TikritJournal(fpharmaceuticalSciences 2005,l(2):63-75
C orrelation B etw een Serum LevelO fA tracurium A nd The D egree O fM uscle R elaxation W hen G iven By Tw o R egim ens ln A nesthetized Patients * H osam A l-deen S.M .saeed and **AliEsm aeelA l-snafi *DeptofPharm acology ,' Fikrit,college OfM edicin 1* D ept.ofPharm acology,Tikrit,college OfPharmacy Received 7/11/2005 :accepted28/12/2005
A bstract This study w as designed to investigate the afficacy of m ultiple intravenous
administrations(top up doses)ofatracurium afterbolus dose in comparison with intravenous infusion regarding the degree of m uscle relaxation and the safety as determ ined by the effects of the treatm ent regim ens on vital function.This study also designed to correlate between these factorsand serum atracurium concentration in b0th treatm entregimens. This study was perform ed in the Operating theatresof Tikritteaching Hospitalthrough the period from A ugust2003 tillSeptem ber2004.
Thetotalpatients'numberwas45.Theyweredividedintotwomajorgroups,groupI (22patients),group 11(23patientsl.theyare aqged 20-50 yearsofboth sexes.Asa conclusion, the continuous intra venous infusion of atracurium is highly recom m ended as a m ethod of adm inistration of this inter m ediate acting non depolarizing m uscle relaxant than the interm ittent top up doses. W here by the infusion m ethod the serum concentration ofthe drug sustained in therelaxantlevel in com parison w ith the sub-relaxantwhen the drug given by m ultiple top up doses. Thisstudy also showed that atracurium by both regim ens did not affect vital functions.How ever the operations that need anaesthetic hypertensive technique asophthalm ic and brain surgery.
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CorrelationBetween Sel'um LevelOfAtracurium AndTheDegreeOfM uscleRelaxa:ë---. l
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Figure 1 :Correlation betw een Serum LevelofAtracurium ng /m I. and TW R w hen Atracurium w as Given as a Bolus Dose 0.5 m g/kg. Follow ed by
5 Top up Doses According to PNS (+ve TW R)in patients ofgroup I Ng/m l
1200 1000 800 600 400 200 0 Figure 2 :Correlation betw een Serum Atracurium Levelng /m land
TW R after Using Atracurium as InitialBolus Dose (0.5 m g/kg) Follow ed by IV Infusion ata Dose of0.5 m g Ikg Ihour.
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Figure 3 :Correlation betw een Serum LevelofAtracurium ng /m I.and TO F w hen Atracurium w as Given as Bolus Dose 0.5 m g/kg.Follow ed
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Correlation BetweenSel' um LevelOfAtracurium And TheDegreeOfM uscleRelaxatit nn- --
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l
72
TikritJournalofpharmaceuticalSciences 2005,1(2):62-75
D iscussion This study was designed to testthe muscle xelaxwxxtatxwokutum w eotftowtty ,ixowuse t< isone ofthe m ostextensively used m uscle
zcvivryvtk zz/ yvcrtzfct, t7 gzx zzzb. yvzy' intensive care patientsasitsrelative safety in com parison w ith other currently used relaxants,itssuitableinterm ediateduration of actfon ,the refatlke fack of- the cum ulative property than other relaxants, its unique property in m etabolism thatitis notdepend on the liverorkidney,and itis availability.13 The selection of the age group forthe patientsincluded in the study based to avoid the continuous controversy in literatures that whether infants, children,young and elderly people do they have any differences in the pharm acokinetic or the pharm acodynam ic variables which can affect the results of such a study. So , there are m any physiologic changes that accompany the aging process,including decreases in total body water, increases in total body fat, decreases in hepatic and renalblood tlow and decreases in cardiac reserve which account for the altered responses of the elderly to muscle relaxants.A num ber of physiologic and anatom ic changes at the
neuromuscular junction also occur with aging. These include an increase the
distance between thejunctionalaxon and the m otor endplate, a tlattening of the folds of the m otor end plate,a decreased concentration and release ofACh from the preterm inal axon in response to a neural im pulse and a decrease in the number of receptors at the m otor endplate with a decrease in the am ount of ACh in each
vesiclein theprejunctionalaxon.(17,18lzgg developm ent of the
neurom uscular
junctionisnotcompleteatbirth (l9,20) jt .
is notapparent from olderstudieswhether the newborn is more sensitive than adults to non depolarizing m uscle relaxants.(21, 22) Therefore to avoid this interdigitating controversy , the age group ofthe patients selected forthisstudy lim ited to the young and m iddle age group people.The present study offer a strong evidence that the
method of adm inistration play a vitalrole to extend the duration of action so that efftqtofkbut qaxvbq txtevdq,d wv' d tïûsts obvious when continuous intra venous pvéozianog' kr v w- .sv wpsmv wyrynwwv,w relaxation through out surgery and anesthesia .Giving a bolus dose ofm uscle relaxantin the startw ith frequentm ultiple top up doses according to PN 5'signaês m ake the patient not fully relaxed and necessitate m ultiple doses to increase serum drug level.ln group 1,the duration of action of the bolus dose was 21.87 : i: 3.03 min.as determ ined by positive TW R and positive T3 by TOF and this render the state ofthe patient from fully relaxed proper surgical situation into partially relaxed patient that render the surgical w ork difficult with some bad anesthetic squealwhen the patientbecom e aw akened through out surgery, but the duration of action of the bolus dose extended by the starting of continuous intra venous inftlsion of atractlrium in group 11 of v
patients (85.00+4.53min.) and the PNS (TWR and Tl by TOF)wasnegative all the tim e through out the surgical work.ln the presentstudy the supplem entaltop up doses given to the patients in group 1 was
one fifth of the initialbolus dose (1/5) which was 0.1 m g Q g while the initial bolus dose was 0.5 m g/kg and this retleeted on the serum levelof atracurium in patients of group 1 which was tluctuating betw een relaxant and sub relaxant levels which detected by the
positivity ofthePNS (+veTWR and +ve T3 by TOF l,which isin agreementwith
M organ and M ikhail (13)w j,o m entjoned that atracurium has a rapid offset tim ea it becom es advisable to m onitor neuro m uscularconduction in orderto adm inister
thet top up dose) of drug before muscle relaxant has w orn off. In contrast, when the bolus dose is
followed by the intravenous infusion,it can m aintaln 95 percent of the block
twitch (no twitch visible on TOF stimulation) which in agreement with Gibson et. A land Ol-lara etal(22,23, 24) .
Correlation Between Serum LevelOfAtracurium And TheDegree OfM uscleRelaxation---
Furtherm ore, good correlation exists between the degree of neurom uscular blockade and the number of responses to TOF stimulation. W hen the 1st response is notdetectable,the degree ofneurom uscular
blockade (the depression in twitch tension) is 95 percent. W hen the three responses reappear,neurom uscularblockade is usually 60 to 80 percent. 613) The presence of no response in the TOF pattern norm ally
indicates suffkient relaxationtblockade k95%) in all-patients .This study also showed that atracurium by 170th rcgim ens did not affect vital functions. However the hypotension that produce4d by continuous intravenous infusion is benefk ial in som e operations that need anaesthetic hypertensive technique as ophthalm ic and brain surgery.As a conclusion, the continuous intra venous infusion of atracurium is highly recom m ended as a m ethod of adm inistration of this inter mediate acting non depolarizing m uscle relaxant than the interm ittenttop up doses. W here by the infusion m ethod the serum concentration of the drug sustained in the relaxant level in com parison with the subrelaxant when the drug given by m ultiple top up doses. References l-l-lughes R .,chapple D .l.Effects of non depolarizing neuro m tlscularblocking agents on peripheral autonom ic m echanism s.Brit.J.Anesth. l976' ,48:59-67. 2- Hughes R, Chapple DJ: The pharm acology of atracurium : A new competitive neurom uscular blocking agent. BrJA naesth :1981, .53:31. 3- Basta SJ, Ali HH , Savarese JJ, et a1. Clinical pharm acology of atracurium
besylate(BW 33A):A new nondepolarizing m uscle relaxant. Anesth A nalg .: 1982a;61:723-9 4-Gencarelli PJ, M iller 1417.Antagonism of .
ORG NC45(vecuronium)andpancuronium neuromuscularblockade by neostigm ine. Br JAnaesth :1982;54:53 6. 5- Bevan DR,Bevan JC, DonatiF:M uscle Relaxants in Clinical Anesthesia. Chicago, YearBook M edicalPublishers:1988. 74
6-W aud BE, W aud DR:Effects of volatiqe anesthetics on directly and indirect''.. .
stim ulated skeletalm uscle. A nesthesiolog): 1979;50:103. 7-AliH .H .,Savaresel.l.,Basta S.J.,Sunder
n.yGionfriddo M .Evaluation of cum ulativkt properties of new non depolarizing m uscle relaxant atracurium .Br it.l.A nestll: 1983, .55:107s-11s. 8- Durant NN .The physiology o:neurom uscular transm ission. ln Katz RL
(ed):MuscleRelaxants:Basic and Clinica
.
Aspects. Orlando, Florida, Grune & Stratton,1984. 9- W ard S, W right D . Com bined pharmacokinetic and pharm acodynam ic study of a single bolus dose of atracurium BrJAnaesth:1983, '55:358 . l0- Foldes FF,Deery A . Protein binding o1atracurium and other short acting neurom uscular blocking agents and their interaction w ith hum an cholinesterase. Br J A naesth:1983;55:318-48. 11-FisherDM ,CanfellPC, Fahey M R etal Elim ination of atracurium in hum ans: contribution of H ofm ann elim ination and ester hydrolysis versus organ-based elim ination.Anesthesiology:1985;65:6 l2- Lundy JS, Balanced anesthesia. M inn M ed:l926, .9:399. l3- M organ G .E., M ikhail M .S. Clinical Anesthesiology 2nd edition. Appleton & Lange.:19991;1:6-7. 14- Atracurium Besilate. M edical and pharm aceutical substances, British Pharm acopia Volum e 1.2001. 15- Feinstein A R:scientific standards in statisticalstudies.Science :1988;242:1257. 16- Riegelm an R K: Studying a Study and Testing a Test: H ow to Read the M edical Literature.Little,Brown, 1981. 17- Frolkis VV, M artynenko OA , Zam ostyan Vp.Aging of the neurom uscular apparatus.Gerontology :1976. ,22:244 . 18-M atteo RS,Backus W W , M cDanielDD et al.pharm acokinetics and pharmacodynam ics of d-tubocurarine and m etocurine in the elderly.A nesth Analg: 1985. ,64:23 . l9-Kelly SS,RobertDV . The effectofage .
on the safety factor in neurom uscular transm ission in the
responses during recovery of block from non-depolarizing muscle relaxants.Acta
isolated rat diaphragm .BrJ Anaesth:1977; 149:271. zo-churchill-Davidson H .C, W iseR.p.l-he
zl-Long G, Bachm an L.Neurom uscular blockade by d-tubocurarine in children.Anesthesiology:1967, .28:723. 22- Gibson FM ,M irakhur RK,Clarke RSJ,
AnaesthesiolScand :1987;31:655. 23-O'Hara DA , Fragen RJ, Shanks CA compariscm of visual and m easured train-of-four recovery after atracurium induced neuromuscular blockade using two anaesthetic techniques.Br J Anaesth:l986, ' 58:1300. 24- Bevan DR, Bevan JC, Donati F.pharmacokinetic principles of M uscle Relaxants in Clinical Anesthesia. Year
BradyMM Quantificationoftrain-of-four
Book,Chicago 1988;100.
response ofthe newborn infant to m uscle relaxants.can J Anaesth : l964. ,l1:1. 