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Revision as of 10:42, 16 February 2012 editBeetstra (talk | contribs)Edit filter managers, Administrators172,031 edits Saving copy of the {{drugbox}} taken from revid 477142344 of page Tubocurarine_chloride for the Chem/Drugbox validation project (updated: 'DrugBank', 'UNII', 'ChEMBL', 'CAS_number').		Latest revision as of 12:15, 24 November 2024 edit Athanelar (talk | contribs)20 edits Updated etymology info with citation and removed 'presumption' about the word's phonetic development.Tags: Visual edit Mobile edit Mobile web edit
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			{{Short description|Obsolete muscle relaxant}}
	{{ambox | text = This page contains a copy of the infobox ({{tl|drugbox}}) taken from revid of page ] with values updated to verified values.}}
			{{Infobox drug
	{{Drugbox
	| Verifiedfields = changed		| Verifiedfields = changed
			| Watchedfields = changed
	| verifiedrevid = 470618589		| verifiedrevid = 477162627
	| IUPAC_name = 6,6'-dimethoxy-2,2,2',2'-tetramethyltubocuraran-2,2'-diium-7',12'-diol		| IUPAC_name = 6,6′-dimethoxy-2,2′,2′-trimethyltubocuraran-2,2′-diium-7′,12′-diol
	| image = Tubocurarine.svg		| image = Tubocurarine.svg
	| image2 = Tubocurarine-3D-sticks.png		| image2 = Tubocurarine-3D-sticks.png
	| width2 = 150		| width2 = 200
	<!--Clinical data-->		<!--Clinical data-->
	| tradename =		| tradename =
	| Drugs.com = {{drugs.com|international|tubocurarine-chloride}}		| Drugs.com = {{drugs.com|international|tubocurarine-chloride}}
	| MedlinePlus = a682860		| MedlinePlus = a682860
	| pregnancy_category =		| pregnancy_AU = C
	| legal_status = worldwide: prescription only medicine		| legal_status = Rx-only
	| routes_of_administration = I.V.		| routes_of_administration = ]
	<!--Pharmacokinetic data-->		<!--Pharmacokinetic data-->
	| bioavailability = 100% (IV)		| bioavailability = 100% (IV)
	| protein_bound = 50%		| protein_bound = 50%
	| metabolism =		| metabolism =
	| elimination_half-life = 1-2 hours		| elimination_half-life = 1–2 hours
	<!--Identifiers-->		<!--Identifiers-->
			| IUPHAR_ligand = 2294
	| CASNo_Ref = {{cascite}}
	| CAS_number_Ref = {{cascite|changed|??}}		| CAS_number_Ref = {{cascite|changed|CAS}}
	| CAS_number = <!-- blanked - oldvalue: 57-95-4 -->		| CAS_number = 6989-98-6
	| CAS_supplemental = (chloride hydrochloride) 6989-98-6 (chloride hydrochloride pentahydrate)		| CAS_supplemental =
	| ATC_prefix = M03		| ATC_prefix = M03
	| ATC_suffix = AA02		| ATC_suffix = AA02
	| ATC_supplemental =		| ATC_supplemental =
	| ChEBI_Ref = {{ebicite|correct|EBI}}		| ChEBI_Ref = {{ebicite|correct|EBI}}
	| ChEBI = 9774		| ChEBI = 9774
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	| StdInChIKey = JFJZZMVDLULRGK-URLMMPGGSA-O		| StdInChIKey = JFJZZMVDLULRGK-URLMMPGGSA-O
	| PubChem = 6000		| PubChem = 6000
	| DrugBank_Ref = {{drugbankcite|changed|drugbank}}		| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
	| DrugBank = DB01199		| DrugBank = DB01199
	| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}		| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
	| ChemSpiderID = 5778		| ChemSpiderID = 5778
	| UNII_Ref = {{fdacite|changed|FDA}}		| UNII_Ref = {{fdacite|changed|FDA}}
	| UNII = <!-- blanked - oldvalue: 900961Z8VR -->		| UNII = 900961Z8VR
	| ChEMBL_Ref = {{ebicite|changed|EBI}}		| ChEMBL_Ref = {{ebicite|changed|EBI}}
	| ChEMBL = <!-- blanked - oldvalue: 1687 -->		| ChEMBL = 1687
⚫	| C=37 | H=42 | Cl=2 | N=2 | O=6
			<!--Chemical data-->
	| molecular_weight = 624.765 g/mol
		⚫	| C=37 | H=42 | Cl=2 | N=2 | O=6
	| smiles = Oc7ccc1cc7Oc5cc6(Cc4ccc(Oc2c3(C1)(C)(C)CCc3cc(OC)c2O)cc4)(C)(C)CCc6cc5OC		| smiles = Oc7ccc1cc7Oc5cc6(Cc4ccc(Oc2c3(C1)(C)(C)CCc3cc(OC)c2O)cc4)(C)(C)CCc6cc5OC
			| synonyms =
	| synonyms = <small>(1''S'',16''R'')-9,21-dihydroxy-10,25-dimethoxy-15,15,30-trimethyl-7,23-dioxa-15,30-diazaheptacyclohexatriaconta-3,5,8(34),9,11,18(33),19,21,24,26,31,35-dodecaene-15,30-diium</small>
			|drug_name=|alt=|caption=|type=|licence_EU=|pregnancy_US=|licence_US=}}
	}}
			'''Tubocurarine''' (also known as '''''d''-tubocurarine''' or '''DTC''') is a toxic ] historically known for its use as an ]. In the mid-1900s, it was used in conjunction with an ] to provide ] relaxation during ] or ]. Safer alternatives, such as ] and ], have largely replaced it as an adjunct for clinical anesthesia and it is now rarely used.
			==History==
			Tubocurarine is a naturally occurring mono-quaternary ] obtained from the bark of the ] South American plant '']'', a climbing vine known to the European world since the Spanish conquest of South America. ] had been used as a source of ] by South American natives to hunt animals, and they were able to eat the animals' contaminated flesh subsequently without any adverse effects because tubocurarine cannot easily cross ]. Thus, tubocurarine is effective only if given ]ly, as demonstrated by ], who also showed that the site of its action was at the neuromuscular junction.<ref>{{cite journal | vauthors = Bernard C |title=Analyse physiologie des propriétés des actions de curare et de la nicotine sure systèmes musculaire et nerveux au moyen du curare |journal=Compt. Rend. |volume=43 |pages=305–319 |year=1856}}</ref> Virchow and Munter confirmed the paralyzing action was limited to ].<ref>{{cite journal | vauthors = Betcher AM | title = The civilizing of curare: a history of its development and introduction into anesthesiology | journal = Anesthesia and Analgesia | volume = 56 | issue = 2 | pages = 305–319 | year = 1977 | pmid = 322548 | doi = 10.1213/00000539-197703000-00032 | doi-access = free }}</ref>
			===Etymology===
			The word ''curare'' comes from a word in the ].<ref>{{Cite web |title=Definition of CURARE |url=https://www.merriam-webster.com/dictionary/curare |access-date=2024-11-24 |website=www.merriam-webster.com |language=en}}</ref> Tubocurarine is so-called because some of the plant extracts designated ''curare'' were stored, and subsequently shipped to Europe, in bamboo tubes. Likewise, curare stored in ] containers was called calabash curare, although this was usually an extract not of Chondrodendron, but of the '']'' species ''S. toxifera'', containing a different alkaloid, namely ]. Pot curare was generally a mixture of extracts from various genera in the families ] and ]. The tripartite classification into "tube", "calabash", and "pot" curares early became untenable, due to inconsistencies in the use of the different types of vessels and the complexities of the dart poison recipes themselves.<ref>The Alkaloids: Chemistry and Physiology ed. R.H.F. Manske (Dominion Rubber Research Laboratory Guelph, Ontario) Academic Press Inc., publishers New York 1955 Volume 5: Pharmacology</ref>
			===Use in anesthesia===
			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.<ref name=Griffith>{{cite journal |doi=10.1097/00000542-194207000-00006 |vauthors=Griffith HR, Johnson GE |title=The use of curare in general anesthesia |journal=Anesthesiology |year=1942 |volume=3 |issue=4 |pages=418–420 |s2cid=71400545|doi-access=free }}</ref> In this sense, tubocurarine is the prototypical adjunctive ]. However, others before Griffith and Johnson had attempted use of tubocurarine in several situations:<ref>{{cite journal | vauthors = Läwen A |title=Ueber die verbindung der lokakanaesthesie und epidurale injektion anesthesiernder losungen bei tabischen magenkrisen |journal=Beitr Klin Chir |volume=80 |pages=168–189 |year=1912}}</ref><ref>{{cite journal | vauthors = Wilkinson DJ | title = Dr F.P. de Caux--the first user of curare for anesthesia in England | journal = Anaesthesia | volume = 46 | issue = 1 | pages = 49–51 | date = January 1991 | pmid = 1996757 | doi = 10.1111/j.1365-2044.1991.tb09317.x | doi-access = free }}</ref><ref>{{cite journal | vauthors = Bennett AE |title=Curare: a preventive of traumatic complications in electroconvulsive shock therapy |journal=Am J Psychiatry |volume=97 |pages=1040–1060 |year=1941 |doi=10.1176/ajp.97.5.1040}}</ref> some under controlled study conditions<ref>{{cite journal | vauthors = West R | title = An excursion into pharmacology: curare in medicine | journal = Medical History | volume = 28 | issue = 4 | pages = 391–405 | date = October 1984 | pmid = 6390032 | pmc = 1140012 | doi = 10.1017/s0025727300036279 }}</ref><ref>{{cite journal | vauthors = Burman MS |title=Therapeutic use of curare and erythroidine hydrochloride for spastic and dystonic states |journal=Arch Neurol Psychiatry |volume=41 |issue=2 |pages=307–327 |year=1939 |doi=10.1001/archneurpsyc.1939.02270140093008}}</ref> while others not quite controlled and remained unpublished.<ref>{{cite journal | vauthors = Bevan DR |year=1992 |title="Curare". In: Maltby JR, Shephard DAE (Eds.), Harold Griffith – His Life and Legacy |journal=Can J Anaesth |volume=39 |issue=1 |pages=49–55}}</ref> Regardless, all in all some 30,000 patients had been given tubocurarine by 1941, although it was Griffith and Johnson's 1942 publication<ref name=Griffith/> that provided the impetus to the standard use of neuromuscular blocking agents in clinical anesthetic practice – a revolution that rapidly metamorphosized into the standard practice of "balanced" anesthesia: the triad of barbiturate hypnosis, light inhalational anesthesia and muscle relaxation.<ref name=Gray>{{cite journal | vauthors = Gray TC, Halton J | title = Curarine with Balanced Anaesthesia | journal = British Medical Journal | volume = 2 | issue = 4469 | pages = 293–295 | date = August 1946 | pmid = 20786887 | pmc = 2054113 | doi = 10.1136/bmj.2.4469.293 }}</ref> The technique as described by Gray and Halton was widely known as the "Liverpool technique",<ref name=Gray/> 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 ] 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.
			==Chemical properties==
			Structurally, tubocurarine is a ] derivative. Its structure, when first elucidated in 1948 and for many years,<ref>{{cite journal | vauthors = King H |title=64. Curare alkaloids. Part VII. Constitution of dextrotubocurarine chloride |journal=J Chem Soc |pages=265 |year=1948 |doi=10.1039/jr9480000265}}</ref> was incorrectly 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,<ref>{{cite journal |vauthors=Everett AJ, Lowe LA, Wilkinson S |title=Revision of the structures of (+)-tubocurarine chloride and (+)-chondrocurine |journal=J. Chem. Soc. Chem. Commun. |issue=16 |pages=1020 |year=1970 |doi=10.1039/c29700001020}}</ref> showing one of the two nitrogens to be tertiary, actually a mono-''N''-methylated alkaloid.
			===Biosynthesis===
			Tubocurarine biosynthesis involves a radical coupling of the two enantiomers of N-methylcoclaurine. (''R'') and (''S'')-''N''-methylcoclaurine come from a Mannich-like reaction between dopamine and 4-hydroxyphenylacetaldehyde, facilitated by norcoclaurine synthase (NCS). Both dopamine and 4-hydroxyphenylacetaldehyde originate from <small>L</small>-tyrosine. Methylation of the amine and hydroxyl substituents are facilitated by ]. One methyl group is present on each nitrogen atom prior to the radical coupling. The additional methyl group is transferred to form tubocurarine, with its single quaternary N,N-dimethylamino group.<ref>Dewick, P. M. Medicinal Natural Products; a Biosynthetic Approach. 3rd ed.; John Wiley and Sons Ltd.: 2009.</ref>
			]
			==Biological effects==
			]
			Without intervention, ] in the peripheral nervous system activates skeletal muscles. Acetylcholine is produced in the body of the neuron by ] and transported down the axon to the synaptic gap. Tubocurarine chloride acts as an ] for the ], meaning it blocks the receptor site from ACh.<ref name="pmid11562442">{{cite journal | vauthors = Wenningmann I, Dilger JP | title = The kinetics of inhibition of nicotinic acetylcholine receptors by (+)-tubocurarine and pancuronium | journal = Molecular Pharmacology | volume = 60 | issue = 4 | pages = 790–796 | date = October 2001 | pmid = 11562442 | url = https://molpharm.aspetjournals.org/content/60/4/790.long }}</ref> This may be due to the quaternary amino structural motif found on both molecules.
			===Clinical pharmacology===
			Unna et al. reported the effects of tubocurarine on humans:
			{{Blockquote|Forty-five seconds after the beginning of the injection, heaviness of the eyelids and transitory ] were perceived. At the completion of the injection, diplopia became fixed, but could be noticed only when the subject's eyelids were raised by the operator. As curarization proceeded, it seemed to the subject as if the facial muscles, those of the tongue, pharynx, and lower jaw, the muscles of the neck and back, and the muscles of the extremities became relaxed in about that order. Accompanying the paralysis of the pharynx and the jaw muscles, inability of the subject to swallow was noted ... Shortly after the injection was completed the subjects experienced a sensation of increased difficulty in breathing, as if an extra effort was necessary to maintain an adequate respiratory exchange. This sensation was present even though there was no objective evidence of impaired oxygenation or of carbon dioxide retention. It reached its maximum about five minutes after the injection, coinciding with the maximum depression of the vital capacity. In the majority of the experiments the respiratory rate was increased by about 50–100 per cent the first minutes after the injection of any one of the drugs while the tidal volume decreased.<ref>{{cite journal | vauthors = Unna KR |title=Evaluation Of Curarizing Drugs in Man |journal=The Journal of Pharmacology and Experimental Therapeutics |date=March 1950 |volume=98}}</ref>}}
			Tubocurarine has a time of onset of around 5 minutes which is relatively slow among ]s, and has a duration of action of 60 to 120 minutes.<ref>{{cite journal | vauthors = Thompson MA | title = Muscle relaxant drugs | journal = British Journal of Hospital Medicine | volume = 23 | issue = 2 | pages = 153–4, 163–4, 167–8 passim | date = February 1980 | pmid = 6102875 }}</ref><ref name=Rang151>Page 151 in: {{cite book | vauthors = Rang HP |title= Pharmacology |publisher=Churchill Livingstone |location=Edinburgh |year=2003 |isbn=0-443-07145-4 |oclc=51622037}}</ref> It also causes ] release,<ref>{{cite book | vauthors = Maclagen J | date = 1976 | veditors = Zaimis E | title = Neuromuscular Junction |chapter= Competitive Neuromuscular Blocking Drugs | series = Handbook of Experimental Pharmacology | volume = 42 | publisher = Springer-Verlag | location = Berlin | pages = 421–486 | doi = 10.1007/978-3-642-45476-9_6 | isbn = 978-3-642-45476-9 }}</ref> now a recognized hallmark of the tetrahydroisioquinolinium class of neuromuscular blocking agents. Histamine release is associated with ]s, ], and ] secretions, making it dangerous for asthmatics, children, and those who are pregnant or lactating.<ref>{{cite web |title=''d''-Tubocurarine (Prototype Nondepolarizing Neuromuscular Blocker) |url=http://tmedweb.tulane.edu/pharmwiki/doku.php/tubocurarine_-_prototype_blocker |website=Tulane University |access-date=4 May 2015}}</ref> However, the main disadvantage in the use of tubocurarine is its significant ganglion-blocking effect,<ref>{{cite journal | vauthors = Bowman WC, Webb SN | title = Neuromuscular blocking and ganglion blocking activities of some acetylcholine antagonists in the cat | journal = The Journal of Pharmacy and Pharmacology | volume = 24 | issue = 10 | pages = 762–772 | date = October 1972 | pmid = 4403972 | doi = 10.1111/j.2042-7158.1972.tb08880.x | s2cid = 27668701 }}</ref> that manifests as hypotension,<ref>{{cite journal | vauthors = Coleman AJ, Downing JW, Leary WP, Moyes DG, Styles M | title = The immediate cardiovascular effects of pancuronium, alcuronium and tubocurarine in man | journal = Anaesthesia | volume = 27 | issue = 4 | pages = 415–422 | date = October 1972 | pmid = 4264060 | doi = 10.1111/j.1365-2044.1972.tb08247.x | doi-access = free }}</ref> 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: ], ], ], ], and ]. ] is a widely used muscle relaxant drug which acts by activating, instead of blocking, the ACh receptor.
			The ] ] (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.
			===Use as spider bite treatment===
			]s of the genus '']'' have ] in their venom. The most well known spider in this genus is the black widow spider. α-latrotoxin causes the release of neurotransmitters into the synaptic gap, including ].<ref>{{cite journal | vauthors = Südhof TC | title = alpha-Latrotoxin and its receptors: neurexins and CIRL/latrophilins | journal = Annual Review of Neuroscience | volume = 24 | pages = 933–962 | date = March 2001 | pmid = 11520923 | doi = 10.1146/annurev.neuro.24.1.933 | s2cid = 906456 }}</ref> Bites are usually not fatal, but do cause a significant amount of pain in addition to muscle spasms. The venom is the most damaging to nerve endings, but the introduction of ''d''-tubocurarine chloride blocks the ], alleviating pain and muscle spasms while an antivenom can be administered.<ref>{{cite journal | vauthors = Allen GW | title = Black widow spider (Latrodectus mactans) poisoning treated with d-tubocurarine chloride | journal = Annals of Internal Medicine | volume = 39 | issue = 3 | pages = 624–625 | date = September 1953 | pmid = 13080907 | doi = 10.7326/0003-4819-39-3-624 }}</ref>
			==Toxicology==
			An individual administered tubocurarine chloride will be unable to move any voluntary muscles, including the ]. A large enough dose will therefore result in death from respiratory failure unless artificial ventilation is initiated. The ] for mice and rabbits are 0.13&nbsp;mg/kg and 0.146&nbsp;mg/kg intravenously, respectively. It releases histamine and causes hypotension.<ref>{{cite journal | vauthors = Gesler RM, Hoppe JO | title = 3, 6-bis(3-diethylaminopropoxy) pyridazine bismethiodide, a long-acting neuromuscular blocking agent | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 118 | issue = 4 | pages = 395–406 | date = December 1956 | pmid = 13385800 }}</ref>
			== References ==
			{{Reflist|2}}{{Muscle relaxants}}
			{{Nicotinic acetylcholine receptor modulators}}
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