Tubocurarine

Tubocurarine

Clinical data
AHFS/Drugs.com	International Drug Names
MedlinePlus	a682860
Pregnancy category	D
Routes of administration	IV
ATC code	M03AA02 (WHO)
Legal status
Legal status	World wide Rx-only medication
Pharmacokinetic data
Bioavailability	100% (IV)
Protein binding	50%
Elimination half-life	1-2 hours
Identifiers
IUPAC name 6,6'-dimethoxy-2,2,2',2'-tetramethyltubocuraran-2,2'-diium-7',12'-diol
CAS Number	57-95-4 N (chloride hydrochloride) 6989-98-6 (chloride hydrochloride pentahydrate)
PubChem CID	6000
DrugBank	DB01199 Y
ChemSpider	5778 Y
UNII	900961Z8VR
ChEBI	CHEBI:9774 Y
ChEMBL	ChEMBL1687 N
E number	{{#property:P628}}
ECHA InfoCard	{{#property:P2566}}
Chemical and physical data
Formula	C37H42Cl2N2O6
Molar mass	624.765 g/mol
3D model (JSmol)	Interactive image
SMILES Oc7ccc1cc7Oc5cc6[C@H](Cc4ccc(Oc2c3[C@@H](C1)[N+](C)(C)CCc3cc(OC)c2O)cc4)[N+](C)(C)CCc6cc5OC
InChI InChI=1S/C37H40N2O6/c1-38-14-12-24-19-32(42-4)33-21-27(24)28(38)16-22-6-9-26(10-7-22)44-37-35-25(20-34(43-5)36(37)41)13-15-39(2,3)29(35)17-23-8-11-30(40)31(18-23)45-33/h6-11,18-21,28-29H,12-17H2,1-5H3,(H-,40,41)/p+1/t28-,29+/m0/s1 Y Key:JFJZZMVDLULRGK-URLMMPGGSA-O Y
NY (what is this?)  (verify)

WikiDoc Resources for Tubocurarine
Articles
Most recent articles on Tubocurarine Most cited articles on Tubocurarine Review articles on Tubocurarine Articles on Tubocurarine in N Eng J Med, Lancet, BMJ
Media
Powerpoint slides on Tubocurarine Images of Tubocurarine Photos of Tubocurarine Podcasts & MP3s on Tubocurarine Videos on Tubocurarine
Evidence Based Medicine
Cochrane Collaboration on Tubocurarine Bandolier on Tubocurarine TRIP on Tubocurarine
Clinical Trials
Ongoing Trials on Tubocurarine at Clinical Trials.gov Trial results on Tubocurarine Clinical Trials on Tubocurarine at Google
Guidelines / Policies / Govt
US National Guidelines Clearinghouse on Tubocurarine NICE Guidance on Tubocurarine NHS PRODIGY Guidance FDA on Tubocurarine CDC on Tubocurarine
Books
Books on Tubocurarine
News
Tubocurarine in the news Be alerted to news on Tubocurarine News trends on Tubocurarine
Commentary
Blogs on Tubocurarine
Definitions
Definitions of Tubocurarine
Patient Resources / Community
Patient resources on Tubocurarine Discussion groups on Tubocurarine Patient Handouts on Tubocurarine Directions to Hospitals Treating Tubocurarine Risk calculators and risk factors for Tubocurarine
Healthcare Provider Resources
Symptoms of Tubocurarine Causes & Risk Factors for Tubocurarine Diagnostic studies for Tubocurarine Treatment of Tubocurarine
Continuing Medical Education (CME)
CME Programs on Tubocurarine
International
Tubocurarine en Espanol Tubocurarine en Francais
Business
Tubocurarine in the Marketplace Patents on Tubocurarine
Experimental / Informatics
List of terms related to Tubocurarine

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

Tubocurarine (also known as d-tubocurarine or DTC) is a toxic alkaloid and 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, antagonist for Nicotinic acetylcholine receptor. It is the active agent of one of the forms 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. Virchow and Munter confirmed the paralyzing action was limited to voluntary and not involuntary muscles. 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, 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, 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. 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 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).

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).

It also causes histamine release, 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, 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, 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.

External links

• Curare - History, Tubocurarine, a more detailed historical account of tubocurare