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Pharmakokinetics, Pharmakokinetics , pharmakodynamics and and pharmakodynamics clinical consequences consequences clinical
Jens Soukup
Department of Anesthesiology and Critical Care Martin Luther University Halle Wittenberg
AMNESIA
ANALGESIA
(Sufentanil, Alfentanil?)
REMIFENTANIL REMIFENTANIL CHEMICAL STRUCTURE STRUCTURE CHEMICAL and and METABOLISM METABOLISM
Metabolism of Remifentanil
Remifentanil
O CH3-O-C-CH2-CH2-N O C-O-CH3 O N-C-CH2-CH3
N o Es n S te pe ra c se ifi s c
N-C-CH2-CH3
GR90291
GR94219
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
00
180 240
240 300
480
Time (min)
Definition
The Context - Sensitive half-time is the time necessary for a 50 % decrease of a drug blood concentration after a continuous application
10 100 75
75
50
50
Alfentanil 58.5 min after 240 Sufentanil 33.9 min after 240
2
25
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
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
Comparative pharmacokinetics
Target Blood Concentration (%)
100 90 80 70 60 50 40 30 20 10 0 0 20 40 60 80 100 120 140
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)
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)
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
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 %
Remifentanil
Intra-operative Titration
100
Pencentage of steady-state concentrations
80 60 40 20
Ultiva
Alfentanil Fentanyl
0 0 10 20 30 40 50
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
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
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