Doxacurium chloride

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Doxacurium chloride
Doxacurium chloride.svg
Clinical data
Routes of
administration
IV only
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability 100% (IV)
Identifiers
  • bis[3-[6,7,8-trimethoxy-2-methyl-1- [(3,4,5-trimethoxyphenyl)methyl]- 3,4-dihydro-1H- isoquinolin-2-yl] propyl] butanedioate dichloride
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
Formula C56H78Cl2N2O16
Molar mass 1106.14 g·mol−1
3D model (JSmol)
  • [Cl-].[Cl-].O=C(OCCC[N@+]2(C)[C@H](c1c(OC)c(OC)c(OC)cc1CC2)Cc3cc(OC)c(OC)c(OC)c3)CCC(=O)OCCC[N@+]5([C@@H](c4c(cc(OC)c(OC)c4OC)CC5)Cc6cc(OC)c(OC)c(OC)c6)C
  • InChI=1S/C56H78N2O16.2ClH/c1-57(23-19-37-33-45(65-7)53(69-11)55(71-13)49(37)39(57)27-35-29-41(61-3)51(67-9)42(30-35)62-4)21-15-25-73-47(59)17-18-48(60)74-26-16-22-58(2)24-20-38-34-46(66-8)54(70-12)56(72-14)50(38)40(58)28-36-31-43(63-5)52(68-10)44(32-36)64-6;;/h29-34,39-40H,15-28H2,1-14H3;2*1H/q+2;;/p-2/t39-,40+,57-,58+;; Yes check.svgY
  • Key:APADFLLAXHIMFU-LGIHQUBZSA-L Yes check.svgY
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Doxacurium chloride (formerly recognized as BW938U80 or BW A938U[ citation needed ]) 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.

Contents

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 of the nicotinic type.[ citation needed ] 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 advantage of doxacurium over that of mivacurium 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 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, 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.

Related Research Articles

<span class="mw-page-title-main">Suxamethonium chloride</span> Chemical compound

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

<span class="mw-page-title-main">Pancuronium bromide</span> Aminosteroid muscle relaxant

Pancuronium is an aminosteroid muscle relaxant with various medical uses. It is used in euthanasia and is used in some states as the second of three drugs administered during lethal injections in the United States.

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.

<span class="mw-page-title-main">Anesthetic</span> 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.

<span class="mw-page-title-main">Vecuronium bromide</span> Muscle relaxant

Vecuronium bromide, sold under the brand name Norcuron among others, is a medication used as part of general anesthesia to provide skeletal muscle relaxation during surgery or mechanical ventilation. It is also used to help with endotracheal intubation; however, 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.

<span class="mw-page-title-main">Curare</span> Group of chemical substances used as poison

Curare is a common name for various plant extract alkaloid arrow poisons originating from indigenous peoples in Central and South America. Used as a paralyzing agent for hunting and for therapeutic purposes, curare only becomes active by a direct wound contamination by a poison dart or arrow or via injection. These poisons function by competitively and reversibly inhibiting the nicotinic acetylcholine receptor (nAChR), which is a subtype of acetylcholine receptor found at the neuromuscular junction. This causes weakness of the skeletal muscles and, when administered in a sufficient dose, eventual death by asphyxiation due to paralysis of the diaphragm. Curare is prepared by boiling the bark of one of the dozens of plant alkaloid sources, leaving a dark, heavy paste that can be applied to arrow or dart heads. Historically, curare has been used as an effective treatment for tetanus or strychnine poisoning and as a paralyzing agent for surgical procedures.

<span class="mw-page-title-main">Tubocurarine chloride</span> 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.

<span class="mw-page-title-main">Neuromuscular-blocking drug</span> Type of paralyzing anesthetic including lepto- and pachycurares

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.

<span class="mw-page-title-main">Rocuronium bromide</span> 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).

Decamethonium (Syncurine) is a depolarizing muscle relaxant or neuromuscular blocking agent, and is used in anesthesia to induce paralysis.

<span class="mw-page-title-main">Atracurium besilate</span> Chemical compound

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.

<span class="mw-page-title-main">Mivacurium chloride</span> Drug used in a hospital setting

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.

<span class="mw-page-title-main">Alcuronium chloride</span> Muscle relaxant

Alcuronium chloride is a neuromuscular blocking (NMB) agent, alternatively referred to as a skeletal muscle relaxant. It is a semi-synthetic substance prepared from C-toxiferine I, a bis-quaternary alkaloid obtained from Strychnos toxifera. C-toxiferine I itself has been tested for its pharmacological action and noted to be a very long acting neuromuscular blocking agent For a formal definition of the durations of actions associated with NMB agents, see page for gantacurium. The replacement of both the N-methyl groups with N-allyl moieties yielded N,N-diallyl-bis-nortoxiferine, now recognized as alcuronium.

<span class="mw-page-title-main">Gantacurium chloride</span>

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.

<span class="mw-page-title-main">Laudexium metilsulfate</span>

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 skeletal muscle relaxation during surgery or mechanical ventilation.

<span class="mw-page-title-main">Candocuronium iodide</span> Chemical compound

Candocuronium iodide is an aminosteroid neuromuscular-blocking drug. Its use in anesthesia for endotracheal intubation and to provide skeletal muscle relaxation during surgery or mechanical ventilation was briefly evaluated in clinical studies in India. However, further development was discontinued due to attendant cardiovascular effects, primarily tachycardia that was about the same as the clinically established pancuronium bromide. Candocuronium demonstrated a short duration and a rapid onset of action, with little or no ganglion blocking activity, with a greater potency than pancuronium.

<span class="mw-page-title-main">BW-A444</span> Chemical compound

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.

<span class="mw-page-title-main">Postoperative residual curarization</span> 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%.

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.

<span class="mw-page-title-main">Cholinergic blocking drugs</span> Group of drugs

Cholinergic blocking drugs are a group of drugs that block the action of acetylcholine (ACh), a neurotransmitter, in synapses of the cholinergic nervous system. They block acetylcholine from binding to cholinergic receptors, namely the nicotinic and muscarinic receptors.

References

    Martinez E, Wooldridge A, Hartsfield S, Mealey K (1998). "Neuromuscular effects of doxacurium chloride in isoflurane-anesthetized dogs". Vet Surg. 27 (3): 279–83. doi:10.1111/j.1532-950X.1998.tb00127.x. PMID   9605239.