural environmen ...
alkaloids.
Tubocurarine
Tubocurarine (also known as ''d''-tubocurarine or DTC) is a toxic alkaloid historically known for its use as an arrow poison. In the mid-1900s, it was used in conjunction with an anesthetic to provide skeletal muscle relaxation during surgery or ...
is one of the major active components in the South American dart poison. As an alkaloid, tubocurarine is a naturally occurring compound that consists of nitrogenous bases, although the chemical structure of alkaloids is highly variable.
![Structures_of_Acetylcholine,_Tubocurarine,_and_Toxiferine](https://upload.wikimedia.org/wikipedia/commons/6/6c/Structures_of_Acetylcholine%2C_Tubocurarine%2C_and_Toxiferine.png)
Like most alkaloids, tubocurarine and C toxiferine consist of a cyclic system with a nitrogen atom in an
amine group
In chemistry, amines (, ) are compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are formally derivatives of ammonia (), wherein one or more hydrogen atoms have been replaced by a substituent ...
. On the other hand, while acetylcholine does not contain a cyclic system, it does contain an amine group. Because of this amine group, curare alkaloids can bind readily to the active site of receptors for acetylcholine (ACh) at the neuromuscular junction, blocking nerve impulses from being sent to the skeletal muscles, effectively paralyzing the muscles of the body.
Pharmacological properties
![Neuro Muscular Junction](https://upload.wikimedia.org/wikipedia/commons/a/ac/Neuro_Muscular_Junction.png)
Curare is an example of a non-depolarizing
muscle relaxant
A muscle relaxant is a drug that affects skeletal muscle function and decreases the muscle tone. It may be used to alleviate symptoms such as muscle spasms, pain, and hyperreflexia. The term "muscle relaxant" is used to refer to two major therapeu ...
that blocks the
nicotinic acetylcholine receptor (nAChR),
one of the two types of acetylcholine (ACh)
receptors
Receptor may refer to:
*Sensory receptor, in physiology, any structure which, on receiving environmental stimuli, produces an informative nerve impulse
*Receptor (biochemistry), in biochemistry, a protein molecule that receives and responds to a n ...
, at the
neuromuscular junction
A neuromuscular junction (or myoneural junction) is a chemical synapse between a motor neuron and a muscle fiber.
It allows the motor neuron to transmit a signal to the muscle fiber, causing muscle contraction.
Muscles require innervation to ...
. The main toxin of curare,
d-tubocurarine
Tubocurarine (also known as ''d''-tubocurarine or DTC) is a toxic alkaloid historically known for its use as an arrow poison. In the mid-1900s, it was used in conjunction with an anesthetic to provide skeletal muscle relaxation during surgery o ...
, occupies the same position on the receptor as ACh with an equal or greater affinity, and elicits no response, making it a
competitive antagonist
A receptor antagonist is a type of receptor ligand or drug that blocks or dampens a biological response by binding to and blocking a receptor rather than activating it like an agonist. Antagonist drugs interfere in the natural operation of r ...
. The antidote for curare poisoning is an
acetylcholinesterase (AChE) inhibitor (anti-cholinesterase), such as
physostigmine
Physostigmine (also known as eserine from ''éséré'', the West African name for the Calabar bean) is a highly toxic parasympathomimetic alkaloid, specifically, a reversible cholinesterase inhibitor. It occurs naturally in the Calabar bean and ...
or
neostigmine
Neostigmine, sold under the brand name Bloxiverz, among others, is a medication used to treat myasthenia gravis, Ogilvie syndrome, and urinary retention without the presence of a blockage. It is also used in anaesthesia to end the effects of n ...
. By blocking ACh degradation, AChE inhibitors raise the amount of ACh in the neuromuscular junction; the accumulated ACh will then correct for the effect of the curare by activating the receptors not blocked by toxin at a higher rate.
The time of onset varies from within one minute (for tubocurarine in
intravenous administration
Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutrie ...
, penetrating a larger vein), to between 15 and 25 minutes (for
intramuscular administration
Intramuscular injection, often abbreviated IM, is the injection of a substance into a muscle. In medicine, it is one of several methods for parenteral administration of medications. Intramuscular injection may be preferred because muscles have ...
, where the substance is applied in muscle tissue).
It is harmless if taken orally
because curare compounds are too large and highly charged to pass through the lining of the digestive tract to be absorbed into the blood. For this reason, people can safely eat curare-poisoned prey, and it has no effect on its flavor.
Anesthesia
Isolated attempts to use curare during anesthesia date back to 1912 by Arthur Lawen of Leipzig, but curare came to anesthesia via
psychiatry
Psychiatry is the medical specialty devoted to the diagnosis, prevention, and treatment of mental disorders. These include various maladaptations related to mood, behaviour, cognition, and perceptions. See glossary of psychiatry.
Initial psych ...
(
electroplexy). In 1939
Abram Elting Bennett used it to modify
metrazol
Pentylenetetrazol, also known as pentylenetetrazole, leptazol, metrazol, pentetrazol (INN), pentamethylenetetrazol, Corazol, Cardiazol, Deumacard, or PTZ, is a drug formerly used as a circulatory and respiratory stimulant. High doses cause convul ...
induced
convulsive therapy.
Muscle relaxants
A muscle relaxant is a drug that affects skeletal muscle function and decreases the muscle tone. It may be used to alleviate symptoms such as muscle spasms, pain, and hyperreflexia. The term "muscle relaxant" is used to refer to two major thera ...
are used in modern
anesthesia
Anesthesia is a state of controlled, temporary loss of sensation or awareness that is induced for medical or veterinary purposes. It may include some or all of analgesia (relief from or prevention of pain), paralysis (muscle relaxation), ...
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
In organic chemistry, ethers are a class of compounds that contain an ether group—an oxygen atom connected to two alkyl or aryl groups. They have the general formula , where R and R′ represent the alkyl or aryl groups. Ethers can again be c ...
,
chloroform
Chloroform, or trichloromethane, is an organic compound with chemical formula, formula Carbon, CHydrogen, HChlorine, Cl3 and a common organic solvent. It is a colorless, strong-smelling, dense liquid produced on a large scale as a precursor to ...
or
cyclopropane
Cyclopropane is the cycloalkane with the molecular formula (CH2)3, consisting of three methylene groups (CH2) linked to each other to form a ring. The small size of the ring creates substantial ring strain in the structure. Cyclopropane itself ...
to achieve these aims. Such deep anesthesia risked killing patients who were elderly or had heart conditions.
The source of curare in the Amazon was first researched by
Richard Evans Schultes
Richard Evans Schultes (''SHULL-tees'';Jonathan Kandell ''The New York Times'', April 13, 2001, Accessed April 26, 2020. January 12, 1915 – April 10, 2001) was an American biologist. He may be considered the father of modern ethnobotany. He is ...
in 1941. Since the 1930s, it was being used in hospitals as a
muscle relaxant
A muscle relaxant is a drug that affects skeletal muscle function and decreases the muscle tone. It may be used to alleviate symptoms such as muscle spasms, pain, and hyperreflexia. The term "muscle relaxant" is used to refer to two major therapeu ...
. 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.
In the 1940s, it was used on a few occasions during surgery as it was mistakenly thought to be an analgesic or anesthetic. The patients reported feeling the full intensity of the pain though they were not able to do anything about it since they were essentially paralyzed.
On January 23, 1942,
Harold Griffith
Harold Randall Griffith (July 25, 1894 – 1985) was a Canadian anesthesiologist and a leader in the fields of anesthesiology.
History
Griffith was born in Montreal the son of Alexander Randall Griffith, a medical doctor and homeopathic pract ...
and
Enid Johnson gave a synthetic preparation of curare (Intercostrin/Intocostrin) to a patient undergoing an appendectomy (to supplement conventional anesthesia). Safer curare derivatives, such as
rocuronium
Rocuronium bromide (brand names Zemuron, Esmeron) is an aminosteroid non-depolarizing neuromuscular blocker or muscle relaxant used in modern anaesthesia to facilitate tracheal intubation by providing skeletal muscle relaxation, most commonly ...
and
pancuronium
Pancuronium (trademarked as Pavulon) is an aminosteroid muscle relaxant with various medical uses. It is used in euthanasia and is used in some states as the second of three drugs administered during lethal injections in the United States.
Mec ...
, have superseded d-tubocurarine for
anesthesia
Anesthesia is a state of controlled, temporary loss of sensation or awareness that is induced for medical or veterinary purposes. It may include some or all of analgesia (relief from or prevention of pain), paralysis (muscle relaxation), ...
during surgery. When used with
halothane
Halothane, sold under the brand name Fluothane among others, is a general anaesthetic. It can be used to induce or maintain anaesthesia. One of its benefits is that it does not increase the production of saliva, which can be particularly useful i ...
d-tubocurarine can cause a profound fall in blood pressure in some patients as both the drugs are
ganglion blockers. However, it is safer to use d-tubocurarine with
ether
In organic chemistry, ethers are a class of compounds that contain an ether group—an oxygen atom connected to two alkyl or aryl groups. They have the general formula , where R and R′ represent the alkyl or aryl groups. Ethers can again be c ...
.
In 1954, an article was published by Beecher and Todd suggesting that the use of
muscle relaxants
A muscle relaxant is a drug that affects skeletal muscle function and decreases the muscle tone. It may be used to alleviate symptoms such as muscle spasms, pain, and hyperreflexia. The term "muscle relaxant" is used to refer to two major thera ...
(drugs similar to curare) increased death due to
anesthesia
Anesthesia is a state of controlled, temporary loss of sensation or awareness that is induced for medical or veterinary purposes. It may include some or all of analgesia (relief from or prevention of pain), paralysis (muscle relaxation), ...
nearly sixfold.
[, reprinted in ] This was refuted in 1956.
Modern anesthetists have at their disposal a variety of
muscle relaxants
A muscle relaxant is a drug that affects skeletal muscle function and decreases the muscle tone. It may be used to alleviate symptoms such as muscle spasms, pain, and hyperreflexia. The term "muscle relaxant" is used to refer to two major thera ...
for use in anesthesia. The ability to produce muscle relaxation irrespective of sedation has permitted anesthetists to adjust the two effects independently and on the fly to ensure that their patients are safely unconscious and sufficiently relaxed to permit surgery. The use of
neuromuscular blocking drugs
Neuromuscular-blocking drugs block neuromuscular transmission at the neuromuscular junction, causing paralysis of the affected skeletal muscles. This is accomplished via their action on the post-synaptic acetylcholine (Nm) receptors.
In c ...
carries with it the risk of
anesthesia awareness
Awareness under anesthesia, also referred to as intraoperative awareness or accidental awareness during general anesthesia (AAGA), is a rare complication of general anesthesia where patients regain varying levels of consciousness during their sur ...
.
Plant sources
There are dozens of plants from which isoquinoline and indole alkaloids with curarizing effects can be isolated, and which were utilized by indigenous tribes of Central and South America for the production of arrow poisons. Among them are:
In family
Menispermaceae
Menispermaceae (botanical Latin: 'moonseed family' from Greek ''mene'' 'crescent moon' and ''sperma'' 'seed') is a family of flowering plants. The alkaloid tubocurarine, a neuromuscular blocker and the active ingredient in the 'tube curare' form ...
:
* Genus ''
Chondrodendron'' notably ''
C. tomentosum''
* Genus ''
Curarea
''Curarea'' is a genus of flowering plants in the family Menispermaceae, found in tropical parts of Central and South America. They are dioecious lianas, with at least some species producing toxic compounds such as curare
Curare ( /kʊˈ ...
'', species ''
C. toxicofera'' and ''
C. tecunarum''
* Genus ''
Sciadotenia toxifera''
* Genus ''
Telitoxicum''
* Genus ''
Abuta
''Abuta'' is a genus in the flowering plant family Menispermaceae, of about 32 species, native to tropical Central and South America.
Description
It consists in dioecious climbers or rarely erect trees or shrubs ('' Abuta concolor'') with ...
''
* Genus ''
Caryomene''
* Genus ''
Anomospermum''
* Genus ''
Orthomene''
* Genus ''
Cissampelos, section L. (Cocculeae) of genus
Other families:
* several species of the genus ''
Strychnos
''Strychnos'' is a genus of flowering plants, belonging to the family Loganiaceae (sometimes Strychnaceae). The genus includes about 100 accepted species of trees and lianas, and more than 200 that are as yet unresolved. The genus is widely dis ...
'' of family
Loganiaceae
The Loganiaceae are a family of flowering plants classified in order Gentianales. The family includes up to 13 genera, distributed around the world's tropics. There are not any great morphological characteristics to distinguish these taxa from ot ...
including ''
S. toxifera'', ''
S. guianensis'', ''
S. castelnaei'', ''
S. usambarensis''
* a plant in the subfamily
Aroideae
Aroideae is a subfamily of flowering plants in the family Araceae. It is the largest subfamily in Araceae and consists of about 72 different genera, and 2,300 species. Many Aroideae have spiny pollen grains without a sporopollenin outer exine la ...
of family
Araceae
The Araceae are a family of monocotyledonous flowering plants in which flowers are borne on a type of inflorescence called a spadix. The spadix is usually accompanied by, and sometimes partially enclosed in, a spathe (or leaf-like bract). Also ...
called
taja
* at least three members of the genus ''
Artanthe'' of family
Piperaceae
The Piperaceae (), also known as the pepper family, are a large family of flowering plants. The group contains roughly 3,600 currently accepted species in 5 genera. The vast majority of species can be found within the two main genera: ''Piper'' ( ...
* ''
Paullinia cururu
''Paullinia'' is a genus of flowering shrubs, small trees and lianas in the soapberry family, Sapindaceae, native to tropical South America, Central America and the Caribbean.
The genus is named after the German medical botanist Christian Fr ...
'' in the family
Sapindaceae
The Sapindaceae are a family of flowering plants in the order Sapindales known as the soapberry family. It contains 138 genera and 1858 accepted species. Examples include horse chestnut, maples, ackee and lychee.
The Sapindaceae occur in tempera ...
Some plants in the family
Aristolochiaceae
The Aristolochiaceae () are a family, the birthwort family, of flowering plants with seven genera and about 400 known species belonging to the order Piperales. The type genus is ''Aristolochia'' L.
Description
They are mostly perennial, he ...
have also been reported as sources.
Alkaloids with curare-like activity are present in plants of the
fabaceous genus ''
Erythrina''.
Toxicity
The toxicity of curare alkaloids in humans has not been established. Administration must be
parenteral
A route of administration in pharmacology and toxicology is the way by which a drug, fluid, poison, or other substance is taken into the body.
Routes of administration are generally classified by the location at which the substance is applied. ...
ly, as gastro-intestinal absorption is ineffective.
LD50 (mg/kg)
human: 0.735 est. (form and method of administration not indicated)
mouse: pot: 0.8–25; tubo: 5-10; calabash: 2–15.
Preparation
In 1807,
Alexander von Humboldt
Friedrich Wilhelm Heinrich Alexander von Humboldt (14 September 17696 May 1859) was a German polymath, geographer, naturalist, explorer, and proponent of Romantic philosophy and science. He was the younger brother of the Prussian minister, p ...
provided the first eye-witness account of curare preparation.
A mixture of young bark scrapings of the Strychnos plant, other cleaned plant parts, and occasionally snake venom is boiled in water for two days. This liquid is then strained and evaporated to create a dark, heavy, viscid paste that would be tested for its potency later.
This curare paste was described to be very bitter in taste.
In 1938,
Richard Gill and his expedition collected samples of processed curare and described its method of traditional preparation; one of the plant species used at that time was
Chondrodendron tomentosum
''Chondrodendron tomentosum'' is one of six accepted species in the small genus Chondrodendron, belonging to the Moonseed family Menispermaceae. It is a large tropical liana native to Central and South America.It contains highly toxic alkaloids ...
.
Adjuvants
Various irritating herbs, stinging insects, poisonous worms, and various parts of amphibians and reptiles are added to the preparation. Some of these accelerate the onset of action or increase the toxicity; others prevent the wound from healing or blood from coagulating.
Diagnosis and management of curare poisoning
Curare poisoning can be indicated by typical signs of
neuromuscular-blocking drug
Neuromuscular-blocking drugs block neuromuscular transmission at the neuromuscular junction, causing paralysis of the affected skeletal muscles. This is accomplished via their action on the post-synaptic acetylcholine (Nm) receptors.
In cl ...
s such as paralysis including respiration but not directly affecting the heart.
Curare poisoning can be managed by
artificial respiration such as
mouth-to-mouth resuscitation
Mouth-to-mouth resuscitation, a form of artificial ventilation, is the act of assisting or stimulating respiration in which a rescuer presses their mouth against that of the victim and blows air into the person's lungs. Artificial respiration ta ...
. In a study of 29 army volunteers that were paralyzed with curare, artificial respiration managed to keep an
oxygen saturation
Oxygen saturation (symbol SO2) is a relative measure of the concentration of oxygen that is dissolved or carried in a given medium as a proportion of the maximal concentration that can be dissolved in that medium at the given temperature. It ca ...
of always above 85%, a level at which there is no evidence of
altered state of consciousness
An altered state of consciousness (ASC), also called altered state of mind or mind alteration, is any condition which is significantly different from a normal waking state. By 1892, the expression was in use in relation to hypnosis, though there ...
. Yet, curare poisoning mimics the
total locked-in syndrome in that there is paralysis of every voluntarily controlled muscle in the body (including the eyes), making it practically impossible for the victim to confirm consciousness while paralyzed.
Spontaneous breathing is resumed after the end of the
duration of action
Pharmacodynamics (PD) is the study of the biochemical and physiologic effects of drugs (especially pharmaceutical drugs). The effects can include those manifested within animals (including humans), microorganisms, or combinations of organisms (for ...
of curare, which is generally between 30 minutes
[For therapeutic dose of tubocurarine by shorter limit as given in: ] and 8 hours, depending on the variant of the toxin and dosage.
Cardiac muscle
Cardiac muscle (also called heart muscle, myocardium, cardiomyocytes and cardiac myocytes) is one of three types of vertebrate muscle tissues, with the other two being skeletal muscle and smooth muscle. It is an involuntary, striated muscle th ...
is not directly affected by curare, but if more than four to six minutes has passed since respiratory cessation the cardiac muscle may stop functioning by oxygen-deprivation, making
cardiopulmonary resuscitation
Cardiopulmonary resuscitation (CPR) is an emergency procedure consisting of chest compressions often combined with artificial ventilation in an effort to manually preserve intact brain function until further measures are taken to restore spont ...
including
chest compressions necessary.
Chemical antidote
Since tubocurarine and the other components of curare bind reversibly to the ACh receptors, treatment for curare poisoning involves adding an acetylcholinesterase (AChE) inhibitor, which will stop the destruction of acetylcholine so that it can compete with curare. This can be done by administration of
acetylcholinesterase (AChE) inhibitors such as
pyridostigmine
Pyridostigmine is a medication used to treat myasthenia gravis and underactive bladder. It is also used together with atropine to end the effects of neuromuscular blocking medication of the non-depolarizing type. It is typically given by mouth ...
,
neostigmine
Neostigmine, sold under the brand name Bloxiverz, among others, is a medication used to treat myasthenia gravis, Ogilvie syndrome, and urinary retention without the presence of a blockage. It is also used in anaesthesia to end the effects of n ...
,
physostigmine
Physostigmine (also known as eserine from ''éséré'', the West African name for the Calabar bean) is a highly toxic parasympathomimetic alkaloid, specifically, a reversible cholinesterase inhibitor. It occurs naturally in the Calabar bean and ...
, and
edrophonium
Edrophonium is a readily reversible acetylcholinesterase inhibitor. It prevents breakdown of the neurotransmitter acetylcholine and acts by competitively inhibiting the enzyme acetylcholinesterase, mainly at the neuromuscular junction. It is so ...
. Acetylcholinesterase is an enzyme used to break down the acetylcholine (ACh) neurotransmitter left over in motor neuron
synapse
In the nervous system, a synapse is a structure that permits a neuron (or nerve cell) to pass an electrical or chemical signal to another neuron or to the target effector cell.
Synapses are essential to the transmission of nervous impulses from ...
s. The aforementioned inhibitors, termed "anticurare" drugs, reversibly bind to the enzyme's active site, prohibiting its ability to bind to its original target, ACh. By blocking ACh degradation, AChE inhibitors can effectively raise the amount of ACh present in the neuromuscular junction. The accumulated ACh will then correct for the effect of the curare by activating the receptors not blocked by toxin at a higher rate, restoring activity to the motor neurons and bodily movement.
Gallery
File:Abuta selloana.jpg, ''Abuta selloana''. Certain species in the menispermaceous genus ''Abuta
''Abuta'' is a genus in the flowering plant family Menispermaceae, of about 32 species, native to tropical Central and South America.
Description
It consists in dioecious climbers or rarely erect trees or shrubs ('' Abuta concolor'') with ...
''—particularly the Colombian species '' A. imene''—have sometimes been used in the preparation of curare.
File:Anomospermum schomburgkii.jpg, ''Anomospermum schomburgkii''. Certain species in the genus '' Anomospermum'' have been used in the preparation of some forms of curare.
File:Cissampelos pareira Blanco2.432 edited.jpg, ''Cissampelos pareira''. Certain species in the genus '' Cissampelos'' have been employed in the preparation of curare.
See also
*
Arrow poison
Arrow poisons are used to poison arrow heads or darts for the purposes of hunting and warfare. They have been used by indigenous peoples worldwide and are still in use in areas of South America, Africa and Asia. Notable examples are the poisons se ...
, what curare was originally used for
*
Poison dart frog
Poison dart frog (also known as dart-poison frog, poison frog or formerly known as poison arrow frog) is the common name of a group of frogs in the family Dendrobatidae which are native to tropical Central and South America. These species are ...
, another source of arrow poison
*
Strychnine
Strychnine (, , US chiefly ) is a highly toxic, colorless, bitter, crystalline alkaloid used as a pesticide, particularly for killing small vertebrates such as birds and rodents. Strychnine, when inhaled, swallowed, or absorbed through the eye ...
, a related alkaloid poison that occurs in some of the same plants as curare
References
Further reading
*
* – contains papers and records pertaining to Griffith's introduction of curare into
anesthesiology
Anesthesiology, anaesthesiology, or anaesthesia is the medical specialty concerned with the total perioperative care of patients before, during and after surgery. It encompasses anesthesia, intensive care medicine, critical emergency medicine, ...
*
*
*
*
*
{{Authority control
Muscle relaxants
Neuromuscular blockers
Neurotoxins
Nicotinic antagonists
Plant toxins
Poisonous plants