Tubocurarine chloride

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Tubocurarine chloride
Tubocurarine.svg
Tubocurarine-3D-sticks.png
Clinical data
AHFS/Drugs.com International Drug Names
MedlinePlus a682860
Pregnancy
category
  • AU:C
Routes of
administration 		IV
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability 100% (IV)
Protein binding 50%
Elimination half-life 1–2 hours
Identifiers
  • 6,6′-dimethoxy-2,2′,2′-trimethyltubocuraran-2,2′-diium-7′,12′-diol
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
ChEBI
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
Formula C37H42Cl2N2O6
Molar mass 681.65 g·mol−1
3D model (JSmol)
  • Oc7ccc1cc7Oc5cc6[C@H](Cc4ccc(Oc2c3[C@@H](C1)[N+](C)(C)CCc3cc(OC)c2O)cc4)[N+](C)(C)CCc6cc5OC
  • 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 Yes check.svgY
  • Key:JFJZZMVDLULRGK-URLMMPGGSA-O Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Tubocurarine (also known as d-tubocurarine or DTC) is a toxic benzylisoquinoline alkaloid historically known for its use as an arrow poison. In the mid-1900s, it was used in conjunction with an anesthetic to provide skeletal muscle relaxation during surgery or mechanical ventilation. Safer alternatives, such as cisatracurium and rocuronium, have largely replaced it as an adjunct for clinical anesthesia and it is now rarely used.

Contents

History

Tubocurarine is a naturally occurring mono-quaternary alkaloid obtained from the bark of the Menispermaceous 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 adverse effects because tubocurarine cannot easily cross mucous membranes. Thus, tubocurarine is effective only if given parenterally, as demonstrated by Bernard, who also showed that the site of its action was at the neuromuscular junction. [1] Virchow and Munter confirmed the paralyzing action was limited to voluntary muscles. [2]

Etymology

The word curare comes from the South American Native name for the arrow poison, ourare.[ what language is this? ] Presumably, the initial syllable was pronounced with a heavy glottal stop.[ original research? ] 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 calabash containers was called calabash curare, although this was usually an extract not of Chondrodendron, but of the Strychnos species S. toxifera, containing a different alkaloid, namely toxiferine. Pot curare was generally a mixture of extracts from various genera in the families Menispermaceae and Strychnaceae. 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. [3]

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. [4] In this sense, tubocurarine is the prototypical adjunctive neuromuscular non-depolarizing agent. However, others before Griffith and Johnson had attempted use of tubocurarine in several situations: [5] [6] [7] some under controlled study conditions [8] [9] while others not quite controlled and remained unpublished. [10] Regardless, all in all some 30,000 patients had been given tubocurarine by 1941, although it was Griffith and Johnson's 1942 publication [4] 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. [11] The technique as described by Gray and Halton was widely known as the "Liverpool technique", [11] 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.

Chemical properties

Structurally, tubocurarine is a benzylisoquinoline derivative. Its structure, when first elucidated in 1948 and for many years, [12] 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, [13] 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 L-tyrosine. Methylation of the amine and hydroxyl substituents are facilitated by S-adenosyl methionine (SAM). 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. [14]

Tubocurarine proposed biosynthesis Tubocurarine proposed biosynthesis.png
Tubocurarine proposed biosynthesis

Biological effects

Acetylcholine in the synaptic gap AChe mechanism of action.jpg
Acetylcholine in the synaptic gap

Without intervention, acetylcholine (ACh) in the peripheral nervous system activates skeletal muscles. Acetylcholine is produced in the body of the neuron by choline acetyltransferase and transported down the axon to the synaptic gap. Tubocurarine chloride acts as an antagonist for the nicotinic acetylcholine receptor (nAChr), meaning it blocks the receptor site from ACh. [16] 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:

Forty-five seconds after the beginning of the injection, heaviness of the eyelids and transitory diplopia 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. [17]

Tubocurarine has a time of onset of around 5 minutes which is relatively slow among neuromuscular-blocking drugs, and has a duration of action of 60 to 120 minutes. [18] [19] It also causes histamine release, [20] now a recognized hallmark of the tetrahydroisioquinolinium class of neuromuscular blocking agents. Histamine release is associated with bronchospasms, hypotension, and salivary secretions, making it dangerous for asthmatics, children, and those who are pregnant or lactating. [21] However, the main disadvantage in the use of tubocurarine is its significant ganglion-blocking effect, [22] that manifests as hypotension, [23] 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 muscle relaxant 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.

Use as spider bite treatment

Spiders of the genus Latrodectus have α-latrotoxin 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 acetylcholine. [24] 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 nAChr, alleviating pain and muscle spasms while an antivenom can be administered. [25]

Toxicology

An individual administered tubocurarine chloride 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 LD50 for mice and rabbits are 0.13 mg/kg and 0.146 mg/kg intravenously, respectively. It releases histamine and causes hypotension. [26]

Related Research Articles

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Suxamethonium chloride, also known as suxamethonium or succinylcholine, or simply sux by medical abbreviation, is a medication used to cause short-term paralysis as part of general anesthesia. This is done to help with tracheal intubation or electroconvulsive therapy. It is administered by injection, either into a vein or into a muscle. When used in a vein, onset of action is generally within one minute and effects last for up to 10 minutes.

<span class="mw-page-title-main">Pancuronium bromide</span> Aminosteroid muscle relaxant

Pancuronium is an aminosteroid muscle relaxant with various medical uses. It is used in euthanasia and is used in some states as the second of three drugs administered during lethal injections in the United States.

A muscle relaxant is a drug that 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. Neuromuscular blockers act by interfering with transmission at the neuromuscular end plate and have no central nervous system (CNS) activity. They are often used during surgical procedures and in intensive care and emergency medicine to cause temporary paralysis. Spasmolytics, also known as "centrally acting" muscle relaxant, are used to alleviate musculoskeletal pain and spasms and to reduce spasticity in a variety of neurological conditions. While both neuromuscular blockers and spasmolytics are often grouped together as muscle relaxant, the term is commonly used to refer to spasmolytics only.

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<span class="mw-page-title-main">Neostigmine</span> Anti-full body paralysis drug treatment

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<span class="mw-page-title-main">Vecuronium bromide</span> Muscle relaxant

Vecuronium bromide, sold under the brand name Norcuron among others, is a medication used as part of general anesthesia to provide skeletal muscle relaxation during surgery or mechanical ventilation. It is also used to help with endotracheal intubation; however, agents such as suxamethonium (succinylcholine) or rocuronium are generally preferred if this needs to be done quickly. It is given by injection into a vein. Effects are greatest at about 4 minutes and last for up to an hour.

<span class="mw-page-title-main">Curare</span> Group of chemical substances used as poison

Curare is a common name for various alkaloid arrow poisons originating from plant extracts. Used as a paralyzing agent by indigenous peoples in Central and South America for hunting and for therapeutic purposes, curare only becomes active when it contaminates a wound. These poisons cause weakness of the skeletal muscles and, when administered in a sufficient dose, eventual death by asphyxiation due to paralysis of the diaphragm. Curare is prepared by boiling the bark of one of the dozens of plant sources, leaving a dark, heavy paste that can be applied to arrow or dart heads. In medicine, curare has been used as a treatment for tetanus and strychnine poisoning and as a paralyzing agent for surgical procedures.

<span class="mw-page-title-main">Neuromuscular-blocking drug</span> Type of paralyzing anesthetic including lepto- and pachycurares

Neuromuscular-blocking drugs, or Neuromuscular blocking agents (NMBAs), block transmission at the neuromuscular junction, causing paralysis of the affected skeletal muscles. This is accomplished via their action on the post-synaptic acetylcholine (Nm) receptors.

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<span class="mw-page-title-main">Gallamine triethiodide</span>

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Presence of iodine makes it radio opaque, and its ampule in a bag at airport's x-ray scanner raise the false suspicion of a bullet in the bag.

<span class="mw-page-title-main">Mivacurium chloride</span> Drug used in a hospital setting

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<span class="mw-page-title-main">Doxacurium chloride</span> Pharmaceutical drug

Doxacurium chloride 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 rarely used adjunctively to facilitate endotracheal intubation.

<span class="mw-page-title-main">Alcuronium chloride</span> Muscle relaxant

Alcuronium chloride is a neuromuscular blocking (NMB) agent, alternatively referred to as a skeletal muscle relaxant. It is a semi-synthetic substance prepared from C-toxiferine I, a bis-quaternary alkaloid obtained from Strychnos toxifera. C-toxiferine I itself has been tested for its pharmacological action and noted to be a very long acting neuromuscular blocking agent For a formal definition of the durations of actions associated with NMB agents, see page for gantacurium. The replacement of both the N-methyl groups with N-allyl moieties yielded N,N-diallyl-bis-nortoxiferine, now recognized as alcuronium.

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<span class="mw-page-title-main">Gantacurium chloride</span> Chemical compound

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<span class="mw-page-title-main">Laudexium metilsulfate</span> Chemical compound

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<span class="mw-page-title-main">Candocuronium iodide</span> Chemical compound

Candocuronium iodide is an aminosteroid neuromuscular-blocking drug. Its use in anesthesia for endotracheal intubation and to provide skeletal muscle relaxation during surgery or mechanical ventilation was briefly evaluated in clinical studies in India. However, further development was discontinued due to attendant cardiovascular effects, primarily tachycardia that was about the same as the clinically established pancuronium bromide. Candocuronium demonstrated a short duration in the body, but a rapid onset of action. It had little to no ganglion blocking activity, with a greater potency than pancuronium.

<span class="mw-page-title-main">Cholinergic blocking drug</span> Drug that block acetylcholine in synapses of cholinergic nervous system

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<span class="mw-page-title-main">Neuromuscular drug</span>

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References

  1. ↑ 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. 43: 305–319.
  2. ↑ Betcher AM (1977). "The civilizing of curare: a history of its development and introduction into anesthesiology". Anesthesia and Analgesia. 56 (2): 305–319. doi: 10.1213/00000539-197703000-00032 . PMID   322548.
  3. ↑ 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
  4. 1 2 Griffith HR, Johnson GE (1942). "The use of curare in general anesthesia". Anesthesiology. 3 (4): 418–420. doi: 10.1097/00000542-194207000-00006 . S2CID   71400545.
  5. ↑ Läwen A (1912). "Ueber die verbindung der lokakanaesthesie und epidurale injektion anesthesiernder losungen bei tabischen magenkrisen". Beitr Klin Chir. 80: 168–189.
  6. ↑ Wilkinson DJ (January 1991). "Dr F.P. de Caux--the first user of curare for anesthesia in England". Anaesthesia. 46 (1): 49–51. doi: 10.1111/j.1365-2044.1991.tb09317.x . PMID   1996757.
  7. ↑ Bennett AE (1941). "Curare: a preventive of traumatic complications in electroconvulsive shock therapy". Am J Psychiatry. 97: 1040–1060. doi:10.1176/ajp.97.5.1040.
  8. ↑ West R (October 1984). "An excursion into pharmacology: curare in medicine". Medical History. 28 (4): 391–405. doi:10.1017/s0025727300036279. PMC   1140012 . PMID   6390032.
  9. ↑ Burman MS (1939). "Therapeutic use of curare and erythroidine hydrochloride for spastic and dystonic states". Arch Neurol Psychiatry. 41 (2): 307–327. doi:10.1001/archneurpsyc.1939.02270140093008.
  10. ↑ Bevan DR (1992). ""Curare". In: Maltby JR, Shephard DAE (Eds.), Harold Griffith – His Life and Legacy". Can J Anaesth. 39 (1): 49–55.
  11. 1 2 Gray TC, Halton J (August 1946). "Curarine with Balanced Anaesthesia". British Medical Journal. 2 (4469): 293–295. doi:10.1136/bmj.2.4469.293. PMC   2054113 . PMID   20786887.
  12. ↑ King H (1948). "64. Curare alkaloids. Part VII. Constitution of dextrotubocurarine chloride". J Chem Soc: 265. doi:10.1039/jr9480000265.
  13. ↑ Everett AJ, Lowe LA, Wilkinson S (1970). "Revision of the structures of (+)-tubocurarine chloride and (+)-chondrocurine". J. Chem. Soc. Chem. Commun. (16): 1020. doi:10.1039/c29700001020.
  14. ↑ Dewick, P. M. Medicinal Natural Products; a Biosynthetic Approach. 3rd ed.; John Wiley and Sons Ltd.: 2009.
  15. ↑ Katzung BG (2001). Basic and clinical pharmacology:Introduction to autonomic pharmacology (8 ed.). The McGraw Hill Companies. pp. 75–91. ISBN   978-0-07-160405-5.
  16. ↑ Wenningmann I, Dilger JP (October 2001). "The kinetics of inhibition of nicotinic acetylcholine receptors by (+)-tubocurarine and pancuronium". Molecular Pharmacology. 60 (4): 790–796. PMID   11562442.
  17. ↑ Unna KR (March 1950). "Evaluation Of Curarizing Drugs in Man". The Journal of Pharmacology and Experimental Therapeutics. 98.
  18. ↑ Thompson MA (February 1980). "Muscle relaxant drugs". British Journal of Hospital Medicine. 23 (2): 153–4, 163–4, 167–8 passim. PMID   6102875.
  19. ↑ Page 151 in: Rang HP (2003). Pharmacology. Edinburgh: Churchill Livingstone. ISBN   0-443-07145-4. OCLC   51622037.
  20. ↑ Maclagen J (1976). "Competitive Neuromuscular Blocking Drugs". In Zaimis E (ed.). Neuromuscular Junction. Handbook of Experimental Pharmacology. Vol. 42. Berlin: Springer-Verlag. pp. 421–486. doi:10.1007/978-3-642-45476-9_6. ISBN   978-3-642-45476-9.
  21. ↑ "d-Tubocurarine (Prototype Nondepolarizing Neuromuscular Blocker)". Tulane University. Retrieved 4 May 2015.
  22. ↑ Bowman WC, Webb SN (October 1972). "Neuromuscular blocking and ganglion blocking activities of some acetylcholine antagonists in the cat". The Journal of Pharmacy and Pharmacology. 24 (10): 762–772. doi:10.1111/j.2042-7158.1972.tb08880.x. PMID   4403972. S2CID   27668701.
  23. ↑ Coleman AJ, Downing JW, Leary WP, Moyes DG, Styles M (October 1972). "The immediate cardiovascular effects of pancuronium, alcuronium and tubocurarine in man". Anaesthesia. 27 (4): 415–422. doi: 10.1111/j.1365-2044.1972.tb08247.x . PMID   4264060.
  24. ↑ Südhof TC (March 2001). "alpha-Latrotoxin and its receptors: neurexins and CIRL/latrophilins". Annual Review of Neuroscience. 24: 933–962. doi:10.1146/annurev.neuro.24.1.933. PMID   11520923. S2CID   906456.
  25. ↑ Allen GW (September 1953). "Black widow spider (Latrodectus mactans) poisoning treated with d-tubocurarine chloride". Annals of Internal Medicine. 39 (3): 624–625. doi:10.7326/0003-4819-39-3-624. PMID   13080907.
  26. ↑ Gesler RM, Hoppe JO (December 1956). "3, 6-bis(3-diethylaminopropoxy) pyridazine bismethiodide, a long-acting neuromuscular blocking agent". The Journal of Pharmacology and Experimental Therapeutics. 118 (4): 395–406. PMID   13385800.
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