Esmeron Mechanism of Action

Pharmacotherapeutic group: Muscle relaxants, peripherally acting agents. ATC code: M03AC09.
Pharmacology: Pharmacodynamics: Mechanism of action: Esmeron (rocuronium bromide) is a fast onset, intermediate acting non-depolarizing neuromuscular blocking agent, possessing all of the characteristic pharmacological actions of this class of drugs (curariform). It acts by competing for nicotinic cholinoceptors at the motor end-plate. This action is antagonized by acetylcholinesterase inhibitors such as neostigmine, edrophonium and pyridostigmine.
Pharmacodynamic effects: The ED90 (dose required to produce 90% depression of the twitch response of the thumb to stimulation of the ulnar nerve) during intravenous anesthesia is approximately 0.3 mg.kg^-1 rocuronium bromide. The ED95 in infants is lower than in adults and children (0.25, 0.35 and 0.40 mg.kg^-1, respectively).
The clinical duration (the duration until spontaneous recovery to 25% of control twitch height) with 0.6 mg.kg^-1 rocuronium bromide is 30-40 minutes. The total duration (time until spontaneous recovery to 90% of control twitch height) is 50 minutes. The mean time of spontaneous recovery of twitch response from 25 to 75% (recovery index) after a bolus dose of 0.6 mg.kg^-1 rocuronium bromide is 14 minutes. With lower dosages of 0.3-0.45 mg.kg^-1 rocuronium bromide (1-1½ x ED90), onset of action is slower and duration of action is shorter.
Should there be reason for selection of larger doses in individual patients, initial doses up to 2 mg.kg^-1 rocuronium bromide have been administered during surgery without adverse cardiovascular effects being noted. The use of these high dosages of rocuronium bromide decreases the onset time and increases the duration of action. With high doses of 2 mg.kg^-1, clinical duration is 110 minutes.
Intubation during routine anesthesia: Within 60 seconds following intravenous administration of a dose of 0.6 mg.kg^-1 rocuronium bromide (2x ED90 under intravenous anesthesia), adequate intubation conditions can be achieved in nearly all patients of which in 80% intubation conditions are rated excellent. General muscle paralysis adequate for any type of procedure is established within 2 minutes. After administration of 0.45 mg.kg^-1 rocuronium bromide, acceptable intubation conditions are present after 90 seconds.
Rapid Sequence Induction: During rapid sequence induction of anesthesia under propofol or fentanyl/thiopental anesthesia, adequate intubation conditions are achieved within 60 seconds in 93% and 96% of the patients respectively, following a dose of 1.0 mg.kg^-1 rocuronium bromide. Of these, 70% are rated excellent. The clinical duration with this dose approaches 1 hour, at which time the neuromuscular block can be safely reversed. Following a dose of 0.6 mg.kg^-1 rocuronium bromide, adequate intubation conditions are achieved within 60 seconds in 81% and 75% of the patients during a rapid sequence induction technique with propofol or fentanyl/thiopental, respectively.
Special populations: Mean onset time in infants and children at an intubation dose of 0.6 mg.kg^-1 is slightly shorter than in adults. The duration of relaxation and the time to recovery tend to be shorter in children compared to infants and adults.
The duration of action of maintenance doses of 0.15 mg.kg^-1 rocuronium bromide might be somewhat longer under enflurane and isoflurane anesthesia in geriatric patients and in patients with hepatic disease and/or renal disease (approximately 20 minutes) than in patients without impairment of excretory organ functions under intravenous anesthesia (approximately 13 minutes) (see Dosage & Administration). No accumulation of effect (progressive increase in duration of action) with repetitive maintenance dosing at the recommended level has been observed.
Intensive Care Unit: Following continuous infusion in the Intensive Care Unit, the time to recovery of the train of four ratio to 0.7 depends on the level of block at the end of the infusion. After a continuous infusion for 20 hours or more the median (range) time between return of T₂ to train of four stimulation and recovery of the train of four ratio to 0.7 approximates 1.5 (1-5) hours in patients without multiple organ failure and 4 (1-25) hours in patients with multiple organ failure.
Cardiovascular surgery: In patients scheduled for cardiovascular surgery the most common cardiovascular changes during the onset of maximum block following 0.6-0.9 mg.kg^-1 Esmeron are a slight and clinically insignificant increase in heart rate up to 9% and an increase in mean arterial blood pressure up to 16% from the control values.
Reversal of muscle relaxation: Administration of acetylcholinesterase inhibitors (neostigmine, pyridostigmine or edrophonium) at reappearance of T₂ or at the first signs of clinical recovery, antagonizes the action of Esmeron.
Pharmacokinetics: After intravenous administration of a single bolus dose of rocuronium bromide the plasma concentration time course runs in three exponential phases. In normal adults, the mean (95% CI) elimination half-life is 73 (66-80) minutes, the (apparent) volume of distribution at steady state conditions is 203 (193-214) ml.kg^-1 and plasma clearance is 3.7 (3.5-3.9) ml.kg^-1.min^-1.
In controlled studies the plasma clearance in geriatric patients and in patients with renal dysfunction was reduced, in most studies however without reaching the level of statistical significance. In patients with hepatic disease, the mean elimination half-life is prolonged with 30 minutes and the mean plasma clearance is reduced by 1 ml.kg^-1.min^-1. (See Dosage & Administration.)
In infants (3 months to 1 yr), the apparent volume of distribution at steady state conditions is increased compared to adults and children (1-8 yr). In older children (3-8 yr), a trend is seen towards higher clearance and shorter elimination half-life (approximately 20 minutes) compared to adults, younger children and infants.
When administered as a continuous infusion to facilitate mechanical ventilation for 20 hours or more, the mean elimination half-life and the mean (apparent) volume of distribution at steady state are increased. A large between patient variability is found in controlled clinical studies, related to nature and extent of (multiple) organ failure and individual patient characteristics. In patients with multiple organ failure a mean (± SD) elimination half-life of 21.5 (± 3.3) hours, a (apparent) volume of distribution at steady state of 1.5 (± 0.8) l.kg^-1 and a plasma clearance of 2.1 (± 0.8) ml.kg^-1.min^-1 were found.
Rocuronium is excreted in urine and bile. Excretion in urine approaches 40% within 12-24 hours. After injection of a radiolabeled dose of rocuronium bromide, excretion of the radiolabel is on average 47% in urine and 43% in feces after 9 days. Approximately 50% is recovered as the parent compound.
Toxicology: Preclinical safety data: Effects in non-clinical studies were observed only at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use.
There is no proper animal model to mimic the usually extremely complex clinical situation of the ICU patient. Therefore the safety of Esmeron when used to facilitate mechanical ventilation in the Intensive Care Unit is mainly based on the results obtained in clinical studies.