Atracurium
Encyclopedia
Atracurium besylate 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.
research group in the Department of Pharmacy
at the Strathclyde University
, Scotland
. Dewar first named this compound "33A74" 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, 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) and its introduction to first human trials in 1979, and then eventually to its first introduction (as a mixture of all ten stereoisomers) 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. 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. Stenlake's research group advanced this concept by systematically synthesizing numerous quaternary ammonium β-aminoesters and β-aminoketones and evaluated them for skeletal muscle relaxant activity: one of these compounds, initially labelled as 33A74, 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
. 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.
Chapple and Clarke 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.
hydrolysis
as components of the in vivo metabolic processes. The initial in vitro studies appeared to indicate a major role for ester
hydrolysis
but, with accumulation of clinical data over time, the preponderence of evidence indicated that Hofmann elimination at physiological pH is the major degradation pathway vindicating the premise for the design of atracurium to undergo an organ-independent metabolism.
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, whereas a decrease in temperature slows down the process. Otherwise, the breakdown process is unaffected by the level of plasma esterase activity, obesity, age, or by the status of renal or hepatic function. 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.
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).
agents, in general, is associated with histamine
release upon rapid administration of a bolus intravenous injection. 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 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. 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, 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 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. However, these ill-willed beguiling notions have persisted through the decades and become ingrained with each successive generation of newly qualified anesthesiologists and CRNA
s (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.
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 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) after several serious events of bronchospasm
, including five "unexplained" fatalities, 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
and succinylcholine, as well as alcuronium, pancuronium
, vecuronium
, and gallamine.
, a tertiary amino alkaloid reported to be a modest CNS stimulant with epileptogenic activity and cardiovascular effects such a hypotension and bradycardia. 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, the purported 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. Fortunate 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. 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 eight to 10 times greater those observed in humans during infusions of atracurium. 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. Furthermore, almost a decade later, work by Cardone et al.. 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.
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.
Neuromuscular-blocking drugs
Neuromuscular-blocking drugs block neuromuscular transmission at the neuromuscular junction, causing paralysis of the affected skeletal muscles. This is accomplished either by acting presynaptically via the inhibition of acetylcholine synthesis or release or by acting postsynaptically at the...
or skeletal muscle relaxant
Muscle relaxant
A muscle relaxant is a drug which affects skeletal muscle function and decreases the muscle tone. It may be used to alleviate symptoms such as muscle spasms, pain, and hyperreflexia. The term "muscle relaxant" is used to refer to two major therapeutic groups: neuromuscular blockers and spasmolytics...
in the category of non-depolarizing neuromuscular-blocking drugs
Neuromuscular-blocking drugs
Neuromuscular-blocking drugs block neuromuscular transmission at the neuromuscular junction, causing paralysis of the affected skeletal muscles. This is accomplished either by acting presynaptically via the inhibition of acetylcholine synthesis or release or by acting postsynaptically at the...
, used adjunctively in anesthesia
Anesthesia
Anesthesia, or anaesthesia , traditionally meant the condition of having sensation blocked or temporarily taken away...
to facilitate endotracheal intubation
Intubation
Tracheal intubation, usually simply referred to as intubation, is the placement of a flexible plastic or rubber tube into the trachea to maintain an open airway or to serve as a conduit through which to administer certain drugs...
and to provide skeletal muscle
Skeletal muscle
Skeletal muscle is a form of striated muscle tissue existing under control of the somatic nervous system- i.e. it is voluntarily controlled. It is one of three major muscle types, the others being cardiac and smooth muscle...
relaxation during surgery
Surgery
Surgery is an ancient medical specialty that uses operative manual and instrumental techniques on a patient to investigate and/or treat a pathological condition such as disease or injury, or to help improve bodily function or appearance.An act of performing surgery may be called a surgical...
or mechanical ventilation
Mechanical ventilation
In medicine, mechanical ventilation is a method to mechanically assist or replace spontaneous breathing. This may involve a machine called a ventilator or the breathing may be assisted by a physician, respiratory therapist or other suitable person compressing a bag or set of bellows...
.
Atracurium is classified as an intermediate-duration non-depolarizing neuromuscular-blocking agent.
History
Atracurium besylate was first synthesized in 1974 by George H. Dewar, a pharmacist and a medicinal chemistry doctoral candidate in John B. Stenlake's medicinal chemistryMedicinal chemistry
Medicinal chemistry and pharmaceutical chemistry are disciplines at the intersection of chemistry, especially synthetic organic chemistry, and pharmacology and various other biological specialties, where it is involved with design, chemical synthesis and development for market of pharmaceutical...
research group in the Department of Pharmacy
Pharmacy
Pharmacy is the health profession that links the health sciences with the chemical sciences and it is charged with ensuring the safe and effective use of pharmaceutical drugs...
at the Strathclyde University
University of Strathclyde
The University of Strathclyde , Glasgow, Scotland, is Glasgow's second university by age, founded in 1796, and receiving its Royal Charter in 1964 as the UK's first technological university...
, Scotland
Scotland
Scotland is a country that is part of the United Kingdom. Occupying the northern third of the island of Great Britain, it shares a border with England to the south and is bounded by the North Sea to the east, the Atlantic Ocean to the north and west, and the North Channel and Irish Sea to the...
. Dewar first named this compound "33A74" 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
Muscle relaxant
A muscle relaxant is a drug which affects skeletal muscle function and decreases the muscle tone. It may be used to alleviate symptoms such as muscle spasms, pain, and hyperreflexia. The term "muscle relaxant" is used to refer to two major therapeutic groups: neuromuscular blockers and spasmolytics...
that undergoes chemodegradation in vivo. The term chemodegradation was coined by Roger D. Waigh, PhD, also a pharmacist and a postdoctoral researcher in Stenlake's research group. Atracurium was licensed by Strathclyde University
University of Strathclyde
The University of Strathclyde , Glasgow, Scotland, is Glasgow's second university by age, founded in 1796, and receiving its Royal Charter in 1964 as the UK's first technological university...
to The Wellcome Foundation Ltd. UK, which developed the drug (then known as BW 33A) and its introduction to first human trials in 1979, and then eventually to its first introduction (as a mixture of all ten stereoisomers) into clinical anesthetic practice in the UK, in 1983, under the tradename of Tracrium.
The premise to the design of atracurium
Atracurium
Atracurium besylate 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...
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. 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
Alkene
In organic chemistry, an alkene, olefin, or olefine is an unsaturated chemical compound containing at least one carbon-to-carbon double bond...
and a tertiary
Tertiary
The Tertiary is a deprecated term for a geologic period 65 million to 2.6 million years ago. The Tertiary covered the time span between the superseded Secondary period and the Quaternary...
amine
Amine
Amines are organic compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are derivatives of ammonia, wherein one or more hydrogen atoms have been replaced by a substituent such as an alkyl or aryl group. Important amines include amino acids, biogenic amines,...
.
The approach to utilizing Hofmann elimination as a means to promoting biodegradation
Biodegradation
Biodegradation or biotic degradation or biotic decomposition is the chemical dissolution of materials by bacteria or other biological means...
had its roots in much earlier observations that the quaternary alkaloid
Alkaloid
Alkaloids are a group of naturally occurring chemical compounds that contain mostly basic nitrogen atoms. This group also includes some related compounds with neutral and even weakly acidic properties. Also some synthetic compounds of similar structure are attributed to alkaloids...
petaline (obtained from the Lebanese plant Leontice leontopetalum) readily underwent facile Hofmann elimination to a tertiary amine
Amine
Amines are organic compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are derivatives of ammonia, wherein one or more hydrogen atoms have been replaced by a substituent such as an alkyl or aryl group. Important amines include amino acids, biogenic amines,...
called leonticine upon passage through a basic (as opposed to an acidic) ion-exchange resin. Stenlake's research group advanced this concept by systematically synthesizing numerous quaternary ammonium β-aminoesters and β-aminoketones and evaluated them for skeletal muscle relaxant activity: one of these compounds, initially labelled as 33A74, eventually led to further clinical development, and came to be known as atracurium
Atracurium
Atracurium besylate 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...
.
Atracurium
Atracurium
Atracurium besylate 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...
's limited clinical utility for the future was presaged with the marketing approval of cisatracurium
Cisatracurium
Cisatracurium 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...
in 1995 under the tradename of Nimbex. Cisatracurium
Cisatracurium
Cisatracurium 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...
is the R-cis R-cis isomer component of the ten stereoisomers that comprise atracurium
Atracurium
Atracurium besylate 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...
. The pharmacodynamic and adverse effects profile of cisatracurium
Cisatracurium
Cisatracurium 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...
proved to be superior to that of atracurium
Atracurium
Atracurium besylate 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...
, which rapidly led to decline in the use of atracurium
Atracurium
Atracurium besylate 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...
. The clinical development of cisatracurium
Cisatracurium
Cisatracurium 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...
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: 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: definitions
Neuromuscular-blocking agents can be classified in accordance to their duration of pharmacological action, defined as follows:| 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
Several publications describe the preclinical pharmacology of atracurium. Hughes and Payne described the preliminary pharmacology of atracurium in anesthethetized cats, dogs and rhesus monkeys. 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.Chapple and Clarke 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
Atracurium is susceptible to degradation by Hofmann elimination and esterEster
Esters are chemical compounds derived by reacting an oxoacid with a hydroxyl compound such as an alcohol or phenol. Esters are usually derived from an inorganic acid or organic acid in which at least one -OH group is replaced by an -O-alkyl group, and most commonly from carboxylic acids and...
hydrolysis
Hydrolysis
Hydrolysis is a chemical reaction during which molecules of water are split into hydrogen cations and hydroxide anions in the process of a chemical mechanism. It is the type of reaction that is used to break down certain polymers, especially those made by condensation polymerization...
as components of the in vivo metabolic processes. The initial in vitro studies appeared to indicate a major role for ester
Ester
Esters are chemical compounds derived by reacting an oxoacid with a hydroxyl compound such as an alcohol or phenol. Esters are usually derived from an inorganic acid or organic acid in which at least one -OH group is replaced by an -O-alkyl group, and most commonly from carboxylic acids and...
hydrolysis
Hydrolysis
Hydrolysis is a chemical reaction during which molecules of water are split into hydrogen cations and hydroxide anions in the process of a chemical mechanism. It is the type of reaction that is used to break down certain polymers, especially those made by condensation polymerization...
but, with accumulation of clinical data over time, the preponderence of evidence indicated that Hofmann elimination at physiological pH is the major degradation pathway vindicating the premise for the design of atracurium to undergo an organ-independent metabolism.
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, whereas a decrease in temperature slows down the process. Otherwise, the breakdown process is unaffected by the level of plasma esterase activity, obesity, age, or by the status of renal
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).
Histamine release - hypotension, reflex tachycardia and cutaneous flush
The tetrahydroisoquinolinium class of neuromuscular blockingBlocking
Blocking may refer to:- Telecommunications and computing :*Block , a sequence of bytes or bits, having a nominal length*Block , technical measures to restrict users' access to certain internet resources...
agents, in general, is associated with histamine
Histamine
Histamine is an organic nitrogen compound involved in local immune responses as well as regulating physiological function in the gut and acting as a neurotransmitter. Histamine triggers the inflammatory response. As part of an immune response to foreign pathogens, histamine is produced by...
release upon rapid administration of a bolus intravenous injection. There are some exceptions to this rule; e.g., cisatracurium
Cisatracurium
Cisatracurium 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...
(Nimbex) is one such agent that does not elicit histamine
Histamine
Histamine is an organic nitrogen compound involved in local immune responses as well as regulating physiological function in the gut and acting as a neurotransmitter. Histamine triggers the inflammatory response. As part of an immune response to foreign pathogens, histamine is produced by...
release even up to 5xED95 doses. The liberation of histamine
Histamine
Histamine is an organic nitrogen compound involved in local immune responses as well as regulating physiological function in the gut and acting as a neurotransmitter. Histamine triggers the inflammatory response. As part of an immune response to foreign pathogens, histamine is produced by...
is a dose-dependent phenomenon such that, with increasing doses administered at the same rate, there is a greater propensity for eliciting histamine
Histamine
Histamine is an organic nitrogen compound involved in local immune responses as well as regulating physiological function in the gut and acting as a neurotransmitter. Histamine triggers the inflammatory response. As part of an immune response to foreign pathogens, histamine is produced by...
release and its ensuing sequelae. Most commonly, the histamine
Histamine
Histamine is an organic nitrogen compound involved in local immune responses as well as regulating physiological function in the gut and acting as a neurotransmitter. Histamine triggers the inflammatory response. As part of an immune response to foreign pathogens, histamine is produced by...
release following administration of these agents is associated with observable cutaneous flushing (facial face and arms, commonly), hypotension
Hypotension
In physiology and medicine, hypotension is abnormally low blood pressure, especially in the arteries of the systemic circulation. It is best understood as a physiologic state, rather than a disease. It is often associated with shock, though not necessarily indicative of it. Hypotension is the...
and a consequent reflex tachycardia
Tachycardia
Tachycardia comes from the Greek words tachys and kardia . Tachycardia typically refers to a heart rate that exceeds the normal range for a resting heart rate...
. 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. 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
Blocking
Blocking may refer to:- Telecommunications and computing :*Block , a sequence of bytes or bits, having a nominal length*Block , technical measures to restrict users' access to certain internet resources...
agents, fact and information peratining to adverse events were distorted to suit taste, and, as a consequence, much misinformation was deliberately disseminated regarding histamine
Histamine
Histamine is an organic nitrogen compound involved in local immune responses as well as regulating physiological function in the gut and acting as a neurotransmitter. Histamine triggers the inflammatory response. As part of an immune response to foreign pathogens, histamine is produced by...
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
Vecuronium
Vecuronium is a muscle relaxant in the category of non-depolarizing blocking agents. Vecuronium bromide is indicated as an adjunct to general anesthesia, to facilitate endotracheal intubation and to provide skeletal muscle relaxation during surgery or mechanical ventilation...
(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
Histamine
Histamine is an organic nitrogen compound involved in local immune responses as well as regulating physiological function in the gut and acting as a neurotransmitter. Histamine triggers the inflammatory response. As part of an immune response to foreign pathogens, histamine is produced by...
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
Tachycardia
Tachycardia comes from the Greek words tachys and kardia . Tachycardia typically refers to a heart rate that exceeds the normal range for a resting heart rate...
are 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
Blocking
Blocking may refer to:- Telecommunications and computing :*Block , a sequence of bytes or bits, having a nominal length*Block , technical measures to restrict users' access to certain internet resources...
agents. However, these ill-willed beguiling notions have persisted through the decades and become ingrained with each successive generation of newly qualified anesthesiologists and CRNA
Nurse anesthetist
A nurse anesthetist is a nurse who specializes in the administration of anesthesia.In the United States, a Certified Registered Nurse Anesthetist is an advanced practice registered nurse who has acquired graduate-level education and board certification in anesthesia...
s (certified registered nurse anesthetists) to the extent that the mere mention of "benzylisoquinolines" (the erroneous but commonly used class name for tetrahydroisoquinolinium neuromuscular-blocking
Blocking
Blocking may refer to:- Telecommunications and computing :*Block , a sequence of bytes or bits, having a nominal length*Block , technical measures to restrict users' access to certain internet resources...
agents) immediately conjures images of histamine
Histamine
Histamine is an organic nitrogen compound involved in local immune responses as well as regulating physiological function in the gut and acting as a neurotransmitter. Histamine triggers the inflammatory response. As part of an immune response to foreign pathogens, histamine is produced by...
release and generates serious anxiety.
Bronchospasm - Pulmonary compliance
Bronchospasm has been reported on occasion with the use of atracurium. 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
Bronchospasm
Bronchospasm or a bronchial spasm is a sudden constriction of the muscles in the walls of the bronchioles. It is caused by the release of substances from mast cells or basophils under the influence of anaphylatoxins...
acquired considerable prominence in the neuromuscular-blocking
Blocking
Blocking may refer to:- Telecommunications and computing :*Block , a sequence of bytes or bits, having a nominal length*Block , technical measures to restrict users' access to certain internet resources...
agents arena after the spectacular failure of a clinically introduced neuromuscular-blocking
Blocking
Blocking may refer to:- Telecommunications and computing :*Block , a sequence of bytes or bits, having a nominal length*Block , technical measures to restrict users' access to certain internet resources...
agent, rapacuronium
Rapacuronium
Rapacuronium is a rapidly acting, non-depolarizing neuromuscular blocker formerly used in modern anaesthesia, to aid and enable endotracheal intubation, which is often necessary to assist in the controlled ventilation of unconscious patients during surgery and sometimes in intensive care...
(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 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) after several serious events of bronchospasm
Bronchospasm
Bronchospasm or a bronchial spasm is a sudden constriction of the muscles in the walls of the bronchioles. It is caused by the release of substances from mast cells or basophils under the influence of anaphylatoxins...
, including five "unexplained" fatalities, following its administration. That is not to say that bronchospasm was an unknown phenomenon prior to rapacuronium: Occasional reports of bronchospasm
Bronchospasm
Bronchospasm or a bronchial spasm is a sudden constriction of the muscles in the walls of the bronchioles. It is caused by the release of substances from mast cells or basophils under the influence of anaphylatoxins...
have been noted also with the prototypical agents, tubocurarine
Tubocurarine
Tubocurarine is a neuromuscular-blocking drug or skeletal muscle relaxant in the category of non-depolarizing neuromuscular-blocking drugs, used adjunctively in anesthesia to provide skeletal muscle relaxation during surgery or mechanical ventilation...
and succinylcholine, as well as alcuronium, pancuronium
Pancuronium
Pancuronium is a muscle relaxant with various purposes. It is the second of three drugs administered during most lethal injections in the United States.- Mode of action :...
, vecuronium
Vecuronium
Vecuronium is a muscle relaxant in the category of non-depolarizing blocking agents. Vecuronium bromide is indicated as an adjunct to general anesthesia, to facilitate endotracheal intubation and to provide skeletal muscle relaxation during surgery or mechanical ventilation...
, and gallamine.
Laudanosine – Epileptic foci
Because atracurium undergoes Hofmann elimination as a primary route of chemodegradation, one of the major metabolites from this process is laudanosineLaudanosine
Laudanosine or N-methyltetrahydropapaverine is a recognized metabolite of atracurium and cisatracurium. Laudanosine decreases the seizure threshold, and thus it can induce seizures if present at sufficient threshold concentrations; however such concentrations are unlikely to be produced consequent...
, a tertiary amino alkaloid reported to be a modest CNS stimulant with epileptogenic activity and cardiovascular effects such a hypotension and bradycardia. 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, the purported 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. Fortunate 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. 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 eight to 10 times greater those observed in humans during infusions of atracurium. 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. Furthermore, almost a decade later, work by Cardone et al.. 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.
Laudanosine is also a metabolite
Metabolite
Metabolites are the intermediates and products of metabolism. The term metabolite is usually restricted to small molecules. A primary metabolite is directly involved in normal growth, development, and reproduction. Alcohol is an example of a primary metabolite produced in large-scale by industrial...
of cisatracurium
Cisatracurium
Cisatracurium 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...
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.