esmeron and clinical experience
TRANSCRIPT
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Rocuronium Bromide Esmeron®
Clinical experiences
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Esmeron®
Clinical Experiences• Chemistry & pharmacology
• Pharmacokinetics
• Pharmacodynamics
• Special patient groups
• Special procedures
• Safety profile
• Summary
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Esmeron®
Clinical Experiences• Chemistry & pharmacology
• Pharmacokinetics
• Pharmacodynamics
• Special patient groups
• Special procedures
• Safety profile
• Summary
![Page 4: Esmeron and Clinical Experience](https://reader033.vdocuments.site/reader033/viewer/2022051820/5525bb164a795934498b4c43/html5/thumbnails/4.jpg)
Esmeron®
Chemistry & pharmacology
a B
C D
HHO
OAc
N+
CH2
CH
CH2
O
N
Br-
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Chemistry & pharmacology
Affinity for receptor in the NMJ
O
OAc
HHO
N
N+
Br CH2
CH
CH2
-a B
C D
Rocuronium
ACh-like fragment on the D-ring
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Chemistry & pharmacology Low potency
O
OAc
HHO
N
N+
Br CH2
CH
CH2
-a B
C D
Rocuronium
Absence ACh-like fragment on A-ring
Replacement methylby allyl group
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Chemistry & pharmacology Stable solution
O
OAc
HHO
N
N+
Br CH2
CH
CH2
-a B
C D
Rocuronium
Replacement acetate by hydroxy group
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Esmeron®
Clinical Experiences• Chemistry & pharmacology
• Pharmacokinetics
• Pharmacodynamics
• Special patient groups
• Special procedures
• Safety profile
• Summary
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Esmeron®
Pharmacokinetics (1)• Highly ionized, low lipid solubility
• Small central volume of distribution (VDc) high initial blood concentration
• Creates gradient between blood & tissues fast onset
• Volume of distribution at steady state (VDss)= ~ 200mg/kg
• Plasma clearance (Clp) = 3.7 mg/kg/min
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Esmeron®
Pharmacokinetics (2)• Elimination
– hepatobiliary 50%– renally 50%
• No accumulation during maintenance infusions lasting up to 140 hours
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Esmeron®
Clinical Experiences• Chemistry & pharmacology
• Pharmacokinetics
• Pharmacodynamics
• Special patient groups
• Special procedures
• Safety profile
• Summary
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Esmeron®
Pharmacodynamics• Rapid onset of action
• Intermediate duration of action
• Dose-response relationship • Rapid recovery
(in 14 min from T1 25% to T1 75%)
• Reversal (on T1 25% in 5 min from T1 25% to T1 75%)
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Pharmacodynamics
Routine intubating dose• Esmeron 0.6 mg/kg ( 2x ED 95 )
gives good to clinically acceptable intubating conditions within 60 sec
• Mean onset time ( until maximum block) 60 - 120 sec
• Clinical duration 30 - 40 min
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Pharmacodynamics
Routine infusion dose
Mean infusion rate for maintenance ofapproximately 90%:
• 0.5 - 0.6 mg/kg/h in IV anesthesia
• 0.3 mg/kg/h in inhalational anesthesia
From: Shanks et al Anesthesiol 1993;78:649-51; Olkkola et al. Anesth Analg 1994;78:691-6.
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Pharmacodynamics
Rapid onset of action (1)Low potency of rocuronium = rapid onset of action• A lower potency drug requires a higher bolus dose for
same effect
• Higher dose leads to higher plasma concentration
• Higher concentration of relaxant = higher plasma to tissue gradient= faster receptor blockade
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Relationship between potency (mg/kg) and onset time
Pharmacodynamics
Rapid onset of action (3)
0123456789
0 50 100 200 300 400 500 600 700 800
Effective dose for 90% block (mcg/kg)
On
se
t ti
me
(m
ins
)
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Pharmacodynamics
Rapid onset of action (4)
• Variation in onset/duration of block in different muscle groups
• Onset at vocal cord adductor muscles faster than at adductor pollicis but less intense
From: Wright et al. Anaesthesiology 1994;81;1110-5; Meistelman et al. Can. J.Anesth 1992;39;665-9
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Pharmacodynamics
Rapid onset of action (5)
Onset of neuromuscular block
at the larynx and adductor pollicis muscles after 0.5 mg/kg rocuronium
bromide
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Pharmacodynamics
Dose-response relationship
0.3 2 15
0.45 1.5 25
0.6 1 30-40
0.9 0.75 50-55
Esmeron onset duration (min) (min)(mg/kg)
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Esmeron®
Clinical Experiences• Chemistry & pharmacology
• Pharmacokinetics
• Pharmacodynamics
• Special patient groups
• Special procedures
• Safety profile
• Summary
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Special patients groups
Elderly total body water
higher peak plasma concentration
lower drug clearance due to: liver blood flow, volume and metabolic
capacity
renal blood flow/ clearance and creatinine
prolonged recovery from NM block
From: Matteo et al. Anesth Analg 1993;77:1193-7
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Special patients groups
PediatricsNeonates/infants:
• less Ach stores sensitivity to NMBA
Vdss lower peak drug levels resistance to NMBA
• reduced capacity to clear drugs
Children:
• higher plasma clearance shorter duration of block
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Varialbe Units Infnts Children NormalAdults
Elderly
OnsetTime
Sec 50 - 60 50 - 60 60 - 120 60 -120
ClinicalDuration
min 42 21- 29 30 - 40 42
Revovery Rate
min 27 9 - 13 14 22
Special patient groups
Influence of age - overview
Following a standard intubating dose of 0.6 mg/kg Esmeron, good to excellent intubation conditions develop within 60 seconds
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Special patients groups
Liver disease (1)Units Liver
diseaseNormaladults
N 17 21
T½-beta min 143 92
Vdss L/kg 0.25 0.21
Cl Ml/kg/min 2.7 3.7
Adapted from: van Miert et al. Br J Clin Pharmacology 1997;44:139-44
Vdss: apparent volume of distribution at steady state; Cl: plasma clearance; T½-beta: terminal elimination half-life; MRT: mean residence time
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Pla
sma
rocu
ron
ium
(n
g/m
l)
10
10000
0 60 120 180 240 300 360 420 480
Time (min)
healthy cirrhotic
Adapted from Van Miert et al. Br J Clin Pharm 1997;44:139-44
Pharmacokinetics
Liver disease (2)Clearance in cirrhotic patients compared to healthy adults
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Special patient groups
Liver disease (3)• Hepatic failure: reduced clearance
• Cirrhosis: recovery time from NM block
T1 25% 54 min (cirrh.) vs 42 min (control)
TOF 70% 115 (cirrh.) vs 76 min (control)
• Significantly reduced plasma clearance and prolonged t ½ elim.
From: Van Miert et al. Br J Clin Pharm 1997;44:139
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Special patient groups
Renal disease (1) Units Renal
FailureNormalAdults
RenalFailure
NormalAdults
N 10 10 9 9
T½-beta Min 97 71 104 97
Vdss L/kg 0.26 0.21 0.21 0.21
Cl Ml/kg/min 2.9 2.9 2.5 3.7
MRT Min NR NR 97 58
Adapted from Szenohradszky J et al. Anesthesiol 1992;77:899-904; Cooper et al. Br J Anaesth 1993;71:222-6;
Vdss: apparent volume of distribution at steady state; Cl: plasma clearance; t½-beta: terminal elimination half-life; MRT: mean residence time
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Special patient groups
Renal disease (2) • Only one study found a significant
longer clinical duration with Esmeron in patients with renal failure
• It is recommended to closely monitor the neuromuscular block in patients with renal dysfunction
From: Robertson et al. Anesthesiol 1998;89:A987
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Special patient groups
ICU patients (1)Issues in ICU patients:
• Slower recovery from block due to longer drug half life
• Many patients have single/multi-organ failure
• Co-existing medications
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Special patient groups
ICU patients (2)Use of Esmeron in critically ill patients:
• No significant cardiovascular effects: slightly increase in HR
• Fast onset
• Intermediate duration
• No active metabolites
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Special patient groups
ICU patients (3)Esmeron infusions in critically ill patients:
• After prolonged administration spontaneous recovery delayed in multi-organ failure patients
• Recovery times and clearance different from short term infusions in surgical patients
• It is important to objectively monitor the degree of neuromuscular block
From: Reeves et al.1999 Crit.Care Med 27suppl, Circeo et al. South Med.J 2001;94:36, Sparr et al. Br.J.Anaesth 1997;78:267
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Esmeron®
Clinical Experiences• Chemistry & pharmacology
• Pharmacokinetics
• Pharmacodynamics
• Special patient groups
• Special procedures
• Safety profile
• Summary
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Clinical experiences
Special procedures• Rapid Sequence Induction (RSI)
• Day care
• Neurosurgery
• Ocular surgery
• Cardiac surgery
• Cesarean section
• Surgery under hypothermic conditions
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Comparison of intubating
conditions with suxamethonium 1.0 mg/kg and
rocuronium 0.6mg/kg and
1.0mg/kg
FairGoodExcellent
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
Sux1mg/kg
Roc 0.6mg/kg
Roc 1.0mg/kg
Special procedures
RSI (1)
Adapted from: McCourt et al 1998Anaesthesia 53:867-87)
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Special procedures
RSI (2)
Esmeron in doses of 0.9-1.2mg/kg provides equally acceptable onset times and intubating conditions to suxamethonium 1mg/kg in both adults and children
From: Mazurek etal. Anesth Analg 1998;87:1259-62; Laurin et al. Acad EMerg MEd 2000;7:1362-9
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Special procedures
Day case anesthesia• Short clinical duration and rapid recovery
are important
• 0.3 - 0.45 mg/kg Esmeron:– Intubation within 90 seconds– Duration of action = 14 - 22 min.
From: Chetty et al. Anaesth Intensive Care 1996;24:37-41; Pollard et al. Eur J Anaesth 1995;12:81-3; Prien et al. Eur J Anaesth 1995;12:85-90
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Special procedures
Ocular and neurosurgeryOcular surgery
• Esmeron has no effect on Intra-Ocular Pressure (IOP)
Neurosurgery
• Esmeron has no effect on Intra-Cranial Pressure (ICP)
From: Robertson et al. Eur J Anaesth 1994;11:116-21; Schramm et al. Br J Anaesth 1996;76:607-11
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Special procedures
Cardiac surgery
• Esmeron has no cardiovascular effects
• Esmeron is rapidly and consistently reversable, therefore it is suitable for fast track anesthesia
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Special procedures
Cesarean Section• Similar pharmacokinetics to other adults
• Clearance unaltered
• Minimal transplacental transfer :
UV/ MV concentration ratio rocuronium = 0.18 (vecuronium = 0.11)
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Special procedures
Hypothermic conditionsPlasma clearance significantly reduced:2.2 ml/min/kg in hypothermia vs. 4.3 ml/kg/min in normothermia
Note: all NMBAs show prolonged duration under hypothermic conditions.
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Esmeron®
Clinical Experiences• Chemistry & pharmacology
• Pharmacokinetics
• Pharmacodynamics
• Special patient groups
• Special procedures
• Safety profile
• Summary
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Safety profile
Hemodynamics
• Minimal cardiovascular side effects even at high doses
• Slightly vagolytic i.e. small increase in heart rate
From: McCoy et al. Can J Anaesth 1993;40:703-8 and Levy et al. Anesth Analg 1994;78:318-21
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Safety profile
Histamine release
Minimal histamine release even at higher doses
30 0.6 mg/kg
0.9 mg/kg
1.2 mg/kg
0 1.0 2.0 3.0 4.0 5.0Time (min)
0
0.5
1.0
1.5
2.0
2.5
Pla
sma
His
tam
ine
(ng/
ml)
Adapted from: Levy et al. Anesth Analg 1994;78:318-21
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Esmeron®
Clinical Experiences• Chemistry & pharmacology
• Pharmacokinetics
• Pharmacodynamics
• Special patient groups
• Special procedures
• Safety profile
• Summary
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Esmeron®
Summary• Rapid onset
• Intermediate duration of action
• Effective & consistently good intubation conditions
• Safe
• Flexible - all procedures
• Titratable dosage - varying duration of action