Tracrium Mechanism of Action

Pharmacology: Pharmacodynamics: Mechanism of Action: Atracurium is a highly selective competitive (non-depolarising) neuromuscular blocking agent with an intermediate duration of action.
Pharmacodynamic Effects: Atracurium has no direct effect on intra-ocular pressure, and is therefore suitable for use in ophthalmic surgery.
Pharmacokinetics: Metabolism: Atracurium is inactivated by Hofmann elimination, a non-enzymatic process which occurs at physiological pH and temperature, and by ester hydrolysis catalysed by non-specific esterases.
Tests with plasma from patients with low levels of pseudocholinesterase show that the inactivation of atracurium proceeds unaffected.
Variations in the blood pH and body temperature of the patient within the physiological range will not significantly alter the duration of action of atracurium.
Elimination: The termination of the neuromuscular blocking action of atracurium is not dependent on its hepatic or renal metabolism or excretion. Its duration of action, therefore, is unlikely to be affected by impaired renal, hepatic or circulatory function.
The elimination half-life of atracurium is approximately 20 minutes, and the volume of distribution is 0.16 L/kg. Atracurium is 82% bound to plasma proteins.
Special Patient Populations: Haemofiltration and haemodiafiltration have a minimal effect on plasma levels of atracurium and its metabolites, including laudanosine. The effects of haemodialysis and haemoperfusion on plasma levels of atracurium and its metabolites are unknown.
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: Atracurium has been evaluated in three short-term mutagenicity tests. It was not mutagenic in either the in vitro Ames salmonella assay at concentrations up to 1000 micrograms/plate or in an in vivo rat bone marrow assay at doses up to those which resulted in neuromuscular blockade. In a second in vitro test, the mouse lymphoma assay, mutagenicity was not observed at doses up to 60 micrograms/mL which killed up to 50% of the treated cells but it was moderately mutagenic at concentrations of 80 micrograms/mL in the absence of metabolising agent and weakly mutagenic at very high concentrations (1200 micrograms/mL) when metabolising enzymes were added. At both concentrations over 80% of the cells were killed.
In view of the nature of human exposure to atracurium, the mutagenic risk to patients undergoing surgical relaxation with atracurium must be considered negligible.
Carcinogenicity: Carcinogenicity studies have not been performed.