Tubocurarine

Tubocurarine

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Tubocurarine is a neuromuscular-blocking drug
Neuromuscular-blocking drugs
Neuromuscular-blocking drugs block neuromuscular transmission at the neuromuscular junction, causing paralysis of the affected skeletal muscles. This is accomplished either by acting presynaptically via the inhibition of acetylcholine synthesis or release or by acting postsynaptically at the...

 or skeletal muscle relaxant
Muscle relaxant
A muscle relaxant is a drug which 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 therapeutic groups: neuromuscular blockers and spasmolytics...

 in the category of non-depolarizing neuromuscular-blocking drugs
Neuromuscular-blocking drugs
Neuromuscular-blocking drugs block neuromuscular transmission at the neuromuscular junction, causing paralysis of the affected skeletal muscles. This is accomplished either by acting presynaptically via the inhibition of acetylcholine synthesis or release or by acting postsynaptically at the...

, used adjunctively in anesthesia
Anesthesia
Anesthesia, or anaesthesia , traditionally meant the condition of having sensation blocked or temporarily taken away...

 to provide skeletal muscle
Skeletal muscle
Skeletal muscle is a form of striated muscle tissue existing under control of the somatic nervous system- i.e. it is voluntarily controlled. It is one of three major muscle types, the others being cardiac and smooth muscle...

 relaxation during surgery
Surgery
Surgery is an ancient medical specialty that uses operative manual and instrumental techniques on a patient to investigate and/or treat a pathological condition such as disease or injury, or to help improve bodily function or appearance.An act of performing surgery may be called a surgical...

 or mechanical ventilation
Mechanical ventilation
In medicine, mechanical ventilation is a method to mechanically assist or replace spontaneous breathing. This may involve a machine called a ventilator or the breathing may be assisted by a physician, respiratory therapist or other suitable person compressing a bag or set of bellows...

. Unlike a number of other related skeletal muscle relaxants, it is now rarely considered clinically to facilitate endotracheal intubation
Intubation
Tracheal intubation, usually simply referred to as intubation, is the placement of a flexible plastic or rubber tube into the trachea to maintain an open airway or to serve as a conduit through which to administer certain drugs...

.

Tubocurarine is classified as a long-duration, non-depolarizing neuromuscular blocking agent that is a competitive antagonist
Receptor antagonist
A receptor antagonist is a type of receptor ligand or drug that does not provoke a biological response itself upon binding to a receptor, but blocks or dampens agonist-mediated responses...

 of nicotinic neuromuscular acetylcholine receptors. It is a type of curare
Curare
Curare is a common name for various arrow poisons originating from South America. The three main types of curare are:* tubocurare...

.

Currently, tubocurarine is rarely used as an adjunct for clinical anesthesia because safer alternatives such as cisatracurium
Cisatracurium
Cisatracurium is a neuromuscular-blocking drug or skeletal muscle relaxant in the category of non-depolarizing neuromuscular-blocking drugs, used adjunctively in anesthesia to facilitate endotracheal intubation and to provide skeletal muscle relaxation during surgery or mechanical ventilation...

 and rocuronium
Rocuronium
Rocuronium is an aminosteroid non-depolarizing neuromuscular blocker or muscle relaxant used in modern anaesthesia, to facilitate endotracheal intubation and to provide skeletal muscle relaxation during surgery or mechanical ventilation.Introduced in 1994, rocuronium has...

 are available.

History


Tubocurare is a naturally occurring mono-quaternary alkaloid
Alkaloid
Alkaloids are a group of naturally occurring chemical compounds that contain mostly basic nitrogen atoms. This group also includes some related compounds with neutral and even weakly acidic properties. Also some synthetic compounds of similar structure are attributed to alkaloids...

 obtained from the bark of the South American plant Chondrodendron tomentosum
Chondrodendron tomentosum
Chondrodendron tomentosum is a species in the Menispermaceae family . It is a large tropical liana native to Central and South America. It is a source of tubocurare arrow poison....

, a climbing vine known to the European world since the Spanish conquest of South America. Curare had been used as a source of arrow poison by South American Natives to hunt animals, and they were able to eat the animals' contaminated flesh subsequently without any untoward effects because tubocurarine cannot easily cross mucous membranes. Tubocurarine is thus effective only if given parenteral
Parenteral
Parenteral is a route of administration that involves piercing the skin or mucous membrane. Parenteral nutrition refers to providing nutrition via the veins.-Etymology:...

ly, as demonstrated by Bernard
Claude Bernard
Claude Bernard was a French physiologist. He was the first to define the term milieu intérieur . Historian of science I. Bernard Cohen of Harvard University called Bernard "one of the greatest of all men of science"...

, who also showed that the site of its action was at the neuromuscular junction. Virchow and Munter confirmed that the paralyzing action was limited to voluntary and not involuntary muscles. Thus, conscious individual administered with this agent will be unable to move any voluntary muscles, including the diaphragm: a large enough dose will therefore result in death from respiratory failure unless artificial ventilation is initiated.

The word curare comes from the South American Indian name for the arrow poison: "ourare". Presumably the initial syllable was pronounced with a heavy glottal stroke
Glottal stop
The glottal stop, or more fully, the voiceless glottal plosive, is a type of consonantal sound used in many spoken languages. In English, the feature is represented, for example, by the hyphen in uh-oh! and by the apostrophe or [[ʻokina]] in Hawaii among those using a preservative pronunciation of...

. Tubocurarine is so called because the plant samples containing the curare were stored and shipped to Europe in tubes. Likewise, curare stored in calabash containers was called Calabash curare. A more detailed historical account of tubocurare can be followed elsewhere.http://science.jrank.org/pages/1908/Curare.html

Structurally, tubocurarine is a benzylisoquinoline
Benzylisoquinoline
1-Benzylisoquinoline is a chemical compound, and the structural backbone of many alkaloids with a wide variety of structures, including papaverine, noscapine, codeine, morphine, apomorphine, berberine, protopine and tubocurarine.-Biosynthesis:...

 derivative. For many years its structure, when first elucidated in 1948, was wrongly thought to be bis-quaternary: in other words, it was thought to be an N,N-dimethylated alkaloid. It was not until 22 years later, in 1970, that the correct structure was finally established, showing one of the two nitrogens to be tertiary, in other words it is actually a mono-N-methylated alkaloid.


Griffith and Johnson are credited with pioneering the formal clinical introduction of tubocurarine as an adjunct to anesthetic practice on 23 January, 1942, at the Montreal Homeopathic Hospital. In this sense, tubocurarine is the prototypical adjunctive neuromuscular blocking agent. However, others before Griffith and Johnson had attempted use of tubocurare in several situations: some under controlled study conditions while others not quite controlled and remained unpublished. Regardless, all in all some ~30,000 patients had been given tubocurare by 1941, although it was Griffith and Johnson's 1942 publication that provided the impetus to the standard use of neuromuscular blocking agents in clinical anesthestic practice - a revolution that rapidly metamorphosized into the standard practice of "balanced" anesthesia: the triad of barbiturate hypnosis, light inhalational anesthesia and muscle relaxation. The technique as described by Gray and Halton was widely known as the "Liverpool technique", and became the standard anesthetic technique in England in the 1950s and 1960s for patients of all ages and physical status. Present clinical anesthetic practice still employs the central principle of balanced anesthesia though with some differences to accommodate subsequent techonological advances and introductions of new and better gaseous anesthetic, hypnotic and neuromuscular blocking agents, tracheal intubation, as well as monitoring techniques that were non-existent in the day of Gray and Halton: pulse oximetry, capnography, peripheral nerve stimulation, non-invasive blood pressure monitoring etc.

Biosynthesis


Tubocurarine biosynthesis involves a radical coupling of two enantiomeric tetrahydrobenzylisoquinolines, more specifically, the two enantiomers of N-methyl-coclaurine. (R) and (S)-N-methyl-coclaurine come from a Mannich-like reaction between dopamine and 4-hydroxyphenyl-acetaldehyde, facilitated by norcoclaurine synthase (NCS). Both dopamine and 4-hydroxyphenylacetyladehyde originate from L-tyrosine. The biosynthetic pathway is described in more detail in the figures. Methylation of the amine and hydroxyl substituents are facilitated by S-adenosyl methionine (SAM).

Clinical Pharmacology and Pharmacokinetics


At normal doses, tubocurarine has a slow onset and a slow recovery. It also causes histamine release that is now a recognized hallmark of the tetrahydroisioquinolinium class of neuromuscular blocking agents. The severity of histamine release in some instances following tubocurarine administration is such that it is contraindicated in asthmatics and patients with allergies. However, the main disadvantage in the use of tubocurarine is its significant ganglion blocking effect, that manifests as hypotension, in many patients; this constitutes a relative contraindication to its use in patients with myocardial ischaemia.

Because of the shortcomings of tubocurare, much research effort was undertaken soon after its clinical introduction to find a suitable replacement. The efforts unleashed a multitude of compounds borne from structure-activity relations developed from the tubocurare molecule. Some key compounds that have seen clinical use are identified in the muscle relaxants template box below. Of the many tried as replacements, only a few enjoyed as much popularity as tubocurarine: pancuronium
Pancuronium
Pancuronium is a muscle relaxant with various purposes. It is the second of three drugs administered during most lethal injections in the United States.- Mode of action :...

, vecuronium
Vecuronium
Vecuronium is a muscle relaxant in the category of non-depolarizing blocking agents. Vecuronium bromide is indicated as an adjunct to general anesthesia, to facilitate endotracheal intubation and to provide skeletal muscle relaxation during surgery or mechanical ventilation...

, rocuronium
Rocuronium
Rocuronium is an aminosteroid non-depolarizing neuromuscular blocker or muscle relaxant used in modern anaesthesia, to facilitate endotracheal intubation and to provide skeletal muscle relaxation during surgery or mechanical ventilation.Introduced in 1994, rocuronium has...

, atracurium
Atracurium
Atracurium besylate is a neuromuscular-blocking drug or skeletal muscle relaxant in the category of non-depolarizing neuromuscular-blocking drugs, used adjunctively in anesthesia to facilitate endotracheal intubation and to provide skeletal muscle relaxation during surgery or mechanical...

, and cisatracurium
Cisatracurium
Cisatracurium is a neuromuscular-blocking drug or skeletal muscle relaxant in the category of non-depolarizing neuromuscular-blocking drugs, used adjunctively in anesthesia to facilitate endotracheal intubation and to provide skeletal muscle relaxation during surgery or mechanical ventilation...

. Succinylcholine is a widely used paralytic drug which acts by activating, instead of blocking, the Ach receptor.