Doxacurium chloride (formerly recognized as BW938U80 or BW A938U) is a
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.
In cl ...
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
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 cli ...
, 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 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 ...
. Unlike a number of other related skeletal muscle relaxants, it is rarely used adjunctively to facilitate endotracheal
intubation
Intubation (sometimes entubation) is a medical procedure involving the insertion of a tube into the body. Patients are generally anesthetized beforehand. Examples include tracheal intubation, and the balloon tamponade with a Sengstaken-Blakemo ...
.
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 to
acetylcholine receptors
An acetylcholine receptor (abbreviated AChR) is an integral membrane protein that responds to the binding of acetylcholine, a neurotransmitter.
Classification
Like other transmembrane receptors, acetylcholine receptors are classified according ...
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 ''bis''benzyltetrahydroisoquinolinium 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
Mivacurium chloride (formerly recognized as BW1090U81, BW B1090U or BW1090U) is a short-duration non-depolarizing neuromuscular-blocking drug or skeletal muscle relaxant in the category of non-depolarizing neuromuscular-blocking drugs, used adjun ...
, was introduced into the clinic very shortly after doxacurium's debut. The only perceived advantage of doxacurium over that of
mivacurium
Mivacurium chloride (formerly recognized as BW1090U81, BW B1090U or BW1090U) is a short-duration non-depolarizing neuromuscular-blocking drug or skeletal muscle relaxant in the category of non-depolarizing neuromuscular-blocking drugs, used adju ...
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
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.,
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
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, 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 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 ...
(
suxamethonium
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 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 o ...
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 ...
. 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
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 ...
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 ...
.
References
{{DEFAULTSORT:Doxacurium Chloride
Quaternary ammonium compounds
Muscle relaxants
Nicotinic antagonists
Norsalsolinol ethers
Pyrogallol ethers
Chlorides
Succinate esters
Neuromuscular blockers