Mivacurium
Encyclopedia
Mivacurium chloride 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
.
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, 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.
The pharmacological action of mivacurium is a function of its competitive antagonism
to acetylcholine receptors of the nicotinic type.
and the United Kingdom
. The drug is marketed worldwide under the tradename of Mivacron.
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
.
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.
Neuromuscular-blocking drugs
Neuromuscular-blocking drugs block neuromuscular transmission at the neuromuscular junction, causing paralysis of the affected skeletal muscles. This is accomplished either by acting presynaptically via the inhibition of acetylcholine synthesis or release or by acting postsynaptically at the...
or skeletal muscle relaxant
Muscle relaxant
A muscle relaxant is a drug which 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...
in the category of non-depolarizing neuromuscular-blocking drugs
Neuromuscular-blocking drugs
Neuromuscular-blocking drugs block neuromuscular transmission at the neuromuscular junction, causing paralysis of the affected skeletal muscles. This is accomplished either by acting presynaptically via the inhibition of acetylcholine synthesis or release or by acting postsynaptically at the...
, used adjunctively in anesthesia
Anesthesia
Anesthesia, or anaesthesia , traditionally meant the condition of having sensation blocked or temporarily taken away...
to facilitate endotracheal intubation
Intubation
Tracheal intubation, usually simply referred to as intubation, is the placement of a flexible plastic or rubber tube into the trachea to maintain an open airway or to serve as a conduit through which to administer certain drugs...
and to provide skeletal muscle
Skeletal muscle
Skeletal muscle is a form of striated muscle tissue existing under control of the somatic nervous system- i.e. it is voluntarily controlled. It is one of three major muscle types, the others being cardiac and smooth muscle...
relaxation during surgery
Surgery
Surgery is an ancient medical specialty that uses operative manual and instrumental techniques on a patient to investigate and/or treat a pathological condition such as disease or injury, or to help improve bodily function or appearance.An act of performing surgery may be called a surgical...
or mechanical ventilation
Mechanical ventilation
In medicine, mechanical ventilation is a method to mechanically assist or replace spontaneous breathing. This may involve a machine called a ventilator or the breathing may be assisted by a physician, respiratory therapist or other suitable person compressing a bag or set of bellows...
.
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 Atracurium the cis-cis isomer is by far the lowest potency relaxant when compared with the other two. It has approximately 10% of the activity of each of the other two structures.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, 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.The pharmacological action of mivacurium is a function of its competitive antagonism
Receptor antagonist
A receptor antagonist is a type of receptor ligand or drug that does not provoke a biological response itself upon binding to a receptor, but blocks or dampens agonist-mediated responses...
to acetylcholine receptors of the nicotinic type.
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 EuropeEurope
Europe is, by convention, one of the world's seven continents. Comprising the westernmost peninsula of Eurasia, Europe is generally 'divided' from Asia to its east by the watershed divides of the Ural and Caucasus Mountains, the Ural River, the Caspian and Black Seas, and the waterways connecting...
and the United Kingdom
United Kingdom
The United Kingdom of Great Britain and Northern IrelandIn the United Kingdom and Dependencies, other languages have been officially recognised as legitimate autochthonous languages under the European Charter for Regional or Minority Languages...
. 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 anesthesiolgist in the Dept. of Anesthesia, Harvard Medical SchoolHarvard Medical School
Harvard Medical School is the graduate medical school of Harvard University. It is located in the Longwood Medical Area of the Mission Hill neighborhood of Boston, Massachusetts....
at the Massachusetts General Hospital
Massachusetts General Hospital
Massachusetts General Hospital is a teaching hospital and biomedical research facility in the West End neighborhood of Boston, Massachusetts...
, Boston
Boston
Boston is the capital of and largest city in Massachusetts, and is one of the oldest cities in the United States. The largest city in New England, Boston is regarded as the unofficial "Capital of New England" for its economic and cultural impact on the entire New England region. The city proper had...
, 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
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...
, 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
Decamethonium
Decamethonium is a depolarizing muscle relaxant or neuromuscular blocking agent, and is used in anesthesia to induce paralysis.- Pharmacology :...
. 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
Decamethonium is a depolarizing muscle relaxant or neuromuscular blocking agent, and is used in anesthesia to induce paralysis.- Pharmacology :...
.
Clinical Pharmacology and Pharmacokinetics
The first clinical trialClinical trial
Clinical trials are a set of procedures in medical research and drug development that are conducted to allow safety and efficacy data to be collected for health interventions...
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
Harvard Medical School is the graduate medical school of Harvard University. It is located in the Longwood Medical Area of the Mission Hill neighborhood of Boston, Massachusetts....
at Massachusetts General Hospital
Massachusetts General Hospital
Massachusetts General Hospital is a teaching hospital and biomedical research facility in the West End neighborhood of Boston, Massachusetts...
, Boston
Boston
Boston is the capital of and largest city in Massachusetts, and is one of the oldest cities in the United States. The largest city in New England, Boston is regarded as the unofficial "Capital of New England" for its economic and cultural impact on the entire New England region. The city proper had...
, 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.