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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