A Pharmacodynamic Explanation for the Rapid Onset/Offset of Rapacuronium Bromide 

1999 ◽  
Vol 90 (1) ◽  
pp. 16-23 ◽  
Author(s):  
Peter M. C. Wright ◽  
Ronald Brown ◽  
Marie Lau ◽  
Dennis M. Fisher
Keyword(s):  
Plasma Concentration ◽  
Time Course ◽  
Plasma Concentrations ◽  
Rapid Onset ◽  
Muscle Relaxants ◽  
Adductor Pollicis ◽  
Effect Compartment ◽  
Nondepolarizing Muscle Relaxants ◽  
Effect Site ◽  
The Hill

Background Nondepolarizing muscle relaxants differ in their time course at the laryngeal adductors and the adductor pollicis, a result of differences in equilibration delays between plasma and effect sites, the sensitivity of each muscle to the relaxant, and the steepness of the concentration-effect relation at each muscle (the Hill factor). To determine whether similar differences exist for rapacuronium, a muscle relaxant with rapid onset and offset, the authors determined its pharmacodynamic characteristics. Methods The twitch tensions of the adductor pollicis and the laryngeal adductors (via a tracheal tube cuff positioned at the vocal cords) were measured in 10 volunteers who were anesthetized with propofoL Rapacuronium, 1.5 mg/kg, was given and blood samples were collected. A semiparametric effect compartment pharmacodynamic model was fit to values for rapacuronium plasma concentrations and twitch tension of the adductor pollicis and laryngeal adductors. Results Equilibration between the rapacuronium plasma concentration and both effect sites was rapid (typical values for the rate constant for equilibration between plasma and the effect site are 0.405 per min for the adductor pollicis and 0.630 per min for the laryngeal adductors) and was more rapid at the laryngeal adductors than at the adductor pollicis (ratio, 1.59+/-0.16; mean +/- SD). The steady state rapacuronium plasma concentration that depressed twitch tension by 50% and the Hill factor were similar for the two muscles. Conclusions The rapid onset and offset of rapacuronium can be explained by the rapid equilibration between concentrations in plasma and at the effect site. Unlike the finding for other nondepolarizing muscle relaxants, the laryngeal muscles are not resistant to rapacuronium.

Are Plasma Concentration Values Necessary for Pharmacodynamic Modeling of Muscle Relaxants?

1997 ◽  
Vol 86 (3) ◽  
pp. 567-575 ◽  
Author(s):  
Dennis M. Fisher ◽  
Peter M. C. Wright
Keyword(s):  
Plasma Concentration ◽  
Traditional Approach ◽  
Muscle Relaxants ◽  
Adductor Pollicis ◽  
Pharmacodynamic Modeling ◽  
Concentration Data ◽  
Mechanical Responses ◽  
Drug Concentrations ◽  
Train Of Four ◽  
The Hill

Background The traditional approach to pharmacokinetic/ pharmacodynamic modeling of muscle relaxants requires sampling of plasma to determine drug concentrations. The authors recently proposed that certain pharmacodynamic characteristics (IR50, the steady-state infusion rate to maintain 50% twitch depression; keo, the rate constant for equilibration between plasma concentration and effect; and gamma, the Hill factor describing sigmoidicity of the concentration-effect relation) could be estimated without plasma concentration data. Here estimates for IR50, keo, and gamma determined with and without plasma concentration data are compared. Methods Six volunteers were given 15-60 micrograms/kg vecuronium on each of two occasions during anesthesia with propofol. Mechanical responses to train-of-four stimulation were measured at the adductor pollicis and at the laryngeal adductors. Various pharmacokinetic models accounting for the presence and potency of vecuronium's 3-desacetyl metabolite and a sigmoid e-max pharmacodynamic model were fit to the resulting plasma concentration and effect (adductor pollicis and laryngeal adductors) data to determine IR50 keo, and gamma for each effect. One model related dose to effect without plasma concentration data. Results Values for IR50(adductor pollicis), IR50(laryngeal adductors), gamma (adductor pollicis), and gamma (laryngeal adductors) were similar when determined with and without plasma concentration values. Values for keo (adductor pollicis) and keo (laryngeal adductors) were larger when determined without plasma concentration values compared with those determined with these values; however, the ratio of keo (adductor pollicis) to keo(laryngeal adductors) was similar when determined with and without plasma concentration values. Conclusions Certain pharmacodynamic parameters were estimated accurately in the absence of plasma concentration values. This suggests limited utility for plasma concentration data under conditions similar to those of the present study.

Onset–potency relationship of nondepolarizing muscle relaxants: a reexamination using simulations

2007 ◽  
Vol 85 (8) ◽  
pp. 774-782 ◽  
Author(s):  
S.B. Bhatt ◽  
A. Amann ◽  
V. Nigrovic
Keyword(s):  
Rate Constant ◽  
Elimination Rate ◽  
Onset Time ◽  
Rapid Onset ◽  
Muscle Relaxants ◽  
Transport Rate ◽  
Effect Compartment ◽  
Double Logarithmic Plot ◽  
Nondepolarizing Muscle Relaxants ◽  
The Impact

Nondepolarizing muscle relaxants (MRs) display an inverse onset–potency relationship, that is, less potent MRs display a more rapid onset. We have conducted the current investigation to estimate the impact of variable pharmacokinetic or pharmacodynamic properties of the MRs on potency and onset time, and on the onset–potency relationship. Using a model of neuromuscular transmission, we changed either the affinity of MRs for the postsynaptic receptors or the pharmacokinetic properties of the MRs. The elimination rate constant, k10, which defines the systemic clearance, was assigned one of 9 values and the transport rate constant, k12, one of 5 values. The transport rate constant into the effect compartment was constant (ke1 = 0.2 min–1). Only one parameter was altered at a time. With constant pharmacokinetics, a 100-fold decrease in affinity caused a proportional decrease in potency, but little change (0.02 min) in onset time. With constant affinity, increasing the clearance from 1 to 250 mL·kg–1·min–1 shortened the onset time from 7.2 to 0.7 min and decreased the potency 12-fold. In a double logarithmic plot, the onset–potency relationship was linear. Lesser affinities produce a nearly parallel rightward shift of the regression lines. The inverse onset–potency relationship may be explained by the pharmacokinetic factors producing changes in both the potency and onset times.

scholarly journals Pharmacokinetic Properties of a Sufentanil Sublingual Tablet Intended to Treat Acute Pain

2018 ◽  
Vol 128 (5) ◽  
pp. 943-952 ◽  
Author(s):  
Dennis M. Fisher ◽  
Peter Chang ◽  
D. Russell Wada ◽  
Albert Dahan ◽  
Pamela P. Palmer
Keyword(s):  
Plasma Concentration ◽  
Acute Pain ◽  
Healthy Subjects ◽  
Time Course ◽  
Plasma Concentrations ◽  
Area Under The Curve ◽  
Rapid Onset ◽  
Maximum Plasma ◽  
Mixed Effect ◽  
Sublingual Tablet

Abstract Background Desirable product attributes for treatment of moderate-to-severe acute pain in many medically supervised settings are rapid onset and a route of administration not requiring intravenous access. The pharmacokinetic characteristics of sublingually administered tablets containing 15 or 30 µg of sufentanil are described. Methods Blood was sampled from healthy subjects (four studies, 122 subjects) and patients (seven studies, 944 patients). Studies in healthy subjects determined bioavailability, effect of inhibition of cytochrome P450 3A4, and the plasma concentration profile with single and hourly sublingual doses. Studies in patients evaluated effects of weight, age, sex, and organ impairment on apparent clearance. Noncompartmental and mixed-effect population methods were used. Results Bioavailability of a single sublingual tablet was 52%, decreasing to 35% with repeat dosing. Ketoconazole (CYP3A4 inhibitor) increased maximum plasma concentration 19% and increased the area under the curve 77%. After a single 30-µg dose, plasma concentrations reached the published sufentanil analgesic threshold (24 pg/ml) within 30 min, peaked at 1 h, and then decreased below therapeutic concentrations by ~3 h. With hourly administration, plasma concentrations plateaued by the fifth dose. Time for concentrations to decrease 50% from maximal values was similar after 1 dose (2.5 ± 0.85 h) and 12 doses (2.5 ± 0.72 h). Clearance increased with weight, decreased with age, and was not affected by renal or hepatic impairment. Conclusions The time course of a single 30-µg dose was consistent with onset of analgesia and redosing frequency observed in clinical trials. Sublingual sufentanil tablets provide the opportunity to noninvasively and rapidly treat moderate-to-severe pain in a monitored setting.

Comparison of the Effect-site keOs of Propofol for Blood Pressure and EEG Bispectral Index in Elderly and Younger Patients

1999 ◽  
Vol 90 (6) ◽  
pp. 1517-1527. ◽  
Author(s):  
Tomiei Kazama ◽  
Kazuyuki Ikeda ◽  
Koji Morita ◽  
Mutsuhito Kikura ◽  
Matsuyuki Doi ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Plasma Concentration ◽  
Bispectral Index ◽  
Time Course ◽  
Drug Infusion ◽  
Time Data ◽  
Aged Patients ◽  
Younger Patients ◽  
Spectral Edge Frequency ◽  
Effect Site

Background Drug effect lags behind the blood concentration. The goal of this investigation was to determine the time course of plasma concentration and the effects of propofol demonstrated by electroencephalogram or blood pressure changes and to compare them between elderly and young or middle-aged patients. Methods A target-controlled infusion was used to rapidly attain and maintain four sequentially increasing, randomly selected plasma propofol concentrations from 1 to 12 microg/ml in 41 patients aged 20-85 yr. The target concentration was maintained for about 30 min. Bispectral index (BIS), spectral edge frequency, and systolic blood pressure (SBP) were used as measures of propofol effect. Because the time courses of these measures following the started drug infusion showed an exponential pattern, the first-order rate constant for equilibration of the effect site with the plasma concentration (k(eO)) was estimated by fitting a monoexponential model to the effect versus time data resulting from the pseudo-steady-state propofol plasma concentration profile. Results The half-times for the plasma-effect-site equilibration for BIS were 2.31, 2.30, 2.29, and 2.37 min in patients aged 20-39, 40-59, 60-69, and 70-85 yr, respectively (n = 10 or 11 each). The half-times for SBP were 5.68, 5.92, 8.87, and 10.22 min in the respective age groups. All were significantly longer than for BIS (P < 0.05). The propofol concentration at half of the maximal decrease of SBP was significantly greater (P < 0.05) in the elderly than in the younger patients. Conclusions The effect of propofol on BIS occurs more rapidly than its effect on SBP. Age has no effect on the rate of BIS reduction with increasing propofol concentration, whereas with increasing age, SBP decreases to a greater degree but more slowly.

Comparison of Plasma Compartment versus  Two Methods for Effect Compartment–controlled Target-controlled Infusion for Propofol

2000 ◽  
Vol 92 (2) ◽  
pp. 399-399 ◽  
Author(s):  
Michel M. R. F. Struys ◽  
Tom De Smet ◽  
Birgit Depoorter ◽  
Linda F. M. Versichelen ◽  
Eric P. Mortier ◽  
...  
Keyword(s):  
Time Course ◽  
Drug Effect ◽  
Peak Effect ◽  
Effect Compartment ◽  
Loss Of Consciousness ◽  
Group Iii ◽  
Time To Peak ◽  
Effect Site ◽  
Effect Site Concentration ◽  
Plasma Effect

Background Target-controlled infusion (TCI) systems can control the concentration in the plasma or at the site of drug effect. A TCI system that targets the effect site should be able to accurately predict the time course of drug effect. The authors tested this by comparing the performance of three control algorithms: plasmacontrol TCI versus two algorithms for effect-site control TCI. Methods One-hundred twenty healthy women patients received propofol via TCI for 12-min at a target concentration of 5.4 microg/ml. In all three groups, the plasma concentrations were computed using pharmacokinetics previously reported. In group I, the TCI device controlled the plasma concentration. In groups II and III, the TCI device controlled the effect-site concentration. In group II, the effect site was computed using a half-life for plasma effect-site equilibration (t1/2k(eo)) of 3.5 min. In group III, plasma effect-site equilibration rate constant (k(eo)) was computed to yield a time to peak effect of 1.6 min after bolus injection, yielding a t1/2keo of 34 s. the time course of propofol was measured using the bispectral index. Blood pressure, ventilation, and time of loss of consciousness were measured. Results The time course of propofol drug effect, as measured by the bispectral index, was best predicted in group III. Targeting the effect-site concentration shortened the time to loss of consciousness compared with the targeting plasma concentration without causing hypotension. The incidence of apnea was less in group III than in group II. Conclusion Effect compartment-controlled TCI can be safely applied in clinical practice. A biophase model combining the Marsh kinetics and a time to peak effect of 1.6 min accurately predicted the time course of propofol drug effect.

Pharmacodynamics of Orally Administered Sustained- release Hydromorphone in Humans

2001 ◽  
Vol 94 (1) ◽  
pp. 63-73 ◽  
Author(s):  
Martin S. Angst ◽  
David R. Drover ◽  
Jörn Lötsch ◽  
Bhamini Ramaswamy ◽  
Sujata Naidu ◽  
...  
Keyword(s):  
Plasma Concentration ◽  
Sustained Release ◽  
Analgesic Effect ◽  
Time Course ◽  
Plasma Concentrations ◽  
Experimental Pain ◽  
Immediate Release ◽  
Double Blind ◽  
Sustained Release Formulation ◽  
Analgesic Effects

Background The disposition kinetics of hydromorphone generally necessitates oral administration every 4 h of the conventional immediate-release tablet to provide sustained pain relief. This trial examined time course and magnitude of analgesia to experimental pain after administration of sustained-release hydromorphone as compared with that after immediate-release hydromorphone or placebo. Methods Using a 4 x 4 Latin square double-blind design, 12 subjects were randomized to receive a single dose of 8, 16, and 32 mg sustained-release hydromorphone and placebo. The same subjects had received 8 mg immediate-release hydromorphone before this study. Using an electrical experimental pain paradigm, analgesic effects were assessed for up to 30 h after administration, and venous hydromorphone plasma concentrations were measured at corresponding times. Results The hydromorphone plasma concentration peaked significantly later (12.0 h [12.0--18.0] vs. 0.8 h [0.8--1.0]; median and interquartile range) but was maintained significantly longer at greater than 50% of peak concentration (22.7 +/- 8.2 h vs. 1.1 +/- 0.7 h; mean +/- SD) after sustained-release than after immediate-release hydromorphone. Similarly, sustained-release hydromorphone produced analgesic effects that peaked significantly later (9.0 h [9.0--12.0] vs. 1.5 h [1.0--2.0]) but were maintained significantly longer at greater than 50% of peak analgesic effect (13.3 +/- 6.3 h vs. 3.6 +/- 1.7 h). A statistically significant linear relation between the hydromorphone plasma concentration and the analgesic effect on painful stimuli existed. Conclusion A single oral dose of a new sustained-release formulation of hydromorphone provided analgesia to experimental pain beyond 24 h of its administration.

scholarly journals Masseter Muscle Rigidity After Initiating Monitored Anaesthesia Care of Propofol and Remifentanil

2020 ◽  
pp. 1-3
Author(s):  
Kyu Nam Kim ◽  
Dong Won Kim ◽  
Kyu Nam Kim ◽  
Jung Eun Sun ◽  
Ji Hee Chang ◽  
...  
Keyword(s):  
Plasma Concentration ◽  
Airway Management ◽  
Masseter Muscle ◽  
Muscle Relaxants ◽  
Muscle Rigidity ◽  
Nondepolarizing Muscle Relaxants ◽  
Target Controlled Infusion ◽  
Effect Site Concentration ◽  
Rapid Effect ◽  
Anaesthesia Care

Masseter muscle rigidity can be seen following administration of opioids, succinylcholine, and nondepolarizing muscle relaxants. We report a case of a 56-year-old male patient in a “Cannot Intubate Cannot Ventilate Situation” due to masseter muscle rigidity after initiating monitored anaesthesia care (MAC) with remifentanil and propofol using target-controlled infusion in procedural cardiology. For rapid effect and equilibrium between plasma-concentration and effect site-concentration using target-controlled infusion, remifentanil overdose is possible during the induction period of MAC. Moreover, the presence of propofol could result in a significantly greater remifentanil concentration. To manage masseter muscle rigidity, muscle relaxants and emergent ventilation systems should be prepared to secure airway maintenance. In addition, alternative airway management devices and techniques should be on hand even if no airway difficulties are expected.

scholarly journals Studies in Man with a Constant-Rate Infusion of Tubocurarine

1979 ◽  
Vol 7 (3) ◽  
pp. 209-214 ◽  
Author(s):  
C. A. Shanks ◽  
M. I. Ramzan ◽  
E. J. Triggs
Keyword(s):  
Plasma Concentration ◽  
Dose Response ◽  
Response Curve ◽  
Time Course ◽  
Regression Line ◽  
Plasma Concentrations ◽  
Pharmacokinetic Parameters ◽  
Response Curves ◽  
Constant Rate ◽  
Post Infusion

Tubocurarine (dTC) was administered to twenty patients by intravenous infusion at a predetermined constant rate, and the twitch responses recorded at stimulus intervals of 10 seconds (0.1 Hz). In half the group dTC plasma concentrations were measured both during and following the infusion. This provided data for derivation of the pharmacokinetic parameters, two plasma concentration-response curves and the dose-response curve. The mean effective dTC plasma concentration for 50% paralysis during the infusion (onset) was 0.93 fig/ml, but was lower post-infusion (offset) (0.54 μg/ml, p < 0.001). The steady state dTC plasma concentration which should produce 95% paralysis was predicted to lie between 0.95 and 1.67 μg/ml. In the range 20 to 80% paralysis the slopes of the two (log) concentration-response lines were similar, although steeper than the associated (log) dose-response regression line, the test for parallelism showed no statistical difference. Combination of the plasma concentration-response curve with pharmacokinetic models was used to predict the time course of paralysis in patients with normal and impaired renal function. Dose-response curves for the other 10 patients were also constructed to stimulus frequencies from 0.02 to 5 Hz. In the range 20 to 80% paralysis the regression lines appeared to be parallel. The results were pooled for all patients at a stimulation rate of 0.1 Hz, giving a mean effective dose of dTC at 95% paralysis of 0.53 mg/kg, and an ED50 of 0.22 mg/kg.

Trigeminal Neuralgia: Time Course of Pain in Relation to Carbamazepine Dosing

Cephalalgia ◽  
1981 ◽  
Vol 1 (2) ◽  
pp. 91-97 ◽  
Author(s):  
Torbjörn Tomson ◽  
Karl Ekbom
Keyword(s):  
Plasma Concentration ◽  
Trigeminal Neuralgia ◽  
Time Course ◽  
Peak Plasma ◽  
Peak Plasma Concentration ◽  
Plasma Concentrations ◽  
Significant Drop ◽  
Idiopathic Trigeminal Neuralgia ◽  
Full Effect ◽  
Pain Distribution

Eight in-patients with idiopathic trigeminal neuralgia (TN) were studied while receiving carbamazepine (CBZ) treatment. The aim was to study diurnal pain distribution, its relation to CBZ dosing and plasma concentration and the effect of decreasing the dose. All pain attacks were registered by the patients at three-hour intervals. CBZ was given b.i.d. in a single blind manner with the patient unaware of dose and dose changes. Plasma concentrations of CBZ were followed every fourth hour during a period of altogether sixteen dosage intervals. The diurnal pain distribution revealed marked intra-individual similarities with pain-free nights and a significant drop in pain during mid-day hours. The latter coincided in time with the peak plasma concentration of CBZ, thus indicating an effect of plasma concentration fluctuations on pain relief. Shorter dosage intervals might therefore be beneficial in problem cases. A significant increase in pain was detected within six to nine hours after a dose reduction, whereas the full effect of the dose change seemed to be established only after one day.

The Changing Pharmacodynamics of Metocurine Identify the Onset and Offset of Canine Gastrocnemius Disuse Atrophy

1995 ◽  
Vol 83 (1) ◽  
pp. 134-140. ◽  
Author(s):  
D. L. Fung ◽  
D. A. White ◽  
G. A. Gronert ◽  
E. Disbrow
Keyword(s):  
Acetylcholine Receptors ◽  
Muscle Relaxants ◽  
Disuse Atrophy ◽  
Pharmacokinetics And Pharmacodynamics ◽  
Cast Immobilization ◽  
Nondepolarizing Muscle Relaxants ◽  
Effect Site ◽  
Muscle Disuse ◽  
Effect Site Concentration

Background Immobilization of skeletal muscle results in disuse atrophy and resistance to nondepolarizing muscle relaxants. We studied the pharmacodynamics of metocurine (MTC) to identify the development and recovery of disuse-related resistance to MTC. Methods Nineteen dogs underwent cast immobilization of a hind limb for as long as 3 weeks. Before, during, and after casting, dogs were intermittently anesthetized with thiamylal-N2O-fentanyl. The blood concentration of MTC and the corresponding degree of paralysis after a brief infusion were recorded and were used to characterize the pharmacokinetics and pharmacodynamics of MTC. Results Pharmacodynamic study of the response to MTC demonstrated resistance by the 4th day of casting. The effect-site concentration associated with 50% paralysis of twitch increased after 3 weeks from approximately 250 to 750 ng/ml. After cast removal, resistance persisted for 2 more weeks. Six weeks after cast removal, the effect-site concentration associated with 50% paralysis of twitch was normal in every dog. Conclusions Within the context of this study of immobilization disuse atrophy, pharmacokinetic and pharmacodynamic characterization of antagonist responses can be used to infer muscle disuse-related changes in acetylcholine receptors.

Sign in / Sign up

Export Citation Format

Share Document