the pharmacology of atracurium: a new …€¦ · the pharmacology of atracurium: a new competitive...

Br.J. Anaesth. (1981), 53, 31

THE PHARMACOLOGY OF ATRACURIUM: A NEW COMPETITIVENEUROMUSCULAR BLOCKING AGENT

R. HUGHES AND D. J. CHAPPLE

SUMMARY

Atracurium besylate, 2,2'-<3)l l-dioxo-4,10-diojtatridecylene)-bis-[6,7-dimethoxy-l-(3,4-dimethoxy-benzyl)-2-methyl-l^>3,4-tetrahydroisoqiiinoliniuin] dibenzenesulphonatc, is one of a new series ofcompetitive neuromuscular blocking agents. Ani.v. dose of 0.25 mg kg" ' produced complete paralysis inanaesthetized cats, dogs and rhesus monkeys; paralysis was of medium duration and was readilyantagonized by neostigmine. Vagal blockade occurred only after doses 8-16 times greater than the fullneuromuscular paralysing dose and effects on sympathetic mechanisms were minimal. Hypotension andbradycardia were evident after supramaximal doses of 4 mg kg" ' i.v. and these effects, together withcirculatory depression, were probably attributable to histamine release. In vitro studies have shown thatthe non-enzymic decomposition of atracurium by "Hofrnann Elimination" was enhanced by increasingpH. In vivo neuromuscular paralysis was significantly reduced when the arterial pH was increased. Therewere indications that neither the liver nor the kidney plays a major role in the metabolism and eliminationof unchanged drug. These results are of sufficient interest to merit the cvaluanon of atracurium inanaesthetized man.

All competitive neuromuscular blocking agentscurrently in general use, in addition to theiractions at the neuromuscular junction, inhibitcholinergic transmission at autonomic sites andmay produce undesirable cardiovascular side-effects (Hughes and Chappie, 1976a).Furthermore, all show a significant increase in theduration of neuromuscular blockade when ex-cretion is inhibited by renal insufficiency(Wingard and Cook, 1977). Atracurium besylate,2,2'-(3,11 -dioxo-4,10-dioxatridecy lene)-bi s- [6,7-dimethoxy-l-(3,4-dimethoxybenzyl) -2- methyl-1,23,4-tetrahydroisoquinolinium] dibenzenesul-phonate, is one of a new series of neuromuscularblocking agents, which has been developed in anattempt to overcome the disadvantages of suchdrugs (Stenlake, 1979).

The chemical structure of atracurium is shownin figure 1 and the arrows indicate the likelymetabolic pathways. These are (1) an enzymicester hydrolysis to give the monoquaternary meta-bolites and (2) decomposition by what is called"Hofmann Elimination". Under mild alkalineconditions fission occurs at the quaternary nitro-gen to give laudanosine as the main metabolite(Stenlake, 1979). No other available neuromus-

ROY HUGHES, B.SC., M.SC., PH.D.; DENNIS J. CHAPPLE, B.SC.;Department of Pharmacology, The Wellcome ResearchLaboratories, Langley Court, Beckenham, Kent.

0007-0912/81/010031-14 801.00

cular blocking agent undergoes this kind of break-down at physiological pH. Moreover, we haveverified that the metabolites from both potentialmetabolic pathways are without neuromuscularand cardiovascular effects in amounts greatly inexcess of those likely to be present after neuromus-cular blocking doses of atracurium (Hughes andChapple, 1978).

We now report in detail the pharmacology ofatracurium in laboratory animals, and a com-parison with known drugs, in order to assess theclinical potential of this agent. A preliminaryaccount of this work has been presented to theAnaesthetic Research Society (Hughes andChapple, 1980).

METHODS

Nerve-muscle preparationsIsolated chick biventer-cervicis preparations

were set up in Krebs solution at 35 °C andequilibrated with 95% oxygen and 5% carbondioxide. The nerve was stimulated at 0.12 Hz withrectangular pulses of supramaximal voltage andduration and the muscle responses were recordedon a smoked drum.

Cats of either sex weighing 2.6-3.7 kg werestudied after anaesthesia had been induced with2-5% halothane and maintained with chloralose60-80 mg kg" ' i.v. and sodium pentobarbitone18—24 mg kg"' i.v. after cannulation of a jugular

© Macmillan Publishers Ltd 1981

32

MeO

MeO

Me

BRITISH JOURNAL OF ANAESTHESIA

OMe

+ N N +" \ CH2.CH2.CO.O[CH2] g . O C O C H C H ^

OMe MeO

OMe OMe

OMe

HofmannElimination

MeO

MeOROH

+ CH^CH.CO.OR'

OMe MeO

OMe OMeFIG. 1. Chemical structure of atracurium; the arrows indicate the likely metabolic pathways.

HOOC.CH2.CH2

Erter Hydrolysis

OMe

OMe

vein as described previously (Hughes andChappie, 1976a). The twitch responses of the rightgastrocnemius muscle were elicited by stimulationof the sciatic nerve at a frequency of 0.1 Hz withrectangular pulses of supramaximal voltage and0.1-0.15 ms duration. In most experiments the leftgastrocnemius muscle was stimulated indirectlywith tetanic pulses of 30-35 Hz for 1 s every 10 s.Arterial pressure was measured from the carotidartery and breathing was monitored with a ther-mistor placed inside a tracheal cannula. Theelectrocardiogram was recorded from chest leadsand heart rate from a cardiotachometer.Simultaneously, effects on autonomic mechanismswere assessed by stimulating at the cervical vagusnerve for 10 s at 10-20 Hz, and measuring theensuing bradycardia (parasympathetic), and thecervical sympathetic nerve for 60 s and recordingthe induced contractions of the nictitating mem-brane. Oesophageal temperature was measuredwith a probe and maintained at 36-37 =C. Similar

techniques were used on beagle dogs of either sexweighing 8.6-14.9 kg and analogous procedureswere carried out using rhesus monkeys of2.8-4.1 kg as described by Hughes and Chappie(1976b). In monkeys anaesthesia was induced withthiopentone 25 rag kg" ' i.v. and maintained with50% nitrous oxide in oxygen supplemented bythiopentone 5-12 mg kg"' i.v. when required.Effects on sympathetic mechanisms were investi-gated by measuring the vasopressor response tocarotid occlusion for 10 s. During neuromuscularparalysis ventilation of the lungs of the cats anddogs was with air using a Starling Ideal pump andof the rhesus monkeys with nitrous oxide andoxygen using a Phillips AVI Ventilator.

Interaction with halothaneInitially, dose-response curves for neuromus-

cular blockade of the single twitch response of thegastrocnemius muscle by atracurium were es-tablished in cats anaesthetized with chloralose

PHARMACOLOGY OF ATRACURIUM 33

followed 60-90 min later by inhalation of concent-rations of 1 or 2% halothane. The same doses werethen repeated 30-60 min after beginning the ad-ministration of halothane. A cross-over design wasadopted in which the sequence of administration

I was reversed. In half the cats used, the controldose-response curves for atracurium followed120 min after the interaction study with halothane.

Cholinesterase inhibitionThe enzyme was extracted from human skeletal

muscle and prepared as a suspension in phosphatebuffer at pH 8. Enzymic activity was measured asdescribed by Ellman and others (1961) usingacetylthiocholine 0.5 mmol litre"1 as substrate.Each drug was tested at a range of concentrationsand the results expressed as the concentrationcausing 50% reduction in the rate of hydrolysis ofsubstrate compared with the non-inhibited con-trols (IC50).

Haemodynamic studiesThese were carried out on open-chest beagle

dogs anaesthetized with chloralose using tech-niques described in detail elsewhere (Hughes,1971). An electromagnetic flow sensor was placedaround the root of the ascending aorta to recordaortic blood flow and a stiflF polyethylene catheterinserted down the left carotid artery to measureaortic pressure. The flow signal was integrated toobtain cardiac output (less coronary flow) anddifferentiated to derive maximum acceleration (anindex of myocardial contractility). Peripheral vas-

1 cular resistance was computed by dividing meanaortic pressure by mean aortic flow.

Inotropic and chronotropic effects were assesedusing guineapig atria preparations set up at 35 CCin modified Ringer Z solution bubbled with 95%oxygen and 5% carbon dioxide. The force andfrequency of each contraction were recorded witha displacement transducer.

Histamine releaseHistamine release was studied in beagle dogs

anaesthetized with chloralose. Initially, effects ofatracurium, tubocurarine (for comparison) and

' histamine on carotid pressure were established ineach dog. I.v. injections of 10 mg kg"' of the H,-receptor antagonist mepyramine and 15 mg kg"'of the H2-receptor antagonist burimamide orcimetidine were then given, followed by histamineto ascertain that its vasodepressor response was

blocked. The established doses of atracurium andtubocurarine were repeated to determine theireffects on carotid pressure during histamine-receptor blockade.

Changes in acid-base balanceEffects of respiratory and metabolic acidosis and

alkalosis on neuromuscular blockade of the tetanicand single twitch responses of the gastrocnemiusmuscles by atracurium were investigated in groupsof cats anaesthetized with chloralose using tech-niques described previously (Hughes, 1970).Arterial blood was sampled frequently for measur-ement of pH, Pco2 and Po2. Controlled venti-lation was used throughout. I.v. doses of atra-curium were given before, during and after theimposed changes in acid-base balance; intervals of45—85 min were allowed between doses.

Elimination of atracuriumA cannula was placed in a branch of the hepatic

portal vein of anaesthetized cats so that atracuriumcould be administered through the liver. A cross-over design was adopted so that half the cats firstreceived increasing doses of atracurium throughthe hepatic portal vein, after which dose-responsecurves were obtained for neuromuscular blockadeof the single twitch response of the gastrocnemiusmuscle. After an interval of 120 min from the lastdose, when recovery was complete, the samesequence of doses was given through the jugularvein and dose-response curves established for thisroute; in the other cats the order of administrationwas reversed.

In other tests, increasing doses of atracurium orgallamine (for comparison) were given to anaes-thetized cats to establish dose-response curves forneuromuscular blockade. After an interval of60 min from the last dose, when recovery wascomplete, renal function was abolished by ligatingthe renal artery and vein and ureter of each kidney.Sixty minutes later administration of the samerange of doses of atracurium and gallamine wasrepeated to obtain dose-response curves in theabsence of renal function.

DrugsSolutions of drugs were made in NaCl

9 mg ml" ' and those of atracurium were acidifiedby addition of one drop of acetic acid 2 mol litre"'to 2-A ml of solution to maintain pH in theoptimum range of stability. Doses stated are those

34 BRITISH JOURNAL OF ANAESTHESIA

of the dibesylate salt of atracurium, the dibromideof dimethyltubocurarine, fazadinium and pan-curonium, the chloride of edrophonium andacetylthiocholine, the dichloride of alcuronium,suxamethonium and tubocurarine, the di-iodide ofdecamethonium, the hydrochloride of cimetidine,the tri-ethiodide of gallamine, the maleate ofmepyramine, the methylsulphate of neostigmine,the acid phosphate of histamine, the sulphate ofphysostigmine. A solution of burimamide wasobtained by suspending the drug in 0.9% sodiumchloride and acidifying with a minimal volume ofHC1 lmol litre"1.

Analysis of resultsStatistical analysis was with Student's t-tests.

RESULTS

Neuromuscular studiesBath concentrations of atracurium

0.5—1.0 ug ml" ', like those of other competitive

Atracurium 0.25 mg kg'1 iv

Carotid pressure

agents tubocurarine (0.5-1.0 ug ml l) and galla-mine (lOugml"1), caused blockade of the iso-lated chick biventer-cervicis preparation withoutproducing an initial contracture. The block wasantagonized by physostigmine 2 ug ml" 'and edro-phonium 2ugml~1 and reversed by washingout the bath medium and refilling with fresh Krebssolution. In contrast the blocking action of thedepolarizing drugs, suxamethonium 0.1 ugml"1

and decamethonium 0.05 ug ml" \ was precededby an initial contracture. Blockade was potentiatedby edrophonium but reversed by washing out.

In anaesthetized cats, i.v. doses of atracurium0.25 mg kg"1 were sufficient to cause completeneuromuscular blockade of the single twitch andtetanic responses of the gastrocnemius muscle andto arrest breathing (fig. 2). The results in cats, andthose in dogs and rhesus monkeys, are summarizedin table I. The dose estimated to produce 50%paralysis shows that, for each species studied, thetetanic response was significantly more sensitive to

200100

0Heart rate

Resp Artificial ventilation Resp

Gastrocnemius twitches 0.1 Hz

I " \\

Gastrocnemius tetanus 3 0 Hz

Nictitating membrane

Flu. z. i racing trom a cat anaesthetized with chJoralose. A dose of atracurium 0.25 mg kg" ' i.v. arrestedbreathing and abolished the single twitch and tetanic responses (30 Hz) of the gastrocnemius muscle toindirect stimulation. Effects on carotid arterial pressure, heart rate, vagal-induced bradycardia andcontractions of the nictitating membrane in response to sympathetic nerve stimulation were minimal.

S = sympathetic nerve stimulation, 10 Hz. V = vagal nerve stimulation, 10 Hz.

TAB

LE I

. Neu

rom

uscu

lar

bloc

king

eff

ects

of a

trac

uriu

m i

n gr

oups

of a

naes

thet

ized

cat

s, d

ogs

and

rhes

us m

onke

ys.

Max

imal

bl

ock

of t

he s

ingl

e tw

itch

es a

nd t

hete

tani

c co

ntra

ctio

ns (

30 H

z fo

r 1

s)is

exp

ress

ed a

s a

perc

enta

ge o

f ini

tial

val

ue.

Mea

n va

lues

are

quo

ted

(± S

EM

w

here

rel

evan

t).

Ast

eris

ks d

enot

e th

at p

oten

cy

Spec

ies

Cat

s (n =

6)

Dog

s(n

-4)

Rhe

sus

mon

keys

(n =

7)

in d

ogs

was

sig

nifi

cant

ly d

iffe

rent

fro

m

that

in

cats

Dos

ei.v

.(in

g kg

"1)

0.06

250.

125

0.25

0.5

1.0

2.0

4.0

0.06

250.

125

0.25

0.5

1.0

2.0

4.0

0.06

250.

125

0.25

0.5

1.0

2.0

4.0

% B

lock

054

±12

.999

±1.

4310

010

010

010

0

16±1

1.5

97 ±

2.0

100

100

100

100

100

lit

51 ±

3.5

99 ±

0.6

100

100

100

100

Sing

le

Ons

etm

ax e

ffect

(min

)

05.

0 ±

0.7

3.0±

0.8

0.9

±0.

050.

5 ±

0.04

2.2

±1.

80.

8 ±

0.4

4.0

±0.

34.

9 ±

0.8

2.3

±0.

31.8

±0.

31.

8±0.

21.

4 ±

0.4

1.1

±0.

25.

5t4.

6 ±

0.3

4.0±

0.5

1.0±

0.04

0.7

±0.0

90.

5 ±

0.04

0.5

±0.

2

twitc

h Full

reco

very

(min

)

011

±2.

229

±2.

545

±4.

161

±6.

28O

±5.5

>8

0

6.5±

1.1

22 ±

2.8

43±

5.5

60±

4.0

80±

5.7

88±

11.4

>4

1

23f

17 ±

3.0

32 ±

2.9

53 ±

5.7

80±8

.0>

96

>6

8

and

rhes

us m

onke

ys a

t th

e 1

%

Tet

anic

res

pons

e

% B

lock

3t93

±3.

210

010

010

010

010

0

80±

5.1

99±

0.3

100

100

100

100

100

20 ±

9.0

90±

1.8

100

100

100

100

100

Ons

etm

ax e

ffect

(min

)

2t5.

9 ±

1.0

2.1

±0.

50.

5 ±0

.04

0.4

±0.0

60.

4±0.

060.

3 ±

0.04

4.3

±0.

93.

4 ±

0.9

1.0±

0.2

1.1

±0.

21.

1 ±

0.2

1.1

±0.

30.

9 ±

0.2

2.1

±0.

23.

7 ±

0.3

1.8 ±

0.4

0.6±

0.07

0.4

±0.

050.

4±0.

120.

3 ±

0.08

leve

l (*

*).

tOne

(30

Hz)

Full

reco

very

(min

)

5t21

±1.

437

±2.

051

±3.

565

±4.

185

±5.

5>

84

14±

1.5

34 ±

2.4

56 ±

5.0

70 ±

3.6

93 ±

8.3

>10

0>

42

8±4.

225

±2.

039

±1.

856

±4.

079

±6.

7>

96

>6

8

resu

lt o

nly 50

% p

aral

ysin

g

dose

(m

g kg

i.v

.)

Sing

le

Tet

anic

twitc

h re

spon

se

0.12

9 0.

095

±0.0

08

±0.0

05P

<0.

01

0.08

0**

0.05

0**

±0.0

07

±0.0

02P

<0.

05

0.12

4 0.

083

±0.0

02

±0.0

08P

<0.

01

COLOC o •> *^ > n cIUM


neuromuscular block than the single twitch andthat atracurium was significantly more potent indogs than in either cats or rhesus monkeys. Thetime-course of neuromuscular blockade is alsoindicated in table I. The onset of maximum blockwas shorter with the greater doses whereas thetime taken to reach full recovery was more pro-longed. The time-course of the single twitch andtetanic contraction was not significantly differentwhen doses which produced the same degree ofblock of these responses were compared.

In each species studied blockade of the singleand tetanic responses of the gastrocnemius by

Resf} Artificial ventilation -,Resp

Gastrocnemius twitches 0.1 Hz

jastrocnemius tetanus 35 Hz

'65min

FIG. 3. Tracings from a cat anaesthetized with chloralose givenatracurium 4 mg kg" ' i.v. Approximately 70 min later, neos-tigmine 0.1 mg kg"' i.v., preceded by atropine0.15 mg kg" ' i.v. rapidly antagonized blockade of the singletwitch and tetanic responses (35 Hz) of the gastroencmius

muscles.

TABLE II . Rate constants for recovery of the peak tetaniccontraction of the gastrocnemius muscle using the first dose of eachdrug which caused complete neuromuscular block m groups ofrhesus monkeys. Mean values are quoted with SEM. Asterisksdenote rait constants significantly different from that of atra-

curium at the 5% (*) and 0.1% (***) levels respectively

Drug

Atracurium

Tubocurarine

Dimethyl tubocurarine

Gallamine

Alcuronium

Pancuronium

Fazadinium

Dose i.v.(mgkg"')

0.25

0.25

0.04-0.12

0.5-2.0

0.08-0.16

0.01-0.02

0.5

Rate constant(% per min)

9.2 ±0.5

4.4±0.6***

6.6±0.8*

7.8±0.8

6.8±1.7

10.6 ±0.3

8.2 ±1.4

atracurium was readily antagonized by neostig-mine 0.05 mgkg"1 i.v. and by edrophonium0.2 mg kg"' i.v. Figure 3 shows a typical antagon-ism by neostigmine in an anaesthetized cat.Recovery from atracurium was compared withthat from established competitive blocking agentsusing rate constants for recovery of the peaktetanic contraction in rhesus monkeys (table II).These rate constants show that recovery fromneuromuscular blockade by atracurium was signi-ficantly faster than that from tubocurarine anddimethyl tubocurarine, but was comparable torecovery from pancuronium and fazadinium.Although the rate constants for gallamine andalcuronium were less than that for atracurium, thedifferences were not significant.

Interaction with halothaneIn dose—response curves obtained from four

anaesthetized cats, the doses of atracurium es-timated to produce 50% neuromuscular paralysiswere 0.110 ±0.007 mgkg"1 i.v. in the presence of1% halothane and 0.142±0.016 mgkg"1 i.v. incontrols without halothane. The value for 2%halothane was 0.130±0.032 mg kg"' i.v.; control0.183 ±0.035 mg kg"' i.v. These results for both1 and 2% halothane were not significantly dif-ferent from the respective controls. Althoughthe mean time taken for recovery aftercomplete blocking doses of atracurium0.25-0.5 mgkg"1 i.v. was increased from22±2.6min to 32+3.3 min with 1% halothaneand from 24 ±3.6 min to 51 ±18.5 min with 2%halothane, differences from the controls did notachieve significance.

Cholinesterase inhibitionThe IC J 0 (umol litre"') values for inhibition of

human cholinesterase with acetylthiocholine assubstrate, for neostigmine, atracurium and knownneuromuscular blocking agents were: neostig-mine, <1; fazadinium, 2; pancuronium, 14; alcu-ronium, 55; atracurium, 56; tubocurarine, 140;gallamine, 900; dimethyl tubocurarine, 1000.

The inhibitory activity of atracurium was lessthan that of neostigmine, fazadinium and pan-curonium, but greater than that of tubocurarine,gallamine and dimethyl tubocurarine.

Autonomic and cardiovascular effectsRecordings from an anaesthetized cat (fig. 2)

show that the bradycardia induced by vagal nerve


stimulation, and the contraction of the nictitatingmembrane in response to sympathetic stimulation,were unimpaired after a dose of atracurium0.25 mg kg"' i.v. Dose—response curves for atra-curium obtained from the results in anaesthetizedcats, dogs and rhesus monkeys demonstrate thatthere is a wide separation between the dosesrequired for neuromuscular paralysis and thosethat inhibit autonomic mechanisms. For example,figure 4 shows that atracurium caused appreciablevagal blockade only at doses 16 times the fullneuromuscular paralysing dose in seven anaesthe-tized rhesus monkeys and that impairment ofsympathetic function was minimal. Results in sixanaesthetized cats and four anaesthetized dogswere similar.

In table III the doses required to produce 50%vagal block and 50% neuromuscular block havebeen estimated from the dose-response curvesobtained from six anaesthetized cats and the ratiosof these doses have been calculated. Results forknown competitive neuromuscular blockingagents, quoted for comparison, have been reportedpreviously (Hughes and Chappie, 1976a, b).There was a wide separation between the vagal andneuromuscular blocking doses for atracurium anddimethyl tubocurarine. For pancuronium and al-curonium, the separation between these doses wassignificantly less than that for atracurium and theseparation had virtually disappeared for tubocu-rarine. In contrast, vagal blockade with gallamineand fazadinium occurred with doses less thanthose required for neuromuscular paralysis.

The lack of cardiovascular effect is illustrated infigure 2, which shows a tracing from an anaesthe-tized cat given atracurium 0.25 mg kg"' i.v. Thesmall transient changes in arterial pressure andheart rate were probably an artefact associated

lOOi

80

60

40

20

Tetanus,(30 Hz)

.^Sympathetic

0O625 0.25 VODose (mg kgJ i v.)

FIG. 4. Dose-response curves showing blockade of ncuromus-cular and autonomic mechanisms by atracurium given to sevenanaesthetized rhesus monkeys (each point represents the meanof seven observations). O O = Percentage inhibition of thetetanic responses of the gastrocnemius muscle to indirectstimulation at 30 Hz for 1 s every 10 s; • • = percentageinhibition of the twitch responses of the gastrocnemius muscleto induce stimulation at 0.1 Hz; -fa—-^-= percentage in-hibition of the bradycardia responses to vagal stimulation at10-20 Hz for 10 s; A- • • = percentage inhibition of the vasop-ressor responses to carotid occlusion for 10 s. Vertical lines

indicate SEM.

with the bolus injection and the commencement ofartificial ventilation. The wide separation betweenthe neuromuscular and cardiovascular effects ofatracurium in six anaesthetized cats is shown infigure 5. Small insignificant increases in meanarterial pressure occurred after doses of

TABLE III . Dose ratios for 50% vagal block (ED50) and 50% neuromuscular (NM) block (EDi0) byatracurium in comparison with those for known competitive blocking agents in groups of anaesthetized cats.Mean values are quoted with SEM. Asterisks denote ratios significantly different from that of atracurium at

the 5% level (*)

Neuromuscularblocking agent

AtracuriumDimethyl tubocurarinePancuroniumAlcuroniumTubocurarineGallamineFazadinium

n

6444444

Vagal blockED50 (mg kg" ' i.v.)

3.08 ±0.760.50±0.070.08 ±0.010.25 ±0.050.19±0.010.56 ±0.070.29 ±0.09

NM blockED30(mgkg-'i.v.)

0.13±0.010.02 ±0.0030.02 ±0.0020.05 ±0.0070.13±0.010.83±0.130.69±0.15

vagal ED50

NM ED50

24.4 ±6.1324.6 ±4.465.2 ±0.80*5.1 ±131*1.5±0.15*0.7 ±0.12*0.5±0.11*


80

0.0625 4.0Q25 10Dose (pig kg"1 i.v.)

FIG. 5. Neuromuscular and cardiovascular effects of atra-curium in six anaesthetized cats measured at time of maximumcflfect (each point represents the mean of six observations).Percentage of control values of: O O = tetanic responses ofthe gastrocnemius muscle to indirect stimulation at 30 Hz for1 s every 10 s; • - - - • = twitch responses of the gastrocnemiusmuscle to indirect stimulation at 0.1 Hz; A- • -A = meanarterial pressure; < » • • • • = heart rate. Vertical lines indicateSEM. Asterisks denote values for heart rate and arterialpressure significantly different from controls at the 1%

level (*).

0.125-1 mg kg"1; heart rate was unchanged.Significant hypotension and slight bradycardiawere evident after 4 mgkg"1 i.v., but this dosewas 16 times that required for full neuromuscularparalysis. Similar results were obtained in sevenanaesthetized rhesus monkeys. In four anaesthe-tized dogs, atracurium 2 mg kg"' i.v. reducedmean arterial pressure to 53 ±20.2% of the controlvalue, but this dose was eight times that requiredfor full neuromuscular paralysis.

Experiments were carried out orvfour anaesthe-tized beagle dogs, allowed to recover fully afterreceiving excessive doses of atracurium. Each oftwo dogs received 2.5 mg kg" ' i.v., 10 times thedose required for full neuromuscular paralysis.Apnoea developed rapidly and artificial ventilationwas required for 76 and 79 min respectively. Heartrate was reduced by 14 and 23% of control and theP and T waves of the electrocardiogram were

reduced. The pupils were still responsive to lightand no salivation was observed. Both dogs made anuneventful recovery after termination of anaes-thesia. Each of the other two dogs, with animplanted aortic catheter for recording arterialpressure, received doses of atracurium 0.25, 0.5,1.0 and 2-Omgkg"1 i.v. (3.75 mgkg"1 total).These doses caused apnoea and artificial venti-lation of the lungs was required for a mean 23,48,66 and 87 min respectively. The correspondingperiod indicates the time required for recoveryafter each dose. Cardiovascular effects were mi-nimal after 0.25 and 0.5 mgkg"1 i.v., but thefollowing changes occurred after doses of 1 and2 mg kg"' i.v. (i.e. four and eight times the fullneuromuscular paralysing dose); in one dog meanaortic pressure was markedly reduced by 45 and68% of control respectively and heart rate wasslightly reduced by 15 and 7 %. The QRS complexof the electrocardiogram was reduced and the Twave enlarged. After the same doses in the otherdog, mean aortic pressure was reduced by 15 and10% respectively and heart rate was increased by20 and 21% of control. The P wave of theelectrocardiogram was enlarged. In both dogssalivation occurred. Although breathing was fullyrestored after the last dose of atracurium, neostig-mine 0.5 mg i.v. preceded by atropine 0.3 or0.6 mg i.v., was given to ensure adequate reversalof the neuromuscular blockade. Both dogs madean uneventful recovery after termination ofanaesthesia.

Haemodyncomc studiesIn each of five anaesthetized dogs i.v. doses of

atracurium 0.0625 and 0.125 mgkg"1 had noimportant effects on the circulatory variablesshown in table IV, including central venous pres-sure (not tabulated).

Doses of 0.25, 0.5 and 1.0 mg kg"' i.v. slightlyreduced phasic aortic flow, mean aortic pressure,heart rate, cardiac output and peripheral resist-ance. Maximum acceleration was reduced only by1.0 mg kg~' i.v. Central venous pressure was vir-tually unchanged; the T wave of the electro-cardiogram was slightly enlarged. These smallcirculatory effects persisted for 5-60 min.

A dose of 2.0 mg kg"' i.v. (eight times the fullneuromuscular paralysing dose) reduced phasicaortic flow, mean aortic pressure, heart rate,cardiac output, maximum acceleration and peri-pheral resistance. Central venous pressure was


TABLE IV. Effects of atracurium on phasic aortic flow, mean aortic pressure, heart rate, cardiac output, maximum acceleration andperipheral resistance in five anaesthetized open-chest dogs. Values at the time of maximum effect are expressed as mean percentages of

initial measurements (=100) with SEM. * Results in four dogs

Do»c(ing kg"

i.v.)

Phasic aortic flowDose

interval(min)

Initial(litre min~')

Effect(initial = 100) (initial

Mean aortic Cardiac Maximum Peripheralpressure Heart rate output acceleration resistance

100) (initial = 100) (initial = 100) (initial - 100) (initial = 100)

0.06250.1250.250.51.02.04.0*

204060759090

9.44 ±0.6510.54 ±0.5110.04+0.738.56 ±0.697.12±0.347.04 ±0.537.2 ±0.49

106±4.1105 ±2.499±3.896±6.093 ±2.477 ±6.461 ±6.5

100±1.6102±1.394 ±3.288±1.581 ±4.861 ±9.645 ±10.1

97±1.197 ±1.897 ±1.690±1.090±1.283±1.977 ±2.3

98 ±5.5107 ±4.589 ±3.486±6.196±7.174 ±8.369 ±5.4

104±4.1104 ±2.098 ±2.7

106±7.690±6.371 ±5.448±8.7

102±2.2101 ±3.7100±3.896±8.685 ±4.880±9.661 ±11.8

slightly increased; the T wave of the electrocar-diogram was enlarged. One dog died after 28 minand a postmortem revealed atrophy of the rightventricle. In the four surviving dogs the cir-culatory effects persisted for about 90 min exceptfor mean aortic pressure which, in two of the fourdogs, was still reduced after this period. The fourdogs received a further dose of 4.0 mg kg"1 i.v.which further reduced the circulatory variables;the T wave of the electrocardiogram was enlarged.All these dogs survived and were recovering for45 min when the experiments were terminated.

In other experiments atracurium, at bath con-centrations of 100 ug ml" ' , had no inotropic orchronotropic effects on spontaneously beatingguineapig atria. This concentration is greatly inexcess of the blood concentrations of atracuriumlikely to be encountered after full neuromuscularparalysing doses.

Histamine releaseEvidence of histamine release was obtained only

after administration of relatively large doses ofatracurium to anaesthetized dogs which are knownto release histamine readily. Doses of10 mg kg"' i.v. mepyramine and 15 mg kg"' i.v.burimamide or cimetidine were sufficient to abol-ish the decrease in mean arterial pressure inducedby histamine 20 or 40 ug kg"' i.v. in each of fourdogs (fig. 6). Such doses of the H,- and H2-receptor antagonists reduced, in part, the mo-derate hypotension caused by atracurium2 mg kg"' i.v. and greatly reduced the markedhypotension produced by tubocurarine0.4 mg kg" ' i.v. It should be noted that the dose ofatracurium used was eight times the neuromus-cular paralysing dose while that of tubocurarinewas, in fact, the paralysing dose in dogs.

20

10

0

I I Before histamine blockade

R ^ After histamne blockade

Tubocurarine0.4 mg kg"1 i.v.

rfetamine Atracurium20-40 pg kg^ i.v. 2 mg kg""i.v

FIG. 6. Effects of atracurium, tubocurarine and histamine onarterial pressure before and after blockade of histamine recep-tors in four anaesthetized dogs. Mean values are shown andvertical lines indicate SEM. Asterisks denote significant dif-ferences after histamine blockade for each drug at the 5% (*),2% (**) and 0.1% (***) levels respectively. (Full neuromuj-cular paralysing doses: atracurium 0.25 mg kg"'; tubocurarine

0.4mgkg~'.)

Changes in acid-base balanceDuring respiratory acidosis, induced by venti-

lation with 20% carbon dioxide, neuromuscularparalysis of both responses was greater than in thecontrol tests carried out before and after theacidosis, but the increase did not achieve statistical


significance (table V). However, recovery of boththe single twitch and tetanic responses was signi-ficantly longer during acidosis. Metabolic acidosis,caused by infusion of 8.4-12.0 mmol of hydro-chloric acid 0.75 mol litre"', significantly enhan-ced blockade of the single twitch and also signific-antly prolonged recovery of the single twitch andtetanic responses as indicated in table V.

Paralysis of both neuromuscular responses wassignificantly reduced and recovery significantlyshortened during respiratory alkalosis producedby increasing the tidal volume four-fold.Similarly, metabolic alkalosis, caused by infusionof 19.6-27.3 mmol of sodium bicarbonate1 mol litre"1, significantly reduced paralysis ofthe single twitch and significantly shortened re-covery of the tetanic response as shown in table V.

In these experiments effects on paralysis of thetetanically stimulated muscles were obscured bythe presence of complete blockade, but changes inrecovery times followed those of the contralateralmuscles stimulated by single shocks.

EliminationThe role of the liver was studied in four anaes-

thetized cats. From dose—response curves, thedoses of atracurium estimated to produce 50%neuromuscular paralysis were 0.119 ±0.013mgkg"1 via the jugular vein and0.121 ±0.016 mg kg"' via the hepatic portal vein;these values were not significantly different.Furthermore, the mean time taken for full re-covery after a complete blocking dose of0.25 mg kg" ' was similar when atracurium wasgiven through the hepatic portal vein(27.1 ±4.3 min) to that when given through thejugular vein (26.5 + 5.8 min).

The involvement of the kidneys was also studiedin four anaesthetized cats. From dose-responsecurves, the dose of atracurium estimated to pro-duce 50% neuromuscular paralysis, was not signi-ficantly changed after renal ligation, whereas thatfor gallamine was significantly reduced (fig. 7).Although the mean time taken for recovery aftercomplete blocking doses of atracurium0.25-0.5 mgkg"1 i.v. was increased from29 ±2.9 min to 43 ±9.2 min after renal ligation,the difference did not achieve significance.However, after complete blocking doses of gal-lamine 0.5-2.0 mgkg"1 i.v., renal ligation signi-ficantly prolonged recovery from 24 ±3.7 min to79±14.3min(P<0.05).

1.0

0.9

08

0.7

Q5

0.4

0.3

0.2

0.1

l i 9 a t i o n

Atracunum Gallamine

FIG. 7. Doses of atracurium and gallamine required to produce50% neuromuscular paralysis (ED50 mg kg" ' i.v.) before andafter bilateral renal ligation in four anaesthetized cats for eachdrug. Mean values are shown and vertical lines indicate SEM.Asterisk denotes result for gallamine significantly different

from control at the 5% level (*).

DISCUSSIONIn a previous study with dimethyl tubocurarine,we concluded that this drug has desirable pharma-cological properties, but there remains a need for aneuromuscular blocking agent with a similarhighly specific action at the neuromuscular junc-tion but of shorter duration (Hughes and Chappie,1976b). It seems from our pharmacological assess-ment, that atracurium may possess these desirableproperties.

The neuromuscular experiments demonstratedthat atracurium is a potent competitive neuromus-cular blocking agent. Paralysis was readily antago-nized by anticholinesterases and, similar to othercompetitive agents, blockade was enhanced byhalothane. The tetanic response was significantlymore sensitive to paralysis than the single twitch,but the time taken for recovery from equal block ofboth responses was similar. It has also beendemonstrated, in anaesthetized man, that the te-tanic response is a more sensitive index than thesingle twitch for the assessment of neuromuscularblockade (Hughes, Ingram and Payne, 1976).

TAB

LB V

. Eff

ects

in a

naes

thet

ized

cat

s of

res

pira

tory

and

met

abol

ic a

ddos

is a

nd a

lkal

osis

on

pH,

Pco

^P

o^

arte

rial

pre

ssur

e an

d ne

urom

uscu

lar p

aral

ysis

by

atra

curi

um. p

H,

Pco

2 a

ndP

o2

mea

sure

men

u sh

own

wer

e m

ade

at m

axim

um e

ffec

t of e

ach

dose

. Par

alys

is w

as d

eter

min

ed i

n bo

th g

astr

ocne

miu

s m

uscl

es s

tim

ulat

ed in

dire

ctly

, on

e w

ith

sing

le s

hock

s at

0.1

Hz

and

the

othe

r te

tani

call

y at

30

Hz

ever

y 10

s. M

ean

valu

es (w

ith

rang

es) f

or g

roup

s of

cat

s (n

= n

umbe

r of

cat

s) a

re s

how

n be

fore

(pr

e-co

ntro

t),

duri

ng, a

nd a

fter

(po

st-c

ontr

ol)

the

trea

tmen

tpe

riod

. A

ster

isks

den

ote

diff

eren

ces

betw

een

cont

rol

and

trea

tmen

t va

lues

sig

nifi

cant

at

the

5%

(*)

, 1%

(**

) an

d 0.

1% (

***)

lev

els

resp

ecti

vely

Tre

t tm

cm

Rei

pim

ory

addo

*ii;

inha

latio

n o

f 20

%ca

rbon

dio

xide

Met

abol

ic *

dd

om;

infu

uon

of

9.8

mm

ol o

fH

C1

0.75

mol

htr

e '

(8 4

-12)

Res

pira

tory

alk

alos

ls;

H y

perv

en d

lari

on,

four

-fol

d

Met

abol

ic a

lkal

osis

;In

fusi

on o

f 24

1 m

mol

of N

ijC

Oj

1 m

ol li

tre

'(1

9.6-

27.3

)

H 5 4 8 4

Atim

cunu

mst

anda

rddo

se I

.V(m

gkg"

1)

0.16

(0 1

25-0

24)

0.15

(0.1

25-0

.175

)

0 15

(0.1

25-0

.2)

0.14

(0 1

25-0

1?)

Pro

cedu

re

Pre

-con

trol

Ad

dos

il

Pos

t-co

ntro

l

Pre

-con

trol

Ad

don

i

Pos

t-co

ntro

l

Pre

-con

trol

Alk

alos

is

Pos

t-co

ntro

l

Pre

-coo

trol

Alk

alos

is

Poi

t-co

ntro

l

pH(u

nits

)

7.3

3*

"(7

.26-

7.36

)

6 85

(6.6

1-7.

00)

736'

"(7

-26-

7.48

)

7J5*

*(7

29-

7.39

)

6.82

(6.6

9-6.

93)

7J2*

**(7

.28-

7J7)

7.31

***

(7 2

6-7

35)"

7.63

(7.5

6-7

73)

7 28

***

(7.2

1-7.

35)

7.2

9"

(7.2

3-7J

3)

7.66

(7.5

5-7.

74)

7.3

2"

(7 2

7-7.

35)

(mm

Hg)

35

"(3

0-41

)

118

(79-

146)

39

"(3

0-51

)

37(2

8-50

)

36(2

7-12

)

37(2

8-44

)

44

"*

(35-

51)

16(1

3-21

)

41**

*(3

2-51

)

40(3

6-13

)

40(3

5-M

)

51(4

3-63

)

Po,

(mm

Hg)

281

(117

-153

)

293

(117

-103

)

277

(122

-120

)

172-

(103

-244

)

258

(157

-360

)

245

(188

-301

)

259

(66-

452)

230

(63-

482)

208

(68-

429)

295

(276

-309

)

297

(273

-315

)

267*

(227

-293

)

Art

eria

lpr

essu

re(m

mH

g)

117

(94-

142)

111

(60-

147)

80(4

8-11

0)

137*

(115

-155

)

108

(83-

135)

106

(96-

119)

121*

"(1

03-1

44)

82(6

1-10

7)

111"

*(8

3-13

3)

116

(95-

140)

106

(103

-113

)

109

(103

-116

)

Sing

le s

hock

sum

ulat

jon

Par

alys

is(%

)

25(0

-66)

63(3

0-99

)

36(0

-93)

29*

(4-6

1)

70(3

5-88

)

44*

(16-

73)

38**

(15-

67)

18(0

-»l)

51**

(9-9

2)

45*

(26-

59)

21(5

-41)

55*

(22-

95)

Rec

over

yti

me

(mm

)

8*(0

-14)

14(1

0-23

)

7*(0

-12)

9*(5

-13)

15(9

-21)

14(7

-21)

9*(7

-13)

6(0

-10)

11*

(7-2

1)

8(5

-12)

8(3

-13)

10(7

-13)

Tet

anic

stim

ulat

ion

Par

alys

is(%

)

90(7

5-99

)

97(9

5-10

0)

94(8

8-99

)

98(9

6-99

)

100

(99-

100)

96(8

6-10

0)

94(8

0-10

0)

85(5

3-1

00

)

94*

(68-

100)

98(9

5-10

0)

91(8

4-10

0)

100

(99-

100)

Rec

over

ytim

e(m

m)

20*

(13-

30)

28(1

9-38

)

21*

(15-

31)

20(1

5-25

)

29(2

3-35

)

20

"(1

6-26

)

19(1

2-26

)

18(9

-41)

22*

(11-

37)

21

"(1

7-27

)

13(1

0-17

)

19*

(15-

22)


Although atracurium was significantly morepotent in dogs than in either cats or rhesusmonkeys, the time-course of neuromuscular block-ade was similar throughout these species. Thisobservation may be important, since it has beenreported that the duration of action of somecompetitive blocking agents was longer in mon-keys, as in man, than in other species (Biggs, Davisand Wien, 1964; Mushin and Mapleson, 1964;Bamford et al., 1967; Busfield et al., 1968;Hughes, 1972; Hughes and Chappie, 1976b;Hughes, Payne and Sugai, 1976). In comparisonwith established drugs, it was shown that atra-curium was intermediate in its course of action.For example, in anaesthetized monkeys, recoveryfrom neuromuscular blockade by atracurium wassignificantly faster than recovery from tubo-curarine and dimethyl tubocurarine, but wascomparable to that of other available competitivedrugs with a medium duration of action.

Cholinesterase inhibition by atracurium is un-likely to be of importance since IC J0 for the humanenzyme corresponds to a concentration of ap-proximately 70ugml~1. This concentration isgreatly in excess of that likely to occur afterneuromuscular paralysing doses of atracurium.

An important feature of atracurium was thewide separation between doses required forneuromuscular paralysis and those which inhibitautonomic mechanisms. It is well established thatvagal blockade in man causes undesirable tachy-cardia and hypertension. In this respect, the vago-lytic effect of atracurium, like that of dimethyltubocurarine, was substantially less than that ofother competitive agents currently used in anaes-thetic practice. Unlike tubocurarine, the impair-ment of sympathetic function was minimal even atsupramaximal neuromuscular paralysing doses.However, some consider that inhibition of cate-cholamine uptake may contribute in part to thecardiovascular effects associated with administ-ration of pancuronium (Ivankovich et al., 1975;Docherty and McGrath, 1977). Dr L. G. Garlandof our laboratories has carried out a preliminarystudy of catecholamine uptake using perfused rathearts similar to that described by Iversen (1963)and used recently by Salt, Barnes and Conway(1980) for experiments with pancuronium ana-logues. It was found that atracurium partiallyblocked both uptake processes, but only at con-centrations in excess of those likely to occur afterneuromuscular paralysing doses. Uptake2 was

inhibited more strongly than Uptake,; the cor-responding ICj0 values were 20ngml~1 and100 ug ml ~' respectively. No doubt the absence ofeffect on the various autonomic mechanisms hascontributed to the cardiovascular stability as-sociated with atracurium. Significant hypotensionand slight bradycardia occurred only with doses 16times that required for full neuromuscular para-lysis in anaesthetized cats and rhesus monkeys andin dogs circulatory depression only became ofimportance at eight times this dose. In vitro atrialpreparations indicated the absence of direct ino-tropic and chronotropic effects. Indirect evidenceobtained from anaesthetized dogs suggests that thecardiovascular effects of atracurium were attribut-able mainly to histamine release; unlike tubo-curarine, such effects occurred only after doses ofatracurium eight times the full neuromuscularparalysing dose. However, since the hypotensiveaction of atracurium was not completely blockedby H]- and H2-receptor antagonists, sympatheticblockade may also play a minor role. The margin ofsafety with atracurium was also exemplified inthose experiments in which very large doses ofatracurium were given to anaesthetized dogswhich made an uneventful recovery from theneuromuscular blockade and anaesthesia.

In vitro studies, carried out by colleagues in ourCentral Analytical Laboratories, Dartford, haveshown that when atracurium is incubated at 37 °Cin buffers of appropriate pH, its non-enzymicdecomposition was at least three times faster whenthe pH was increased from 6.9 to pH 7.6. Analysisof the decomposition products by high perform-ance liquid chromatography verified that thisroute of inactivation was by "HofmannElimination". We may have demonstrated the"Hofmann" mechanism in vivo in anaesthetizedcats, since neuromuscular paralysis by atracuriumwas significantly reduced when the arterial pH wasincreased by respiratory and metabolic alkalosis;conversely, paralysis was significantly enhancedwhen the arterial pH was reduced by respiratoryand metabolic acidosis.

Experiments in anaesthetized cats indicate thatatracurium was not rapidly taken up by the liver,unlike a previous neuromuscular blocker,BW403C65, with which there was a three-foldreduction in its paralysing potency when thecompound was given through the hepatic portalvein (Hughes, 1972). Furthermore, the resultsafter renal ligation indicated that, unlike gal-


lamine, the kidneys are not a major route for theelimination of unchanged atracurium.

We conclude from this study that the pharmaco-logical properties of atracurium are of sufficientinterest to merit its evaluation as a neuromuscularblocking agent in anaesthetized man.

ACKNOWLEDGEMENTS

We are grateful to Dr J. E. Tateson and Miss M. Webb forcarrying out the cholinesterase inhibition experiments and toMr M. D. Shelley and Mrs J. S. Clark for skilled technicalassistance.

REFERENCES

Bamford, D. G., Biggs, D . F., Davis, M., and Parness, E. W.(1967). Neuromuscular blocking properties of stcreoiso-meric androstane-3,17,bisquaternary ammonium salts. Br.J.Pharmacol., 30, 194.

Biggs, R. S., Davis, M., and Wien, R. (1964). Muscle relaxantproperties of a steroid bis-quaternary ammonium salt.Experientia (Basel), 20, 119.

Busfield, D., Child, K. J., Clark, A. J., Davis, B., and Dodds,M. G. (1968). Neuromuscular blocking activities of somesteroidal mono and bis-quaternary ammonium compoundswith special reference to N,N'-dimethyl conessine. Br. J.Pharmacol., 32, 609.

Docherty, J. R., and McGrath, J. C. (1977). Potcntiation ofcardiac sympathetic nerve responses in vivo by pancuroniumbromide. Br. J. Pharmacol, 61, 472P.

EUman, G. L., Courtney, K. D., Andres, V., and Featherstone,R. M. (1961). A new and rapid colorimetric determination ofacetylcholinesterase activity. Biochem. Pharmacol., 7, 88.

Hughes, R. (1970). The influence of changes in acid-basebalance on neuromuscular blockade in cats. Br. J. Anaesth.,42, 658.

(1971). Continuous measurement of peripheral vascularresistance and circulatory function. Med. Biol. Eng., 9, 603.

(1972). Evaluation of the neuromuscular blocking pro-perties and side-effects of the two new isoquinoliniumbisquatemary compounds (BW252C64 and BW403C65).Br. J. Anaesth., 44, 27.

Chappie, D. J. (1976a). Effects of non-depolarizingneuromuscular blocking agents on peripheral autonomicmechanisms in cats. Br. J. Anaesth., 48, 59.

(1976b). Cardiovascular and neuromuscular effectsof dimethyl tubocurarine in anaesthetized cats and rhesusmonkeys. Br. J. Anaesth., 48, 847.

(1978). Application for the issue of a clinical trialcertificate to the Committee for Safety of Medicines, com-pound BW33A.

(1980). Experimental studies with atracurium, a newneuromuscular blocking agent. Br. J. Anaesth., 52, 238P.

Ingram, G. S., and Payne, J. P. (1976). Studies ondimethyl tubocurarine in anaesthetized man. Br.J. Anaesth.,48,969.

Payne, J. P., and Sugai, N. (1976). Studies on fazadiniumbromide (AH 8165), a new non-depolarizing neuromuscularblocking agent. Can. Anaesth. Soc. J., 23, 36.

Ivankovich, A. D., Miletich, D. J., Albrecht, R. F., and Zahed,B. (1975). The effect of pancuronium on myocardial contrac-tion and catecholamine metabolism. J. Pharm. Pharmacol.,27, 837.

Iversen, L. L. (1963). The uptake of noradrenaline by theisolated perfused heart. Br. J. Pharmacol., 21, 532.

Mushin, W. W., and Mapleson, W. W. (1964). Relaxant actionin man of dipyrandium chloride (M & B 9105A). Br. J.Anaesth., 36, 761.

Salt, P. J., Barnes, P. K., and Conway, C. M. (1980). Inhibitionof neuronal uptake of noradrenaline in the isolated perfusedrat heart by pancuronium and its homologues, Org. 6368,Org. 7688 and NC 45. Br. J. Anaesth., 52, 313.

Stenlake, J. B. (1979). Ions—cyclic nucleotids—cholinergy; inAdvances in Pharmacology and Therapeutics (ed. J. C.Stoclet), p. 303. Oxford and New York: Pcrgamon Press.

Wingard, L. B., and Cook, D. R. (1977). Clinical pharmacoki-netics of muscle relaxants. Clin. Pharmacoktn., 2, 330.

PHARMACOLOGIE DE L'ATRACURIUM: NOUVELAGENT DE BLOCAGE NEUROMUSCULAIRE

CONCURRENT

RESUME

L'Atracurium besylate, 2,2'-(3,ll-dioxo-4,10-dioxatri-decylene) -bis- [6,7-dimethoxy -1 - (3,4-dimethoxybenzyl) -2-mcthyl-l,2,3,4,-tetrahydroisoquinolinium] dibenzenesulph-onate, appartient a une nouvelle serie d'agentt de blocageneuromusculaire concurrent. Une dose intraveineuse de0,25 mg kg" \ produit une paralysie complete chez les chats,chiens et singes rhesus anesthcsies; la paralysie a etc de dureemoyenne et a ete immediatcment neutralisce par la nco-stigmine. Le blocage pneumogastrique ne s'cst produitqu'aprcs des doses de 8 a 16 fois superieures a la doseproduisant la paralysie neuromusculaire complete et les effetssur les mecanismes sympathiques ont ete minimaux.L'hypotcnsion et la bradycardie se sont manifestoes aprcs desdoses supramaximales de 4mgkg~ ' administrees par voieintraveincuse, et ccs effets, de meme que la depression circula-toire, sont probablemcnt attribuablcs au degagementd'histamine. Les etudes que Ton a faites in vitro ont montre quela decomposition non enzymatique de l'atracurium par"Elimination d'Hoffmann" est activee par l'augmentation dupH. In vivo, la paralysie neuromusculaire a etc reduite d'unemaniere significative lorsquc le pH arteriel a ete augmente. IIn'y a aucune indication permettant dc dire que le foie ou lesreins joucnt un role important dans le mctabolisme ct dansl'elimination du medicament inchange. Ces resultats pre-sentent un interct suffisant pour meriter que Ton precede arevaluation de l'atracurium sur rhomme ancsthesie.

DIE PHARMAKOLOGIE VON ATRACURIUM: EINNEUES, KONKURRENZFAHIGES

NEUROMUSKULARES BLOCKIERUNGSMITTEL

ZUSAMMENFASSUNG

Atracuriumbesylat, 2,2 '-(3.11 -dioxo-4,10-dioxatridecylen)-bis - [6,7-dimethoxy - 1 - (3,4-dimethoxybenzyl) - 2 - methyl-1,2,3,4-tetrahydroisoquinolinium] dibenzenesulphonat, isteincs aus einer neucn Serie konkurrenzfahiger neuro-muskularer Blockierungsmittel. Eine intravendte Dosis von0^5mgkg"' bewirkte vollige Lahmung bei narkotisienenKatzen, Hunden und Rhesusaffen; die Lahmung war von


mittlerer Dauer und konntc schnell von Neostigmin auf-gehoben werden. Vagus-Blockierung trat erst nach Dosen auf,die 8-16 mal grosser waren als die voile Dosis fur neuro-muskulire Lahmung, und die Auswirkungen auf sympatbischeMechanismen waren minimal. Hypotension und Bradykardiezeigten sich nach ubermaximalen intravenosen Dosen von4 mg kg" ', was zusammen mit Kreislaufdampfungen wahr-scheinlich auf Histaminfreigabe zuruckzufuhren war. Studienin vitro zeigten, dass der nichtenzymische Abbau vonAtracurium durch "Hoffmannsche Ausscheidung" durch eineErhohung von pH gefordert wurde. In vivo wurde neuro-muakulare Lahmung wesentlich reduziert, wcnn arterielles pHerhoht wurde. Es gab Anzeichen dafur, dass weder Leber nochNieren eine wesentliche Rolle im Abbau und der Ausscheidungder unveranderten Droge spiclen. Diese Ergebnisse sindinteressant genug, urn eine Beurteilung von Atracurium beinarkotisierten Menschen zu rechtfertigen.

LA FARMACOLOGIA DEL ATRACURIOM: UNNUEVO Y COMPETITIVO AGENTE DE BLOQUEO

MUSCULAR

sulfuro, forma pane de una nueva serie de competitivos agentcsde bloqueo ncuromuscular. Una dosis intravenosa dc0^5mgkg"' produjo una paralisis total en gatos, perros ymacacos de la India anestesiados; la paralisis fue de durationmedia y rapidemente contrarrestada por la neostigmina. Elbloqueo vagal tuvo lugar tan solo despues de administrar dosisde 8 a 16 veces mayores que la correspondiente a la dosis deparalisis neuromuscular total y los efectos sobre losmecanismos simpaucos fueron minimos. La hipotension y labradicadia fueron evidentes despues de dosis supramaximas de4 mg kg"' dc caracter intravenoso, y estos efectos, junto con ladepresion circulatoria, pueden seguramente atribuirse a laaparicion de histamina. Los estudios in vitro nan demostradoque la descomposicion no enzimica del atracuriom, mediante la"Eliminacion Hofmann", fue intensificada por el pH creciente.La paralisis neuromuscular in vivo se redujo de forma signifi-cative cuando el pH arterial se incremento. Hubo indicacionesde que el higado y el rinon no jucgan un papel importante en elmetabolismo ni en la eliminacion de drogas inalteradas. Estosrcsultados son dc suficiente interes como para merecer laevaluacion del atracuriom en el hombre anestesiado.

El atracuriom besilate, con composicion de 2,2-<3,11-dioxo-4,10-dioxatndecileno)-bis-[6, 7-dimetoxi-1-(3, 4-dimetoxiben-cilo)-2-metilo-l,23,4-tetrahidroisoquinoliniom] dibenceno de

the pharmacology of atracurium: a new …€¦ · the pharmacology of atracurium: a new competitive...

Documents