Klinische Farmacologie van
Hypnotica en Opioïden
Jaap Vuyk
Anesthesiologie LUMC
“Within 1 year after marketing, Hoffmann-LaRoche had
received 48 case reports of serious cardiorespiratory events,
including 23 deaths, associated with the use of midazolam.
The majority of these events occurred in older patients.”
Farmacologie: Opzet
Basale farmacologie: PK/PD.
Interindividuele variabiliteit.
Basale farmacologie
Basale Farmacologie
Effect
Patiënt
Dosis
Basale Farmacologie
Effect
Farmacodynamie
Farmacokinetiek
Dosis
Basale farmacokinetiek
 PK: dosis-concentratie relatie.
 Distributie, redistributie (flow) en klaring (cyt P450).
 Bloed-brein equilibratie.
 Context sensitive half-time
 Farmacokinetische kengetallen:
V1, V2, V3 en Cl1 , Cl2 en Cl3.
Basale farmacokinetiek
Blood propofol concentration (µg/ml)
3
●●
●
●
2
●
1 mg/kg propofol
●
●
●
●
●
1
●
●
●
●
●
0
0
5
10
Time (min)
15
Basale farmacokinetiek
Blood propofol concentration (µg/ml)
3
●●
●
●
2
●
1 mg/kg propofol
●
●
●
●
●
1
●
●
●
●
●
0
0
5
10
Time (min)
15
Basale farmacokinetiek
Blood propofol concentration (µg/ml)
3
Redistributie
2
1
Klaring
Distributie
0
0
5
10
Time (min)
15
Farmacokinetisch model
Dosis
k13
k12
V2
V1
k21
V3
k31
k10
Klaring
Farmacokinetisch model
 Farmacokinetische kengetallen:
V1, V2, V3 en Cl1, Cl2 en Cl3.
Dosis
 Fysisch-chemische eigenschappen medicament.
k
13
- lipofiliteit k12
V2
V1
- ionisatiegraad
(pH-pKa
verhouding)
k21
k31
- mate van eiwitbinding
k10
 Werkzame fractie Klaring
(diffusable fraction).
V3
Basale farmacokinetiek
 Zwakke basen (benzo’s, opioiden).
- pH > pKa : ongeïoniseerd.
- pH = pKa : ongeïoniseerd = geïoniseerd.
- pH < pKa : geïoniseerd.
 Zwakke zuren (propofol, thiopental).
- pH > pKa : geïoniseerd.
- pH = pKa : ongeïoniseerd = geïoniseerd.
- pH < pKa : ongeïoniseerd.
 Diazepam pKa 3.7, midazolam pKa 6.1, alfentanil pKa 6.5
propofol pKa 11, thiopental pKa 7.6
Diffusable fractie opioiden
Niet-eiwit
Ongeïoniseerd
gebonden (%)
(%)
Diffusable
fractie (%)
10
89
8.9
Sufentanil
10
20
2
Fentanyl
20
9
1.8
80
5
4
Alfentanil
(pKa 6.5)
(pKa 8.4)
Morfine
(pKa 8.6)
Farmacokinetisch Model
Inductie Anesthesie
 Hypnotica en opioiden
werken niet aan de naald.
Dosis
 Distributie en receptorbinding kosten tijd.
k13
k12
V
V
 Bloed-brein
equilibratie:
t½k
2
1
k21
e0
k31
V3
 (Te) snelle inductie → overdosis → bijwerkingen.
k10
Klaring
Bloed-brein equilibratie: Ideaal
100
Sedatiegraad
80
60
40
20
0
0
1
2
Plasma concentratie propofol (ng/ml)
3
Bloed-brein equilibratie: hysterese
100
Sedatiegraad
80
60
40
20
0
0
1
2
Plasma concentratie propofol (ng/ml)
3
Farmacokinetisch Model
Continuering Anesthesie
 Doel: stabiele concentratie
→ stabiel effect
Dosis
 Herhaalde bolusdosis: sterker effect
- reduceer dosis
k12
- verleng
dosisinterval
V2
V1
k21
k13
V3
k31
 Continue infusie: reduceer infusiesnelheid in de tijd.
k10
Klaring
Farmacokinetisch Model
Beeindiging Anesthesie
 Staken toediening ≠Dosis
effect beeindiging
 Effect beeindiging met name door redistributie.
k13
k12
V
V grotere totale dosisV
 Langere
toediening →
2
1
3
k21
Langere toediening
→ V2 enk31V3 meer gevuld
Langere toediening →k10minder redistributie, meer Cl
Klaring
 Context sensitive half-time
Propofol versus midazolam
Equihypnotische concentratie (µg/ml)
Beeindiging Sedatie
4
Propofol
50% en 75% daling Cp
3
8 min
2
35 min
1
0
0
60
120
Time (min)
180
240
Propofol versus midazolam
Equihypnotische concentratie (µg/ml)
Beeindiging Sedatie
Propofol
Midazolam
4
50% en 75% daling Cp
3
40 min
135 min
2
1
0
0
60
120
Time (min)
180
240
Remifentanil versus fentanyl
Beeindiging Sedatie
Remifentanil
1,25
Equi-opioid concentratie
50% en 75% daling Cp
1,00
3 min
0,75
9 min
0,50
0,25
0,00
0
60
120
Time (min)
180
240
Remifentanil versus fentanyl
Beeindiging Sedatie
Fentanyl
Remifentanil
1,25
Equi-opioid concentratie
50% en 75% daling Cp
1,00
34 min
0,75
139 min
0,50
0,25
0,00
0
60
120
Time (min)
180
240
Context sensitive half-time
Context sensitive half-time (min)
120
90
60
Midazolam
30
0
0
60
120
Infusion duration (min)
180
240
Context sensitive half-time
Context sensitive half-time (min)
120
27 min
40 min
64 min
76 min
90
60
Midazolam
30
0
0
60
120
Infusion duration (min)
180
240
Context sensitive half-time
Context sensitive half-time (min)
120
90
Midazolam
60
30
Propofol
0
0
60
120
Infusion duration (min)
180
240
Context sensitive half-time
Context sensitive half-time (min)
120
Fentanyl
90
60
30
0
0
60
120
Infusion duration (min)
180
240
Context sensitive half-time
Context sensitive half-time (min)
120
Fentanyl
90
60
30
Remifentanil
0
0
60
120
Infusion duration (min)
180
240
Context sensitive half-time
Context sensitive half-time (min)
120
Fentanyl
90
60
Midazolam
30
Propofol en Remifentanil
0
0
60
120
Infusion duration (min)
180
240
Basale farmacodynamie
 Concentratie-effect relatie.
 Anesthetica (bij)werken door receptorbinding.
 Receptorbinding → ionkanalen (Cl , Ca
-
→ de- of hyperpolarisatie.
 EC
50,
EC95 en γ
2+,
Na+, K+)
PD: Sigmoid Emax Curve
100
Hypnotisch Effect
80
60
40
20
0
0
10
20
Concentration (ng/ml)
30
40
PD: Sigmoid Emax Curve
100
γ
Hypnotisch Effect
80
60
40
20
0
0
10
20
Concentration (ng/ml)
30
40
PD: Sigmoid Emax Curve
100
Hypnotisch Effect
80
60
40
20
0
0
10
EC50
20
EC95
Concentration (ng/ml)
30
40
PD: Sigmoid Emax Curve
Hypnose
Lethale Bloeddrukdaling
100
80
Therapeutische index
Effect
60
EC50/LC50
40
20
0
0
10
20
Concentratie (ng/ml)
30
40
Werking Midazolam
Factors of Influence on
Perioperative Opioid PK-PD
 What is the magnitude of PK-PD variability?
 Which factors are involved in PK-PD variability?
 How do we deal with PK-PD variability
in clinical practice?
What is the magnitude of the
PK-PD variability in
Anesthesia?
Midazolam PD in the ICU
Somma et al: Anesthesiology 89 (6), 1430-1443, 1998.
Midazolam PD in the ICU
Somma et al: Anesthesiology 89 (6), 1430-1443, 1998.
Midazolam PD in the ICU
Somma et al: Anesthesiology 89 (6), 1430-1443, 1998.
Alfentanil PD during Surgery
Ausems et al: Anesthesiology 1986; 65: 362-373
Alfentanil PD during Surgery
EC50
Ausems et al: Anesthesiology 1986; 65: 362-373
Remifentanil PD during Surgery
Drover et al: Anesthesiology. 1998 Oct;89(4):869-77
Remifentanil PD during Surgery
Drover et al: Anesthesiology. 1998 Oct;89(4):869-77
EC50
What is the magnitude of the
PK-PD variability in
Anesthesia?
What is the magnitude of the
PK-PD variability in
Anesthesia?
Up to 1000%
Which factors are responsible for
the PK-PD variability?
 Genetic causes of variability.
 “Classical” causes of variability.
Which factors are responsible for
the PK-PD variability?
 Genetic causes of variability.
- Single nucleotide polymorphism (SNP).
- Ethnicity
- Gender
 “Classical” causes of variability.
- Weight
- Organ function (age)
- Comedication (PK-PD interactions)
Which factors are involved in
the PK-PD variability?
 Genetic causes of variability.
- Single nucleotide polymorphism (SNP).
- Variability in nociception.
- Ethnicity
- Gender
 “Classical” causes of variability.
- Weight
- Organ function (age)
- Comedication (PK-PD interactions)
µ-opioid Receptor Mutations
at the OPRM1 gene at Chr 6
Lotsch et al. Trends in Molec Medic 2005, 2: 82-89.
µ-opioid Receptor Mutations
at the OPRM1 gene at Chr 6
Lotsch et al. Trends in Molec Medic 2005, 2: 82-89.
Polymorphism 118A>G.
 Adenine is exchanged by guanine in exon 1.
 Asparagine is exchanged to aspartate at position 40 of
the receptors.
 Naturally existing in an allelic frequency of 10-19%.
 Carriers need more alfentanil for postoperative pain
relief.
 Carriers need more morphine for cancer pain relief.
 Increased demands for M6G to produce analgesia.
Polymorphism 118A>G.
Pharmacodynamics of Morphine and M6G
Lotsch et al. Pharmacogenetics 2002; 12: 3-9
Polymorphism A118G.
Pharmacodynamics of Morphine and M6G
Lotsch et al. Pharmacogenetics 2002; 12: 3-9
Polymorphism A118G.
Pharmacodynamics of Morphine and M6G
EC50
700 to 3000 nmol/L
Lotsch et al. Pharmacogenetics 2002; 12: 3-9
EC50: 34-54 nmol/L
Polymorphism A118G.
Pharmacodynamics of Morphine and M6G
Lotsch et al. Pharmacogenetics 2002; 12: 3-9
Cancer pain and 118A>G.
 Of
215 cancer patients 176 were homozygote AA (wild
type), 35 were heterozygote AG and 4 were homozygote
GG.
 AA,
AG and GG-type patients did not differ in
performance status, primary tumor location, time since
start morphine etc..
 Of
the patients with adequate pain control, daily
morphine consumption in GG-type patients doubled that
of the AA-wild type (225 versus 97 mg/24 h).
Klepstad et al. Act. Anaesth. Scan. 2004: 48, 1232-39
Which factors are responsible for
the PK-PD variability?
 Genetic causes of variability.
- Single nucleotide polymorphism (SNP).
- Ethnicity
- Gender
 “Classical” causes of variability.
- Weight
- Organ function (age)
- Comedication (PK-PD interactions)
- Underlying disease
Male-female differences
PK-PD Variability
 Men have 4% more brain cells and on average
100 g more brain tissue.
 In general women have a (little) lower (experimental) pain
threshold than men, and less tolerance to noxious stimulation.
 Men consume 30 to 40% more PCA morphine. Miaskowski et
al. Pain Forum 1999; 8: 34-40
 Women emerge from anesthesia more rapidly than men after
equivalently dosed propofol-alfentanil anesthesia (Glass et al.,
Anesthesiology 1999, Hoymark et al., Acta Scan 2004).
Authors
Year
Gordon et al.
1995
Drover et al.
Setting
Greater/
faster in
Type
End-point
morphine after molar
extraction surgery
pro
pain relief
no difference
1998
abdominal anesthesia
with 66% N2O
pro
remifentanil
women
Miakowski
1999
review of 18 studies on
PCA morphine
retro
opioid consumption
men
Dahan et al.
Sarton et al.
1989
1999
0.13 mg/kg morphine
given to volunteers
po
effect on CO2 and hypoxic
response
women
Gan et al.
1999
recovery from
alfentanil/propofol/N2O
anesthesia
retro
wake-up time
women
Sarton et al.
2000
0.13 mg/kg morphine
given to volunteers
pro
opioid potency
women
Zacny
2001
10 mg/kg morphine
given to volunteers
retro
subjective effects
women
Averbuch &
Katzper
2001
placebo after molar
surgery
retro
pain relief
no difference
Romberg
2002
0.3 mg/kg M6G
pro
opioid potency
women
Authors
Year
Gordon et al.
1995
Drover et al.
Setting
Stronger/
faster in
Type
End-point
morphine after molar
extraction surgery
pro
pain relief
no difference
1998
abdominal anesthesia
with 66% N2O
pro
remifentanil
women
Miakowski
1999
review of 18 studies on
PCA morphine
retro
opioid consumption
men
Dahan et al.
Sarton et al.
1989
1999
0.13 mg/kg morphine
given to volunteers
po
effect on CO2 and hypoxic
response
women
Gan et al.
1999
recovery from
alfentanil/propofol/N2O
anesthesia
retro
wake-up time
women
Sarton et al.
2000
0.13 mg/kg morphine
given to volunteers
pro
opioid potency
women
Zacny
2001
10 mg/kg morphine
given to volunteers
retro
subjective effects
women
Averbuch &
Katzper
2001
placebo after molar
surgery
retro
pain relief
no difference
Romberg
2002
0.3 mg/kg M6G
pro
opioid potency
women
Authors
Year
Gordon et al.
1995
Drover et al.
Setting
Greater/
faster in
Type
End-point
morphine after molar
extraction surgery
pro
pain relief
no difference
1998
abdominal anesthesia
with 66% N2O
pro
remifentanil
women
Miakowski
1999
review of 18 studies on
PCA morphine
retro
opioid consumption
men
Dahan et al.
Sarton et al.
1989
1999
0.13 mg/kg morphine
given to volunteers
po
effect on CO2 and hypoxic
response
women
Gan et al.
1999
recovery from
alfentanil/propofol/N2O
anesthesia
retro
wake-up time
women
Sarton et al.
2000
0.13 mg/kg morphine
given to volunteers
pro
opioid potency
women
Zacny
2001
10 mg/kg morphine
given to volunteers
retro
subjective effects
women
Averbuch &
Katzper
2001
placebo after molar
surgery
retro
pain relief
no difference
Romberg
2002
0.3 mg/kg M6G
pro
opioid potency
women
Pain Tolerance with
Morphine 0.13 mg/kg
Women
Men
Conclusions Morphine Study
 Baseline pain parameters were equal in women and
men.
 Women showed greater morphine potency (EC50: 40
versus 74 nmol/L) but the analgesic effect had a
slower speed of on- and offset (t½ke0: 240 versus 90
min).
 No differences between male and females in the
pharmacokinetics of of morphine, morphine-6glucuronide and morphine-3-glucuronide.
Computer Simulation of Morphine
Administration for Equal Analgesia
F:
Computer Simulation of Morphine
Administration for Equal Analgesia
F:
Female: after 7 h total M-dose is 22 mg
Male : after 7 h total M-dose is 33 mg
Miaskowski et al.
Pain Forum 1999; 8: 34-40
Men consume 30 to 40% more
PCA morphine
Does gender matter?
 Women emerge from anesthesia more quickly than men.
 Women do not differ from men in morphine PK.
 Women are more sensitive to morphine, men need + 40%
more morphine to experience equianalgesia.
 Morphine t½ke0 is longer in women than in men.
Which factors are responsible for
the PK-PD variability?
 Genetic causes of variability.
- Single nucleotide polymorphism (SNP).
- Ethnicity
- Gender
 “Classical” causes of variability.
- Weight
- Organ function (age)
- Comedication (PK-PD interactions)
- Underlying disease
How does weight
affect the PK of
IV-Anesthetics?
Pharmacokinetics - Weight
 Obese (BMI > 30): larger Fat mass and LBM.
 Weak lipophilic agents distribute to lean tissues.
NMBA : dosage on IBW/LBM (lithium, vecuronium,
atracurium).
 Lipophilic agents: lipophilicity not clearly related to
distribution.
Propofol: effect of weight
Propofol concentration (µg/ml).
6
25 yr male, 70 kg
5
2 mg/kg bolus
4
8 mg/kg/h for 60 min
3
2
1
0
0
30
60
Time (min)
90
120
Propofol: effect of weight
Propofol concentration (µg/ml).
6
25 yr male, 70 kg
25 yr male, 140 kg
5
2 mg/kg bolus
4
8 mg/kg/h for 60 min
3
2
1
0
0
30
60
Time (min)
90
120
Remifentanil concentration (ng/ml)
Remifentanil: effect of weight
12
25 yr male, 70 kg
10
1 mcg/kg bolus
8
0.25 mcg/kg/min for 60 min
6
4
2
0
0
30
60
Time (min)
90
120
Remifentanil concentration (ng/ml)
Remifentanil: effect of weight
12
25 yr male, 70 kg
25 yr male, 140 kg
10
1 mcg/kg bolus
8
0.25 mcg/kg/min for 60 min
6
4
2
0
0
30
60
Time (min)
90
120
LBM versus TBW
In a male/female being 180 cm tall
Male LBM
Female LBM
Lean body mass (kg)
80
60
40
20
LBM (kg) = a * TBW (kg) – b * (TBW/height (cm))2
a and b are 1.1 and 120 for men
a and b are 1.07 and 148 for women
0
0
25
50
75
100
Total body weight (kg)
125
150
LBM versus TBW
In a male/female being 180 cm tall
Male LBM
Female LBM
Lean body mass (kg)
80
LBM: +40%
60
TBW: +100%
40
20
LBM (kg) = a * TBW (kg) – b * (TBW/height (cm))2
a and b are 1.1 and 120 for men
a and b are 1.07 and 148 for women
0
0
25
50
75
100
Total body weight (kg)
125
150
Remifentanil dosing
200 kg TBW ≈ 90 kg LBM
40 kg TBW ≈ 40 kg LBM
Does weight matter?
 NMBA: hydrophilic - small Vd: dosing on
LBM/IBW.
 Propofol: lipophilic - Vss and Cl1 increase;
elimination half-life remains unchanged, dosing on
TBW (Servin et al.).
 Remifentanil: large Cl1, small V’s: dosing on LBM.
Which factors are responsible for
the PK-PD variability?
 Genetic causes of variability.
- Single nucleotide polymorphism (SNP).
- Ethnicity
- Gender
 “Classical” causes of variability.
- Weight
- Organ function (age)
- Comedication (PK-PD interactions)
- Underlying disease
Does age
matter?
Age and the PK-PD of
Anesthetics
 Pharmacokinetics
and age.
Cardiac output ↓: distribution ↓ and V ↓
1
Hepatic perfusion ↓ : agents with high extraction ratio: Cl1 decreases.
 Pharmacodynamics
and age.
- loss of neuronal substance
- brain weight decreases by 15% from 20-80 yr
- CBF ↓
- changes in µ-, GABA- and NMDA-receptors (animal studies)
Result: EC50 decreases with age.
Propofol: effect of age
Propofol concentration (µg/ml).
6
25 yr male
5
2 mg/kg bolus
4
8 mg/kg/h for 60 min
3
2
1
0
0
30
60
Time (min)
90
120
Propofol: effect of age
Propofol concentration (µg/ml).
6
25 yr male
80 yr male
5
2 mg/kg bolus
4
8 mg/kg/h for 60 min
3
2
1
0
0
30
60
Time (min)
90
120
Remifentanil concentration (ng/ml)
Remifentanil: PK effect of age
12
25 yr male
10
1 mcg/kg bolus
8
0.25 mcg/kg/min for 60 min
6
4
2
0
0
30
60
Time (min)
90
120
Remifentanil concentration (ng/ml)
Remifentanil: PK effect of age
12
25 yr male
80 yr male
10
1 mcg/kg bolus
8
0.25 mcg/kg/min for 60 min
6
4
2
0
0
30
60
Time (min)
90
120
Remifentanil PK.
Effect of Age
Minto et al., Anesthesiology 1997; 86 (1): 10-23
Effect of Age on Propofol LOC
Schnider et al., Anesthesiology 1999; 90 (6): 1502-1516.
Effect of Age on Propofol LOC
EC50: 2.5 to 1.2 µg/ml
Schnider et al., Anesthesiology 1999; 90 (6): 1502-1516.
Remifentanil PD.
Effect of Age
Minto et al., Anesthesiology 1997; 86 (1): 10-23
Remifentanil PD.
Effect of Age
16 ng/ml
8 ng/ml
Minto et al., Anesthesiology 1997; 86 (1): 10-23
PK-PD: The effect of Age
 Pharmacokinetics: with age distribution and clearance
decrease.
Pharmacodynamics: with age (20-80 yr) EC50 is halved.
 This all because with age, cardiovascular function and
CNS function diminish.
 Reduce dose by 50% with age 20-80 yr.
Anesthetics in
Children
Infants: physiology and PK
 Infants (< 6 months):
1: TBW↑ (80-90%), adults (40-50%)
Extracellular Fluid Volume ↑
2: Protein binding ↓
(less protein and less binding capacity)
3: Enzymatic activity : ↓ adult values at age < 6 months
: high interindividual variability
Morphine Clearance
in Children
Bouwmeester, N. J. et al. Br. J. Anaesth. 2004 92:208-217
Morphine Clearance
in Children
 Morphine PK in infants < 3-6
months:
Cl ↓ , Vdss ↓ and T½β ↑
 Young infants need a 50% lower
dose.
Bouwmeester, N. J. et al. Br. J. Anaesth. 2004 92:208-217
Fentanyl PK in Newborns
Saarenmaa, E et al. J. Ped. 2000; 767-700.
Remifentanil Pharmacokinetics in
Neonates, Young and Older Children
Ross AK et al. Anesth Analg 2001; 93: 1393-401
Remifentanil PK in Children
Ross, A. K. et al. Anesth Analg 2001;93:1393-1401
Remifentanil PK in Children
 Remifentanil PK in young
children:
 Young children may need a higher
dose.
Ross, A. K. et al. Anesth Analg 2001;93:1393-1401
Opioids in infants
 Scarcity on PK-PD data in infants.
 Enzymatic activity ≈ adult levels at 6 months.
 PD: adults ≈ children?
 Reduce Alf/Suf/Fent and Morphine dose <3-6
months
Bjorkman S. Clinical Pharmacokinetics 2006:45 (1): 1-11
Which factors are responsible for
the PK-PD variability?
 Genetic causes of variability.
- Single nucleotide polymorphism (SNP).
- Ethnicity
- Gender
 “Classical” causes of variability.
- Weight
- Organ function (age)
- Comedication (PK-PD interactions)
- Underlying disease
PD-variability:
Propofol-Opioid
Interactions
Propofol-Remifentanil Interaction
Remifentanil concentration (ng/ml)
10
EC50 Surgery
8
6
4
2
0
0
2
4
6
8
10
Propofol concentration (µg/ml)
Mertens, Vuyk et al., Anesthesiology 2003; 99: 347-59.
12
14
Propofol-Remifentanil Interaction
Remifentanil concentration (ng/ml)
10
EC50 Surgery
EC50 Awakening
8
6
4
2
0
0
2
4
6
8
10
Propofol concentration (µg/ml)
Mertens, Vuyk et al., Anesthesiology 2003; 99: 347-59.
12
14
Optimal Propofol-Opioid EC50-95's
Propofol (µg/ml)
3.2-4.5
Alfentanil (ng/ml)
89-131
Fentanyl (ng/ml)
Sufentanil (ng/ml)
Remifentanil (ng/ml)
Vuyk et al, Anesthesiology 1997; 87 (6): 1549-1562.
5.0
3.3-4.5
2.5
1.9
0.14-0.23
8.3
Optimal Propofol-Opioid EC50-95's
Propofol (µg/ml)
3.2-4.5
Alfentanil (ng/ml)
89-131
Fentanyl (ng/ml)
Sufentanil (ng/ml)
Remifentanil (ng/ml)
Vuyk et al, Anesthesiology 1997; 87 (6): 1549-1562.
5.0
3.3-4.5
2.5
1.9
0.14-0.23
8.3
Propofol-Remifentanil Interactie
Ventilatie
.
resting Vi (l/min
)
10
8
6
4
2
0.00
pr 0.5
op
of
ol 1.0
co
nc
0.0
0.5
1.0
1.5
(µ
g/
m 2.0
l)
2.0
1.5
if e
m
e
r
nta
co
nil
nc
)
/ml
g
(n
Propofol-Remifentanil Interactie
Ventilatie
.
resting Vi (l/min
)
10
8
Vm: 9 naar 8 L/min
6
4
2
0.00
pr 0.5
op
of
ol 1.0
co
nc
0.0
0.5
1.0
1.5
(µ
g/
m 2.0
l)
2.0
1.5
if e
m
e
r
nta
co
nil
nc
)
/ml
g
(n
Propofol-Remifentanil Interactie
Ventilatie
.
resting Vi (l/min
)
10
8
6
Vm: 9 naar 6 L/min
4
2
0.00
pr 0.5
op
of
ol 1.0
co
nc
0.0
0.5
1.0
1.5
(µ
g/
m 2.0
l)
2.0
1.5
if e
m
e
r
nta
co
nil
nc
)
/ml
g
(n
Propofol-Remifentanil Interactie
Ventilatie
.
resting Vi (l/min
)
10
8
6
Vm: 9 naar 2 L/min
4
2
0.00
pr 0.5
op
of
ol 1.0
co
nc
0.0
0.5
1.0
1.5
(µ
g/
m 2.0
l)
2.0
1.5
if e
m
e
r
nta
co
nil
nc
)
/ml
g
(n
PK-PD Knowledge Improves
Drug Delivery
 PK-PD variability exceeds 1000%.
 SNP’s: significant opioid PD variability.
 Women are more sensitive to opioids,
men need 30-40% more morphine for postoperative analgesia.
 Weight: Remifentanil and NMBA: dosage based on LBM.
Propofol dosage based on TBW.
 Age: reduce dose by 50% with age 20-80 year (PK-PD).
 Drug interactions: use optimal combinations.
Propofol
 Lipofiel alkylfenol, GABA
agonist cortex en subcortex,
opgelost in sojaboonolie/ei-lecithine emulsie.
A
 Snelle in- en uitwerking, groot distributievolume, hoge klaring,
hepatisch en extrahepatisch, geen werkzame metabolieten.
 Toediening via continue infusie: (1 mg/kg,1-6 mg/kg/h).
 Anxiolyse, amnesie, sedatie, hypnose, analgesie, anti-emetisch.
Spierrelaxatie, ademwegobstructie, pijn bij injectie.
Propofol
 Respiratoire depressie: klein Vt, hogere ademfrequentie.
Balans: PaCO2 - nociceptie - Cpropofol - comedicatie
 Vasodilatie, myocarddepressie, ↓baroreceptorrespons.
R/ vullen en/of sympaticomimetica.
 Contraïndicaties:
- Allergie soja of pinda’s.
- Hartfalen, hypovolemie
 Geen antagonist.
Propofol Inductie
Propofol concentration (µg/ml).
4
Cblood
Effect-BIS
3
1 mg/kg bolus
Piekeffect na 3-4 min
2
1
0
0
3
6
9
Time (min)
12
15
Midazolam
 Benzodiazepine, GABA
agonist, hydrofiel in ampul (pH = 3),
in bloed na sluiten benzeenring (pH >4): lipofiel.
A
 Tragere in- en uitwerking, hepatische klaring, werkzame
metaboliet: α-hydroxymidazolam (80% potentie van M).
 Toediening via bolus of infusie: (1-2 mg, 5-20 mg/h).
Door tragere PK minder stuurbaar ivm propofol.
 Anxiolyse, amnesie, sedatie, hypnose, anticonvulsief
Spierrelaxatie, ademwegobstructie.
Midazolam
 Luchtwegobstructie tgv larynx relaxatie.
Balans: PaCO2 - nociceptie - Cmidazolam – comedicatie
 Beperkte bloeddrukdaling tgv vasodilatatie.
 Relatieve contraindicaties:
- Cave leverfalen, eliminatie ↓
- Cave cyt P450-inhibitie (erythromycine, verapamil,
cimetidine).
- NB. cyt P450-inductie (phenytoine, carbamazepine)
- Nierfalen: ↓ albumine: hogere vrije fractie.
 Antagonist: flumazenil (Anexate)
Midazolam concentratie (ng/ml)
Midazolam Sedatie
150
Blood conc.
Effect conc.
Piekeffect na 12 min
Midazolam bolus (1 mg)
100
50
0
0
15
30
Time (min)
45
60
Midazolam concentratie (ng/ml)
Midazolam Sedatie
200
Blood conc.
Effect conc.
150
Multipele doses midazolam (1 mg)
100
50
0
0
60
120
Time (min)
180
240
Flumazenil
 Competitieve antagonist van
benzodiazepinen op GABAA receptor.
 Korte werkingsduur; cave resedatie.
 Dosis: 0.1 – 0.2 mg tot max 1 mg.
Evt infusie 0.1-0.2 mg/h.
 Flumazenil na respiratoire depressie bij midazolam is een
PACU/MC/IC indicatie.
Opioiden
(Fentanyl en remifentanil)
 Synthetische opioiden, μ, δ en κ-receptor agonisten:
spinale en supraspinale analgesie.
 Opioiden bootsen effect na van endorfines en enkefalines.
 Receptorbinding: ↓ Ca influx, hyperpolarisatie, ↓ Substance P
 Analgesie, ademdepressie, sedatie, euforie, misselijkheid en
+
braken, miosis, urineretentie, ↓ peristaltiek, spierrigiditeit, jeuk
 Stabiele hemodynamiek en vagotone effecten
Farmacokinetiek Opioiden
(fentanyl, en remifentanil)
 Zwakke basen met hoge eiwitbinding (84-92% aan α1-zure GP).
 Piekeffect Remi na 2-3 min, Fent na 4-5 min.
 Fent effectbeeindiging tgv redistributie.
Remi tgv Cl (3-4 L/min door plasma en weefsel-esterasen).
 Fent: bolustoediening (0.05-0.1 mg)
Remi: infusie 0.1-2 µg/kg/min
 Antagonist naloxone (kortwerkend).
- competitieve binding μ, δ en κ-receptor
- dosis 0.04-0.4 mg
- cave re-apnoe, resedatie
Fentanyl bolus dosering
Fentanyl concentratie (ng/ml)
4
Blood conc.
Effect conc.
3
100 mcg/kg bolus
Piekeffect na 4-5 min
2
1
0
0
3
6
9
Time (min)
12
15
Fentanyl bolus dosering
Fentanyl concentratie (ng/ml)
3
Blood conc.
1 ml fentanyl
Cp = 0.8 ng/ml
2
1
0
0
60
120
180
Time (min)
240
300
Fentanyl bolus dosering
Fentanyl concentratie (ng/ml)
3
Blood conc.
Effect conc.
1 ml fentanyl
Cp = 0.8 ng/ml
2
1
0
0
60
120
180
Time (min)
240
300
Fentanyl bolus dosering:
Werkingsduur
Fentanyl concentratie (ng/ml)
3
Effect conc.
2
45 min
20 min
1 ml fentanyl
Cp = 0.8 ng/ml
1
0
0
60
120
180
Time (min)
240
300
Spierverslappers
Spierverslappers
 Relatief hydrofiele stoffen met kleine verdelingsvolumina;
doseer op geleide van ideale gewicht.
 Competitieve reversibele (itt botuline) remming van
acetylcholine op neuromusculaire eindplaat (nicotine receptor).
Gevolg: actiepotentiaal niet doorgegeven.
 Depolariserende (sux) en niet-depolariserende spierveslappers.
 Doel: spierverslapping voor intubatie, abdominale chirurgie
etc.., soms om beademing te faciliteren.
Spierverslappers
 T.g.v. spierverslapping ademstilstand: beademen, cave
awareness.
 Bijwerkingen: K-uitstoot, histamine-release (hypotensie,
roodheid, tachycardie),
 Antagonist (NDSV): acetylcholinesterase remmers (neostigine),
cave bradycardie (werking Ach op muscarine receptoren hart).
 Registratie effect dmv zenuwstimulatie (ulnaris: adductie duim),
TOF.
Which factors are responsible for
the PK-PD variability?
 Genetic causes of variability.
- Single nucleotide polymorphism (SNP).
- Ethnicity
- Gender
 “Classical” causes of variability.
- Weight
- Organ function (age)
- Comedication (PK-PD interactions)
- Underlying disease
Ethnicity and PK
variability
Selected drugs metabolized by specific
cytochrome P450-2D6
Stamer U, Stuber F. Current opinion in Anaesthesiology. 20(5):478-484,
October 2007.
Selected drugs metabolized by specific
cytochrome P450-2D6
Stamer U, Stuber F. Current opinion in Anaesthesiology. 20(5):478-484, October
2007.
Metabolism of tramadol and site of action
Allele frequencies of variant CYP2D6
alleles (%) in different ethnic populations
Stamer U, Stuber F. Current opinion in Anaesthesiology. 20(5):478-484,
October 2007.
CYP2D6 Ultra-rapid Metabolizers
Metabolism of tramadol and site of action
Hepatic enzyme activity and
Tramadol consumption
Does ethnic background
affect PK-PD ?
 Cytochrome P450 activity varies widely between patients.
 Ultrarapid metabolizers (CYP 2D6) exist with increasing
frequency going from North to South.
 As a result some agents may have a weaker effect (agonist
agents), while others may have a stronger effect
(prodrugs).
Optimal Propofol-opioid Combinations
After 300 min of infusion
Lichtenbelt et al., Clin Pharmacokinet 2004, 43 (9): 577-593
Optimal Propofol-opioid Combinations
After 300 min of infusion
Lichtenbelt et al., Clin Pharmacokinet 2004, 43 (9): 577-593
Optimal Propofol-opioid Combinations
After 300 min of infusion
Lichtenbelt et al., Clin Pharmacokinet 2004, 43 (9): 577-593
Optimal Propofol-opioid Combinations
After 300 min of infusion
40 min
8 min
Lichtenbelt et al., Clin Pharmacokinet 2004, 43 (9): 577-593
Optimal Propofol-opioid Combinations
After 300 min of infusion
2.5 µg/ml
Lichtenbelt et al., Clin Pharmacokinet 2004, 43 (9): 577-593
5.0 µg/ml
PK- modelling
Effect
k1e
Dose
k13
k12
V2
ke1
V1
k21
V3
k31
k10
Elimination
ke0