Mivacurium chloride

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Mivacurium chloride
Clinical data
Trade namesMivacron
Other namesbis[3-[6,7-dimethoxy-2-methyl-1-[(3,4,5-trimethoxyphenyl)methyl]-3,4-dihydro-1H-isoquinolin-2-yl]propyl] oct-4-enedioate
AHFS/Drugs.comInternational Drug Names
Routes of
administration		IV
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability100% (IV)
Metabolismester hydrolysis by plasma cholinesterases
Identifiers
  • (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]
JSmol)
SMILES
  • C[N+]1(CCc2cc(c(cc2[C@H]1Cc3cc(c(c(c3)OC)OC)OC)OC)OC)CCCOC(=O)CC/C=C/CCC(=O)OCCC[N+]4(CCc5cc(c(cc5[C@H]4Cc6cc(c(c(c6)OC)OC)OC)OC)OC)C.[Cl-].[Cl-]
  • InChI=1S/C58H80N2O14.2ClH/c1-59(25-21-41-35-47(63-3)49(65-5)37-43(41)45(59)29-39-31-51(67-7)57(71-11)52(32-39)68-8)23-17-27-73-55(61)19-15-13-14-16-20-56(62)74-28-18-24-60(2)26-22-42-36-48(64-4)50(66-6)38-44(42)46(60)30-40-33-53(69-9)58(72-12)54(34-40)70-10;;/h13-14,31-38,45-46H,15-30H2,1-12H3;2*1H/q+2;;/p-2/b14-13+;;/t45-,46-,59?,60?;;/m1../s1
  • Key:WMSYWJSZGVOIJW-ONUALHDOSA-L

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

neuromuscular-blocking drugs,[2] used adjunctively in anesthesia to facilitate endotracheal intubation[3] and to provide skeletal muscle relaxation during surgery or mechanical ventilation
.

Structure

Mivacurium is a symmetrical molecule existing as a mixture of three of 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

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 erroneously[

editorializing][citation needed
] referred to as "benzylisoquinolines;" mivacurium is in fact 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 blocking agents, the pharmacological action of mivacurium is

succinylcholine).[4]

Availability

Mivacurium is available worldwide. It became unavailable in the United States in 2006 due to manufacturing issues, but was reintroduced in 2016.[5]

History

Mivacurium represents the second generation of tetrahydroisoquinolinium

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,

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.[6] 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[7][8] and BWA444U,[9] 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 neuromuscular blocking action.

References

  1. PMID 19352159
    .
  2. PMID 15989744
    .
  3. PMID 16464937
    .
  4. ISBN 978-0-07-173616-9
    .
  5. ^ Soto RG, Dunipace D (May 2017). "Mivacurium: Return of a Drug Seeking an Indication?". ASA Monitor. 81 (5): 30–31.
  6. doi:10.1097/00000542-198509001-00318
    .
  7. doi:10.1097/00000542-198009001-00274
    .
  8. doi:10.1097/00000542-198009001-00275
    .
  9. S2CID 22212818
    .
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