Atracurium besilate

Last updated
Atracurium besilate
Atracurium besilate.svg
Clinical data
Trade names Tracrium, Acurium
Other namesAtracurium besylate
AHFS/Drugs.com Monograph
Pregnancy
category
  • C
Routes of
administration
IV
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability 100% (IV)
Protein binding 82%
Metabolism Hofmann elimination (retro-Michael addition) and ester hydrolysis by nonspecific esterases
Elimination half-life 17–21 minutes
Identifiers
  • 2,2'-{1,5-Pentanediylbis[oxy(3-oxo-3,1-propanediyl)]}bis[1-(3,4-dimethoxybenzyl)-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinolinium] dibenzenesulfonate
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.058.840 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C65H82N2O18S2
Molar mass 1243.49 g·mol−1
3D model (JSmol)
Melting point 85 to 90 °C (185 to 194 °F)
  • C[N+]1(CCc2cc(c(cc2C1Cc3ccc(c(c3)OC)OC)OC)OC)CCC(=O)OCCCCCOC(=O)CC[N+]4(CCc5cc(c(cc5C4Cc6ccc(c(c6)OC)OC)OC)OC)C.c1ccc(cc1)S(=O)(=O)[O-].c1ccc(cc1)S(=O)(=O)[O-]
  • InChI=1S/C53H72N2O12.2C6H6O3S/c1-54(22-18-38-32-48(62-7)50(64-9)34-40(38)42(54)28-36-14-16-44(58-3)46(30-36)60-5)24-20-52(56)66-26-12-11-13-27-67-53(57)21-25-55(2)23-19-39-33-49(63-8)51(65-10)35-41(39)43(55)29-37-15-17-45(59-4)47(31-37)61-6;2*7-10(8,9)6-4-2-1-3-5-6/h14-17,30-35,42-43H,11-13,18-29H2,1-10H3;2*1-5H,(H,7,8,9)/q+2;;/p-2 Yes check.svgY
  • Key:XXZSQOVSEBAPGS-UHFFFAOYSA-L Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)    (verify)

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. [1] It can also be used to help with endotracheal intubation but suxamethonium (succinylcholine) is generally preferred if this needs to be done quickly. [1] It is given by injection into a vein. [1] Effects are greatest at about 4 minutes and last for up to an hour. [1]

Contents

Common side effects include flushing of the skin and low blood pressure. [1] [2] Serious side effects may include allergic reactions; however, it has not been associated with malignant hyperthermia. [1] [2] Prolonged paralysis may occur in people with conditions like myasthenia gravis. [1] It is unclear if use in pregnancy is safe for the baby. [1] Atracurium is in the neuromuscular-blocker family of medications and is of the non-depolarizing type. [1] It works by blocking the action of acetylcholine on skeletal muscles. [1]

Atracurium was approved for medical use in the United States in 1983. [1] It is on the World Health Organization's List of Essential Medicines. [3] Atracurium is available as a generic medication. [1]

Medical uses

Atracurium is a medication used in addition to other medications in to provide skeletal muscle relaxation during surgery or mechanical ventilation. It can be used to help with endotracheal intubation but takes up to 2.5 minutes to result in appropriate intubating conditions. [1]

Duration of action

Neuromuscular-blocking agents can be classified in accordance to their duration of pharmacological action, defined as follows:

Classification of neuromuscular-blocking agents by duration of pharmacological action (minutes)
ParameterUltra-short DurationShort DurationIntermediate DurationLong Duration
Clinical Duration
(Time from injection to T25% recovery)
6-812-20

30-45

>60
Recovery Time
(Time from injection to T95% recovery)
<1525-30

50-70

90-180
Recovery Index (T25%-T75% recovery slope)2-36

10-15

>30

Side effects

Cardiovascular

The tetrahydroisoquinolinium class of neuromuscular blocking agents, in general, is associated with histamine release upon rapid administration of a bolus intravenous injection. [4] There are some exceptions to this rule; cisatracurium (Nimbex), for example, is one such agent that does not elicit histamine release even up to 5×ED95 doses. The liberation of histamine is a dose-dependent phenomenon such that, with increasing doses administered at the same rate, there is a greater propensity for eliciting histamine release and its ensuing sequelae. Most commonly, the histamine release following administration of these agents is associated with observable cutaneous flushing (facial face and arms, commonly), hypotension and a consequent reflex tachycardia. These sequelae are very transient effects: the total duration of the cardiovascular effects is no more than one to two minutes, while the facial flush may take around 3–4 minutes to dissipate. Because these effects are so transient, there is no reason to administer adjunctive therapy to ameliorate either the cutaneous or the cardiovascular effects.

Bronchospasm

Bronchospasm has been reported on occasion with the use of atracurium. [5] [6] [7] [8] However, this particular undesirable effect does not appear to be observed nearly as often as that seen with rapacuronium, which led to the latter's withdrawal of approval for clinical use worldwide.

The issue of bronchospasm acquired prominence in the neuromuscular-blocking agents arena after the withdrawal from clinical use of rapacuronium (Raplon - a steroidal neuromuscular-blocking agent marketed by Organon) in 2001 [9] [10] after several serious events of bronchospasm, [11] [12] including five unexplained fatalities, [13] following its administration. Bronchospasm was not an unknown phenomenon prior to rapacuronium: occasional reports of bronchospasm have been noted also with the prototypical agents, tubocurarine [14] [15] [16] and succinylcholine, [17] [18] [19] [20] [21] as well as alcuronium, [22] pancuronium, [23] [24] vecuronium, [25] [26] and gallamine. [27]

Seizures

Seizures rarely occur. [1]

Because atracurium undergoes Hofmann elimination as a primary route of chemodegradation, one of the major metabolites from this process is laudanosine, a tertiary amino alkaloid reported to be a modest CNS stimulant with epileptogenic activity [28] and cardiovascular effects such a hypotension and bradycardia. [29] As part of the then fierce marketing battle between the competing pharmaceutical companies (Burroughs Wellcome Co. and Organon, Inc.) with their respective products, erroneous information was quickly and subtly disseminated very shortly after the clinical introduction of atracurium that the clinical use of atracurium was likely to result in a terrible tragedy because of the significant clinical hazard by way of frank seizures induced by the laudanosine by-product [28] - the posited hypothesis being that the laudanosine produced from the chemodegradation of parent atracurium would cross the blood–brain barrier in sufficiently high enough concentrations that lead to epileptogenic foci. [30] Fortunately, both for the public and for atracurium, rapid initial investigations irrefutably failed to find any overt or EEG evidence for a connection between atracurium administration and epileptogenic activity. [31] [32] Indeed, because laudanosine is cleared primarily via renal excretion, a cat study modelling anephric patients went so far as to corroborate that EEG changes, when observed, were evident only at plasma concentrations 8 to 10 times greater than those observed in humans during infusions of atracurium. [33] Thus, the cat study predicted that, following atracurium administration in an anephric patient, laudanosine accumulation and related CNS or cardiovascular toxicity were unlikely - a prediction that correlated very well with a study in patients with kidney failure and undergoing cadaveric renal transplantation. [34] Furthermore, almost a decade later, work by Cardone et al.. [35] confirmed that, in fact, it is the steroidal neuromuscular-blocking agents pancuronium and vecuronium that, when introduced directly into the CNS, were likely to cause acute excitement and seizures, owing to accumulation of cytosolic calcium caused by activation of acetylcholine receptor ion channels. Unlike the two steroidal agents, neither atracurium nor laudanosine caused such accumulation of intracellular calcium. Just over two decades later with availability of atracurium, there is little doubt that laudanosine accumulation and related toxicity will likely never be seen with the doses of atracurium that are generally used. [29]

Laudanosine is also a metabolite of cisatracurium that, because of its identical structure to atracurium, undergoes chemodegradation via Hofmann elimination in vivo. Plasma concentrations of laudanosine generated are lower when cisatracurium is used. [29]

Pharmacokinetics

Atracurium is susceptible to degradation by Hofmann elimination and ester hydrolysis as components of the in vivo metabolic processes. [36] [37] The initial in vitro studies appeared to indicate a major role for ester hydrolysis [36] but, with accumulation of clinical data over time, the preponderance of evidence indicated that Hofmann elimination at physiological pH is the major degradation pathway [37] vindicating the premise for the design of atracurium to undergo an organ-independent metabolism. [38]

Hofmann elimination is a temperature- and pH-dependent process, and therefore atracurium's rate of degradation in vivo is highly influenced by body pH and temperature: An increase in body pH favors the elimination process, [39] [40] whereas a decrease in temperature slows down the process. [38] Otherwise, the breakdown process is unaffected by the level of plasma esterase activity, obesity, [41] age, [42] or by the status of renal [43] [44] [45] [46] or hepatic function. [47] On the other hand, excretion of the metabolite, laudanosine, and, to a small extent, atracurium itself is dependent on hepatic and renal functions that tend to be less efficient in the elderly population. [42] [45] The pharmaceutical presentation is a mixture of all ten possible stereoisomers. Although there are four stereocentres, which could give 16 structures, there is a plane of symmetry running through the centre of the diester bridge, and so 6 meso structures (structures that can be superimposed by having the opposite configuration then 180° rotation) are formed. This reduces the number from sixteen to ten. There are three cis-cis isomers (an enantiomeric pair and a meso structure), four cis-trans isomers (two enantiomeric pairs), and three trans-trans isomers (an enantiomeric pair and a meso structure). The proportions of cis−cis, cis−trans, and trans−trans isomers are in the ratio of 10.5 :6.2 :1. [cis-cis isomers ≈ 58% cis-trans isomers ≈ 36% trans-trans isomers ≈ 6%]. One of the three cis-cis structures is marketed as a single-isomer preparation, cisatracurium (trade name Nimbex); it has the configuration 1R, 2R, 1′R, 2′R at the four stereocentres. The beta-blocking drug nebivolol has ten similar structures with 4 stereocentres and a plane of symmetry, but only two are presented in the pharmaceutical preparation.

Intramuscular function parameters

History

Atracurium besilate was first made in 1974 by George H. Dewar, [48] a pharmacist and a medicinal chemistry doctoral candidate in John B. Stenlake's medicinal chemistry research group in the Department of Pharmacy at Strathclyde University, Scotland. Dewar first named this compound "33A74" [48] before its eventual emergence in the clinic as atracurium. Atracurium was the culmination of a rational approach to drug design to produce the first non-depolarizing non-steroidal skeletal muscle relaxant that undergoes chemodegradation in vivo. The term chemodegradation was coined by Roger D. Waigh, Ph.D., [49] also a pharmacist and a postdoctoral researcher in Stenlake's research group. Atracurium was licensed by Strathclyde University to the Wellcome Foundation UK, which developed the drug (then known as BW 33A [50] ) and its introduction to first human trials in 1979, [40] [51] and then eventually to its first introduction (as a mixture of all ten stereoisomers [52] ) into clinical anesthetic practice in the UK, in 1983, under the tradename of Tracrium.

The premise to the design of atracurium and several of its congeners stemmed from the knowledge that a bis-quaternary structure is essential for neuromuscular-blocking activity: ideally, therefore, a chemical entity devoid of this bis-quaternary structure via susceptibility to inactive breakdown products by enzymic-independent processes would prove to be invaluable in the clinical use of a drug with a predictable onset and duration of action. Hofmann elimination provided precisely this basis: It is a chemical process in which a suitably activated quaternary ammonium compound can be degraded by the mildly alkaline conditions present at physiological pH and temperature. [53] In effect, Hofmann elimination is a retro-Michael addition chemical process. It is important to note here that the physiological process of Hofmann elimination differs from the non-physiological Hofmann degradation process: the latter is a chemical reaction in which a quaternary ammonium hydroxide solid salt is heated to 100 °C, or an aqueous solution of the salt is boiled. Regardless of which Hofmann process is referenced, the end-products in both situations will be the same: an alkene and a tertiary amine.

The approach to utilizing Hofmann elimination as a means to promoting biodegradation had its roots in much earlier observations that the quaternary alkaloid petaline (obtained from the Lebanese plant Leontice leontopetalum) readily underwent facile Hofmann elimination to a tertiary amine called leonticine upon passage through a basic (as opposed to an acidic) ion-exchange resin. [54] Stenlake's research group advanced this concept by systematically synthesizing numerous quaternary ammonium β-aminoesters [55] [56] [57] [58] and β-aminoketones [59] and evaluated them for skeletal muscle relaxant activity: one of these compounds, [51] [57] initially labelled as 33A74, [48] [60] eventually led to further clinical development, and came to be known as atracurium.

Related Research Articles

<span class="mw-page-title-main">Isoflurane</span> General anaesthetic given via inhalation

Isoflurane, sold under the brand name Forane among others, is a general anesthetic. It can be used to start or maintain anesthesia; however, other medications are often used to start anesthesia, due to airway irritation with isoflurane. Isoflurane is given via inhalation.

<span class="mw-page-title-main">Sevoflurane</span> Inhalational anaesthetic

Sevoflurane, sold under the brand name Sevorane, among others, is a sweet-smelling, nonflammable, highly fluorinated methyl isopropyl ether used as an inhalational anaesthetic for induction and maintenance of general anesthesia. After desflurane, it is the most volatile anesthetic with the fastest onset. While its offset may be faster than agents other than desflurane in a few circumstances, its offset is more often similar to that of the much older agent isoflurane. While sevoflurane is only half as soluble as isoflurane in blood, the tissue blood partition coefficients of isoflurane and sevoflurane are quite similar. For example, in the muscle group: isoflurane 2.62 vs. sevoflurane 2.57. In the fat group: isoflurane 52 vs. sevoflurane 50. As a result, the longer the case, the more similar will be the emergence times for sevoflurane and isoflurane.

Awareness under anesthesia, also referred to as intraoperative awareness or accidental awareness during general anesthesia (AAGA), is a rare complication of general anesthesia where patients regain varying levels of consciousness during their surgical procedures. While anesthesia awareness is possible without resulting in any long-term memory of the experience, it is also possible for victims to have awareness with explicit recall, where they can remember the events related to their surgery.

<span class="mw-page-title-main">Bispectral index</span> Technology for monitoring anesthesia

Bispectral index (BIS) is one of several technologies used to monitor depth of anesthesia. BIS monitors are used to supplement Guedel's classification system for determining depth of anesthesia. Titrating anesthetic agents to a specific bispectral index during general anesthesia in adults allows the anesthetist to adjust the amount of anesthetic agent to the needs of the patient, possibly resulting in a more rapid emergence from anesthesia. Use of the BIS monitor could reduce the incidence of intraoperative awareness during anaesthesia. The exact details of the algorithm used to create the BIS index have not been disclosed by the company that developed it.

<span class="mw-page-title-main">Tubocurarine chloride</span> Obsolete muscle relaxant

Tubocurarine is a toxic benzylisoquinoline 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. Safer alternatives, such as cisatracurium and rocuronium, have largely replaced it as an adjunct for clinical anesthesia and it is now rarely used.

Minimum alveolar concentration or MAC is the concentration, often expressed as a percentage by volume, of a vapour in the alveoli of the lungs that is needed to prevent movement in 50% of subjects in response to surgical (pain) stimulus. MAC is used to compare the strengths, or potency, of anaesthetic vapours. The concept of MAC was first introduced in 1965.

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

Neuromuscular-blocking drugs, or Neuromuscular blocking agents (NMBAs), block 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">Trimetaphan camsilate</span> Chemical compound

Trimetaphan camsilate (INN) or trimethaphan camsylate (USAN), trade name Arfonad, is a sympatholytic drug used in rare circumstances to lower blood pressure.

Entropy monitoring is a method of assessing the effect of certain anaesthetic drugs on the brain's EEG. It was commercially developed by Datex-Ohmeda, which is now part of GE Healthcare.

<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">Cisatracurium besilate</span> Chemical compound

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.

Selective relaxant binding agents (SRBAs) are a new class of drugs that selectively encapsulates and binds neuromuscular blocking agents (NMBAs). The first drug introduction of an SRBA is sugammadex.. SRBAs exert a chelating action that effectively terminates an NMBA ability to bind to nicotinic receptors.

Dogliotti's principle is a principle in epidural anaesthesia first described by Professor Achille Mario Dogliotti in 1933. It is a method for the identification of the epidural space, a potential space. As a needle is advanced through the ligamentum flavum, to the epidural space, with constant pressure applied to the piston of a syringe, loss of resistance occurs once the needle enters the epidural space due to the change in pressure. The identification of this space, allows subsequent administration of epidural anaesthesia, a technique used primarily for analgesia during childbirth.

The Outcomes Research Consortium is an international clinical research group that focuses on the perioperative period, along with critical care and pain management. The Consortium's aim is to improve the quality of care for surgical, critical care, and chronic pain patients and to "Provide the evidence for evidence-based practice." Members of the Consortium are especially interested in testing simple, low-risk, and inexpensive treatments that have the potential to markedly improve patients' surgical experiences.

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

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> Chemical compound

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">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%.

<span class="mw-page-title-main">Neuromuscular drug</span>

Neuromuscular drugs are chemical agents that are used to alter the transmission of nerve impulses to muscles, causing effects such as temporary paralysis of targeted skeletal muscles. Most neuromuscular drugs are available as quaternary ammonium compounds which are derived from acetylcholine (ACh). This allows neuromuscular drugs to act on multiple sites at neuromuscular junctions, mainly as antagonists or agonists of post-junctional nicotinic receptors. Neuromuscular drugs are classified into four main groups, depolarizing neuromuscular blockers, non-depolarizing neuromuscular blockers, acetylcholinesterase inhibitors, and butyrylcholinesterase inhibitors.

Paravertebral block is a technique used in medicine in order to ease chest pain. An analgetic agent, usually Bupivacaine or morphine, is injected into a narrow space that lies next to the spine. A fine tube is left in place in order to re-administer the local anesthetic whenever necessary. Complications of the paravertebral block are rare. They include vascular or lung injury, hypotension and pneumothorax. Paravertebral block is used in thoracic surgery, general surgery.

References

  1. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 "Atracurium Besylate". The American Society of Health-System Pharmacists. Archived from the original on 21 December 2016. Retrieved 8 December 2016.
  2. 1 2 "Atracurium Besilate 10 mg/ml Injection - (eMC)". www.medicines.org.uk. March 2015. Archived from the original on 20 December 2016. Retrieved 16 December 2016.
  3. World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl: 10665/325771 . WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
  4. Savarese JJ, Wastila WB (1995). "The future of the benzylisoquinolinium relaxants". Acta Anaesthesiologica Scandinavica. 106 Suppl: 91–93. doi:10.1111/j.1399-6576.1995.tb04317.x. PMID   8533554. S2CID   39461057.
  5. Ortalli GL, Tiberio I, Mammana G (Mar 1993). "A case of severe bronchospasm and laryngospasm after atracurium administration". Minerva Anestesiologica. 59 (3): 133–135. PMID   8515854.
  6. Siler JN, Mager JG Jr, Wyche MQ Jr (May 1985). "Atracurium: hypotension, tachycardia and bronchospasm". Anesthesiology. 62 (5): 645–646. doi: 10.1097/00000542-198505000-00020 . PMID   2581480.
  7. Woods I, Morris P, Meakin G (Feb 1985). "Severe bronchospasm following the use of atracurium in children". Anaesthesia. 40 (2): 207–208. doi: 10.1111/j.1365-2044.1985.tb10733.x . PMID   3838421. S2CID   43519278.
  8. Sale JP (May 1983). "Bronchospasm following the use of atracurium". Anaesthesia. 38 (5): 511–512. doi: 10.1111/j.1365-2044.1983.tb14055.x . PMID   6687984. S2CID   5484390.
  9. Shapse D. "Voluntary market withdrawal - Adverse Drug Reaction 27 March 2001. Raplon (rapacuronium bromide) for Injection" (PDF). Archived (PDF) from the original on 7 March 2010.
  10. Lim R (Feb 2003). "Rapacuronium: premarket drug evaluation can be very effective for the identification of drug risks". Anesthesia & Analgesia. 96 (2): 631–632. doi: 10.1213/00000539-200302000-00070 . PMID   12538231.
  11. Goudsouzian NG. (2001). "Rapacuronium and bronchospasm". Anesthesiology. 94 (5): 727–728. doi: 10.1097/00000542-200105000-00006 . PMID   11388519.
  12. Jooste E, Klafter F, Hirshman CA, Emala CW (Apr 2003). "A mechanism for rapacuronium-induced bronchospasm: M2 muscarinic receptor antagonism". Anesthesiology. 98 (4): 906–911. doi: 10.1097/00000542-200304000-00017 . PMID   12657852. S2CID   13063601.
  13. Grady D. (2001-03-31). "Anesthesia drug is removed from market after the deaths of 5 patients". The New York Times. Archived from the original on 2016-03-03.
  14. Harrison GA (Aug 1966). "A case of cardiac arrest associated with bronchospasm and d-tubocurarine". Australian and New Zealand Journal of Surgery. 36 (1): 40–42. doi:10.1111/j.1445-2197.1966.tb04394.x. PMID   5225576.
  15. Bevan DR. (1992) "Curare". In: Maltby JR, Shephard DAE (Eds.), Harold Griffith - His Life and Legacy; Suppl. to Canadian Journal of Anaesthesiology vol. 39 (1); 49-55.
  16. Takki S, Tammisto T (Apr 1971). "Severe bronchospasm and circulatory collapse following the administration of d-tubocurarine". Annals of Clinical Research. 3 (2): 112–115. PMID   4104054.
  17. Fellini AA, Bernstein RL, Zauder HL (Oct 1963). "Bronchospasm due to suxamethonium; report of a case". British Journal of Anaesthesiology. 35 (10): 657–659. doi: 10.1093/bja/35.10.657 . PMID   14073484.
  18. Bele-Binda N, Valeri F (Jan 1971). "A case of bronchospasm induced by succinylcholine". Canadian Anaesthetists' Society Journal. 18 (1): 116–119. doi: 10.1007/BF03025433 . PMID   5545731.
  19. Katz AM, Mulligan PG (Oct 1972). "Bronchospasm induced by suxamethonium. A case report". British Journal of Anaesthesiology. 44 (10): 1097–1099. doi: 10.1093/bja/44.10.1097 . PMID   4639831.
  20. Eustace BR (Oct 1967). "Suxamethonium induced bronchospasm". Anaesthesia. 22 (4): 638–641. doi: 10.1111/j.1365-2044.1967.tb10161.x . PMID   4168012. S2CID   1501797.
  21. Cardan E, Deacu E (Jan 1972). "Bronchospasm following succinyl choline". Der Anaesthesist. 21 (1): 27–29. PMID   4111555.
  22. Yeung ML, Ng LY, Koo AW (Feb 1979). "Severe bronchospasm in an asthmatic patient following alcuronium and D-tubocurarine". Anaesthesia and Intensive Care. 7 (1): 62–64. doi: 10.1177/0310057X7900700111 . PMID   434447.
  23. Heath ML (Jul 1973). "Bronchospasm in an asthmatic patient following pancuronium". Anaesthesia. 28 (4): 437–440. doi:10.1111/j.1365-2044.1973.tb00494.x. PMID   4268667. S2CID   21429279.
  24. Kounis NG (Apr 1974). "Letter: Bronchospasm induced by althesin and pancuronium bromide". British Journal of Anaesthesiology. 46 (4): 281. doi: 10.1093/bja/46.4.281-a . PMID   4451602.
  25. Uratsuji Y, Konishi M, Ikegaki N, Kitada H (Jan 1991). "Possible bronchospasm after administration of vecuronium". Masui. 40 (1): 109–112. PMID   1675699.
  26. O'Callaghan AC, Scadding G, Watkins J (Aug 1985). "Bronchospasm following the use of vecuronium". Anaesthesia. 40 (8): 801–805. doi: 10.1111/j.1365-2044.1985.tb11010.x . PMID   3839980. S2CID   22700697.
  27. Okazaki K, Saito T, Wakisaka K, Hirano T, Kozu K (Jun 1969). "Bronchospasm possible due to gallamine. A case report". Tokushima Journal of Experimental Medicine. 16 (1): 9–14. PMID   5348343.
  28. 1 2 Standaert FG (Dec 1985). "Magic bullets, science, and medicine". Anesthesiology. 63 (6): 577–578. doi:10.1097/00000542-198512000-00002. PMID   2932980.
  29. 1 2 3 Fodale V, Santamaria LB (Jul 2002). "Laudanosine, an atracurium and cisatracurium metabolite". European Journal of Anaesthesiology. 19 (7): 466–473. doi:10.1017/s0265021502000777. PMID   12113608.
  30. Katz Y, Weizman A, Pick CG, Pasternak GW, Liu L, Fonia O, et al. (May 1994). "Interactions between laudanosine, GABA, and opioid subtype receptors: implication for laudanosine seizure activity". Brain Research. 646 (2): 235–241. doi:10.1016/0006-8993(94)90084-1. PMID   8069669. S2CID   35031924.
  31. Lanier WL, Milde JH, Michenfelder JD (Dec 1985). "The cerebral effects of pancuronium and atracurium in halothane-anesthetized dogs". Anesthesiology. 63 (6): 589–597. doi: 10.1097/00000542-198512000-00007 . PMID   2932982. S2CID   26776273.
  32. Shi WZ, Fahey MR, Fisher DM, Miller RD, Canfell C, Eger EI 2nd (Dec 1985). "Laudanosine (a metabolite of atracurium) increases the minimum alveolar concentration of halothane in rabbits". Anesthesiology. 63 (6): 584–589. doi: 10.1097/00000542-198512000-00006 . PMID   2932981. S2CID   2814293.
  33. Ingram MD, Sclabassi RJ, Cook DR, Stiller RL, Bennett MH (1986). "Cardiovascular and electroencephalographic effects of laudanosine in "nephrectomized" cats". British Journal of Anaesthesiology. 58 (Suppl 1): 14S–18S. doi: 10.1093/bja/58.suppl_1.14s . PMID   3707810.
  34. Fahey MR, Rupp SM, Canfell C, Fisher DM, Miller RD, Sharma M, et al. (Nov 1985). "Effect of renal failure on laudanosine excretion in man". British Journal of Anaesthesiology. 57 (11): 1049–1051. doi: 10.1093/bja/57.11.1049 . PMID   3840380.
  35. Cardone C, Szenohradszky J, Yost S, Bickler PE (May 1994). "Activation of brain acetylcholine receptors by neuromuscular blocking drugs. A possible mechanism of neurotoxicity". Anesthesiology. 80 (5): 1155–1161. doi: 10.1097/00000542-199405000-00025 . PMID   7912481. S2CID   9064617.
  36. 1 2 Stiller RL, Cook DR, Chakravorti S (1985). "In vitro degradation of atracurium in human plasma". British Journal of Anaesthesiology. 57 (11): 1085–1088. doi: 10.1093/bja/57.11.1085 . PMID   3840382.
  37. 1 2 Nigrovic V, Fox JL (1991). "Atracurium decay and the formation of laudanosine in humans". Anesthesiology. 74 (3): 446–454. doi: 10.1097/00000542-199103000-00010 . PMID   2001023.
  38. 1 2 Merrett RA, Thompson CW, Webb FW (1983). "In vitro degradation of atracurium in human plasma". British Journal of Anaesthesiology. 55 (1): 61–66. doi: 10.1093/bja/55.1.61 . PMID   6687375. S2CID   10006364.
  39. Hughes R, Chapple DJ (1981). "The pharmacology of atracurium: a new competitive neuromuscular blocking agent". British Journal of Anaesthesiology. 53 (1): 31–44. doi: 10.1093/bja/53.1.31 . PMID   6161627. S2CID   12663014.
  40. 1 2 Payne JP, Hughes R (1981). "Evaluation of atracurium in anaesthetized man". British Journal of Anaesthesiology. 53 (1): 45–54. doi: 10.1093/bja/53.1.45 . PMID   7459185.
  41. Varin F, Ducharme J, Théorêt Y, Besner JG, Bevan DR, Donati F (1990). "Influence of extreme obesity on the body disposition and neuromuscular blocking effect of atracurium". Clinical Pharmacology and Therapeutics. 48 (1): 18–25. doi:10.1038/clpt.1990.112. PMID   2369806. S2CID   31131670.
  42. 1 2 Kent AP, Parker CJ, Hunter JM (1989). "Pharmacokinetics of atracurium and laudanosine in the elderly". British Journal of Anaesthesiology. 63 (6): 661–666. doi: 10.1093/bja/63.6.661 . PMID   2611066.
  43. Fahey MR, Rupp SM, Fisher DM, Miller RD, Sharma M, Canfell C, et al. (Dec 1984). "The pharmacokinetics and pharmacodynamics of atracurium in patients with and without renal failure". Anesthesiology. 61 (6): 699–702. doi:10.1097/00000542-198412000-00011. PMID   6239574. S2CID   39573578.
  44. Parker CJ, Jones JE, Hunter JM (1988). "Disposition of infusions of atracurium and its metabolite, laudanosine, in patients in renal and respiratory failure in an ITU". British Journal of Anaesthesiology. 61 (5): 531–540. doi: 10.1093/bja/61.5.531 . PMID   3207525.
  45. 1 2 Hunter JM. (1993). "Atracurium and laudanosine pharmacokinetics in acute renal failure". Intensive Care Medicine. 19 (Suppl. 2): S91–S93. doi:10.1007/bf01708808. PMID   8106685.
  46. Vandenbrom RH, Wierda JM, Agoston S (1990). "Pharmacokinetics and neuromuscular blocking effects of atracurium besylate and two of its metabolites in patients with normal and impaired renal function". Clinical Pharmacokinetics. 19 (3): 230–240. doi:10.2165/00003088-199019030-00006. PMID   2394062. S2CID   37966268.
  47. Parker CJ, Hunter JM (1989). "Pharmacokinetics of atracurium and laudanosine in patients with hepatic cirrhosis". British Journal of Anaesthesiology. 62 (2): 177–183. doi: 10.1093/bja/62.2.177 . PMID   2923767.
  48. 1 2 3 Dewar GH (1976). "Potential short-acting neuromuscular blocking agents". Ph.D. Thesis - the Department of Pharmacy, University of Strathclyde, Scotland.
  49. Waigh R.D. (1986). "Atracurium". Pharmaceutical Journal. 236: 577–578.
  50. Basta SJ, Ali HH, Savarese JJ, Sunder N, Gionfriddo M, Cloutier G, et al. (1982). "Clinical pharmacology of atracurium besylate (BW 33A): a new non-depolarizing muscle relaxant". Anesthesia and Analgesia. 61 (9): 723–729. doi: 10.1213/00000539-198209000-00002 . PMID   6213181. S2CID   32126218.
  51. 1 2 Coker GG, Dewar GH, Hughes R, Hunt TM, Payne JP, Stenlake JB, et al. (1981). "A preliminary assessment of atracurium, a new competitive neuromuscular blocking agent". Acta Anaesthesiologica Scandinavica. 25 (1): 67–69. doi:10.1111/j.1399-6576.1981.tb01608.x. PMID   7293706. S2CID   37109119.
  52. Stenlake JB, Waigh RD, Dewar GH, Dhar NC, Hughes R, Chapple DJ, et al. (1984). "Biodegradable neuromuscular blocking agents. Part 6. Stereochemical studies on atracurium and related polyalkylene di-esters". European Journal of Medicinal Chemistry. 19 (5): 441–450.
  53. Stenlake JB, Waigh RD, Urwin J, Dewar GH, Coker GG (1983). "Atracurium: conception and inception". Br J Anaesth. 55 (Suppl. 1): 3S–10S. PMID   6688014.
  54. McCorkindale NJ, Magrill DS, Martin-Smith M, Smith SJ, Stenlake JB (1964). "Petaline: A 7,8-dioxygenated benzylisoquinoline". Tetrahedron Letters. 5 (51): 3841–3844. doi:10.1016/s0040-4039(01)93303-9.
  55. Stenlake JB, Urwin J, Waigh RD, Hughes R (1979). "Biodegradable neuromuscular blocking agents. I. Quaternary esters". European Journal of Medicinal Chemistry. 14 (1): 77–84.
  56. Stenlake JB, Waigh RD, Urwin J, Dewar GH, Hughes R, Chapple DJ (1981). "Biodegradable neuromuscular blocking agents. Part 3. Bis-quaternary esters". European Journal of Medicinal Chemistry. 16: 508–514.
  57. 1 2 Stenlake JB, Waigh RD, Dewar GH, Hughes R, Chapple DJ, Coker GG (1981). "Biodegradable neuromuscular blocking agents. Part 4. Atracurium besylate and related polyalkylene di-esters". European Journal of Medicinal Chemistry. 16 (6): 515–524.
  58. Stenlake JB, Waigh RD, Dewar GH, Hughes R, Chapple DJ (1983). "Biodegradable neuromuscular blocking agents. Part 5. α,ω-Bisquaternary polyalkylene phenolic esters". European Journal of Medicinal Chemistry. 18: 273–276.
  59. Stenlake JB, Urwin J, Waigh RD, Hughes R (1979). "Biodegradable neuromuscular blocking agents. II. Quaternary ketones". European Journal of Medicinal Chemistry. 14 (1): 85–88.
  60. Stenlake JB. (2001). "Chance, coincidence and atracurium". Pharmaceutical Journal. 267 (7167): 430–441.