Tubocurarine chloride

Tubocurarine chloride

Systematic (IUPAC) name
6,6'-dimethoxy-2,2,2',2'-tetramethyltubocuraran-2,2'-diium-7',12'-diol
Clinical data
AHFS/Drugs.com	International Drug Names
MedlinePlus	a682860
Pregnancy cat.	?
Legal status	worldwide: prescription only medicine
Routes	I.V.
Pharmacokinetic data
Bioavailability	100% (IV)
Protein binding	50%
Half-life	1-2 hours
Identifiers
CAS number	57-95-4 N (chloride hydrochloride) 6989-98-6 (chloride hydrochloride pentahydrate)
ATC code	M03AA02
PubChem	CID 6000
DrugBank	APRD00176
ChemSpider	5778 Y
UNII	900961Z8VR N
ChEBI	CHEBI:9774 Y
ChEMBL	CHEMBL1687 N
Synonyms	(1S,16R)-9,21-dihydroxy-10,25-dimethoxy-15,15,30-trimethyl-7,23-dioxa-15,30-diazaheptacyclo[22.6.2.23,6.18,12.118,22.027,31.016,34]hexatriaconta-3,5,8(34),9,11,18(33),19,21,24,26,31,35-dodecaene-15,30-diium
Chemical data
Formula	C37H42Cl2N2O6
Mol. mass	624.765 g/mol
SMILES	eMolecules & PubChem
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
N(what is this?)  chloride (verify)

Tubocurarine (also known as D-tubocurare or DTC) is a neuromuscular-blocking drug or 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] non-depolarizing neuromuscular blocking agent that is a competitive antagonist of nicotinic neuromuscular acetylcholine receptors.^[2] It is a type 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 that the site of its action was at the neuromuscular junction.^[3] Virchow and Munter confirmed that the paralyzing action was limited to voluntary and not involuntary muscles.^[4] 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. 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.[1]

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. It was not until 22 years later, in 1970, that the correct structure was finally established,^[6] 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.^[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 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). ^[15]

• 

  (S)-norcoclaurine is derived from two tyrosine molecules after decarboxylation.

• 

  Compound 6 to compound 7 requires two methylations by SAM at the hydroxyl and amine position.

Clinical Pharmacology and Pharmacokinetics

At normal doses, tubocurarine has a slow onset and a slow recovery. It also causes histamine release^[16] 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.^{[citation needed]} However, the main disadvantage in the use of tubocurarine is its significant ganglion blocking effect,^[17] that manifests as hypotension,^[18] 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.

References

1. ^ Thompson MA (1980). "Muscle relaxant drugs". Br J Hosp Med 23 (2): 153. PMID 6102875. 
2. ^ Wenningmann I, Dilger JP (October 2001). "The kinetics of inhibition of nicotinic acetylcholine receptors by (+)-tubocurarine and pancuronium". Molecular pharmacology 60 (4): 790–6. PMID 11562442. http://molpharm.aspetjournals.org/cgi/pmidlookup?view=long&pmid=11562442. 
3. ^ Bernard C (1856). "Analyse physiologie des propriétés des actions de curare et de la nicotine sure systèmes musculaire et nerveux au moyen du curare". Compt Rend Acad d'sc 43: 305–319. 
4. ^ Bechter AM (1977). "The civilizing of curare: a history of its development and introduction into anesthesiology". Anesth Analg 56 (2): 305–319. PMID 322548. 
5. ^ King H (1948). "64. Curare alkaloids. Part VII. Constitution of dextrotubocurarine chloride". J Chem Soc: 265. doi:10.1039/jr9480000265. 
6. ^ Everett AJ, Lowe LA, Wilkinson S (1970). J Chem Soc, Chem Commun: 1020. 
7. ^ ^{a b} Griffith HR, Johnson GE (1942). "The use of curare in general anesthesia". Anesthesiol 3 (4): 418–420. doi:10.1097/00000542-194207000-00006. 
8. ^ Läwen A (1912). "Ueber die verbindung der lokakanaesthesie und epidurale injektion anesthesiernder losungen bei tabischen magenkrisen". Beitr Klin Chir 80: 168–189. 
9. ^ Wilkinson DJ (1991). "Dr. F.P. de Caux - the first user of curare for anaesthesia in England". Anaesthesia 46 (1): 49–51. doi:10.1111/j.1365-2044.1991.tb09317.x. PMID 1996757. 
10. ^ Bennett AE (1941). "Curare: a preventive of traumatic complications in electroconvulsive shock therapy". Am J Psychiatry 97: 1040–1060. 
11. ^ West R (1984). "An excursion into pharmacology: curare in medicine". Medical History 28 (4): 391–405. PMC 1140012. PMID 6390032. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1140012. 
12. ^ Burman MS (1939). "Therapeutic use of curare and erythroidine hydrochloride for spastic and dystonic states". Arch Neurol Psychiat 41: 307–327. 
13. ^ Bevan DR. (1992) "Curare". In: Maltby JR, Shephard DAE (Eds.), Harold Griffith - His Life and Legacy; Suppl. to Can J Anaesth Vol. 39 (1); 49-55.
14. ^ ^{a b} Gray TC, Halton J (1946). "Technique for the use of d-tubocurarine chloride with balanced anaesthesia". Br Med J 2: 293–295. PMID 20996123. 
15. ^ Dewick, P. M. Medicinal Natural Products; a Biosynthetic Approach. 3rd ed.; John Wiley and Sons Ltd.: 2009.
16. ^ Maclagen J. (1976) In: Zaimis E. (Ed.), "Neuromuscular Junction". Hand. Exp. Pharm.; Vol. 42; Springer-Verlag, Berlin: 421-486.
17. ^ Bowman WC, Webb SN (1972). "Neuromuscular blocking and ganglion blocking activities of some acetylcholine antagonists in the cat". J Pharm Pharmacol 24 (10): 762. PMID 4403972. 
18. ^ Coleman AJ, Downing JW, Leary WP, Moyes DG (1972). "The immediate cardiovascular effects of pancuronium, alcuronium and tubocurarine in man". Anaesthesia 27 (4): 415. doi:10.1111/j.1365-2044.1972.tb08247.x. PMID 4264060.