Cisatracurium besilate

Cisatracurium besilate

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Systematic (IUPAC) name
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-dimethoxy phenyl)methyl]-6,7-dimethoxy-2-methyl-3,4-dihydro- 1H-isoquinolin-2-yl]propanoate
Clinical data
Pregnancy category	B
Routes of administration	IV use only
Legal status
Legal status	Worldwide: prescription only medicine
Pharmacokinetic data
Bioavailability	100% (IV)
Metabolism	80% Hoffman degradation/ Hepatic
Biological half-life	20-29 minutes
Excretion	10-15% unchanged
Identifiers
CAS Number	96946-42-8
ATC code	M03AC11 (WHO)
PubChem	CID 62887
DrugBank	APRD00874
Chemical data
Formula	C53H72N2O12
Molar mass	929.145 g/mol[[]]

Cisatracurium (formerly recognized as 51W89, and marketed as Nimbex™) is a neuromuscular blocking drug or skeletal muscle relaxant in the category of 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 is a bisbenzyltetrahydroisoquinolinium agent with an intermediate duration of action. Cisatracurium is one of the ten isomers of the parent molecule, atracurium. Moreover, cisatracurium represents ~15% of the atracurium mixture.

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 the cis-cis isomer comprising the ten isomers of the parent, atracurium. 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, Mary M. Jackson and James C. Wisowaty, PhD (both chemists within the Chemical Development Laboratories at Burroughs Wellcome Co.) first synthesized cisatracurium as an individual molecule in its own right. The pharmacological research of these individual isomers 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 anesthesiolgist 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.

Owing to the intense marketing rivalry, during the 1980s and 1990s, between the then two major competitors in this area of anesthesia (i.e., Organon Inc. and Burroughs Wellcome, Co.), it was not surprising then that the knives of scrutiny and skepticism were already being sharpened against cisatracurium in the court of peer-reviewed publications even before the voluminous documentation necessary for impartial review and approval of the drug had barely been dispatched to the desks at the US Food and Drug Administration.

Preclinical Pharmacology

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

Clinical pharmacology

As is evident with the parent molecule, atracurium, cisatracurium is also susceptible to degradation by Hofmann elimination and ester hydrolysis as components of the in vivo metabolic processes. 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, whereas a decrease in temperature slows down the process.

One of the metabolites of cistracurium via Hofmann elimination is laudanosine - see the atracurium page for further discussion of the issue regarding this metabolite and its undesirable CNS effects. 80% of cisatracurium is metabolized eventually to laudanosine and 20% is metabolized hepatically or excreted renally. 10-15% of the dose is excreted unchanged in the urine.

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.

Adverse effects

Histamine release - hypotension, reflex tachycardia and cutaneous flush

Unlike the parent, atracurium, cisatracurium affords a much better pharmacological profile with respect to eliciting histamine release.

Bronchospasm - Pulmonary compliance

To date, cisatracurium has not been reported to elicit bronochospasm 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 and cardiovascular effects such a hypotension and bradycardia. Presently, 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.

Further reading

• Caldwell JE (1995). "New skeletal muscle relaxants". Int Anesthesiol Clin. 33 (1): 39–60. PMID 7635557. 
• Hull CJ (1995). "Pharmacokinetics and pharmacodynamics of the benzylisoquinolinium muscle relaxants". Acta Anaesthesiol Scand. 106 Suppl: 13–17. PMID 8533537. 
• Savarese JJ, Wastila WB (1995). "The future of the benzylisoquinolinium relaxants". Acta Anaesthesiol Scand. 106 Suppl: 91–93. PMID 8533554. 
• Esmaoglu A, Akin A, Mizrak A, Turk Y, Boyaci A (2006). "Addition of cisatracurium to lidocaine for intravenous regional anesthesia". J Clin Anesth. 18 (3): 194–7. doi:10.1016/j.jclinane.2005.08.003. PMID 16731321. CS1 maint: Multiple names: authors list (link)
• Melloni C, Devivo P, Launo C, Mastronardi P, Novelli G, Romano E (2006). "Cisatracurium versus vecuronium: a comparative, double blind, randomized, multicenter study in adult patients under propofol/fentanyl/N₂O anesthesia". Minerva Anestesiol. 72 (5): 299–308. PMID 16675938. CS1 maint: Multiple names: authors list (link)
• Serra C, Oliveira A (2006). "Cisatracurium: myographical and electrophysiological studies in the isolated rat muscle". Fundam Clin Pharmacol. 20 (3): 291–8. doi:10.1111/j.1472-8206.2006.00395.x. PMID 16671964. 

de:Cis-Atracurium pt:Cis-atracúrio