Atracurium Besylate

ATRACURIUM BESYLATE- atracurium besylate injection, solution
Mayne Pharma (USA) Inc.

Rx Only

This drug should be used only by adequately trained individuals familiar with its actions, characteristics, and hazards.

DESCRIPTION

Atracurium Besylate Injection is an intermediate-duration, nondepolarizing, skeletal muscle relaxant for intravenous administration.

Atracurium besylate is designated as 2,2’-[1,5-pentanediylbis[oxy (3-oxo-3,1-propanediyl)]]bis[1-[(3,4 dimethoxyphenyl)methyl]- 1,2,3,4-tetrahydro-6,7-dimethoxy-2-methylisoquinolinium]dibenzenesulfonate. It has a molecular weight of 1243.51, and its molecular formula is C65 H82 N2 O18 S2 . The structural formula is:

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Atracurium Besylate is a complex molecule containing four sites at which different stereochemical configurations can occur. The symmetry of the molecule, however, results in only ten, instead of sixteen, possible different isomers. The manufacture of atracurium besylate results in these isomers being produced in unequal amounts but with a consistent ratio. Those molecules in which the methyl group attached to the quaternary nitrogen projects on the opposite side to the adjacent substituted-benzyl moiety predominate by approximately 3:1.

Atracurium Besylate Injection is a sterile, nonpyrogenic aqueous solution. Each mL contains 10 mg atracurium besylate. The pH is adjusted to 3.25 to 3.65 with benzenesulfonic acid. The multiple-dose vial contains 0.9% benzyl alcohol added as a preservative. Atracurium Besylate Injection slowly loses potency with time at the rate of approximately 6% per year under refrigeration (5°C). Atracurium Besylate Injection should be refrigerated at 2° to 8°C (36° to 46°F) to preserve potency. Rate of loss in potency increases to approximately 5% per month at 25°C (77°F). Upon removal from refrigeration to room temperature storage conditions (25°C/77°F), use Atracurium Besylate Injection within 14 days even if re-refrigerated.

CLINICAL PHARMACOLOGY

Atracurium Besylate is a nondepolarizing skeletal muscle relaxant. Nondepolarizing agents antagonize the neurotransmitter action of acetylcholine by binding competitively with cholinergic receptor sites on the motor end-plate. This antagonism is inhibited, and neuromuscular block reversed, by acetylcholinesterase inhibitors such as neostigmine, edrophonium, and pyridostigmine.

Atracurium Besylate can be used most advantageously if muscle twitch response to peripheral nerve stimulation is monitored to assess degree of muscle relaxation.

The duration of neuromuscular block produced by Atracurium Besylate is approximately one third to one half the duration of block by d-tubocurarine, metocurine, and pancuronium at initially equipotent doses. As with other nondepolarizing neuromuscular blockers, the time to onset of paralysis decreases and the duration of maximum effect increases with increasing Atracurium Besylate doses.

The ED95 (dose required to produce 95% suppression of the muscle twitch response with balanced anesthesia) has averaged 0.23 mg/kg (0.11 to 0.26 mg/kg in various studies). An initial Atracurium Besylate dose of 0.4 to 0.5 mg/kg generally produces maximum neuromuscular block within 3 to 5 minutes of injection, with good or excellent intubation conditions within 2 to 2.5 minutes in most patients. Recovery from neuromuscular block (under balanced anesthesia) can be expected to begin approximately 20 to 35 minutes after injection. Under balanced anesthesia, recovery to 25% of control is achieved approximately 35 to 45 minutes after injection and recovery is usually 95% complete approximately 60 to 70 minutes after injection. The neuromuscular blocking action of Atracurium Besylate is enhanced in the presence of potent inhalation anesthetics. Isoflurane and enflurane increase the potency of Atracurium Besylate and prolong neuromuscular block by approximately 35%; however, halothane’s potentiating effect (approximately 20%) is marginal (see DOSAGE AND ADMINISTRATION).

Repeated administration of maintenance doses of Atracurium Besylate has no cumulative effect on the duration of neuromuscular block if recovery is allowed to begin prior to repeat dosing. Moreover, the time needed to recover from repeat doses does not change with additional doses. Repeat doses can therefore be administered at relatively regular intervals with predictable results. After an initial dose of 0.4 to 0.5 mg/kg under balanced anesthesia, the first maintenance dose (suggested maintenance dose is 0.08 to 0.10 mg/kg) is generally required within 20 to 45 minutes, and subsequent maintenance doses are usually required at approximately 15 to 25 minute intervals.

Once recovery from the neuromuscular blocking effects of Atracurium Besylate begins, it proceeds more rapidly than recovery from d-tubocurarine, metocurine, and pancuronium. Regardless of the Atracurium Besylate dose, the time from start of recovery (from complete block) to complete (95%) recovery is approximately 30 minutes under balanced anesthesia, and approximately 40 minutes under halothane, enflurane, or isoflurane. Repeated doses have no cumulative effect on recovery rate.

Reversal of neuromuscular block produced by Atracurium Besylate can be achieved with an anticholinesterase agent such as neostigmine, edrophonium, or pyridostigmine, in conjunction with an anticholinergic agent such as atropine or glycopyrrolate. Under balanced anesthesia, reversal can usually be attempted approximately 20 to 35 minutes after an initial Atracurium Besylate dose of 0.4 to 0.5 mg/kg, or approximately 10 to 30 minutes after a 0.08 to 0.10 mg/kg maintenance dose, when recovery of muscle twitch has started. Complete reversal is usually attained within 8 to 10 minutes of the administration of reversing agents. Rare instances of breathing difficulties, possibly related to incomplete reversal, have been reported following attempted pharmacologic antagonism of Atracurium Besylate-induced neuromuscular block. As with other agents in this class, the tendency for residual neuromuscular block is increased if reversal is attempted at deep levels of block or if inadequate doses of reversal agents are employed.

The pharmacokinetics of Atracurium Besylate in humans are essentially linear within the 0.3 to 0.6 mg/kg dose range. The elimination half-life is approximately 20 minutes. THE DURATION OF NEUROMUSCULAR BLOCK PRODUCED BY ATRACURIUM BESYLATE DOES NOT CORRELATE WITH PLASMA PSEUDOCHOLINESTERASE LEVELS AND IS NOT ALTERED BY THE ABSENCE OF RENAL FUNCTION. This is consistent with the results of in vitro studies which have shown that Atracurium Besylate is inactivated in plasma via two nonoxidative pathways: ester hydrolysis, catalyzed by nonspecific esterases; and Hofmann elimination, a nonenzymatic chemical process which occurs at physiological pH. Some placental transfer occurs in humans.

Radiolabel studies demonstrated that Atracurium Besylate undergoes extensive degradation in cats, and that neither kidney nor liver plays a major role in its elimination. Biliary and urinary excretion were the major routes of excretion of radioactivity (totaling >90% of the labeled dose within 7 hours of dosing), of which Atracurium Besylate represented only a minor fraction. The metabolites in bile and urine were similar, including products of Hofmann elimination and ester hydrolysis.

Elderly patients may have slightly altered pharmacokinetic parameters compared to younger patients, with a slightly decreased total plasma clearance which is offset by a corresponding increase in volume of distribution. The net effect is that there has been no significant difference in clinical duration and recovery from neuromuscular block observed between elderly and younger patients receiving Atracurium Besylate.

Atracurium Besylate is a less potent histamine releaser than d-tubocurarine or metocurine. Histamine release is minimal with initial Atracurium Besylate doses up to 0.5 mg/kg, and hemodynamic changes are minimal within the recommended dose range. A moderate histamine release and significant falls in blood pressure have been seen following 0.6 mg/kg of Atracurium Besylate. The histamine and hemodynamic responses were poorly correlated. The effects were generally short-lived and manageable, but the possibility of substantial histamine release in sensitive individuals or in patients in whom substantial histamine release would be especially hazardous (e.g., patients with significant cardiovascular disease) must be considered.

It is not known whether the prior use of other nondepolarizing neuromuscular blocking agents has any effect on the activity of Atracurium Besylate. The prior use of succinylcholine decreases by approximately 2 to 3 minutes the time to maximum block induced by Atracurium Besylate, and may increase the depth of block. Atracurium Besylate should be administered only after a patient recovers from succinylcholine-induced neuromuscular block.

Atracurium Besylate Indications and Usage

Atracurium Besylate Injection is indicated, as an adjunct to general anesthesia, to facilitate endotracheal intubation and to provide skeletal muscle relaxation during surgery or mechanical ventilation.

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