remifentanil pharmacology.pdf
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Remifentanil pharmacology in reference booksTRANSCRIPT
Pharmakokinetics, pharmakodynamics and clinical consequences
PharmakokineticsPharmakokinetics, , pharmakodynamicspharmakodynamics and and clinical consequencesclinical consequences
Jens SoukupDepartment of Anesthesiology and Critical Care
Martin Luther University Halle – Wittenberg
REMIFENTANILREMIFENTANIL
Current Changes in anaesthetic practice
Current Changes in anaesthetic Current Changes in anaesthetic practicepractice
LongLong--actingacting ShortShort--actingacting
InpatientInpatient Outpatient/DayOutpatient/Day--casecase
Need for more flexible anesthetic drugs
“Triad” of anaesthesia““Triad” of anaesthesiaTriad” of anaesthesiaHYPNOSIS
(Sevorane)
RELAXATION(mivacron, rapacuronium)
ANALGESIA(Sufentanil, Alfentanil?)
AMNESIA
GENERALANAESTHESIA
REMIFENTANIL
CHEMICAL STRUCTURE and
METABOLISM
REMIFENTANILREMIFENTANIL
CHEMICAL STRUCTURE CHEMICAL STRUCTURE and and
METABOLISMMETABOLISM
The “reverse ester”-RemifentanilThe “reverse ester”The “reverse ester”--RemifentanilRemifentanil
N+ - C - C - O - C - C - R
=
O
“true” ester
• Elimination Plasmacholinesterase
• Metabolite with alcohol-structure
N+ - C - C - C - O - C - R
=
O
“reverse” ester
• Elimination non-specific esterase
• Metabolite with acid-structure
Metabolism ofMetabolism of RemifentanilRemifentanil
N-C-CH2-CH3
C-O-CH3
Remifentanil
CH3-O-C-CH2-CH2-N
O
O
O
C-O-CH3
Major Metabolite (> 95 %)
N-C-CH2-CH3
H-O-C-CH2-CH2-N
O
O
O
GR90291
N-C-CH2-CH3
C-O-CH3
H-N
O
O
GR94219Non–S
pecific
Esteras
es
REMIFENTANIL
PHARMAKOKINETIC
PROFILE
REMIFENTANILREMIFENTANIL
PHARMAKOKINETICPHARMAKOKINETIC
PROFILEPROFILE
PharmacokineticPharmacokinetic profileprofileRemifentanilRemifentanil
third compartment not relevant
central
compartment
k 12
k 21
0.85t1/2 α = 0.9 min
EZRk23
k32
0.15t1/2 β = 0.6–14 min
IZR
0.002t1/2 γ = 35–137 min
Mean concentration over timeMean concentration over timeMean Concentration
(ng/mL)
0 60 120 180 240 300 360 420 480
1
10
100
Time (min)
0 60 120 180 240 300 360 420 480
Alfentanil (n = 5)0.5 mcg/kg/min
Remifentanil (n = 6)0.05 mcg/kg/min
Discontinuation of Infusion
distribution volume 5.7–8 l
protein binding capacity 70 %
clearance 30–40 ml/min/kg
onset time 1–1.5 min
PharmacokineticPharmacokinetic profile (2)profile (2)RemifentanilRemifentanil
Context Context -- Sensitive halfSensitive half--timetimeDefinitionDefinition
Three compartment model do not describe the elimination after long-term application sufficiently
Definition
The “Context - Sensitive half-time” is the time necessary for a 50 % decrease of a drug blood concentration after a continuous application
Context Context -- Sensitive halfSensitive half--timetime
Adapted from Egan TD, et al. Anesthesiology. 1993;79:881-892.
Time to 50 % Decreasein Blood Concentration(Minutes)
0 100 200 300 400 500 600
2
50
75
10
Minutes Since Beginning of Continuous Infusion
100
75
50
25
0 100 200 300 400 500 600
Fentanyl
Alfentanil
Sufentanil
Remifentanil
262.5 min after 240´
58.5 min after 240´
33.9 min after 240´
3.7 min after 240´
Comperative pharmacokineticsComperative pharmacokinetics
* Based on 3-hour infusion duration.
Egan TD, et al. Anesthesiology. 1993;79:881-892.Glass PSA. J Clin Anesth. 1995;7:558-563.
Vdss (L/kg)
Alfentanil Fentanyl Remifentanil
Cl (mL/min/kg)
elimination [t1/2 ;min]
distribution [t1/2; min]
Context-sensitivehalf time*
0.25–0.75
3–8
60–120
0.6–1.2
50–55
3–5
10–20
180–300
4–5
100
0.3–0.4
40–60
6–14
0.9–1.5
3
Comparative Comparative pharmacokineticspharmacokineticsChildren versus AdultsChildren versus Adults
* Values are mean ± SD.† Range of means across studies.
Glass PSA. J Clin Anesth. 1995; 7: 558-563.
Parameter Children*2–6 yrs 7–12 yrs
Young Healthy Adults†
Vdss (mL/kg)
Cl (mL/min/kg)
t1/2 (min)
550 ± 808 339 ± 217 300–400
40–60
8–20
56 ± 20 38 ± 13
20 ± 36 14±12
Comparative Comparative pharmacokineticspharmacokineticsAge and GenderAge and Gender
* Initial dose in the elderly should be reduced by 1/2.Data on file, Glaxo Wellcome Inc.
Target Blood Concentration (%)
Elderly Female*Elderly Male*Middle-Aged FemaleMiddle-Aged MaleYoung FemaleYoung Male
100
90
80
70
60
50
40
30
20
10
00 20 40 60 80 100 120 140
Time (min)
Comparative Comparative pharmacokineticspharmacokineticsHHepatic failureepatic failure
Values shown are geometric mean (95 % confidence interval).
Dershwitz M, et al. Anesthesiology. 1996;84:812-820.
Clearance(mL/min/kg)
Vd(mL/kg)
Hepatic impairment (n = 5)
Control (n = 5)
33.3 (23.0–48.3) 272 (162–456)
33.0 (28.5–38.1) 205 (178–235)
Comparative Comparative pharmacokineticspharmacokineticsRenal failure Renal failure
Values shown are mean (SD)
Clearance(mL/min/kg)
Vd(mL/kg)
Renal impairment (n = 9)
Control (n = 5)
36.0 (5.7) 230 (26)
34.2 (8.0) 197 (52)
Summary of theSummary of the pharmacokineticpharmacokinetic profileprofileRemifentanilRemifentanil
Kinetics follow a two (or three) compartment model
Context-sensitive half-time of 3–5 minutes
Elimination unaffected by gender, weight or
renal/hepatic function
Non-specific esterase metabolism
No change in duration of action on prolonged administration
Onset time of 1.0–1.5 minutes
REMIFENTANIL
PHARMAKODYNAMIC
PROFILE
REMIFENTANIL REMIFENTANIL
PHARMAKODYNAMICPHARMAKODYNAMIC
PROFILEPROFILE
Relative potency of Relative potency of µµ--opioidsopioids
Sufentanil > Fentanyl > Alfentanil
Analgetic potency determined by receptor affinity and intrinsic activity
Remifentanil
↓ 6–10 16–30 ↑similar
RemifentanilRemifentanilElectroencephalicElectroencephalic activityactivity
dose-dependent suppression of EEG-frequencyRemifentanil 19× higher potency compared to Alfentanil
(EC50 R: 20 ng/ml A: 376 ng/ml)high-dose Remifentanil: persistent Delta-Activity no burst-suppressionno convulsion activitydose dependent modification of SEP’s and MLAEP’s
RemifentanilRemifentanilHemodynamicHemodynamic effectseffects
Hypotension and bradycardia after rapid bolus injectionand dosages more than 2–30 µg/kg
Atropine prior injection, vasopressors
should be administered over 30 to 60 seconds
RemifentanilRemifentanilRespiratory effectsRespiratory effects
Depression of spontaneous breathingThorax rigidity after rapid bolus injection Maximum after 5 minutesNormal after 15 minutesRenal failure after 15 minutes 85 % recovery without
clinical relevanceAntagonist: Naloxon
REMIFENTANIL
CLINICAL CONSEQUENCES
REMIFENTANILREMIFENTANIL
CLINICAL CLINICAL CONSEQUENCESCONSEQUENCES
IndicationsIndications
Remifentanil is indicated for IV administration as an analgesic agent for use:
during the induction and maintenance of general anesthesia
for inpatient and outpatient procedures
for continuation as an analgesic into the immediate postoperative period under the direct supervision of an anesthesia practitioner in a PACU or intensive care setting
ContraindicationsContraindications
epidural or intrathecal administration (glycine)
patients with known hypersensitivity
to fentanyl analogs
RemifentanilRemifentanil administrationadministrationReconstruction and dilutionReconstruction and dilution
1 mg, 2 mg and 5 mg vials
solvent: Aqua ad inject, Glucose 5 %, NaCl 0.9 %, NaCl 0.45 %
Recommendation3 mg Remifentanil (i.e. 3 vials à 1 mg) with 50 ml NaCl 0.9 %
60 µg/ml
body weight = ml Remifentanil = 1 µg/kg/min
RemifentanilRemifentanil dosing guidelinesdosing guidelinesInductionInduction
Bolus application 0.5–1.0 µg/kg/min, onset 1–1.5 minMain adverse effects:Hypotension: Remifentanil: 5 %
Other opioids: 2 %
Muscle rigidity: Related to the dose and speed of administration
should be administered over 30 to 60 secondsRigidity < 1 % with prior or concurrent hypnotic or
NMB administrationReduced propofol and thiopental requirements for loss of consciousness
RemifentanilRemifentanil dosing guidelinesdosing guidelinesMaintananceMaintanance
Nitrous oxide (66 %) 0.4 0.1–2 1
Isoflurane (0.4 to 1.5 MAC) 0.5 0.05–2 1
Propofol (100 to 200 µg/kg/min) 0.25 0.05–2 1
Continuous IV Infusion(µg/kg/min)
Infusion Dose Range
(µg/kg/min)
Supplemental IV Bolus Dose
(µg/kg)
RemifentanilRemifentanilIntraIntra--operative Titrationoperative Titration
100
80
60
40
20
00 10 20 30 40 50 60
Ultiva
Alfentanil
Fentanyl
Pen
cent
age
ofst
eady
-sta
te c
once
ntra
tions
Minutes since beginning of infusion
steady state within 5–10 minutes of infusion rate
changes
The depth of anaesthesia and analgesia can be rapidly titrated to patient’s and anaesthetist’s needs
suitable for TCI
RemifentanilRemifentanil –– HighHigh--DoseDose--AnalgesiaAnalgesia
Camu F et al. 11th World Congress Anesthesiologists 1996, Abs p645Royston D et al. Anesthesiology 1996: 85 (3A): A239
Intra-operative response to skin incision
Pat
ient
s sh
owin
g on
e or
mor
e re
spon
ses
to s
urgi
cal s
timul
i (%
)
35
30
25
20
15
10
5
0
Ultiva, 0.4 µg/kg/min
Ultiva, 0.2 µg/kg/min
Fentanyl,1.5–3 µg/kg intermittent bolus doses
4%
12 %
33 %
(n=91) (n=98) (n=97)
*
* p < 0.001
- systolic blood pressure > 15 mmHg above baseline for > 1 minute- heart rate > 90 beats per minute for > 1 minute- gross movement, sweating or lacrimation
Responses defined as:
4 %(n=91)
High-dose analgesia right up to the end of surgery with improved haemodynamicstability and without compromising recovery
RemifentanilRemifentanil Dosing GuidelinesDosing GuidelinesSpecial PopulationsSpecial Populations
No dosage adjustment:Renal/hepatic dysfunction2–12 years of agePseudocholinesterase deficiency
Adjust dosing in:Elderly (> 65)—reduce initial dose by 50 %Obese (> 30 % above IBW)—dose to ideal body weight
Recovery from AnesthesiaRecovery from Anesthesia
Recovery from opioid effects in 5 to 10 minutesNo recurrent respiratory depressionConsistent offset of action, regardless of gender, age,
weight, or renal/hepatic statusRecovery rate limited by concurrent longer-acting
anesthetics, not remifentanil
Recovery of Respiratory DriveRecovery of Respiratory Drive
-30 0 30 60 90 120 150 180 210 240 27020
40
60
80
100
120
140
Time (min)
Remifentanil (n=11)Alfentanil (n=10)
During Infusion Post Infusion
140
120
100
80
60
40
20
Minutes Ventilation (% of Baseline)
-30 0 30 60 90 120 150 180 210 240 270
Postoperative AnalgesiaPostoperative AnalgesiaConsiderationsConsiderations
GoalSmooth transition to alternative analgesia
Early planning important because:Rapid offset of action (within 5–10 min)Lack of cumulative effects
Postoperative Analgesia Postoperative Analgesia Management OptionsManagement Options
Initiate before discontinuation of remifentanil
Nonsteroidal agent
Local anesthetic: Infiltration, Epidural administration
Long-acting opioids administered 20–30 minutes before discontinuation of remifentanil
PostoperativePostoperative AnalgesiaAnalgesiaManagementManagement with Remifentanilwith Remifentanil
Initial infusion rate: 0.1 mcg/kg/min
Infusion rate may be adjusted every 5 minutes inincrements of 0.025 mcg/kg/min to balance analgesia and respiratory rate
Infusion rates > 0.2 mcg/kg/min are associatedwith respiratory depression
Bolus injections not recommended
In select patients under the direct supervision ofan anesthesia practitioner:
PRACTICAL CONSIDERATIONS
and SUMMARY
PRACTICAL PRACTICAL CONSIDERATIONS CONSIDERATIONS
and and SUMMARYSUMMARY
RemifentanilRemifentanilPractical considerationsPractical considerations
Initial Bolus should be administered over 30 to 60 secondsReduce propofol and thiopental requirements for loss of
consciousnessRapid offset of analgesic effect requires early postoperative
analgesiaIn the postoperative setting, bolus doses are not recommended
Rapid onset of action (~ 1 min)
Rapid response to titration
Rapid, predictable recovery from opioid effects (within 5–10’)“reverse” ester metabolized by non-specific esterases in the blood and tissues
No opioid accumulation, regardless of dose or duration of infusion
Elimination unchanged in patients with renal or hepatic dysfunction; dosage adjustment is necessary in elderly
RemifentanilRemifentanilSummarySummary
Allows decreased administration of hypnotic agents (eg. propofol, isoflurane, and thiopental) by up to 75
%
Suitable for computer assisted application (TCI)May lead to early extubation after inpatient procedures
No cases of recurrent respiratory depression
Consistent offset may help speed PACU discharge
RemifentanilRemifentanilSummary (2)Summary (2)