Atracurium besilate

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Atracurium besilate
Atracurium.svg
Systematic (IUPAC) name
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] dibenzenesulphonate
Clinical data
AHFS/Drugs.com International Drug Names
Legal status
  • Worldwide: Prescription only medicine
Routes IV
Pharmacokinetic data
Bioavailability 100% (IV)
Protein binding 82%
Metabolism Hofmann elimination (retro-Michael addition) and ester hydrolysis by nonspecific esterases
Half-life 17–21 minutes
Identifiers
CAS number 64228-79-1 YesY
ATC code M03AC04
PubChem CID 47319
DrugBank DB00732
ChemSpider 43067 YesY
UNII 40AX66P76P N
ChEBI CHEBI:2914 YesY
ChEMBL CHEMBL1360 YesY
Chemical data
Formula C53H72N2O122+
Mol. mass 929.145 g/mol
 N (what is this?)  (verify)

Atracurium besylate[1] is a 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. Atracurium is classified as an intermediate-duration non-depolarizing neuromuscular-blocking agent.

It is on the World Health Organization's List of Essential Medicines, a list of the most important medication needed in a basic health system.[2]

Neuromuscular function parameters[edit]

  • ED95: the dose of any given neuromuscular-blocking agent required to produce 95% suppression of muscle twitch (e.g., the adductor pollicis) response with balanced anesthesia
  • Clinical duration: difference in time between time of injection and time to 25% recovery from neuromuscular block
  • Train-of-Four (TOF) response: stimulated muscle twitch response in trains of four when stimuli are applied in a burst of four as opposed to a single stimulus, equal depression in depolarising and fading response with non-depolarising blocker.
  • 25%-75% recovery index: an indicator of the rate of skeletal muscle recovery - essentially, the difference in time between the time to recovery to 25% and time to recovery to 75% of baseline value
  • T4:T1 ≥ 0.7: a 70% ratio of the fourth twitch to the first twitch in a TOF - provides a measure of the recovery of neuromuscular function
  • T4:T1 ≥ 0.9: a 90% ratio of the fourth twitch to the first twitch in a TOF - provides a measure of the full recovery of neuromuscular function

Duration of action[edit]

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)
Parameter Ultra-short Duration Short Duration Intermediate Duration Long Duration
Clinical Duration
(Time from injection to T25% recovery)
6-8 12-20

30-45

>60
Recovery Time
(Time from injection to T95% recovery)
<15 25-30

50-70

90-180
Recovery Index (T25%-T75% recovery slope) 2-3 6

10-15

>30

Preclinical pharmacology[edit]

Several publications describe the preclinical pharmacology of atracurium. Hughes and Payne described the preliminary pharmacology of atracurium in anesthethetized cats, dogs and rhesus monkeys.[3] A 14C radiolabeled metabolism study in cats confirmed the lack of hepatic or renal involvement in the metabolism of atracurium: radioactivity eliminated in bile and urine was predominantly from metabolites rather than the unchanged parent drug.[4]

Chapple and Clarke[5] reported on the neuromuscular and cardiovascular effects of the breakdown products of atracurium and related substances in anesthetized cats. They concluded that the metabolites were of low potencies, and quite likely that the quantities present either as an impurity or formed after administration of therapeutic doses of atracurium (0.3–0.6 mg kg-1 i.v.) would be of no pharmacological importance. Laudanosine, the quaternary acid and metholaudanosine were devoid of neuromuscular blocking activity within the dose range 0.5–4 mg kg-1. However, within this dose range, they reported that the quaternary monoacrylate, the quaternary alcohol and the monoquaternary analogue produced a dose-dependent neuromuscular block. Administration of the quaternary monoacrylate, laudanosine, the quaternary alcohol, metholaudanosine and the monoquaternary analogue at 4 mg kg-1 doses resulted in a significant reduction in mean arterial pressure (by 30–70 mm Hg). Significant sympathetic blockade after preganglionic nerve stimulation was observed only with the monoquaternary analogue at a dose of 4 mg kg-1, whereas significant vagal blockade occurred after 4 mg kg-1 of the quaternary monoacrylate, the quaternary acid, the quaternary alcohol, and the monoquaternary analogue.

Clinical pharmacology[edit]

Atracurium is susceptible to degradation by Hofmann elimination and ester hydrolysis as components of the in vivo metabolic processes.[6][7] The initial in vitro studies appeared to indicate a major role for ester hydrolysis[6] but, with accumulation of clinical data over time, the preponderence of evidence indicated that Hofmann elimination at physiological pH is the major degradation pathway[7] vindicating the premise for the design of atracurium to undergo an organ-independent metabolism.[8]

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,[9][3] whereas a decrease in temperature slows down the process.[8] Otherwise, the breakdown process is unaffected by the level of plasma esterase activity, obesity,[10] age,[11] or by the status of renal[12][13][14][15] or hepatic function.[16] 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.[11][14] 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.

Adverse effects[edit]

Histamine release - hypotension, reflex tachycardia and cutaneous flush[edit]

The tetrahydroisoquinolinium class of neuromuscular blocking agents, in general, is associated with histamine release upon rapid administration of a bolus intravenous injection.[17] There are some exceptions to this rule; e.g., cisatracurium (Nimbex) is one such agent that does not elicit histamine release even up to 5xED95 doses.[citation needed] 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.[citation needed] 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.[citation needed] It should be noted though that 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.[citation needed] Because these effects are so transient, there is no reason to administer adjunctive therapy to ameliorate either the cutaneous or the cardiovascular effects. Thus, in the fierce battle to win market share for sales of the "steroidal" versus the terahydroisoquinolinium class of neuromuscular-blocking agents, fact and information pertaining to adverse events were distorted to suit taste, and, as a consequence, much misinformation was deliberately disseminated regarding histamine release and its effects: this was particularly so in the 1980s and 1990s shortly after the near simultaneous competitive clinical introduction of atracurium (Tracrium - a bistetrahydroisoquinolinium neuromuscular-blocking agent marketed by Burroughs Wellcome Co., now subsumed into GlaxoSmithKline) and vecuronium (Norcuron - a steroidal neuromuscular-blocking agent marketed by Organon, now subsumed into Merck & Co. Inc.). The most common misinformation seeded into the minds of anesthesiologists was the failure to categorically state that the cardiovascular effects following histamine release were transient, and, instead, the marketing focus was single-mindedly to regurgitate and emphasize that the tetrahydroisoquinolinium class elicited histamine release that could prove to be a danger to the cardiovascular stability of the patient during surgical procedures. There was complete failure to disseminate the true picture that not only are these effects transient but that the extent of the hypotensive effect and the reflex tachycardia are rarely of clinical significance and therefore did not require adjunctive therapy, as evidenced by the complete lack of any clinical literature advocating the need for adjunctive antihistamine use concomitantly with the administration of tetrahydroisoquinolinium neuromuscular-blocking agents. However, these ill-willed beguiling notions have persisted through the decades and become ingrained with each successive generation of newly qualified anesthesiologists and CRNAs (certified registered nurse anesthetists) to the extent that the mere mention of "benzylisoquinolines" (the erroneous but commonly used class name for tetrahydroisoquinolinium neuromuscular-blocking agents) immediately conjures images of histamine release and generates serious anxiety.

Bronchospasm - Pulmonary compliance[edit]

Bronchospasm has been reported on occasion with the use of atracurium.[18][19][20][21] 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 considerable prominence in the neuromuscular-blocking agents arena after the spectacular failure of a clinically introduced neuromuscular-blocking agent, rapacuronium (Raplon - a steroidal neuromuscular-blocking agent marketed by Organon, now subsumed into Merck & Co. Inc.), which had to be withdrawn voluntarily during the week of March 19, 2001[22] from clinical use (<2 years after its approval by the US FDA on August 18, 1999 - see NME Drug and New Biologic Approvals in 1999)[23] after several serious events of bronchospasm,[24][25] including five "unexplained" fatalities,[26] following its administration. That is not to say that bronchospasm was an unknown phenomenon prior to rapacuronium: Occasional reports of bronchospasm have been noted also with the prototypical agents, tubocurarine[27][28][29] and succinylcholine,[30][31][32][33][34] as well as alcuronium,[35] pancuronium,[36][37] vecuronium,[38][39] and gallamine.[40]

Laudanosine – Epileptic foci[edit]

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[41] and cardiovascular effects such a hypotension and bradycardia.[42] 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[41] - 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.[43] 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.[44][45] 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.[46] 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 renal failure and undergoing cadaveric renal transplantation.[47] Furthermore, almost a decade later, work by Cardone et al..[48] 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 uninterrupted clinical availability of atracurium, there is now little doubt that laudanosine accumulation and related toxicity will likely ever be seen with the doses of atracurium that are administered in clinical practice.[42]

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.[42]

History[edit]

Atracurium besylate was first synthesized in 1974 by George H. Dewar,[49] 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"[49] 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, PhD,[50] also a pharmacist and a postdoctoral researcher in Stenlake's research group. Atracurium was licensed by Strathclyde University to The Wellcome Foundation Ltd. UK, which developed the drug (then known as BW 33A[51]) and its introduction to first human trials in 1979,[52][9] and then eventually to its first introduction (as a mixture of all ten stereoisomers[53]) 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.[54] 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 hydoxide 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.[55] Stenlake's research group advanced this concept by systematically synthesizing numerous quaternary ammonium β-aminoesters[56][57][58][59] and β-aminoketones[60] and evaluated them for skeletal muscle relaxant activity: one of these compounds,[52][58] initially labelled as 33A74,[49][61] eventually led to further clinical development, and came to be known as atracurium.

Atracurium's limited clinical utility for the future was presaged with the marketing approval of cisatracurium in 1995 under the tradename of Nimbex. Cisatracurium is the R-cis R-cis isomer component of the ten stereoisomers that comprise atracurium.[53] The pharmacodynamic and adverse effects profile of cisatracurium proved to be superior to that of atracurium, which rapidly led to decline in the use of atracurium. The clinical development of cisatracurium was undertaken by Burroughs Wellcome Co. (and its parent The Wellcome Foundation Ltd.), from 1992 to 1994, and by the time of its approval for use in humans by the US Food and Drug Administration, Burroughs Wellcome Co. had merged with Glaxo Inc., and Nimbex was subsequently marketed worldwide by GlaxoWellcome Inc.

References[edit]

  1. ^ Hughes R. (1986). "Atracurium: an overview". British Journal of Anaesthesia. 58 Suppl. 1 (6): 2S–5S. doi:10.1093/bja/58.suppl_1.2s. PMID 2423104. 
  2. ^ "WHO Model List of EssentialMedicines". World Health Organization. October 2013. Retrieved 22 April 2014. 
  3. ^ a b Hughes R, Chapple DJ. (1981). "The pharmacology of atracurium: a new competitive neuromuscular blocking agent". Br J Anaesth 53 (1): 31–44. doi:10.1093/bja/53.1.31. PMID 6161627. 
  4. ^ Neill EA, Chapple DJ. (1982). "Metabolic studies in the cat with atracurium: a neuromuscular blocking agent designed for non-enzymic inactivation at physiological pH". Xenobiotica 12 (3): 203–210. doi:10.3109/00498258209046795. PMID 7113256. 
  5. ^ Chapple DJ, Clark JS (1983 Suppl. 1). "Pharmacological action of breakdown products of atracurium and related substances". Br J Anaesth 55: 11S–15S. PMID 6688001.  Check date values in: |date= (help)
  6. ^ a b Stiller RL, Cook DR, Chakravorti S. (1985). "In vitro degradation of atracurium in human plasma". Br J Anaesth 57 (11): 1085–1088. doi:10.1093/bja/57.11.1085. PMID 3840382. 
  7. ^ a b Nigrovic V, Fox JL. (1991). "Atracurium decay and the formation of laudanosine in humans". Anesthesiol 74 (3): 446–454. doi:10.1097/00000542-199103000-00010. PMID 2001023. 
  8. ^ a b Merrett RA, Thompson CW, Webb FW. (1983). "In vitro degradation of atracurium in human plasma". Br J Anaesth 55 (1): 61–66. doi:10.1093/bja/55.1.61. PMID 6687375. 
  9. ^ a b Payne JP, Hughes R. (1981). "Evaluation of atracurium in anaesthetized man.". Br J Anaesth. 53 (1): 45–54. doi:10.1093/bja/53.1.45. PMID 7459185. 
  10. ^ 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". Clin Pharmacol Ther 48 (1): 18–25. doi:10.1038/clpt.1990.112. PMID 2369806. 
  11. ^ a b Kent AP, Parker CJ, Hunter JM. (1989). "Pharmacokinetics of atracurium and laudanosine in the elderly.". Br J Anaesth 63 (6): 661–666. doi:10.1093/bja/63.6.661. PMID 2611066. 
  12. ^ Fahey MR, Rupp SM, Fisher DM, Miller RD, Sharma M, Canfell C, Castagnoli K, Hennis PJ (Dec 1984). "The pharmacokinetics and pharmacodynamics of atracurium in patients with and without renal failure". Anesthesiol 61 (6): 699–702. doi:10.1097/00000542-198412000-00011. PMID 6239574. 
  13. ^ 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". Br J Anaesth 61 (5): 531–540. doi:10.1093/bja/61.5.531. PMID 3207525. 
  14. ^ a b Hunter JM. (1993). "Atracurium and laudanosine pharmacokinetics in acute renal failure". Intensive Care Med. 19 Suppl. 2: S91–S93. doi:10.1007/bf01708808. PMID 8106685. 
  15. ^ 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". Clin Pharmacokinet 19 (3): 230–240. doi:10.2165/00003088-199019030-00006. PMID 2394062. 
  16. ^ Parker CJ, Hunter JM. (1989). "Pharmacokinetics of atracurium and laudanosine in patients with hepatic cirrhosis". Br J Anaesth 62 (2): 177–183. doi:10.1093/bja/62.2.177. PMID 2923767. 
  17. ^ Savarese JJ, Wastila WB (1995). "The future of the benzylisoquinolinium relaxants". Acta Anaesthesiol Scand. 106 Suppl: 91–93. PMID 8533554. 
  18. ^ Ortalli GL, Tiberio I, Mammana G (May 1985). "A case of severe bronchospasm and laryngospasm after atracurium administration". Anesthesiol 62 (5): 645–646. PMID 2581480. 
  19. ^ Siler JN, Mager JG Jr, Wyche MQ Jr (Mar 1993). "Atracurium: hypotension, tachycardia and bronchospasm". Minerva Anestesiol 59 (3): 133–135. PMID 8515854. 
  20. ^ 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. 
  21. ^ 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. 
  22. ^ Shapse D. "Voluntary market withdrawal - Adverse Drug Reaction 27 March 2001. Raplon (rapacuronium bromide) for Injection". 
  23. ^ Lim R (Feb 2003). "Rapacuronium: premarket drug evaluation can be very effective for the identification of drug risks". Anesth Analg 96 (2): 631–632. doi:10.1213/01.ANE.0000033791.25469.D8. PMID 12538231. 
  24. ^ Goudsouzian NG. (2001). "Rapacuronium and bronchospasm". Anesthesiol 94 (5): 727–728. doi:10.1097/00000542-200105000-00006. PMID 11388519. 
  25. ^ Jooste E, Klafter F, Hirshman CA, Emala CW (Apr 2003). "A mechanism for rapacuronium-induced bronchospasm: M2 muscarinic receptor antagonism". Anesthesiol 98 (4): 906–911. doi:10.1097/00000542-200304000-00017. PMID 12657852. 
  26. ^ Grady D. (2001-03-31). "Anesthesia drug is removed from market after the deaths of 5 patients". The New York Times. 
  27. ^ Harrison GA (Aug 1966). "A case of cardiac arrest associated with bronchospasm and d-tubocurarine". Aust N Z J Surg 36 (1): 40–42. doi:10.1111/j.1445-2197.1966.tb04394.x. PMID 5225576. 
  28. ^ Bevan DR. (1992) "Curare". In: Maltby JR, Shephard DAE (Eds.), Harold Griffith - His Life and Legacy; Suppl. to Can J Anaesth Vol. 39 (1); 49-55.
  29. ^ Takki S, Tammisto T (Apr 1971). "Severe bronchospasm and circulatory collapse following the administration of d-tubocurarine". Ann Clin Res 3 (2): 112–115. PMID 4104054. 
  30. ^ Fellini AA, Bernstein RL, Zauder HL (Oct 1963). "Bronchospasm due to suxamethonium; report of a case". Br J Anaesth 35: 657–659. PMID 14073484. 
  31. ^ Bele-Binda N, Valeri F (Jan 1971). "A case of bronchospasm induced by succinylcholine". Can Anaesth Soc J 18 (1): 116–119. doi:10.1007/BF03025433. PMID 5545731. 
  32. ^ Katz AM, Mulligan PG (Oct 1972). "Bronchospasm induced by suxamethonium. A case report". Br J Anaesth 44 (10): 1097–1099. doi:10.1093/bja/44.10.1097. PMID 4639831. 
  33. ^ Eustace BR (Oct 1967). "Suxamethonium induced bronchospasm". Anaesthesia 22 (4): 638–641. doi:10.1111/j.1365-2044.1967.tb10161.x. PMID 4168012. 
  34. ^ Cardan E, Deacu E (Jan 1972). "Bronchospasm following succinyl choline". Anaesthesist 21 (1): 27–29. PMID 4111555. 
  35. ^ Yeung ML, Ng LY, Koo AW (Feb 1979). "Severe bronchospasm in an asthmatic patient following alcuronium and D-tubocurarine". Anaesth Intensive Care 7 (1): 62–64. PMID 434447. 
  36. ^ 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. 
  37. ^ Kounis NG (Apr 1974). "Letter: Bronchospasm induced by althesin and pancuronium bromide". Br J Anaesth 46 (4): 281. doi:10.1093/bja/46.4.281-a. PMID 4451602. 
  38. ^ Uratsuji Y, Konishi M, Ikegaki N, Kitada H (Jan 1991). "Possible bronchospasm after administration of vecuronium". Masui 40 (1): 109–112. PMID 1675699. 
  39. ^ 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. 
  40. ^ Okazaki K, Saito T, Wakisaka K, Hirano T, Kozu K (Jun 1969). "Bronchospasm possible due to gallamine. A case report". Tokushima J Exp Med 16 (1): 9–14. PMID 5348343. 
  41. ^ a b Standaert FG (Dec 1985). "Magic bullets, science, and medicine". Anesthesiol 63 (6): 577–578. doi:10.1097/00000542-198512000-00002. PMID 2932980. 
  42. ^ a b c Fodale V, Santamaria LB (Jul 2002). "Laudanosine, an atracurium and cisatracurium metabolite". Eur J Anaesthesiol 19 (7): 466–473. doi:10.1017/s0265021502000777. PMID 12113608. 
  43. ^ Katz Y, Weizman A, Pick CG, Pasternak GW, Liu L, Fonia O, Gavish M (May 1994). "Interactions between laudanosine, GABA, and opioid subtype receptors: implication for laudanosine seizure activity". Brain Res 646 (2): 235–241. doi:10.1016/0006-8993(94)90084-1. PMID 8069669. 
  44. ^ Lanier WL, Milde JH, Michenfelder JD (Dec 1985). "The cerebral effects of pancuronium and atracurium in halothane-anesthetized dogs". Anesthesiol 63 (6): 589–597. doi:10.1097/00000542-198512000-00007. PMID 2932982. 
  45. ^ 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". Anesthesiol 63 (6): 584–589. doi:10.1097/00000542-198512000-00006. PMID 2932981. 
  46. ^ Ingram MD, Sclabassi RJ, Cook DR, Stiller RL, Bennett MH (1986). "Cardiovascular and electroencephalographic effects of laudanosine in "nephrectomized" cats". Br. J Anaesth. 58 Suppl 1: 14S–18S. doi:10.1093/bja/58.suppl_1.14s. PMID 3707810. 
  47. ^ Fahey MR, Rupp SM, Canfell C, Fisher DM, Miller RD, Sharma M, Castagnoli K, Hennis PJ (Nov 1985). "Effect of renal failure on laudanosine excretion in man". Br J Anaesth 57 (11): 1049–1051. doi:10.1093/bja/57.11.1049. PMID 3840380. 
  48. ^ Cardone C, Szenohradszky J, Yost S, Bickler PE (May 1994). "Activation of brain acetylcholine receptors by neuromuscular blocking drugs. A possible mechanism of neurotoxicity". Anesthesiol 80 (5): 1155–1161. doi:10.1097/00000542-199405000-00025. PMID 7912481. 
  49. ^ a b c Dewar GH. (1976). "Potential short-acting neuromuscular blocking agents". PhD Thesis - the Department of Pharmacy, University of Strathclyde, Scotland. 
  50. ^ Waigh RD. (1986). "Atracurium". Pharm J 236: 577–578. 
  51. ^ Basta SJ, Ali HH, Savarese JJ, Sunder N, Gionfriddo M, Cloutier G, Lineberry C, Cato AE. (1982). "Clinical pharmacology of atracurium besylate (BW 33A): a new non-depolarizing muscle relaxant". Anesth Analg 61 (9): 723–729. doi:10.1213/00000539-198209000-00002. PMID 6213181. 
  52. ^ a b Coker GG, Dewar GH, Hughes R, Hunt TM, Payne JP, Stenlake JB, Waigh RD. (1981). "A preliminary assessment of atracurium, a new competitive neuromuscular blocking agent". Acta Anaesthesiol Scand 25 (1): 67–69. doi:10.1111/j.1399-6576.1981.tb01608.x. PMID 7293706. 
  53. ^ a b Stenlake JB, Waigh RD, Dewar GH, Dhar NC, Hughes R, Chapple DJ, Lindon JC, Ferrige AG. (1984). "Biodegradable neuromuscular blocking agents. Part 6. Stereochemical studies on atracurium and related polyalkylene di-esters.". Eur J Med Chem 19 (5): 441–450. 
  54. ^ 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. 
  55. ^ McCorkindale NJ, Magrill DS, Martin-Smith M, Smith SJ, Stenlake JB. (1964). "Petaline: A 7,8-dioxygenated benzylisoquinoline". Tetrahedron Lett 51: 3841–3844. doi:10.1016/s0040-4039(01)93303-9. 
  56. ^ Stenlake JB, Urwin J, Waigh RD, Hughes R. (1979). "Biodegradable neuromuscular blocking agents. I. Quaternary esters". Eur J Med Chem 14 (1): 77–84. 
  57. ^ Stenlake JB, Waigh RD, Urwin J, Dewar GH, Hughes R, Chapple DJ. (1981). "Biodegradable neuromuscular blocking agents. Part 3. Bis-quaternary esters". Eur J Med Chem 16: 508–514. 
  58. ^ a b 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". Eur J Med Chem 16 (6): 515–524. 
  59. ^ Stenlake JB, Waigh RD, Dewar GH, Hughes R, Chapple DJ. (1983). "Biodegradable neuromuscular blocking agents. Part 5. α,ω-Bisquaternary polyalkylene phenolic esters". Eur J Med Chem 18: 273–276. 
  60. ^ Stenlake JB, Urwin J, Waigh RD, Hughes R. (1979). "Biodegradable neuromuscular blocking agents. II. Quaternary ketones". Eur J Med Chem 14 (1): 85–88. 
  61. ^ Stenlake JB. (2001). "Chance, coincidence and atracurium". Pharm J 267 (7167): 430–441. 

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