Cisatracurium besilate

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Cisatracurium besilate
Cisatracurium Besylate.png
Clinical data
Trade names Nimbex
Other names51W89, cisatracurium besylate (USAN US)
AHFS/Drugs.com Monograph
License data
Pregnancy
category
  • AU:C
Routes of
administration
Intravenous
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • CA: ℞-only
  • UK: POM (Prescription only)
  • US: ℞-only
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability 100% (IV)
Metabolism 80% Hofmann degradation/ liver
Elimination half-life 20–29 minutes
Excretion 10-15% unchanged
Identifiers
  • 5-[3-[(1R,2R)-1-[(3,4-Dimethoxyphenyl)methyl]-6,7-dimethoxy-2-methyl-3,4-dihydro-1H-isoquinolin-2-yl]propanoyloxy]pentyl 3-[(1R,2R)-1-[(3,4-dimethoxyphenyl)methyl]-6,7-dimethoxy-2-methyl-3,4-dihydro-1H-isoquinolin-2-yl]propanoate benzenesulfonate (1:2)
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.149.509 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C65H82N2O18S2
Molar mass 1243.49 g·mol−1
3D model (JSmol)
  • [O-]S(=O)(=O)c1ccccc1.[O-]S(=O)(=O)c1ccccc1.O=C(OCCCCCOC(=O)CC[N@@+]2([C@@H](c1c(cc(OC)c(OC)c1)CC2)Cc3ccc(OC)c(OC)c3)C)CC[N@+]5(C)[C@@H](c4cc(OC)c(OC)cc4CC5)Cc6ccc(OC)c(OC)c6
  • InChI=1S/C53H72N2O12.2C6H6O3S/c1-54(22-18-38-32-48(62-7)50(64-9)34-40(38)42(54)28-36-14-16-44(58-3)46(30-36)60-5)24-20-52(56)66-26-12-11-13-27-67-53(57)21-25-55(2)23-19-39-33-49(63-8)51(65-10)35-41(39)43(55)29-37-15-17-45(59-4)47(31-37)61-6;2*7-10(8,9)6-4-2-1-3-5-6/h14-17,30-35,42-43H,11-13,18-29H2,1-10H3;2*1-5H,(H,7,8,9)/q+2;;/p-2/t42-,43-,54-,55-;;/m1../s1 Yes check.svgY
  • Key:XXZSQOVSEBAPGS-DONVQRBFSA-L Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Cisatracurium besilate (INN; cisatracurium besylate (USAN); formerly recognized as 51W89; [1] trade name Nimbex) is a bisbenzyltetrahydroisoquinolinium that has effect as a neuromuscular-blocking drug non-depolarizing neuromuscular-blocking drugs, used adjunctively in anesthesia to facilitate endotracheal intubation and to provide skeletal muscle relaxation during surgery or mechanical ventilation. It shows intermediate duration of action. Cisatracurium is one of the ten isomers of the parent molecule, atracurium. [2] Moreover, cisatracurium represents approximately 15% of the atracurium mixture. [3]

Contents

History

The generic name cisatracurium was conceived by scientists at Burroughs Wellcome Co. (now part of GlaxoSmithKline) by combining the name "atracurium" with "cis" [hence cisatracurium] because the molecule is one of the three cis-cis isomers comprising the ten isomers of the parent, atracurium. [2] Atracurium itself was invented at Strathclyde University and licensed to Burroughs Wellcome Co., Research Triangle Park, NC, for further development and subsequent marketing as Tracrium. As the secondary pharmacology of atracurium was being developed, it became clear that the primary clinical disadvantage of atracurium was likely to be its propensity to elicit histamine release. To address this issue, a program was initiated to investigate the individual isomer constituents of atracurium to identify and isolate the isomer(s) associated with the undesirable histamine effects as well as identify the isomer that might possibly retain the desirable properties without the histamine release. Thus, in 1989, D A Hill and G L Turner, PhD (both chemists at Burroughs Wellcome Co., Dartford, UK) first synthesized cisatracurium as an individual isomer molecule. The pharmacological research of cisatracurium and the other individual isomers [4] was then developed further primarily by R. Brandt Maehr and William B. Wastila, PhD (both of whom were pharmacologists within the Division of Pharmacology at Burroughs Wellcome Co.) in collaboration with John J. Savarese MD (who at the time was an anesthesiologist in the Dept. of Anesthesia, Harvard Medical School at the Massachusetts General Hospital, Boston, MA). Thereafter, the entire clinical development of cisatracurium was completed in a record short period from 1992 to 1994: the team of scientists was led by J. Neal Weakly PhD, Martha M. Abou-Donia PhD, and Steve Quessy PhD, in the Division of Clinical Neurosciences at Burroughs Wellcome Co., Research Triangle Park, NC. By the time of its approval for human use, in 1995, by the US Food and Drug Administration, Burroughs Wellcome Co. had merged with Glaxo Inc., and cisatracurium was approved to be marketed as Nimbex by GlaxoWellcome Inc. The trade name "Nimbex" was derived from inserting an "i" to the original proposal "Nmbex," which stood for excellent Neuromuscular blocker.[ citation needed ]

Preclinical pharmacology

In vitro studies using human plasma indicated that cisatracurium spontaneously degrades at physiological pH via Hofmann elimination to yield laudanosine and the quaternary monoacrylate. Subsequent ester hydrolysis of the monoacrylate generates the monoquaternary alcohol, although the rate-limiting step is Hofmann elimination. [3] In rat plasma, cisatracurium is also metabolized by non-specific carboxylesterases (a rate-limiting step) to the monoquaternary alcohol and the monoquaternary acid. [3]

Clinical pharmacology

As is evident with the parent molecule, atracurium, [5] [6] cisatracurium is also susceptible to degradation by Hofmann elimination and ester hydrolysis as components of the in vivo metabolic processes.[ citation needed ] See the atracurium page for information on Hofmann elimination in vivo versus the Hofmann degradation chemical reaction.

Because Hofmann elimination is a temperature- and plasma pH-dependent process, cisatracurium's rate of degradation in vivo is highly influenced by body pH and temperature just as it is with the parent molecule, atracurium: thus, an increase in body pH favors the elimination process,[ citation needed ] whereas a decrease in temperature slows down the process.

One of the metabolites of cisatracurium via Hofmann elimination is laudanosine – see the atracurium page for further discussion of the issue regarding this metabolite. 80% of cisatracurium is metabolized eventually to laudanosine and 20% is metabolized hepatically or excreted renally.[ citation needed ] 10-15% of the dose is excreted unchanged in the urine.[ citation needed ]

Since Hofmann elimination is an organ-independent chemodegradative mechanism, there is little or no risk to the use of cisatracurium in patients with liver or renal disease when compared with other neuromuscular-blocking agents. [7]

The two reverse ester linkages in the bridge between the two isoquinolinium groups make atracurium and cisatracurium poor targets for plasma cholinesterase, unlike mivacurium which has two conventional ester linkages.

Adverse effects

Histamine release – hypotension, reflex tachycardia and cutaneous flush

Bronchospasm – Pulmonary compliance

To date, cisatracurium has not been reported to elicit bronchospasm at doses that are clinically prescribed.

Laudanosine – Epileptic foci

Cisatracurium undergoes Hofmann elimination as a primary route of chemodegradation: consequently one of the metabolites from this process is laudanosine, a tertiary amino alkaloid reported to be a modest CNS stimulant with epileptogenic activity [8] and cardiovascular effects such as low blood pressure and a slowed heart rate. [9] As a tertiary amine, Laudanosine is unionised and readily crosses the blood–brain barrier. Presently,[ when? ] there is little evidence that laudanosine accumulation and related toxicity will likely ever be seen with the doses of cisatracurium that are administered in clinical practice especially given that the plasma concentrations of laudanosine generated are lower with cisatracurium than those seen with atracurium. [9]

Research

A recent[ when? ] study showed that cisatracurium pretreatment effectively decreases the incidence and severity of pain induced by propofol general anaesthesia. [10] Another study showed that hiccups accompanied by vomiting, insomnia, shortness of breath can also be relieved by the nondepolarizing muscle relaxant, cisatracurium, during total intravenous anesthesia. [11]

Synthesis

Cisatracuronium synthesis: Cisatracuronium synthesis.svg
Cisatracuronium synthesis:

Treatment of 1,5-Pentanediol with 3-bromopropionyl chloride gives the corresponding ester; dehydrohalogenation of the ester with triethylamine then gives the bis-acrylate (2). Reaction of that unsaturated ester with tetrahydropapaverine [13] [14] (3) leads to conjugate addition of the secondary amine and formation of the intermediate (4). Alkylation with methyl benzenesulfonate forms the bis-quaternary salt, affording cisatracuronium (5).

Related Research Articles

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Sodium thiopental, also known as Sodium Pentothal, thiopental, thiopentone, or Trapanal, is a rapid-onset short-acting barbiturate general anesthetic. It is the thiobarbiturate analog of pentobarbital, and an analog of thiobarbital. Sodium thiopental was a core medicine in the World Health Organization's List of Essential Medicines, but was supplanted by propofol. Despite this, thiopental is listed as an acceptable alternative to propofol, depending on local availability and cost of these agents. It was previously the first of three drugs administered during most lethal injections in the United States, but the US manufacturer Hospira stopped manufacturing the drug in 2011 and the European Union banned the export of the drug for this purpose. Although thiopental abuse carries a dependency risk, its recreational use is rare.

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

Suxamethonium chloride, [Scoline, Sucostrin] 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">Sevoflurane</span> Inhalational anaesthetic

Sevoflurane, sold under the brand name Sevorane, among others, is a sweet-smelling, nonflammable, highly fluorinated methyl isopropyl ether used as an inhalational anaesthetic for induction and maintenance of general anesthesia. After desflurane, it is the volatile anesthetic with the fastest onset. While its offset may be faster than agents other than desflurane in a few circumstances, its offset is more often similar to that of the much older agent isoflurane. While sevoflurane is only half as soluble as isoflurane in blood, the tissue blood partition coefficients of isoflurane and sevoflurane are quite similar. For example, in the muscle group: isoflurane 2.62 vs. sevoflurane 2.57. In the fat group: isoflurane 52 vs. sevoflurane 50. As a result, the longer the case, the more similar will be the emergence times for sevoflurane and isoflurane.

<span class="mw-page-title-main">General anaesthesia</span> Medically induced loss of consciousness

General anaesthesia (UK) or general anesthesia (US) is a method of medically inducing loss of consciousness that renders a patient unarousable even with painful stimuli. This effect is achieved by administering either intravenous or inhalational general anaesthetic medications, which often act in combination with an analgesic and neuromuscular blocking agent. Spontaneous ventilation is often inadequate during the procedure and intervention is often necessary to protect the airway. General anaesthesia is generally performed in an operating theater to allow surgical procedures that would otherwise be intolerably painful for a patient, or in an intensive care unit or emergency department to facilitate endotracheal intubation and mechanical ventilation in critically ill patients.

<span class="mw-page-title-main">Propofol</span> Intravenous medication used in anesthesia

Propofol is the active component of an intravenous anesthetic formulation used for induction and maintenance of general anesthesia. It is chemically termed 2,6-diisopropylphenol. The formulation was originally approved under the brand name Diprivan. Numerous generic offerings of this formulation now exist. Intravenous administration is used to induce unconsciousness after which anesthesia may be maintained using a combination of medications. It is manufactured as part of a sterile injectable emulsion formulation using soybean oil and lecithin, giving it a white milky coloration.

<span class="mw-page-title-main">Anesthetic</span> Drug that causes anesthesia

An anesthetic or anaesthetic is a drug used to induce anesthesia ⁠— ⁠in other words, to result in a temporary loss of sensation or awareness. They may be divided into two broad classes: general anesthetics, which result in a reversible loss of consciousness, and local anesthetics, which cause a reversible loss of sensation for a limited region of the body without necessarily affecting consciousness.

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<span class="mw-page-title-main">Atracurium besilate</span> Chemical compound

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

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References

  1. Meretoja OA, Taivainen T, Wirtavuori K (January 1995). "Pharmacodynamic effects of 51W89, an isomer of atracurium, in children during halothane anaesthesia". British Journal of Anaesthesia. 74 (1): 6–11. doi: 10.1093/bja/74.1.6 . PMID   7880708.
  2. 1 2 Stenlake JB, Waigh RD, Dewar GH, Dhar NC, Hughes R, Chapple DJ, Lindon JC, Ferrige AG (1984). "Biodegradable neuromuscular blocking agents. Part 6. Stereochemical studies on atracurium and related polyalkylene di-esters". Eur J Med Chem. 19 (5): 441–450.
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  4. Wastila WB, Maehr RB, Turner GL, Hill DA, Savarese JJ (July 1996). "Comparative pharmacology of cisatracurium (51W89), atracurium, and five isomers in cats". Anesthesiology. 85 (1): 169–177. doi: 10.1097/00000542-199607000-00023 . PMID   8694363. S2CID   23963554.
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  6. Nigrovic V, Fox JL (March 1991). "Atracurium decay and the formation of laudanosine in humans". Anesthesiology. 74 (3): 446–454. doi: 10.1097/00000542-199103000-00010 . PMID   2001023.
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  9. 1 2 Fodale V, Santamaria LB (July 2002). "Laudanosine, an atracurium and cisatracurium metabolite". European Journal of Anaesthesiology. 19 (7): 466–473. doi:10.1017/s0265021502000777. PMID   12113608.
  10. Kim YH, Namgung J, Lim CH (April 2014). "Cisatracurium pretreatment with tourniquet reduces propofol injection pain: a double-blind randomized controlled trial". The Journal of International Medical Research. 42 (2): 360–367. doi: 10.1177/0300060514522602 . PMID   24573971.
  11. Wu JP, An JX, Qian XY, Wang Y (April 2018). "Successful Treatment of Idiopathic Intractable Hiccup With Cisatracurium Under Intravenous General Anesthesia: A Case Report". A&A Practice. 10 (7): 171–172. doi:10.1213/XAA.0000000000000651. PMID   29210718. S2CID   4576656.
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  13. Schmidt A (2003). Heterocyclic Mesomeric Betaines and Analogs in Natural Product Chemistry. Betainic Alkaloids and Nucleobases. Advances in Heterocyclic Chemistry. Vol. 85. pp. 67–171. doi:10.1016/S0065-2725(03)85002-X. ISBN   978-0-12-020785-5.
  14. Chandra R, Kaur J, Talwar A, Ghosh NN (2001). "Synthesis and antispasmodic effect of aryl substituted N-carbamoyl/thiocarbamoyl isoquinolines". Arkivoc. 2001 (8): 129–135. doi: 10.3998/ark.5550190.0002.814 . hdl: 2027/spo.5550190.0002.814 .

Further reading