World Library  
Flag as Inappropriate
Email this Article

Tubocurarine

Article Id: WHEBN0026837787
Reproduction Date:

Title: Tubocurarine  
Author: World Heritage Encyclopedia
Language: English
Subject: Alkaloid, Acetylcholine, Anticholinergic, Anesthetic, ATC code M03, Basic Instinct 2, Glossitis, Neuromuscular-blocking drug, Benzylisoquinoline
Collection:
Publisher: World Heritage Encyclopedia
Publication
Date:
 

Tubocurarine

Tubocurarine (also known as D-tubocurarine or DTC) is a skeletal muscle relaxant in the category of non-depolarizing neuromuscular-blocking drugs, used adjunctively in anesthesia to provide skeletal muscle relaxation during surgery or mechanical ventilation. Unlike a number of other related skeletal muscle relaxants, it is now rarely considered clinically to facilitate endotracheal intubation.

Tubocurarine is classified as a long-duration,[1] antagonist for Nicotinic acetylcholine receptor.[2] It is the active agent of curare.

Currently, tubocurarine is rarely used as an adjunct for clinical anesthesia because safer alternatives, such as cisatracurium and rocuronium, are available.

History

Tubocurare is a naturally occurring mono-quaternary alkaloid obtained from the bark of the South American plant Chondrodendron tomentosum, 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 parenterally, as demonstrated by Bernard, who also showed the site of its action was at the neuromuscular junction.[3] Virchow and Munter confirmed the paralyzing action was limited to voluntary and not involuntary muscles.[4] Thus, a conscious individual administered 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. 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.

Structurally, tubocurarine is a benzylisoquinoline derivative. For many years, its structure, when first elucidated in 1948,[5] was wrongly thought to be bis-quaternary: in other words, it was thought to be an N,N-dimethylated alkaloid. In 1970, the correct structure was finally established,[6] showing one of the two nitrogens to be tertiary, 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.[7] 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:[8][9][10] some under controlled study conditions[11][12] while others not quite controlled and remained unpublished.[13] Regardless, all in all some ~30,000 patients had been given tubocurare by 1941, although it was Griffith and Johnson's 1942 publication[7] 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.[14] The technique as described by Gray and Halton was widely known as the "Liverpool technique",[14] 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 technological advances and introductions of new and better gaseous anesthetic, hypnotic and neuromuscular blocking agents, and tracheal intubation, as well as monitoring techniques that were nonexistent in the day of Gray and Halton: pulse oximetry, capnography, peripheral nerve stimulation, noninvasive 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).[15]

Clinical pharmacology and pharmacokinetics

Tubocurarine has a time of onset of 300 seconds or more (which is relatively slow among neuromuscular-blocking drugs), and has a duration of action of 60 to 120 minutes (which is relatively long time).[16]

It also causes histamine release,[17] now a recognized hallmark of the tetrahydroisioquinolinium class of neuromuscular blocking agents. The amount 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,[18] that manifests as hypotension,[19] 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, vecuronium, rocuronium, atracurium, and cisatracurium. Succinylcholine is a widely used paralytic drug which acts by activating, instead of blocking, the ACh receptor.

The potassium channel blocker tetraethylammonium (TEA) has been shown to reverse the effects of tubocurarine. It is thought to do so by increasing ACh release, which counteracts the antagonistic effects of tubocurarine on the ACh receptor.

References

External links

  • Curare - History, Tubocurarine, a more detailed historical account of tubocurare
This article was sourced from Creative Commons Attribution-ShareAlike License; additional terms may apply. World Heritage Encyclopedia content is assembled from numerous content providers, Open Access Publishing, and in compliance with The Fair Access to Science and Technology Research Act (FASTR), Wikimedia Foundation, Inc., Public Library of Science, The Encyclopedia of Life, Open Book Publishers (OBP), PubMed, U.S. National Library of Medicine, National Center for Biotechnology Information, U.S. National Library of Medicine, National Institutes of Health (NIH), U.S. Department of Health & Human Services, and USA.gov, which sources content from all federal, state, local, tribal, and territorial government publication portals (.gov, .mil, .edu). Funding for USA.gov and content contributors is made possible from the U.S. Congress, E-Government Act of 2002.
 
Crowd sourced content that is contributed to World Heritage Encyclopedia is peer reviewed and edited by our editorial staff to ensure quality scholarly research articles.
 
By using this site, you agree to the Terms of Use and Privacy Policy. World Heritage Encyclopedia™ is a registered trademark of the World Public Library Association, a non-profit organization.
 



Copyright © World Library Foundation. All rights reserved. eBooks from World eBook Library are sponsored by the World Library Foundation,
a 501c(4) Member's Support Non-Profit Organization, and is NOT affiliated with any governmental agency or department.