Dose-response curves and pharmacokinetics.
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Alfentanil↗
Biomedical subjects
B E Waud
Publications and source records attributed to B E Waud.
Tubocurarine sensitivity of the diaphragm after limb immobilization.
The effect of immobilization of a limb on subsequent sensitivity of the diaphragm to d-tubocurarine was examined in the guinea pig. A forelimb was immobilized in a plaster cast for 1 or 3 weeks. An isolated nerve-diaphragm preparation was then set up and the sensitivity to d-tubocurarine measured. Parallel assays on a nerve-lumbrical muscle preparation from the limb in the cast were also examined for comparison. The diaphragm from unimmobilized animals showed the normal decreased sensitivity relative to the lumbrical. After immobilization the sensitivity of the lumbrical decreased, whereas that of the diaphragm did not change. Thus in contrast to previously observed behavior in limb muscles, changes in d-tubocurarine sensitivity produced by immobilization do not involve the diaphragm.
Analysis of Variance↗
Interaction among agents that block end-plate depolarization competitively.
The influence of gallamine, metocurine, pancuronium, and tubocurarine on depolarization of a mammalian muscle end-plate region was examined to determine whether the antagonists given in combination exerted a degree of block consistent with the simple classical competitive model. Depolarization was produced by carbachol in isolated guinea pig lumbrical muscles and recorded by the moving fluid electrode technique. The dose-response values obtained were fitted to a regression embedded in a split plot factorial experimental design such as both to control and to measure effects of variation among preparations, order of administration, time, and level of block. Of the six possible pairings of the four drugs, four showed the simple additivity expected from a competitive mechanism, while two (pancuronium plus metocurine and metocurine plus gallamine) showed potentiation beyond additivity. In these latter two pairs the combination shifted the carbachol dose-response curve, respectively, 41 and 21% further than predicted from the classical model. The significance of this deviation in the light of alternative receptor models is discussed, and a model consistent with the observed results is outlined.
Animals↗
Atracurium-receptor kinetics: simple behavior from a mixture.
The apparent atracurium-receptor dissociation constant was assayed at the end-plate region of isolated guinea pig muscles. In a parallel series of experiments, the ED50 for producing neuromuscular block in the lumbrical muscle was also determined. The ratio of these two values was similar to the ratio found with classical competitive neuromuscular blocking agents like d-tubocurarine or pancuronium. We conclude that the commercial preparation of atracurium, though a mixture containing isomers of different configurations, behaves kinetically in a manner indistinguishable from what would be expected from a single substance.
Animals↗
Disuse and d-tubocurarine sensitivity in isolated muscles.
The effect of immobilization on subsequent sensitivity of limb muscles to d-tubocurarine was examined in a guinea pig model. A foreleg was immobilized in a cast for 1-4 weeks. At the end of this period, isolated nerve-lumbrical muscle preparations were set up and sensitivity to d-tubocurarine assayed. Immobilization increased the ED50 of the drug not only in muscles from the limb in the cast but also those from contralateral forelimbs and from hindlimbs. The increase in ED50 was not accompanied by atrophy. In a parallel series of experiments measuring the effect of d-tubocurarine on depolarization by carbachol, the apparent d-tubocurarine-receptor dissociation constant was determined. Immobilization produced no change in this parameter. Because immobilization of one extremity produced sensitivity changes in others, the anesthesiologist must be careful not to assume that monitoring from any limb will yield normal values in a patient with partial immobility.
Analysis of Variance↗
Quantitative examination of the interaction of competitive neuromuscular blocking agents on the indirectly elicited muscle twitch.
Gallamine, metocurine, pancuronium, and d-tubocurarine were compared when given alone and in combination with isolated guinea pig nerve-lumbrical preparations stimulated via the nerve. The experimental design was set up to control the effects of variation among preparations, order of administration, and time of administration (i.e., fresh vs. older preparation). The result was an assay able to measure potentiation with a coefficient of variation of 3%. A format for a graphic presentation to summarize such results is presented and discussed. Two combinations, gallamine plus d-tubocurarine and gallamine plus pancuronium, showed no sign of an interaction beyond that to be expected from a simple competitive interaction. Two others, metocurine plus pancuronium and gallamine plus metocurine, showed about a twofold greater potency when combined than would have been expected. The last two sets, pancuronium plus d-tubocurarine and metocurine plus d-tubocurarine, showed a slight degree of potentiation. These studies demonstrate that the deviation from simple additivity seen in vivo persists when examined in a system free from artifacts associated with uptake and distribution in the whole organism.
Animals↗
Chronic potassium depletion and sensitivity to tubocurarine.
The effect of low potassium diets with and without deoxycorticosterone (DOCA), furosemide, chlorothiazide, or ethacrynic acid on sensitivity of isolated guinea pig lumbrical nerve-muscle preparations to d-tubocurarine was examined. The ED50 of d-tubocurarine was found to fall as the potassium level was lowered by dietary restriction. Addition of DOCA or furosemide was without effect while chlorothiazide reduced and ethacrynic acid enhanced the effect of diet alone. Acute restoration of potassium levels of 5.9 mM reversed considerably, but not completely, the effect of chronic depletion. Thus, a patient suffering from chronic potassium depletion would be expected to require a decreased dose of d-tubocurarine, and although acute replacement of potassium preoperatively would tend to return the dose requirement toward normal, such reversal might not be complete.
Animals↗
Lithium and neuromuscular transmission.
The actions of lithium on end-plate depolarization and on indirect and direct twitch response of isolated guinea pig muscle were investigated. At clinical concentrations lithium did not cause depolarization, nor did it affect the depolarizing action of carbachol. Lithium also had no effect on the twitch response to nerve stimulation throughout its therapeutic serum concentration range and it did not alter the ED50 of pancuronium. When animals were chronically pretreated with lithium there appeared to be a slight reduction in dosage requirement for d-tubocurarine. At concentrations well above therapeutic serum levels, end-plate depolarization as well as indirect and direct twitch responses were depressed. It is concluded that, at therapeutic levels, there is minimal interaction of lithium with competitive neuromuscular blocking agents.
Animals↗
Effect of bretylium on neuromuscular transmission.
The effect of bretylium on the response of an isolated muscle (guinea pig lumbrical) to direct and indirect stimulation was examined. An initial increase in twitch response to both indirect and direct stimulation was followed at higher concentrations of bretylium by block of the indirect response only. The ED50 for this latter effect was 106.9 +/- 9.25 microM. However, in the presence of subthreshold levels of d-tubocurarine the ED50 was markedly reduced to 1.31 +/- 1.11 microM, a concentration that could occur during clinical use of bretylium. Thus, the physician is cautioned to consider the possibility that neuromuscular block may be produced when bretylium is administered in close temporal proximity to neuromuscular blocking agents.
Animals↗
A comparison of the neuromuscular blocking and vagolytic effects of ORG NC45 and pancuronium.
ORG NC45, a neuromuscular blocking agent not producing tachycardia, was examined first, to establish the kinetics of the anatagonism it produces, and second, to test the hypothesis that the tachycardia seen with pancuronium and gallamine reflects an action on vagal postganglionic nerve endings. The action of ORG NC45 was studied on end-plate depolarization and neuromuscular transmission in the guinea pig lumbrical muscle. Also, the effect of ORG NC45 on the response of the cardiac pacemaker to carbachol and on the response of the pacemaker to pre- and postganglionic vagal stimulation was examined in isolated guinea pig atria. ORG NC45 was a potent neuromuscular blocking agent (twice as potent as pancuronium) in this species and showed typical competitive kinetics with a dissociation constant of 0.0103 micro M. However, ORG NC45 affected the atrial system only at very high concentrations and did not affect release of transmitter from vagal nerve terminals. These results thus confirm the hypothesis that presence or absence of vagolytic action goes hand-in-hand with tachycardia or its absence clinically.
Animals↗
Temperature and potency of d-tubocurarine and pancuronium in vitro.
The concentrations of d-tubocurarine and pancuronium producing 50% block of the indirectly elicited twitch were determined in isolated mouse nerve-diaphragm preparations at 37 and 25 C. The contralateral side was used as a control in a 2 x 2 factorial analysis of variance. Cooling shifted the dose-response curves for both drugs to the left, but only slightly (from 1.69 +/- 0.022 microM to 1.49 +/- 0.021 microM with d-tubocurarine and from 0.65 +/- 0.012 microM to 0.46 +/- 0.009 microM with pancuronium). The dose-response relationship was, however, so steep (Hill coefficient approximately 5 to 6) that a slight horizontal shift of the dose-response curve corresponds to a considerable decrease in the twitch response at a concentration midway between the curves. Thus, studies using only the concentration that produces partial block of twitch responses misleadingly suggest a large effect of temperature. Similarly, if in another system the curve were to shift to the right even only slightly, a temperature effect in the reverse direction might be reported. It is concluded that temperature appears to have little influence on cellular potency of neuromuscular blocking agents.
Animals↗
Interaction of calcium and potassium with neuromuscular blocking agents.
Dose-response curves for blockade of the indirectly elicited twitch of isolated guineapig nerve-lumbrical muscle preparations were determined for tubocurarine and pancuronium in the presence of potassium 2,4 and 6 mmol litre-1 and calcium 1,2 and 3 mmol litre-1. Increases in concentration of either ion decreased the sensitivity of the preparation to both drugs. Over the physiological range of concentrations of potassium and calcium, 36% and 27% variation in dosage can be expected.
Animals↗
Effects of volatile anesthetics on directly and indirectly stimulated skeletal muscle.
Isolated guinea pig nerve-lumbrical muscle preparations were exposed to halothane, methoxyflurane, isoflurane, enflurane, fluroxene, and diethyl ether. The temporal courses of the effects on indirectly and directly elicited twitch responses were determined over a range of concentrations for each agent. When the anesthetics were compared at concentrations equivalent in terms of minimum alveolar concentration (MAC), a spectrum was observed in which halothane, methoxyflurane and isoflurane depressed the indirect twitch response at 3.5--5 MAC and the direct twitch response at 8--10 MAC. Diethyl ether and fluroxene depressed the indirect twitch response at 2--3.5 MAC and the direct twitch response at 3--6 MAC. Enflurane depressed the indirect response at 1.5--2.5 MAC and the direct response at 6--8 MAC. When the anesthetics were compared at concentrations equivalent in terms of their abilities to depress end-plate depolarization, however, all anesthetics were equipotent. Depression of the indirect twitch response occurred only when anesthetic concentrations were great enough to depress depolarization by 50 per cent.
Anesthetics↗
Decrease in dose requirement of d-tubocurarine by volatile anesthetics.
Volatile anesthetics are known to decrease the requirements for neuromuscular blocking agents. To obtain a quantitative measure of the extent of this drug interaction, studies were performed on isolated guinea pig nerve--lumbrical muscle preparations exposed to methoxyflurane, halothane, isoflurane, diethyl ether, fluroxene, and enflurane in concentrations equal to MAC. From the relationship between indirect twitch height and d-tubocurarine concentration, the concentration depressing the twitch height by 50 per cent was determined. In the presence of MAC levels of anesthetic, the ED50 was decreased by the following fractional amounts: methoxyflurane, 0.311; halothane, 0.334; isoflurane, 0.335; diethyl ether, 0.462; fluroxene, 0.580; enflurane, 0.697. Comparison of the fractional decrease of d-tubocurarine dose requirement by an anesthetic at MAC and previously obtained values for the fractional depression of end-plate depolarization by an anesthetic at MAC showed that the more the anesthetic depresses depolarization, the smaller the d-tubocurarine dose requirement. Thus, clinically observed decreases in dose requirements may be explained by the effects of the anesthetics on chemosensitivity of the end-plate region.
Anesthetics↗
Kinetic analysis of the AH8165-receptor interaction at the mammalian neuromuscular junction.
The effect of a new neuromuscular blocking agent, AH8165, on carbachol-induced end-plate depolarization was measured in isolated guinea pig lumbrical muscles. The results showed that the kinetics were competitive (parallel shift of dose-response curves to the right and a slope of Schild plot of 1.09 +/- 0.07) and the AH8165-receptor dissociation constant was estimated as 0.337 +/- 0.008 muM. Once the dissociation constant was known, the fraction of receptors occupied by any given concentration of AH8165 could be determined. This fractional receptor occupancy was then compared with the indirect twitch response in an isolated guinea pig nerve-lumbrical muscle preparation. These measurements of the effect of AH8165 on the margin of safety of neuromuscular transmission gave values comparable to those obtained with d-tubocurarine, i.e., the twitch remained normal until 75-80 per cent of the receptors were blocked and was abolished when 90-95 per cent of the receptors were occluded. Thus, the neuromuscular blocking action of AH8165 appears to be consistent with a simple postsynaptic competitive interaction with the transmitter.
Animals↗
Potencies of neuromuscular blocking agents at the receptors of the atrial pacemaker and the motor endplate of the guinea pig.
Drug receptor dissociation constants (KB) were determined for four neuromuscular relaxants at the cardiac pacemaker as well as at the motor endplate. The ratios KB(atrium)/KB(lumbrical) were found to be high for d-tubocurarine and dimethyltubocurarine, 264 and 136, respectively. Thus, interaction at muscarinic sites would occur only with large doses of these drugs. In contrast, the ratios were low for pancuronium and gallamine, 5.3 and 2.4, respectively. Hence, the concentrations of these drugs needed for clinical neuromuscular blockade would occupy appreciable fractions of cardiac muscarinic receptors, and thus might produce vagal blockade and thereby produce the tachycardia seen clinically with these two agents.
Chemoreceptor Cells↗
Partition coefficients of volatile anesthetics in Kreb's solution.
Partition coefficients of volatile anesthetics between Krebs' solution and air were determined at 37 C. The mean values obtained were: enflurane, 0.74; diethyl ether, 11.9; fluroxene, 0.81; halothane, 0.75; isoflurane, 0.55; methoxyflurane, 3.8.
Anesthetics↗
The effects of diethyl ether, enflurane, and isoflurane at the neuromuscular junction.
The actions of diethyl ether, enflurane, and isoflurane at the neuromuscular junction were examined in isolated guinea pig lumbrical muscles. These anesthetics depressed the ability of carbachol to depolarize the endplate region; this depression of depolarization did not show competitive kinetics. None of the anesthetics altered the affinity of the acetylcholine receptor for d-tubocurarine, i.e., the dissociation constant of d-tubocurarine was unchanged. Since diethyl ether, enflurane, and isoflurane produced no observable alteration of the receptor, the antagonism of the drug-induced depolarization of the neuromuscular junction appears to be exerted at a stage subsequent to reaction with the receptor. (Key words: Anesthetics, volatile, diethyl ethers; Anesthetics, volatile, euflurane; Anesthetics, volatile, isoflurane; Neuromuscular relaxants, d-tubocurarine; Neuromuscular junction.).
Acetylcholine↗