Nimbex
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Nimbex - Scientific Information

Manufacture: AbbVie
Country: Canada
Condition: Anesthesia, Light Anesthesia
Class: Neuromuscular blocking agents
Form: Liquid solution, Intravenous (IV)
Ingredients: cisatracurium besylate, benzenesulfonic acid, benzyl alcohol, water for injection

Pharmaceutical Information

Proper name:cisatracurium besylate
Chemical name:(1R,1'R,2R,2'R)-2,2'-(3,11-dioxo-4,10-dioxatrideca-

[IUPAC]:methylene)bis(1,2,3,4-tetrahydro- 6,7-dimethoxy-2-methyl-1- veratrylisoquinolinium) dibenzenesulfonate

[Chem. Abst.]: {1R-[1,2 (1'R*,2'R*)]}-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
Molecular formula and molecular mass:C65H82N2O18S21243.50
Structural formula:



Physicochemical properties:Cisatracurium besylate is a white to pale yellow powder. The log of the partition coefficient of cisatracurium besylate is – 2.12 in a 1-octanol/distilled water system at 25°C. It has a pH of 5.1 for 1% w/v aqueous solution at 22.4°C.
Solubility:SolventEquilibrium Solubility (mg/mL, 25°C)
Water54
0.1 M HCl55
octan-1-ol0.4

Detailed Pharmacology

Pharmacodynamics

In Vitro Studies

Other than the frog isolated nerve muscle preparation, NIMBEX (cisatracurium besylate injection) at concentrations up to 10-5 M had no significant stimulant or depressant effect on several isolated tissue preparations. In receptor binding assays, 1x10-5 M cisatracurium had essentially no affinity for the following receptors: adenosine (A1 and A2), adrenergic (alpha1, alpha2 and beta), angiotensin II, benzodiazepine, calcium channel (dihydropyridine and phenylalkylamine), calcium release channel (ryanodine), dopamine2, GABA-gated chloride channel (TBPS), glutamate, neurotensin, platelet activating factor, serotonergic (5HT1A and 5HT2), and substance P receptors. A weak potency in blocking cholinergic (M1 and M2) receptors was observed.

In Vivo Studies

The overall neuromuscular blocking profile of cisatracurium in anesthetized cats, dogs and monkeys is very similar to the neuromuscular blocking profile of atracurium. Spontaneous recovery times from neuromuscular blockade produced by single intravenous bolus injections or infusions were independent of both the administered dose and the duration of blockade, and indicated that cisatracurium was devoid of cumulative effects on the neuromuscular junction. High multiples of the ED95 (the effective dose required to produce 95% suppression of the adductor polices muscle twitch response to ulnar nerve stimulation) neuromuscular blocking dose did not produce a correspondingly long duration of action. Like other non-depolarizing neuromuscular blocking agents (e.g., atracurium, vecuronium, mivacurium, doxacurium, d-tubocurarine), the in vivo and in vitro effects of cisatracurium on the neuromuscular junction were reversed by the acetylcholinesterase inhibitor neostigmine.

Bolus intravenous administration of cisatracurium besylate at doses that produced clinically useful levels of neuromuscular blockade had no effects on sympathetic efferent pathways and had no vagolytic action. There was at least a fifteen-fold separation between the ED95 neuromuscular blocking dose and doses that produced transient inhibition of the autonomic nervous system.

The cardiovascular effects of cisatracurium in cats, dogs, and monkeys, at doses that produced complete neuromuscular paralysis, were minimal. Cumulative doses of cisatracurium equivalent to approximately 10 times the ED95 decreased mean arterial blood pressure 15 to 20% and had smaller effects on heart rate, cardiac index, total peripheral resistance and left ventricular dP/dt (the change in pressure over the change in time) in anesthetized dogs. Doses of cisatracurium greater than 10 times the ED95 produced significantly smaller cardiovascular effects than approximately equal doses of atracurium in anesthetized dogs. In anesthetized cats, cisatracurium, unlike atracurium, did not increase plasma histamine concentrations and did not produce histamine-like cardiovascular effects at high multiples of the ED95 neuromuscular blocking dose. Doses of cisatracurium equivalent to 20 to 25 times the ED95 neuromuscular blocking dose had minimal (<10%) effects on arterial blood pressure and heart rate in nitrous oxide:oxygen and halothane anesthetized rhesus and cynomolgus monkeys. Significantly, no histamine-like cardiovascular effects were observed after bolus intravenous administration of doses as high as 20 to 25 times the estimated ED95 neuromuscular blocking dose in monkeys.

Pharmacokinetics

The pharmacokinetics of cisatracurium was studied in cats (0.25 mg/kg intravenous), dogs (1.0 and 2.0 mg/kg intravenous) and monkeys (1.875 and 3.75 mg/kg intravenous) (see Table 1).

Table 1. Pharmacokinetics of Cisatracurim in Animals
ParameterDose (mg/kg)
CatDogCynomologus
Monkey
0.251.02.01.8753.75
Plasma elimination t½ (min)9.022.619.418.622.6
Plasma clearance (mL/min/kg)12.28.57.36.97.2
Volume of distribution at steady-state (L/kg)0.1250.2540.2000.1530.173

Definitions: min = minute; t½ = half life

Metabolism

Metabolic studies in cats and dogs showed that the monoquaternary alcohol metabolite was the major metabolite, suggesting that ester hydrolysis is an important pathway in the elimination of cisatracurium. Both laudanosine, formed via Hofmann elimination, and the acid metabolite were detected in low concentrations.

Toxicology

Acute Toxicity

In a study conducted with non-respired rats, lethality was observed at a subcutaneous dose of cisatracurium as low as 5.0 mg/kg. Intravenous dosing of non-respired rats revealed drug-related clinical signs at 0.1 mg/kg and lethality at 0.2 mg/kg or higher.

Subacute Toxicity

Subacute studies were conducted in monkeys and dogs. Cisatracurium besylate was administered intravenously to anesthetized, ventilated monkeys (n=12) and dogs (n=12) twice weekly for three weeks under conditions simulating clinical usage. The doses represented up to 75 and 40 times the human ED95 dose for monkeys and dogs, respectively. Observations in these studies included clinical signs, body weights, food consumption (dogs), electrocardiography, ophthalmology, clinical pathology, gross necropsy, organ weights, histopathology and drug plasma assays. There were no deaths or drug-induced toxicity noted in either study.

Mutagenicity and Carcinogenicity

Cisatracurium was not found to be mutagenic in the Ames Salmonella assay, a rat bone marrow cytogenic assay, and in vitro human lymphocyte cytogenics assay. No structural or numerical chromosome aberrations were noted in the presence or absence of metabolic activation.

Cisatracurium was tested for its ability to induce mutations at the heterozygous thymidine kinase (tk+/-) locus in the L5178/tk+/- mouse lymphoma assay both in the presence and in the absence of exogenous metabolic activation (rat liver S9). There was a dose-related mutagenic response in the absence of exogenous mammalian metabolic activation at concentrations of 40 mcg/mL and higher. There was minimal evidence of mutagenicity in the presence of metabolic activation at an isolated concentration of 300 mcg/mL. It is unlikely that these mutagenicity results indicate any significant risk with therapeutic use of cisatracurium in humans.

Reproduction and Teratology

A teratology study was conducted in anesthetized, mechanically respired rats given intravenous doses of cisatracurium at 10 or 20 times the human ED95 on days 6 through 15 of the gestational period. There was no evidence of embryotoxicity, fetotoxicity, or teratogenicity.

A second rat teratology study was conducted with cisatracurium at doses up to 10 mg/kg/day via subcutaneous route. Maternal toxicity, including some deaths, were noted in the high dose group. When the dose was reduced to 4.0 mg/kg/day, there were no further indications of maternal toxicity. There was no evidence of embryotoxicity, fetotoxicity, or teratogenicity in this study.

Other Studies

A 5 mg/mL solution of cisatracurium did not flocculate plasma protein nor excessively hemolyze a 50% suspension of type O human erythrocytes when tested at ratios of 1:5 and 1:40 for protein flocculation or 1:7 and 1:35 for hemolysis. The degree of hemolysis seen was essentially equivalent to that noted with sterile water for injection (a known hemolytic agent).

Pigs of Pietrain breeding, susceptible to malignant hyperthermia (MH), were given cisatracurium at doses up to 3 x ED95 (2000 mcg/kg) and evaluated for the emergence of MH. None of the pigs developed signs of MH, whereas they all developed MH when challenged with halothane/succinylcholine upon return of the twitch response to baseline.

A solution of cisatracurium besylate was shown to be minimally irritating in beagle dogs when injected either perivenously or intramuscularly, simulating a misdosing situation.