Esmeron and Clinical Experience

Rocuronium Bromide Esmeron®

Clinical experiences

Esmeron®

Clinical Experiences• Chemistry & pharmacology

• Pharmacokinetics

• Pharmacodynamics

• Special patient groups

• Special procedures

• Safety profile

• Summary

Esmeron®






• Safety profile

• Summary

Esmeron®

Chemistry & pharmacology

a B

C D

HHO

OAc

N+

CH2

CH

CH2

O

N

Br-

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

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

Chemistry & pharmacology Stable solution

O

OAc

HHO

N

N+

Br CH2

CH

CH2

-a B

C D

Rocuronium

Replacement acetate by hydroxy group

Esmeron®






• 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®






• 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 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.

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

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

)

Pharmacodynamics


• 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


Onset of neuromuscular block

at the larynx and adductor pollicis muscles after 0.5 mg/kg rocuronium

bromide

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)

Esmeron®






• 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


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

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


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

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


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


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


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


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


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


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®






• Safety profile

• Summary

Clinical experiences

Special procedures• Rapid Sequence Induction (RSI)

• Day care

• Neurosurgery

• Ocular surgery

• Cardiac surgery

• Cesarean section

• Surgery under hypothermic conditions

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)

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 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

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 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.

Esmeron®






• 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

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

Esmeron®






• 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

Documents

Esmeron and Clinical Experience