PHARMACOKINETICS OF ATRACURIUM AND LAUDANOSINE IN THE ELDERLY

The pharmacokinetics of a bolus dose of atracurium 0.6 mg kg^–1and its metabolite laudanosine were studied in 11 elderly (meanage 80.9 yr) and 10 young patients (mean age 23.8 yr) undergoingelective surgery. The elimination half-'life (T^ß)of atracurium was significantly longer in the elderly group(23.1 v. 20.1 min), but there was no significant differencebetween the two groups in clearance (Cl), the volume of distribution(Vß) or the mean residence time (MRT) of atracurium.Laudanosine T^ß was also significantly longer (229.1v. 173.1 min) and the clearance significantly slower (4.85 v.7.29 ml min^–1 kg^–1) in the elderly. There was, however,no significant difference in V^ß for laudanosine betweenthe two groups. These data suggest that atracurium depends toa small extent on the liver or the kidney for its metabolismand excretion, and that, as these routes of excretion are lessefficient in the elderly, T^ß is prolonged in thisage group. The deteriorating function of these organs with increasingage may also explain the altered pharmacokinetics of laudanosine. ^*Present address: Broadgreen Hospital, Thomas Drive, LiverpoolL14 3LB.     

HEPATOTOXICITY TESTING OF ATRACURIUM AND LAUDANOSINE IN THE ISOLATED, PERFUSED RAT LIVER

The pharmacokinetics of atracurium, which is degraded by Hofmanndecomposition and ester hydrolysis, is not altered by impairedliver function. Atracurium should, therefore, be ideal for patientswith hepatic failure, and is now widely used in clinical practice.However, some studies reported considerable hepatotoxicity afteratracurium, especially from its breakdown products–forexample, leakage of lactate dehydrogenase (LDH) from isolatedrat hepatocytes. Therefore, we have studied, in an isolatedperfused rat liver model, biochemical and morphological changesafter administration of either atracurium or its main metabolite,laudanosine. Despite using extremely high concentrations ofthese substances, we could not detect, biochemically (releaseof LDH or aspartate amino-transferase (AST)) or histologically,any signs of liver cell damage.     

PHARMACOKINETICS OF ATRACURIUM AND LAUDANOSINE IN PATIENTS WITH HEPATIC CIRRHOSIS

The pharmacokinetic profiles of atracurium and one of its derivatives,laudanosine were studied following an i.v. bolus of atracurium0.6 mg kg^–1 administered to eight patients with hepaticcirrhosis and to seven healthy controls. The central volumeof distribution of atracurium was greater in the patients withcirrhosis (104.6 ml kg^–1) compared with the controls (69.6ml kg^–1) (P < 0.05), as was the total volume of distribution(281.8 ml kg^–1 and 202.1 ml kg^–1, respectively)(P < 0.05). There was no significant difference in the eliminationhalf-life of atracurium between the two groups. The total volumeof distribution of laudanosine was increased in cirrhotic patients(2.68 litre kg^–1) compared with healthy controls (1.97litre kg^–1) (P < 0.05), as was its elimination half-life(277 min in cirrhotic individuals; 168 min in controls) (P <0.05). There was no significant difference in the clearanceof laudanosine between the two groups.     

EFFECT OF ATRACURIUM AND LAUDANOSINE ON THE RELEASE OF 3H-NORADRENALINE

We examined the effects of atracurium and its breakdown product,laudanosine, on resting and stimulation-evoked release of ³H-noradrenaline(³H-NA) from sympathetic axon terminals of isolated right atriaof guineapigs. Both atra-curium 1–100 µmol litre^–1and laudanosine 1–50 µmol litre^–1 enhancedthe release of ³H-NA evoked by field stimulation (2 Hz, 24 stimuli),but did not affect resting release. When the production of laudanosinefrom atracurium was inhibited by maintaining the atracuriumsolution at 4 °C, atracurium did not enhance the releaseof ³H-NA as occured when it was kept at 37 °C. However,atracurium antagonized the inhibitory effect of oxotremorineon release of ³H-NA, whereas laudanosine did not. These datasuggest that atracurium possesses and antimuscarinic effect.Its metabolite, laudanosine, in concentrations which would beexpected following prolonged administration of atracurium, produceda marked increase in release of ³H-NA. This effect of laudanosinemay explain some of the unwanted effects seen following administrationof atracurium.     

CONCENTRATIONS OF ATRACURIUM AND LAUDANOSINE IN CEREBROSPINAL FLUID AND PLASMA DURING INTRACRANIAL SURGERY

Concentrations of atracurium and laudanosine in cerebrospinalfluid (CSF) and plasma were assayed in nine patients receivingatracurium infusions of 111–251 min duration to maintainneuromuscular block during intracranial surgery. The total doseof atracurium was 1.57–2.60 mg kg^–1 and the plasmaconcentration of atracurium was 1.27–5.44 µg ml^–1.Concentrations of laudanosine in CSF and plasma increased duringthe infusion period, and after 125–140 min reached meansof 202.5 ng ml^–1 and 1448.7 ng ml^–1, respectively.The highest recorded concentration of laudanosine in CSF was570 ng ml^–1, in one of two CSF samples found to containatracurium. After operation, two patients had fits, but thesewere not thought to be related to laudanosine. It is concludedthat during infusion of atracurium, laudanosine accumulatesin both plasma and CSF.     

CONCENTRATIONS OF ATRACURIUM AND LAUDANOSINE IN CEREBROSPINAL FLUID AND PLASMA IN THREE INTENSIVE CARE PATIENTS

We have measured concentrations of atracurium and laudanosinein cerebrospinal fluid (CSF) and plasma in three intensive carepatients receiving atracurium infusions of 22.5–106 hduration to maintain neuromuscular block. Two patients had sufferedsevere closed head injuries and the third patient had developedrespiratory failure following the clipping of two intracranialaneurysms. The total dose of atracurium given was 14.3–136.6mg kg^–1; rate of infusion was 0.6–1.38 mg kg^–1h^–1. Plasma concentrations of atracurium and laudanosinewere 0.73–3.11 µg ml^–1 and 0.48–8.65µg ml^–1, respectively; CSF concentration of laudanosinewas 70–440 ng ml^–1. No adverse effects attributableto these concentrations of laudanosine were observed.     

CLINICAL EXPERIENCE AND PLASMA LAUDANOSINE CONCENTRATIONS DURING THE INFUSION OF ATRACURIUM IN THE INTENSIVE THERAPY UNIT

Twenty patients in the intensive care unit received an infusionof atracurium to permit mechanical ventilation. The durationof infusion ranged from 38 to 219 h and the average rate ofinfusion during the study was 0.76 mg kg^–1 h^–1.In 14 patients an increase in atracurium requirement occurredwithin the first 72 h of the infusion. Recovery from neuromuscularblockade after a prolonged infusion was sufficiently rapid toavoid pharmacologically induced reversal. In six patients maximumplasma concentrations of laudanosine were 1.9–5 µgml^–1 and there was no evidence of cerebral excitation.     

PRODUCTION OF LAUDANOSINE FOLLOWING INFUSION OF ATRACURIUM IN MAN AND ITS EFFECTS ON AWAKENING

Twenty patients were given maximal doses of atracurium or vecuroniumby infusion during surgery. Anaesthesia was maintained withan infusion of thiopentone, nitrous oxide and fentanyl. In patientsadministered atracurium, the plasma laudanosine concentrationat cessation of surgery was 0.34 (SD 0.22) µg ml^–1;there was little tendency to cumulate during operation. A 20%higher arterial concentration of thiopentone was found at awakeningin patients given atracurium, suggesting CNS stimulation bylaudanosine, although the effect is too modest to be of clinicalsignificance.     

DISPOSITION OF INFUSIONS OF ATRACURIUM AND ITS METABOLITE, LAUDANOSINE, IN PATIENTS IN RENAL AND RESPIRATORY FAILURE IN AN ITU

A study of plasma atracurium and laudanosine concentrationswas undertaken in 14 critically ill patients who received abolus dose of atracurium 0.6 mg kg^–1 followed by an infusionof 0.6mg kg^–1 h^–1 for a period of 11–47 h.Seven of the patients had normal renal function and seven werein acute renal failure. In both groups plasma concentrationsof atracurium reached a plateau of approximately 1300 ng ml^–1within30 min of the bolus dose. The drug disappeared from the plasmawithin 120 min after discontinuation of the infusion. Therewas no difference between the two groups with respect to thepharmacokinetic parameters derived for atracurium. In the patientswith normal renal function, plasma laudanosine concentrationreached a plateau of apprpximately 1200ng ml^–1 within10h. In patients with renal failure there was a greater variationin the plasma laudanosine concentration: the highest value recordedwas 4300 ng ml^–1. Patients with renal failure had a significantlylonger mean elimination half-life for laudanosine (1418 minv. 375min; P < 0.05) and Vd (4.52 litre kg^–1 v. 240litre kg^–1; P < 0.01) than the patients with normalrenal function. ^*Present address: Southport General Hospital, Scarisbrick NewRoad, Southport, Merseyside PR8 6LF.     

CEREBROSPINAL FLUID CONCENTRATIONS OF LAUDANOSINE AFTER ADMINISTRATION OF ATRACURIUM

The concentration of laudanosine in cerebro-spinal fluid (CSF)was measured in four patients undergoing brain electrode placementafter the administration of atracurium. CSF: plasma laudanosineconcentration ratios ranged from < 1 to 14%, with a rangeof CSF laudanosine concentration of <2–14 ng ml^–1.One patient had no detectable laudanosine in CSF, but samplingin this patient was possible for only 30 min. There was no atracuriumdetectable in the CSF of any patient. We conclude that laudanosinecrosses the blood-brain barrier and further study of its centralnervous system effects in man is warranted.     

MODIFICATION BY DRUGS USED IN ANAESTHESIA OF CNS STIMULATION INDUCED IN MICE BY LAUDANOSINE AND STRYCHNINE

We have investigated in mice the effects of several drugs whichmay be administered as part of an anaesthetic technique on theconvulsive threshold to laudanosine and to strychnine, whichis reported to have a similar mechanism of action, l.v. administeredpropofol, thiopentone and midazolam increased the dose of convulsantnecessary to produce seizure when administered 2 min beforethe convulsive stimulus. In contrast, methohexitone and etomidateexhibited a pro-convulsant effect, although with the latterthis was significant only in laudanosine-treated mice. Pethidinewas proconvusant in both laudanosine- and strychnine-treatedmice, but morphine was proconvusant only in strychnine-treatedmice. The effects of morphine, but not pethidine, were antagonizedby naloxone 1 mg kg^–1. Laudanosine, but not strychninecaused arousal from anaesthesia in subconvulsive doses. Thisand other evidence suggests that the mechanism of the CNS excitationproduced by strychnine and laudanosine are not the same. Communicated in pan to the Anaesthetic Research Society, November1990.     

TRANSPLACENTAL DISTRIBUTION OF ATRACURIUM, LAUDANOSINE AND MONOQUATERNARY ALCOHOL DURING ELECTIVE CAESAREAN SECTION

Maternal venous (MV), umbilical venous (UV) and umbilical arterial(UA) blood samples were obtained for assay of atracurium, laudanosineand monoquaternary alcohol concentrations in 22 healthy patientsundergoing elective Caesarean section under general anaesthesia.At delivery (at a mean time of 8.2 min after atracurium 0.3mg kg^–1), the mean UV concentrations were 103 ng ml^–1(range 44–189 ng ml^–1) for atracurium, 26 ng ml^–1(range 6–60 ng ml^–1) for laudanosine and 59 ng ml^–1(range 21–148 ng ml^–1) for monoquaternary alcohol.The ratios of UV: MV, UA:MV and UA:UV blood concentrations wererelated positively to time since injection of atracurium forall three substances (P < 0.01 in each instance). The UV:MVratio at delivery was greatest for laudanosine: mean 19.4% (range1-35%), compared with 7% (range 2-21%) for atracurium and 10%(range 0-15%) for monoquaternary alcohol. These low values confirmthat, although atracurium crosses the placental barrier andits metabolites may be found in the fetus, the drug is safeto use during Caesarean section.     

PHARMACOKINETICS OF ATRACURIUM DURING CONTINUOUS INFUSION

The pharmacokinetics of atracurium were investigated by a model-independentmethod during continuous infusion under propofol anaesthesia.Following an intubating dose of suxamethonium, atracurium wasinfused according to a predetermined profile which continuallyset the infusion rate to maintain stable muscle paralysis anda target steady state plasma concentration when equilibriumbetween the bio-phase and plasma had occurred. Atracurium wasinfused for the first 1 h to maintain a target steady stateplasma concentration of 1.0 µg ml^–1. Thereafter,the target plasma concentration was adjusted to maintain 90%muscle paralysis. The maintenance infusion rate required tomaintain 90% paralysis was 4.25 (SD) 1.11 µg kg^–1min^–1, with an estimated steady state plasma concentrationof atracurium required to maintain 90% paralysis (Cp^SS 90) of1.13 (0.24) µg ml^–1. The clearances of atracurium,estimated by the constant infusion rate required to maintainthe steady state plasma concentration, at 50–60 min andduring estimation of Cp^SS 90 were 3.8 (1.0) and 3.9 (1.1) mlkg^–1 min^–1 (ns), respectively. The volume of distributionat steady state of atracurium after 1 h of infusion, calculatedusing the clearance and the area under the plasma concentration-timecurve to 1 h, was 130 (50) ml kg^–1. These estimates ofthe pharmacokinetic parameters of atracurium are markedly differentfrom those derived from pharmacokinetic analysis of single bolusdose data. Normalization of the pharmacokinetic parameter estimatesby lean body mass decreased interpatient variability and improvedprecision in comparison with the un-weighted data and normalizationby total body weight.     

COMPARISON OF THE TRAIN-OF-FOUR FADE PROFILES PRODUCED BY VECURONIUM AND ATRACURIUM

In this double-blind study, we have allocated randomly 40 ASAI-III patients to one of four groups. After a standard anaestheticinduction, patients received vecuronium 0.08 mg kg^–1 or0.10 mg kg^–1, or atracurium 0.4 mg kg^–1 or 0.5 mgkg^–1. Using an electromyogram (Datex Relaxograph) thetrain-of-four (TOF) response was measured during onset of andrecovery from neuromuscular block. A greater degree of fadeof TOF was observed with atracurium during onset of neuromuscularblock than with equivalent doses of vecuronium. During recoveryof neuromuscular transmission, vecuronium was associated withmore fade than atracurium. The differences in the TOF profilesof these two drugs may be important when judging the adequacyof antagonism of neuromuscular block using the TOF response.     

USE OF CONTINUOUS PROLONGED ADMINISTRATION OF ATRACURIUM IN THE ITU TO A PATIENT WITH MYASTHENIA GRAVIS

The case is described of a patient with myasthenia gravis whorequired prolonged controlled ventilation for respiratory failure.Muscular relaxation was obtained with a continuous infusionof atracurium 5 mg h^–1 for 45 h. Following cessation ofthe infusion, paralysis disappeared rapidly.     

从血浆与尿中儿茶酚胺和它的代谢产物含量说明推拿的镇痛作用

为了解推拿的镇痛作用与致痛物质的关系，分组进行了观察。第一组推拿前后９例急性软组织损伤病人血浆中儿茶酚胺（ＣＡ）的变化。第二组推拿前后３４例腰椎间盘突出症尿中儿茶酚胺（ＣＡ）和它的代谢产物含量变化。结果表明，推拿后血浆中ＮＡ含量下降非常显著，ＤＡ含量显著下降。推拿后尿中ＣＡ，ＤＡ，ＶＭＡ含量均明升高。说明体液中ＣＡ与推拿作用密切相关。ＣＡ含量在血浆中下降越显著，在尿中升高越显著，临床疗效越好。提示：在推拿过程中，体液内儿茶酚胺是参与调整镇痛的主要物质之一。     

NEOSTIGMINE IN THE ANTAGONISM OF THE ACTION OF ATRACURIUM

Antagonism of atracurium-induced neuromuscular blockade withneustigmine (one or two doses of 2.5 mg) was compared, usingelectromyography, with spontaneous recovery. Two levels of blockadewere studied, one in which the initial response of the train-of-fourhas reached 10% of control and the other 50% of control. Adequaterecovery was considered to be present when the ratio of thefourth response to the first (train-of-four ratio) had reached70%. Neostigmine always accelerated recovery and "neostigmineblock" was not detected. This acceleration of recovery afterneostigmine was most marked with the greater degree of blockade,but two doses of neostigmine were no more effective than one.Spontaneous recovery to the train-of-four ratio of 70% was slow,in the order of 1 h after an initial dose of 0.5 mg kg^–1and 45 min after incremental doses of 0.2 mg kg^–1. Itis concluded that antagonism of atracurium with one dose ofneostigmine is usually desirable, that two doses are unnecessary,and that spontaneous recovery is slower than is generally realized. ^*Present address: Royal Preston Hospital, Fulwood, Preston,Lanes.     

RECOVERY OF ATRACURIUM AND VECURONIUM NEUROMUSCULAR BLOCK IN THE ISOLATED FOREARM

The duration of recovery from neuromuscular block after a 3x ED₉₀ dose of atracurium or vecuronium is similar in spiteof a three-fold difference in their elimination half-lives.We have investigated simultaneous spontaneous recovery fromequipotent doses of atracurium and vecuronium in the isolatedforearms of volunteers in order to attempt to explain this paradox.Simultaneous administration of the two drugs, one in each ofthe subject's forearms, allowed direct comparison of recoveryto be made against the same plasma concentration of drug. Therecovery index of atracurium was found to be significantly longerthan that of vecuronium. We suggest that this observation, whenconsidered with the different plasma concentrations after a3xED₉₀ dose, helps to explain the similar duration of actionof the two drugs during the recovery phase after a large systemicbolus. (Br. J. Anaesth. 1993; 71: 730–731)     

INVOLVEMENT OF NUCLEOPHILES IN THE INACTIVATION OF ATRACURIUM

Atracurium was incubated in 0.9% sodium chloride solution atpH 7.4 and 37 °C. The following compounds were added tothe incubation solution: propionic acid, alanine and cysteine(0.1 mol litre–^–1 final concentration). Metocurinewas also incubated with cysteine under identical conditions.Aliquots of the incubation solutions were injected i.v. to anaesthetizedrats at the start (0 min) and at the end of incubation (45 min),and the indirectly elicited, single twitches of the gastrocnemiusmuscle were observed. Whereas inactivation of atracurium proceededslowly in the control solution and in the presence of sodiumpropion-ate, the presence of alanine and, especially, of cysteinemarkedly enhanced the inactivation. Incubation of metocurinewith cysteine did not alter the pharmacological responses. Theconcentration of cysteine decreased progressively during itsincubation with atracurium (37 °C, pH 7.4). We concludethat the data are compatible with the postulate that a nucleophilemay enhance the degradation of atracurium by a reaction withthe parent compound (nucleophilic substitution reaction), byreaction with acrylates (Michael addition) or both.     

THE ROLE OF HISTAMINE IN THE CARDIOVASCULAR EFFECTS OF ATRACURIUM

We have investigated the effect of a bolus injection of atracurium0.6mg kg^–1 on the cardiovascular system in 16 patientsundergoing aortocoronary bypass surgery. H₁- and H₂-receptorantagonists were administered to eight patients before the neuromuscularblocker. A standard anaesthetic was used comprising fentanyl,flunitrazepam, etomidate and enflurane. After administrationof atracurium, haemodynamic changes and plasma histamine concentrationswere measured at frequent intervals. In the first group, whoreceived only atracurium, a brief but marked decrease in SVRand MAP occurred, accompanied by an increase in Cl, togetherwith a marked increase in plasma concentration of histamine.In the second group, who received H₁ and H₂-receptor block,there was no decrease in MAP and only a small increase in plasmahistamine concentration. However, there were significant changesin SVR and Cl similar to those in the atracurium group.