Clinical pharmacology of GW280430A in humans.
(65/306)
BACKGROUND: An ultrashort-acting nondepolarizing neuromuscular blocking agent that could be an alternative to succinylcholine has been the focus of a concerted effort in the field of muscle relaxants. GW280430A showed a promising pharmacodynamic profile in preclinical work and a wide margin of safety and so was selected for study in humans. METHODS: Thirty-one volunteers participated in this study, which determined the dose producing 95% block (ED95) and the safety and pharmacodynamics of increasing ED95 multiples. Anesthesia was induced and maintained with propofol, midazolam, and fentanyl. Neuromuscular transmission was measured at the adductor pollicis using ulnar nerve stimulation, and responses were recorded continuously by standard mechanomyographic monitoring. RESULTS: The ED95 for GW280430A is 0.19 mg/kg. The time to onset of 90% block ranged from 1.3 to 2.1 min, depending on the dose. Clinical durations ranged from 4.7 to 10.1 min and increased with increasing dose. Five to 95% and 25-75% recovery rates were approximately 7 and 3 min, respectively, and were independent of the dose administered. Transient cardiovascular side effects were observed at doses beginning at 3 x ED95 and above and were suggestive of histamine release. Most volunteers receiving 4 x ED95 exhibited plasma histamine concentrations indicative of significant histamine release. CONCLUSIONS: GW280430A has a rapid onset and ultrashort duration of action. The recovery rate is rapid, predictable, and independent of dose. Doses at least up to 2.5 x ED95 seem to be free of side effects and seem to be able to provide relaxation within 60-90 s. (+info)
A single point mutation confers properties of the muscle-type nicotinic acetylcholine receptor to homomeric alpha7 receptors.
(66/306)
Although the muscle-type and homomeric alpha7-type nicotinic acetylcholine receptors (nAChRs) share many structural features and bind alpha-bungarotoxin with high affinity, several important functional and pharmacological properties distinguish these two major nAChR subtypes. We have shown previously that amino acid sequence in the second transmembrane (TM) domain of the beta subunit is critical for pharmacological distinction between muscle type and heteromeric neuronal (e.g., ganglionic) nAChRs. We tested the hypothesis that homologous substitution of amino acid sequence from the muscle beta1 subunit into the alpha7 subunit would confer specific properties of muscle-type receptors to mutant alpha7 nAChRs. In this study, we show that a single amino acid substitution at the alpha7 TM2 6' position makes both biophysical and pharmacological properties of the mutant receptors resemble those of wild-type muscle nAChR. This mutation produces significant changes in acetylcholine potency and response kinetics, eliminating the characteristic fast desensitization of alpha7 and dramatically reducing divalent ion permeability relative to wild-type alpha7. The TM2 T6'F mutation also produces a profound increase in activation by succinylcholine compared with either wild-type alpha7 or neuronal beta-subunit-containing receptors and the loss of potentiation by 5-hydroxyindole. Thus, the alpha7 TM2 T6'F mutant displays several features that are similar to the muscle nAChR, some of which are not typically thought to be regulated by the pore-lining domain of the receptor. (+info)
Succinylcholine dosage and apnea-induced hemoglobin desaturation in patients.
(67/306)
BACKGROUND: The authors examined the notion that a reduction in succinylcholine dose from 1 mg/kg to approximately 0.6 mg/kg would allow a faster recovery of spontaneous ventilation and reduction in the incidence of hemoglobin desaturation during the period of apnea in simulated complete upper airway obstruction situations. METHODS: This prospective, randomized, double-blind study involved 60 patients. After preoxygenation to an end-tidal oxygen concentration >90%, patients were anesthetized with 2 microg/kg fentanyl and 2 mg/kg propofol. After loss of consciousness, patients were randomly allocated to receive 0.56 or 1.0 mg/kg succinylcholine or saline (control group). Oxygen saturation was monitored continuously at the index finger. When the patient became apneic, the face mask was removed and the patient's airway was left unsupported. If the oxygen saturation decreased to 90%, the face mask was reapplied, and ventilation was assisted until the patient was awake. Time from injection of the study drug to the first visible spontaneous diaphragmatic movements was noted. RESULTS: Oxygen saturation decreased <90% in 45%, 65%, and 85% of patients in the control, 0.56 mg/kg, and 1.0 mg/kg succinylcholine groups, respectively (P = 0.03). Corresponding times (mean +/- SD) to spontaneous of diaphragmatic movements were 2.7 +/- 1.2, 4.8 +/- 2.5, and 4.7 +/- 1.3 min, respectively. These times were longer (P < 0.001) after either dose of succinylcholine compared with controls. CONCLUSIONS: Reduction in succinylcholine dose from 1.0 mg/kg to 0.56 mg/kg decreased the incidence of hemoglobin saturation <90% from 85% to 65% but did not shorten the time to spontaneous diaphragmatic movements. A significant fraction of patients would be at risk if there were failure to intubate and ventilate whether succinylcholine is administered or not and regardless of the dose of succinylcholine administered. (+info)
Na+-K+ pump stimulation restores carbacholine-induced loss of excitability and contractility in rat skeletal muscle.
(68/306)
Intense exercise results in increases in intracellular Na+ and extracellular K+ concentrations, leading to depolarization and a loss of muscle excitability and contractility. Here, we use carbacholine to chronically activate the nicotinic acetylcholine (nACh) receptors to mimic the changes in membrane permeability, chemical Na+ and K+ gradients and membrane potential observed during intense exercise. Intact rat soleus muscles were mounted on force transducers and stimulated electrically to evoke short tetani at regular intervals. Carbacholine produced a 2.6-fold increase in Na+ influx that was tetrodotoxin (TTX) insensitive, but abolished by tubocurarine, resulting in a significant 36% increase in intracellular Na+, and 8% decrease in intracellular K+ content. The mid region, near the motor end plate, had much larger alterations than the more distal regions of the muscle, and showed a larger membrane depolarization from -73 +/- 1 to -60 +/- 1 mV compared with -64 +/- 1 mV. Carbacholine (10(-4) M) significantly reduced tetanic force to 31 +/- 3% of controls, which underwent significant recovery upon application of Na+-K+ pump stimulators: salbutamol (10(-5) M), adrenaline (10(-5) M) and calcitonin gene-related peptide (CGRP; 10(-7) M). The force recovery with salbutamol was accompanied by a recovery of intracellular Na+ and K+ contents, and a small but significant 4-5 mV recovery of membrane potential. Similar results were obtained using succinylcholine (10(-4) M), indicating that Na+-K+ pump stimulation may prevent or restore succinylcholine-induced hyperkalaemia. The stimulation of the Na+-K+ pump allows muscle to partially recover contractility by regaining excitability through electrogenically driven repolarization of the muscle membrane. (+info)
Genotyping the butyrylcholinesterase in patients with prolonged neuromuscular block after succinylcholine.
(69/306)
BACKGROUND: Succinylcholine remains the standard neuromuscular blocking drug for tracheal intubation in emergency situations. The short duration of action is due to its rapid hydrolytic degradation by butyrylcholinesterase (plasmacholinesterase). Multiple variants of this enzyme are known (A, F, S, H, J, K variants) with different effects on enzyme activity. This study was undertaken to evaluate the use of molecular genetic methods in patients with clinically prolonged neuromuscular block. METHODS: Nine patients with a neuromuscular block of 14 min to 5 h were selected. All four exons of the butyrylcholinesterase were amplified by polymerase chain reaction and analyzed by automated sequencing. Molecular genetic results were compared with clinical relaxation time and with biochemical test results (total butyrylcholinesterase activity, dibucaine and fluoride inhibition). RESULTS: Seven of nine patients were mutation carriers. Five of these had more than one mutation. The A and K variants were the most frequent variations. Three of four patients who were homozygous for the A variant were also carriers of the K allele. The authors identified one novel mutation (G1294T) introducing a stop codon at amino acid position 432. The duration of neuromuscular block was substantially different between patients with identical butyrylcholinesterase genotypes. CONCLUSIONS: Variations in the genetic sequence of butyrylcholinesterase are frequent in patients with prolonged duration of action of succinylcholine. Direct sequencing of the whole butyrylcholinesterase gene is an appropriate method for genotyping and, accordingly, should be used in future clinical studies with drugs metabolized by this enzyme (e.g., succinylcholine, mivacurium). (+info)
Tracheal intubating conditions and apnoea time after small-dose succinylcholine are not modified by the choice of induction agent.
(70/306)
BACKGROUND: In a randomized, double-blind clinical trial, we studied the effect of different i.v. induction drugs on tracheal intubation conditions and apnoea time after small-dose (0.6 mg kg(-1)) succinylcholine used to facilitate orotracheal intubation at an urban, university-affiliated community medical centre. METHODS: One hundred and seventy-five ASA I and II adult patients scheduled to undergo surgical procedures requiring general anaesthesia and tracheal intubation were allocated to one of five groups according to i.v. anaesthetic induction drug used. General anaesthesia was induced by i.v. administration of lidocaine 30 mg and propofol 2.5 mg kg(-1) (Group 1), thiopental 5 mg kg(-1) (Group 2), lidocaine 30 mg and thiopental 5 mg kg(-1) (Group 3), etomidate 0.3 mg kg(-1) (Group 4), or lidocaine 30 mg and etomidate 0.3 mg kg(-1) (Group 5). After loss of consciousness, succinylcholine 0.6 mg kg(-1) was given i.v. followed by direct laryngoscopy and tracheal intubation after 60 s. Measurements included intubation conditions recorded during laryngoscopy 60 s after succinylcholine administration, and apnoea time. RESULTS: Overall, clinically acceptable intubation conditions were met in 168 out of the 175 patients studied (96%). They were met in 35/35 patients in Group 1, 33/35 patients in Group 2, 34/35 patients in Group 3, 33/35 patients in Group 4, and 33/35 patients in Group 5. Mean (SD) apnoea time was 4.0 (0.4), 4.2 (0.3), 4.2 (0.6), 4.1 (0.2) and 4.1 (0.2) min respectively in Groups 1-5. There were no differences in the intubation conditions or apnoea times between the groups. CONCLUSIONS: The use of succinylcholine 0.6 mg kg(-1) produced the same favourable intubation conditions and a short apnoea time regardless of the induction drug used. (+info)
Prevention of succinylcholine-induced fasciculation and myalgia: a meta-analysis of randomized trials.
(71/306)
Fifty-two randomized trials (5,318 patients) were included in this meta-analysis. In controls, the incidence of fasciculation was 95%, and the incidence of myalgia at 24 h was 50%. Nondepolarizing muscle relaxants, lidocaine, or magnesium prevented fasciculation (number needed to treat, 1.2-2.5). Best prevention of myalgia was with nonsteroidal antiinflammatory drugs (number needed to treat, 2.5) and with rocuronium or lidocaine (number needed to treat, 3). There was a dose-dependent risk of blurred vision, diplopia, voice disorders, and difficulty in breathing and swallowing (number needed to harm, < 3.5) with muscle relaxants. There was evidence of less myalgia with 1.5 mg/kg succinylcholine (compared with 1 mg/kg). Opioids had no impact. Succinylcholine-induced fasciculation may best be prevented with muscle relaxants, lidocaine, or magnesium. Myalgia may best be prevented with muscle relaxants, lidocaine, or nonsteroidal antiinflammatory drugs. The risk of potentially serious adverse events with muscle relaxants is not negligible. Data that allow for a risk-benefit assessment are lacking for other drugs. (+info)
Succinylcholine-induced hyperkalemia in acquired pathologic states: etiologic factors and molecular mechanisms.
(72/306)
Lethal hyperkalemic response to succinylcholine continues to be reported, but the molecular mechanisms for the hyperkalemia have not been completely elucidated. In the normal innervated mature muscle, the acetylcholine receptors (AChRs) are located only in the junctional area. In certain pathologic states, including upper or lower motor denervation, chemical denervation by muscle relaxants, drugs, or toxins, immobilization, infection, direct muscle trauma, muscle tumor, or muscle inflammation, and/or burn injury, there is up-regulation (increase) of AChRs spreading throughout the muscle membrane, with the additional expression of two new isoforms of AChRs. The depolarization of these AChRs that are spread throughout the muscle membrane by succinylcholine and its metabolites leads to potassium efflux from the muscle, leading to hyperkalemia. The nicotinic (neuronal) alpha7 acetylcholine receptors, recently described to be expressed in muscle also, can be depolarized not only by acetylcholine and succinylcholine but also by choline, persistently, and possibly play a critical role in the hyperkalemic response to succinylcholine in patients with up-regulated AChRs. (+info)