Benzodiazepines and Hypnotics

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Benzodiazepinesand Hypnotics
May 14, 2002 Steven L. Shafer, M.D. Professor of
Anesthesia Stanford University School of
Medicine Adjunct Professor of Pharmaceutical
Science University of California at San Francisco
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Outline

• GABA
• Comparative PK of hypnotics
• Sedation Midazolam vs. Propofol
• Midazolam vs. Diazepam
• Aging
• Drug interactions
• Maintenance with propofol
• ICU Sedation with propofol
• ICU Sedation with midazolam or lorazepam

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?-aminobutyric acid

• a.k.a GABA
• Most widespread inhibitory neurotransmitter in
  the CNS
• Three classes of receptors
• GABAA
• Ligand gated ion channel
• Cl- channel
• Site of action of benzodiazepines, barbiturates,
  and propofol
• Not the site of action of inhaled anesthetics
• GABAB
• Slow inhibitory post-synaptic potentials,
  regulates K and Ca conductance
• Not a binding site of anesthetic drugs
• GABAC
• Also a Cl- channel
• Not a binding site of anesthetic drugs

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GABAA Receptor

• Transmembrane pentamer composed of 2 ?, 2 ?, and
  1 ? or ? subunits
• Each has a binding site for GABA
• Benzodiazepines
• Bind a cleft of ? and ? subunits
• Increases frequency of channel opening
• Barbiturates, (propofol)
• Bind ? subunit
• Increase duration of channel opening
• Agonist muscimol
• Antagonist bicuculine

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Cl- currents in the presence of GABA
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50 Effect Site Decrement Time
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20 Effect Site Decrement Time
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80 Effect Site Decrement Time
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Sedation and AmnesiaPropofol vs. Midazolam

• 67 volunteers, randomized, open label
• No difference between relative sedative and
  amnestic profiles for propofol and midazolam
• Big difference with thiopental and fentanyl from
  propofol or midazolam
• Vesalis et al, Anesthesiology 1997 87749-64

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Sedation and AmnesiaPropofol vs Midazolam

• Randomzed, blinded cross-over trial in 10
  voluneers
• Titrated to different levels of sedation
• Steep change in effect with small change in
  concentration
• Could not distinguish memory impairment between
  propofol and midazolam
• de Roode, et al, Anesth Analg 2000 911056-61

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Sedation does not equal amnesia

• Memory vs Sedation trial 65 adults
• Auditory Event-Related Potentials (ERP) recorded
  in patients during propofol or midazolam
  administration.
• Subjects memorized 16 words during pseudo-steady
  state infusion (STANPUMP)
• Vesalis et al, Anesthesiology 2001 95896-907
• ERPs map to specific neuroanatomical structures
• N2 latency predicted reaction times (sedation).
• N2P3 amplitude predicted memory for midazolam,
  propofol, and thiopental

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Midazolam vs. Diazepam
The Introduction of Versed
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Midazolam and Diazepam Clinical Pharmacology
(as originally introduced into clinical practice)
Elimination
Equipotent
Onset
Half-Life
Duration
Doses
Diazepam
"slow"
40 hr
"long"
10 mg
Midazolam
"fast"
4 hr
"short"
5 mg
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Result of initial dosing guidelines

• 1600 adverse reactions and 86 deaths associated
  with midazolam in the first 5 years after its
  introduction in the United States.
• Department of Health and Human Services, Office
  of Epidemiology and Biostatistics, Center for
  Drug Evaluation and Research, Data Retrieval Unit
  HFD-737, June 27, 1989
• Nearly all were associated with midazolam for
  sedation during endoscopy

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FDAS REGULATION OF THE NEW DRUG
VERSED
HEARINGS
BEFORE A
SUBCOMMITTEE OF THE
COMMITTEE ON
GOVERNMENT OPERATIONS
HOUSE OF REPRESENTATIVES
ONE HUNDREDTH CONGRESS
SECOND SESSION
MAY 5 AND 10, 1988
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Midazolam Sedation for Endoscopy
Adapted from Bell, J Clin Pharmacol 1987
Feb23(2)241-3
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Midazolam-Opioid Interactions(young volunteers)
Adapted from Kissen et al, Anesth Analg 7265-69,
1990
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Benzodiazepine EEG Effects
Midazolam
V/sec)
Flumazenil
m
EEG Amplitude within 11.5-30 Hz (
Bretazenil
Ro 19-4603
m
Blood concentration (
g/ml)
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EEG Effects of Midazolam
Adapted from Bührer, CPT 48555-567, 1990
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Revised Midazolam Comparative Pharmacology
Plasma-Effect Site
Equilibration Half-Life
Potency
range (average)
range (mean)
1-2.4 min
406-1256 ng/ml
Diazepam
(1.6 min)
(958 ng/ml)
1.6-6.8 min
94-385 ng/ml
Midazolam
(4.8 min)
(190 ng/ml)
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Drug Interaction Model
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Midazolam dosing and age
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Age and Midazolam Recovery50 Decrement Time
(context-sensitive half time)
360
Age
80
240
60
20 and 40
Minutes to 50 decrement
120
0
0
120
240
360
480
600
Minutes since beginning of infusion
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Propofol/Alfentanil Interaction
400

• Adapted from Vuyk et al, Anesthesiology 838-22,
  1995
• Characterizes the concentrations for
• intubation
• maintenance
• on emergence
• Concentrations are 50 response level

Intubation
300
Maintenance
200
Alfentanil Concentration (ng/ml)
Emergence
100
0
0
2
4
6
8
10
Propofol Concentration (mg/ml)
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Optimal Propofol/Alfentanil

• Infusion rates for propofol and alfentanil
• Propofol levels during maintenance and at
  emergence from anesthesia
• Alfentanil concentrations during maintenance and
  at emergence
• Time from ending the infusion to awakening from
  anesthesia
• The percent decrease in concentration required
  for emergence from anesthesia

Stanski and Shafer Anesthesiology 831-5, 1995
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Propofol/Opioid Technique
Stanski and Shafer Anesthesiology 831-5, 1995
Shafer SL, ASA Refresher Course, Chapter 19, 1996
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Propofol/OpioidTime to Awakening
Alfentanil Technique
Remifentanil Technique
20
15
10
5
0
600

120
240
360
480
600
0
120
240
360
480
Time (Minutes)
Time (Minutes)
Shafer SL, ASA Refresher Course, Chapter 19, 1996
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Propofol/OpioidInfusion rates
Alfentanil Technique
Remifentanil Technique
400
300
Remifentanil (ng/kg/min)
Alfentanil (ng/kg/min)
200
Propofol (mg/kg/min)
Propofol (mg/kg/min)
100
0
600

120
240
360
480
600
0
120
240
360
480
Time (Minutes)
Time (Minutes)
Shafer SL, ASA Refresher Course, Chapter 19, 1996
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Propofol/OpioidPropofol Levels (mg/ml)
Alfentanil Technique
Remifentanil Technique
6
4
Maintenance
Maintenance
2
Emergence
Emergence
0
600

120
240
360
480
600
0
120
240
360
480
Time (Minutes)
Time (Minutes)
Shafer SL, ASA Refresher Course, Chapter 19, 1996
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Propofol/OpioidPercent Decrease on Emergence
Alfentanil Technique
Remifentanil Technique
100
75
Remifentanil
Propofol
50
Propofol
25
Alfentanil
0
600

120
240
360
480
600
0
120
240
360
480
Time (Minutes)
Time (Minutes)
Shafer SL, ASA Refresher Course, Chapter 19, 1996
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Propofol/Remifentanil TIVA

• Remifentanil
• 0.25 mg/kg/min
• Propofol
• 80 mg/kg/min
• Requires controlled ventilation

Shafer SL, ASA Refresher Course, Chapter 19, 1996

• Little tolerance for interruption of
  remifentanil or propofol infusion

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Propofol/opioid vs Isoflurane/opioid
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Propofol/opioid vs Isoflurane/opioid
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Propofol for MAC Sedation

• Acknowledgements
• Paul White
• David Goodale

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Initiation of MAC Sedation   For initiation of
MAC sedation, either an infusion or a slow
injection method may be utilized while closely
monitoring cardiorespiratory function. With the
infusion method, sedation may be initiated by
infusing DIPRIVAN Injectable Emulsion at 100 to
150 µg/kg/min (6 to 9 mg/kg/h) for a period of 3
to 5 minutes and titrating to the desired
clinical effect while closely monitoring
respiratory function. With the slow injection
method for initiation, patients will require
approximately 0.5 mg/kg administered over 3 to 5
minutes and titrated to clinical responses. When
DIPRIVAN Injectable Emulsion is administered
slowly over 3 to 5 minutes, most patients will be
adequately sedated, and the peak drug effect can
be achieved while minimizing undesirable
cardiorespiratory effects occurring at high
plasma levels. In the elderly, debilitated, or
ASA III/IV patients, rapid (single or repeated)
bolus dose administration should not be used for
MAC sedation. (See WARNINGS .) The rate of
administration should be over 3-5 minutes and the
dosage of DIPRIVAN Injectable Emulsion should be
reduced to approximately 80 of the usual adult
dosage in these patients according to their
condition, responses, and changes in vital signs.
(See DOSAGE AND ADMINISTRATION .) Maintenance of
MAC Sedation   For maintenance of sedation, a
variable rate infusion method is preferable over
an intermittent bolus dose method. With the
variable rate infusion method, patients will
generally require maintenance rates of 25 to 75
µg/kg/min (1.5 to 4.5 mg/kg/h) during the first
10 to 15 minutes of sedation maintenance.
Infusion rates should subsequently be decreased
over time to 25 to 50 µg/kg/min and adjusted to
clinical responses. In titrating to clinical
effect, allow approximately 2 minutes for onset
of peak drug effect.
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Propofol PK and age
Schnider et al, Anesthesiology 881170-1182, 1998
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The elderly brain is more sensitive to
propofolProbability of unconsciousness after a 1
hour infusion
Unconscious
1.0
0.8
75
50
25
0.6
Probability
0.4
0.2
Conscious
0.0
0
2
4
6
8
Plasma propofol concentration (mg/ml)
Schnider et al, Anesthesiology 1999 (in press)
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After a propofol bolus, everyone falls asleep
quickly
2.0
1.5
Minutes
1.0
0.5
0.0
20
30
40
50
60
70
Age
Schnider et al, Anesthesiology 1999 (in press)
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But the elderly sleep longer
12
10
8
Minutes
6
4
2
0
20
30
40
50
60
70
Age
Schnider et al, Anesthesiology 1999 (in press)
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Propofol Induction
100
90
80
Dose as fraction of dose in a 20 year old
70
60
50
20
40
60
80
Age
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Propofol dosing and ageRate to maintain
adequate anesthesia
350
300
g/kg/min)
m
250
25 years old
(
rate
50 years old
200
75 years old
Infusion
150
100
0
10
20
30
40
50
60
Time in minutes
Based on data in Schnider et al, Anesthesiology
881170-1182, 1998
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Propofol Recovery50 effect site decrement curve
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Age
20
30
40
Minutes to a 50 decrement
60
80
0
0
120
240
360
480
600
Minutes since beginning of infusion
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Propofol in the elderlybringing it all together

• PK the early distribution pharmacokinetics are
  slower in the elderly
• PD the brain is more sensitive
• Ke0 no change with age
• Lower the dose in the elderly, and they should
  wake up just as fast as younger patients

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Propofol in Kids
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Propofol in Kids
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Thiopental and Aging
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Age and recovery from thiopental
Reduce the dose properly, and the elderly will
recovery as quickly as younger patients.
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Thiopental Midazolam Interaction
3
D
for thiopental
50
Isobole
2
(Antagonism)
D
for thiopental
Thiopental (mg/kg)
50
plus midazolam
(Synergy)
1
D
for midazolam
50
0
0
0.05
0.1
0.15
0.2
Midazolam (mg/kg)
Adapted from Tverskoy, Anesthesia and Analgesia
67342-345, 1988
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Propofol for ICU Sedation

• Acknowledgements
• Dr. Juliana Barr
• Katie Zomorodi
• David Goodale

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Optimal Pharmacokinetic Model
Best 13 MDAPE
Worst 70MDAPE
Plasma Propofol Concentration (mg/ml)
Hours Since Initial Dose
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Prospective Pharmacokinetic Test
Retrospective MDAPE24
Prospective MDAPE29
Performance Error
Hours since initial dose
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Probability Pharmacodynamics(NONMEM analysis)
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Propofol Pharmacodynamics
1.00
gt Level 2
gt Level 4
Light
0.75
Probability of Sedation Score
0.50
0.25
Deep
0.00
0
1
2
3
m
Plasma Propofol Concentration (
g/ml)
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Propofol Dosing in the ICU
For 25, 50, and 75 mg/kg/min
2.5

Women
Men
2.0
75
1.5
50
1.0
Small
25
0.5
0.0
2.5
2.0
Plasma Propofol Concentration (mg/ml)
1.5
Big
1.0
0.5
0.0
2.5
2.0
1.5
Obese
1.0
0.5
0.0
1
10
100
1000
10000
1
10
100
1000
10000
Minutes Since Beginning of Infusion
Based on Lean Body Mass correction for gender
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ICU decrement times
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The FDA perspective
Target plasma concentration
1.00
Recovery after
10 day infusion
10 hour infusion
0.75
1 hour infusion
Awakening
Plasma propofol concentration
0.50
0.25
0.00
0
20
40
60
80
Minutes after end of infusion
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Population Pharmacokinetics of Midazolam
Administered by Target Controlled Infusion for
Sedation Following Coronary Artery Bypass
Grafting Katayoun Zomorodi, Andrew Donner,
Jacques Somma, Juliana Barr, Robert Sladen,
James Ramsay, Eran Geller, Steven L.
Shafer Supported by Roche
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Pharmacokinetic Model Performance
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Pharmacokinetic Model Context-Sensitive
Decrement Curves
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Pharmacodynamic Models Tested
n
C
³

P
Sedation
(
ss
)

n
n
C
C
ss
,
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Models for C (concentration)
Model A
C
midazolam
Model B
C
midazolam
q

sufentanil
S


midazolam
sufentanil
Model C
C
midazolam
q

sufentanil
q
S
MS
Model D
C
midazolam virtual drug
-Kt

virtual drug
q

e
V
Model E
C
midazolam virtual drug
sufentanil
q

S
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Probability (sedation³3)
1
Probability (sedation³3)
0
10
100
1000
Total Concentration (ng/ml)
(midazolamvirtual drug)
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Virtual Drug Implications
1.0
0.8
P(sedationgt2)
P(sedationgt3)
P(sedationgt4)
0.6
P(sedationgt5)
P(sedation6)
Probability
0.4
Time0 h
0.2
0.0
1
10
100
1000
10000
Midazolam Concentration (ng/ml)
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Virtual Drug Implications
1.0
0.8
P(sedationgt2)
P(sedationgt3)
0.6
P(sedationgt4)
Probability
P(sedationgt5)
0.4
P(sedation6)
Time12 h
0.2
0.0
1
10
100
1000
10000
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Virtual Drug Implications
1.0
0.8
0.6
Probability
P(sedationgt2)
P(sedationgt3)
0.4
P(sedationgt4)
P(sedationgt5)
0.2
Time24 h
P(sedation6)
0.0
1
10
100
1000
10000
Midazolam Concentration (ng/ml)
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The Clinical Pharmacology of Lorazepam vs.
Midazolam for Sedation of ICU Patients

• Double Blinded
• Randomized
• Target-Controlled Drug Administration
• Stepped Titration to Ramsey Sedation Score of 3
  to 4
• Frequent Arterial Samples
• Frequent Assessments of Mental Status

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Infusion Profiles
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Sedation Scores
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Infusion Performance
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Infusion Performance
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Raw Sedation Scores
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Pharmacodynamic Model Results
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Pharmacodynamic Model Results