Anticolinestherases 2004

Gli anticolinesterasici:
quando,come e perché
Claudio Melloni
Anestesia e Rianimazione
Ospedale di Faenza(RA)
melloniclaudio@libero.it

Fisiologia e farmacologia degli
anticolinesterasici

Colinesterasi
• Colinesterasi vera:o acetilcolinesterasi
legata alle membr basali ,giunzioni colinergiche

• Pseudo o
butirilcolinesterasi,plasmatica,libera nel
plasma e presente anche nel
fegato,rene,cervello ,pelle,musc liscio intest.
• Essa idrolizza anche SCC,mivacurium,AL
esterei,diamorfina,aspirina
• (altre esterasi aspecifiche tissutali metabolizzano remif. e
esmolol…)

Modello schematico del recettore Ach
nicotinico(sec.Imoto,Alberts,Taylor)

Composizione delle subunità nel recettore Ach
nicotinico

The active surface of the acetylcholinesterase is best viewed as having two
subunits, the anionic site and esteratic site. The anionic site is concerned with
binding and orienting the substrate molecule. The esteratic site is responsible
for the hydrolytic process. A second “anionic” site, which became known as
the “peripheral” anionic site, was proposed based on binding of bisquaternary ammonium compounds. Binding of ligands to the peripheral
anionic site causes inactivation of the enzyme, although the mechanism of
inhibition is not clear. There is also evidence for a role of the peripheral
anionic site of acetylcholinesterase in neurite regeneration and outgrowth and
in the growth and differentiation of spinal motor neurons.
Neostigmine and edrophonium are the most commonly used
anticholinesterases in the operating room. Edrophonium is a prosthetic
inhibitor that binds to the anionic site on the acetylcholinesterase by

electrostatic attachment and to the esteratic subsite by hydrogen
bonding. The dissociation half-life of this reaction is less than 0.5 min. The in
vivo activity of edrophonium is predicted to be rapid in onset, and, clinically,
edrophonium has a more rapid onset of action than neostigmine.

Neostigmine and pyridostigmine are oxydiaphoretic (acid transferring)
inhibitors of acetylcholinesterase. Neostigmine and pyridostigmine
transfer a carbamate group to the acetylcholinesterase, which forms a
covalent bond at the esteratic site. The dissociation half-life of the
carbamate-enzyme bond of neostigmine is at least 7 min. However, it should
be noted that the pharmacologic actions of neostigmine and edrophonium are
not limited to enzyme inhibition. Evidence suggests that the direct influences
of the acetylcholinesterase inhibitors on neuromuscular transmission

Condizioni accompagnate da up o down
regolazione del recettore per Ach.
• Up regulation
•
•
•
•
•

Traumi midollari
Ictus
Ustioni
Immobilità prolungata
Prolungata esposizione a
bloccanti nm.
• Sclerosi multipla
• Sindr di Guillain Barrè

• Down regulation
• Myastenia gravis
• Avvelenamento da
anticolinesterasici
• Avvelenamento da
organofosforici

Tanito Y, Miwa T,Endou M, Hirose Y,Gamoh
M,Nakaya H, Okumura F.Interaction of Edrophonium
with Muscarinic Acetylcholine M2 and M3
Receptors .Anesthesiology 94:804-814, 2001
•
•

•

Background: It has been reported that edrophonium can antagonize the negative chronotropic
effect of carbachol. This study was undertaken to evaluate in detail the interaction of
edrophonium with muscarinic M2 and M3 receptors.
Methods: A functional study was conducted to evaluate the effects of edrophonium on the
concentration–response curves for the negative chronotropic effect and the bronchoconstricting
effect of carbachol in spontaneously beating right atria and tracheas of guinea pigs. An
electrophysiologic study was conducted to compare the effects of edrophonium on carbachol-,
guanosine triphosphate (GTP)g S-, and adenosine-induced outward K+ currents in guinea pig
atrial cells by whole cell voltage clamp technique. A radioligand binding study was conducted to
examine the effects of edrophonium on specific [3H]N-methyl-scopolamine (NMS) binding to
guinea pig atrial (M2) and submandibular gland (M3) membrane preparations, and on atropineinduced dissociation of [3H]NMS.
Results: Edrophonium shifted rightward the concentration–response curves for the negative
chronotropic and bronchoconstricting effects of carbachol in a competitive manner. The pA2
values for cardiac and tracheal muscarinic receptors were 4.61 and 4.03, respectively.
Edrophonium abolished the carbachol-induced outward current without affecting the GTPg Sand adenosine-induced currents in the atrial cells. Edrophonium inhibited [3H]NMS binding to
M2 and M3 receptors in a concentration-dependent manner. The pseudo-Hill coefficient values
and apparent dissociation constants of edrophonium for M2 and M3 receptors were 1.02 and
1.07 and 21 and 34 mm, respectively. Edrophonium also changed dissociation constant values
of [3H]NMS without affecting its maximum binding capacities.

• Conclusion: Edrophonium binds to
muscarinic M2 and M3 receptors
nonselectively, and acts as a competitive
antagonist.

Recettori per ACH
•
•
•
•

Nicotinici:giunzione nm
Muscarinici:M1cell ventric
M2,cardiaci (musc liscio vie aeree,intest)
M3musc liscio vie aeree,intest:tipica risp
contrattile
• M4

Legame spezzato
Legame spezzato
dall’Acetilcolinesterasi
dall’Acetilcolinesterasi

O
H3C

C

O

CH2 CH2

+
N

CH3
CH3
CH3

Acetilcolina

Topologia dell’AchR visto dal lato sinaptico
Lee C. Structure, conformation and action of neuromuscular blocking drugs. Br J Anaesth 2001;
87:755-69.

Sito anionico

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
Bisquaternaria blocca
2 siti anionici di 2
recettori

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
2001;87:755-69.

AntiChE
• 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

• L’azione degli antiChE passa attraverso una
fase intermedia dopo il legame con l’enzima,
con formazione di un complesso carbamilato
relativamente stabile ,la cui decarbamilazione è
lenta con emivita di circa 30 min. La cessazione
degli effetti della neostigmina potrebbe essere
dovuta proprio alla fase di decarbamilazione del
complesso enzima/neostigmina piuttosto che
solo dal decremento nella concentrazione
plasmatica della neostigmina.A questo punto
l’enzima è pronto a reagire nuovamente e il ciclo
può riprendere.

Variabili farmacocinetiche medie dei principali
antichE. (da 99 a 102 ref)
t/12
T1/2
α(min) β(min)

V1(lt/kg) Vdss(Lt/kg) Cl
(ml/kg/min)

3,4

77

0,2

0,7

9,1

prostigmina

6,7

113

0,3

1,1

8,6

piridostigmi
na

7,2

110

9,3

1,1

9,5

edrofonio

Matteo RS, Young WL, Ornstein E, et al.
Pharmacokinetics and pharmacodynamics of
edrophonium in elderly surgical patients. Anesth
Analg 1990; 71:334-9.

•
•
•
•
•

7 pts 76-87 vs 7 27-57 years
Elective intracranial surg.
Tps/scc/N2O/Haloth 1 MAC age adiusted
Force monit
Metocurine bolus + inf aimed at 90% block

Matteo et al 1990.
• In elderly pts edrophonium exhibited a
significant decrease in plasma clearance
and a prolonged elimination hl.
• Plasma cl was correlated with age
• Plasma conc of edrophonium at equal
response levels always greater in thr elderly
than in the younger

Young WL, Matteo RS, Ornstein E. Duration of
action of neostigmine and pyridostigmine in the
elderly. Anesth Analg 1988; 67:775-8.

•
•
•
•
•

14 pts>60 years(68+/-2) vs young 38+/-5)
Tps/scc/N2O/haloth 1 mac age adjiusted
EMG monit
Metoc bolus + cont infus
Atropa 0.02+ neost 0.07 or pyrido 0.14
mg/kg

anziani

35

anziani

onset risp max
durata risp.max
T175%
Tempi
* 10
T150%
T125%

30
25
20
giovani

giovani

15
10
5
0

prostigmina

piridostigmina

• Dur risposta max + lunga negli anziani
• Durate di ripresa 75,50,25% prolungate
negli anziani.
• Durate di azione di neostigm e
piridostigm prolungate nell’anziano;poiché
anche le durate di dtc,metoc,panc sono
prolungate nell’anziano è meglio usare
neo o pirido nell’antag dei miorila a lunga
durata piuttosto che edrophonium….

Duration of action(max response) of antiChE
35,0
30,0
25,0
min

edrophonium
neostigmine
pyridostigmine

20,0
15,0
10,0
5,0
0,0
Matteo
elderly

Matteo
young

Young
elderly

Young
young

Cronnelly R, Stanski DR, Miller RD, et al. Renal function
and the pharmacokinetics of neostigmine in
anesthetized patients. Anesthesiology 1979; 51:222-6.

Pazienti normali

Cronnelly R, Stanski DR, Miller RD, et al. Renal
function and the pharmacokinetics of neostigmine in
anesthetized patients. Anesthesiology 1979; 51:222-6

Paz appena trapiantati di rene

anesthetized patients. Anesthesiology 1979; 51:222-6

Pazienti anefrici


anesthetized patients. Anesthesiology 1979; 51:222-6.

Morris RB,Cronnelly R,Miller RD,Stanski DR,Fahey
MR.Pharmacokinetics of edrophonium and neostigmine
when antagonizing d-tubocurarine neuromuscular blockade
in man.Anesthesiology 1981;54:399-402.

Stone JG,Matteo RS, Ornstein E,Schwartz AE, Ostapkovich
N,Jamdar SC,Diaz J.Aging Alters the Pharmacokinetics of
Pyridostigmine. Anesthesia & Analgesia 81:773-776: 1995.

• tps 3–6 mg/kg /IV / isoflurane 0.5% /N2O
• Dtc 0.18 mg/kg + pancuronium 0.024
mg/kg T1 5% : atropine 1 mg
+pyridostigmine 0.25 mg/kg.

Pyridostigmine and age Stone JG,Matteo RS, Ornstein E,Schwartz
AE, Ostapkovich N,Jamdar SC,Diaz J.Aging Alters the Pharmacokinetics of

Pyridostigmine clearance and age

Stone JG,Matteo
RS, Ornstein E,Schwartz AE, Ostapkovich N,Jamdar SC,Diaz J.Aging Alters the
Pharmacokinetics of Pyridostigmine. Anesthesia & Analgesia 81:773-776: 1995.

Pyridostigmine kineticsStone JG,Matteo RS, Ornstein E,Schwartz
AE, Ostapkovich N,Jamdar SC,Diaz J.Aging Alters the Pharmacokinetics of

Recovery parameters following
neostigmine administration

min

(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)

20
18
16
14
12
10
8
6
4
2
0

6 groups ,20 each
Rocuronium,
Force,
neo at tof 25%!

*
**

*

prop prop sevo sevo iso
iso
cont stop cont stop cont stop

onset
Tof 0.80
RI
pts at 0.8 tof at 15 min

TOF vs time after neostigmine 40 µgr/kg (from T1
25%);control(fent/N2O),isoflurane stopped,isoflurane
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
rovesciamento……

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,
blockade

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.


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:
37-43.
100


90
80
70
60
atrac at 5'
atrac at 10'
vecu at 5'
vecu at 10'

50
40
30
20
10
0
neo 0.02
mg/kg

neo 0.04
mg/kg

edroph 0.5
mg/kg

edroph 1
mg/kg

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.

80


70
60
50

atrac at 5'
atrac at 10'
vecu at 5'
vecu at 10'

40
30
20
10
0
neo 0.02
mg/kg

neo 0.04
mg/kg

edroph
edroph 1
0.5 mg/kg
mg/kg

Neo vs edrofonio e profondità
del blocco nm.

Ist twitch height vs dose 10 min. after
neostigmine or edrophonium administered at 90
or 99% block.

Conclusione 1
• 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
circle)

Insomma,l’antagonismo
dipende da:
• Profondità di blocco al momento della
somministrazione dell’antagonista
• 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.

Conclusione 2
• E’ meglio somministrare gli antidoti quando la
ripresa nm è iniziata
• È meglio cessare la somministrazione degli
alogenati ( e monitorizzare la % et)…….

BEEMER, G. H.; BJORKSTEN, A. R.; DAWSON, P. J.;
DAWSON, R. J.; HEENAN, P. J.; ROBERTSON, B. A.
Determinants of the reversal time of competitive
nurmuscular block by anticholinesterases. BJA
•
1991;66:469-475.
• 200 patients
• reversal time of competitive neuromuscular block by
anticholinesterase
• alcuronium and atracurium neuromuscular block were
• antagonized by neostigmine 0.04 and 0.08 mg kg-1
and edrophonium 0.5 and 1.0 mg kg-1. A
• biexponential relationship between the reversal time
(time from injection of anticholinesterase to a train-offour ratio of 70%) and the degree of neuromuscular
block at reversal (all groups; F ratio, P < 0.05).

BEEMER, G. H.; BJORKSTEN, A. R.; DAWSON, P. J.;
DAWSON, R. J.; HEENAN, P. J.; ROBERTSON, B. A.
Determinants of the reversal time of competitive
nurmuscular block by anticholinesterases. BJA
1991;66:469-475.

• Reversal time was determined by two processes: direct
antagonism by the anticholinesterase and spontaneous
recovery of the neuromuscular blocking agent, with the latter
becoming the major determinant at profound levels of
neuromuscular block (0–10% of control twitch height).
Neostigmine, in the doses studied, appeared to have a higher
“ceiling” of neuromuscular block which it completely
antagonized, although edrophonium had a more rapid onset of
action. The reversal time for alcuronium became progressively
longer relative to atracurium as neuromuscular block increased
because of the slower spontaneous recovery rate. Avoidance of
profound neuromuscular block at the completion of surgery is
required to ensure reliable antagonism of the block within 5–10
min by an anticholinesterase. Neostigmine 0.08 mg kg-1 was
found to be the most effective agent in antagonizing profound

• The most important determinant of reversal time
is the depth of neuromuscular block at the time
of antagonism and this should determine the
anticholinesterase and its dose. Another factor
which should be considered is the type and dose
of competitive neuromuscular blocking agent.
When large doses of long acting competitive
neuromuscular blocking agents are administered
during surgery, it may be anticipated that
antagonism of profound block by an
anticholinesterase will be prolonged.
•

Mean Reversal times for the different nmb/antiAchE
at deep (0-10%T1) and light (>30% T1) degrees of
blockade BEEMER, G. H.; BJORKSTEN, A. R.; DAWSON, P. J.; DAWSON, R. J.;
HEENAN, P. J.; ROBERTSON, B. A. Determinants of the reversal time of competitive nurmuscular
block by anticholinesterases. BJA 1991;66:469-475.

60

atrac neo 0.04

50

atrac neo 0.08
atrac edroph 0.5
atrac neo 1
alcuronium neo 0.04
alcur neo 0.08

40

alcur edroph 0.5
alcur edroph 1

min 30
20
10
0
profound block

light block

Reversal times for the different nmb/antiAchE

BEEMER,
G. H.; BJORKSTEN, A. R.; DAWSON, P. J.; DAWSON, R. J.; HEENAN, P. J.; ROBERTSON, B. A.
Determinants of the reversal time of competitive nurmuscular block by anticholinesterases. BJA
1991;66:469-475.

Perché la piridostigmina non è
idonea…

Kim KS.,,Lew SH,Cho Y, Cheong Mi A.Residual
paralysis induced by either vecuronium or
rocuronium after reversal with pyridostigmine.
Anesthesia & Analgesia 2002; 95:1656-1660
•
•
•
•
•
•
•
•

602 pts without nm monitoring
vecuronium or rocuronium
reversal by pyridostigmine 10 or 20 mg/kg
RR TOF ( acceleromyography i)+ head-lift for >5 s + tonguedepressor test.
Postoperative residual curarization(PORC) defined as a TOF
ratio <0.7:
vecuronium, 24.7%; rocuronium, 14.7%
no signif. Diff.in the TOFR between 10 mg and 20 mg of
pyridostigmine.
The patients with residual block had several associated factors:
1) absence of perioperative neuromuscular monitoring
2)the use of pyridostigmine, which is less potent than neostigmine,


21 % !!!

Effetti collaterali degli anti
AchE

Effetti fisiologici della presenza
di Ach
•
•
•
•

Bradicardia
Salivazione
Iperperistalsi
Secrezioni bronchiali

Meuret P,Backman SB, Bonhomme V, Plourde
G,Fiset P.Physostigmine Reverses Propofol-induced
Unconsciousness and Attenuation of the Auditory
Steady State Response and Bispectral Index in
Human Volunteers . Anesthesiology 93:708-17, 2000
•

•

•

Background: It is postulated that alteration of central cholinergic
transmission plays an important role in the mechanism by which
anesthetics produce unconsciousness. The authors investigated the
effect of altering central cholinergic transmission, by physostigmine and
scopolamine, on unconsciousness produced by propofol.
Methods: Propofol was administered to American Society of
Anesthesiologists physical status 1 (n = 17) volunteers with use of a
computer-controlled infusion pump at increasing concentrations until
unconsciousness resulted (inability to respond to verbal commands,
abolition of spontaneous movement). Central nervous system function
was assessed by use of the Auditory Steady State Response (ASSR)
and Bispectral Index (BIS) analysis of electrooculogram. During
continuous administration of propofol, reversal of unconsciousness
produced by physostigmine (28 mg/kg) and block of this reversal by
scopolamine (8.6 mg/kg) were evaluated.

Meuret P et al .Physostigmine Reverses Propofolinduced Unconsciousness and Attenuation of the
Auditory Steady State Response and Bispectral
Index in Human Volunteers . Anesthesiology 93:70817, 2000
•

•

Results: Propofol produced unconsciousness at a plasma concentration of
3.2 ± 0.8 (± SD) mg/ml (n = 17). Unconsciousness was associated with
reductions in ASSR (0.10 ± 0.08 mV [awake baseline 0.32 ± 0.18 mV], P <
0.001) and BIS (55.7 ± 8.8 [awake baseline 92.4 ± 3.9], P < 0.001).
Physostigmine restored consciousness in 9 of 11 subjects, with concomitant
increases in ASSR (0.38 ± 0.17 mV, P < 0.01) and BIS (75.3 ± 8.3, P <
0.001). In all subjects (n = 6) scopolamine blocked the physostigmineinduced reversal of unconsciousness and the increase of the ASSR and BIS
(ASSR and BIS during propofol-induced unconsciousness: 0.09 ± 0.09 mV
and 58.2 ± 7.5, respectively; ASSR and BIS after physostigmine
administration: 0.08 ± 0.06 mV and 56.8 ± 6.7, respectively, NS).
Conclusions: These findings suggest that the unconsciousness produced
by propofol is mediated at least in part via interruption of central cholinergic
muscarinic transmission.

Effetti della fisostigmina sul Auditory steady state
response (ASSR) :basale,dopo propofol,dopo
fisostigmina e al risveglio.

Effetti della fisostigmina sul BIS :basale,dopo
propofol,dopo fisostigmina e al risveglio.

Pericoli degli AntiAchE: arresto
cardiaco
•

Bjerke, Richard J., MD; Mangione, Michael P.Asystole after
intravenous neostigmine in a heart transplant
recipient.Can.Anaesth.J. 2001;48:305-07.

•

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
risposta ventricolare…..
•

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,
Yahatahigashi-ku,
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.

Caldwell JE. Reversal of residual nm block with
neostigmine qt 1 to 4 hours after a single intubating
dose of vecuronium.Anesth.Analg 1995;80:1168-74
•

The purpose of this study was to measure the degree of residual neuromuscular
block at different times after a single dose of vecuronium, and to evaluate the
effectiveness of two different doses of neostigmine in antagonizing this residual
block. Train-of-four (TOF) ratios were examined for up to 4 h after a single dose
of vecuronium, 0.1 mg/kg, in 60 patients during nitrous oxide/isoflurane/fentanyl
anesthesia. The effect of neostigmine, 40 mg/kg, was studied at 1, 2, 3, or 4 h.
The effect of neostigmine, 20 mg/kg, was studied at 2 or 4 h after the
vecuronium. Before neostigmine administration, the TOF ratio was less than
0.75 in 17 patients (including one patient at 4 h). Neostigmine produced an
increase in TOF ratio in 52 patients and a decrease in 8. The TOF ratio
decreased after neostigmine only, at 2, 3, or 4 h after vecuronium, when the
TOF ratio was ³0.9 and when neostigmine 40 mg/kg was administered. One
patient, at 1 h, had a TOF ratio of 0.00 and this did not reach 0.75 until 57 min
after neostigmine, 40 mg/kg. There was a high incidence (50%) of adverse
cardiovascular effects after both doses of neostigmine. In making the decision as
to whether neostigmine should be administered, the risk to the patient of residual
neuromuscular block must be balanced against the adverse cardiovascular
effects of the neostigmine.

• 10-20% incidenza di aritmie(ritmi giunzionali)
• This study had three important findings: 1)
clinically significant residual neuromuscular
block (TOF ratio <0.75) could be present for up
to 4 h after a single dose of vecuronium 0.1
mg/kg; 2) neostigmine in a dose of 40 mg/kg,
but not 20 mg/kg, could produce a decrease in
the TOF ratio; 3) both doses of neostigmine and
glycopyrrolate are associated with clinically
significant cardiovascular effects.

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
anticholinesterase drugs.Can.Anaesth.J.1998;45:1190-95
phosphaticlylinositol (PI)
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
drugs.Can.Anaesth.J.1998;45:1190-95

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!!!

Antagonism of mivacurium
block
• 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
variability high:

Dott. Melloni:
Dott. Melloni:
cDevcic et
cDevcic et
al.Anesthesia
al.Anesthesia
Analgesia,1995,8
Analgesia,1995,8
1:1005-1009
1:1005-1009

Antagonism of deep mivacurium
block.
placebo
edrophonium

20

neostigmine

15
nin 10
5

neostigmine

0

placebo
T1
25%

T1
50%

T1
75%

TOF
25%

TOF
50%

TOF
75%

Lien CA,Belmont MR,Wray R, Doreen L,Okamoto M,Abalos
A,Savarese JJ.Pharmacodynamics and the Plasma Concentration of
Mivacurium during Spontaneous Recovery and Neostigminefacilitated Recovery .Anesthesiology 91:119-26, 1999

• Background: The authors examined the plasma
concentrations of the isomers of mivacurium and
its pharmacodynamics during spontaneous and
neostigmine-facilitated recovery after a
mivacurium infusion.
•
Methods: Sixteen patients receiving nitrous
oxide—opioid anesthesia received 0.25 mg/kg
mivacurium. Patient response to neuromuscular
stimulation was determined using a
mechanomyograph. Once T1 had recovered to
25% of its baseline height, a mivacurium
infusion was begun and adjusted to maintain 95
—99% neuromuscular block. The infusion was

Attività della colinesterasi plasmatica espressa
come % rispetto al valore basale di attività al termine
dell’infusione di mivacurium Lien CA,Belmont MR,Wray R, Doreen
L,Okamoto M,Abalos A,Savarese JJ.Pharmacodynamics and the Plasma Concentration of
Mivacurium during Spontaneous Recovery and Neostigmine-facilitated Recovery .Anesthesiology
91:119-26, 1999

Ripresa spontanea
Ripresa spontanea

Ripresa dopo neostigmin
Somm. A T1 25%

Farmacodinamica della ripresa dopo mivacurium
,spontanea e indotta da neostigmina(somm al T1
25%)

Lien CA,Belmont MR,Wray R, Doreen L,Okamoto M,Abalos A,Savarese

JJ.Pharmacodynamics and the Plasma Concentration of Mivacurium during Spontaneous Recovery
and Neostigmine-facilitated Recovery .Anesthesiology 91:119-26, 1999

20

*

18

*

16
14

12
min
10

*

8

spontaneo

6
4

indotto da
neostigmina

2
0
T1 25%

T1 75%

T! 95%

TOF 70%

TOF 90%

Concentrazioni degli isomeri del
mivacurium al termine della
infusione

Lien CA,Belmont MR,Wray R, Doreen L,Okamoto M,Abalos A,Savarese

JJ.Pharmacodynamics and the Plasma Concentration of Mivacurium during Spontaneous Recovery
and Neostigmine-facilitated Recovery .Anesthesiology 91:119-26, 1999

Baurain, M. J.; Dernovoi, B. S.; d'Hollander,A.;
Hennart, D. A. Comparison of neostigmine
induced recovery with spontaneous recovery
from mivacurium induced block.BJA 1994;73:791•
794.
• In 24 ASA I–II adults anaesthetized with
thiopentone, fentanyl and nitrous oxide in
oxygen, we studied neuromuscular transmission
with isometric adductor pollicis monitoring.
Patients received mivacurium 0.2 mg kg-1
followed by an infusion lasting at least 60 min
and adjusted to maintain twitch height at 1–5%.
After termination of the mivacurium infusion,
when twitch height spontaneously regained 25%
of its control value, the patients were allocated to
two groups of 12 patients each. In group NEO
patients received neostigmine 40 mg kg-1 and

Recovery indexes following discontinuation of
mivacurium infusion;neostigmine vs spontaneous
Baurain, M. J.; Dernovoi, B. S.; d'Hollander,A.; Hennart, D. A. Comparison of neostigmine induced
recovery with spontaneous recovery from mivacurium induced block.BJA 1994;73:791-794.

14
12
10
min

8
6

Neostigm
spont

4
2
0
end
infusT125%

t1 2575%

T1 25- T1 25% T1 25%90% tof 70% Tof90%

TOFR Evolution at T1 25% following mivacurium
discontinuation:neostigmine vs spontaneous
recovery:Baurain, M. J.; Dernovoi, B. S.; d'Hollander,A.; Hennart, D. A. Comparison of
neostigmine induced recovery with spontaneous recovery from mivacurium induced block.BJA
1994;73:791-794.

Purified human plasma cholinesterase
Naguib et al.Anesthesiology 1995;82:1288.

Effetti analgesici
• 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.

Rapporti di potenza antagonistica per
neostigmina e edrofonio (da Donati AA 1989,Smith
Anesthesiology 1989,Naguib Anesthesiology 1993,Naguib BJA 1993)

DTC

PANC

VECU

ATRAC ROCU MIVA

ED50

17±1

13±2

10±1

10±1

17±1

2±0.1

ED80

45±3

45±6

24±2

22±2

33±1

5±0.1

ED50

270±27

170±24

180±50

110±30

161±10

3±0.1

ED80

880±93

680±102

460±13

440±110

690±10

9±0.1

Neostigmina

Edrofonio

Comportamento suggerito per l’antagonismo dei
miorilassanti a lunga e media durata di azione secondo
le risposte al Tof
TOF

esaurimento

farmaco

dose

nessuno

Posponi
antagonismo

Finchè almeno 1 o 2
contrazioni
visibili!!

1-2

++++

neostigmina

0.07 mg/kg

3-4

+++

neostigmina

0.04 mg/kg

4

++

edrofonio

0.5 mg/kg

4

+/-

edrofonio

0.25

Twitch visibili

Kirkegaard H,Heier T,Caldwell JE Efficacy of tactile
guided reversal from cisatracurium induced
neuromuscular block.Anesthesiology 2002;96:45-50

• Anest with fent/prop/N2O
• cisatrac 0.15 mg/kg
• neostigmine 0.07 mg/kg administered at
reappearance of I,II,III,IV of TOF;tactile vs
Meccanomyography contralateral.

Time from neostigmine
administration to TOFR 0.80


80

25,00

70
20,00
low
max
min
mediana

15,00
10,00
5,00

60
low
max
min
mediana

50
40
30
20

0,00
I twitch

II twitch

III twitch

10

IV twitch

0
I twitch

II twitch

III twitch

IV twitch

MMG magnitude of the first TOF twitch(T1)
measured at the reappearance of each of the 4
tactile TOF responses.

80

80

70

70

60
40
30
20

T1 %

60

low
max
min
mediana

50

low
max
min
mediana

50
40
30
20
10

10

0

0
I twitch

II twitch

III twitch

IV twitch

I twitch

II twitch

III twitch

IV twitch


• This study shows that achieving a
TOFR of 0.90 in <10 min following
neostigmine reversal is not a
realistic goal;therefore counting the number of
tactile responses to tof stimulation cannot be used as
a guide for neostigmine admninistration if the end
point of reversal is a TOFR of 0.90 or higher within 10
min;but is a good predictor of TOFR

0.70.

Kopman et al.Relationship of the train of four fade
ratio to clinical signes and symptoms of residual
paralysis in awake
volunteers.Anesthesioloogy,1997;86:765-71.

•
•
•
•
•
•

Volontari sani
infusione di mivacurium
monitoraggio Datex 221 NMT
valutazione;stretta di mano
sollev,testa & gamba per 5 sec.
Ritenzione di abbassalingua

Clinical signs of residual weakness vs tof at
the AP(Kopman,Anesthesiology,1997;86:765-71)
0,90
0,80
0,70
0,60
0,50
0,40
0,30
0,20
0,10
0,00

head lift
leg lift
retain tongue
depressor

lowest tof

highest tof

at which test passed or failed

Osservazioni cliniche sulla relazione fra tof e
correlati di forza:

• disturbi visivi sempre con tof di
0.90(diplopia,diff.seguire oggetti in moto,ecc)
• forza dei masseteri ridotta sempre
• sollev.testa e gamba sempre possibile > 0.60
• stretta di mano variabile,ma 83% del basale a
tof 0.90
• per tof < 0.75 tutti disturbati

Conclusioni delle correlazioni fra segni clinici di
forza muscolare e tof

• Capacità di ritenzione dell’abbassalingua è un
test più sensibile del sollevamento del capo
• tof <1 ancora residuano disturbi visivi e senso
generalizzato di fatica
• tof = 1 (o altri monitoraggi) per dimissione in
chirurgia ambulatoriale??

Assiomi della ripresa nm.
• TOF > 0.70 sicuro indice della ripresa
nm……….. Ali HH, Wilson RS, Savarese JJ, Kitz RJ:
The effect of tubocurarine on indirectly elicited train-offour muscle response and respiratory measurements in
humans. Br J Anaesth 47:570-4, 1975
• Brand JB, Cullen DJ, Wilson NE, Ali HH: Spontaneous
recovery from nondepolarizing neuromuscular blockade:
Correlation between clinical and evoked responses.
Anesth Analg 56:55-8, 1977

Mutazioni occorse
• Esplosione della chirurgia ambulatoriale
• pressione per la diminuzione della spesa
sanitaria
• aumento delle persone anziane e
debilitate anche in chir amb.
• Disponibilità di nuovi farmaci

Implicazioni del lavoro di
Kopman:1
• I paz chirurgici sono in genere più anziani e ammalati
dei volontari sani dello studio di Kopman/( ASA 1,
entro il 15% del peso ideale,tra 23—33 anni….)
• gli effetti residui dei miorilassanti è probabile possano
essere + significativi nella pratica ambulatoriale con
pazienti + anziani e debilitati.
• Si potrebbe arguire che i paz.con sedazione residua
siano meno attenti a disturbi visivi e
• debolezza dei muscoli facciali;ma è anche vero che
dal punto di vista della sicurezza i paz postop siano
esposti a rischio maggiore di aumento della
morbilità,poichè la debolezza residua nm può essere
aggravata da residui dell’anestesia.

Implicazioni del lavoro di
Kopman:2
• mivacurium non è rappresentativo dei miorilassanti
usati in chir amb;il mercato è dominato dai
miorilassanti ad azione intermedia quali vecuronium,
atracurium, rocuronium, cisatracurium
• se una paralisi residua permane per un’ora dopo
interruzione del mivac,caratterizzato da un RI di pochi
min,che succede dopo la somministrazione dei mioril
a durata intermedia(RI 20-30 min )?

Conclusions form
Kopman,Brull,Erikkson…..
•

indicators of recovery of nm function should be
changed.

• The TOF ratio <0.9 was also associated with functional
impairment of the pharynx and upper correlated
volunteers' subjective feelings of partial neuromuscular
weakness with the clinical counterpart of neuromuscular
recovery. All subjects had significant signs and symptoms
of residual paralysis at a TOF ratio of 0.7 and satisfactory
recovery of neuromuscular function after mivacuriuminduced neuromuscular block required return of the TOF
ratio to >0.9 . According to these studies, the absence of
muscle relaxant-induced clinical effects may be defined as
the return to a TOF ratio ³0.9 at the AP.

Ciclodestrine……….
• Gamma CD le + potenti
• Potenza di legame legata al diametro
della cavità interna(> 7.5 A) lipofilica
• Elevata idrosolubilità
• Ottima tolleranza biologica
• Inclusione del miorilassante all’interno
della cavità :incapsulazione

Infusion of Org 25969 at a rate of 50 nmol·kg-1·min-1 caused
rapid reversal of neuromuscular block, combined with an
increase in plasma concentration of rocuronium (free and
bound to Org 25969).

Gijsenberg F, Ramael S, De Bruyn S, Rietbergen,
van Iersel T. Preliminary assessment of Org 25969
as a reversal agent for rocuronium in healthy male
volunteers. Anesthesiology 2002; 96: A1008
Placeb ORG
o
25969
Mg/kg 0,1
0,5

1,0

2,0

5,0

35-69

23-31

13-17

2,5-3,2 1-1,2

43

71

Min for TOF 0.90

8,0

Effect of Org 25969 on recovery from rocuroniuminduced neuromuscular block after bilateral renal
ligation
35

spont norm

30

spont art ren legate

25

org25969 norm

20

org 25969 art ren
legate

15
10
5
0
onset
time

block
50%
90%
duration recovery recovery

25-75%

Problems of tactile or visual assesment
using
ST
basal

TOF
fade assessment needs
experience

frequence..
sensibility when IV reappears:which
is the IV/I ratio > 25-30%?

tetanic
fade assessment
needs experience
do not repeat < 5
min..

tactile assessment

Tetanus
DBS
TOF

Correlazione soggettiva-oggettiva(palpazionemeccanomiografia)

• 1 Twitch= T110%
• 3 twitches=T1 25%

Clinical signs
correlation with residual force

patient cooperation!

tongue
tongue
depressor
depressor
clenching
clenching

head lift
head lift
> 5 sec
> 5 sec

arm or leg
arm or leg
lift> 5 sec
lift> 5 sec

sustained
sustained
hand grip
hand grip
strenght
strenght

clinical signs
reliable vs not reliable
reliable vs not reliable

TV normal
TV normal

Neg Press < 25 mmHg
Neg Press < 25 mmHg

Neg press < 50 mmHg
Neg press < 50 mmHg

cough
cough

eye opening
eye opening

tongue protrusion
tongue protrusion

unreliable
unreliable
unreliable
unreliable

reliable
reliable

unreliable
unreliable

unreliable
unreliable

unreliable
unreliable

before patient cooperationri....
before patient cooperationri....

Special neuromuscular
monitoring
Mantiene quello che
promette?

TOF,DBS , Tetanus

Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)

Drenck NE, Ueda N, Olsen NV, et al. Manual
evaluation of residual curarization using double
burst stimulation: A comparison with train-of-four.
Anesthesiology 1989; 70:578-81

• - Double burst stimulation (DBS) is a new mode of stimulation

developed to reveal residual neuromuscular blockade under
clinical conditions. The stimulus consists of two short bursts of
:
50 Hz tetanic stimulation, separated by 750 ms, and the
response to the stimulation is two short muscle contractions.
Fade in the response results from neuromuscular blockade as
AB
with train-of-four stimulation (TOF). The authors compared the
sensitivity of DBS and TOF in the detection of residual
neuromuscular blockade during clinical anaesthesia. Fifty-two
healthy patients undergoing surgery were studied. For both
stimulation patterns the frequencies of manually detectable
fade in the response to stimulation were determined and
compared at various electromechanically measured TOF ratios.
A total of 369 fade evaluations for DBS and TOF were
performed. Fade frequencies were statistically significantly higher

Probability of being within defined TOFR intervals
when different clinical fade evaluations are given
(Drenck NE, Ueda N, Olsen NV, et al. Manual evaluation of residual
curarization using double burst stimulation: A comparison with train-of-four.
Anesthesiology 1989; 70:578-81)

60
50
40

tof<0.4
tof 0.41-0.50
tof 051-0.60
tof 0.61-0.70
tof >0.70

% 30
20
10
0
no tof fade

no tof,no dbs fade fade in dbs,not tof

Dbs 3-3
Drenck NE, Ueda N, Olsen NV, et al. Manual evaluation of residual curarization
using double burst stimulation: A comparison with train-of-four. Anesthesiology
1989; 70:578-81)

• Absence of fade with tof implies a 52%
probability than tof>0.60
• absence of fade with dbs implies a tof >0.60 in
91% of cases
• only tOFR<0.40 can be assessedd manually
• therefore,evaluation of DBS is relevant only
when there is no fade to tof

Conclusions:
Drenck NE, Ueda N, Olsen NV, et al. Manual evaluation of residual curarization
using double burst stimulation: A comparison with train-of-four. Anesthesiology
1989; 70:578-81)

• absence of fade to DBS normally
excludes severe residual nm
blockade(tofr<0.60) BUT DOES
NOT NECESSARILY INDICATE
ADEQUATE CLINICAL RECOVERY.

Meccanomiographic vs tactile
evaluation
Drenck et al.Anesthesiology 79;578:1989.

qualitative tof
evaluation

48% chances of
evaluating a real fade

qualitative DBS
evaluation

9% chances of non
discerning a real fade

Viby-Mogensen J, Jensen NH, Engbæk J, Ørding H,
Skovgaard LT, Chæmmer-Jørgensen B. Tactile and
visual evaluation of response to train-of-four nerve
stimulation. Anesthesiology 1985; 63:440-3.

• Diaz/tps/N2O 66%/haloth 0.75-1.5%
• IOT with SCC ,then panc
• simult MMG in one arm & visual/tactile
evaluation in the opposite.
• Experienced and (inexperienced)
anesthesiologists
• 6 different TOFR forn every patient

Viby-Mogensen et al Tactile and visual evaluation of
response to train-of-four nerve stimulation.
Anesthesiology 1985; 63:440-3.
100
90
80
70
60
fade
observed 50
40
%
30

true tofr <0.30
true tof 0.31-0.40
true tof 0.41-0.50
true tof 0.51-0.60
true tof 0.61-0.70
true tof>0.70

20
10
0
inexp.observers

exp.observers

Threshold fade by 3 very experienced
observers (Viby-Mogensen et al. Tactile and visual evaluation of
response to train-of-four nerve stimulation. Anesthesiology 1985; 63:440-3 )

0,7
0,6
0,5
0,4

onset
offset

0,3
0,2
0,1
0

visual

manual

Threshold fade by 3 very experienced
observers (Viby-Mogensen et al. Tactile and visual evaluation of

TOFR

response to train-of-four nerve stimulation. Anesthesiology 1985; 63:440-3.)
1
0,9
0,8
0,7
0,6
0,5
0,4
0,3
0,2
0,1
0

max
min
mean

visual onset

visual recovery

manual onset manual recovery

• Which is the TOFR level that can be
reliably detected visually by observing
tetanic fade of the AP in response to
100-Hz, 5-s tetanus in anesthetized
patients.?

Baurain M,Hennart DA,Godschalx A,Huybrechts I,Nasrallah
G,d'Hollander AA., Cantraine F.Visual Evaluation of Residual
Curarization in Anesthetized Patients Using One HundredHertz, Five-Second Tetanic Stimulation at the Adductor Pollicis
• We were looking for a .Anesth Analg 1998; 87:185–9
Muscle clinical test to indicate a train-of-four (TOF) ratio of
approximately 0.9. We compared the adductor pollicis muscle (AP) visually
evaluated response to ulnar nerve 100-Hz, 5-s tetanus (RF100 Hz) with the
measured AP TOF ratio in 30 ASA physical status I or II adult anesthetized
(propofol, sufentanil, N2O/O2) patients. After the induction of anesthesia,
the left ulnar nerve was stimulated at the wrist (single twitch and TOF) and
the resultant isometric force was measured. When TOF was assessed, the
independent investigators, unaware of the left AP-measured TOF ratios,

visually evaluated the presence or absence of AP fading elicited by right
ulnar nerve 100-Hz, 5-s tetanus. The 30 patients were randomly allocated to
receive either 0.5 mg/kg atracurium (n = 15) or 0.1 mg/kg vecuronium (n =
15). The neuromuscular blockade was allowed to resolve spontaneously. A
multiple logistic regression analysis was performed by computing the 771
visual observations. The probabilities of success of 100-Hz, 5-s tetanus to
detect TOF ratios of 0.8, 0.85, and 0.9 were 99%, 96%, and 67%,
respectively. The sensitivity and specificity of 100-Hz, 5-s tetanus as an
indicator of TOF ratios of 0.85 and 0.9 are 100% and 75%, 54% and 67%,
respectively. We conclude that RF100 Hz visual assessment seems to be

Baurain et al.Visual Evaluation of Residual
Curarization in Anesthetized Patients Using One
Hundred-Hertz, Five-Second Tetanic Stimulation at
the Adductor Pollicis Muscle .Anesth Analg 1998;
87:185–9

Saitoh, Y, Narumi Y,Fujii Y, Ueki M. Tactile
evaluation of fade of the train-of-four and doubleburst stimulation using the anaesthetist's nondominant hand Br. J. Anaesth. 1999; 83:275-278
• We have studied detection of fade in response to train-of-four
(TOF), double-burst stimulation3,3 (DBS3,3) or DBS3,2,
assessed tactilely by the anaesthetist using the index finger of
the non-dominant hand and the thumb of the patient, compared
with that assessed when the index finger of the dominant hand
was used. The probability of detection of any fade in response
to TOF or DBS3,3 using the non-dominant hand was
significantly less than when the dominant hand was used
(P<0.05). The probability of identification of fade in response to
DBS3,2 assessed using the non-dominant hand was
comparable with that evaluated using the dominant hand when
TOF ratios were 0–0.9, but when TOF ratios reached 0.91–
1.00, detection using the non-dominant hand was significantly
less common than with the dominant hand (12% vs 33%;

Saitoh Y,Nakazawa K, Makita K,Tanaka H, Amaha
K.Evaluation of Residual Neuromuscular Block
Using Train-of-Four and Double Burst Stimulation at
the Index Finger Anesth Analg 1997; 84:1354
• We examined the percentage of tactile detection
of fade in response to train-of-four (TOF), double
burst stimulation3,3 (DBS3,3), or DBS3,2 at the
index finger compared with that at the thumb
during continuous infusion of vecuronium. One
hundred five adult patients were studied. At TOF
ratios (T4/T1) of 0.41–0.70, fades in response to
TOF were more frequently identified by tactile
means at the index finger than at the thumb
(58% vs 26%, P < 0.05). Similarly, at TOF ratios
of 0.61–0.90, fades in response to DBS3,3 were
more frequently detected at the index finger than
at the thumb (55% vs 15%, P < 0.05), and at

Percentage of tactile detection of fade in response to TOF at
the index finger compared with that at the thumb during
continuous infusion of vecuronium (Saitoh Y,Nakazawa K, Makita
K,Tanaka H, Amaha K.Evaluation of Residual Neuromuscular Block Using Train-of-Four
and Double Burst Stimulation at the Index Finger Anesth Analg 1997; 84:1354)

True tof

index

>0,90

0,81-0,90

0,71-0,80

0,61-0,70

0,51-0,60

0,41-0,50

0,31-0,40

0,21--0.30

<0,20

thumb

100
80
60
true
40
20
0

<0,20
0,21--0.30
0,31-0,40
0,41-0,50
TOFR
0,51-0,60
0,61-0,70
0,71-0,80
0,81-0,90
>0,90

Percentage of tactile detection of fade in response to DBS 3,3
at the index finger compared with that at the thumb during
continuous infusion of vecuronium (Saitoh Y,Nakazawa K, Makita
K,Tanaka H, Amaha K.Evaluation of Residual Neuromuscular Block Using Train-of-Four
and Double Burst Stimulation at the Index Finger Anesth Analg 1997; 84:1354)

100
80
60 true
40TOFR
20
0

index
0-0,40 0,41- 0,51- 0,61- 0,71- 0,81- >0,90
0,50 0.60 0,70 0,80 0,90

0-0,40
0,41-0,50
0,51-0.60
0,61-0,70
0,71-0,80
0,81-0,90
>0,90

At TOFR>0.60 fade at index 55% vs thumb 15%

Correlaz clinico-meccaniche del
monitoraggio nm
• Pohihill SL BrJ Anaesth 1998
• Acta Anesth Belg.1999 Fezing AK

Mahdy AM. Tactile evaluation of the response
to double burst stimulation decreases, but not
eliminates, the problem of postoperative
residual paralysis. Acta Anaesthesiol Scand
• BACKGROUND: Routine perioperative monitoring with accelero-myography
1998; 42:1168-74
might prevent residual block, whereas routine tactile evaluation of the
response to train-of-four (TOF) nerve stimulation does not. The purpose of
this prospective, randomised and blinded study was to evaluate the effect of
manual evaluation of the response to double burst stimulation (DBS3.3)
upon the incidence of residual block. METHODS: Sixty adult patients
scheduled for elective abdominal surgery were included in the study.
Pancuronium 0.08 to 0.1 mg kg-1 was given for relaxation and tracheal
intubation. For maintenance of neuromuscular block, pancuronium 1-2 mg
was administered. The patients were randomly allocated into two groups. In
group DBS (double burst stimulation) the degree of block during
anaesthesia was assessed by manual evaluation of the response to TOF
nerve stimulation. During reversal, when no fade was detectable in the TOF
response, the stimulation pattern was changed to DBS3.3. The trachea was
extubated when the anaesthetist judged the neuromuscular function to have
recovered adequately and no fade in the DBS3.3 response could be felt. In
group CC (clinical criteria) patients were managed without the use of a
nerve stimulator, and the level of neuromuscular block and reversal were
evaluated solely on the basis of clinical criteria. In both groups, the TOF

Shorten GD, Merk H, Sieber T. Perioperative
train-of-four monitoring and residual
curarization. Can J Anaesth 1995; 42:711-15
•

It has been suggested that perioperative train-of-four (TOF)
monitoring does not reduce the incidence of postoperative
residual curarization (PORC). The purpose of this study was to
examine whether the use of tactile assessment of the
response of the adductor pollicis to supramaximal TOF
stimulation of the ulnar nerve at the wrist during anaesthesia
affected the incidence of PORC. Thirty-nine ASA I or II
surgical patients were studied during thiopentone/fentanyl
N2O/enflurane anaesthesia. Pancuronium (70-100
micrograms.kg-1) was used to facilitate tracheal intubation and
additional pancuronium increments used to maintain surgical
relaxation. The requirement for incremental doses of
pancuronium and adequacy of recovery following reversal
were assessed according to random allocation, either with
(Group A; n = 20) or without (Group B; n = 19) access to TOF
monitoring. Patients in the two groups received neostigmine in
similar doses (Group A: 53 micrograms.kg-1 (5.9); Group B:
55 micrograms.kg-1 (5.4)). On arrival of the patient to the
recovery area, neuromuscular function was assessed

Cominciano le doppie….o le
esplicative

• Fisher DM, Cronnelly R, Miller RD. The
neuromuscular pharmacology of neostigmine in
infants and children. Anesthesiology 1983;
59:220-5.
• 2: 3: Meyer HS, Lukey BJ, Gepp RT, et al. A
radioimmunoassay for pyridostigmine. J
Pharmacol Exp Ther 1988; 2:432-8.
• 7: Matteo RS. Use in the elderly. Clin
Anesthesiol 1985; 3:421-34.
• 8: Bevan DR, Donati F, Kopman AK. Reversal
of neuromuscular blockade. Anesthesiology
1992; 77:785-805.

Pharmacoeconomics of
Neuromuscular Blocking
Drugs. Anesthesia & Analgesia.
90(5S) Supplement:S19-S23,
May 2000.

Zhou TJ,Chiu JW, White PF,Forestner JE,Murphy
MT Reversal of rocuronium with edrophonium
during propofol versus sevoflurane anesthesia. Acta
Anaesthesiologica Scandinavica. 45;246-249:2001.

Cutter TW. What is the role of neuromuscular
blocking drugs in ambulatory anesthesia? Current
Opinion in Anaesthesiology. 15:635-639, 2002.

action of neostigmine and pyridostigmine in
the elderly. Anesth Analg 1988; 67:775-8.

Rivalutazione della pratica
clinica
• Età e stato di salute differiscono fra volontari sani
e pazienti!
• La prassi clinica e l’utilizzo dei miorilassanti
variano fra i diversi centri ambulatoriali
• il monitoraggio degli effetti nm non è praticato in
ospedale,figurarsi nei centri ambulatoriali!
• I metodi di monitoraggio usati da Kopman et al si
applicano ad una ampia gamma di situazioni
cliniche.
• Esistono pesanti pressioni economiche per la
diminuzione della spesa sanitaria.

25,00
20,00
low
max
min
mediana

15,00
10,00
5,00
0,00
I twitch

II twitch

III twitch

IV twitch

80
70
60
low
max
min
mediana

50
40
30
20
10
0
I twitch

II twitch

III twitch

IV twitch

MMG magnitude of the first TOF twitch(T1)
measured at the reappearance of each of the 4
tactile TOF responses.
80
70

T1 %

60
low
max
min
mediana

50
40
30
20
10
0
I twitch

II twitch

III twitch

IV twitch

• Eventuale altra figura del file **90813
• Lavori su fx501…………

• Pyridostigmine, like neostigmine and many nondepolarizing
muscle relaxants, has a prolonged duration of action in the
elderly . This study demonstrates a decreased plasma
clearance of pyridostigmine in the elderly which we believe
to be the probable explanation.
•
By comparing the elimination half-life of pyridostigmine in
anephric patients and those with normal renal function,
Cronnelly et al. . determined that approximately 75% of IV
administered pyridostigmine is eliminated by the kidneys.
Patients with normal renal function cleared pyridostigmine
through the kidneys much faster than could be achieved by
glomerular filtration alone . Consequently, renal tubular
secretory function must play a major role in the excretion of
pyridostigmine .

•

•

Abnormal renal function has a profound effect on the
excretion of pyridostigmine, and renal function declines with
aging. In fact, deterioration occurs at a rate of approximately
1% per year after middle age . Parenchymal mass is lost as
nephrons decrease in size and number. Sclerotic changes
in renal vasculature limit the effective glomerular filtering
surface and decrease renal cortical blood flow and
glomerular filtration. Renal tubular function wanes to an
even greater extent. Serum creatinine, however, usually
remains within normal limits, because muscle atrophy and
the creatinine load decrease comparably .

•

•

The elderly patients in this study all appeared to have
normal renal function, as every individual's blood
chemistry screening test was within normal limits for our
laboratory. Nevertheless, it was not unexpected that the
mean blood urea nitrogen level was higher in the elderly
group than in the younger controls. Had we measured
urinary pyridostigmine clearance, a more specific and
quantitative comparison would have been possible.
Hepatic function, cardiac reserve, and blood volume also
decline with advancing age, but these are relatively small
changes and should have only minor effects on the
kinetics of pyridostigmine, a drug excreted primarily by
the kidneys .

•

Although the elderly patients in this study demonstrated a
decreased plasma clearance for pyridostigmine, significant
differences between groups were not demonstrable for
volumes of distribution or elimination half-life. The mean
values indicated a tendency for the elderly population to
have smaller volumes of distribution and a greater
elimination half-life, and perhaps statistical significance
would have been achieved if plasma sampling continued
beyond 6 h or if group size had been larger. It is well
established that elderly patients have a diminished body
water content and a smaller cellular mass . Elimination halflife is derived from plasma clearance and volume of
distribution , and since both are usually decreased in the
elderly, elimination half-life may remain unchanged. Indeed,
it has been pointed out that elimination half-life may not be
an accurate reflection of drug excretion , and that plasma
clearance is the best pharmacokinetic indicator of an

•

In young adult patients with normal renal and hepatic
function, there are not significant pharmacokinetic
differences between pyridostigmine, neostigmine, and
edrophonium . Nevertheless, elimination half-life and
plasma clearance of the anticholinesterase drugs used in
anesthesia tend to be influenced by age. For instance,
Fisher et al. found that when neonates, children, and young
adults received neostigmine or edrophonium to antagonize
incomplete neuromuscular blockade, the younger patients
demonstrated progressively shorter elimination half-life
values and progressively faster plasma clearance values.
The groups were small and, although a tendency was
evident, differences did not always achieve statistical
significance. Similarly, Matteo et al. compared kinetic
variables in elderly patients and younger adults after they
received edrophonium. Again aging was associated with a

• To accurately determine anticholinesterase onset
times and peak action times, steady-state
neuromuscular blockade should first be established by
constant infusion . Our group has already done a fullfledged pharmacodynamic study of pyridostigmine . It
required a time-consuming and cumbersome protocol
which we elected not to repeat for this
pharmacokinetic study. Nevertheless, pyridostigmine
onset and peak action times were estimated for the
two groups, and the validity of the data is confirmed by
previous work . Both the young and the elderly
patients demonstrated the same onset times and very
similar initial volumes of distribution. As cardiac index
decreases only slightly throughout adult life in healthy,

•

patients were premedicated with midazolam 0.05 mg/kg IM approximately 1 h
before the operation. Anesthesia was induced with thiopental 3–5 mg/kg and
fentanyl 2 mg/kg until the patient was asleep and maintained with either 1%–
2% enflurane or 1%–1.5% isoflurane and 50% N2O in oxygen. Endotracheal
intubation was performed after the administration of either vecuronium 0.1
mg/kg or rocuronium 0.6 mg/kg. If required, relaxation was maintained with a
supplementary dose of either vecuronium 2 mg or rocuronium 10 mg,
respectively, according to the clinical judgement of the anesthesiologist. After
completion of the surgical procedure, a bolus of pyridostigmine was
administered in a dose of either 0.143 mg/kg (equivalent to 10 mg/70 kg) or
0.286 mg/kg (equivalent to 20 mg/70 kg) and glycopyrrolate 8 mg/kg,
respectively. The timing and dose of administration of pyridostigmine were
chosen by the participating anesthesiologist. Adequacy of recovery from
neuromuscular block and the decision to extubate the endotracheal tube
before arrival in the recovery room were based on clinical criteria only.

• There was no difference between adequate
(TOF ratio >0.7) and inadequate (TOF ratio
<0.7) groups concerning ASA physical status,
sex, age, weight, and height. Inadequate
recovery from neuromuscular block in the
recovery room was found in 125 (20.8%)
patients (). There were no differences in TOF
ratio between 10 mg and 20 mg of
pyridostigmine after the use of either
vecuronium or rocuronium. Similarly, no
differences were found between the enflurane or
isoflurane groups. The recovery of TOF ratio
was greater in patients who had received

• Head-lift for 5 s and the tongue-depressor test could
not be sustained by any patients at a TOF ratio of 0.5.
Clinical testing was only possible in cooperative
patients. The failed patients in the 5-s head-lift group
were a larger proportion than those in the tonguedepressor test group after either vecuronium or
rocuronium, respectively (P < 0.001). The TOF ratio of
the recovered patients was greater than that of the
failed patients in the 5-s head-lift group after either
vecuronium or rocuronium, respectively (P < 0.001).
There were no differences in the recovery of TOF ratio
between the 5-s head-lift test and the tonguedepressor test of patients who were either recovered
or failed in the recovery room ().

• The onset of action of neostigmine was seven to
11 minutes. However, pyridostigmine took as
long as 16 minutes to exert its full effect and had
one-fifth the potency of neostigmine . In the
present study, the average time from
pyridostigmine administration to TOF recording
was 28 minutes. Therefore, we suspect that the
difference of potency might be the main reason
for a more frequent incidence of postoperative
residual neuromuscular block after reversal by
pyridostigmine rather than neostigmine.
However, pyridostigmine produced fewer
complications such as bradycardia, increased

• Diapo sull PONV seguono……

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
laparoscopy.BJA 1998;81:757.-760
•
•
•

ABSTRACT:
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
neostigmine 70
micrograms/kg +
glycopyrrolate 10
micrograms/kg,
edrophonium 1 mg/kg +
atropine 10
micrograms/kg.

60
50
40

*

% 30

*

20

saline

10
0

PONV

antiemetici
necess

Vomito entro
24 ore

Ding Y,Fredman B, White PF.Use of mivacurium
during laparoscopic surgery:effect of reversal
drungs on postoperaive recovery.Anesth Analg
1994; 78:450–4
•
•
•
•

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%
+67% N2O
• 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.
80
70

*

*

succi/miva/no antag

60

miva/miva/ no antag

*

50

miva/miva/antag

*

% 40
30
20
10
0

nausea

vomit

antiemetici

neck pain

shoulder pain

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
• iot
• IPPV 66% N2O/ haloth. 0.5%

Incid.di PONV nello studio di
Boeke et al.
20
18
16
14
12
num.paz 10
8
6
4
2
0

*

PONV RR

PONV II

antag
non antag

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
group B.
• 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;
77(Suppl):A1120.

Minilap per PPTL.Tps/succi/iot/fent/isof/N2O
.Stomaco svuotato.
Atrac 0.15 mg/kg.
35
30
25
% 20
15
10
5
0

no antag

*
PONV

A 0.15 micrG/kg + edroph 1
mg/kg
A 0.15 micrg/kg+neo 0.05
mg/kg
A 0.15 icrg/kg+pirido 0.25
mg/KG

• Enzymatic Antagonism of Mivacurium-induced
Neuromuscular Blockade by Human Plasma
Cholinesterase. Anesthesiology. 83(4):694-701,
October 1995.
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,
March 2000.

• Devcic A, Munshi CA, Gandhi SK, Kampine JP:
Antagonism of mivacurium neuromuscular block:
Neostigmine versus edrophonium. Anesth Analg
81:1005-9, 1995<ldn>!
• 12: Szenohradszky J, Lau M, Brown R, Sharma
ML, Fisher DM: The effect of neostigmine on
twitch tension and muscle relaxant concentration
during infusion of mivacurium or vecuronium.
ANESTHESIOLOGY 83:83-7, 1995<ldn>!
• 13: Kao YJ, Le ND: The reversal of profound
mivacurium-induced neuromuscular blockade.
Can J Anaesth 43:1128-33, 1996<ldn>!
• 14: Naguib M, Abdulatif M, Al-Ghamdi A, Hamo

Epemolu O,Bom A,Hope F,Mason R.Reversal of
Neuromuscular Blockade and Simultaneous Increase in
Plasma Rocuronium Concentration after the Intravenous
Infusion of the Novel Reversal Agent Org 25969.
Anesthesiology. 2003;99;632-637

The cyclodextrin derivative Org 25969, which forms
complexes with steroidal neuromuscular blocking
agents, causes selective reversal of normal and
profound neuromuscular block. A nesthesiology
2001; 95: A1020

Mason R, Bom A: Org 25969 causes selective
reversal of neuromuscular block induced steroidal
NMBs in anaesthetised guinea pigs (abstract 18).
Eur J Anaesthesiol 2001; 18 (suppl 23): 100

. Hope F, Bom A: Org 25969 reverses rocuroniuminduced neuromuscular blockade in the cat without
important hemodynamic effects (abstract 17). Eur J
Anaesthesiol 2001; 18 (suppl 23): 99

Neuromuscular blockade induced by steroidal NMBs
can be rapidly reversed by Org 25969 in the
anaesthetized monkey (abstract 19). Eur J
Anaesthesiol 2001; 18 (suppl 23): 100

MacLean EJ, Muir A, Palin R, Rees
DC, Zhang M-Q: Chemical
encapsulation of rocuronium by a
cyclodextrin based synthetic host.
Angew Chem 2002; 41: 265–70
[Context Link]

B,Gronert GA, Moss J.Cholinesterase Inhibition by
Potato Glycoalkaloids Slows Mivacurium
Metabolism Anesthesiology 93:510-9, 2000
• ABSTRACT:
Background: The duration of
action for many pharmaceutical agents is
dependent on their breakdown by endogenous
hydrolytic enzymes. Dietary factors that interact
with these enzyme systems may alter drug
efficacy and time course. Cholinesterases such
as acetylcholinesterase (AChE) and
butyrylcholinesterase (BuChE) hydrolyze and
inactivate several anesthetic drugs, including
cocaine, heroin, esmolol, local ester anesthetics,
and neuromuscular blocking drugs. Natural
glycoalkaloid toxins produced by plants of the
family Solanaceae, which includes potatoes and

• Testo sulla cinetica
edrophonium/enzima…. Da Matteo

• Donati F, Lahoud J, McCready D, Bevan
DR. Neostigmine, pyridostigmine and
edrophonium and neostigmine as
antagonists of deep pancuronium
blockade. Can J Anaesth 1987; 34:589–
93.<ldn>!

• Characterization of the Interactions Between
Volatile Anesthetics and Neuromuscular
Blockers at the Muscle Nicotinic Acetylcholine
Receptor
• ANESTHETIC PHARMACOLOGY
•
• AUTHOR(S): Paul, Matthias, MD, DEAA*; Fokt,
Ralf M.; Kindler, Christoph H., MD, DEAA†;
Dipp, Natalie C. J.; Yost, C. Spencer, MD*
• Volatile anesthetics enhance the neuromuscular
blockade produced by nondepolarizing muscle
relaxants (NDMRs). The neuromuscular junction

• PARASYMPATHOMIMETIC effects of acetylcholinesterase
inhibitors such as neostigmine and edrophonium are thought to
be theoretically inevitable, and side effects, including
bradycardia, bronchoconstriction, and increased bowel
movement, are encountered when used to reverse the muscle
weakness induced by nondepolarizing muscle relaxants. In the
clinical setting, however, the bradycardic effect of edrophonium
was reported to be less potent than that of neostigmine,
although the doses of the drugs to reverse the effects of the
muscle relaxants to a comparable degree were used.
Consistent with the clinical data, Backman et al. suggested that
the bradycardic effect of edrophonium is solely a result of the
anticholinesterase effect, whereas neostigmine possesses an
additional effect on cholinergic receptors within the cardiac
parasympathetic pathway, thereby producing profound
bradycardia. Recently, we also demonstrated that neostigmine

• Molecular cloning studies have identified five subtypes of
muscarinic acetylcholine receptors (mAChRs) (m1–m5)
expressed in various tissues, while pharmacologic studies
revealed four different subtypes of mAChRs (M1–M4) based on
their binding affinities to specific ligands.
• Although recent studies have shown the existence of M1
receptors in ventricular cells, M2 is thought to be the
predominant subtype of cardiac mAChR and mediates the
typical cardiodepressant effects of parasympathetic activation
such as bradycardia. Coexpression of M2 and M3 receptors
seems to be a common feature of smooth muscle cells in
various tissues such as airway and intestinal smooth muscles.
Although the amount of M3 receptors is less than that of M2
receptors in these tissues, the M3 receptors are usually
responsible for the direct contractile effect of muscarinic
agonists on smooth muscles, including guinea pig and human

Anticolinestherases 2004

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