Diabetes mellitus affects the duration of action of vecuronium in dogs.

OBJECTIVE: To compare the duration of action of vecuronium in diabetic dogs with a control group. STUDY DESIGN: Prospective clinical study. ANIMALS: Forty client-owned diabetic (n = 20) and non-diabetic dogs. METHODS: Dogs were considered free from other concurrent disease based on clinical examination and laboratory data. After pre-anaesthetic medication with acepromazine and methadone, anaesthesia was induced with intravenous (IV) propofol and maintained with isoflurane-nitrous oxide in oxygen. Neuromuscular blockade (NMB) was achieved with vecuronium, 0.1 mg kg(-1) IV and its effects recorded by palpation (pelvic limb digital extension) and electromyography (m. tibialis cranialis) of responses (twitches; T) to repeated train-of-four (TOF) nerve stimulation. Time to onset of NMB was the period between vecuronium injection and loss of fourth twitch (T4) in the TOF pattern recorded by EMG and palpation. Duration of NMB was defined as the time from drug administration to return of T1 by palpation (T1(tactile) ) and EMG (T1(EMG) ). Times to return of T2-4 were also recorded. Time from induction of anaesthesia to vecuronium injection was recorded. Heart rate, non-invasive mean arterial pressure, body temperature, end-tidal isoflurane and end-tidal CO(2) concentrations were recorded at onset of NMB and when T1(EMG) returned. Loss and return of palpable and EMG responses for diabetic and non-diabetic dogs were compared using t-tests and Mann Whitney U-tests. RESULTS: There were significant (p < 0.05) differences between diabetic and non-diabetic dogs for the return of all four palpable and EMG responses. Times (mean ± SD) for return of T1(tactile) were 13.2 ± 3.5 and 16.9 ± 4.2 minutes in diabetic and non-diabetic dogs respectively. There were no differences between diabetic and non-diabetic dogs in the time to onset of vecuronium with EMG or tactile monitoring. CONCLUSIONS AND CLINICAL RELEVANCE: The duration of action of vecuronium was shorter in diabetic dogs as indicated by both tactile and EMG monitoring.

Neuroactive steroids, WIN-compounds and cholesterol share a common binding site on muscarinic acetylcholine receptors.

Endogenous neurosteroids and their synthetic analogues-neuroactive steroids-have been found to bind to muscarinic acetylcholine receptors and allosterically modulate acetylcholine binding and function. Using radioligand binding experiments we investigated their binding mode. We show that neuroactive steroids bind to two binding sites on muscarinic receptors. Their affinity for the high-affinity binding site is about 100 nM. Their affinity for the low-affinity binding site is about 10 µM. The high-affinity binding occurs at the same site as binding of steroid-based WIN-compounds that is different from the common allosteric binding site for alcuronium or gallamine that is located between the second and third extracellular loop of the receptor. This binding site is also different from the allosteric binding site for the structurally related aminosteroid-based myorelaxants pancuronium and rapacuronium. Membrane cholesterol competes with neurosteroids/neuroactive steroids binding to both high- and low-affinity binding site, indicating that both sites are oriented towards the cell membrane..

Interaction of protein ligands with receptor fragments. On the residues of curaremimetic toxins that recognize fragments 128-142 and 185-199 of the alpha-subunit of the nicotinic acetylcholine receptor.

Using a solid-phase assay, we found that 3H-labeled alpha Cobtx from Naja naja siamensis, a long-chain curaremimetic toxin, and 3H-labelled toxin alpha from Naja nigricollis, a short-chain toxin both bind specifically but with substantially different affinities (Kd = 4 x 10(-7) M and 50 x 10(-6) M) to fragment 185-199 (T alpha 185-199) of the alpha-subunit of the acetylcholine receptor (AcChoR) from Torpedo marmorata. Then we show that monoderivatizations of residues common to both long-chain and short-chain toxins (Tyr-25, Lys-27, Trp-29, and Lys-53) or to long-chain toxins only (Cys-30 and Cys-34) do not affect the binding of the toxins to T alpha 185-199, suggesting that none of these invariant residues in implicated in the recognition of this AcChoR region. alpha Cobtx and toxin alpha bind to the fragment 128-142 (T alpha 128-142) with more similar affinities (Kd = 3 x 10(-7) M and 1.4 x 10(-6) M) and their binding is dramatically affected by the single abolition of the positive charge of Lys-53, an invariant residue that contributes to AcChoR recognition. Therefore, the data indicate that Lys-53 more specifically recognizes the 128-142 region of AcChoR. Other monoderivatizations have no effect on toxin binding. The approach described in this paper may be of great help to identify toxin residues that establish direct contact with receptor fragments.

New approaches to reversal of neuromuscular block.

Although numerous reversal agents for neuromuscular block (NMB) have been known for some time, investigations on new approaches were initiated only recently. The different approaches used in an attempt to avoid the muscarinic side effects associated with the antagonists of NMB that are currently available are reviewed.

Clinical pharmacokinetics of cisatracurium besilate.

Cisatracurium besilate, one of the 10 stereoisomers that comprise atracurium besilate, is a nondepolarising neuromuscular blocking agent with an intermediate duration of action. Following a 5- to 10-sec intravenous bolus dose of cisatracurium besilate to healthy young adult surgical patients, elderly patients and patients with renal or hepatic failure, the concentration versus time profile of cisatracurium besilate is best characterised by a 2-compartment model. The volume of distribution (Vd) of cisatracurium besilate is small because of its relatively large molecular weight and high polarity. Cisatracurium besilate undergoes Hofmann elimination, a process dependent on pH and temperature. Unlike atracurium besilate, cisatracurium besilate does not appear to be degraded directly by ester hydrolysis. Hofmann elimination, an organ independent elimination pathway, occurs in plasma and tissue, and is responsible for approximately 77% of the overall elimination of cisatracurium besilate. The total body clearance (CL), steady-state Vd and elimination half-life of cisatracurium besilate in patients with normal organ function are approximately 0.28 L/h/kg (4.7 ml/min/kg), 0.145 L/kg and 25 minutes, respectively. The magnitude of interpatient variability in the CL of cisatracurium besilate is low (16%), a finding consistent with the strict physiological control of the factors that effect the Hofmann elimination of cisatracurium besilate (i.e. temperature and pH). There is a unique relationship between plasma clearance and Vd because the primary elimination pathway for cisatracurium besilate is not dependent on organ function. There are minor differences in the pharmacokinetics of cisatracurium besilate in various patient populations. These differences are not associated with clinically significant differences in the recovery profile of cisatracurium besilate, but may be associated with differences in the time to onset of neuromuscular block.

Clinical pharmacology of muscle relaxants in patients with burns.

Pathophysiologic changes accompanying burn trauma can alter the pharmacokinetics and pharmacodynamic responses to neuromuscular relaxants. Pathophysiologic changes that can potentially affect kinetics in the hypermetabolic phase of burn injury include increased hepatic blood flow, increased glomerular filtration, and increased protein binding. Except for D-tubocurarine, the pharmacokinetics of neuromuscular relaxants relative to burn trauma have not been studied. The unbound volume of distribution, clearance, and half-life of D-tubocurarine were not significantly different from controls, but the plasma binding and renal elimination at 24 hours was increased in burn patients. The aberrant pharmacodynamic responses to neuromuscular relaxants in burn patients include the potential for lethal hyperkalemia with the administration of depolarizing relaxant, succinylcholine, and a 2.5- to 5.0-fold increase in the dose or plasma concentration requirement for nondepolarizing relaxant, including D-tubocurarine, metocurine, pancuronium, and atracurium. The altered pharmacodynamic responses are probably related to an increase in nicotinic acetylcholine receptor number. An alternative to succinylcholine to produce rapid-onset neuromuscular paralysis include the administration of 3XED95 doses of pancuronium and metocurine in combination (but recovery from paralysis is prolonged). Vecuronium and atracurium have good cardiovascular stability and faster recovery times even in high dosages in healthy patients, but the pharmacokinetics and pharmacodynamics of these drugs in patients with burns have not been fully characterized.

Vecuronium: a new nondepolarizing neuromuscular-blocking agent. Clinical pharmacology, pharmacokinetics, cardiovascular effects and use in special clinical situations.

Vecuronium provides additional flexibility to the clinician using neuromuscular-blocking drugs. Its shorter duration of action, lack of significant cardiovascular effects and lack of dependence on the kidney for elimination provide clinical advantages over, or alternatives to, currently available, nondepolarizing neuromuscular-blocking drugs.

Neuromuscular blockers in surgery and intensive care, Part 2.

The historical development, pharmacology, pharmacodynamics, pharmacokinetics, clinical applications, pharmacologic basis for selection, adverse effects, and cost of neuromuscular blockers (NMBs) are discussed. The first NMB to be used was tubocurarine. During neurotransmission, acetylcholine is synthesized, stored in vesicles at the neuromuscular junction, released into the synapse, and bound to nicotinic receptors in the muscle end plate. For muscle contraction to occur, the impulse generated in a neuron's cell body must create an action potential that is chemically transmitted across the synapse. The postsynaptic nicotinic receptor at the neuromuscular junction is the major site of action of depolarizing and nondepolarizing NMBs. All NMBs have the potential for cross-reactivity at other nicotinic and muscarinic sites. Drug interactions most commonly occur between NMBs and inhalation anesthetics, certain antimicrobials, calcium-channel blockers, and anticholinesterases. When selecting an NMB, an agent's onset and duration of action must be considered. NMBs can be used on a short-term or long-term basis. Apart from cost, the choice of an NMB is made on the basis of its adverse-reaction profile, pharmacokinetics, and indications for use. Monitoring tools, their use, the rationale for their use, and the interpretation of the results they provide are unique. The patterns of peripheral nerve stimulation vary and elicit different characteristics of nondepolarizing neuromuscular blockade. The effectiveness of reversal agents is proportional to the degree of blockade. The mechanism of action of anticholinesterases involves inhibition of acetylcholinesterase. The expensive NMBs should be conserved for use in surgery, while the cheaper, long-acting [corrected] agents should be used in the intensive care unit. An understanding of the pharmacology, pharmacodynamics, and pharmacokinetics of NMBs will help health care providers gain expertise in the selection and use of these agents.

Neuromuscular blockade: offset anomalies. Are they simply potency-related receptor bonding effects?

Rapid making and breaking of bonds between quaternary ammonium compounds and cholinergic receptors is typical of ion-pair bonding, which is weak, and ion-pair reactions, which are extremely fast. These properties explain the observed rapid association and dissociation of turbocurarine at receptors. The time course receptor offset is determined by two factors, buffered diffusion due to repetitive bonding, and a potency-related offset-retarding effect. The strength of the latter is a function of chemical structure, which determines the microscopic molecular rate of drug-receptor association and dissociation. Together, buffered diffusion and the potency-related offset-retarding effect provide a complete rational physico-chemical explanation for the marked, yet variable, differences between onset and offset times of non-depolarizing neuromuscular blocking agents. The influence of a potency-related offset-retarding effect together with differing structural requirements for neuromuscular blocking potency and plasma carboxyesterase hydrolysis, suggests that a high potency ultrashort duration block is unlikely to be achieved in a non-depolarizing compound metabolized by plasma esterases alone.

Clinical pharmacology of mivacurium chloride: a review.

Mivacurium chloride (Mivacron) is a new benzylisoquinolinium choline-like diester neuromuscular blocking drug with an onset of action at equipotent doses that is comparable to atracurium and vecuronium but slower than succinylcholine. Its clinical duration (injection-25% recovery and injection-95% recovery) is twice that of succinylcholine but one-half to one-third that of atracurium and vecuronium. Mivacurium is easy to use as a continuous infusion and when used this way its recovery characteristics are unchanged. It is readily antagonized by anticholinesterase drugs. The ED95 in adults under narcotic-based anesthesia is 0.07-0.08 mg/kg. At twice the ED95 (0.15 mg/kg) onset time is about 2 to 3 minutes, duration to 25% recovery is 15 to 20 minutes, and 5-95% recovery time about 14 minutes. The mean infusion rate in adults is 6 micrograms/kg/min (range 2-15) with a 5-95% recovery time of 14 minutes. Enflurane and isoflurane require a 20-30% decrease in dosage; halothane, enflurane, and isoflurane prolong the duration of mivacurium 25-30%. The ED95 in children 2 to 12 years of age is slightly higher (0.09-0.11 mg/kg) with a faster onset and shorter duration. In these young patients, a dose of 0.2 mg/kg has an onset comparable to succinylcholine. Being chemically related to atracurium, mivacurium may cause histamine release. When administered rapidly at doses of 0.2 mg/kg or greater in adults, histamine release and transient hypotension have been observed. Doses of 0.2 mg/kg or higher are not recommended by the manufacturer. Mivacurium is metabolized by plasma cholinesterase. In vitro, the rate is about 70% that of succinylcholine. In patients with normal or slightly less than normal plasma cholinesterase activity, no prolonged durations of action have been observed. In patients heterozygous for the atypical gene and at a dose of 0.2 mg/kg, 50% prolongation has been shown. Those individuals homozygous for the atypical gene are exquisitely sensitive to mivacurium and have a markedly prolonged blockade that is readily reversible. In these patients and those with acquired deficiencies, mivacurium should not be used. The duration of action in elderly patients is comparable to that in the young, while in prerenal transplant patients, its duration is prolonged by about 50%, and in prehepatic transplant patients, duration of block is increased threefold. Mivacurium possesses the advantages of short duration, unchanged recovery characteristics following infusions (without phase II block or tachyphylaxis), and precise control.(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical importance of plasma cholinesterase for the anaesthetist.

Plasma cholinesterase is a glycoprotein synthesized in the liver and is found in plasma, liver, intestinal mucosa and other tissues. Six percent to 7% of patients in most surgical populations have an abnormal plasma cholinesterase activity and about 65% of all cases of prolonged neuromuscular blockade following succinylcholine are due to genetic factors. This review focuses on the causes and clinical significance of plasma cholinesterase for the hydrolyses of succinylcholine. Diagnosis and treatment of prolonged response to succinylcholine in phenotypically normal patients, heterozygous abnormal patients and patients homozygous for the atypical gene is mentioned. Also presented is the relationship between plasma cholinesterase and the new relaxant mivacurium, and bambuterol, a prodrug to terbutaline. Additionally, the recent developments in the identification of the plasma cholinesterase genotypes are presented.

[Current data on curarization]. / Données actuelles de la curarisation.

The knowledge of the mechanism of action of neuromuscular blocking agents has improved together with the better understanding of the physiology of the neuromuscular junction at the molecular and cellular levels. The main action of competitive neuromuscular relaxants is the blockade of the acetylcholine binding site of the acetylcholine receptor when the latter is its inactive-closed conformation. Owing to the high margin of safety of the neuromuscular transmission, the blockade of an important fraction (75-90%) of acetylcholine receptors is necessary to cause a decrease in muscle strength. An other mechanism of action of competitive agents is the blockade of presynaptic secretion of acetylcholine during repetitive stimulations which may explain the phenomenon of train of four fade or of tetanic fade.

[Metabolism and pharmacokinetics of atracurium]. / Métabolisme et pharmacocinétique de l'atracurium.

Atracurium is a new neuromuscular blocking agent which has an unique mode of elimination by spontaneous degradation in slightly alkali solution, according to the Hofmann elimination. The Hofmann elimination is completed in plasma (in vitro or in vivo) by an ester hydrolysis. The major degradation product is laudanosine. Metabolites can be considered as pharmacologically inactive with the usual doses of atracurium. Spontaneous degradation of atracurium in plasma is the major route of elimination in man and contributes to a short elimination half-life (approximatively 20 min). Distribution half-life is short and central and peripheral volumes are small when compared with the usual neuromuscular blocking agents. The pharmacokinetic parameters give a rapid dynamic equilibrium so that incremental doses will not lead to accumulation phenomenon. Because of spontaneous degradation of atracurium in plasma, its kinetics are theoretically independent of renal and liver functions. Only a slight increase of distribution volumes can be seen in very severe renal/hepatic failure. Atracurium pharmacokinetics could theoretically be modified by some modifications of acid-base equilibrium or alterations of thermoregulation. Pharmacokinetic studies are not yet available in these areas.

[Role of vecuronium in comparison with curariform drugs used in man]. / Place du vécuronium par rapport aux curares utilisés en clinique humaine.

Vecuronium, a new non-depolarizing muscle relaxant, was more powerful than d-tubocurarine, gallamine and alcuronium. Its muscle blocking effect was similar to that of pancuronium. It had a smaller distribution volume and a quicker elimination half-life than the other non-depolarizing muscle blocking drugs. The time of onset and duration of action, as well as the time for recovery were also shorter, being 3-5 min, 17-22 min and 25 min respectively. The accumulation of vecuronium in the body was low; increasing the dose increases the duration of action, but not the recovery time. No adverse effect has been reported as yet. Compared with suxamethonium, a depolarizing muscle relaxant, it had a longer time of onset and duration of action. Vecuronium cannot therefore replace suxamethonium for endotracheal intubation.

[Prolonged neuromuscular block after mivacurium injection]. / Bloc neuromusculaire prolongé après injection de mivacurium.

Mivacurium, a new short acting non depolarizing neuromuscular blocker, is metabolized, as suxamethonium, by plasma cholinesterase. Therefore its duration of action is increased in patients with reduced plasma cholinesterase activity. We report a case of prolonged neuromuscular block after an i.v. bolus of mivacurium (0.20 mg.kg-1) in a 69 year-old ASA II woman with an unrecognized cholinesterase deficiency undergoing a lumbar sympathectomy for arteriopathy of the lower limbs. The duration of the block was 6 h and plasma cholinesterase concentrations were very low (540 and 610 UI.L-1), as well as the dibucaine number (16%), which suggests an homozygous enzymatic deficiency. Mechanical ventilation and sedation were continued until spontaneous return of full neuromuscular function.

[Prolonged neuromuscular block after administration of mivacurium caused by plasma psueudocholinesterase deficiency]. / Curarisation prolongée après mivacurium par déficit en pseudocholinestérases plasmatiques.

Mivacurium is a new neuromuscular blocking agent with a short acting time of about 30 min, due to a fast hydrolysis by pseudocholinesterases. This metabolism carries a risk for prolonged neuromuscular block in case of an acquired or congenital pseudocholinesterase deficiency. We report the case of a 75-year-old woman who experienced a neuromuscular block prolonged for 10 h after a single dose of 0.35 mg.kg-1 of mivacurium, because of a major pseudocholinesterase (1800 UI.L-1, normal value: 5400-13200 UI.L-1). The likely cause was a congenital deficiency by a homozygote genetic mutation, as usual causes of an acquired deficiency had been eliminated.

[Value of the monitoring of curarisation during prolonged mivacurium induced neuromuscular block]. / Intérêt du monitorage de la curarisation lors d'un bloc neuromusculaire prolongé par mivacurium.

A case of neuromuscular blockade of about 200 min of duration, in a 9-year-old boy from mivacurium 0.15 mg.kg-1 is reported. The diagnosis was delayed, after onset of the first signs of recovery, due to the lack of monitoring of neuromuscular transmission. The neuromuscular blockade was reversed with neostigmine 0.04 mg.kg-1. Complete reversal required fifty minutes. The presence of an abnormal genetic variant of pseudocholinesterases was demonstrated by the measurements of pseudocholinesterase activity and dibucaine number. The importance of monitoring of neuromuscular transmission for diagnosis and treatment of mivacurium-induced neuromuscular blockade is underlined.

[Atracurium and cirrhosis: clinical study of the curariform action]. / Atracurium et cirrhose: étude clinique de l'action curarisante.

Hepatic function influences the action of muscle relaxants. Among these drugs, the elimination of atracurium does not depend on liver function. The clinical effects of atracurium were studied in ten patients with portal hypertension and some degree of liver dysfunction and in ten normal patients. The cirrhotic patients underwent resection of oesophageal varices while control patients underwent abdominal surgery. All patients received 0.6 mg X kg-1 atracurium as a first intravenous bolus injection and 0.2 mg X kg-1 incremental doses. The delay of action, the degree of neuromuscular block and the delay of reversal of the block were compared. No statistically significant differences were observed. It is suggested that non significant differences observed could be attributed to an increased volume of distribution of drugs in the cirrhotic patient. These results would suggest that atracurium may be the best relaxant in patients with severe liver failure.

[Atracurium in the elderly subject]. / L'atracurium chez le sujet âgé.

The effects of age on the pharmacodynamics of atracurium have been studied in twenty-four consenting adult patients undergoing elective surgery. They were divided in three groups according to their age (mean +/- SEM): group 1 (n = 8; 26 +/- 3 yr), group 2 (n = 8; 53 +/- 2 yr) and group 3 (n = 8; 76 +/- 2 yr). Anaesthesia was induced with methohexitone (1 mg . kg-1) and fentanyl (5 micrograms . kg-1), and maintained with 66% N2O plus fentanyl on demand. Ventilation was controlled and adjusted to produce normocapnia. The isometric contraction of the adductor pollicis muscle in response to supramaximal cubital nerve stimulation delivered at 0.1 Hz was measured with a force displacement transducer. A loading dose of atracurium (0.3 mg . kg-1) was given before tracheal intubation. Thereafter, twitch height (TH) was maintained at 10% of its baseline reading by adjusting the flow of a Harvard syringe containing 0.5 mg . ml-1 of atracurium in saline. The amount of atracurium required to maintain a stable twitch height, calculated for a 60 min period, was 14.7 +/- 1 mg . m-2 . h-1 for group 1, 13.6 +/- 1.5 mg . m-2 . BSA-1 for group 2 and 15 +/- 2.1 mg . m-2 . BSA-1 for group 3. At the end of the infusion period, the TH25-75 recovery rates were not statistically different in the three groups: 15.4 +/- 1.9 min for group 1, 14.8 +/- 1.1 min for group 2 and 14.5 +/- 1.6 min for group 3.(ABSTRACT TRUNCATED AT 250 WORDS)