Doxacurium chloride
Encyclopedia
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
.
The pharmacological action of doxacurium is a function of its competitive antagonism
to acetylcholine receptors of the nicotinic type. The drug is marketed worldwide under the tradename of Nuromax, and it is classified as a long-duration non-depolarizing neuromuscular blocking agent in a class of compounds commonly and most erroneously referred to as "benzylisoquinolines" when, in fact, it is a bisbenzyltetrahydroisoquinolinium agent.
The pharmaceutical preparation comprises the three trans-trans isomers (a meso structure R,S-S,R-doxacurium and an enantiomeric pair R,S-R,S-doxacurium and S,R-S,R-doxacurium)
is its superior cardiovascular profile, with particular reference to the lack of histamine release when administered as a rapid bolus dose.
at the Massachusetts General Hospital
, Boston
, MA). Specifically, doxacurium was first synthesized in 1980.
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 heritages of doxacurium and mivacurium hark back to the synthesis of numerous compounds following structure-activity relationships that drove researchers to find the ideal replacement for succinylcholine (suxamethonium). Both doxacurium and mivacurium are descendants of early vigorous attempts to synthesize potent non-depolarizing agents with pharmacophoric elements derived from cross-combinations of the non-depolarizing agent, laudexium, and the well-known depolarizing agent, succinylcholine (suxamethonium). Ironically, laudexium itself was invented by a cross-combination between the prototypical non-depolarizing agent, d-tubocurarine and the depolarizing agent, decamethonium
. In the 1950s and 1960s, 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
.
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 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...
. Unlike a number of other related skeletal muscle relaxants, it is rarely used adjunctively 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...
.
Chemistry
Doxacurium is a symmetrical molecule because it is a diester of succinic acid.The pharmacological action of doxacurium 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. The drug is marketed worldwide under the tradename of Nuromax, and it is classified as a long-duration non-depolarizing neuromuscular blocking agent in a class of compounds commonly and most erroneously referred to as "benzylisoquinolines" when, in fact, it is a bisbenzyltetrahydroisoquinolinium agent.
The pharmaceutical preparation comprises the three trans-trans isomers (a meso structure R,S-S,R-doxacurium and an enantiomeric pair R,S-R,S-doxacurium and S,R-S,R-doxacurium)
Availability
Doxacurium is available worldwide although, for a number of years, its use has not been popular because of considerably long duration of action. Its decline from clinical use was even further hastened when the sister molecule, mivacurium chloride, was introduced into the clinic very shortly after doxacurium's debut. The only perceived advantange of doxacurium over that of mivacuriumMivacurium
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...
is its superior cardiovascular profile, with particular reference to the lack of histamine release when administered as a rapid bolus dose.
History
Doxacurium 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 anesthesiologist 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, doxacurium was first synthesized in 1980.
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 heritages of doxacurium and mivacurium hark back to the synthesis of numerous compounds following structure-activity relationships that drove researchers to find the ideal replacement for succinylcholine (suxamethonium). Both doxacurium and mivacurium are descendants of early vigorous attempts to synthesize potent non-depolarizing agents with pharmacophoric elements derived from cross-combinations of the non-depolarizing agent, laudexium, and the well-known depolarizing agent, succinylcholine (suxamethonium). 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 :...
. In the 1950s and 1960s, 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 :...
.