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Atracurium

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Atracurium

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.

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 Strathclyde University, Scotland. Dewar first named this compound "33A74"[2] 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,[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: 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:

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

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]

Chapple and Clarke[18] 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 ester hydrolysis as components of the in vivo metabolic processes.[19][20] The initial in vitro studies appeared to indicate a major role for ester hydrolysis[19] but, with accumulation of clinical data over time, the preponderence of evidence indicated that Hofmann elimination at physiological pH is the major degradation pathway[20] vindicating the premise for the design of atracurium to undergo an organ-independent metabolism.[21]

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.[21] Otherwise, the breakdown process is unaffected by the level of plasma esterase activity, obesity,[22] age,[23] or by the status of renal[24][25][26][27] or hepatic function.[28] 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.[23][26] 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

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.[29] 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 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

Bronchospasm has been reported on occasion with the use of atracurium.[30][31][32][33] 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

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[53] and cardiovascular effects such a hypotension and bradycardia.[54] 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[53] - 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.[55] 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.[56][57] 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.[58] 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.[59] Furthermore, almost a decade later, work by Cardone et al..[60] 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.[54]

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.[54]

References

External links

  • Medical Subject Headings (MeSH)
  • [1]
  • [2]
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