Mivacurium chloride

Mivacurium chloride

File:Mivacurium.svg
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
Routes of administration	IV
Legal status
Legal status	Worldwide: prescription only medicine
Pharmacokinetic data
Bioavailability	100% (IV)
Metabolism	ester hydrolysis by plasma cholinesterases
Identifiers
CAS Number	106791-40-6
ATC code	M03AC10 (WHO)
PubChem	CID 71316
DrugBank	APRD01119
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
Molar mass	1029.26 g/mol[[]]

Mivacurium chloride (formerly recognized as BW1090U81, BW B1090U or BW1090U) 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.

Chemistry

Mivacurium is a symmetrical molecule although it is a mixture of three isomers: the isomerism stems from chirality at the C-1 carbon position of the tetrahydroisoquinoline ring as well as the positively charged nitrogen (onium) heads. Thus, owing to the symmetry and chirality, the three isomers of mivacurium are R,R-R,R (identified as BW1217U84), R,R-R,S (BW1333U83) and R,S-R,S (BW1309U83).

The pharmacological action of mivacurium is a function of its competitive antagonism to acetylcholine receptors of the nicotinic type. The drug is marketed worldwide under the tradename of Mivacron®, and is classified as a short-duration non-depolarizing neuromuscular blocking agent: it belongs to a class of compounds that is commonly and most erroneously referred to as "benzylisoquinolines" when, in fact, it is a bisbenzyltetrahydroisoquinolinium agent.

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.

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 anesthesiolgist 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 agent, BW785U77, which was discontinued from further clinical development. However, unlike BW785U, mivacurium was not an agent with an ultra-short 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

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