Mivacurium chloride

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Mivacurium chloride
Mivacurium.svg
Clinical data
Trade names Mivacron
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.com International Drug Names
Routes of
administration
IV
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability 100% (IV)
Metabolism ester 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]
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
Formula C58H80N2O14+2
Molar mass 1029.278 g·mol−1
3D model (JSmol)
  • 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 drug [1] or skeletal muscle relaxant in the category of 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.

Contents

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 (also known as 51W89 and eventually produced 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 erroneously 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 antagonism to nicotinic acetylcholine receptors. However, unlike other non-depolarizing neuromuscular blockers, it is metabolized by plasma cholinesterase (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. [4]

History

Mivacurium represents the second generation of tetrahydroisoquinolinium neuromuscular blocking drugs 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., 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. [5] 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 [6] [7] and BWA444U, [8] 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.

Related Research Articles

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 electroconvulsive therapy. It is given either by injection into a vein or muscle. When used in a vein onset of action is generally within one minute and effects last for up to 10 minutes.

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 therapeutic groups: neuromuscular blockers and spasmolytics. Neuromuscular blockers act by interfering with transmission at the neuromuscular end plate and have no central nervous system (CNS) activity. They are often used during surgical procedures and in intensive care and emergency medicine to cause temporary paralysis. Spasmolytics, also known as "centrally acting" muscle relaxant, are used to alleviate musculoskeletal pain and spasms and to reduce spasticity in a variety of neurological conditions. While both neuromuscular blockers and spasmolytics are often grouped together as muscle relaxant, the term is commonly used to refer to spasmolytics only.

Anesthetic Drug that causes anesthesia

An anesthetic or anaesthetic is a drug used to induce anesthesia ⁠— ⁠in other words, to result in a temporary loss of sensation or awareness. They may be divided into two broad classes: general anesthetics, which result in a reversible loss of consciousness, and local anesthetics, which cause a reversible loss of sensation for a limited region of the body without necessarily affecting consciousness.

Pseudocholinesterase deficiency is an autosomal recessive inherited blood plasma enzyme abnormality in which the body's production of butyrylcholinesterase is impaired. People who have this abnormality may be sensitive to certain anesthetic drugs, including the muscle relaxants succinylcholine and mivacurium as well as other ester local anesthetics.

Tubocurarine chloride Obsolete muscle relaxant

Tubocurarine 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 mechanical ventilation. It is now rarely used as an adjunct for clinical anesthesia because safer alternatives, such as cisatracurium and rocuronium, are available.

Neuromuscular-blocking drug

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.

Rocuronium bromide Chemical compound

Rocuronium bromide is an aminosteroid non-depolarizing neuromuscular blocker or muscle relaxant used in modern anaesthesia to facilitate tracheal intubation by providing skeletal muscle relaxation, most commonly required for surgery or mechanical ventilation. It is used for standard endotracheal intubation, as well as for rapid sequence induction (RSI).

Atracurium besilate

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 intubation but suxamethonium (succinylcholine) is generally preferred if this needs to be done quickly. It is given by injection into a vein. Effects are greatest at about 4 minutes and last for up to an hour.

Gallamine triethiodide

Gallamine triethiodide (Flaxedil) is a non-depolarising muscle relaxant. It acts by combining with the cholinergic receptor sites in muscle and competitively blocking the transmitter action of acetylcholine. Gallamine is a non-depolarising type of blocker as it binds to the acetylcholine receptor but does not have the biological activity of acetyl choline. Gallamine triethiodide has a parasympatholytic effect on the cardiac vagus nerve, which causes tachycardia and occasionally hypertension. Very high doses cause histamine release.

Sugammadex Selective relaxant binding agent

Sugammadex, sold under the brand name Bridion, is a medication for the reversal of neuromuscular blockade induced by rocuronium and vecuronium in general anaesthesia. It is the first selective relaxant binding agent (SRBA).

Doxacurium chloride

Doxacurium chloride 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 muscle relaxation during surgery or mechanical ventilation. Unlike a number of other related skeletal muscle relaxants, it is rarely used adjunctively to facilitate endotracheal intubation.

Cisatracurium besilate

Cisatracurium besilate is a bisbenzyltetrahydroisoquinolinium that has effect as a neuromuscular-blocking drug 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 shows intermediate duration of action. Cisatracurium is one of the ten isomers of the parent molecule, atracurium. Moreover, cisatracurium represents approximately 15% of the atracurium mixture.

Bambuterol

Bambuterol (INN) is a long-acting β adrenoceptor agonist (LABA) used in the treatment of asthma; it also is a prodrug of terbutaline. Commercially, the AstraZeneca pharmaceutical company produces and markets bambuterol as Bambec and Oxeol.

Butyrylcholinesterase

Butyrylcholinesterase, also known as BChE, BuChE, pseudocholinesterase, or plasma (cholin)esterase, is a nonspecific cholinesterase enzyme that hydrolyses many different choline-based esters. In humans, it is made in the liver, found mainly in blood plasma, and encoded by the BCHE gene.

Laudanosine Chemical compound

Laudanosine or N-methyltetrahydropapaverine is a recognized metabolite of atracurium and cisatracurium. Laudanosine decreases the seizure threshold, and thus it can induce seizures if present at sufficient threshold concentrations; however such concentrations are unlikely to be produced consequent to chemodegradable metabolism of clinically administered doses of cisatracurium or atracurium.

Gantacurium chloride

Gantacurium chloride is a new experimental 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 skeletal muscle relaxation during surgery or mechanical ventilation. Gantacurium is not yet available for widespread clinical use: it is currently undergoing Phase III clinical development.

BW-A444

BW A444U was an experimental neuromuscular blocking drug or skeletal muscle relaxant in the category of non-depolarizing neuromuscular-blocking drugs, intended to be used adjunctively in surgical anesthesia to facilitate endotracheal intubation and to provide skeletal muscle relaxation during surgery or mechanical ventilation. It was synthesized and developed in the early 1980s.

Postoperative residual curarization Medical condition

Postoperative residual curarization (PORC) or residual neuromuscular blockade (RNMB) is a residual paresis after emergence from general anesthesia that may occur with the use of neuromuscular-blocking drugs. Today residual neuromuscular blockade is defined as a train of four ratio of less than 0.9 when measuring the response to ulnar nerve stimulation at the adductor pollicis muscle using mechanomyography or electromyography. A meta-analysis reported that the incidence of residual neuromuscular paralysis was 41% in patients receiving intermediate neuromuscular blocking agents during anaesthesia. It is possible that > 100,000 patients annually in the USA alone, are at risk of adverse events associated with undetected residual neuromuscular blockade. Neuromuscular function monitoring and the use of the appropriate dosage of sugammadex to reverse blockade produced by rocuronium can reduce the incidence of postoperative residual curarization. In this study, with usual care group receiving reversal with neostigmine resulted in a residual blockade rate of 43%.

Tetanic fade refers to the diminishing muscle twitch response from an evoked potential stimulation of muscle under the effect of either a non-depolarizing neuromuscular blocking agent, or a muscle that is under a phase 2 depolarizing neuromuscular blocking agent.

Neuromuscular blocking agents, or in abbreviation, NMBAs, are chemical agents that paralyse skeletal muscles by blocking the movement of neurotransmitter at the neuromuscular junction. They are often used during general anesthesia to optimize intubating and surgical conditions, specifically to facilitate endotracheal intubation. This class of medications helps to reduce patient movement, breathing, or ventilator dyssynchrony and allows lower insufflation pressures during laparoscopy including the generation of nerve impulses. It has several indications for use in the intense care unit. It can help reduce hoarseness in voice as well as injury to the vocal cord during intubation. In addition, it plays an important role in facilitating mechanical ventilation in patients with poor lung function. In the following section, neuromuscular blocking agent's history, usages, mechanisms, side effects, interactions and pharmacology will further be elaborated and discussed.

References

  1. Ihmsen H, Schmidt J, Schwilden H, Schmitt HJ, Muenster T (May 2009). "Influence of disease progression on the neuromuscular blocking effect of mivacurium in children and adolescents with Duchenne muscular dystrophy". Anesthesiology. 110 (5): 1016–9. doi: 10.1097/ALN.0b013e31819daf31 . PMID   19352159.
  2. Stout RG, Shine TS, Silverman DG, Brull SJ (September 2004). "Recovery of neuromuscular function after a combination of mivacurium and rocuronium". Yale J Biol Med. 77 (5–6): 149–54. PMC   2259125 . PMID   15989744.
  3. Dempsey EM, Al Hazzani F, Faucher D, Barrington KJ (July 2006). "Facilitation of neonatal endotracheal intubation with mivacurium and fentanyl in the neonatal intensive care unit". Arch. Dis. Child. Fetal Neonatal Ed. 91 (4): F279–82. doi:10.1136/adc.2005.087213. PMC   2672731 . PMID   16464937.
  4. Soto RG, Dunipace D (May 2017). "Mivacurium: Return of a Drug Seeking an Indication?". ASA Monitor. 81 (5): 30–31.
  5. Basta SJ, Savarese JJ, Ali HH, Scott RP, Gargarian M, Embree PB, Murphy B, Weakly JN, Batson AG (1985). "The neuromuscular pharmacology of BW B1090u in anesthetized patients". Anesthesiology. 63 (3): A318. doi:10.1097/00000542-198509001-00318.
  6. Savarese JJ, Ali HH, Basta SJ, Ramsey FM, Rosow CE, Lebowitz PW, Lineberry CG, Cloutier G (1980). "Clinical neuromuscular pharmacology of Bw785u, an ultra-short-acting nondepolarizing ester neuromuscular blocking agent". Anesthesiology. 53 (3): S274. doi:10.1097/00000542-198009001-00274.
  7. Ali HH, Savarese JJ, Basta SJ, Ramsey F, Rosow CE, Lebowitz PW (1980). "Prediction of clinical neuromuscular Ed95 of Bw785u from low dose studies in awake volunteers". Anesthesiology. 53 (3): S275. doi:10.1097/00000542-198009001-00275.
  8. Savarese JJ, Ali HH, Basta SJ, Sunder N, Moss J, Gionfriddo MA, Lineberry CG, Wastila WB, El-Sayad HA, Montague D, Braswell L (1983). "The clinical pharmacology of BW A444U. A nondepolarizing ester relaxant of intermediate duration". Anesthesiology. 58 (4): 333–341. doi:10.1097/00000542-198304000-00006. PMID   6220623. S2CID   22212818.