Nimbex Mechanism of Action

Pharmacotherapeutic Group: Peripherally acting muscle relaxants: Other quaternary ammonium compounds. ATC Code: M03AC11.
Pharmacology: Pharmacodynamics: Mechanism of Action: Cisatracurium is an intermediate-duration, non-depolarising benzylisoquinolinium skeletal muscle relaxant.
Pharmacodynamic Effects: Clinical studies in man indicated that NIMBEX is not associated with dose-dependent histamine release even at doses up to and including 8 x ED₉₅.
Cisatracurium binds to cholinergic receptors on the motor end-plate to antagonise the action of acetylcholine, resulting in a competitive block of neuromuscular transmission. This action is readily reversed by anticholinesterase agents such as neostigmine or edrophonium.
The ED₉₅ (dose required to produce 95% depression of the twitch response of the adductor pollicis muscle to stimulation of the ulnar nerve) of cisatracurium is estimated to be 0.05 mg/kg body weight during opioid anaesthesia (thiopentone/fentanyl/midazolam).
The ED₉₅ of NIMBEX in children during halothane anaesthesia is 0.04 mg/kg.
Pharmacokinetics: Non-compartmental pharmacokinetics of NIMBEX are independent of dose in the range studied (0.1 to 0.2 mg/kg, i.e., 2 to 4 x ED₉₅).
Population pharmacokinetic modelling confirms and extends these findings up to 0.4 mg/kg (8 x ED₉₅).
Distribution: After doses of 0.1 and 0.2 mg/kg NIMBEX administered to healthy adult surgical patients volume of distribution at steady-state is 121 to 161 ml/kg.
Metabolism: Cisatracurium undergoes degradation in the body at physiological pH and temperature by Hofmann elimination (a chemical process) to form laudanosine and the monoquaternary acrylate metabolite. The monoquaternary acrylate undergoes hydrolysis by non-specific plasma esterases to form the monoquaternary alcohol metabolite.
These metabolites do not possess neuromuscular blocking activity.
Elimination: Elimination of cisatracurium is largely organ-independent but the liver and kidneys are primary pathways for the clearance of its metabolites.
I.V. bolus injection: Pharmacokinetic parameters after doses of 0.1 and 0.2 mg/kg NIMBEX administered to healthy adult surgical patients are summarised in Table 1 as follows. (See Table 1.)

Click on icon to see table/diagram/image

I.V. infusion: The pharmacokinetics of cisatracurium after infusion are similar to those after single bolus injection. Pharmacokinetics were studied in healthy adult surgical patients who received an initial 0.1 mg/kg bolus dose of cisatracurium followed by a maintenance infusion of NIMBEX to maintain 89 to 99% T₁ suppression. Mean clearance of cisatracurium was 6.9 ml/kg/min and elimination half-life was 28 minutes. The recovery profile after infusion of NIMBEX is independent of duration of infusion and is similar to that after single bolus injections.
Special Patient Populations: Elderly: There are no clinically important differences in the pharmacokinetics of cisatracurium in elderly and young adult patients. In a comparative study, plasma clearance was not affected by age.
Minor differences in volume of distribution (+17%) and half-life (+4 minutes) did not affect the recovery profile (see Dosage & Administration).
Patients with renal impairment: There are no clinically important differences in the pharmacokinetics of cisatracurium in patients with end-stage renal failure and in healthy adult patients. In a comparative study, there were no statistically significant or clinically important differences in pharmacokinetic parameters of NIMBEX. The recovery profile of NIMBEX is unchanged in the presence of renal failure (see Dosage & Administration).
Patients with hepatic impairment: There are no clinically important differences in the pharmacokinetics of cisatracurium in patients with end-stage liver disease and in healthy adult patients. In a comparative study of patients undergoing liver transplantation and healthy adults, there were small differences in volume of distribution (+21%) and clearance (+16%), but no difference in elimination half-life of cisatracurium. The recovery profile was unchanged (see Dosage & Administration).
ICU patients: The pharmacokinetics of cisatracurium in ICU patients receiving prolonged infusions are similar to those in healthy surgical adults receiving infusions or single bolus injections. Mean clearance of cisatracurium was 7.5 mL/kg/min and elimination half-life was 27 minutes. The recovery profile after infusions of NIMBEX in ICU patients is independent of duration of infusion.
Concentrations of metabolites are higher in ICU patients with abnormal renal and/or hepatic function (see Precautions). These metabolites do not contribute to neuromuscular block.
Toxicology: Pre-Clinical Safety Data: Mutagenicity: The mutagenic risk to patients undergoing muscle relaxation with NIMBEX is considered negligible.
Carcinogenicity: Carcinogenicity studies have not been performed.