benzylisochinolinum compounds, 2008

I miorilassanti steroidei e benzilisochinolinici

Dott.Claudio Melloni

Storia (Aminosteroidi Benzilisochinoline)

• 1942: Curaro• 1949: d-Tubocurarina• 1951: Succinilcolina

• 1960: Pancuronio• 1964: Alcuronio

• 1980: Atracurio• 1980: Vecuronio• 1992: Mivacurio• 1994: Rocuronio

• 1995: Cisatracurio

Classificazione dei curari:MECCANISMO d’AZIONE

recett.Nicotinico

Depolarizzanti mimano l’azione

dell’Ach depolarizzazione

prolungata la fibra muscolare

ineccitabileSuccinilcolina

(suxametonio)

Non depolarizz.

inibizione competitiva dell’ACh.

Sono antagonizzabili

1. Benzilisochinolinici

2. Aminosteroidei

Curari classificazione Chimica

AMINOSTEROIDEI

(derivati da alcaloidi estratti dalla Malouetia bequaertiana, pianta africana)

Pancuronio (Pavulon) Vecuronio (Norcuron) Rocuronio (Esmeron)

BENZILISOCHINOLINE(derivati da alcaloidi estratti dal

Chondodendrum e Strychnos, piante dell’America del Sud)

Atracurio (Tracrium ) Mivacurio (Mivacron) Cis-Atracurio (Nimbex)

NBM aminosteroidei:CHIMICA

PancuroniumPancuroniumRocuroniumRocuronium

VecuroniumVecuronium

Farmacocinetica

Amine bis quaternarieSuccinilcolinaPancuronioAtracurio

Cisatracurio

Amine mono quaternarieD-tubocurarina

VecuronioRocuronio

Farmacocinetica

Volume di distribuzione• I composti dell’ammonio quaternario -N+- rimangono ionizzati idrosolubili

Vd = ECF (0.2-0.5 L/kg)

Potenza• Bassa affinità – dose alta – inizio rapido

• Elevata affinità – dose bassa – inizio lento

Perfusione• Inizio ritardato con ridotta portata cardiaca

• Flusso ematico regionale

Temperatura• Azione prolungata in condizioni di ipotermia

• Eliminazione di Hoffmann rallentata• Degradazione del Mivacurium indipendente dalla temperatura.

Modello idraulico analogo al modello farmacocinetico tricompartimentale

Pharmacokinetic parameters at different ages

Plasma clearance(ml/kg)

Volume of distribution(ml/kg)

Elimination half life(min)

children adults elderly children adults elderly children adults elderly

Atracurium

5.1-9.1 5.0-6.2 5.4-6.5 113-210 100-140 150-190 14-20 17-23 22-23

Cisatracurium

6.5-6.8 4.1-6.5 5-6.5 85-90 110-180 125- 20 19-25 25-35

Mivacurium

130-230(cis trans,tran

s trans)

40-120 54 5.5/51/30 each isomer

120-410 290 1-3 2

Vecuronium

2.8-5.9 4.2-6.3 2.6-3.7 130-360 210-280 180-440 28-123 50-90 58-125

Rocuronium

11.4-13.5

2.2-3.5 3.4 220-300 140-220 620 38-56 70-106 137

pancuronium

1.8 1.0-2.0 0.8-1.2 200 100-280 220-320 103 115-155 151-204

Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)

NBM classificazione:METABOLISMO-ELIMINAZIONE

*Eliminazione Renale/Epatica incide meno del 20%° metabolizzato per < 10%

Pancuronium

Rocuronium°

Vecuronium

Cisatracurium

Atracurium

Mivacurium

Succinilcolina

Farmaco

-20- 25%-80- 100%

-5-10%15-40%60- 80%

-60%-30%

-40 -75%20-30%30%

Eliminazione di Hofmann(80%)-R/E <20%*R/E <20%*

Eliminazione di Hofmann (40%), idrolisi esterica(20-50%)

--10-40%

Plasma CHE (95-99%)Minima-5-10%

Plasma CHE--<10%

PlasmaticaBiliare Epatica Renale

Pipecuronium

A.W. Hofmann (1818-1892)

Hofmann degradation – a way to convert quaternary amines to tertiary amines

pH and temperature dependent

Diifferences in pharmacokinetics in older patients

onset Vd Cl effect

pancuronium RI

Vecuronium & rocuronium

IR 30% RI 30-40%

Atracurium & cisatracurium ~ ~ ~ ~ ~

mivacurium Plasma cholinest

RI 30%

Nbm classificazione :

ONSET - DURATA

Farmacocinetica (inizio)

•Dose (relativa alla ED95)

• Potenza (numero di molecole)

• Keo (chimica/flusso ematico)

• Clearance

• Età

Factors influencing pharmacokinetics of relaxants

Volume of distribution Plasma protein binding Pharmacologic potency: affinity toward Ach R Speed of injection Perfusion Temperature Obesity Age Pregnancy Gender


Onset(sec) dei principali miorilassantia 2*ED95.

0,0

20,0

40,0

60,0

80,0

100,0

120,0

140,0

160,0

180,0

sec

onset

succinilcolina

rocuroniumvecuronium

atracuriummivacurium

cisatracurium


Terminologia

Ricorda: Onset è definito come il tempo necessario per la

massima depressione della risposta muscolare alla stimolazione di un nervo motore specificato e,in genere,segnala il momento idoneo per intubazione tracheale

T1 25 indica,per convenzione,il momento in cui è necessario una dose aggiuntiva di miorilassante

Durate e riprese dei principali miorilassanti a 2ED95

05

101520253035404550

min

dur T1 25% R 25-75%

succirocuvecuatracmivacis

tempi di ripresa 25-75%

0

2

4

6

8

10

12

14

16

18

RI 25-75%

cisatr

vecu

rocu

atrac

miva inf

Farmacodinamica del cisatracurium

0

20

40

60

80

100

120

140

t125% T4/T1>70% RI5-95%

dati da Belmont(A.,1995,82,1139)

0.1 mg/kg0.2 mg/kg0.4 mg/kginf cont

min

Farmacodinamica del rocuronium

Wright et al.Anesthesiology81:1110-1115, 1994

Cinetica

Farmacocinetica del cisatracurium nell’anziano(Ornstein et

al,Anesthesiology,1996,84,520)

5 4,6

57,857,2

126

108

25,521,5

0

20

40

60

80

100

120

140

Clp V1 Vss T 1/2 beta

anzianigiovani

*

*

Farmacocinetica del cisatracurium nell’anziano(Sorooshian et al,Anesthesiology,1996)

319319

47,6 4713,39,7

36,328,4

0

50

100

150

200

250

300

350

Clp ml/min V1 lt Vss lt T 1/2 betamin

anzianigiovani

De Wolf AM.,Freeman JA, Scott VL,Tullock W,Smith DA,Kisor DF, Kerls S,Cook,DR. Pharmacokinetics and pharmacodynamics of cisatracurium in patients with end-stage liver disease undergoing liver transplantation. Br. J. Anaesth. 1996; 76:624-628

020406080

100120140160180200

Vd ml/kg Clp ml/kg/min T 1/2 min T1 25 RI 25-75 Peaklaudanosine

conc

ng/ml

liver transpl

normal

farmacodinamica del rocuronium nei cirrotici(da Boyd et al,Bja,1994,73,262p)

0

20

40

60

80

100

120

140

T110% T125% T175% RI25-75%

Tof70

rocu 0.6 mg/kg,isoflurane 0.6%

sanicirrotici

min

*

Repeated doses of rocuronium in cirrhotic and control patients receiving isoflurane(Servin et

al.,Anesthesiology,1996,84,)1092

05

101520253035404550

T1 25%a 75

microgr

T1 25%150

micrg

T1 25%225

micrg

T1 90% TOF70%

RI 25-75%

cirroticinormali

min

Mivacurium e insufficienza epatica

0

10

20

30

40

50

t15% t110% t125% t150% t175% tof70% RI25-75%

dati da Devlin et al.,BJA,1993

normcirrotici

Rocuronium nella insuff renale ed epatica

010

2030

4050

6070

80

t1/tc25% t1/tc50% t1/tc75% t1/tc90% RI25-75% R125-75%

dati da Magorian,Khalil e Szenohradsky

normali

insuff ren

insuff epati

min

Variazioni % dei tempi di ripresa dei miorilassanti nella insuff.epatica dati medi da diverse ref:bibliografiche

0

10

20

30

40

50

60

aum

ento

%

T 1 25 T1 90 RI 25-75

rocu ins epatrocu cirrosivecuatraccisatracmivac

OBESITÀ E MIORILASSANTI

vecuronium

Schwartz AE, Matteo RS, Ornstein E, Halevy JD, Diaz J.Pharmacokinetics and pharmacodynamics of

vecuronium in the obese surgical patient.Anesth Analg. 1992 Apr;74(4):515-8.

0

100

200

300

400

500

600

700

800

900

1000

Vd tot CL pl ml/min/kg HL el min

obese

nonobese

Calcolati su IBW

Principali tempi di ripresa dopo vecuronium 0.1 mg/kgSchwartz AE, Matteo RS, Ornstein E, Halevy JD, Diaz J.Pharmacokinetics and pharmacodynamics of vecuronium in the

obese surgical patient.Anesth Analg. 1992 Apr;74(4):515-8.

0

10

20

30

40

50

60

70

80

T1 50% T1 5-25% T1 25-75%

obesi

norm

Vecu 0.1 mg/kg Anest TPS

/N2O/Haloth7 obesi vs 6

norm

Schwartz AE, Matteo RS, Ornstein E, Halevy JD, Diaz J.Pharmacokinetics and pharmacodynamics of vecuronium

in the obese surgical patient.Anesth Analg. 1992 Apr;74(4):515-8.

Poichè i parametri cinetici(VD,Vdss,Cl) sono simili fra obesi e non,ma la durata di azione è maggiore negli obesi per via dell’aumento della dose somministrata in accordo al TBW,gli AA raccomandano di somministrare vecu sec IBW.

–Ma gli obesi erano (93.4 +/- 13.9 kg, 166% +/- 30% di IBW

Kirkegaard-Nielsen H,Helbo-Hansen HS, Toft P,Severinsen IK.Anthropometric Variables as Predictors for Duration of Action of Vecuronium-Induced Neuromuscular Block . Anesth Analg 1994; 79:1003–6 .

67 femmine obese,,45–126 kg Tps,fent,drop,N2O

Variabili antropometriche studiate: (%IBW)

BMIBSAsomma di pieghe cutanee subscapularis and suprailiac /BSA.

% IBWKirkegaard-Nielsen H,Helbo-Hansen HS, Toft P,Severinsen IK.Anthropometric Variables as Predictors for Duration of Action of Vecuronium-Induced Neuromuscular Block . Anesth Analg 1994;

79:1003–6 .

(Subscapularis+ suprailiac skinfolds)/surface area (mm/m2)Kirkegaard-Nielsen H,Helbo-Hansen HS, Toft P,Severinsen IK.Anthropometric Variables as Predictors for Duration of Action of Vecuronium-Induced Neuromuscular Block . Anesth Analg 1994; 79:1003–6

Duration of action of vecu according to anthropometric variablesKirkegaard-Nielsen H,Helbo-Hansen HS, Toft P,Severinsen IK.Anthropometric Variables as Predictors for Duration of Action of Vecuronium-Induced Neuromuscular Block . Anesth Analg 1994; 79:1003–6

Durata di azione della dose induttiva (min.) = 0.112 * (Sub SF + Si SF) + 0.493 * BMI + 17.22 (r2 = 0.406, P = 0.0001),

Durata di azione della dose supplementare (min) = 0.174 * ([Sub SF + Si SF]/BSA) + 0.243 * BMI + 12.09 (r2 = 0.287, P = 0.0001).

Vecu

Durata di azione= 0.291 * dose vecuronium micrograms -1.88 min.

Opp Dur az=0.18*%IBW+12.66 From this equation it appears that a reduction in duration of

action by 1.8 min (the increase in duration of action when %IBW increases 10%) corresponds to a reduction in dose of vecuronium by 6.19 microg/kg

162 microgr-(0.62* % IBW)

Messaggio da portare a casa per il vecuronium

Calcola la dose sull’IBWMonitorizza!!!!

CISATRACURIUM

Tempi di ripresa dopo cisatracurium 0.2 mg/kg Leykin Y, Pellis T, Lucca M, Lomangino G, Marzano B, Gullo A.The effects of cisatracurium on morbidly obese women. Anesth Analg. 2004 Oct;99(4):1090-4

0

20

40

60

80

100

120

140

160

180

200

onset sec dur 25%min dose mg

obesi RBW

obesi IBW

normali RBW

*

Cisatr 0.2 mg/kgRemifentanil propofol

Messaggio da portare a casa per il cisatracurium

Dose iniziale e supplementari basate sull’IBW

Atracurium

Kirkegaard-Nielsen H, Lindholm P, Petersen HS, Severinsen IK.Antagonism of atracurium-induced block in obese patients.Can J Anaesth. 1998 Jan;45(1):39-41

Antagonismo con prostigmina 0.07 mg/kg restituisce alla norma la funzione neuromuscolare anche negli obesi con blocco nm mantenuto fra TOF 1-3.

Kirkegaard-Nielsen H, Helbo-Hansen HS, Lindholm P, Severinsen IK, Pedersen HS. Anthropometric variables as predictors for duration of action of atracurium-induced neuromuscular block. Anesth Analg 1996; 83:1076-80.

. The predictors with the greatest correlation coefficients for duration of action of the atracurium induction dose (0.5 mg/kg) were :

total body weight divided by surface area (r2 = 0.284, P < 0.0001), body mass index (r2 = 0.265, P < 0.0001), total body weight (r2 = 0.264, P < 0.0001). The most significant predictors for the duration of action of the first supplemental atracurium dose (0.15

mg/kg) were: total body weight divided by surface area (r2 = 0.170, P < 0.0001) total body weight (r2 = 0.160, P < 0.0001). We propose that the atracurium dose should be reduced with 0.23 mg for each kilogram of total body weight above 70 kg. We conclude that the

duration of action of atracurium block is prolonged in obese patients, and that atracurium dose in milligrams per kilogram of total body weight should be reduced in these patients. Total body weight divided by the surface area and total body weight were the best predictors for duration of action of atracurium-induced neuromuscular block.

Total body weight/surface area kg/m2Kirkegaard-Nielsen H, Helbo-Hansen HS, Lindholm P, Severinsen IK, Pedersen HS. Anthropometric variables as predictors for duration of action of atracurium-induced neuromuscular block. Anesth Analg 1996; 83:1076-80.

Total body weightKirkegaard-Nielsen H, Helbo-Hansen HS, Lindholm P, Severinsen IK, Pedersen HS. Anthropometric variables as predictors for duration of action of atracurium-induced neuromuscular block. Anesth Analg 1996; 83:1076-80

Kirkegaard-Nielsen H, Helbo-Hansen HS, Lindholm P, Severinsen IK, Pedersen HS. Anthropometric variables as predictors for duration of action of atracurium-induced neuromuscular block. Anesth Analg 1996; 83:1076-80

La durata di azione di atracurium è prolungata negli obesi TBW/BSA ,BMI e TBW sono gli indici predittivi migliori La durata di azione di atrac 0.5 mg/Kg di TBW=0.294 * TBW + 23.9

min Aumenta di 2.9 min per ogni 10 kg di aum del TBW Allora propongono di diminuire la dose di atrac di 2.3 mg per ogni 10 kg di

peso>70 kg Allora 80 kg atrac dose 37.7 90 Kg 41.4 100 kg 43.1 110 kg 45.8 120 kg 48.5 130 kg 51.2 140 kg 53.9 150 kg 56.6 . Per la prima dose supplementare diminuiamo la dose di 0.15 mg/kg di 0.7 mg (=6.6% di 10.5 mg) per ogni

10 kg TBW > 70 kg Only women were included in the present study.

Rocuronium

Puhringer FK,Keller C;Kleinsasser A,Giesinger S,Benzer A.Pharmacokinetics of rocuronum bromide in obese female patients.Eur J Anesth.1999;16:507-10.

0

50

100

150

200

250

Vdss ml/kg Hl dist min HL el min MRTmin CL ml/kg/min

obese

non obese

Tutto NS

•0.6 mg/ kg rocu,•6 obesi vs 6 controli

•Anest bilanciata .

Leykin Y, Pellis T, Lucca M, et al. The pharmacodynamic effects of rocuronium when dosed according to real body weight or ideal body weight in morbidly obese patients. Anesth Analg 2004; 99:1086-9.

12 paz femmine obese (body mass index >40 kg/m(2)) Per laparoscopic gastric banding Gruppo 1 (n = 6) 0.6 mg/kg rocuronium RBW Gruppo 2 (n = 6) 0.6 mg/kg rocuronium IBW Gruppo controllo 6 paz normali operati per chir

laparoscopica Acceleromiografia dell’ adductor pollicis remifentanil /propofol.

Rocuronium 0.6 mg/kg Leykin Y, Pellis T, Lucca M, et al. The pharmacodynamic effects of rocuronium when dosed according to real body weight or ideal body weight in morbidly obese

patients. .Anesth Analg 2004; 99:1086-9

0

10

20

30

40

50

60

70

80

90

onset sec dur 25%min dose mg RI 25-75%min

obesi RBW

obesi IBW

normali RBW

Confronto dei dati fra Leykin e Puhringher

0

10

20

30

40

50

60

70

80

90

100

onset sec dur 25%min dose mg RI 25-75% min

obesi RBW Leykin

obesi RBW Puhringer

obesi IBW Leykin

normali RBW Leykin

normali RBW Puhringer

Leykin morbid obesity class (BMI 43.8 ± 2.1) Puhringer moderate obesity class (BMI 33.5 ± 4.4).

Messaggio da portare a casa per il rocuronium

Meglio somministrare secondo IBW,specialmente in infusione continua,ma dati scarsi…..

Messaggio da portare a casa per tutti i miorilassanti

Non somministrare miorilassante a demand dei chirurghi;potrebbero richiederne molto di più per le difficoltà tecniche legate all’intervento(esposizione) più che per reali necessità di miorisoluzione…..

Monitorizzare almeno semiquantitativamente

Miorilassanti e ustioni

Correlation comparing ED 50 and ED 95 doses of DTC on twitch suppression of gastrocnemius muscle with

number of AchRs in the same muscle following 40-50% BSA burn injury.Each point indicate one

animal.Anesthesiology 822-843,1992.

A fixed dose of atracurium reduces rhe maximum twitch depression at the Adductor pollicis as the size of burn

increases .Anesthesiology 89:749-70,1998.

Diseases with altered Ach Receptor(AchR ) expression

Upper motor neuron lesions Lower motor neuron lesions Muscle trauma Burn injury Immobilization Sepsis/infection --------------------normal Myasthenia gravis Organophosphate poisoning Chronic cholinesterase inhibition

Up regulation of AchR» Increasing requirements for non

depolarizing muscle relaxants» Hyperkalemia after Scc

administration

Receptor unaltered------Down regulation of AchR

» Decreased requirements with nondepolarizing muscle relaxants

0

20

40

60

80

100

120

onset clin duration RI

male

female

sec

min

Eur J Anaesthesiol. 2008 Jul;25(7):589-95.Influence of gender on the course of neuromuscular block following a single bolus

dose of cisatracurium or rocuronium.Adamus M, Gabrhelik T, Marek

Dose-response curve of vecuronium in male and female patients

Dose-response curve and time-course of effect of vecuronium in male and female patients

Xue FS.Liao X, Liu J H, Tong SY, Zhang YM, Zhang R J, An G L. Br. J. Anaesth. 1998; 80:720-724

time-course of effect of vecuronium in male and female patients after 80 microgr/kg.

Dose-response curve and time-course of effect of vecuronium in male and female patients Xue FS.Liao X, Liu J H, Tong SY, Zhang YM, Zhang R J, An G L. Br. J. Anaesth. 1998; 80:720-724

0

10

20

30

40

50

60

70

dur T1 5% dur 25 RI 25-75 T1 90

male

female

Interaction of relaxants with other drugs

Pharmacokinetic:» Decrease or increase CO(RSI)» Inhibition or induction of Cy P450

– Cimetidine antiepileptics

at the NMJ:Presynaptic:furosemide (cAMP),volatile anesthetics,Mg,Ca antg,aminoglycoside antibiotics

Postsynaptic:inhalat anesth,aminoglycoside AB,tryciclic

antidepr,ket,midaz,barbit.

Muscular effects:dantrolene

Bloccanti neuromuscolari:struttura chimica e caratteristiche chiave

Aminosteroidi

• VagoliticiBloccano parzialmente i recettori cardiaci muscarinici ad azione

bradicardizzante, con conseguente aumento della frequenza cardiaca:pancuronio > rocuronio = vecuronio

• Non provocano il rilascio di istamina

• Eliminazione organo-dipendenteReni e fegato

Bloccanti neuromuscolari:struttura chimica e caratteristiche chiave

Benzilisochinoline

• Assenza di effetto vagoliticoQuesti farmaci non bloccano i recettori cardiaci vagali (muscarinici)

• Rilascio di istaminad- tubocurarina>atracurio>mivacurio>cisatracurio possono provocare

raramente broncospasmo, ipotensione, tachicardia

• eliminazione organo-indipendente

Cumulation characteristics of cisatracurium and rocuronium during continuous infusion

Conclusioni

Dopo aggiustamento per l’equipotenza, le richieste di infusione di

cisatracurio e rocuronio variano con tassi simili durante l’anestesia

generale. Nonostante le differenze farmacocinetiche, nessuno dei

due farmaci dimostra un accumulo per infusione con durata fino a

3.5 ore.

Can J Anaesth 2000 Oct;47(10):943-9

Single twitch heights (expressed as per cent of control)during continuous infusions of cisatracurium and rocuronium.

Loading doses were administered at t=0 min. Adjustments of the infusion rates of cisatracurium and rocuronium allowed the depth of neuromuscular block to be maintained at a level representing

95 ± 5% T1 suppression throughout surgery with bothneuromuscular blocking drugs

Mean infusion rates of cisatracurium and rocuroniumrequired to maintain 95 ± 5% T1 suppression of the singletwitch height during balanced anesthesia. An initial decrease in

infusion requirements of both drugs represents a stabilization period, after which potency-adjusted infusion requirements were similar with both drugs. The number of patients (observations) foreach group and time period are displayed above and below

thecorresponding standard deviation bar.

non cumulatività del cisatracurium

0

5

10

15

20

25

I II III IV V VI VII VIII IX X

Intervallo in min fra le dosi refratte o velocità medie di infusione per un blocco del 95%

dosi ripinf cont

min

microgr/kg/min

Preclinical pharmacology of GW280430A (AV430A) in the rhesus monkey and in the cat

Anesthesiology 2004;100:835-45

GW280430A Gantacurium

Un sostituto della succinilcolinaE’ desiderabile?????

Dati da Blobner M, Sohnel AM, van de Roemer A, Bachmann H, Geldner G, Hofmockel R,

Fuchs-Buder T, Diefenbach C, Ulm K: Anwendung von Muskelrelaxanzien in Deutschland. Eine Umfrage an Deutschen Anasthesieeinrichtungen. Anaesthesist 2003; 52:427–34

In Germania la Succi è ancor a oggi il miorilassante più usato

Sarebbe utile un sostituto della SCC?

SIIIIIII,ma» Non depolarizzante» Rapido come la Scc» Senza gli effetti collat della Scc

Belmont M, Lien C, Tjan J, Bradley E, Stein B, Patel S, Savarese J: Clinical

pharmacology of GW280430A in humans. Anesthesiology 2004; 100:768–73

Time to onset gantacurium

0,0

0,5

1,0

1,5

2,0

2,5

3,0

O.18 O.30 O.36 0.40 0.45 0.54 0,72

bolus dosing mg/kg

min onset

Gantacurium Tof time to onset

0,00

0,20

0,40

0,60

0,80

1,00

1,20

1,40

0.30 0.40

min

max

mean

Belmont M, Lien C, Tjan J, Bradley E, Stein B, Patel S, Savarese J: Clinical pharmacology of GW280430A in humans. Anesthesiology

2004; 100:768–73

Duration and recovery profile of gantacurium

0,0

5,0

10,0

15,0

20,0

O.18 O.30 O.36 0.40 0.45 0.54 0,72

bolus dosing mg/kg

min

T1 25

T195

Tof 0.70

Tof 0.90

Belmont M, Lien C, Tjan J, Bradley E, Stein B, Patel S, Savarese J: Clinical pharmacology of GW280430A in humans. Anesthesiology

2004; 100:768–73

Blocking profile and reversal after 0.40 mg/kg gantacurium

0

5

10

15

20

25

T1 95 Tof 0.90

Min

non reversal

reversal

Average maximum change from baseline mean arterial pressure is small for doses through 0.72 mg/kg.

From: Belmont: Anesthesiology, Volume 100(4).April 2004.768-773

Average maximum change from baseline heart rate increases as dose goes above 0.45 mg/kg.



Graphic representation of maximum changes in heart rate (HR) and mean arterial pressure (MAP) for individuals receiving a first dose of GW280430A.


The mean maximal heart rate (HR) and blood pressure changes after bolus administration of GW280430A2 and mivacurium. From:

Lien: Anesthesiology, Volume 102(4).April 2005.861-862

Sommario degli effetti secondari alla istaminoliberazione

Conclusions from Gantacurium

Ultrashort rather than rapid onset

NMB:Indicazioni pediatria ICU inf.conti T.cesareo

da ricost diluire

freddo

succinilcolina NO NO SI SI / (NO) NO SI

mivacurio SI

> 2 anni NO SI NO NO NO

atracurio SI

da 1 mese SI SI SI NO SI

cisatracurio SI

da 1 mese SI SI NO/si NO SI

rocuronio SI

da 1 mese NO SI NO/si NO SI

vecuronio SI

da 5 mesi NO SI

SI /no

SI NO

pancuronio SI non spec da che età

SI NO NO NO SI


Ce la racconti bella ma…

…quanto costa???

CostiCosti

Cost of care acquisition cost

The real, substantial savings accrue from use of intermediate- and short-acting drugs because:

• Inexpensive, long-acting drugs are associated with prolonged postoperative recovery (Ballantyne JC, et al. Anesth Analg. 1997; 85:476

Fast recovery means shorter risk periods of residual blockade. This translates into fewer postoperative complications(2Berg H, et al. Acta

Anaesthesiol Scand. 1997;41:1095

• Postoperative complications are very expensiveAvoiding these is where the real cost savings accrue

Cost of care acquisition cost

The real, substantial savings accrue from use of intermediate- and short-acting drugs because:

• Inexpensive, long-acting drugs are associated with prolonged postoperative recovery (Ballantyne JC, et al. Anesth Analg. 1997; 85:476

Fast recovery means shorter risk periods of residual blockade. This translates into fewer postoperative complications(2Berg H, et al. Acta

Anaesthesiol Scand. 1997;41:1095

• Postoperative complications are very expensiveAvoiding these is where the real cost savings accrue

evitare l’impiego di NBM a lunga durata

a favore dei composti a durata breve-

intermediaViby Mogensenn, 1997


Cisatracurium nell’anziano

Vantaggi a confronto del vecuronium


Tempi di ripresa spontanei completi dopo cisatracurium e vecuronium.Confronto fra

pazienti giovani e anzianiPühringer FK, Heier T, Dodgson M, Erkola O, Goonetilleke P, Hofmockel R, Gaetke MR,

Mortensen CR, Upadhyaya B, Eriksson LIActa Anaesthesiol Scand. Double-blind comparison of the variability in spontaneous recovery of cisatracurium- and vecuronium-induced

neuromuscular block in adult and elderly patients.2002 ;46:364-71.

0

10

20

30

40

50

60

70

80

90

25%

T 1 -

TO

F r

ati

o

> 0

.8 (

min

)

cisatracurium vecuronium

18 - 64 years

> 65 years

p < 0.001


5665 6365N =

Time Interval final 25%T1 to Tof Ratio >=0.8

Treatment

VecuroniumNimbex

min

ute

s

140

120

100

80

60

40

20

0

Age Category

<65

>=65

Variabilità dei tempi di ripresa completa spontaneaPühringer FK, Heier T, Dodgson M, Erkola O, Goonetilleke P, Hofmockel R, Gaetke MR, Mortensen CR, Upadhyaya B, Eriksson LIActa Anaesthesiol Scand. Double-blind comparison of the variability in spontaneous recovery of cisatracurium- and

vecuronium-induced neuromuscular block in adult and elderly patients.2002 ;46:364-71.


Durata clinica del bloccoPühringer FK, Heier T, Dodgson M, Erkola O, Goonetilleke P, Hofmockel R, Gaetke MR,

Mortensen CR, Upadhyaya B, Eriksson LIActa Anaesthesiol Scand. Double-blind comparison of the variability in spontaneous recovery of cisatracurium- and

vecuronium-induced neuromuscular block in adult and elderly patients.2002 ;46:364-

71.

0

10

20

30

40

50

60

70

Tim

e t

o 2

5%

T 1 (m

in)

cisatracurium0.15 mg/kg

vecuronium0.1 mg/kg

18 - 64 years > 65 years

p < 0.001


Potenziamento :da parte dei vapori anestetici,terapia

anticonvulsivante


Richard A, Girard F, Girard DC, Boudreault D, Chouinard P, Moumdjian R, Bouthilier A, Ruel M, Couture J, Varin F. Cisatracurium-induced neuromuscular blockade is affected by chronic phenytoin or carbamazepine treatment in neurosurgical patients.Anesth Analg. 2005 Feb;100(2):538-44.

» La terapia anticonvulsivante cronica con carbamazepina e fenitoina aumenta del 44% la necessità di cis per mantenere costante un blocco del 95%

» Aumenta la CL 7.12 vs 5.72 lt/kg » Aumenta la Cp(ss)95 :191 +/- 45 versus 159 +/- 36

ng/mL, P = 0.04)» Insomma, i paz in terapia anticonvulsivante cronica

necessitano di dosi maggiori a parità di profondità di blocco,ossia hanno una ripresa più rapida,ossia risultano più resistenti al cisatracurium


Il potenziamento del blocco neuromuscolare indotto dal cisatracurium in presenza dei vapori:isoflurano,sevoflurano,desflurano.Wulf,H,Kahl,M,Ledowski,T.Augmentation of the neuromuscular blocking effects of cisatracurium during desflurane,sevoflurane,isoflurane or total i.v.anesthesia.British Journal of Anesthesia 1998,80:308-312.

84 paz,18-65 anni,ASA 1 & 2 procedure elettive minori extraddominali ed

extratoraciche anestesia a 1.5 MAC(DES 4.2%,SEVO 1.05%,ISO

0.75%)+N2O 70%. Vs TIVA Propofol/fentanil. Monitoraggio neuromuscolare: Tof Guard con Tof

ogni 12 sec dosi cumulative di cisatracurium 15 g/kg fino a T1

5%.quando equilibrio fra Fi/Fe del vapore


Risultati dello studio di Wulf et al.

0%10%20%30%40%50%60%70%80%90%

100%

depressione % di T1

15 mu/kg 30 mu/kg 45 mu/kg

dosi di cisatracurium

DESISOSEVOTIVA

*

**


Durate cliniche del cisatracurium

0

5

10

15

20

25

30

35

40

45

min

T125% RI25-75% TOF0.70

DESISOSEVOTIVA

**

* *


Diagramma Log-probit delle curve dose-risposta del cisatracurium e depressione del T1/T0 % :confronto fra 1.5 Mac di DES,ISO,SEVO e tiva (Wulf ).

10

100

15 30 45

microgr/kg di cisatracurium

depressione

T1/T0%

DESISSEVOTIVA


Le durate cliniche del cisatracurium sono poco influenzate dalla presenza di sevoflurano : Turan G, Dincer E, Ozgultekm A, Akgun N.R Recovery from neuromuscular block following infusion of cisatracurium using either sevoflurane or propofol for anaesthesia.Eur J Anaesthesiol. 2004 Sep;21(9):751-753

0

10

20

30

40

50

60

70

min

T1 25 dose bolo T1 25 infus RI 25-75 Tof 70

Sevoflurane 1-2%

propofol 75-150microgr/kg/min


Riprese neuromuscolari dopo cisatracurium in

infusione :confronto fra TIVA e isoflurane :da Jellish

WS, Brody M, Sawicki K, Slogoff S. Recovery from neuromuscular blockade after either bolus and prolonged infusions of cisatracurium

or rocuronium using either isoflurane or propofol-based anesthetics. Anesth Analg. 2000

Nov;91(5):1250-5.

05

101520253035404550

min

T1 25 T1 75 TOF 0.70 RI 25-75

ISOfluranepropofol

benzylisochinolinum compounds, 2008

Health & Medicine

mgkg rocuronium rbw

ideal body weight

real body weight

obesi vs

obese female patients

classificazione dei

miorilassanti e ustioni

obese patientsanesth