Originator
Tracrium,Burroughs-Wellcome,US,1983
Definition
ChEBI: The bisbenzenesulfonate salt of atracurium.
Manufacturing Process
Acryloyl chloride (0.2 mol) in dry benzene (60 ml) was added over 0.5 hour
with mechanical stirring to pentane-1,5-diol (0.1 mol), triethylamine (0.2 mol)
and pyrogallol (0.1 g) in dry benzene (100 ml). Further dry benzene (ca 100
ml) was added followed by triethylamine (10 ml), and the mixture stirred at
50°C for 0.5 hour. The triethylamine hydrochloride was filtered off and the
solvent removed in vacuum to leave a yellow oil which was distilled in the
presence of a trace of p-methoxyphenol, excluding light, to give 1,5-
pentamethylenediacrylate (12.9 g, 61%, BP 90° to 95°C/0.01 mm Hg).
A solution of tetrahydropapaverine (4.43 g) and 1,5-pentamethylene
diacrylate (1.30 g) in dry benzene (15 ml) was stirred under reflux for 48
hours excluding light. The solvent was removed in vacuum and the residual
pale red oil dissolved in chloroform (10 ml). Addition of ether (ca 400 ml),
followed by saturated ethereal oxalic acid solution (ca 500 ml) gave a
flocculent white precipitate, which was filtered off, washed with ether and dried. Crystallization (twice) from ethanol gave N,N'-4,10-dioxa-3,11-
dioxotridecylene-1,13-bis-tetrahydropapaverine dioxalate as a white powder
(3.5 g, 51%, MP 117° to 121°C).
The free base, N,N'-14,10-dioxa-3,11-dioxotridecylene-1,13-bistetrahydropapaverine,
was obtained by basifying an aqueous solution of the
dioxalate with sodium bicarbonate solution, followed by extraction with
toluene and evaporation of the solvent, to give a colorless viscous oil.
Scrupulously dried base (0.5 g) in spectroscopically pure acetonitrile (8 ml)
was treated with methyl benzene sulfonate at room temperature for 22 hours.
The filtered reaction mixture was added dropwise to mechanically stirred,
filtered, dry ether (ca 450 ml). The flocculent white precipitate was filtered off,
washed with dry ether, and dried in vacuum over P2O5 at 50°C to yield the
product, an off-white powder melting at 85° to 90°C.
In practice it is usually used as dibenzenesulfonate.
Brand name
Tracrium (Hospira).
Therapeutic Function
Neuromuscular blocker
Biological Functions
Atracurium besylate (Tracrium) is a benzylisoquinolinium
compound like d-tubocurarine. Its actions are similar
to those of d-tubocurarine, but its duration of action
is shorter (45 minutes) because of spontaneous degradation
of the molecule (Hofmann elimination). Because
of this, atracurium is useful in patients with low or atypical
plasma cholinesterase and in patients with renal or
hepatic impairment.
General Description
Atracurium besylate, 2-(2-carboxyethyl)-1,2,3,4-tetrahydro-6,7-dimethoxy-2-methyl-1-veratrylisoquinolinium benzenesulfonate pentamethyleneester (Tracrium), is a nondepolarizing neuromuscular blockingagent that is approximately 2.5 times more potent thand-tubocurarine. Its duration of action (half-life, 0.33 hours)is much shorter than that of d-tubocurarine.
Biochem/physiol Actions
Nicotinic acetylcholine receptor antagonist.
Clinical Use
Atracurium Besylate is metabolized rapidly and nonenzymatically to yield laudanosineand a smaller quaternary compound ,which do not have neuromuscular blocking activity. In vitroexperiments show that atracurium besylate breaks down atpH 7.4 and 37°C by a Hoffman elimination reaction.Atracurium besylate undergoes enzymatic decompositionof its ester function to yield an inactive quaternary alcoholand quaternary acid. AChE inhibitors such as neostigmine,edrophonium, and pyridostigmine antagonize paralysis byatracurium besylate.
Veterinary Drugs and Treatments
Atracurium is indicated as an adjunct to general anesthesia to
produce muscle relaxation during surgical procedures or mechanical
ventilation and also to facilitate endotracheal intubation.
Atracurium can be used in patients with significant renal or hepatic
disease.
Drug interactions
Potentially hazardous interactions with other drugs
Anaesthetics: effects enhanced by ketamine;
enhanced effect with volatile liquid general
anaesthetics.
Anti-arrhythmics: procainamide enhances muscle
relaxant effect.
Antibacterials: aminoglycosides, clindamycin,
polymyxin and piperacillin enhance effect of
atracurium.
Antiepileptics: muscle relaxant effects antagonised by
carbamazepine; effects reduced by long-term use of
phenytoin but might be increased by acute use.
Atracurium enhances the neuromuscular block
produced by botulinum toxin (risk of toxicity)
Metabolism
Atracurium besilate undergoes spontaneous degradation
via Hofmann elimination (a non-enzymatic breakdown
process occurring at physiological pH and temperature)
to produce laudanosine and other metabolites. There is
also ester hydrolysis by non-specific plasma esterases.
The metabolites have no neuromuscular blocking activity.
Excretion of atracurium is in urine and bile, mostly as
metabolites.
