Neuromuscular Blocking Properties of Dantrolene at the Neuromuscular Junction and Its Recovery with Various Antagonists / 대한마취과학회지

BACKGROUND: Dantrolene produces skeletal muscle relaxation by a direct action on excitation-contraction coupling, presumably by decreasing the amount of calcium released from the sarcoplasmic reticulum. The mechanism underlying this action is extrajunctional. The aim of this study was to evaluate the pharmacodynamic properties of dantrolene at the neuromuscular junction and the reversal effects of substances as possible dantrolene antagonists in vitro. METHODS: The effects of evoked twitch tension response have been studied on the isolated phrenic nerve hemidiaphragm muscle strips of the rat, using a single twitch (0.1 Hz) and the train of four (TOF; 2 Hz for 2s) stimulation. The maximum effect (E(max)) and TOF ratio at each point of twitch depression after cumulative doses of dantrolene were measured mechanomyographically. The EC(50) and EC(95) of dantrolene were calculated using an inhibitory sigmoid E(max) model. The reversal effect to E(max) after administration of 10 mM of dantrolene was determined by various doses of neostigmine, pyridostigmine or 4-aminopyridine respectively. RESULTS: The E(max) was 76.14% of the initial twitch tension, but the residual twitch tension was remained until five times (10 mM) of the dose for the E(max) was administered. TOF stimulation to the residual twitch tension did not demonstrate any fade. The EC(50) and EC(95) of dantrolene were 0.379 and 3.177 mM respectively. Neostigmine and pyridostigmine produced a transient but incomplete recovery of twitch tension, which rapidly fell to the level of the twitch response before the drugs were given. However, 4-aminopyridine produced a dose-dependent recovery of the twitch response. The addition of neostigmine (0.5 mg/ml) or pyridostigmine (2.5 mg/ml) did not decrease the EC(50) and EC(95) of 4-aminopyridine in reversing the effect of dantrolene. CONCLUSIONS: These RESULTS have demonstrated the evidence that dantrolene did not completely depress the twitch tension, leaving if at nearly 25%, and accompanying TOF response without fade, and that anticholinesterases were ineffective in antagonizing its blockade. However, 4-aminopyridine was effective and may not be related to the propensity for pre- and postjunctional cholinergic receptor blockade at the neuromuscular junction.

The Effects of Temperature Changes on the Acetylcholine and Neostigmine Induced Contraction of Rabbit Trcheal Smooth Muscle / 대한마취과학회지

BACKGROUND: The body temperature of a patient changes changes during general anesthesia and cholinesterase inhibitor is usually administered at the end of general anesthesia to reverse the neuromuscular blocker effect. We tried to evaluate the effect of temperature changes on the contraction of tracheal smooth muscle induced by acetylcholine (Ach) exogenously administered and neostigmine, cholinesterase inhibitor. METHODS: Isolated tracheal preparations(3 mm wide) of rabbit were mounted in organ baths filled with Tyrode's solution. Cumulative dose responses(isometric contractin) of Ach (10-6, 10-5, 10-4 & 10-3 M) & neostigmine (10-8, 10-7, 10-6, 10-4) at 37oC, 39oC and 27oC were measured with force displacement transducer and pD2 was calculated. RESULTS: Warming from 37oC to 39oC, contraction by Ach weakened significantly and contraction by neostigmine did not change significantly. Cooling from 37oC to 27oC, contraction by Ach were changed significantly and contraction by neostigmine, at low concentration, was inhibited significantly, but at high concentration, was not potentiated significantly. pD2 of Ach did not change significantly by cooling from 37oC to 27oC and decreased significantly by warming from 37oC to 39oC. pD2 of neostigmine was significantly reduced by cooling from 37oC to 27oC and did not change significantly by warming from 37oC to 39oC. CONCLUSIONS: Warming from 37oC to 39oC, the contraction of tracheal smooth muscle induced by Ach was decreased significantly,and cooling from 37oC to 27oC, contraction induced by neostigmine was decreased significantly at low concentration of neostigmine. But it is not sure wheter these effects can be observed in clinical practice when neostigmine is administered to patients,so further study is necessary.

Reversal of Neuromuscular Blockade with Neostigmine Does not Increase the Incidence of Postoperative Nausea and Vomiting / 대한마취과학회지

BACKGROUND: Postoperative nausea and vomiting (PONV) are still very common complications after general anesthesia. Some studies have reported that reversal of neuromuscular block by neostigmine is an important factor contributing to PONV. Whereas other studies have shown that when neostigmine is given as a reversal for muscle relaxation using mivacurium, it does not contribute to the incidence and severity of PONV. This study was designed to compare the reversible effect of neuromuscular block using neostigmine with the spontaneous recovery of neuromuscular block on the incidence and severity of PONV. METHODS: Sixty female patients undergoing laparoscopic zygote intra-fallopian transfer were studied and were allocated randomly into two groups. In Group 1 (n=30), neuromusclar block produced by mivacurium was antagonized by 1.5 mg neostigmine and 0.4 mg glycopyrrolate intravenously, whereas Group 2 (n=30) received no drugs to facilitate antagonism of blockade. The incidence and severity of PONV was assessed up to 3 hours after the operation. RESULTS: Both groups were comparable, and no differences were found in age, weight, duration of anesthesia, and the amount of mivacurium given during surgery. There were no significant differences between the two groups in the incidence and severity of PONV. CONCLUSION: This investigation has shown that when neostigmine is given as a reversal for muscle relaxation with mivacurium, it does not contribute to the incidence and severity of PONV.

The Effects of Magnesium-Pretreatment on the Neuromuscular Blocking Actions of Cis-atracurium in the Cat / 대한마취과학회지

BACKGROUND: Cis-atracurium is more potent, and less likely to release histamine and has better autonomic and cardiovascular stability, compared to atracurium. It is eliminated mainly by Hofmann reaction and produces less amounts of laudanosine, the first metabolite which has the CNS stimulating property. However, drug interactions with several ions, such as magnesium that is popular in treating eclampsia have not yet to be known. METHODS: Using sciatic nerve-anterior tibialis preparation in the cat, we tried to find out whether cis-atracurium has the cumulation effect by administering four consecutive 100 microgram/kg of cis-atracurium. After confirming that the cis-atracurium had no cumulation effect, we proceeded the dose-response study to find out the ED50, ED95 and action duration of cis-atracurium in control group(II) and magnesium-pretreated group(III). After cumulative dose -response study, in the half of the group II and III, the infusion rate to maintain 90% twitch depression at least for 20 minutes was obtained, and afterwards, the recovery index was measured after the discontinuation of infusion. In the other half of the group II and III, while maintaining 90% twitch depression at least for 20 minutes through continuous infusion of cis-atracurium, we administered the 10 microgram/kg of neostigmine to measure the onset time, action duration and antagonism effect of the drug. RESULTS: The cis-atracurium did not have the cumulation effect and in group III, ED50 and ED95 were decreased significantly from 234+/-82 microgram/kg to 103+/-18 microgram/kg and from 399+/-123 microgram/kg to 173+/-28 microgram/kg, respectively, compared with group II. The action duration of cis-atracurium ED95 in group III(190+/-52 sec) was significantly longer than in group II(143+/-29 sec). The infusion rate of cis-atracurium to maintain 90% twitch depression was significantly higher in group II in the spontaneous recoveryand the neostigmine-induced antagonism(6.63+/-2.37 and 4.47+/-1.58 microgram/kg/min), respectively. CONCLUSION: The cis-atracurium do not have the cumulation effect. And, the magnesium potentiates the neuromuscular blocking actions of cis-atracurium. However, it has no effect on the antagonism action of neostigmine.

The Effects of Magnesium on Pipecuronium-induced Neuromuscular Blockade and its Reversal in the Isolated Rat Phrenic Nerve-Hemidiaphragm / 대한마취과학회지

BACKGROUND: Magnesium sulfate (MgSO4) is widely utilized in the treatment of preeclamptic hyperreflexia. It is well known that magnesium enhances nondepolarizing neuromuscular blockade. Eclamptic convulsions are almost always prevented by magnesium in plasma concentrations of 4 to 7 mEq/L. METHODS: The effects of various concentration of magnesium on the potency and reversibility of pipecuronium were investigated in vitro rat phrenic nerve-hemidiaphragm. The phrenic nerve-hemidiaphragm was dissected and suspended in organ bath containing modified Krebs' solution. Forty samples were divided into 4 groups (n=10 in each group). Group I was studied at the physiologic magnesium concentration(2.4 mEq/L, control group). Group II, III, IV were studied at the concentration of 4, 5.5, and 7 mEq/L, respectively. In each group, we added pipecuronium until twitch height decreased more than 90% of initial level. To compare the recovery, we added neostigmine and calcium, and then, measured TOF ratio. RESULTS: The amounts of added pipecuronium were 73.8+/-15.2 microgram (mean+/-S.D.) in Group I, 38.1+/-5.0 microgram in Group II, 33.0+/-4.1 microgram in Group III and 16.1+/-1.7 microgram in Group IV. The amounts of pipecuronium in Group II, III, IV were significantly less than Group I. After the addition of neostigmine, the values of TOF ratio were under 0.6 in all groups. But after the addition of calcium, all groups were recovered with TOF ratio over 0.85 except Group I. CONCLUSIONS: This study indicated that the increased magnesium concentration potentiated pipecuronium-induced neuromuscular blockade and at higher level, it was more apparent. Neostigmine was not significantly effective to reverse the pipecuronium-induced neuromuscular blockade potentiated with magnesium. But calcium was significantly effective.