Condizioni accompagnate da up o down
regolazione del recettore per Ach.
• Up regulation
Prolungata esposizione a
• Sclerosi multipla
• Sindr di Guillain Barrè
• Down regulation
• Myastenia gravis
• Avvelenamento da
• Avvelenamento da
Topologia dell’AchR visto dal lato sinaptico
Lee C. Structure, conformation and action of neuromuscular blocking drugs. Br J Anaesth 2001;
Sito H donatore
Canale ionico chiuso
Canale ionico aperto da 2 molecole di Ach
Legame dell’ACH al substrato enzimatico,
formazione dell’intermedio tetraedrale,
perdita della colina e
formazione dell’enzima acetilato ,idrolisi dell’enzima.
Il decametonio blocca
entrambi i siti anionici
Il vecuronium blocca
sia il sito anionico che
quello donante H di
un unico recettore
Una grossa molecola
2 siti anionici di 2
Modificazioni di forma;il decametonio preferisce una
struttura lineare ,mentre Ach e SCC si piegano per le
interazioni elettrostatiche fra i gruppi
funzionali(methonium,gruppo carbonilico, O estereo).BJA
• Prevenzione dell’idrolisi dell’Ach a livello
dei siti di trasmissione colinergica.
• Ne consegue che ACh rimane presente
nella giunzione nm per un periodo di
tempo + lungo e ciascuna molecola può
legarsi ripetutamente con il recettore e
quindi dare origine a maggiore corrente
alla placca terminale …….
Legame dell’inibitore reversibile edrofonio e
neostigmina,formazione dell’enzima carbamilato e
idrolisi dell’enzima carbamilato
Variabili farmacocinetiche medie dei principali
antichE. (da 99 a 102 ref)
V1(lt/kg) Vdss(Lt/kg) Cl
Recovery parameters following
(Reid J, Breslin DS,Mirakhur R, Hayes A.Neostigmine antagonism of rocuronium block during anesthesia with sevoflurane,isoflurane or
propofol.Can.Anesth.J. 2001:48 :351-55)
6 groups ,20 each
neo at tof 25%!
prop prop sevo sevo iso
cont stop cont stop cont stop
pts at 0.8 tof at 15 min
TOF vs time after neostigmine 40 µgr/kg (from T1
continued (1.25%)Baurain MJ, d'Hollander AA,Melot C, Dernovoi BS,Barvais
L.Effects of residual concentrations of isoflurane on the reversal of vecuronium induced
neuromuscular blockade.Anesthesiology 1991:71:474- )
Valori del tetanic fade (stimolazione a 50 Hz sn,100
Hz dx)dopo 15 min dalla somministrazione di
neostigmina 40 microgr/kg Baurain MJ, d'Hollander AA,Melot C,
Dernovoi BS,Barvais L.Effects of residual concentrations of isoflurane on the reversal of
vecuronium induced neuromuscular blockade.Anesthesiology 1991:71:474- )
• Insomma,continuare la soministraz del
vapore ritarda la ripresa nm anche dopo
Antagonism of atracurium or cisatracurium nm
blockade(at T1 10%)with various dosages of
neostigmine(fent,tps,N2O,isof anesth;Accel.) Naguib
M,Riad W.Dose response relationship for edrophonijm and neostigmine antagonism of atracurium
and cisatracurium induced neuromuscular block.Can.Anaesth.J 2000;47:1074-1081
Antagonism of atracurium or cisatracurium nm
blockade(at T1 10%)with various dosages of
edrophonium (fent,tps,N2O,isof anesth;Accel.) Naguib
M,Riad W.Dose response relationship for edrophonijm and neostigmine antagonism of atracurium
and cisatracurium induced neuromuscular block.Can.Anaesth.J 2000;47:1074-1081
Neostigmine vs edrophonium reversal
of atracurium or cisatracuriun nm,
Mean first twitch height vs time after administration of
various doses of neostigmine and edrophonium starting from
T 1 10% following atracurium and vecuronium Smith, CE, Donati F.,
Bevan DR.Dose‑Response Relationships for Edrophonium and Neostigmine as Antagonists of
Atracurium and Vecuronium neuromuscular Blockade.Anesthesiology 1989;71: 37-43.
Inspired enflurane concentration maintained at 0.5-1%
Dose response relationship of first twitch and TOF assisted
recovery 5 and 10 min. following administration of the
antagonist as a function of the dose of neostigmine and
edrophonium following atracurium and vecuronium. Smith, CE,
Donati F., Bevan DR.Dose‑Response Relationships for Edrophonium and Neostigmine as
Antagonists of Atracurium and Vecuronium Neuromuscular Blockade.Anesthesiology 1989;71: 3743.
Inspired enflurane concentration maintained at 0.5-1%
Effect on T1 of 2 doses of neostigmine and
edrophonium following atracurium and vecuronium
Smith, CE, Donati F., Bevan DR.Dose‑Response Relationships for Edrophonium and Neostigmine
as Antagonists of Atracurium and Vecuronium Neuromuscular Blockade.Anesthesiology 1989;71:
Inspired enflurane concentration maintained at 0.5-1%
atrac at 5'
atrac at 10'
vecu at 5'
vecu at 10'
Effect on Tof of 2 doses of neostigmine and edrophon
following atracurium and vecuronium Smith, CE, Donati F., Bevan
DR.Dose‑Response Relationships for Edrophonium and Neostigmine as Antagonists of Atracurium an
Vecuronium Neuromuscular Blockade.Anesthesiology 1989;71: 37-43.
Inspired enflurane concentration maintained at 0.5-1%
atrac at 5'
atrac at 10'
vecu at 5'
vecu at 10'
Ist twitch height vs dose 10 min. after
neostigmine or edrophonium administered at 90
or 99% block.
• La dose giusta di neostigmina è…………
• Meditate gente meditate………………
Relationship between dose of neostigmine and
percentage recovery during continuous infusion of
vecuronium(filled circle) or pancuronium(empty
• Profondità di blocco al momento della
• Presenza o meno di potenzianti nmb.
• Tipo di antagonista somministrato
• Tipo di miorilassante somministrato
• Dose dell’antagonista somministrato
• end point scelto;T1/Tc,Tof,ecc.
• E’ meglio somministrare gli antidoti quando la
ripresa nm è iniziata
• È meglio cessare la somministrazione degli
alogenati ( e monitorizzare la % et)…….
Effetti fisiologici della presenza
Pericoli degli AntiAchE: arresto
Bjerke, Richard J., MD; Mangione, Michael P.Asystole after
intravenous neostigmine in a heart transplant
Purpose: To describe a heart transplant recipient who developed asystole
after administration of neostigmine which suggests that surgical
dennervation of the heart may not permanently prevent significant
responses to anticholinesterases.
Clinical features: A 67-yr-old man, 11 yr post heart transplant underwent left
upper lung lobectomy. He developed asystole after intravenous
administration of 4 mg neostigmine with 0.8 mg glycopyrrolate for reversal of
the muscle relaxant. He had no history of rate or rhythm abnormalities either
prior to or subsequent to the event.
Conclusion: When administering anticholinesterase medications to heart
transplant patients, despite surgical dennervation, one must be prepared for
a possible profound cardiac response.
Pericoli degli ACHE:FA con rapida
Kadoya, TSA, Aoyama K, Takenaka I.Development of rapid atrial
fibrillation with wide QRS complex after neostigmine in a patient with
intermittent WPW stndrome.BJA 1999;83:815-818
1Department of Anaesthesia, Nippon Steel Yawata Memorial Hospital, 1-1-1 Harunomachi,
ABSTRACT: We report the case of a 67-yr-old man with intermittent Wolff-Parkinson-White
(WPW) syndrome in whom neostigmine produced life-threatening tachyarrhythmias. The patient
was scheduled for microsurgery for a laryngeal tumour. When he arrived in the operating room,
the electrocardiogram showed normal sinus rhythm with a rate of 82 beat min-1 and a narrow
QRS complex which remained normal throughout the operative period. On emergence from
anaesthesia, the sinus rhythm (87 beat min-1) changed to atrial fibrillation with a rate of 80–120
beat min-1 and a normal QRS complex. We did not treat the atrial fibrillation because the patient
was haemodynamically stable. Neostigmine 1 mg without atropine was then administered to
antagonize residual neuromuscular block produced by vecuronium. Two minutes later, the narrow
QRS complexes changed to a wide QRS complex tachycardia with a rate of 110–180 beat min-1,
which was diagnosed as rapid atrial fibrillation. As the patient was hypotensive, two synchronized
DC cardioversions of 100 J and 200 J were given, which restored sinus rhythm. No
electrophysiological studies of anticholinesterase drugs have been performed in patients with
WPW syndrome. We discuss the use of these drugs in this condition.
Pericoli degli antiAchE:broncocostrizione
Shibata O,Tsuda A,Makita T, Iwanaga S,Hara T,Shibata S,Sumikawa K.
Contractile and phosphadytilinositol responses of rat trachea to
response. Although a direct relationship was suggested between the increase in PI response and airway
smooth muscle contraction, there are no data regarding the effects of anti-ChE drugs on airway smooth
muscle. Thus, we examined the contractile properties and PI responses produced by anti-ChE drugs.
Methods: Contractile response. Rat tracheal ring was suspended between two stainless hooks in KrebsHenseleit (K-H) solution. (1) Carbachol (CCh), anti-ChE drugs (neostigmine, pyridostigmine, edrophonium)
or DMPP (a selective ganglionic nicotinic agonist) were added to induce active contraction. (2) The effects of
4-diphenylacetoxy-N-methyl-piperidine methobromide (4-DAMP), an M3 muscarinic receptor antagonist, on
neostigmine- or pyridostigmine-induced contraction of rat tracheal ring were examined. (3) Tetrodotoxin
(TTX) was tested on the anti-ChE drugs-induced responses. PI response. The tracheal slices were incubated
in K-H solution containing LiCl and 3[H]myo-inositol in the presence of neostigmine or pyridostigmine with or
without 4-DAMP, an M3 muscarinic receptor antagonist. 3[H]inositol monophosphate (IP1) formed was
counted with a liquid scintillation counter.
Results: Carbachol (0.1 mM), neostigmine. (1 mM), pyridostigmine (10 mM) but not edrophonium or DMPP,
caused tracheal ring contraction. 4-DAMP, but not tetrodotoxin, inhibited neostigmine and pyridostigmineinduced contraction. Neostigmine- or pyridostigmine-induced IP1 accumulation was inhibited by 4-DAMP.
Conclusions: The data suggest that anti-ChE drugs activate the M3 receptors at the tracheal effector site.
Purpose: Some anticholinesterases (anti-ChE) such as neostigmine and pyridostigmine but not edrophonium, stimulate
Schema delle afferenze
parasimpatiche a livello tracheale
Effetti contrattili di antiACHE,carbacolo e
dimetilfenilpiperazinio sugli anelli tracheali di ratto .
Shibata O,Tsuda A,Makita T, Iwanaga S,Hara T,Shibata S,Sumikawa K. Contractile and
phosphadytilinositol responses of rat trachea to anticholinesterase
Tramèr, M. R. Fuchs-Buder, T..Omitting antagonism
of nm block:effect on PONV and risk of residual
paralysis.A systematic review.BJA 1999;82:379-386
A systematic search (MEDLINE, EMBASE, Biological Abstracts, Cochrane
library, reference lists and hand searching; no language restriction, up to
March 1998) was performed for relevant randomized controlled trials. In
eight studies (1134 patients), antagonism with neostigmine or edrophonium
was compared with spontaneous recovery after general anaesthesia with
pancuronium, vecuronium, mivacurium or tubocurarine. On combining
neostigmine data, there was no evidence of an antiemetic effect when it was
omitted. However, the highest incidence of emesis with neostigmine 1.5 mg
was lower than the lowest incidence of emesis with 2.5 mg. These data
suggested a clinically relevant emetogenic effect with the
higher dose of neostigmine in the immediate postoperative
period but not thereafter.
Numbers-needed-to-treat to prevent emesis by omitting neostigmine
compared with using it were consistently negative with 1.5 mg, and
consistently positive (3–6) with 2.5 mg. There was a lack of evidence for
edrophonium. In two studies, three patients with spontaneous recovery after
mivacurium or vecuronium needed rescue anticholinesterase drugs because
of clinically relevant muscle weakness (number-needed-to-harm, 30).
Omitting neostigmine may have a clinically relevant
antiemetic effect when high doses are used. Omitting
Risk of omitting neostigmine….
• Residual paralysis!!!
Nelskylä, K.; Yli-Hankala, A.; Soikkeli, A.; Korttila, K.
Noestigmine with glycopirrolate does not increase the incidence
and severity of PONV in outpatients undergoing gynecological
We studied 100 healthy women undergoing outpatient gynaecological laparoscopy in
a randomized, double-blind and placebo-controlled study to evaluate the effect of
neostigmine on post-operative nausea and vomiting (PONV). After induction of
anaesthesia with propofol, anaesthesia was maintained with sevoflurane and 66%
nitrous oxide in oxygen. Mivacurium was used for neuromuscular block. At the end of
anaesthesia, neostigmine 2.0 mg and glycopyrrolate 0.4 mg, or saline, was given i.v.
The incidence of PONV was evaluated in the postanaesthesia care unit, on the ward
and at home. The severity of nausea and vomiting, worst pain, antiemetic and
analgesic use, times to urinary voiding and home readiness were recorded. During
the first 24 h after operation, 44% of patients in the neostigmine group and 43% in the
saline group did not have PONV. We conclude that neostigmine with glycopyrrolate
did not increase the occurrence of PONV in this patient group.
Watcha MF, Safavi FZ, McCulloch DA, et al.
Effect of antagonism of mivacurium-induced
neuromuscular block on postoperative emesis
in children. Anesth Analg 1995; 80:713-7.
Incidenza di PONV nella PACU
edrophonium 1 mg/kg +
Ding Y,Fredman B, White PF.Use of mivacurium
during laparoscopic surgery:effect of reversal
drungs on postoperaive recovery.Anesth Analg
outpatient laparoscopic tubal ligation
60 healthy, nonpregnant women.
midazolam / fentanyl/tps
succ 1 mg/kg (Group I) vs mivacurium 0.2 mg/kg
(Groups II and III)
• Anesthesia maintained with isoflurane (0.5%-2%
• Muscle relaxation maintained in all three groups with
intermittent bolus doses of mivacurium, 2–4 mg, IV.
• In Group III, residual neuromuscular block reversed
with neostigmine 2.5 mg +glycopyrrolate, 0.5 mg,
Effetti collat dello studio di Ding et al.
miva/miva/ no antag
Boeke AJ, de Lange JJ, van Druenen B, Langemeijer
JJM. Effect of antagonizing residual neuromuscular
block by neostigmine and atropine on postoperative
vomiting. Br J Anaesth 1994; 72:654-6.
• 80 patients undergoing outpatient surgery
• allocated randomly to two groups: in group A
residual neuromuscular block was antagonized
with a mixture of neostigmine 1.5 mg and
atropine 0.5 mg; in group B spontaneous
recovery was allowed.
• patients assessed after operation in hospital
and 24 h after discharge.
Boeke AJ, de Lange JJ, van Druenen B, Langemeijer JJM.
Effect of antagonizing residual neuromuscular block by
neostigmine and atropine on postoperative vomiting. Br J
Anaesth 1994; 72:654-6.
• inguinal hernia repair & stripping of the major
saphenous vein of one leg.
• no premed
• atropine 0.5 mg i.v.
• anaesthesia : tps 5–8 mg/kg + fent 2 µg/kg
• vecu.0.1 mg kg-1.
• 100% oxygen * 3 min
• IPPV 66% N2O/ haloth. 0.5%
Incid.di PONV nello studio di
Boeke et al.
Boeke et al.;risultati e conclusioni.
• We found a significant difference (P < 0.05) in
requirements for antiemetic therapy with a smaller need
in the group which received neostigmine (in group A four
of 40 patients received an antiemetic compared with 12
in group B).
• no significant difference in frequency of nausea or
vomiting between the two groups.
• The incidence of postoperative nausea was 14 in group
A and 18 in group B and the number of patients with
postoperative vomiting was 10 in group A and 15 in
• In conclusion, as there was an increase in the number
of patients requiring antiemetics in group B compared
with group A (P < 0.05), the results of this study may
suggest an antiemetic effect of neostigmine.
Kao YJ, Mian T, McDaniel KE, et al. Neuromuscular
blockade reversal agents induce postoperative nausea
and vomiting [abstract] Anesthesiology 1992;
Minilap per PPTL.Tps/succi/iot/fent/isof/N2O
Atrac 0.15 mg/kg.
A 0.15 micrG/kg + edroph 1
A 0.15 micrg/kg+neo 0.05
A 0.15 icrg/kg+pirido 0.25
Antagonism of mivacurium
• Savarese et al:neo accelerates recovery form
mivac by 40%
• Kaoo:neo may delay complete recovery from
deep mivac block
• Baurain,Naguib:neo accelerates recovery fron
mivac block by 7-9 min vs 15-17 spont.
• Devcic:mean recovery accelerated by neo,but
Antagonism of deep mivacurium
T1 T1 T1 TOF TOF TOF
25% 50% 75% 25% 50% 75%
• Enzymatic Antagonism of Mivacurium-induced
Neuromuscular Blockade by Human Plasma
Cholinesterase. Anesthesiology. 83(4):694-701,
Fisher, Dennis M. ,Szenohradszky, Janos , Hart,
Paul S. .Antagonism of Residual Mivacurium
Blockade: Setting the Record Straight.
Anesthesiology. 84(6):1527-1528, June 1996.
• . Szenohradszky, Janos ,Fogarty, Declan
Kirkegaard-Nielsen, Hans , Brown, Ronald,
Sharma, Manohar L,Fisher, Dennis M. Effect of
Edrophonium and Neostigmine on the
Pharmacokinetics and Neuromuscular Effects
of Mivacurium. Anesthesiology. 92(3):708-714,
• a muscarinic presynaptic inhibition of glutamatergic
afferents, similar to how it has been described in the
neostriatum. An important prerequisite for the
effectiveness of neostigmine is a tonic cholinergic
Comportamento suggerito per l’antagonismo dei
miorilassanti a lunga e media durata di azione secondo
le risposte al Tof
Finchè almeno 1 o 2
Szenohradszky, Janos, M.D.*; Fogarty, Declan, M.D.†; Kirkegaard-Nielsen, Hans, M.D.‡; Brown,
Ronald, B.S.§; Sharma, Manohar L., Ph.D.ï÷; Fisher, Dennis M.,effect of edrophonium and
neostigmine on the pharmacokinetics amnd neuromuscular effectsof mivacurium .
Background: Previous studies demonstrated that both edrophonium and
neostigmine affect mivacurium's pharmacokinetics, thereby potentially affecting its recovery
profile. However, those studies were not clinically relevant because mivacurium was still infused
after the antagonists were given. In the present study, the authors gave antagonists (or placebo)
after discontinuing a mivacurium infusion, thereby obtaining data that are more clinically relevant.
Methods: In 18 patients, mivacurium was infused at 10 mg × kg-1 × min-1 for 40 min, the
infusion was discontinued for 15 min and then restarted at the same rate for another 40 min.
Patients were randomized to receive 500 mg/kg edrophonium, 50 mg/kg neostigmine, or saline at
discontinuation of the second infusion; all subjects received 1 mg atropine. Plasma was sampled
during the final 10 min of each infusion to determine steady state mivacurium concentrations and
for 15 min after each infusion. Twitch tension was recorded. Mivacurium concentrations after
each of the two infusions were compared.
Results: After discontinuation of the second infusion, mivacurium concentrations were larger
than those after the first infusion at 2 min with edrophonium and at 2, 4, and 7 min with
neostigmine. With both neostigmine and edrophonium, twitch tension recovered after infusion #2
more rapidly than after infusion #1; however, the magnitude of this effect was small.
Conclusion: Edrophonium transiently slows the rate at which mivacurium concentrations
decrease; this is consistent with our previous findings. Neostigmine has a similar, although
longer, effect. Despite altering mivacurium's elimination characteristics, both drugs facilitate
neuromuscular recovery, although their benefit is small.
Atropine and glycopyrrolate have muscarinic blocking (parasympatholytic)
effects, but no activity at nicotinic receptors. They are given to prevent the
cardiovascular changes induced by the anticholinesterases. Atropine has a
rapid onset of action (approximately 1 min) and a duration of 30–60 min, and it
crosses the blood-brain barrier. Glycopyrrolate has a slower onset (2–3 min)
and approximately the same duration of action, but does not cross the bloodbrain barrier. Atropine has been associated with an increased incidence of
memory deficit after anesthesia compared with glycopyrrolate. It is desirable to
give an anticholinergic with a faster onset of action than the
anticholinesterase, because it is easier to manage transient tachycardia than
bradycardia. Thus, when edrophonium is given, atropine is preferred. Doses of
7 mg/kg atropine were recommended for edrophonium 0.5 mg/kg, but at least
one study has shown that this dose of atropine might be too low. Bradycardia
is more frequent with an opioid-nitrous oxide anesthetic, and a dose of 10–15
mg/kg may be more appropriate in certain circumstances. Because of the
variability in atropine requirement, it is recommended that atropine be given
either before edrophonium or at the same time but slowly.
Neostigmine has a much slower onset of action, so that either atropine or
glycopyrrolate may be given as an anticholinergic. The simultaneous
administration of atropine and neostigmine leads to an initial tachycardia
because of the more rapid action of atropine, followed 10–20 min later by a
bradycardia. Atropine requirements are greater with neostigmine than with
equipotent reversal doses of edrophonium. The dose of atropine required is
approximately half that of neostigmine; i.e., 40 mg/kg neostigmine requires
about 20 mg/kg atropine. Because the time course of action of glycopyrrolate
matches that of neostigmine more closely, simultaneous administration of both
drugs results in more stable heart rates over time. A dose equivalent to one
Factors Affecting Reversal
Intensity of Block
The depth of neuromuscular blockade at the time of the administration of reversal agents has a profound influence on their effect. The
time to a specific endpoint, such as 95% T1 or 0.7 TOF, is inversely related to the T1 when the reversal agent is administered. The data
obtained with pancuronium, dTC, atracurium, vecuronium, or doxacurium, showed a large increase in the recovery time if T1 was < 10–
20% of control when neostigmine was given. Similarly, reversal of a profound atracurium or vecuronium blockade proceeded more slowly
than reversal of less intense block. In other words, the dose response of reversal agents is shifted to the right in the presence of profound
blockade. However, the magnitude of this shift is greater with either edrophonium or pyridostigmine than with neostigmine.
An additional question is whether it is preferable to give the reversal agent when profound block is present or to wait for some
spontaneous recovery before antagonizing the block. Those who have studied nostigmine, the agent of choice to reverse deep blockade,
agree that administering the reversal agent accelerated recovery compared with spontaneous recovery. However, it appears that giving
neostigmine early offers no advantage to waiting for 10–25% spontaneous recovery, and the results might be less predictable with the
early administration of reversal agents.
Dose of Reversal Agent
When given at 10% spontaneous T1 recovery (the twitch height most frequently tested), neostigmine, pyridostigmine, and edrophonium
produced larger effects when the dose was increased. The ceiling effect demonstrated during in vitro experiments does not appear to be
present for the doses used clinically, i.e. neostigmine up to 0.04 mg/kg, pyridostigmine up to 0.2 mg/kg, and edrophonium 1 mg/kg. In the
reversal of an intense vecuronium block, a second dose of neostigmine (0.07 mg/kg) did not result in further recovery, suggesting that the
ceiling had been reached. Although the time required to reach a given effect is reduced if a large dose is given, this does not mean that a
large dose of reversal agent is always indicated. When spontaneous recovery is almost complete, large doses might, at best, be
unnecessary. For example, when used to reverse 50% T1 blockade produced by vecuronium, neostigmine 5 mg produced recovery to a
TOF of 0.7 in 1.1 min compared with 1.2 min after neostigmine 2.5 mg. Clearly, the larger dose was unnecessary, and the smaller dose
produced adequate and rapid recovery with the potential for fewer cardiovascular effects.
Choice of Relaxant
The neuromuscular block produced by gallamine is reversed more slowly by neostigmine than is that of pancuronium or dTC. Similar
conclusions have been reached when the neostigmine was administered as repeated small doses (0.25 mg) every 3 min or by a single
large bolus (0.05 mg/kg). Doses required to produce a desired level of recovery within a given time after the administration of reversal
agents are less for atracurium and vecuronium than for dTC or pancuronium (). As discussed earlier, the differences in reversal between
the long- and intermediate-acting relaxants are likely due to a faster rate of spontaneous recovery for the latter. Small differences in
reversibility have been described among the long-acting and short-acting agents, but these differences appear to be clinically
Bolus versus Infusion
Differences in the recovery of neuromuscular function when reversal agents were administered either during the course of a relaxant
infusion or after bolus doses have been discussed. Kopman demonstrated that when reversal agents were given within 2 min of
discontinuation of infusions of atracurium, vecuronium, or pancuronium, recovery was slower than after bolus injections. Under these
conditions, neostigmine (0.05 mg/kg) produced more rapid and complete recovery than did edrophonium (0.75 mg/kg). In particular,
Kopman found that edrophonium did not produce TOF > 0.7 at 20 min after its administration to patients receiving a pancuronium infusion
even at a dose of 1 mg/kg. No differences in recovery were demonstrated between atracurium or vecuronium infusions after either
neostigmine or edrophonium.
Engbæk et al. demonstrated that when an infusion of atracurium was used to maintain a very intense block producing greater than
100% depression of T1, reversal after discontinuation of the infusion was slow. When neostigmine was administered at different levels of
posttetanic count, the time to reach TOF > 0.7 depended on the degree of block. Total recovery time, spontaneous and after reversal,
was not reduced by the earlier administration of neostigmine. Slower spontaneous recovery has been demonstrated previously after
vecuronium infusions during surgery, presumably because of equilibration of drug concentrations in the circulation and peripheral tissues.
After prolonged infusions, recovery becomes dependent on elimination and metabolism of the relaxant rather than redistribution. The
differences between vecuronium and pancuronium then tend to disappear because they have similar terminal half-lives.
Recently, prolonged neuromuscular blockade has been reported after long-term (2–6 days) administration of vecuronium to two
critically ill patients. In this situation, the persistent paralysis was considered to be due to accumulation of the vecuronium metabolite 3desacetylvecuronium. This metabolite, which is as potent as the parent compound, was not eliminated because the patients had
developed renal failure. Such a situation is unlikely to occur during anesthesia.
Thus, it appears that the duration of action and reversal of neuromuscular blocking drugs is influenced both by the choice of agent and
by the method of administration.
Infants and Children
The consequences of persistent neuromuscular paralysis are considered to be more serious in children, especially in infants, than in adults. In
general, spontaneous recovery from neuromuscular blocking drugs is more rapid in children aged 1–10 yr than in adults. Recovery in infants is slower
than in children for pancuronium, atracurium, and vecuronium. In infants, vecuronium appears to behave like a longer-acting drug. The reason for the
slower recovery probably is related to the larger volume of distribution of the drugs in infants. Consequently, some reduction in the rate of recovery
might be expected after reversal.
As in adults, recovery after reversal is dependent on the level of paralysis when the anticholinesterase is given. Recovery is more rapid after
atracurium than after the longer-acting alcuronium. When the reversal agent is administered at a fixed point of recovery, reversal occurs more rapidly
and the dose of reversal agent required to produce equivalent effects is less in infants and children than in adults. Dose-response curves for
neostigmine, administered during continuous infusion of dTC to maintain 90% block, demonstrated that doses producing 50% reversal were 13.1
mg/kg in infants and 15.5 mg/kg in children compared with 22.9 mg/kg obtained in a similar study in adults. The difference in dose requirement could
not be explained by different volumes of distribution for neostigmine. When fixed doses of neostigmine or edrophonium were administered at 90% T1
depression during recovery from a bolus dose of pancuronium, recovery was achieved more rapidly in infants and children than in adults; this has been
confirmed after the administration of neostigmine to infants, children, and adults given bolus doses of vecuronium.
Thus, reversal of neuromuscular blockade in infants and children should be expected to occur at least as rapidly as in adults. In one study examining
neuromuscular activity of children on arrival in the recovery room, the authors were unable to demonstrate weakness in patients who had received
pancuronium, atracurium, or vecuronium during anesthesia. This is in marked contrast to the numerous studies that show a high incidence of
incomplete recovery in adults.
The duration of action of most nondepolarizing relaxants is prolonged in the elderly person, probably as a result of age-related decreases in hepatic
metabolism and renal clearance. Consequently, the action of pancuronium, dTC, metocurine, and vecuronium is prolonged. As a result, the reversal of
these nondepolarizing relaxants may be impaired. Atracurium, because of metabolism by Hofmann elimination and enzyme hydrolysis, is not affected.
Such a delay was reported when neostigmine was administered in a dose of 0.04–0.05 mg/kg 30 min after the last dose of pancuronium but not after
dTC. It was observed that the duration of antagonism of metocurine infusion block was prolonged in the elderly patient. Thus, it appears that although
the elderly person may demonstrate impaired clearance of both relaxants and reversal agents, the speed and extent of recovery is no different between
young and old if the reversal agent is given at the same level of neuromuscular blockade.
Several drugs have been shown to potentiate neuromuscular blocking drugs. These include inhalational, intravenous, and
Clinical strategies for the reversal of muscle relaxants should be based
on pharmacologic principles. In particular, the choice of agent and dose
should be made according to the intensity of the block to be reversed.
Reversal agents should always be given after the use of muscle relaxants
unless full recovery of neuromuscular activity is confirmed. Because small
degrees of block are difficult to assess clinically, reversal agents usually are
given to all patients. Neostigmine is preferred for intense blocks, but the
advantages of speed of onset and reduced cholinergic effects of
edrophonium make it suitable, in the appropriate dose, when return of
neuromuscular activity is well established. One suggested regimen using
these principles is shown in . It should be recognized that these
recommendations are based on response of the adductor pollicis to TOF
ulnar nerve stimulation. No attempts have been made to differentiate
between differences in the required doses of anticholinesterases necessary
to reverse block produced by the intermediate- and longer-acting muscle
relaxants. Using these doses, it is expected that recovery of neuromuscular
activity will occur within 10 min. However, this must be confirmed by clinical
testing when the patient has recovered from anesthesia.
Salib, Y. M., FFARCSI; Donati, F., PhD FRCPC; Bevan, D. R., MRCP FFARCS
From the Departments of Anaesthesia, Royal Victoria Hospital and McGill University, 687 Pine Avenue West,
Address correspondence to: Dr. F. Donati, Department of Anaesthesia, Royal Victoria Hospital, 687 Pine
Avenue West, Suite S5.05, Montreal, Quebec, Canada H3A 1A1.
Accepted for publication June 1, 1993.
ABSTRACT: The purpose of this study was to determine the optimal dose of edrophonium needed for successful
antagonism (train-of-four ratio, or T4/T1 > 0.7) of vecuronium-induced blockade when all four twitches were
visible in response to indirect train-of-four (TOF) stimulation. Forty patients, scheduled for elective surgical
procedures not exceeding 120 min, received vecuronium, 0.08 mg × kg-1, during thiopentone-N2O-isoflurane
anaesthesia. Train-of-four stimulation was applied every 20 sec and the force of contraction of the adductor
pollicis muscle was recorded. Increments of vecuronium, 0.015 mg × kg-1, were given as required. At the end of
surgery, and provided that neuro-muscular activity had recovered to four visible twitches, edrophonium, 0.1 mg ×
kg-1, was given. Two minutes later, edrophonium, 0.1 mg × kg-1, was given if T4/T1 did not reach 0.7. After
another two minutes, edrophonium, 0.2 mg × kg-1, was given if T4/T1 did not reach 0.7 or more. Finally, if T4/T1
was still < 0.7, a dose of 0.4 mg × kg-1 was given. Seventeen patients (42.5%) required 0.1 mg × kg-1 of
edrophonium for successful reversal, sixteen patients (40%) needed a cumulative dose of 0.2 mg × kg-1 and six
patients (15%) required 0.4 mg × kg-1. Only one patient received 0.8 mg × kg-1. There was a good correlation
between T4/T1 two minutes after the first dose of edrophonium and pre-reversal T4/T1 (r = 0.6; P = 0.00014). All
patients with pre-reversal T4/T1 > 0.23 required at most 0.2 mg × kg-1 of edrophonium for successful reversal.
We conclude that when all four twitches are clearly visible following train-of-four stimulation, small doses of
edrophonium (0.1–0.2 mg × kg-1) might be sufficient to antagonize vecuronium neuromuscular blockade.
Anticolinesterasici e dolore
Dougherty, Patrick M., Ph.D.*; Staats, Peter S., M.D.†
* Associate Professor, Departments of Neuroscience and Neurosurgery.
† Associate Professor, Department of Anesthesiology and Critical Care Medicine.
Received from the Departments of Neuroscience and Neurosurgery and the Department of Anesthesiology and
Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland. Submitted for
publication November 6, 1997. Accepted for publication April 30, 1999. Supported by the National Insitutes of
Health (grant NS-32386; project 2), Bethesda, Maryland.
Address reprint requests to Dr. Dougherty: Department of Neurosurgery, The Johns Hopkins University School
of Medicine, 600 North Wolfe Street, Meyer 5-109, Baltimore, Maryland 21287-5354. Address electronic mail to:
KEY WORDS: Dorsal horn; primary afferents; spinal cord
SYSTEMIC analgesics and conservative therapies are effective in controlling chronic pain for the majority of
patients. However, many other patients, such as those with advanced head and neck carcinoma and those with
neuropathic pain, require more aggressive therapy to directly modulate pain transmission in the central nervous
system. Reversible methods of aggressive therapy in the spinal cord include electrical stimulation procedures and
intrathecal delivery of analgesics by implanted pumps, both of which are finding ever-expanding roles in pain
control. Of these, long-term intrathecal drug therapy is likely to show the largest near-term expansion because the
numbers of agents approved for this route of administration are likely soon to increase substantially. Moreover,
drug therapy itself will change as treatments using microsome drug encapsulation and novel suspension media
are introduced. Further on the clinical horizon is intrathecal cell implantation for the relief of chronic pain. The goal
of this review is to update the reader regarding each of these pending advances in intrathecal drug therapy for
• In ogni caso testa la ripresa clinica prima
di inviare il paziente al reparto!!!
Domande per ECM
• La dose di neostigmina(somministrata al
T1 10%) necessaria per antagonizzare
completamente il blocco neuromuscolare
da atracurium e cisatracurium è di:
• 0.2 mg/kg
• 0.02 mg/kg
• X 0.05 mg/kg
Being mindful of the need for greater precision, I have updated the topology of the receptive sites
and fitted molecules of Ach into the picture with what appears to be the correct dimensions and
orientation, as follows:
If 20 Å separates the receptive sites and each of the two Ach molecules that open the ionic
channel occupies 6 Å with its methonium head, 8 Å remains in the lumen for the influx of the
cations. This is just enough to prevent a bottleneck at the level of the receptive sites, considering
that the trans-membrane tube portion of the channel also measures about 8 Å. Relative to the
depolarizing cations and the channel, Ach is a large molecule.
Each subunit has a positive and a negative face, arranged so that the positive face of each
subunit faces the negative face of its neighbour (). It is the negative face of the g (or e) subunit
that faces the a subunit and attracts the positively charged methonium head of Ach to their
interface. For Ach to be bound to the a subunit, and if its methonium head fits the inferface, its
acetyl portion has to point to the a subunit, not the other way around. Looking from the synaptic
cleft down the receptor channel, this means that Ach sits clockwise from the carbonyl O to the
quaternary N. This is because the subunits are clockwise from the a to the g (or e).
Scientists may one day taylor the relaxant molecule to fit the specific receptive site; however,
specific targeting of neuromuscular blocking agents to the adult or fetal type AchR seems a
• Fletcher GH, Steinbach JH. Ability of nondepolarizing
neuromuscular blocking drugs to act as partial agonists
at fetal and adult mouse muscle nicotinic receptors. Mol
Pharmacol 1996; 49:938-47.<ldn>!
• 2: Lee C. Thoughts on the channel size of the motor
endplate acetylcholine receptor. Br J Anaesth 2002;
• 3: Prince RJ, Sine SM. The ligand binding domains of
the nicotinic acetylcholine receptor. In: Barrantes FJ, ed.
The Nicotinic Acetylcholine Receptor, Current Views and
Future Trends. Berlin, Heidelberg, New York, Barcelona,
Budapest, Hong Kong, London, Milan, Paris, Santa
Clara, Singapore, Tokyo: Springer, 1998; 31-59
Editor—Anaesthesia textbooks, chapters and monographs on neuromuscular pharmacology often present artistic diagrams of the acetylcholine receptor (AchR) of the
motor endplate. Accuracy of the diagram is of obvious importance to neuromuscular pharmacology. The size of the ionic channel determines the passage of the cations
that generate the endplate potential. The topology of the channel at the receptive sites affects how muscle relaxants work.
The endplate AchR channel is generally conceived as a funnel. The extracellular portion is a
cone; the membrane-crossing portion is a tube. When the channel is closed, the tube is
impermeable. When the channel is open, the tube passes Na+, K+ and other cations as large as
tetraethylammonium (TEA) and Tris, but nothing much larger. Based on the permeability of TEA,
Tris, and other cations, the cross-sectional diameter of the open tube is quoted as 7.4 Å.
Decamethonium (C10) has two methonium heads. A methonium cation measures 5.2 Å in one
direction and 6.0 Å in another. As a result, C10 can pass the channel to end up intracellularly.
Of greater interest to neuromuscular pharmacology is the dimension of the cone at the level of
the two receptive sites where the relaxant molecule binds to the receptor. The inner border of the
receptive sites has been estimated to be 30 Å apart in the nicotinic AchR of the electric organ.
Based on the optimal neuromuscular-blocking potency of muscle relaxants, Lee has proposed
that, at one point of drug-receptor interaction, the space actually available to neuromuscular
blocking agents measures about 20 Å. It seems reasonable to assume that the helical
arrangement of the amino acid residues lining the channel, their variable side chains, and the
possible existence of intervening water molecules may account for the unavailability of the 10 Å
(5 Å on each side). Other explanations are possible.
On further thought, if TEA will pass through the tube, it must first descend through the cone
between the receptive sites. The passage happens when the channel is open; namely, when the
two molecules of acetylcholine occupy 12 Å (6 Å for each methonium head) of the inter-site
length. Subtracting from 20 Å, 8 Å remains, just enough room for passage of TEA through this
portion of the cone.
It is commonly said that the cone formation of the channel increases its cross-sectional area to
facilitate convergent entrance of the cations down the tube. This notion needs be qualified at the
level of the receptive sites. Unless the bound acetylcholine molecules sink into the wall, they will
protrude into the lumen. From the above calculation, the cone formation adds just enough room
to accommodate the acetylcholine molecules, so that the remaining free space between the
Villarroel A. Ion conduction through the acetylcholine receptor
channel. In: Barrantes FJ, ed. The Nicotinic Acetylcholine Receptor,
Current Views and Future Trends. Berlin, Heidelberg, New York,
Barcelona, Budapest, Hong Kong, London, Milan, Paris, Santa
Clara, Singapore, Tokyo: Springer; 1998; 109-44
2: Dilger JP. Structure and function of the nicotinic acetylcholine
receptor. In: Yaksh TL, Lynch III C, Zapol WM, Maze M, Biebuyck
JF, Saidman LJ, eds. Anesthesia Biologic Foundations.
Philadelphia, New York: Lippincott-Raven Publishers, 1998; 221-37
4: Dwyer TM, Adams DJ, Hille B. The permeability of the endplate
channel to organic cations in frog muscule. J Gen Physiol 1980;
5: Marshall CG, Ogden DC, Colquhoun D. The actions of
suxamethonium (succinyldicholine) as an agonist and channel
blocker at the nicotinic receptor of frog muscle. J Physiol (Lond)
Lee C. Structure, conformation and action of
neuromuscular blocking drugs. Br J Anaesth
Ach, skeletal muscle endplate AchR, and cholinergic agonists
Ach is a flexible molecule capable of adopting several conformations without significant energy penalty. This
allows it to be physiologically multifunctional. Its symmetrical conformers can flip easily. The structure of Ach,
CH3-CO-O-(CH2)2-N+(CH3)3, although simple, has several important functional features, namely the methonium
head centred on the positively charged quaternary N atom, the alcohol O atom that forms the ester (-O-), and the
acetyl group with the carbonyl O atom (-CO-).
The skeletal muscle endplate Ach receptor (AchR) is generally modelled after the electric organ nicotinic AchR
as a pentameric structure of a2bg (or e) d subunits arranged in a rosette around a sodium—potassium ionic
channel (). Each receptor has two Ach receptive sites, one on each a subunit in a pocket near where the a
subunit interfaces with its neighbour g or d subunit. Pedersen and Cohen proposed that it is unlikely for the b
subunit to be between the a subunits, and accordingly, one likely arrangement of the rosette is agabd, or agadb
viewed from the other direction. It takes two Ach molecules acting concomitantly, one on each receptive site, to
open one AchR channel. The neighbouring subunits make the receptive sites different in affinity. The distance
between the two receptive sites has been estimated to be about 50 Å between their outer limits and 30 Å between
their inner limits (A). The space available for NMB agents could be smaller, but the cross-section of the entire
receptor is larger and could exceed 80 Å. The pentameric arrangement in a circle indicates that the two Ach
receptive sites are not symmetrical or mirror image to each other (B).
Each receptive site, in turn, has two subsites, namely, an anionic subsite to attract the positively charged onium
head and a hydrogen bond donor to attract the hydrogen bond acceptor of Ach (B). The asymmetrical
arrangement makes it possible for subsites of like charges to completely avoid facing each other directly.
Various cholinergic receptors and cholinesterases have different conformational requirements or preferences of
their agonists (or substrates in the case of cholinesterase) and antagonists. Of the cholinergic compounds, a
1970 report, rarely quoted in literature on neuromuscular pharmacology, proposed that the distance from the
centre of the cationic N to the van der Waals (vdw) extension of the respective O atom (or equivalent hydrogen
bond acceptor) is important in determining whether a cholinergic agonist will be nicotinic or muscarinic (). A
distance of 4.4 Å will impart muscarinic action, while a distance of 5.9 Å will impart nicotinic action. For
convenience, these two rules will be referred to in this review as the Beers and Reich's rule of 4.4 Å for
muscarinic action and rule of 5.9 Å for nicotinic action, respectively. The ester O and the carbonyl O of Ach can
fulfil these respective rules readily.
The receptive sites are chiral-sensitive or chiral-selective, if not chiral-specific. For example, cisatracurium is
more potent than its stereoisomers supposedly because it fits the receptor at the receptive site better. A
conformation of Ach bound to a Torpedo nicotinic receptor has been published. For medicinal chemistry and
clinical anaesthesia, however, one must realize that species variation and status of desensitization may alter the
conformation of Ach bound to the receptor and/or that of the receptor itself. Free Ach may prefer a bent
Farmacocinetica e dinamica
After a single bolus dose, the plasma concentrations of
neostigmine, pyridostigmine, and edrophonium reach a peak and
decrease rapidly during the first 5–10 min. Then, a slower decline,
corresponding to the elimination phase can be observed. In most
studies, a two-compartment analysis was performed and the results
are similar for all three drugs. The volume of distribution of these
anticholinesterases is in the range of 0.7–1.4 L/kg and the
elimination half lives are 60–120 min. Some authors have obtained
shorter elimination half-lives (15–33 min) for neostigmine and
edrophonium, but these probably resulted from too short a sampling
time. The clearance of these drugs is in the range of 8–16 ml × kg-1
× min-1, which is much greater than the glomerular filtration rate.
However, in patients with renal failure, clearance is reduced
markedly and elimination half-life increases, and it is probable that
these drugs are actively secreted by the renal tubules ().
Duration of Action
Onset of Action
The duration of action of these drugs corresponds to their pharmacokinetic
profiles. In clinical practice, anticholinesterases usually are given when the effect of
the nondepolarizing muscle relaxant is wearing off. Thus, the net effect consists of
two components: the diminishing effect of the relaxant and the antagonistic effect of
the anticholinesterase agent. No recurarization would be expected in this setting as
long as the duration of action of the latter exceeds that of the former. However, to
remove the confounding effect of the neuromuscular relaxant, which is
progressively eliminated, it is possible to study the action of anticholinesterases
during a constant infusion of the nondepolarizing blocker. With the infusion rate of
dTC adjusted to maintain 90% block, it has been shown that neostigmine (0.043
mg/kg), pyridostigmine (0.21 mg/kg), or edrophonium (0.5 mg/kg) has an anticurare
effect of 1–2 h, with no clinically important differences among them.
The three agents have markedly different onset characteristics. During steadystate infusion of muscle relaxant, the onset of action of edrophonium is 1–2 min and
that of neostigmine is 7–11 min; pyridostigmine may take as long as 16 min to exert
its full effect. Similar results have been obtained with neostigmine as an antagonist
of pancuronium, vecuronium, and edrophonium when used to reverse metocurine
blockade. The difference in times to peak effect can also be observed when these
drugs are given during the spontaneous recovery phase of neuromuscular blockade
(). The slow recovery from pyridostigmine is quite different from the rapid
achievement of a pseudoplateau after edrophonium.
Traditionally, the different onset times have been attributed to the different rates
of binding to the enzyme. However, if acetylcholinesterase inhibition is not the only
mechanism involved in the reversal of neuromuscular blockade, this might not be
the only reason for these differences.
PK-PD of neostigmine
Heier, Tom, M.D., Ph.D.*; Clough, David, M.B.Ch.B.†; Wright, Peter M. C., M.D.‡; Sharma, Manohar L., Ph.D.§; Sessler, Daniel I.,
M.D.½½; Caldwell, James E., M.B.Ch.B.‡
* Assistant Professor of Anesthesia. Current position: Consultant Anaesthetist, Ullevaal University, Norway. † Assistant Professor of
Anesthesia. Current position: Consultant, Monklands District General Hospital, United Kingdom. ‡ Professor of Anesthesia, § Research
Chemist, University of California, San Francisco. ½½Associate Dean for Research, Director OUTCOMES RESEARCHä Institute,
Weakley Distinguished University Professor, and Acting Chair in Anesthesiology, University of Louisville; Professor and Vice-Chair,
Ludwig Boltzmann Institute, University of Vienna, Vienna, Austria.
Received from the Department of Anesthesia and Perioperative Care, University of California, San Francisco, California.
Supported by the Department of Anesthesia and Perioperative Care, University of California, San Francisco, California.
The laboratory in which the work was performed and Dr. Caldwell have in the past (but not currently) received funding support from
Organon Incorporated, West Orange, New Jersey. Presented in part at the annual meeting of the American Society of Anesthesiologists,
New Orleans, Louisiana, October 19-23,1996.
Background: The pharmacokinetics, maximum effect, and time course of action of neostigmine were studied in seven human volunteers.
Methods: Each volunteer was studied twice, during both normothermia and hypothermia. Anesthesia was induced with 30 mg/kg alfentanil
and 3 mg/kg propofol, and was maintained with 60-70% nitrous oxide and 0.7-0.9% isoflurane. The mechanical response of the adductor
pollicis to train-of-four stimulation of the ulnar nerve was recorded, and central body temperature maintained stable at either less than
34.5°C or greater than 36.5°C by surface cooling or warming. Before neostigmine administration, a stable 5% twitch height was obtained
by an infusion of vecuronium, and the infusion rate remained unchanged thereafter. Neostigmine, 70 mg/kg, was then infused over 2 min,
and blood samples for estimation of neostigmine concentrations were collected at intervals for 240 min.
Results: With hypothermia, the central volume of distribution of neostigmine decreased by 38%, and onset time of maximum effect
increased (4.6 vs. 5.6 min). Hypothermia did not change the clearance (696 ml/min), maximum effect, or duration of action of
Conclusions: The efficacy of neostigmine as an antagonist of vecuronium-induced neuromuscular block is not altered by mild
The duration of action of neostigmine as an antagonist of vecuroniuminduced block is dependent on both the rate of decrease of the plasma
concentration and the interaction with the enzyme acetylcholinestearase.
During the interaction of neostigmine with acetylcholinesterase, a relatively
stable carbamylated complex is formed. Decarbamylation of this complex is
slow, and the process has a half-life of approximately 30 min. Termination of
the effect of neostigmine may be rate limited by decarbamylation of the
neostigmine/enzyme complex rather than simply the decrease in the plasma
concentration of neostigmine. Hypothermia may slow the decarbamylation
process, but this has been studied only in vitro and at temperatures of 30°C
and below, and these results cannot be related directly to our study. The
lack of effect of hypothermia on neostigmine Cl is consistent with its lack of
effect on its duration of action.
In the clinical situation, reversal of neuromuscular block is dependent on two
processes, the interaction of neostigmine with acetylcholinesterase and the
inherent duration of action of the neuromuscular blocking drug.
• 14: Barber HE, Calvey TN, Muir KT: The relationship
between the pharmacokinetics, cholinesterase inhibition
and facilitation of twitch tension of the quaternary
ammonium anticholinesterase drugs, neostigmine,
pyridostigmine, edrophonium and 3hydroxyphenyltrimethylammonium. Br J Pharmacol
• 15: Wilson IB, Harrison MA, Ginsberg S: Carbamyl
derivatives of acetylcholinesterase. J Biol Chem
• 16: Verotta D, Kitts J, Rodriguez R, Coldwell J, Miller
RD, Sheiner LB: Reversal of neuromuscular blockade in
humans by neostigmine and edrophonium. J
Pharmacokinet Biopharm 19:713–29, 1991<ldn>!
Reid J, Breslin DS,Mirakhur R, Hayes A.Neostigmine
antagonism of rocuronium block during anesthesia
with sevoflurane,isoflurane or
propofol.Can.Anesth.J. 2001:48 :351-55
Purpose: To examine the influence of continuing administration of sevoflurane or isoflurane
during reversal of rocuronium induced neuromuscular block with neostigmine.
Methods: One hundred and twenty patients, divided into three equal groups, were randomly
allocated to maintenance of anesthesia with sevoflurane, isoflurane or propofol. Neuromuscular
block was induced with rocuronium and monitored using train-of-four (TOF) stimulation of the
ulnar nerve and recording the force of contraction of the adductor pollicis muscle. Neostigmine
was administered when the first response in TOF had recovered to 25%. At this time the volatile
agent administration was stopped or propofol dosage reduced in half the patients in each group
(n = 20 in each group). The times to attain TOF ratio of 0.8, and the number of patients attaining
this end point within 15 min were recorded.
Results: The times (mean ± SD) to recovery of the TOF ratio to 0.8 were 12.0 ± 5.5 and 6.8 ± 2.3
min in the sevoflurane continued and sevoflurane stopped groups, 9.0 ± 8.3 and 5.5 ± 3.0 min in
the isoflurane continued and isoflurane stopped groups, and 5.2 ± 2.8 and 4.7 ± 1.5 min in the
propofol continued and propofol stopped groups (P < 0.5– 01). Only 9 and 15 patients in the
sevoflurane and isoflurane continued groups respectively had attained a TOF ratio of 0.8 within
15 min (P < 0.001 for sevoflurane).
Conclusions: The continued administration of sevoflurane, and to a smaller extent isoflurane,
results in delay in attaining adequate antagonism of rocuronium induced neuromuscular block.
Baurain MJ, d'Hollander AA,Melot C, Dernovoi
BS,Barvais L.Effects of residual concentrations of
isoflurane on the reversal of vecuronium induced
ABSTRACT: Thirty-six anesthetized patients (ASA physical status 1 or 2) undergoing elective surgery were monitored
(isometric adductor pollicis mechanical activity) to detect the effects of discontinuing isoflurane anesthesia upon the reversal of
vecuronium-induced neuromuscular blockade. Neuromuscular blockade was produced by vecuronium 100 mg/kg and
additional doses of 20mg/kg until completion of surgery. The patients were randomly divided into three groups: in the control
group (n = 12), only fentanyl/N2O was given; in the “isostable” group (n = 12), isoflurane at an end-tidal concentration of 1.25%
was maintained throughout anesthesia; in the “isostop” group (n = 12), isoflurane 1.25% was discontinued before neostigmine
administration. In all groups, paralysis was antagonized with 15 mg/kg intravenous (iv) atropine and 40 mg/kg iv neostigmine
when the twitch height (0.1 Hz) had regained 25% of its control value. The measured parameters were twitch height, train-offour, and 50–100-Hz tetanic fade. No significant differences were found among the three groups with respect to the final twitch
heights and tetanic fades at 50 Hz. In the isostable group, final mean train-of-four was significantly less (75%) than in the other
patients (88%) (P < 0.01). Mean tetanic fade at 100 Hz was significantly less in the isostable group (31%) than in the isostop
group (57%) (P < 0.01) and control group (84%) (P < 0.01). We conclude that discontinuing isoflurane anesthesia for 15 min
improves the reversal of a vecuronium paralysis. In addition, after the antagonism of vecuronium-induced neuromuscular
blockade, tetanic fade at 100 Hz appears useful to detect the slight impairment of the neuromuscular transmission that is
induced by residual isoflurane concentrations and that is undetected by train-of-four measurements.
KEY WORDS: Anesthetics, volatile: isoflurane; Antagonists, neuromuscular relaxants: neostigmine; Neuromuscular
Neostigmine to be preferred to
Driessen, J. J.; Robertson, E. N.; Booij, L.H.D. J.; Fisher, D. M.
Editor,—We read with interest the review article by Fisher on neuromuscular blocking agents in paediatric anaesthesia. It was a concise
summary of the use
of these agents in paediatric practice today. The author's preference for edrophonium over neostigmine,
however, did not seem to be a true reflection of what is known about antagonism of neuromuscular block in
There have been few comparative studies in children of the speed of action of edrophonium and
neostigmine. In comparable mg per kg doses, recovery from an intense atracurium-induced neuromuscular
block in children is faster after neostigmine than edrophonium. In adults, it has been shown that in the
reversal of profound block produced by vecuronium or atracurium, neostigmine is more effective than
edrophonium and its maximal effect is reached more quickly, even though edrophonium is faster in its initial
onset. Monitoring of the depth of neuromuscular block in infants and children is technically more difficult and
not perhaps as widespread as in Dr Fisher's department. This suggests that the chance of profound
neuromuscular block at the end of surgery is greater in paediatric anaesthetic practice. Neostigmine would
therefore be a better choice than edrophonium.
In his article, Fisher stated that less neostigmine is needed in children than in adults, and quoted Fisher
and colleagues. Quoting the same article, he then stated that the ED50 of neostigmine for antagonism was
greater for children than for adults. It is possible that this is a typing error and that the author means to
suggest that edrophonium has a higher ED50 in children than in adults. For this reason, the author suggests
the use of higher doses of edrophonium for antagonism in infants and children. These studies, however,
were carried out under steady-state infusion of tubocurarine and not during the recovery phase from the
newer non-depolarizing agents. Moreover, there was no significant difference in the dose of edrophonium
required to antagonize tubocurarine-induced neuromuscular block in children and adults. In contrast, several
studies have shown that neostigmine antagonizes residual non-depolarizing neuromuscular
block more effectively in children than in adults. Debaene, Meistelman and d'Hollander
showed that, when twitch height recovered to 10% of control after vecuronium,
neostigmine 30 mg kg-1 had a more rapid onset in children than in adults, and that a TOF
of 0.7 was obtained in less than 10 min in all patients, including infants. The dose of
neostigmine to effectively antagonize 90% block produced by rocuronium is indeed
smaller in children (mean 7 mg kg-1) than in adults (56 mg kg-1). The effects of 2 x ED95
1: Fisher DM. Neuromuscular blocking agents in paediatric anaesthesia. Br J Anaesth 1999;
2: Gwinnutt CL, Walker RWM, Meakin G. Antagonism of intense atracurium-induced
neuromuscular block in children. Br J Anaesth 1991; 67:13-6.<ldn>!
3: Caldwell JE, Robertson EN, Baird WLM. Antagonism of profound neuromuscular blockade
induced by vecuronium or atracurium. Comparison of neostigmine with edrophonium. Br J
Anaesth 1986; 58:1285-9.<ldn>!
4: Caldwell JE, Robertson EN, Baird WLM. Antagonism of vecuronium and atracurium:
comparison of neostigmine and edrophonium administered at 5% twitch height recovery. Br J
Anaesth 1987; 59:478-81.<ldn>!
5: Fisher DM, Cronelly R, Miller RD, Sharma M. The neuromuscular pharmacology of
neostigmine in infants and children. Anesthesiology 1983; 59:220-5.
6: Fisher DM, Cronelly R, Sharma M, Miller RD. Clinical pharmacology of edrophonium in
infants and children. Anesthesiology 1984; 61:428-33.<ldn>!
7: Debaene B, Meistelman C, d'Hollander A. Recovery from vecuronium neuromuscular
blockade following neostigmine administration in infants, children and adults during halothane
anaesthesia. Anesthesiology 1989; 71:840-4.<ldn>!
8: Abdulatif M, Mowafi H, Al-Ghamdi A, El-Sanabary M. Dose-response relationships for
neostigmine antagonism of rocuronium-induced neuromuscular block in children and adults. Br J
Anaesth 1996; 77:710-15.<ldn>!
9: Leuwer M, Motsch J, Schledt U, et al. Dose-response, time course of action and recovery of
ORG 9426 (rocuronium) in infants during halothane anaesthesia. Br J Anaesth 1994; 73:716P.
7: Cronnelly R, Morris RB, Miller RD. Edrophonium: Duration of action and atropine requirement
in humans during halothane anesthesia. Anesthesiology 1982; 57:261-6.<ldn>!
8: Miller RD, VanNyhuis LS, Eger EI II, et al. Comparative times to peak effect and durations of
action of neostigmine and pyridostigmine. Anesthesiology 1974; 41:27-33.
D. M. Fisher
Department of Anesthesia
University of California
San Francisco, CA, USA
Smith, CE, Donati F., Bevan DR.Dose‑ Response
Relationships for Edrophonium and Neostigmine
as Antagonists of Atracurium and Vecuronium
Anesthesiology 1989;71: 37-43.
To determìne the potencies of edrophoniurn and neostigmine as gonists of nondepolarizing
neuromuscular blockade produced
atracuriunì and vecuronium, dose‑ response curves were coned for hoth antagonists when given at 10%
of first twitch height. Ninety ASA physical status 1 and 2 ts were given either 0.4 mg/kg atracurium or 0.08
mg/kg venium during thiopental‑ nitrous oxide‑ enfiurane anesthesia. n ‑ of ‑ four stimulation was applied to
the uInar nerve every 12 the force of contraction of the adduetor pollicis muscle was rded. When
spontaneous recovery of first twitch height reached of its initial control value, edrophonium (0. 1, 0.2, 0.4,
or 1 mg/
or neostigmine (0.005, 0.01, 0.02, or 0.05 tng/kg) was adminisby random allocation. Neuromuscular
function in another ten was allowed to recover spontancously. Assísted recovery defined as actual
recovery minus mean spontancous recovery in patients who were not given antagonists. First twitch was
initiatty more rapid when vecuroniunì was antagonized red with atracurium, but no difference was
detected after 10 At 10 min the neostigmine EDgO was 0.022 ± 0.003 (SEM) mg/
dter atracurium and 0.024 0.003 mg/kg after vecuroniunì. edrophonium ED80 was 0.44 0.11 mg/kg with
atracurium and ± 0.12 mg/kg with vecuronium, giving a neostigmine:edroi poteney ratio of 20. Atracurium
train‑ of‑ four fade could
antagonized more easily with edrophonium, whereas that of vewas more easily antagonized by
neostigmine. It ìs conthat edrophoniunt and neostigmine are not equally effective
atracurium and vecuronium. (Key words: Antagonists, neuar relaxants: edrophonium; neostigmine.
Monitoring. trainr. Neuromuscular relaxants: atracurium; vecuronium.)
WHEN neostigmine is used to reverse neuromuscular blockade, it
inhibits acetylcholine (ACh) metabolism at the muscarinic receptors
of airway smooth muscle as well as at the nicotinic receptors of the
neuromuscular junction. Thus, neostigmine may induce an increase
in ACh in muscarinic receptors which results in bronchoconstriction.
However, the mechanisms involved in anticholinesterase (anti-ChE)
drug-induced bronchoconstriction have not been clarified.
In a previous study we demonstrated that accumulation of inositol
monophosphate (IP1), a degradation product of the
phosphatidylinositol (PI) response, was stimulated by neostigmine
and by pyridostigmine, not by edrophonium in rat tracheal slices,
and that these increases were inhibited by atropine. The results
suggest that neostigmine and pyridostigmine stimulate PI response
in the airway smooth muscle, while edrophonium does not. Although
a direct relationship was suggested between the increase in PI
response and airway smooth muscle contraction,
Muscarinic ACh receptors in the airway are divided into M2 and M3
receptors. The M3 muscarinic receptors exist on airway smooth
muscle cell membrane, and M2 muscarinic receptors exist on
postganglionic nerve terminals. Stimulation of M3 receptors induces
bronchoconstriction, whereas stimulation of M2 receptors inhibits
ACh release, resulting in attenuation of vagally-induced
bronchoconstriction. In the present study, the contraction by
neostigmine or pyridostigmine of rat tracheal rings was completely
inhibited by 4-DAMP, a selective M3 antagonist at a dose of 10 nM.
Ten Berge et al. tested the effects of 4-DAMP on the twitch
response of electrical field-stimulated guinea pig tracheal ring
preparations, and found that twitch contraction was nearly inhibited
by 4-DAMP at a dose of 10 nM. Their result is consistent with our
data. Thus, in the present study the contractile response to anti-ChE
drugs is likely to be mediated via M3 muscarinic receptors.
Reversal of neuromuscular
blockade. Anesthesiology 77:785–
Potency: Dose-Response Curves
Dose-response curves for edrophonium, neostigmine, and pyridostigmine can be constructed after their
administration during the constant infusion of nondepolarizing blockers. Peak effect is measured and plotted
against dose. Experiments performed with dTC and with halothane as the background anesthetic indicated that
edrophonium had approximately one twelfth and pyridostigmine one fifth the potency of neostigmine. Similar
dose-response curves have been obtained during the spontaneous recovery phase of dTC or pancuronium block.
In this situation, the apparent potency of the anticholinesterases increases with time because of spontaneous
recovery of the block and because no recurarization takes place. Taking the measurements at 10 min leads to
results similar to those obtained during constant infusion, with the advantage of greater clinical application (). The
dose-response curve for edrophonium is flatter than that for neostigmine or pyridostigmine, which makes it
difficult to establish potency ratios unless the part of the curve for which comparisons are made is specified.
Furthermore, the potency ratio is not the same for single twitch and TOF. For example, if reversal is attempted at
10% T1 recovery during pancuronium blockade, 12 times as much edrophonium as neostigmine is required to
achieve 80% T1, but 25 times as much is needed to reach a TOF ratio of 0.5. If vecuronium is used instead of
pancuronium, 80% T1 recovery is achieved with 19 times as much edrophonium as neostigmine, and to obtain
50% T4/T1, the potency ratio is 26. Thus, the neostigmine-edrophonium potency ratio, previously estimated at 12,
varies depending on the relaxant used, the depth of block, and the endpoint chosen.
If the constant-infusion technique is used, there is no difference in the dose-response relationship for
anticholinesterase agents if vecuronium is used instead of pancuronium (). However, there is a marked shift to the
left for vecuronium if the data are obtained when the reversal agent is given while neuromuscular blockade is
wearing off spontaneously (). This is related to the more rapid spontaneous recovery of vecuronium than of
pancuronium. There are slight differences between atracurium and vecuronium. For example, the effect of
neostigmine is greater 5 min after its administration in the reversal of vecuronium, but by 10 min there are no
differences. Edrophonium appears to be less predictable if vecuronium is used as the relaxant.
Reversal of Intense Block
The previous discussion pertained to reversing the block at 10% T1
height. When reversal is attempted at 1% T1, i.e., 99% block, the doseresponse curves are shifted to the right. However, the shift is more
important for edrophonium than for neostigmine (). The neostigmineedrophonium potency ratio is 16.6 for 80% T1 recovery when given at 90%
atracurium block, compared with 35.3 when administered at 99% block.
Pyridostigmine also is comparatively less potent in reversing deep block.
Thus, neostigmine appears preferable to either edrophonium or
pyridostigmine when profound (> 90%) blockade is to be antagonized. The
time taken to reach adequate recovery of neuromuscular function (TOF >
0.7) is dependent on the dose of anticholinesterase agent given. For
example, neostigmine accelerates the rate of recovery from atracurium or
vecuronium blockade, and this acceleration is dose-dependent.
Potent anesthetic vapors potentiate neuromuscular block. Thus, their
cessation at the end of surgery will assist the overall recovery of
neuromuscular activity. (See also the section “Factors affecting reversal:
Complications of Reversal Agents
Anticholinesterases may cause neuromuscular weakness in patients with myasthenia
gravis when the dose administered was too high. There are no convincing reports of this
occurring in the postanesthetic period after the administration of a nondepolarizing
muscle relaxant and neostigmine, pyridostigmine, or edrophonium. However, when
relatively high doses of neostigmine are administered in the presence of little residual
nondepolarizing blockade, tetanic fade is sometimes seen; this effect is reversed by the
administration of small doses of a nondepolarizing blocker. TOF is usually not affected in
this setting. The clinical importance of this brief (< 5 min) finding is uncertain. (See also
the section “Anticholinesterase pharmacology: neostigmine block.”)
Anticholinesterases have pronounced vagal effects. Bradycardia and/or other
bradyarrhythmias such as nodal and ventricular escape beats and asystole may occur.
These can be attenuated by the administration of an anticholinergic drug such as atropine
or glycopyrrolate, both of which block muscarinic but not nicotinic receptors.
Interestingly, some bradycardia occurs in the denervated heart, but the magnitude of this
effect is not as great as in hearts with a normal vagus nerve. The time course of
bradycardia parallels that of the reversal of block. Its onset is rapid for edrophonium,
slower for neostigmine, and slowest for pyridostigmine.
Anticholinesterases are associated with increased salivation and increased bowel
motility. Atropine seems to block the former, but there is debate concerning its
effectiveness in inhibiting peristalsis. Some studies claimed an increase of bowel
anastomotic leakage when neostigmine was used to reverse neuromuscular blockade.
Schäfer, Michael, M.D.
(Accepted for publication November 30, 1999.)
To the Editor:-In recent years, the journal ANESTHESIOLOGY has published several
reports on the analgesic effectiveness of the cholinesterase inhibitor neostigmine.
Although there is good evidence for a spinal action of neostigmine, a rationale for a
peripheral mechanism of action is lacking. Intrathecal injection of neostigmine produces
analgesic effects in animals, including humans, accompanied by a high incidence of side
effects. The inhibition of spinal cholinesterase results in an increase of endogenous
acetylcholine, which is most likely released from intrinsic cholinergic neurons within the
dorsal horn of the spinal cord. These cholinergic neurons terminate in the vicinity of
primary afferents, which express muscarinic receptors. Consistently, analgesic effects of
intrathecal neostigmine could be reversed by muscarinic receptor antagonists. The
analgesic effect may be explained by a muscarinic presynaptic
inhibition of glutamatergic afferents, similar to how it has been
described in the neostriatum. An important prerequisite for the
effectiveness of neostigmine is a tonic cholinergic activity.
Although these mechanisms are clearly described for the spinal cord, evidence is
lacking for the periphery. Therefore, the negative result of adding neostigmine to a
mepivacaine axillary plexus block in the study by Bouaziz et al. is not surprising. How
would neostigmine exert an effect within the nerve sheath of the axillary plexus? An
endogenous release of acetylcholine does not exist. Interestingly, the authors
hypothesized a peripheral action of neostigmine based on the demonstration of peripheral
muscarinic receptors only; however, this is not enough. In their discussion, they refer to
studies that investigated the effects of muscarinic agonists in spinal cord slice
preparations in vitro or intrathecally in vivo. However, these effects are not described for
Potenza degli antiAche
Naguib M,Riad W.Dose response relationship for edrophonijm
and neostigmine antagonism of atracurium and cisatracurium
induced neurmuscular block.Can.Anaesth.J 2000;47:1074-1081
Purpose: To study the dose-response relationships for neostigmine and edrophonium during antagonism of
neuromuscular block induced by atracurium and cisatracurium.
Methods: One hundred and twenty eight, ASA group 1 or 2 adults were given either 0.5 mg×kg-1 atracurium or
0.1 mg×kg-1 cisatracurium during fentanyl-thiopental-nitrous oxide-isoflurane anesthesia. The neuromuscular
block was measured by an acceleration-responsive transducer. Responses were defined in terms of percent
depression in the first twitch (T1) and train-of-four (TOF) response. When spontaneous recovery of first twitch
height reached 10% of its initial control value, edrophonium (0.1, 0.2, 0.4, or 1 mg×kg-1) or neostigmine (0.005,
0.01, 0.02, or 0.05 mg×kg-1) was administered by random allocation. Neuromuscular function in another sixteen
subjects was allowed to recover spontaneously.
Results: At five minutes, unlike edrophonium, neostigmine was equally effective against atracurium and
cisatracurium with respect to T1 recovery. The neostigmine T1-ED50 was 10.3 ± 1.06 (SEM) mg×kg-1 after
atracurium and 11.2 ± 1.06) mg×kg-1 after cisatracurium. The edrophonium ED50 was 157 ± 1.07 mg×kg-1 with
atracurium and 47.4 ± 1.07 mg×kg-1 with cisatracurium, giving a neostigmine:edrophonium potency ratios of 15.2
± 1.7 and 4.2 ± 0.41 (P < 0.001) for atracurium and cisatracurium, respectively. At 10 min neostigmine was 13 ±
1.4 times as potent as edrophonium for achieving 50% TOF recovery after atracurium paralysis. After
cisatracurium the potency ratio was 11.8 ± 1.3 (NS).
Conclusions: Although there were differences at five minutes, neostigmine:edrophonium potency ratios at 10 min,
were similar in both relaxants studied.
Watcha MF, Safavi FZ, McCulloch DA, et al. Effect
of antagonism of mivacurium-induced
neuromuscular block on postoperative emesis in
children. Anesth Analg 1995; 80:713-7.
The routine use of cholinesterase inhibitors to antagonize residual
neuromuscular block may be associated with increased postoperative
Rapid spontaneous recovery from mivacurium may obviate the need for
randomized, double-blind, placebo-controlled study
113 healthy children
incidence of postoperative complications after spontaneous recovery and
after the use of neostigmine-glycopyrrolate or edrophonium-atropine.
anesthetic regimen :halothane, nitrous oxide, fentanyl, 2 micrograms/kg
mivacurium in an initial dose of 0.2 mg/kg, followed by an infusion, adjusted
to maintain > or = 1 evoked contraction response to a supramaximum trainof-four stimulus.
At the end of the procedure, patients received by random assignment one of
three drug combinations: 1) neostigmine 70 micrograms/kg + glycopyrrolate
10 micrograms/kg, i.v., 2) edrophonium 1 mg/kg + atropine 10