Atracurium: Wikis

  

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Atracurium
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

Identifiers
CAS number 64228-79-1
ATC code M03AC04
PubChem 47319
DrugBank APRD00806
ChemSpider 43067
Chemical data
Formula C53H72N2O122+
Mol. mass 929.145 g/mol
SMILES eMolecules & PubChem
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
Therapeutic considerations
Pregnancy cat.  ?
Legal status Worldwide: Prescription only medicine
Routes IV
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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.

Contents

History

Atracurium besylate was first synthesized in 1974 by George H. Dewar,[2] a pharmacist and a medicinal chemistry doctoral candidate in John B. Stenlake's medicinal chemistry research group in the Department of Pharmacy at the Strathclyde University, Scotland. Dewar first named this compound "33A74"[2] before its eventual emergence 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,[3] 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[4]) and its introduction to first human trials in 1979,[5][6] and then eventually to its first introduction (as a mixture of all ten stereoisomers[7]) 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.[8] 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.[9] Stenlake's research group advanced this concept by systematically synthesizing numerous quaternary ammonium β-aminoesters[10][11][12][13] and β-aminoketones[14] and evaluated them for skeletal muscle relaxant activity: one of these compounds,[5][12] initially labelled as 33A74,[2][15] 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.[7] 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.

Neuromuscular function parameters: definitions

  • 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: differerence in time between time to maximum onset of neuromuscular block 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
  • 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 70% 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: definitions

The confusion in precisely defining the duration of activity that would eventually provide pharmaceutical companies with a weapon to wield in the battle for market share of sales of their respective steroidal versus bisbenzyltetrahydorisoquinolinium neuromuscular blocking drugs eventually forced a formal definition in 1995.[citation needed] This finally settled the dust and provided the gold standard for designating a label for any neuromuscular blocking drug based on its onset and duration of action - the definitions are as follows:

  • Ultra-short duration:
  • Short-duration:
  • Medium duration:
  • Long duration:

Preclinical pharmacology

Several publications describe the preclinical pharmacology of atracurium. Hughes and Payne described the preliminary pharmacology of atracurium in anesthethetized cats, dogs and rhesus monkeys.[16] 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.[17]

Clinical pharmacology

Atracurium is susceptible to degradation by Hofmann elimination and ester hydrolysis as components of the in vivo metabolic processes.[18][19] The initial in vitro studies appeared to indicate a major role for ester hydrolysis[18] but with accumulation of clinical data over time, the preponderence of evidence indicated that Hofmann elimination at physiological pH was the major degradation pathway[19] vindicating the premise for the design of atracurium to undergo an organ-independent metabolism.[20]

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,[6][16] whereas a decrease in temperature slows down the process.[20] Otherwise, the breakdown process is unaffected by the level of plasma esterase activity, obesity,[21] age,[22] or by the status of renal[23][24][25] or hepatic function.[26] 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.[22][24]

Adverse effects

Histamine release - hypotension, reflex tachycardia and cutaneous flush

The tetrahydroisoquinolinium class of neuromuscular blocking agents, in general, is associated with histamine release upon rapid administration of a bolus intravenous injection.[citation needed] 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 elicting 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 that 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 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 peratining to adverse events were distorted to suit taste, and, consequently, 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 bisterahydroisoquinolinium 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 these effects were not only transient but that the extent of the hypotensive effect and the reflex tachycardia were rarely of clinical significance and therefore did not require adjuntive 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. Unfortunately, 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.[citation needed]

Bronchospasm - Pulmonary compliance

There are, to date, no clinically reported cases of bronchospasm associated with atracurium.

The issue of bronchospasm only came to the forefront 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[27] from clinical use (<2 years after its clinical introduction[citation needed]) after several serious events of bronchospasm,[28] including five "unexplained" fatalities,[29] following its administration.

Laudanosine - Epileptic foci

Laudanosine is a metabolite associated with cisatracurium and atracurium - both of which are knowm to undergo Hofmann elimination and hence generate laudanosine as a by-product.[citation needed]

References

  1. ^ Hughes R. (1986). "Atracurium: an overview". British Journal of Anaesthesia 58 Suppl. 1 (6): 2S–5S. PMID 2423104. 
  2. ^ a b c Dewar GH. (1976). "Potential short-acting neuromuscular blocking agents". PhD Thesis - The Department of Pharmacy, University of Strathclyde, Scotland. 
  3. ^ Waigh RD. (1986). "Atracurium". Pharm J 236: 577-578. 
  4. ^ 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. PMID 6213181. 
  5. ^ 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. 
  6. ^ 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. 
  7. ^ 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. 
  8. ^ 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. 
  9. ^ McCorkindale NJ, Magrill DS, Martin-Smith M, Smith SJ, Stenlake JB. (1964). "Petaline: A 7,8-dioxygenated benzylisoquinoline". Tetrahedron Lett 51: 3841–3844. 
  10. ^ Stenlake JB, Urwin J, Waigh RD, Hughes R. (1979). "Biodegradable neuromuscular blocking agents. I. Quaternary esters". Eur J Med Chem 14 (1): 77–84. 
  11. ^ 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. 
  12. ^ 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. 
  13. ^ 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. 
  14. ^ Stenlake JB, Urwin J, Waigh RD, Hughes R. (1979). "Biodegradable neuromuscular blocking agents. II. Quaternary ketones". Eur J Med Chem 14 (1): 85–88. 
  15. ^ Stenlake JB. (2001). "Chance, coincidence and atracurium". Pharm J 267 (7167): 430–441. 
  16. ^ a b Hughes R, Chapple DJ. (1981). "The pharmacology of atracurium: a new competitive neuromuscular blocking agent". Br J Anaesth 53 (1): 31-44. PMID 6161627. 
  17. ^ 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. PMID 7113256. 
  18. ^ a b Stiller RL, Cook DR, Chakravorti S. (1985). "In vitro degradation of atracurium in human plasma". Br J Anaesth 57 (11): 1085–1088. PMID 3840382. 
  19. ^ a b Nigrovic V, Fox JL. (1991). "Atracurium decay and the formation of laudanosine in humans". Anesthesiol 74 (3): 446–454. PMID 2001023. 
  20. ^ a b Merrett RA, Thompson CW, Webb FW. (1983). "In vitro degradation of atracurium in human plasma". Br J Anaesth 55 (1): 61–66. PMID 6687375. 
  21. ^ 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. PMID 2369806. 
  22. ^ a b Kent AP, Parker CJ, Hunter JM. (1989). "Pharmacokinetics of atracurium and laudanosine in the elderly.". Br J Anaesth 63 (6): 661–666. PMID 2611066. 
  23. ^ 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. PMID 3207525. 
  24. ^ a b Hunter JM. (1993). "Atracurium and laudanosine pharmacokinetics in acute renal failure". Intensive Care Med 19 Suppl. 2: S91-S93. PMID 8106685. 
  25. ^ 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. PMID 2394062. 
  26. ^ Parker CJ, Hunter JM. (1989). "Pharmacokinetics of atracurium and laudanosine in patients with hepatic cirrhosis". Br J Anaesth 62 (2): 177–183. PMID 2923767. 
  27. ^ Shapse D. Voluntary market withdrawal - Adverse Drug Reaction 27 March 2001. Raplon® (rapacuronium bromide) for Injection. 
  28. ^ Goudsouzian NG. (2001). "Rapacuronium and bronchospasm.". Anesthesiol 94 (5): 727-728. 
  29. ^ Grady D. (2001). "Anesthesia drug is removed from market after the deaths of 5 patients". The New York Times. 

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