Chemical formula: C₆₅H₈₂N₂O₁₈S₂ Molecular mass: 929.16 g/mol PubChem compound: 62886
Cisatracurium is an intermediate-duration, non-depolarising benzylisoquinolinium skeletal muscle relaxant.
Clinical studies in man indicated that cisatracurium 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 anti-cholinesterase 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 bodyweight during opioid anaesthesia (thiopentone/fentanyl/midazolam).
The ED95 of cisatracurium in children during halothane anaesthesia is 0.04 mg/kg.
Biotransformation/Elimination
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. Elimination of cisatracurium is largely organ independent but the liver and kidneys are primary pathways for the clearance of its metabolites.
These metabolites do not possess neuromuscular blocking activity.
Non-compartmental pharmacokinetics of cisatracurium 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). Pharmacokinetic parameters after doses of 0.1 and 0.2 mg/kg cisatracurium administered to healthy adult surgical patients are summarised in the table below:
| Parameter | Range of Mean Values |
|---|---|
| Clearance | 4.7 to 5.7 mL/min/kg |
| Volume of distribution at steady state | 121 to 161 mL/kg |
| Elimination half-life | 22 to 29 min |
There are no clinically important differences in the pharmacokinetics of cisatracurium in elderly and young adult patients. The recovery profile is also unchanged.
There are no clinically important differences in the pharmacokinetics of cisatracurium in patients with end-stage renal failure or end stage liver disease and in healthy adult patients. Their recovery profiles are also unchanged.
The pharmacokinetics of cisatracurium after infusions are similar to those after single bolus injection. The recovery profile after infusion of cisatracurium is independent of duration of infusion and is similar to that after single bolus injection.
The pharmacokinetics of cisatracurium in ICU patients receiving prolonged infusions are similar to those in healthy surgical adults receiving infusions or single bolus injections. The recovery profile after infusions of cisatracurium in ICU patients is independent of duration of infusion.
Concentrations of metabolites are higher in ICU patients with abnormal renal and/or hepatic function. These metabolites do not contribute to neuromuscular block.
Meaningful acute studies with cisatracurium could not be performed.
Studies with repeated administration for three weeks in dogs and monkeys showed no compound specific toxic signs.
Cisatracurium was not mutagenic in an in vitro microbial mutagenicity test at concentrations up to 5000μg/plate.
In an in vivo cytogenetic study in rats, no significant chromosomal abnormalities were seen at s.c doses up to 4mg/kg.
Cisatracurium was mutagenic in an in vitro mouse lymphoma cell mutagenicity assay, at concentrations of 40μg/ml and higher.
A single positive mutagenic response for a drug used infrequently and/or briefly is of questionable clinical relevance.
Carcinogenicity studies have not been performed.
Fertility studies have not been performed. Reproductive studies in rats have not revealed any adverse effects of cisatracurium on foetal development.
The result of an intra-arterial study in rabbits showed that cisatracurium injection is well tolerated and no drug related changes were seen.
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