Mivacurium
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Mivacurium chloride (formerly recognized as BW1090U81, BW B1090U or BW1090U) is a short-duration non-depolarizing neuromuscular-blocking drug or
skeletal muscle relaxant A muscle relaxant is a drug that affects skeletal muscle function and decreases the muscle tone. It may be used to alleviate symptoms such as muscle spasms, pain, and hyperreflexia. The term "muscle relaxant" is used to refer to two major therapeu ...
in the category of non-depolarizing neuromuscular-blocking drugs, used adjunctively in
anesthesia Anesthesia is a state of controlled, temporary loss of sensation or awareness that is induced for medical or veterinary purposes. It may include some or all of analgesia (relief from or prevention of pain), paralysis (muscle relaxation), ...
to facilitate endotracheal intubation and to provide
skeletal muscle Skeletal muscles (commonly referred to as muscles) are organs of the vertebrate muscular system and typically are attached by tendons to bones of a skeleton. The muscle cells of skeletal muscles are much longer than in the other types of muscl ...
relaxation during
surgery Surgery ''cheirourgikē'' (composed of χείρ, "hand", and ἔργον, "work"), via la, chirurgiae, meaning "hand work". is a medical specialty that uses operative manual and instrumental techniques on a person to investigate or treat a pat ...
or
mechanical ventilation Mechanical ventilation, assisted ventilation or intermittent mandatory ventilation (IMV), is the medical term for using a machine called a ventilator to fully or partially provide artificial ventilation. Mechanical ventilation helps move air ...
.


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
atracurium Atracurium besilate, also known as atracurium besylate, is a medication used in addition to other medications to provide skeletal muscle relaxation during surgery or mechanical ventilation. It can also be used to help with endotracheal intubatio ...
(also known as 51W89 and eventually produced as the drug
cisatracurium Cisatracurium besilate (INN; cisatracurium besylate (USAN); formerly recognized as 51W89; trade name Nimbex) is a bisbenzyltetrahydroisoquinolinium that has effect as a neuromuscular-blocking drug non-depolarizing neuromuscular-blocking drugs, u ...
), 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 referred to as "benzylisoquinolines;" mivacurium is in fact a ''bis''benzyltetrahydroisoquinolinium 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 Doxacurium chloride (formerly recognized as BW938U80 or BW A938U) is a neuromuscular-blocking drug or skeletal muscle relaxant in the category of non-depolarizing neuromuscular-blocking drugs, used adjunctively in anesthesia to provide skeletal m ...
(which has twelve). Like other non-depolarizing neuromuscular blocking agents, the pharmacological action of mivacurium is antagonism to nicotinic acetylcholine receptors. However, unlike other non-depolarizing neuromuscular blockers, it is metabolized by
plasma cholinesterase Butyrylcholinesterase (HGNC symbol BCHE; EC 3.1.1.8), also known as BChE, BuChE, BuChase, pseudocholinesterase, or plasma (cholin)esterase, is a nonspecific cholinesterase enzyme that hydrolyses many different choline-based esters. In humans, it ...
(similar to the depolarizing neuromuscular blocking agent succinylcholine).


Availability

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


History

Mivacurium represents the second generation of tetrahydroisoquinolinium
neuromuscular blocking drugs Neuromuscular-blocking drugs block neuromuscular transmission at the neuromuscular junction, causing paralysis of the affected skeletal muscles. This is accomplished via their action on the post-synaptic acetylcholine (Nm) receptors. In c ...
in a long lineage of nicotinic acetylcholine receptor antagonists synthesized by Mary M. Jackson and James C. Wisowaty, PhD (both chemists within the Chemical Development Laboratories at
Burroughs Wellcome Co. GSK plc, formerly GlaxoSmithKline plc, is a British multinational pharmaceutical and biotechnology company with global headquarters in London, England. Established in 2000 by a merger of Glaxo Wellcome and SmithKline Beecham. GSK is the tent ...
,
Research Triangle Park, NC Research Triangle Park (RTP) is the largest research park in the United States, occupying in North Carolina and hosting more than 300 companies and 65,000 workers. The facility is named for its location relative to the three surrounding cities ...
) in collaboration with John J. Savarese MD (who at the time was an anesthesiologist in the Dept. of Anesthesia,
Harvard Medical School Harvard Medical School (HMS) is the graduate medical school of Harvard University and is located in the Longwood Medical Area of Boston, Massachusetts. Founded in 1782, HMS is one of the oldest medical schools in the United States and is consi ...
at the
Massachusetts General Hospital Massachusetts General Hospital (Mass General or MGH) is the original and largest teaching hospital of Harvard Medical School located in the West End neighborhood of Boston, Massachusetts. It is the third oldest general hospital in the United Stat ...
,
Boston Boston (), officially the City of Boston, is the state capital and most populous city of the Commonwealth of Massachusetts, as well as the cultural and financial center of the New England region of the United States. It is the 24th- mo ...
, 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 Laudexium metilsulfate is a neuromuscular blocking drug or skeletal muscle relaxant in the category of non-depolarizing neuromuscular-blocking drugs, used adjunctively in surgical anesthesia to facilitate endotracheal intubation and to provide ske ...
, and the well-known depolarizing agent, succinylcholine (
suxamethonium chloride Suxamethonium chloride, 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 ele ...
). Ironically,
laudexium Laudexium metilsulfate is a neuromuscular blocking drug or skeletal muscle relaxant in the category of non-depolarizing neuromuscular-blocking drugs, used adjunctively in surgical anesthesia to facilitate endotracheal intubation and to provide ske ...
itself was invented by a cross-combination between the prototypical non-depolarizing agent,
d-tubocurarine Tubocurarine (also known as ''d''-tubocurarine or DTC) is a toxic alkaloid historically known for its use as an arrow poison. In the mid-1900s, it was used in conjunction with an anesthetic to provide skeletal muscle relaxation during surgery or ...
and the depolarizing agent,
decamethonium Decamethonium (Syncurine) is a depolarizing muscle relaxant or neuromuscular blocking agent, and is used in anesthesia to induce paralysis. Pharmacology Decamethonium, which has a short action time, is similar to acetylcholine and acts as a p ...
. 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 Decamethonium (Syncurine) is a depolarizing muscle relaxant or neuromuscular blocking agent, and is used in anesthesia to induce paralysis. Pharmacology Decamethonium, which has a short action time, is similar to acetylcholine and acts as a p ...
.


Clinical pharmacology and pharmacokinetics

The first
clinical trial Clinical trials are prospective biomedical or behavioral research studies on human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel vaccines, drugs, dietar ...
of mivacurium (BW1090U), in 1984, was conducted in a cohort of 63 US patients undergoing surgical anesthesia. at the
Harvard Medical School Harvard Medical School (HMS) is the graduate medical school of Harvard University and is located in the Longwood Medical Area of Boston, Massachusetts. Founded in 1782, HMS is one of the oldest medical schools in the United States and is consi ...
at
Massachusetts General Hospital Massachusetts General Hospital (Mass General or MGH) is the original and largest teaching hospital of Harvard Medical School located in the West End neighborhood of Boston, Massachusetts. It is the third oldest general hospital in the United Stat ...
,
Boston Boston (), officially the City of Boston, is the state capital and most populous city of the Commonwealth of Massachusetts, as well as the cultural and financial center of the New England region of the United States. It is the 24th- mo ...
, 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 neuromuscular blocking action.


References

{{DEFAULTSORT:Mivacurium Chloride Nicotinic antagonists Norsalsolinol ethers Chlorides Carboxylate esters