Curare

Curare is a generic term for a variety of plant-derived alkaloid arrow poisons used by indigenous peoples in Central and South America. Curare is a paralysing agent that is only activated by direct wound contamination by a poison dart or arrow or by injection. It is used for hunting and therapeutic purposes. These poisons work by inhibiting the nicotinic acetylcholine receptor (nAChR), a subtype of acetylcholine receptor located at the neuromuscular junction, competitively and reversibly. This causes skeletal muscle weakness and eventually death by asphyxiation due to diaphragm paralysis when given in large enough doses. Curare is made by boiling the bark of one of the hundreds of plant alkaloid sources, resulting in a thick, hard paste that can be applied to the heads of arrows and darts. Curare has long been used as a remedy for tetanus and strychnine poisoning, as well as a paralysing agent during surgical procedures.

Structure of Curare

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Curare is made up of organic compounds that are known as isoquinoline or indole alkaloids. Tubocurarine is a main active ingredient in the South American dart poison tubocurarine. Tubocurarine is an alkaloid, a naturally occurring compound made up of nitrogenous bases, though the chemical composition of alkaloids varies greatly.

Curare binds to Acetylcholine receptors because the three compounds have similar functional groups.

Tubocurarine and C toxiferine, like most alkaloids, are made up of a cyclic framework with a nitrogen atom in an amine group. Acetylcholine, on the other hand, does not have a cyclic system but does have an amine group.

Properties of Curare

• Curare is a non-depolarizing muscle relaxant that works at the neuromuscular junction by blocking the nicotinic acetylcholine receptor (nAChR), one of two forms of acetylcholine (ACh) receptors. 

• Curare's key toxin, d-tubocurarine, binds to the same receptor as ACh with equal or greater affinity and produces no response, rendering it a competitive antagonist. 

• Curare compounds are too large and highly charged to move through the lining of the digestive tract and be absorbed into the bloodstream if taken orally. As a result, people can easily consume curare-poisoned prey, and the taste is unaffected.

• The onset time of curare ranges between one minute (for tubocurarine in intravenous administration, entering a larger vein) and 15 to 25 minutes (for tubocurarine in intravenous administration, penetrating a smaller vein) (for intramuscular administration, where the substance is applied in muscle tissue).

Role of Curare as an Anesthesia

Curare was first used in anaesthesia in 1912 by Arthur Lawen of Leipzig, but it was a psychiatry that brought it to anaesthesia (electroplexy). It was first used in 1939 by Abram Elting Bennett to alter metrazol-induced convulsive therapy. Muscle relaxants are used in modern anaesthesia for a variety of purposes, including improving working conditions and making trachea intubation easier. To meet these goals before muscle relaxants, anesthesiologists had to use higher doses of anaesthetic agents like ether, chloroform, or cyclopropane. Patients who were aged or had heart problems were at risk of dying as a result of such deep anaesthesia.

Richard Evans Schultes was the first to investigate the origins of curare in the Amazon in 1941. It has been used as a muscle relaxant in hospitals since the 1930s. He discovered that different types of curare needed up to 15 ingredients, and over time, he assisted in the identification of more than 70 species that developed the drug.

It was used during surgery on a few occasions in the 1940s because it was wrongly believed to be an analgesic or anaesthetic. The patients said they felt the full extent of the pain but couldn't do anything about it because they were practically paralysed.

Harold Griffith and Enid Johnson gave synthetic curare preparation (Intercostrin/Intocostrin) to a patient undergoing an appendectomy on January 23, 1942. (to supplement conventional anaesthesia). For anaesthesia during surgery, safer curare derivatives such as rocuronium and pancuronium have supplanted d-tubocurarine. Since both d-tubocurarine and halothane are ganglion blockers, they can cause a significant drop in blood pressure in certain patients when used together. When using d-tubocurarine with ether, however, it is better.

Some scientists have claimed that using muscle relaxants (drugs similar to curare) increased death from anaesthesia by nearly sixfold. In 1956, this was debunked.

Anaesthetists today have access to a wide range of muscle relaxants for use in anaesthesia. Since anaesthetists can achieve muscle relaxation without sedation, they can change the two effects individually and on the fly to ensure that their patients are comfortably unconscious and comfortable enough to undergo surgery. Anaesthesia awareness is a concern associated with the use of neuromuscular blocking medications.

Lethal Dose 

The lethal dose (LD) is a measure of a substance's or form of radiation's lethal toxicity in toxicology. Since resistance varies from person to person, the "lethal dose" refers to the dose at which a certain percentage of subjects will die (usually expressed as a dose per kilogramme of subject body weight). The lethal concentration is a calculation of the lethal dose of gases or particulates. The LD may be based on the definition of a "standard person," a hypothetical person with perfectly "natural" characteristics, and therefore may not extend to all sub-populations. In humans, the toxicity of curare alkaloids has yet to be determined. Since gastrointestinal absorption is inefficient. The administration of curare must be done intravenously. When administering skeletal muscle relaxants, especially curare or other analogous agents targeted to the neuromuscular junction, gender-specific differences can be an important factor, according to some studies.

Preparation of Curare

Alexander von Humboldt published the first first-hand account of curare preparation in 1807. For two days, a mixture of young Strychnos plant bark scrapings, other washed plant bits, and sometimes snake venom is boiled in water. This liquid is then strained and evaporated, yielding a dark, thick, viscid paste that will be checked later for potency. The flavour of this curare paste has been characterised as bitter.

Richard Gill and his expedition collected samples of processed curare and identified its traditional preparation method in 1938; Chondrodendron tomentosum was one of the plant species used at the time.

The preparation includes a variety of irritating plants, stinging insects, poisonous worms, and assorted amphibian and reptile pieces. Some of these hasten the onset of action or increase toxicity, while others obstruct wound healing or blood coagulation.

Diagnosis of Curare

Typical symptoms of neuromuscular-blocking medications, such as paralysis, including breathing, but not directly affecting the heart, may indicate Curare poisoning.

Artificial respiration, such as mouth-to-mouth resuscitation, can be used to treat Curare poisoning. Artificial respiration managed to keep an oxygen saturation of always above 85 percent in a study of 29 army volunteers who were paralysed with curare, a stage at which there is no evidence of the altered state of consciousness. Curare poisoning, on the other hand, is similar to complete lock-in syndrome in that it causes paralysis of all voluntarily operated muscles in the body (including the eyes), making it almost impossible for the victim to confirm consciousness when paralysed.

After the time of action of curare has passed, which varies between 30 minutes and 8 hours depending on the toxin variant and dose, spontaneous breathing is resumed. Curare does not affect cardiac muscle, but if breathing has stopped for more than four to six minutes, the cardiac muscle can stop working due to oxygen deprivation, necessitating cardiopulmonary resuscitation with chest compressions.

Role of Anti Curare Compound

Since tubocurarine and the other components of curare bind reversibly to ACh receptors, treating curare poisoning entails using an acetylcholinesterase (AChE) inhibitor to prevent acetylcholine from being destroyed, allowing it to compete with curare. Acetylcholinesterase (AChE) inhibitors such as pyridostigmine, neostigmine, physostigmine, and edrophonium can be used to do this. 

Acetylcholinesterase is an enzyme that breaks down the neurotransmitter acetylcholine (ACh) that is leftover in motor neuron synapses. The aforementioned inhibitors, known as "anticurare" drugs, bind to the enzyme's active site in a reversible manner, preventing it from binding to its original target, ACh. AChE inhibitors effectively increase the amount of ACh present in the neuromuscular junction by blocking ACh degradation. The accumulated ACh would then compensate for the curare's impact by stimulating the receptors not blocked by the toxin at a faster pace, restoring motor neuron activity and movement.

An acetylcholinesterase (AChE) inhibitor (anti-cholinesterase), such as physostigmine or neostigmine, is used as an antidote for curare poisoning. AChE inhibitors increase the amount of ACh in the neuromuscular junction by preventing ACh degradation; the accumulated ACh can then compensate for the impact of the curare by activating the receptors not inhibited by the toxin at a faster rate

Classification of Alkaloid

In 1895, pharmacologist Rudolf Boehm attempted to identify alkaloid poisons based on the containers in which they were prepared. During his research, he concluded that curare could be divided into three categories. It quickly became obsolete, no matter how useful it appeared to be. A plant collector named Richard Gill discovered that indigenous peoples started to use a range of containers for their curare preparations, invalidating Boehm's classification system. The classification of curare is shown below:

• Curare in tube or bamboo: This poison, which is mostly made up of the toxin D-tubocurarine, is packed into hollow bamboo tubes derived from Chondrodendron and other Menispermaceae genera. Tube curare is considered to be the most toxic, based on its LD50 values.

• Pot curare (the active ingredient), pot curare (weak toxicity), and pot curare (non-toxic) are alkaloid components found in both Menispermaceae and Loganiaceae/Strychnaceae. Originally, this subtype was found in terra cotta pots.

• Curare calabash or gourd: This toxin, which is mostly made up of C toxiferine I, was originally packed into hollow gourds from Loganiaceae/Strychnaceae.

Because of the difficulty and variety in the composition of the mixtures of alkaloids involved, the findings of early [pre-1900] work were extremely inaccurate. The alkaloids in question were impure and non-crystalline. Almost all curare preparations were and are complex mixtures, and many of the physiological effects attributed to early curarizing preparations were almost certainly due to impurities, especially other alkaloids. 

Division of Curare Preparation

Curare preparations are now divided into two categories: 

Those derived from Chondrodendron or other Menispermaceae members.

Those derived from Strychnos, a genus of the Loganiaceae [ now Strychnaceae ] family.

Some preparations can contain alkaloids from both sources, and the majority contain additional ingredients.

Uses of Curare

Many South American indigenous peoples used curare as a paralysing toxin. Curare was mostly used for hunting because it was too costly to be used in warfare. The prey was shot with curare-dipped arrows or blowgun darts, resulting in asphyxiation due to the victim's respiratory muscles' failure to contract. The Island Caribs, an indigenous group of the Caribbean's Lesser Antilles, used the poison on the tips of their arrows in particular. Furthermore, the Yagua people of Colombia and northeastern Peru used these toxins in their blowpipes to kill prey at a distance of 30 to 40 paces.

Certain tribes will create monopolies on curare production due to its popularity among indigenous peoples as a means of paralysing prey. Curare became a symbol of wealth among indigenous peoples as a result.

Sir Walter Raleigh mentioned the arrow poison in his book Discovery of the Large, Rich, and Beautiful Empire of Guiana (published in 1596 and based on his travels in Trinidad and Guyana), though the poison he described may not have been curare. In 1780, Abbe Felix Fontana discovered that it operated on the voluntary muscles, not the nerves or the heart. Alexander von Humboldt published the first western account of how Orinoco River natives prepared the toxin from plants in 1832.

Sir Benjamin Collins Brody experimented with curare from 1811 to 1812. (woorara). He was the first to demonstrate that curare does not kill the animal and that if the animal's respiration is artificially preserved, the recovery is complete. In 1825, Charles Waterton described a classic experiment in which he artificially respired a curarized female donkey through a tracheostomy with a bellows.

Curare is also attributed to Waterton for introducing it to Europe. The vine was described as a member of the genus Strychnos by botanist Robert Hermann Schomburgk, who gave it the now-accepted name Strychnos toxifera curare.

Medicinal Use of Curare

Curare treatment (wourali) was discovered to be useful in the treatment of tetanus and strychnine poisoning by George Harley (1829–1896) in 1850. Claude Bernard (1813–1878) published the findings of his studies in 1857, demonstrating that curare's mechanism of action was caused by interference in the conduction of nerve impulses from the motor nerve to the skeletal muscle, which occurred at the neuromuscular junction. From 1887, the Burroughs Wellcome catalogue listed tablets of curare at 12 grain (price 8 shillings) for use in preparing a solution for hypodermic injection under the 'Tabloids' brand name. Henry Hallett Dale (1875–1968) identified acetylcholine's physiological behaviour in 1914. He discovered that acetylcholine is responsible for neuromuscular transmission, which can be blocked by curare, after 25 years of research.

D-tubocurarine is the most well-known and historically significant toxin (due to its medical applications). Harold King of London, working in Sir Henry Dale's laboratory, extracted it from the crude drug – a museum sample of curare – in 1935.

Its chemical structure was also developed by King. Curare as a potential paralysing agent for patients during surgical procedures was extensively researched by Pascual Scannone, a Venezuelan anesthesiologist who trained and specialised in New York City. When he successfully performed tracheal intubation in a patient to whom he administered curare for muscle paralysis at the El Algodonal Hospital in Caracas, Venezuela, in 1942, he became the first individual in all of Latin America to use curare during a medical procedure.

Did You Know?

• Anti curare compounds like hexamethonium show effect at the mammalian neuromuscular junction.

• Curare grows as a large liana, or vine, found in the canopy of the Ecuadorian rainforest. Therefore, it is known as curare liana.