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Anesthesia and the Patient with Epilepsy
Published in Stanley R. Resor, Henn Kutt, The Medical Treatment of Epilepsy, 2020
Samantha L. Mullis, A. Donald Finek
Atracurium, a short-acting nondepolarizing competitive neuromuscular blocking agent, has gained popularity among anesthesiologists because its elimination from the body is not dependent upon hepatic metabolism or renal excretion but by nonenzymatic Hoffman elimination and by ester hydrolysis. Though the products of its metabolism have no inherent adverse neuromuscular or cardiovascular effects, one of these metabolites, laudanosine, can produce epileptiform activity when large concentrations of it are injected rapidly into animals, especially in the presence of hyperventilation and halothane anesthesia (92). Since the elimination of laudanosine is primarily dependent upon renal excretion, concern was initially voiced that the nephrectomized patient given atracurium for extended periods of time may be at an increased risk of developing CNS irritability and epileptiform activity. Subsequent studies have shown, however, that the plasma concentration of laudanosine that produces epileptiform activity in laboratory animals, 11 pg/ml, is not likely to be achieved from the use of atracurium in the clinical setting whether the drug is given by continuous infusion or bolus technique in the dosages normally employed (93–95). To date, no investigation has looked at the effect of these “normal” blood levels of laudanosine upon EEG activity in patients.
Neuromuscular blockade and opioids
Published in Hemanshu Prabhakar, Charu Mahajan, Indu Kapoor, Manual of Neuroanesthesia, 2017
Prasanna U. Bidkar, Lakshmi K. Narmadha
Atracurium is an intermediate-acting NMBA with minimal cardiovascular adverse effects and is associated with histamine release at higher doses. It undergoes ester hydrolysis and Hofmann elimination. ED90 of atracurium is 0.5 mg/kg. Laudanosine is a metabolite9 of atracurium and cisatracurium that is shown to decrease seizure threshold. The concentrations required to produce seizures are not achieved in clinically administered doses. But caution is advised in elderly patients and in patients with hepatic failure (laudanosine is metabolized by the liver). There has been only one report of a surgical patient who had a seizure while receiving atracurium.10
Paper 5 Answers
Published in James Day, Amy Thomson, Tamsin McAllister, Nawal Bahal, Get Through, 2014
James Day, Amy Thomson, Tamsin McAllister, Nawal Bahal
The atracurium molecule is metabolized by Hofmann degradation (60%) and ester hydrolysis (40%). Hofmann degradation occurs by cleavage of the link between the central chain and quaternary amine group, releasing laudanosine and a quaternary monoacrylate. This process occurs spontaneously in the plasma at physiological pH and temperature. Laudanosine is an inactive metabolite and is cleared from the plasma by the liver. Ester hydrolysis (of the ester bonds in the central methyl chain) occurs in the presence of non-specific esters in the plasma, producing laudanosine, a quaternary alcohol and a quaternary acid. These metabolites have insignificant neuromuscular blocking activity.
Use of neuromuscular blocking agents in acute respiratory distress syndrome
Published in Baylor University Medical Center Proceedings, 2018
G. Tsai-Nguyen, Ariel M. Modrykamien
A neuromuscular junction is composed of a presynaptic motor axon that abuts acetylcholine receptors of skeletal muscle cells. Upon activation, the neuron releases acetylcholine, activating the skeletal muscle cell and thereby allowing the flow of sodium and potassium to trigger a muscle contraction.11 NMBAs competitively bind to the acetylcholine receptor, preventing activation of the muscle cell by acetylcholine. NMBAs are classified as depolarizing or nondepolarizing agents. Depolarizing agents mimic the effect of acetylcholine at the neuromuscular junction, and these include succinylcholine and decamethonium. Normally, when acetylcholine binds to the acetylcholine receptor on muscle cells, the channel opens for a very short duration because acetylcholinesterase rapidly degrades the transmitter in the perijunctional area.12 Conversely, depolarizing agents have a biphasic action, because they mimic acetylcholine by causing muscle contractions and, subsequently, they cause paralysis due to decreased susceptibility to degradation by acetylcholinesterase. Nondepolarizing NMBAs are also competitive antagonists at the nicotinic acetylcholine receptor but differ from depolarizing agents because they bind for longer periods of time, preventing acetylcholine from binding.13 Importantly, these agents are lipophobic, so they do not cross the blood-brain barrier. Among nondepolarizing agents, pancuronium, cisatracurium, and atracurium have all been studied in the ARDS population. Atracurium was developed in 1981 by Stenlake and colleagues.14 It is a benzylisoquinoline molecule that breaks down irreversibly at physiological pH and temperature based on the principles of Hofmann elimination.15 This characteristic presents important advantages in critically ill subjects, allowing its utilization in patients with kidney, liver, or multiorgan failure.16 However, atracurium may cause histamine release with consequent cardiovascular effects, hypotension, cutaneous flushing, and tachycardia. These effects are usually reversible within 5 minutes postadministration. As previously stated, atracurium undergoes Hofmann elimination; one of the metabolites associated with this elimination path is laudanosine, which has been reported to cross the blood-brain barrier and decrease the seizure threshold. Nevertheless, multiple studies demonstrated that concentrations of laudanosine needed to trigger seizures are much higher than those generated by doses of atracurium used in clinical practice.17 Cisatracurium is an optical isomer of atracurium and is slightly more potent. It also undergoes Hoffman elimination. Because cisatracurium causes less histamine release and concentrations of laudanosine are reportedly lower compared with atracurium, this NMBA presents hypothetical advantages.18