Remifentanil pharmacology.pdf

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


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


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´



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


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)

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Remifentanil pharmacology.pdf