Pharmacokinetic modelling of a parent drug and its metabolite. Atracurium and laudanosine.

A pharmacokinetic model was designed to describe simultaneously the plasma concentrations of atracurium and its metabolite laudanosine. The proposed model satisfactorily fits the observations and is based on the assumptions that the parent drug spontaneously degrades to laudanosine at the rate comparable with that observed in vitro at pH 7.4 and 37 degrees C; that 2 molecules of laudanosine are formed from 1 molecule of atracurium; that an initial very rapid decay of a fraction of the atracurium dose is responsible for the initially high plasma laudanosine concentrations; that the rapid disappearance of atracurium from plasma is accounted for by its spontaneous degradation and by the sequestration of atracurium in a deep compartment; and that laudanosine formed from atracurium is added to its central compartment, with its disposition described by a simple 2-compartment model with elimination from the central compartment. The model projects that about 43% of the atracurium dose is rapidly converted to laudanosine and that nearly the whole injected amount of atracurium is degraded to laudanosine.

Generation of reactive metabolites during spontaneous degradation of atracurium in vitro.

The hypothesis was tested in vitro that the spontaneous degradation of atracurium leads to formation of electrophilic metabolites. Variable amounts of atracurium were incubated in saline (0.9% NaCl) for 120 minutes at pH 8.0 and 37 degrees C. Subsequently, cysteine was added to the incubation solutions and the incubation was continued at pH 7.4 and 37 degrees C. Frequent determination of the mercapto groups of cysteine revealed a progressive diminution of the mercapto groups remaining in the incubation solutions. The consumption of sulfhydryl groups was maximal at 20 minutes after the addition of cysteine and amounted to approximately twice the molar amount of atracurium. Kinetic analysis indicated that one mercapto group was consumed almost instantly, whereas the consumption of the other proceeded with a half-life of 4 minutes. No consumption of mercapto groups was observed when laudanosine was incubated with cysteine. Incubation of atracurium or of its degradation products with carboxylesterase markedly reduced the amount of reactive metabolites present in the incubation solutions. The results are compatible with the working hypothesis that spontaneous degradation of atracurium via Hofmann elimination results in generation of two equivalents of reactive electrophilic esters, probably acrylates. We propose that in vivo the portion of the aliphatic chain in the atracurium molecule that is converted to acrylates by Hofmann elimination may be eliminated in part in urine as a conjugate of mercapturic acid.

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

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, k(10), which defines the systemic clearance, was assigned one of 9 values and the transport rate constant, k(12), one of 5 values. The transport rate constant into the effect compartment was constant (k(e1) = 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 x kg(-1) x 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.

Succinylcholine, cholinoceptors and catecholamines: proposed mechanism of early adverse haemodynamic reactions.

An hypothesis is proposed to account for the occurrence of adverse haemodynamic reactions to succinylcholine. Interaction of succinylcholine with cholinergic receptors is postulated to result in release of endogenous catecholamines (predominantly norepinephrine). The occurrence and the clinical manifestations of the adverse reactions would be dependent on the extent of the release. Based on literature reports of findings in experimental animals with nicotinic and muscarinic agents, a mechanism for the release of norepinephrine is outlined. Interaction of succinylcholine with muscarinic and nicotinic receptors is proposed to result in an initial activation which is followed by a phase of chemical insensitivity. Activation of the presynaptic nicotinic receptors on the postganglionic sympathetic terminals leads to a short-lasting release of norepinephrine. Activation of the presynaptic muscarinic receptors produces attenuation of the norepinephrine release. In the majority of patients these opposing actions are balanced and the net result is small, variable, and of little clinical importance. An unbalanced response leading to clinical manifestations can be expected if the two types of the presynaptic cholinoceptors are differentially activated.

Neuromuscular block by vecuronium: simulation with a flow-volume model.

The time profile of the neuromuscular block produced by a single bolus administration of vecuronium was simulated by a new model for the access of the relaxant to the receptors on the motor end plates. The receptors were assumed to be kinetically a part of the interstitial space of the muscle. The time course of the neuromuscular block was defined by the time course of the vecuronium concentration in the interstitial space. The concentration there was derived from the plasma flow to muscle, the volume of the interstitial space in muscle, and the time profile of vecuronium concentrations in plasma. The model describes well the time lag needed to reach the peak submaximal block, its magnitude, as well as the time course of recovery from the maximal block. The limits of the model, evident in less than optimal simulation of the neuromuscular block by two doses of vecuronium in rapid succession, were attributed to the inadequate description of the vecuronium concentrations in plasma immediately after the bolus injection.

Plasma drug concentrations: description and interpretation of the biexponential decay.

Information about the time course of the plasma concentrations of a drug after its i.v. bolus injection is necessary for understanding the time course of the effect of the drug. If an investigator has established that the time course of the plasma concentrations conforms to a biexponential function, understanding the data is facilitated by description of the time course which simply summarizes the data in a quantitative fashion and interpretation of the findings based on certain assumptions. Interpretation may be based on the assumption of compartments, or on a "whole body" approach. The experimentally obtained plasma concentrations of a drug may be described quantitatively by an equation and, if the "whole body" interpretation is selected in preference tot he compartmental interpretation, the four parameters are: the initial and the terminal volumes of distribution (Vc and Vterm) and the rate constants for the loss from Vc and for the dilution within the whole body (k(loss) and k(mix), respectively).

Involvement of nucleophiles in the inactivation of atracurium.

Atracurium was incubated in 0.9% sodium chloride solution at pH 7.4 and 37 degrees C. The following compounds were added to the incubation solution: propionic acid, alanine and cysteine (0.1 mol litre-1 final concentration). Metocurine was also incubated with cysteine under identical conditions. Aliquots of the incubation solutions were injected i.v. to anaesthetized rats at the start (0 min) and at the end of incubation (45 min), and the indirectly elicited, single twitches of the gastrocnemius muscle were observed. Whereas inactivation of atracurium proceeded slowly in the control solution and in the presence of sodium propionate, the presence of alanine and, especially, of cysteine markedly enhanced the inactivation. Incubation of metocurine with cysteine did not alter the pharmacological responses. The concentration of cysteine decreased progressively during its incubation with atracurium (37 degrees C, pH 7.4). We conclude that the data are compatible with the postulate that a nucleophile may enhance the degradation of atracurium by a reaction with the parent compound (nucleophilic substitution reaction), by reaction with acrylates (Michael addition) or both.

Simulation of the onset of neuromuscular block based on the early oscillations in the arterial plasma concentrations.

OBJECTIVE: The aim of the study was to describe by simulation the true plasma concentrations of non-depolarizing muscle relaxants (NDMRs) as a continuous function of time. In contrast to standard pharmacokinetic analysis of the time course of action via extrapolated plasma concentrations, the derived curve was to reflect zero plasma concentration initially and one or more cycles of peaks and troughs subsequently. We desired to study the influence of the initial delay and the early oscillations in the plasma concentrations on the time to onset of peak but submaximal neuromuscular block (NMB). Hypothetical NDMRs were postulated to display in humans a pattern of early arterial plasma concentrations similar to the reported pattern of indocyanine green plasma concentrations in dogs (an initial delay period and subsequent peaks and troughs). METHODS: Two hypothetical NDMRs with either a very rapid or a slow decay in plasma concentrations were used for the simulations. A delay and oscillations were imposed on a multiexponential function for the plasma concentrations of the NDMRs by an additional, biexponentially dampened sinusoid function. The time between intravenous bolus administration of the NDMRs and the first rise in plasma concentrations was fixed at 0.2 min. As experimentally observed with indocyanine green in dogs, the oscillations were limited to the first minute after injection. The NDMRs were simulated to diffuse from plasma into and out of the interstitial space of muscles according to a rate constant and the concentration gradient. The NDMRs were postulated to have free access from the interstitial space to the receptors, and the neuromuscular block was calculated using the Hill equation. RESULTS: The delay and the peak and trough plasma concentrations during the first minute after bolus injection of the NDMRs were simulated well by the postulated dampened sinusoidal function. The times to peak submaximal NMB and the equieffective doses were similar whether calculated on the basis of oscillatory or extrapolated multiexponential functions. Both simulations demonstrated that a rapid initial decay of the plasma concentrations is associated with a slightly faster onset of peak NMB and a slightly higher equieffective dose. CONCLUSION: Consideration of early oscillations in the plasma concentrations of a NDMR barely alters the simulated time course of action from that simulated by an extrapolated multiexponential function.

Onset of the nondepolarizing neuromuscular block in humans: quantitative aspects.

The purpose of our study was a unified description of the time course for the onset of the neuromuscular block produced by different muscle relaxants after bolus intravenous injections. The environment of the receptors on the motor end plate was assumed to be a part of the interstitial space of the muscle. A unified consideration of four muscle relaxants was accomplished by expressing the concentrations of each relaxant in the interstitial space as multiples of the relaxant's dissociation constant. A flow-limited model was developed to describe the time course of the relaxant's concentration in the interstitial space as a function of its plasma concentration, the plasma flow to the muscle, and the volume of the interstitial space. The results show that those relaxants whose plasma concentrations decrease rapidly achieve an earlier (4-8 min), but relatively lower, peak concentration in the interstitial space. The relaxants with more sustained plasma concentrations reach the peak concentration later, 9-16 min after the bolus intravenous injection. The model allows the interpretation of several observations encountered with the clinical use of the muscle relaxants.

Enzymatic hydrolysis of atracurium in vivo.

Inactivation of atracurium in vivo has been postulated to proceed along two pathways: Hofmann elimination and ester hydrolysis. Since an end product of Hofmann elimination (acrylate) may be potentially toxic, the authors conducted a study to determine the extent of degradation via enzyme-catalyzed hydrolysis relative to that via Hofmann elimination. The enzyme carboxylesterase was inhibited by the pretreatment of rats with an organophosphorous compound, triorthotolyl phosphate (TOTP). Skeletal muscle relaxation produced either by d-tubocurarine or succinylcholine was not influenced by the pretreatment. This indicates that TOTP does not alter directly the paralyzing properties of either depolarizing or nondepolarizing muscle relaxants. Relaxation produced by atracurium, however, was prolonged markedly and the rate of recovery from relaxation was decreased. The authors conclude: 1) enzyme-catalyzed hydrolysis is probably responsible for the short duration of action of atracurium; 2) Hofmann elimination, at least in rats, probably is not the principal degradation pathway; and 3) the opportunity for in vivo generation of large amounts of potentially toxic end products is less than previously implied.

Muscle relaxants: a clinical update.

The new nondepolarizing muscle relaxant rocuronium belongs to the chemical group of aminosteroidal muscle relaxants and is similar to vecuronium in its chemical structure and pharmacologic action. The principal clinical advantage of rocuronium over vecuronium is the short time to onset of the neuromuscular block. The two other new muscle relaxants, mivacurium and cis-atracurium, belong to the group of benzylisoquinoline muscle relaxants. Mivacurium is rapidly degraded in plasma and its principal characteristic is, hence, a short duration of action. Cis-atracurium is one of the 10 stereoisomers of atracurium. While its action is similar to that of atracurium, it does not release histamine and its administration is not accompanied by marked changes in blood pressure or heart rate. Even the simple tactile monitoring of the neuromuscular transmission enables the clinician to adjust the doses of these and other muscle relaxants to the needs of individual patients. Precise adjustment of the doses of muscle relaxants contributes to their safer clinical use by avoiding an excessively deep and unnecessarily prolonged neuromuscular block.

A pharmacokinetic-pharmacodynamic model for a muscle relaxant: atracurium.

Our goal was to develop a pharmacokinetic-pharmacodynamic model that describes the fate of atracurium and its metabolite laudanosine as well as the time course of the neuromuscular block. The model was based on the consideration of mass balance of atracurium and was constructed by postulating an effect compartment linked to the central compartment in the previously described open mammillary model for atracurium. The entry and exit rate constants, kCE and kEC, were adjusted to satisfy the requirement that the peak amount in the effect compartment coincides with the peak submaximal block. We used previously published clinical data to arrive at the times to 50% neuromuscular block either during the onset of the block following an ED50 dose or during the recovery following larger doses of atracurium. Laplace transforms were used to define the model, and the solution was obtained by iterative numeric adjustments of the rate constants. The model provides an excellent fit of the observed plasma concentrations of atracurium and laudanosine and simulates well the development and waning of the neuromuscular block. The model projects that the peak amount of atracurium in the effect compartment amounts to 14% of the injected dose and is reached at 7.6 min after the injection.

Atracurium decay and the formation of laudanosine in humans.

Several groups of investigators have reported that the plasma concentrations of laudanosine, a metabolite of atracurium, are high immediately after administration of atracurium and thereafter decline. Such a time profile of a metabolite in plasma is very unusual. The authors describe a model of atracurium decay and laudanosine disposition that satisfactorily explains these data. The model reveals the following: 1) each atracurium molecule is degraded into two of laudanosine; 2) the generation of laudanosine occurs through two processes--a rapid one, involving approximately 31% of the atracurium dose and proceeding with a half-life of 0.25 min, and a slower one, involving the residual 69% and proceeding with a half-life of 51 min; 3) atracurium degradation by Hofmann elimination proceeds in the central and the noncentral compartments; 4) laudanosine formed from atracurium gains access to its central compartment and disappears from plasma in a biexponential pattern; 5) in cirrhotic patients, only 18% of the atracurium dose is degraded rapidly and laudanosine is disposed of more slowly. The authors propose that the rapid degradation of atracurium in plasma proceeds through a nucleophilic substitution reaction, with plasma nucleophiles substituting for the laudanosine moiety in atracurium. Because both laudanosine moieties in atracurium are required to establish and sustain plasma concentrations of laudanosine, excretion of atracurium or its degradation through pathways not generating laudanosine must be small.

[Esters and stereoisomers]. / Ester und Stereoisomere.

This review discusses concepts of isomers, stereoisomers, chirality, and enantiomers as applied to drugs used in anaesthesia. The inhalational anaesthetics enflurane and isoflurane are examples of stereoisomers. A chiral centre is formed when a carbon or quaternary nitrogen atom is connected to four different atoms. A molecule with one chiral centre is then present in one of two possible configurations termed enantiomers. A racemate is a mixture of both enantiomers in equal proportions. Many of the drugs used in anaesthesia are racemic mixtures (the inhalation anaesthetics, local anaesthetics, ketamine, and others). The shape of the atracurium molecule is comparable to that of a dumb-bell:the two isoquinoline groups representing the two bulky ends connected by an aliphatic chain. In each isoquinoline group there are two chiral centres, one formed by a carbon and the other by a quaternary nitrogen atom. From a geometric point of view, the connections from the carbon atom to a substituted benzene ring and from the quaternary nitrogen to the aliphatic chain may point in the same direction (cis configuration) or in opposite directions (trans configuration). The two isoquinoline groups in atracurium are paired in three geometric configurations: cis-cis, trans-trans, or cis-trans. However, the two chiral centres allow each isoquinoline group to exist in one of four stereoisometric configurations. In the symmetrical atracurium molecule, the number of possible stereoisomers is limited to ten. Among these, 1 R-cis, 1'R-cis atracurium was isolated and its pharmacologic properties studied. This isomer, named cis-atracurium, offers clinical advantages over the atracurium mixture, principally due to the lack of histamine-releasing propensity and the higher neuromuscular blocking potency. The ester groups appear in one of two steric configurations true and reverse esters. In the true esters, oxygen is positioned between the nitrogen atom and the carbonyl group, while in the reverse esters in its positioned on the other side of the carbonyl group. True esters, suxamethonium and mivacurium, are hydrolysed by the enzyme plasma cholinesterase (butyrylcholinesterase), albeit at different rates. The more rapid degradation of suxamethonium is responsible for its fast onset and short duration of action in comparison with mivacurium. The reverse esters, atracurium, cisatracurium, and remifentanil, are hydrolysed by nonspecific esterases in plasma (carboxyesterases). Remifentanil is hydrolysed rapidly; the degradation leads to its inactivation and short duration of action. Cis-atracurium is preferentially degraded and inactivated by a process known as Hofmann elimination. In a second step, one of the degradation products, the monoester acrylate, is hydrolysed by a nonspecific esterase.

Inactivation of atracurium in human and rat plasma.

The contribution of enzyme-catalyzed hydrolysis to inactivation of atracurium in human and rat plasma was determined in vitro by inhibiting the enzyme carboxylesterase with triorthotolyl phosphate. The inhibitor was removed by centrifugation and aspiration. Atracurium was then added to both the control and the inhibited plasma samples, and all samples were incubated at 37 degrees C for 45 min. The amount of atracurium present in aliquots of plasma was determined using a bioassay technique in anesthetized rats. Inactivation of atracurium proceeded rapidly in control rat plasma but was markedly slowed in samples treated with the inhibitor of carboxylesterase. In contrast, the inactivation was slow in control human plasma, and inhibition of carboxylesterase produced only marginal, if any, effects. We conclude that the inactivation of atracurium proceeds, in part, by enzyme-catalyzed ester hydrolysis. In species with high enzyme activity in plasma, e.g., the rat, enzyme-catalyzed hydrolysis is clearly evident. In humans, the level of enzyme activity is low and the contribution of enzyme-catalyzed inactivation is less manifest. By exclusion, Hofmann elimination or other reactions probably represent the major inactivation pathway in humans.

[Muscle relaxants. New substances and neuromuscular monitoring]. / Muskelrelaxanzien. Neue Substanzen und neuromuskuläres Monitoring.

INTRODUCTION: Recent developments in both the quantitative evaluation of neuromuscular blockade and new muscle relaxants are reviewed. With respect to nerve stimulation, neuromuscular recording, and definition of parameters, the results of the 1994 Copenhagen International Consensus Conference are highlighted. Future clinical studies should adhere to these standards. MUSCLE RELAXANTS: Rocuronium, cisatracurium, and mivacurium are new muscle relaxants that were released for clinical use in 1995/1996. Of these, rocuronium has the shortest time of onset, whereas its recovery characteristics closely resemble those of vecuronium. Rocuronium is five times less potent than vecuronium. Twice the ED95 of rocuronium provides good or excellent intubating conditions within 60 to 90 s. Slight vagolytic effects were reported following injection of 0.6 mg/kg rocuronium, while histamine release was not observed. Cisatracurium is one of the ten steroisomers of atracurium. It is five times as potent as the chiral mixture while having a similar pharmacodynamic and -kinetic profile. Up to eight times the ED95 did not cause significant histamine release or clinically relevant cardiovascular effects. Mivacurium is a short-acting nondepolarizing benzylisoquinoline muscle relaxant that undergoes rapid break-down by plasma cholinesterase (PChE). Its duration of action is about one-half as long as that of equipotent doses of atracurium and vecuronium and three times as long as succinylcholine. Mivacurium has a moderate histamine-releasing potential. In patients with atypical or reduced PChE activity, the duration of action of mivacurium is prolonged.

Succinylcholine-induced increases in plasma catecholamine levels in humans.

Given the hypothesis that interaction of succinylcholine with nicotinic receptors releases endogenous catecholamines, plasma levels of epinephrine and norepinephrine were determined in anesthetized and manually ventilated patients immediately before and 2 min after intravenous administration of succinylcholine. Anesthesia was induced with intravenous thiopental (3-4 mg/kg) followed by the administration of nitrous oxide and oxygen (1:1) and 0.5-1.0% halothane. Stimulation of the patients was avoided. Succinylcholine (1 mg/kg) or metocurine (0.3 mg/kg) was injected intravenously and ventilation was controlled without intubation. Plasma norepinephrine levels increased from 301 pg/ml to 491 pg/ml (SEM = +/- 19 pg/ml, P less than 0.01, N = 5) 2 min after the injection of succinylcholine; the increase in plasma epinephrine was not statistically significant. The time course of catecholamine elevation was studied in three additional patients. The increase of norepinephrine occurred immediately after the injection of succinylcholine, peaked (647 +/- 67 pg/ml) around the third minute, and disappeared by the 10th min. The increase in epinephrine was less marked. Plasma levels of catecholamines did not change after the injection of metocurine (N = 2). The possibility that succinylcholine stimulates nicotinic receptors on the postganglionic sympathetic terminals is discussed. We propose that the elevation of plasma norepinephrine might contribute to the development of early adverse cardiovascular reactions to succinylcholine.

Potentiation of atracurium toxicity in isolated rat hepatocytes by inhibition of its hydrolytic degradation pathway.

This study tested the hypothesis that the esters of acrylic acid might be responsible for the previously observed cytotoxic effect of atracurium. Rats were pretreated with triorthotolyl phosphate (TOTP), an inhibitor of the hydrolytic degradation of atracurium. Because hydrolysis of acrylates is also inhibited by TOTP and because the hydrolysis represents a detoxification pathway for these esters, we postulated that the leak of lactic dehydrogenase (LDH) induced by atracurium would be enhanced in hepatocytes harvested from rats pretreated with TOTP. Hepatocytes isolated from rats previously treated with TOTP (25 or 50 mg/kg intraperitoneally, 20 hr before induced death) were incubated for 4 hr in the absence of muscle relaxants or in the presence of either atracurium (0.008-0.8 mM) or metocurine (0.015-0.85 mM). Atracurium produced a concentration-dependent leakage of LDH. The leakage out of cells obtained from TOTP-pretreated rats was greater than was the leakage out of hepatocytes harvested from animals pretreated only with corn oil (a vehicle for TOTP). Metocurine did not produce a leak of LDH. It is concluded that the LDH leakage was produced by ester-type products of atracurium degradation. Acrylates appear to be the toxic agent.