mivacurium

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mivacurium chloride

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2013/02/03 14:14:45」(JST)

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Mivacurium chloride

Systematic (IUPAC) name
(1R,1'R)-2,2'-[[(4E)-1,8-dioxooct-4-ene-1,8-diyl]bis(oxypropane-3,1-diyl)]bis[6,7-dimethoxy-2-methyl-1-(3,4,5-trimethoxybenzyl)-1,2,3,4-tetrahydroisoquinolinium]
Clinical data
AHFS/Drugs.com	International Drug Names
Pregnancy cat.	?
Legal status	Worldwide: prescription only medicine
Routes	IV
Pharmacokinetic data
Bioavailability	100% (IV)
Metabolism	ester hydrolysis by plasma cholinesterases
Identifiers
CAS number	106791-40-6
ATC code	M03AC10
PubChem	CID 71316
DrugBank	DB01226
UNII	600ZG213C3 Y
ChEMBL	CHEMBL984 Y
Synonyms	bis[3-[6,7-dimethoxy-2-methyl-1-[(3,4,5-trimethoxyphenyl)methyl]-3,4-dihydro-1H-isoquinolin-2-yl]propyl] oct-4-enedioate
Chemical data
Formula	C58H80N2O14+2
Mol. mass	1029.26 g/mol

Mivacurium chloride (formerly recognized as BW1090U81, BW B1090U or BW1090U) is a short-duration non-depolarizing 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.

Structure

Mivacurium is a symmetrical molecule although it is a mixture of three of the twenty possible isomers: the isomerism stems from chirality at the C-1 carbon position of both the tetrahydroisoquinolinium rings, as well as both the positively charged nitrogen (onium) heads, and the E/Z diastereomerism at the C=C double bond of the oct-4-ene diester bridge. Thus, owing to the symmetry and chirality, the three isomers of mivacurium are (E)-1R,1'R,2R,2'R, (identified as BW1217U84), (E)-1R,1'R,2R,2'S, (BW1333U83) and (E)-1R,1'R,1'S,2'S, (BW1309U83). These are also known as cis-cis, cis-trans and trans-trans Mivacurium. The proportions are; (E)-cis-cis 6% of the mixture, (E)-cis-trans 36% of the mixture and (E)-trans-trans 56% of the mixture. Unlike the potency of the cis-cis isomer of Atracurium (also known as 51W89 and eventually marketed as the drug cisatracurium), the cis-cis isomer of mivacurium has by far the lowest potency as a muscle relaxant when compared with its other two stereoisomers. It has approximately 10% of the activity of each of the other two structures.

Mivacurium belongs to a class of compounds that is commonly and most erroneously referred to as "benzylisoquinolines" when, in fact, it is a bisbenzyltetrahydroisoquinolinium agent, often abbreviated to bbTHIQ.

The orientation of the two O atoms in the bridge is to the THIQ side of the carbonyl C=O group, whereas in Atracurium the O atom is on the bridge side. Atracurium's groups are "reversed ester" linkages. This makes ester hydrolysis degradation by plasma cholinesterase more favourable.

Pharmacology

Having ten methoxy -OCH₃ groups, mivacurium is a more potent neuromuscular blocking drug than Atracurium, which has eight, but is less potent than Doxacurium, which has twelve.

Like other non-depolarizing neuromuscular blockers, the pharmacological action of mivacurium antagonism to nicotinic acetylcholine receptors. However, unlike other non-depolarizing neuromuscular blockers, it is metabolized by plasma cholinesterase. Metabolism can therefore be very slow in people with pseudocholinesterase deficiency, resulting in prolonged paralysis. The same problem exists with the depolarizing NMB succinylcholine.

Availability

Mivacurium is available worldwide although, in recent years, its use in the United States has declined rapidly in favor of alternative agents perceived to offer a more rapid onset of action and a safer cardiovascular profile when administered in a rapid bolus dose. It is far more commonly used in Europe and the United Kingdom. The drug is marketed worldwide under the tradename of Mivacron.

History

Mivacurium represents the second generation of tetrahydroisoquinolinium neuromuscular blocking drugs in a long lineage of nicotinic acetylcholine receptor anatagonists synthesized by Mary M. Jackson and James C. Wisowaty, PhD (both chemists within the Chemical Development Laboratories at Burroughs Wellcome Co., Research Triangle Park, NC) 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). Specifically, mivacurium was first synthesized in 1981. Early structure-activity studies had confirmed that the bulky nature of the "benzylisoquinolinium" entity provided a non-depolarizing mechanism of action. Partial saturation of the benzylisoquinoline ring to the tetrahydroisoquinoline ring provided an even further increase in potency of the molecules without detrimental effects to other pharmacological properties: this key finding led to the rapid adoption of the tetrahydroisoquinolinium structures as a standard building block (along with a 1-benzyl attachment), and it is the primary reason why the continued unwarranted reference to "benzylisoquinolinium" is a complete misnomer for all clinically introduced and currently used neuromuscular blocking agents in this class because they are all, in fact, tetrahydroisoquinoline derivatives. By definition, therefore, there has never been, in the history of clinical anesthetic practice, the use of a benzylisoquinoline neuromuscular blocking agent.

The heritage of mivacurium and indeed its very closely related cousin, doxacurium chloride, harks back to the synthesis of numerous compounds following structure-activity relationships that drove researchers to find the ideal replacement for succinylcholine (suxamethonium). Both mivacurium and doxacurium are descendants of early vigorous attempts to synthesize potent non-depolarizing agents with pharmacophores derived from cross-combinations of the non-depolarizing agent, laudexium, and the well-known depolarizing agent, succinylcholine (suxamethonium chloride). Ironically, laudexium itself was invented by a cross-combination between the prototypical non-depolarizing agent, d-tubocurarine and the depolarizing agent, decamethonium. From the 1950s through to the 1970s, the present-day concept of a neuromuscular blocking agent with a rapid onset and an ultra-short duration of action had not taken root: researchers and clinicians were still on the quest for potent but non-depolarizing replacements devoid of the histamine release and the dreaded "recurarizing" effects seen with tubocurarine and, more importantly, the absence of a depolarizing mechanism of action as seen with succinylcholine and decamethonium.

Clinical pharmacology and pharmacokinetics

The first clinical trial of mivacurium (BW1090U), in 1984, was conducted in a cohort of 63 US patients undergoing surgical anesthesia. at the Harvard Medical School at Massachusetts General Hospital, Boston, MA. Preliminary data from the study confirmed a promise for this agent to elicit considerably lesser severity of histamine release than that observed with its immediate predecessor clinically tested agents, BW785U77 and BWA444U, which were discontinued from further clinical development. Mivacurium did not exhibit the ultra-short duration of action seen with BW785U; whereas, BW A444U produced an intermediate duration of action.

Mivacurium is a biodegradable neuromuscular blocking agent owing to its degradation by plasma cholinesterases - the esterases rapidly hydrolyze one ester moiety initially resulting in a two mono-quaternary metabolites of which one still has an intact ester moiety. The second ester is metabolized much more slowly, although the lack of a bis-quaternary structure effectively terminates the neuromusuclar blocking action.

References

UpToDate Contents

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• 1. 重症患者における神経筋遮断剤の使用 use of neuromuscular blocking medications in critically ill patients
• 2. 成人における迅速導入気管挿管のための神経筋遮断剤（NMBA） neuromuscular blocking agents nmba for rapid sequence intubation in adults
• 3. 周術期アナフィラキシー：臨床症状、病因、および診断 perioperative anaphylaxis clinical manifestations etiology and diagnosis
• 4. 周術期アナフィラキシー：再発反応の評価および予防 perioperative anaphylaxis evaluation and prevention of recurrent reactions
• 5. 非心臓手術施行時の肥満患者に対する麻酔 anesthesia for the obese patient undergoing non cardiac surgery

English Journal

• Sex-related differences in the relationship between acceleromyographic adductor pollicis train-of-four ratio and clinical manifestations of residual neuromuscular block: a study in healthy volunteers during near steady-state infusion of mivacurium.

• Heier T, Feiner JR, Wright PM, Ward T, Caldwell JE.SourceDepartment of Anesthesia and Perioperative Care, University of California, San Francisco, CA, USA. tom.heier@medisin.uio.no
• British journal of anaesthesia.Br J Anaesth.2012 Mar;108(3):444-51. Epub 2011 Dec 26.
• BACKGROUND: Studies in volunteers suggest that train-of-four (TOF) ratios >0.9 are needed to retain normal function of muscles involved in upper airway patency, swallowing, and vital capacity breathing. We determined if sex-related differences exist in the relationship between adductor pollicis (
• PMID 22201183

• Early and late parameters describing the offset of neuromuscular blockade are highly intercorrelated.

• Dubois PE, Gourdin M, Jamart J, Broka SM, Eucher P, D'Hollander A.SourceDepartment of Anaesthesiology, University of Louvain, CHU Mont-Godinne, Yvoir, Belgium. phil.dubois@uclouvain.be
• Acta anaesthesiologica Scandinavica.Acta Anaesthesiol Scand.2012 Jan;56(1):76-82. doi: 10.1111/j.1399-6576.2011.02596.x.
• BACKGROUND: Neuromuscular blocking agents have always shown wide inter-individual variability when it comes to their duration of action. This prevents clinicians from anticipating the evolution of the neuromuscular block for any given patient. With this study, we aimed to assess the nature of the re
• PMID 22150409

Japanese Journal

• Comparative fading responses induced by mivacurium, cisatracurium, and d-tubocurarine in the evoked muscular compound action potentials of the cat

• SUZUKI TAKAHIRO,MUNAKATA KAZUHIKO,WATANABE NAOTO,FUKANO NAOKO,SAEKI SHIGERU,OGAWA SETSURO
• Journal of anesthesia 17(2), 98-103, 2003-05-20
• NAID 50000854127

• Evaluation of neuromuscular and cardiovascular effects of two doses of rapacuronium (ORG 9487) versus mivacurium and succinylcholine

• MIGUEL R
• Anesthesiology 91, 1648-1654, 1999
• NAID 30009125937

• Interactions between mivacurium and pancuronium

• KIM KS
• Br J Anaesth 79, 19-23, 1997
• NAID 10009924837

Related Links

• Mivacurium - FDA prescribing information, side effects and uses

mivacurium official prescribing information for healthcare professionals. Includes: indications, dosage, adverse reactions, pharmacology and more. ... Administration of mivacurium over 30 to 60 seconds does not alter the time to ...

• mivacurium - definition of mivacurium by Medical dictionary

mivacurium /mi·va·cu·rium/ (mi″vah-ku?re-um) a nondepolarizing neuromuscular blocking agent of short duration, used as the chloride salt as an adjunct to anesthesia. mivacurium, a nondepolarizing neuromuscular blocker. indications ...

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