Atracurium Besilate

12/7/2015 Atracurium besilate - Wikipedia, the free encyclopedia
Atracurium besilate
From Wikipedia, the free encyclopedia
Atracurium besylate [1] is a neuromuscular-blocking Atracurium besilate

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. Systematic (IUPAC) name
2,2'-{1,5-Pentanediylbis[oxy(3-oxo-3,1-propanediyl)]}bis[1-
It is on the World Health Organization's List of Essential (3,4-dimethoxybenzyl)-6,7-dimethoxy-2-methyl-1,2,3,4-
Medicines, a list of the most important medication
tetrahydroisoquinolinium] dibenzenesulphonate
needed in a basic health system.[2]
Clinical data
AHFS/Drugs.com International Drug Names
Contents Legal status Worldwide: Prescription

only medicine
1 Neuromuscular function parameters Routes of IV
2 Duration of action administration
3 Preclinical pharmacology Pharmacokinetic data
4 Clinical pharmacology Bioavailability 100% (IV)
5 Adverse effects Protein binding 82%
5.1 Histamine release - hypotension, reflex
Metabolism Hofmann elimination (retro-
tachycardia and cutaneous flush
Michael addition) and ester
5.2 Bronchospasm - pulmonary compliance
5.3 Laudanosine Epileptic foci hydrolysis by nonspecific
6 History esterases
7 References Biological half- 1721 minutes
8 External links life
Identifiers
CAS Registry 64228-79-1
Number
Neuromuscular function ATC code M03AC04
parameters PubChem CID: 47319
DrugBank DB00732
ED95 : the dose of any given neuromuscular-
blocking agent required to produce 95% ChemSpider 43067
suppression of muscle twitch (e.g., the adductor UNII 40AX66P76P
pollicis) response with balanced anesthesia
ChEBI CHEBI:2914
Clinical duration: difference in time between time ChEMBL CHEMBL1360
of injection and time to 25% recovery from
neuromuscular block Chemical data
https://en.wikipedia.org/wiki/Atracurium_besilate 1/10
Train-of-Four (TOF) response: stimulated muscle Formula C53H72N2O122+

twitch response in trains of four when stimuli are
applied in a burst of four as opposed to a single Molecular mass 929.145 g/mol
stimulus, equal depression in depolarising and SMILES
fading response with non-depolarising blocker.
InChI
25%-75% recovery index: an indicator of the rate (what is this?) (verify)
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
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)

Ultra-short Short Intermediate Long
Parameter
Duration Duration Duration Duration
Clinical Duration
(Time from injection to T25% 6-8 12-20 30-45 >60
recovery)
Recovery Time
(Time from injection to T95% <15 25-30 50-70 90-180
recovery)
Recovery Index (T25%-T75% recovery
2-3 6 10-15 >30
slope)
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.[3] A 14 C
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 (0.30.6 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 0.54 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 3070 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
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 ciscis, cistrans, and transtrans 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, 1R, 2R 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
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.[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. 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. 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 34 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 - pulmonary compliance
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 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[22][23] after several serious events of bronchospasm,[24][25] including five
unexplained fatalities,[26] 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[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
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
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 -
aminoesters[56][57][58][59] and -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.
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External links
Neuromuscular blocking agents (https://www.nlm.nih.gov/cgi/mesh/2011/MB_cgi?
mode=&term=Neuromuscular+blocking+agents) at the US National Library of Medicine Medical
Subject Headings (MeSH)
[1] (http://www.nytimes.com/2001/03/31/us/anesthesia-drug-is-removed-from-market-after-the-
deaths-of-5-patients.html?pagewanted=1)
[2]
(http://www.fda.gov/downloads/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalP
roducts/UCM173891.pdf)
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12/7/2015 Atracurium besilate - Wikipedia, the free encyclopedia

Atracurium besylate [1] is a neuromuscular-blocking Atracurium besilate

Contents Legal status Worldwide: Prescription

Train-of-Four (TOF) response: stimulated muscle Formula C53H72N2O122+

Classification of neuromuscular-blocking agents by duration of pharmacological action (minutes)

The tetrahydroisoquinolinium class of neuromuscular blocking agents, in general, is associated with

Bronchospasm - pulmonary compliance

Laudanosine Epileptic foci

Retrieved from "https://en.wikipedia.org/w/index.php?title=Atracurium_besilate&oldid=668319723"

Categories: Muscle relaxants Quaternary ammonium compounds Tetrahydroisoquinolines

This page was last modified on 23 June 2015, at 17:50.

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