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Rocuronium Bromide

Esmeron ®

Clinical experiences
Esmeron®
Clinical Experiences
• Chemistry & pharmacology
• Pharmacokinetics
• Pharmacodynamics
• Special patient groups
• Special procedures
• Safety profile
• Summary
Esmeron®
Clinical Experiences
• Chemistry & pharmacology
• Pharmacokinetics
• Pharmacodynamics
• Special patient groups
• Special procedures
• Safety profile
• Summary
Esmeron®
Chemistry & pharmacology
OAc
+
O N
C D
N CH2
a B
CH
HO H -
Br CH2
Chemistry & pharmacology
Affinity for receptor in the NMJ
ACh-like fragment
on the D-ring
OAc
+
O N
C D
N CH2
a B
CH
HO H -
Br CH2
Rocuronium
Chemistry & pharmacology
Low potency
Absence ACh-like fragment on A-ring
Replacement methyl
OAc
by allyl group
+
O N
C D
N CH2
a B
CH
HO H -
Br CH2
Rocuronium
Chemistry & pharmacology
Stable solution
Replacement acetate
by hydroxy group OAc
+
O N
C D
N CH2
a B
CH
HO H -
Br CH2
Rocuronium
Esmeron®
Clinical Experiences
• Chemistry & pharmacology
• Pharmacokinetics
• Pharmacodynamics
• Special patient groups
• Special procedures
• Safety profile
• Summary
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
Esmeron®
Pharmacokinetics (2)
• Elimination
– hepatobiliary 50%
– renally 50%
• No accumulation during maintenance
infusions lasting up to 140 hours
Esmeron®
Clinical Experiences
• Chemistry & pharmacology
• Pharmacokinetics
• Pharmacodynamics
• Special patient groups
• Special procedures
• Safety profile
• Summary
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%)
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
Pharmacodynamics
Routine infusion dose

Mean infusion rate for maintenance of


approximately 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.
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
Pharmacodynamics
Rapid onset of action (3)
9
8
Onset time (mins)

7
6
5
4
3
2
1
0
0 50 100 200 300 400 500 600 700 800
Effective dose for 90% block (mcg/kg)

Relationship between potency (mg/kg) and onset time


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
Pharmacodynamics
Rapid onset of action (5)

Onset of
neuromuscular block
at the larynx and
adductor pollicis
muscles after 0.5
mg/kg rocuronium
bromide
Pharmacodynamics
Dose-response relationship
Esmeron onset duration
(mg/kg) (min) (min)
0.3 2 15
0.45 1.5 25
0.6 1 30-40
0.9 0.75 50-55
Esmeron®
Clinical Experiences
• Chemistry & pharmacology
• Pharmacokinetics
• Pharmacodynamics
• Special patient groups
• Special procedures
• Safety profile
• Summary
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
Special patients groups
Pediatrics
Neonates/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
Special patient groups
Influence of age - overview
Varialbe Units Infnts Children Normal Elderly
Adults
Onset Sec 50 - 60 50 - 60 60 - 120 60 -120
Time
Clinical min 42 21- 29 30 - 40 42
Duration
Revover min 27 9 - 13 14 22
y Rate

Following a standard intubating dose of 0.6 mg/kg Esmeron, good to


excellent intubation conditions develop within 60 seconds
Special patients groups
Liver disease (1)
Units Liver Normal
disease adults
N 17 21
T½-beta min 143 92
Vdss L/kg 0.25 0.21
Cl Ml/kg/min 2.7 3.7

Vdss : apparent volume of distribution at steady state; Cl: plasma clearance; T½-
beta: terminal elimination half-life; MRT: mean residence time

Adapted from: van Miert et al. Br J Clin Pharmacology 1997;44:139-44


Pharmacokinetics
Liver disease (2)
Clearance in cirrhotic patients compared to healthy adults
Plasma rocuronium (ng/ml)

10000
healthy cirrhotic

10
0 60 120 180 240 300 360 420 480
Time (min)
Adapted from Van Miert et al. Br J Clin Pharm 1997;44:139-44
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


Special patient groups
Renal disease (1)
Units Renal Normal Renal Normal
Failure Adults Failure Adults
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

Vdss : apparent volume of distribution at steady state; Cl: plasma clearance; t½-
beta: terminal elimination half-life; MRT: mean residence time

Adapted from Szenohradszky J et al. Anesthesiol 1992;77:899-904; Cooper et al. Br J Anaesth


1993;71:222-6;
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
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
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
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
Esmeron®
Clinical Experiences
• Chemistry & pharmacology
• Pharmacokinetics
• Pharmacodynamics
• Special patient groups
• Special procedures
• Safety profile
• Summary
Clinical experiences
Special procedures
• Rapid Sequence Induction (RSI)
• Day care
• Neurosurgery
• Ocular surgery
• Cardiac surgery
• Cesarean section
• Surgery under hypothermic conditions
Special procedures
RSI (1)
100%
Comparison of 90%
80%
intubating
70%
conditions with
60% Fair
suxamethonium 50% Good
1.0 mg/kg and 40% Excellent
rocuronium 30%
0.6mg/kg and 20%
1.0mg/kg 10%
0%
Sux Roc Roc
1mg/kg 1.0mg/kg
0.6mg/kg
Adapted from: McCourt et al 1998Anaesthesia 53:867-87)
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
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
Special procedures
Ocular and neurosurgery
Ocular 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
Special procedures
Cardiac surgery

• Esmeron has no cardiovascular effects


• Esmeron is rapidly and consistently
reversable, therefore it is suitable for
fast track anesthesia
Special procedures
Cesarean Section
• Similar pharmacokinetics to other adults
• Clearance unaltered
• Minimal transplacental transfer :
UV/ MV concentration ratio rocuronium
= 0.18 (vecuronium = 0.11)
Special procedures
Hypothermic conditions
Plasma 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.
Esmeron®
Clinical Experiences
• Chemistry & pharmacology
• Pharmacokinetics
• Pharmacodynamics
• Special patient groups
• Special procedures
• Safety profile
• Summary
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
Safety profile
Histamine release
30 0.6 mg/kg
0.9 mg/kg
2.5
Plasma Histamine (ng/ml)

1.2 mg/kg

2.0

1.5
Minimal histamine release
even at higher doses
1.0

0.5

0
0 1.0 2.0 3.0 4.0 5.0
Time (min)

Adapted from: Levy et al. Anesth Analg 1994;78:318-21


Esmeron®
Clinical Experiences
• Chemistry & pharmacology
• Pharmacokinetics
• Pharmacodynamics
• Special patient groups
• Special procedures
• Safety profile
• Summary
Esmeron®
Summary
• Rapid onset
• Intermediate duration of action
• Effective & consistently good intubation conditions
• Safe
• Flexible - all procedures
• Titratable dosage - varying duration of action