POSTSYNAPTIC EFFECT OF I.V. ANAESTHETIC AGENTS AT THE NEUROMUSCULAR JUNCTION

The effects of sodium thiopentone 19–757µmol/litre,sodium pentobarbitone 25–806 µmol/litre, propanidid74–1186 µol/litre, Althesin 55–220 µol/litre,diazepam 17.6–140 µmol/litre and ketamine 1.8–116.8µmol/litre on the time–course of miniature end–platecurrents of the excised mouse diaphragm were investigated. Thecurrents were detected by means of extracellular electrodesand recorded with a transient recorder. The drugs had no significanteffect on the growth phase of the current, but all six shortenedthe time-constant of the decay phase. This reduction in theduration of end-plate currents reduced the amplitude of postsynapticpotentials. A similar effect at central synapses may accountfor a failure of synaptic transmission caused by anaestheticdrugs and it is suggested that a reduction in the lifetime ofopen postsynaptic ionic channels is a common action of anaestheticdrugs.     

EFFECT OF DIAZEPAM AT THE NEUROMUSCULAR JUNCTION: A clinical study

In patients undergoing surgery under general anaesthesia diazepam0.16 mg kg^–1 had no effect on mechanical twitch heightof the adductor pollicis muscle of the thumb when the ulnarnerve was stimulated at the wrist. The muscle responses wereevoked by single, repeated supramaximal stimuli at 0.2 Hz and"train-of-four" stimulation at 2 Hz for 2 s. Diazepam 0.16 mgkg^–1 had no effect on the depth or recovery of neuromuscularblockade produced by suxamethonium, tubocurarine, pancuronium,fazadinium or alcuronium.     

EFFECT OF SOME I.V. ANAESTHETIC AGENTS ON CANINE GASTROINTESTINAL MOTILITY

Thiopentone 20 mg kg^–1, ketamine 8 mg kg^–1 and minaxolone2 mg kg^–1 were administered to fasting greyhound dogs.Mechanical and electrical activities from stomach, duodenum,jejunum and ileum were recorded using strain gauge force transducersand implanted bipolar electrodes. Thiopentone and minaxolonecaused intense activity in the duodenum and jejunum (phase Iand phase II of the interdigestive cycle), but not the stomachor ileum. The activity following injection of thiopentone orminaxolone was prevented by premedication with either atropine0.05 mg kg^–1 or pentolinium 0.2 mg kg^–1. Ketaminehad no influence on gastrointestinal activity or the responseto thiopentone or minaxolone. None of these drugs altered thebasal electrical rhythm of the intestine     

EFFECT OF NALOXONE ON THE LOSS OF CONSCIOUSNESS INDUCED BY I.V. ANAESTHETIC AGENTS IN MAN

The effect of a specific opioid antagonist, naloxone, was studiedin two comparable groups of patients who received i.v. the doseof an anaesthetic agent required to produce loss of consciousnessin 50% of subjects. The first group received naloxone 0.006mg kg^–1 5 min before induction of anaesthesia; the secondgroup received a similar volume of saline solution. Thiopentone,Althesin, diazepam, ketamine and propanidid were studied. Thedifferences in percentage of unconscious patients between thenaloxone-treated group and the control group were statisticallysignificant for diazepam, ketamine and propanidid. Naloxonedid not modify the induction of anaesthesia with thiopentoneor Althesin     

CYTOTOXICITY OF I.V. ANAESTHETIC AGENTS ON THE ISOLATED RAT HEPATOCYTE

The isolated rat hepatocyte model has been used to assess thehepatotoxicity of a number of i.v. anaesthetic induction agents.Ketamine, Althesin and CCI 12923 (minaxolone) all inhibitedgluconeogenesis and urea formation from alanine. There was alsoa decrease in the cell ATP concentration, and a dose-relatedincrease in leakage of LDH. Of these indices of cell toxicity,gluconeogenesis from alanine was found to be the most sensitive.Fifty per cent inhibition of gluconeogenesis for all three agentsoccurred in the range 150–300 µmol. The effectsof these agents on the isolated hepatocyte may be attributedto a primary impairment of mitochondrial function through achange in the ATP concentration. The plasma concentration ofanaesthetic agents measured during their clinical use is atleast one order of magnitude less than that required to cause50% inhibition of gluconeogenesis.     

THE EFFECT OF GENERAL ANAESTHETIC AGENTS ON NERVE CONDUCTION VELOCITIES

Nerve conduction velocity has been studied in the ulnar nerveof human subjects before and during anaesthesia. No significantchanges in velocity were observed following the administrationof thiopentone, nitrous oxide, oxygen and halothane in normalclinical quantities. A transient increase in nerve conductionvelocity was noted following the administration of paralyticdoses of gallamine triethiodide to subjects receiving nitrousoxide, oxygen and halothane anaesthesia in whom ventilationwas controlled.     

INTERACTION OF ADRENALINE WITH NEOSTIGMINE AND TUBOCURARINE AT THE SKELETAL NEUROMUSCULAR JUNCTION

The effects of neostigmine, and of neostigmine with adrenaline,on the response of the rat isolated hemidiaphragm to stimulationof the phrenic nerve are reported. Neostigmine augmented theresponse: a maximum augmentation occurred at a concentrationof 6.4 x 10^–7 mol litre^–1. At greater concentrationsof neostigmine the response was reduced. Adrenaline in the absenceof neostigmine produced no significant change in the contractionresponse. However, in the presence of neostigmine further augmentationoccurred and achieved a maximum in the presence of adrenaline3.2 x 10^–7–1.3x10^–6 mol litre^–1. Adrenaline4.0 x 10^–8–1.3x10^–6 mol litre^–1 combinedwith neostigmine 4.0x10^–8–6.4 x10^–7 mol litre^–1reversed tubocurarine-in-duced neuromuscular blockade more effectivelythan neostigmine alone(P < 0.001). Adrenaline appeared toenhance the antagonistic effect of neostigmine by increasingacetylcholine release and by enhancing the response at the post-junctionalacetylcholine receptor.     

IN VITRO STUDY OF INTERACTIONS BETWEEN I.V. ANAESTHETICS AND NEUROMUSCULAR BLOCKING AGENTS

The interactions of four anaesthetic drugs (ketamine, propanidid,Althesin and methohexitone) with two neuromuscular blockingagents (suxamethonium and pancuronium) have been investigated.On the isolated rat phrenic nerve—diaphragm preparation,all the anaesthetic drugs examined potentiated suxamethoniummore than they potentiated pancuronium. The anticholinesteraseagent, ecothiopate, had no significant effect on the potentiationof suxamethonium caused by the anaesthetic drugs. At low concentrationsthe anaesthetic drugs increased the twitch tension elicitedby stimulation of the phrenic nerve, whilst at high concentrationsthis potentiation was followed by blockade of neuromusculartransmission. With the exception of Althesin, all the anaestheticsdecreased the sensitivity of the frog rectus preparation toacetylcholine. The possible sites and mechanisms of these interactionsare discussed.     

AN ANIMAL MODEL FOR THE INVESTIGATION OF ADVERSE RESPONSES TO I.V. ANAESTHETIC AGENTS AND THEIR SOLVENTS

In man the number of adverse responses to the Cremophor-containinganaesthetic agents Althesin and propanidid (Epontol) has beenreported to be greater than that encountered with thiopentone.The response of the mini-pig to repeated injection of a rangeof i.v. anaesthetics and their solvents has been investigatedin an attempt to ascertain the possible role of Cremophor inthe production of these responses. A second injection of CremophorEL or the Cremophor/Micellophor-containing agents Althesin andpropanidid (Epontol), given 7 days after the first, produceda high frequency of adverse responses. On only one occasion,when alphaxalone and alphadolone were given in a mixture ofalcohol and propylene glycol, was an abnormal response seenon the first administration of any agent. The second administrationof alphaxalone and alphadolone in the same solvent producedabnormal responses in two of four pigs. No such responses wereseen when propanidid was administered in alcohol and propyleneglycol or when this solvent mixture was given alone. No abnormalresponses were seen following the repeated administration ofthiopentone. A marked increase in arterial pressure, and animmediate but transient marked decrease in the numbers of circulatingpolymorphonuclear leucocytes, were consistent findings in animalsshowing adverse responses. No abnormal responses were foundwhen the interval between two administrations of Althesin wasextended to 3 weeks.     

COMPARISON OF INFUSION RATES OF THREE I.V. ANAESTHETIC AGENTS FOR INDUCTION IN ELDERLY PATIENTS

We have compared the effect of different rates of injectionof 2.5% thiopentone, 0.5% methohexitone and 0.2% etomidate forinduction of anaesthesia in 90 premedicated, elderly patients.The agents were administered by infusion pump at rates of 1200ml h^-1, 600ml h^-1 and 300 mlh^-1 respectively until anaesthesiawas induced as judged by loss of verbal contact with the patient.The times for induction were significantly greater with theslower infusion rates (thiopentone 41 s, 57 s and 91 s (P<0.001); methohexitone 44 s, 62 s and 84 s (P<0.01); etomidate48 s, 59 s and 87 s (P < 0.001 )). The doses were significantlysmaller (P < 0.001) with the slower infusion rates for allthree agents (thiopentone 5.0,3.7and2.8mg kg^-1; methohexitone1.00, 0.75 and 0.56 mg kg^-1; etomidate 0.26, 0.15 and 0.11 mgkg^-1). For each drug there was no significant difference ininduction characteristics, oxygen saturation, heart rate ormean arterial pressure, at the different infusion rates. (Br.J. Anaesth. 1993; 70: 423–427)     

THE EFFECT OF ANAESTHETIC AGENTS UPON CALF MUSCLE BLOOD FLOW IN THE ISCHAEMIC LIMB

The effect of anaesthesia using trichloroethylcne, halothane,and tubocurarine was studied on the calf blood flow before surgicalstimulation using venous occlusion plethysmography. There weretwenty-seven patients in the study divided into three groups,each group receiving one of the three anaesthetic agents. Allpatients had a history of intermittent claudication and weresubsequently shown to have abnormal aortograms. There was adecrease in calf blood flow in all three groups. Those patientsanaesthetized with halothane showed a considerably smaller decreasein flow compared to the other two groups. It is suggested thathalothane might be a more suitable agent for anaesthesia inpatients with lower limb ischaemia.     

DOXAPRAM AND THE NEUROMUSCULAR JUNCTION

We have studied the action of doxapram on neuromuscular transmissionin the rat phrenic nerve—diaphragm preparation. Doxapramaugmented neuromuscular transmission in a doserelated mannerwhen a threshold concentration of 5 x 10^–5 mol litre^–1had been exceeded. The activity of the acetylcholinesterasein rat diaphragm has been examined also in the presence of doxapram.No inhibitory effect was seen in the concentration range whichaugmented neuromuscular transmission, thus excluding cholinesteraseinhibition as the underlying mechanism. In contrast, in thepresence of partial neuromuscular block, a dose-related depressionof neuromuscular transmission with doxapram was revealed. Thiswas greatest when the neuromuscular blocking agents possessedsignificant presynaptic activity (ß-bungarotoxin andtubocurarine). In this situation any facilitatory action ofdoxapram was severely reduced or abolished. In contrast, thefacilitatory effects of doxapram were apparent in the presenceof partial block produced by agents with less or no presynapticactivity (pancuronium and -bungarotoxin). This study suggeststhat doxapram has a presynaptic facilitatory action at the neuromuscularjunction. In the presence of partial neuromuscular block, aninhibitory action is revealed which may be post-junctional.The concentrations of doxapram at which these effects appearare approximately five times greater than those reached in plasmaafter a standard clinical dose. An abstract of part of this work was presented to the 9th AnnualMeeting of the European Academy of Anaesthesiology, in Ghent,Belgium, September 1987.     

PAIN ON I.V. INJECTION OF SOME ANAESTHETIC AGENTS IS EVOKED BY THE UNPHYSIOLOGICAL OSMOLALITY OR pH OF THEIR FORMULATIONS

We have studied the intensity and time-course of pain duringand after injection into an isolated vein segment in seven normalsubjects of saline or glucose of different osmolalities (0–6osmol kg^–1) or pH (2–13). Pain scores were recordedcontinuously by a modified visual analogue scale apparatus.With osmolar stimulation, pain occurred at 1.0 osmol kg^–1during perfusion and 3.0 osmol kg^–1 with rapid injectionand increased with osmolar concentration of both saline andglucose solutions. Acidic and alkaline solutions evoked painat a pH value < 4 or > 11. We conclude that pain on i.v.injection of some sedative and hypnotic drugs is likely to becaused by formulations of extremely unphysiological osmolalitiesor pH values.     

THE EFFECT OF FOUR VOLATILE ANAESTHETIC AGENTS ON THE IMPULSE ACTIVITY OF TWO TYPES OF PULMONARY RECEPTOR

The effect of halothane, ether, chloroform and trichloroethyleneon the impulse discharge of two types of pulmonary receptorhas been investigated in cats and dogs under chloralose or barbiturateanaesthesia. Afferent impulses were recorded from pulmonarystretch fibres and also from slowly-conducting vagal fibreswhose pulmonary endings were stimulated by hyperinflation (high-thresholdinflation receptors). Ventilating the lungs with low concentrationsof each agent (e.g. 1–3 per cent halothane) caused sensitizationof the pulmonary stretch receptors but had no effect on thehigh-threshold endings. With high concentrations (e.g. 5–20per cent halothane), pulmonary stretch receptors showed an initialsensitization followed by a reduction or abolition of activity,while the high-threshold receptors showed a marked increasein impulse activity during inflation. The possibility is discussedthat the high-threshold inflation receptors may be involvedin some of the reflex effects that have been observed duringsurgical anaesthesia with high concentrations of halothane.     

NON-COMPETITIVE EFFECTS OF DISOPYRAMIDE AT THE NEUROMUSCULAR JUNCTION: EVIDENCE FOR ENDPLATE ION CHANNEL BLOCK

The effects of disopyramide were studied at the neuromuscularjunction in an attempt to elucidate the mechanism of its blockingaction at this site. Disopyramide 5 x 10^–5-10^–3mol litre^–1 produced a concentration-dependent reductionof twitch amplitude in the indirectly stimulated chick biventercervicis preparation, but greater concentrations were requiredto reduce twitches elicited directly in the presence of erabutoxin-b1µg ml^–1. Equieffective twitch blocking doses ofeither disopyramide or tubocurarine greatly reduced agonistresponses to acetylcholine and carbachol, but the reductionwas less for magnesium-blocked twitches. Neostigmine antagonizedtubocurarine-induced, but not diso-pyramide-induced, blockadeof twitches. Concentration-response profiles to acetylcholineand carbachol were shifted to the right in a non-parallel fashionand the maximal response was depressed by disopyramide 5 x 10^–5-5x 10^–4 mol litre^–1. Intracellular recording studiescarried out in the cut, voltage-clamped costo-cutaneous muscleof the garter snake showed that disopyramide 5 x 10^–5-5x 10^–4 mol litre^–1 produced a concentration- andvoltage-dependent reduction of the amplitude of neurally evokedendplate-currents (EPC) and of the time constant of decay ()of EPC. We conclude that disopyramide possesses a non-competitiveblocking action at the neuromuscular junction, which is notreversible by anticholinesterase agents. The voltage-dependentnature of the block suggests that it is mediated via blockadeof the open form of the acetylcholine-activated receptor-ionchannel complex.     

EFFECT OF CERTAIN ANAESTHETIC AGENTS ON THE ACTIVITY OF RAT HEPATIC {delta}-AMINOLAEVULINATE SYNTHASE

The activity of -aminolaevulinic acid synthase (E.C. 2.3.1.37 [EC] )(the rate-limiting enzyme for haem and porphyrin biosynthesis)has been measured in the rat liver after the repeated administrationof anaesthetic agents in vivo. The activity of the enzyme wasincreased by Althesin, chlordiazepoxide, enflurane, etomidate,lignocaine, methohexitone, methoyflurane, pentazocine and thiopentoneand decreased by procaine. No significant changes in activityoccurred after the administration of amethocaine, atropine,bupivacaine, diazepam, droperidol, halothane, ketamine, morphine,nitrous oxide, pethidine, phenoperidine, prilocaine and propanidid.It is suggested that those anaesthetic agents which inducedactivity of the enzyme should not be administered to patientswith an acute porphyria.     

INTERACTIONS BETWEEN THE NEUROMUSCULAR BLOCKING DRUG ORG NC45 AND SOME ANAESTHETIC, ANALGESIC AND ANTIMICROBIAL AGENTS

The effects of some ansestheucs and other agents used in anaestheticpractice on the neuromuscular blocking activity of cumulativedoses of Org NC45 have been studied in cats anaesthetized withchioralose. As expected from studies with other neuromuscularblocking drugs, both inhalation and i.v. anaesthencs reducedthe doses of Org NC 45 required for neuromuscular blockade.An apparently specific potentiating interaction between OrgNC45 and metromdazole was observed.     

EFFECT OF ANAESTHETIC AGENTS ON BILE FLOW AND BILIARY EXCRETION OF 131I- CHOLYLGLYCYLTYROSINE IN THE RAT

We have compared in the rat the effects of i.v. anaestheticagents on bile flow rate and on the biliary excretion of a novelbile acid, ^131l-cholylglycyltyrosine (¹³¹l-cholylgly.tyr.).Etomidate 1-mg bolus and 2-mg h^–1 infusion, Althesin 3-mgbolus and 14.5-mg h^–1 infusion and propofol 3.3-mg bolusand 3.3-mg h^–1 were given via a tail vein cannula andpentobarbitone 50 mg kg^–1 was given by the intraperitonealroute, to groups of six rats. Each animal received only oneanaesthetic agent. One hour after cannulation of the commonbile duct, ¹³¹l-cholylgly.tyr. 5 µCi was injected intothe jugular vein and bile was collected every 1 min for 10 min.The mean (SD) percentage cumulative biliary excretion of ¹³¹l-cholylgly.tyr.at the end of 10 min was: propofol group 74.1 (5.2)% Althesingroup 82.3 (2.2)%; etomidate group 69.4 (17.6)%; pentobarbitonegroup 76.4 (3.2)%. Propofol and Althesin were relatively morecholeretic, causing bile flow rates twice that produced by pentobarbitone.Only Althesin caused a significant increase in biliary excretionof ¹³¹l-cholylgly.tyr. relative to that in rats that receivedpentobarbitone. Bile flow rates for the respective anaesthetictechniques (µl min^–1/100 g body weight) (mean (SD))were: propofol group 14.1 (1.8); Althesin group 12.5 (1.7);etomidate 8.5 (1.4); pentobarbitone group 7.3 (1.0). There wasa marked metabolic acidosis in all rats except in the propofolgroup, in which normal acid-base status and oxygenation wereobserved. Previously presented at the Medical Research Society and published(abstract form) in Clinical Science and Molecular Medicine 1986;71: 71–72.     

DIFFERING INTERACTIONS BETWEEN HEXAMETHONIUM AND TUBOCURARINE, PANCURONIUM OR ALCURONIUM AT THE NEUROMUSCULAR JUNCTION

The action of hexamethonium has been investigated in the ratphrenic nerve-hemidiaphragm preparation, alone and in combinationwith the neuromuscular blocking agents tubocurarine, pancuroniumand alcuronium. Hexamethonium alone in concentrations between3.55x10^–3 and 7.1x10^–3 mol litre^–1 producedneuromuscular blockade in a dose-dependent manner. Low concentrationsof hexamethonium antagonized the neuromuscular blocking effectof all three neuromuscular blocking drugs, less with tubocurarinethan with the other two. Increasing the concentration of hexamethoniumproduced potentiation of the neuromuscular blocking effect,this being greater with tubocurarine than with either pancuroniumor alcuronium. The cholines-terase activity in rat diaphragmhomogenates was inhibited by hexamethonium. This inhibitionwas only significant at concentrations greater than those whichresulted in antagonism and cannot, therefore, explain the observedantagonism. The mechanism of these observations is discussedwith respect to the known behaviour of a combination of antagonistsacting within a receptor system. An abstract of this work was presented to the 7th European Congressof Anaesthesiology, Vienna, Austria, September 1986. *Present addresses: Department of Anaesthesia, University ofManchester, Manchester Royal Infirmary Oxford Road, ManchesterM13 9WL Present address: University of Michigan, Department of Anesthesiology,Mott Children's Hospital Rm. C4139, Box 0800, Ann Arbor, Mi.48109-0800, U.S.A.     

THE PRODUCTION OF LARYNGOSPASM IN THE CAT BY VOLATILE ANAESTHETIC AGENTS

Laryngospasm and apnoea or alterations in the rhythm of respirationhave been produced in decerebrate preparations of cats and incats anaesthetized with chloralose during the start of inhalationof volatile anaesthetic agents. Ether, halothane and methoxyfluraneall produced these effects when they were placed in contactwith the larynx. The responses to ether occurred more rapidlythan those to halothane, which in turn had a faster effect thanmethoxyflurane. In the concentrations used, ether vapour (10–20per cent) and halothane vapour (6–8 per cent) stimulatedlaryngospasm and apnoea when administered through either thenasopharynx and larynx, the mid-cervical trachea or the distaltrachea and lungs. Methoxyflurane (2.9 per cent) did not havethese actions in the trachea and lungs. The responses obtainedwere detected in the absence of the continuity of the olfactorypathway, due to decerebration in which no loss of trigeminalafferents was occasioned. The importance of nasal, laryngeal,pharyngeal, tracheal and pulmonary stimulation in the productionof laryngospasm and apnoea caused by inhaling; anaesthetic vapourshas been demonstrated. Present address: Veterinary Clinical Centre, University of Melbourne,Werribee, Victoria, 3030, Australia.