REMIFENTANIL

Pharmakokinetics, Pharmakokinetics , pharmakodynamics and and pharmakodynamics clinical consequences consequences clinical
Jens Soukup
Department of Anesthesiology and Critical Care Martin Luther University Halle Wittenberg

Current Changes in anaesthetic practice

Inpatient Long-acting Outpatient/Day-case Short-acting

Need for more flexible anesthetic drugs

 Triad of anaesthesia Triad

HYPNOSIS
(Sevorane)

AMNESIA

GENERAL ANAESTHESIA RELAXATION

(mivacron, rapacuronium)

ANALGESIA
(Sufentanil, Alfentanil?)

REMIFENTANIL REMIFENTANIL CHEMICAL STRUCTURE STRUCTURE CHEMICAL and and METABOLISM METABOLISM

The reverse ester -Remifentanil ester-Remifentanil

O reverse ester N+ - C - C - C - O - C - R

Elimination non-specific esterase Metabolite with acid-structure O true ester N+ - C - C - O - C - C - R

Elimination Plasmacholinesterase Metabolite with alcohol-structure

Metabolism of Remifentanil
Remifentanil
O CH3-O-C-CH2-CH2-N O C-O-CH3 O N-C-CH2-CH3

Major Metabolite (> 95 %)

O O H-O-C-CH2-CH2-N C-O-CH3 O

N o Es n S te pe ra c se ifi s c

O C-O-CH3 H-N O N-C-CH2-CH3

N-C-CH2-CH3

GR90291

GR94219

REMIFENTANIL REMIFENTANIL PHARMAKOKINETIC PHARMAKOKINETIC PROFILE PROFILE

Pharmacokinetic profile
Remifentanil
k 12 k23

central compartment
k 21

EZR
k32

IZR 0.002
t1/2 = 35137 min

0.85
t1/2 = 0.9 min

0.15
t1/2 = 0.614 min

third compartment not relevant

Mean concentration over time

Mean Concentration (ng/mL)
100 Alfentanil (n = 5) 0.5 mcg/kg/min 10 Discontinuation of Infusion

1 Remifentanil (n = 6) 0.05 mcg/kg/min

00

60 60 120 120 180

180 240

240 300

300 420 360480 420 360

480

Time (min)

Pharmacokinetic profile (2)

Remifentanil
onset time 11.5 min protein binding capacity 70 % distribution volume 5.78 l clearance 3040 ml/min/kg

Context - Sensitive half-time

Definition 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 - Sensitive half-time

Time to 50 % Decrease in Blood Concentration (Minutes)

10 100 75

262.5 min after 240 Fentanyl

75

50
50

Alfentanil 58.5 min after 240 Sufentanil 33.9 min after 240

2
25

Remifentanil 3.7 min after 240

0 0

100 100

200 200

300 300

400 400

500 500

600 600

Minutes Since Beginning of Continuous Infusion Adapted from Egan TD, et al. Anesthesiology. 1993;79:881-892.

Comperative pharmacokinetics
Alfentanil Vdss (L/kg) Cl (mL/min/kg) elimination [t1/2 ;min] distribution [t1/2; min] Context-sensitive half time* * 0.250.75 38 60120 0.61.2 5055 Fentanyl 35 1020 180300 45 100 Remifentanil 0.30.4 4060 614

0.91.5 3

Based on 3-hour infusion duration.

Egan TD, et al. Anesthesiology. 1993;79:881-892. Glass PSA. J Clin Anesth. 1995;7:558-563.

Comparative pharmacokinetics
Children versus Adults
Children* 26 yrs 712 yrs 550 808 56 20 20 36 339 217 38 13 1412 Young Healthy Adults 300400 4060 820

Parameter Vdss (mL/kg) Cl (mL/min/kg) t1/2 (min)

Values are mean SD. Range of means across studies.

Glass PSA. J Clin Anesth. 1995; 7: 558-563.

Comparative pharmacokinetics
Target Blood Concentration (%)
100 90 80 70 60 50 40 30 20 10 0 0 20 40 60 80 100 120 140

Age and Gender

Elderly Female* Elderly Male* Middle-Aged Female Middle-Aged Male Young Female Young Male

Time (min)
* Initial dose in the elderly should be reduced by 1/2. Data on file, Glaxo Wellcome Inc.

Comparative pharmacokinetics

Hepatic failure
Clearance (mL/min/kg) Hepatic impairment (n = 5) Control (n = 5) 33.3 (23.048.3) Vd (mL/kg) 272 (162456)

33.0 (28.538.1)

205 (178235)

Values shown are geometric mean (95 % confidence interval).

Dershwitz M, et al. Anesthesiology. 1996;84:812-820.

Comparative pharmacokinetics
Renal failure
Clearance (mL/min/kg) Renal impairment (n = 9) 36.0 (5.7) Vd (mL/kg) 230 (26)

Control (n = 5)

34.2 (8.0)

197 (52)

Values shown are mean (SD)

Summary of the pharmacokinetic profile

Remifentanil
Kinetics follow a two (or three) compartment model Onset time of 1.01.5 minutes Context-sensitive half-time of 35 minutes Non-specific esterase metabolism Elimination unaffected by gender, weight or renal/hepatic function No change in duration of action on prolonged administration

REMIFENTANIL REMIFENTANIL PHARMAKODYNAMIC PHARMAKODYNAMIC PROFILE PROFILE

Relative potency of -opioids

Analgetic potency determined by receptor affinity and intrinsic activity Sufentanil >
610

Fentanyl

>

Alfentanil
1630

similar

Remifentanil

Remifentanil
Electroencephalic activity
dose-dependent suppression of EEG-frequency Remifentanil 19 higher potency compared to Alfentanil (EC50 R: 20 ng/ml A: 376 ng/ml) high-dose Remifentanil: persistent Delta-Activity no burst-suppression no convulsion activity dose dependent modification of SEPs and MLAEPs

Remifentanil
Hemodynamic effects
Hypotension and bradycardia after rapid bolus injection and dosages more than 230 g/kg
should be administered over 30 to 60 seconds Atropine prior injection, vasopressors

Remifentanil
Respiratory effects
Depression of spontaneous breathing Thorax rigidity after rapid bolus injection Maximum after 5 minutes Normal after 15 minutes Renal failure after 15 minutes 85 % recovery without clinical relevance Antagonist: Naloxon

REMIFENTANIL CLINICAL CONSEQUENCES

Indications
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

Contraindications
epidural or intrathecal administration (glycine) patients with known hypersensitivity to fentanyl analogs

Remifentanil administration
Reconstruction and dilution
1 mg, 2 mg and 5 mg vials solvent: Aqua ad inject, Glucose 5 %, NaCl 0.9 %, NaCl 0.45 %

Recommendation
3 mg Remifentanil (i.e. 3 vials 1 mg) with 50 ml NaCl 0.9 %

60 g/ml body weight = ml Remifentanil = 1 g/kg/min

Remifentanil dosing guidelines

Induction
Bolus application 0.51.0 g/kg/min, onset 11.5 min Main 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 seconds Rigidity < 1 % with prior or concurrent hypnotic or NMB administration Reduced propofol and thiopental requirements for loss of consciousness

Remifentanil dosing guidelines

Maintanance
Continuous IV Infusion (g/kg/min) Nitrous oxide (66 %) Isoflurane (0.4 to 1.5 MAC) Propofol (100 to 200 g/kg/min) 0.4 0.5 0.25 Supplemental IV Bolus Dose (g/kg) 1 1 1

Infusion Dose Range (g/kg/min) 0.12 0.052 0.052

Remifentanil
Intra-operative Titration
100
Pencentage of steady-state concentrations

80 60 40 20

Ultiva

Alfentanil Fentanyl

steady state within 510 minutes of infusion rate changes

60

0 0 10 20 30 40 50

Minutes since beginning of infusion

The depth of anaesthesia and analgesia can be rapidly titrated to patients and anaesthetists needs suitable for TCI

Remifentanil High-Dose-Analgesia
Intra-operative response to skin incision
Patients showing one or more responses to surgical stimuli (%)

35 30 25 20 15 10 5 0
*

33 %

Ultiva, 0.4 g/kg/min Ultiva, 0.2 g/kg/min Fentanyl, 1.53 g/kg intermittent bolus doses
Responses defined as: - systolic blood pressure > 15 mmHg above baseline for > 1 minute - heart rate > 90 beats per minute for > 1 minute - gross movement, sweating or lacrimation

12 %

4 % 4% (n=91)
(n=91)

(n=98)

(n=97)

* p < 0.001

High-dose analgesia right up to the end of surgery with improved haemodynamic stability and without compromising recovery
Camu F et al. 11th World Congress Anesthesiologists 1996, Abs p645 Royston D et al. Anesthesiology 1996: 85 (3A): A239

Remifentanil Dosing Guidelines

Special Populations
No dosage adjustment: Renal/hepatic dysfunction 212 years of age Pseudocholinesterase deficiency Adjust dosing in: Elderly (> 65)reduce initial dose by 50 % Obese (> 30 % above IBW)dose to ideal body weight

Recovery from Anesthesia

Recovery from opioid effects in 5 to 10 minutes No recurrent respiratory depression Consistent offset of action, regardless of gender, age, weight, or renal/hepatic status Recovery rate limited by concurrent longer-acting anesthetics, not remifentanil

Recovery of Respiratory Drive

Minutes Ventilation (% of Baseline)
140 140 120 120 100 100 80 80 60 60 40 40

Remifentanil (n=11) Alfentanil (n=10)

During Infusion
20 20 -30 -30 0 0 30 30 60 60 90 90 120 120 150 150

Post Infusion
180 180 210 210 240 240 270 270

Time (min)

Postoperative Analgesia
Considerations
Goal Smooth transition to alternative analgesia Early planning important because: Rapid offset of action (within 510 min) Lack of cumulative effects

Postoperative Analgesia
Management Options
Initiate before discontinuation of remifentanil Nonsteroidal agent Local anesthetic: Infiltration, Epidural administration Long-acting opioids administered 2030 minutes before discontinuation of remifentanil

Postoperative Analgesia
Management with Remifentanil
In select patients under the direct supervision of an anesthesia practitioner: Initial infusion rate: 0.1 mcg/kg/min Infusion rate may be adjusted every 5 minutes in increments of 0.025 mcg/kg/min to balance analgesia and respiratory rate Infusion rates > 0.2 mcg/kg/min are associated with respiratory depression Bolus injections not recommended

PRACTICAL CONSIDERATIONS and SUMMARY

Remifentanil
Practical considerations
Initial Bolus should be administered over 30 to 60 seconds Reduce propofol and thiopental requirements for loss of consciousness Rapid offset of analgesic effect requires early postoperative analgesia In the postoperative setting, bolus doses are not recommended

Remifentanil
Summary
Rapid onset of action (~ 1 min) Rapid response to titration Rapid, predictable recovery from opioid effects (within 510) 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

Remifentanil
Summary (2)
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