Transcript conscious sedation

Triazolam
Triazolam
Halcion™
Halcion™
Oral
Oral Sedation
Sedation
6/6/05
Copyright Quarnstrom Donaldson
Is
Halcion
the
Fred Quarnstrom, DDS
theFADSA,
ugly FAGD,
Dirty FICD
Duck
Diplomate, American Dental Board of Anesthesionogy
orDiplomate,
beautiful
Black
Swan?
National Dental
Board of Anesthesiology
6/6/05
Certified, American
Association
of Dental Consultants
Copyright
Quarnstrom Donaldson
patients - AAOMS - OCS
Where is the ADA?
6/6/05
Copyright Quarnstrom Donaldson
6/6/05
WouldCopyright
youQuarnstrom
please
try to relax.
Donaldson
Mortality from Anesthesia 1970-1979 U. K.
Dentists
1:260,000
Physicians
1:248,000
Single Operator / Anesthetist
Anesthetist
1:143,000
One Operator One Anesthetist
Anesthetist
1:598,000
Conscious sedation
1:1,000,000
(patient
(patient died
died on
on aa motorcycle
motorcycle later
later the
the same
same day)
day)
note - this study was pre
pre pulse
pulse oximeter
oximeter useage
useage
Dionne,
Dionne, Pharmacologic
Pharmacologic Considerations
Considerations in
in Training
Training of
of Dentists
Dentists in
in
Anesthesia
Anesthesia and
and Sedation,
Sedation, Anes
Anes Prog
Prog 36:113-116
36:113-116 1989
1989
6/6/05
Copyright Quarnstrom Donaldson
The Spectrum of Anesthesia
Normal
Anxiolysis
Conscious
Sedation
1. Protective reflexes intact
Patient can independently
and continuously maintain
an airway
Patient can respond
appropriately to verbal
commands
6/6/05
Deep
Sedation
2. Partial loss of
protective reflexes
Inability to
independently maintain
an airway
May not respond to
verbal commands
Copyright
Quarnstrom Donaldson
General
Anesthesia
3. Loss of protective
reflexes
Inability to independently
maintain an airway
No pain sensation or reflex
withdrawal from stimuli
Total unconsciousness
Risks of Anesthesia
high
Deep
Sedation
Moderate
Sedation
Local
Anesthesia
Anxiolysis
low
6/6/05
N20
Copyright Quarnstrom Donaldson
General
Anesthesia
AGE VS ANESTHETIC-INDUCED,
CARDIAC ARREST / DEATH
incidence
rate
0.05
0.04
0.03
0.02
0.01
<< 11
1-10
60
1-10 11-20
11-20 21-30
21-30 31-40
31-40 41-60
41-60 >> 60
Marx,
Marx,Anes.,
Anes., 39:54-58,
39:54-58, 1973
1973
6/6/05
Copyright Quarnstrom Donaldson
AGE VERSUS SEVERE
SEVERE MORBIDITY/MORTALITY
MORBIDITY/MORTALITY
44
33
22
11
00
<10
<10
11-20
11-20
21-30
21-30 31-40
31-40 41-60
41-60
age range = 21 mo. - 59 yr.
Jastak,
Jastak,Anes
Anes Prog
Prog,, 38:39-44
38:39-44 1991
1991
6/6/05
Copyright Quarnstrom Donaldson
AGE VERSUS SEVERE MORBIDITY/MORTALITY
44
33
22
11
00
<10
<10
11-20
11-20
21-30
21-30 31-40
31-40 41-60
41-60
age range = 21 mo. - 59 yr.
Jastak,
Jastak,Anes
Anes Prog
Prog,, 38:39-44
38:39-44 1991
1991
6/6/05
Copyright Quarnstrom Donaldson
Standards for Conscious Sedation
Level 1 minimal sedation - Anxiolysis
Level 2 Moderate Sedation/Analgesia Conscious Sedation
Level 3 Deep Sedation/Analgesia
Level 4 Anesthesia
Anesthesia
Today
vol.11 No. 2 Fall 2000 p. 2
6/6/05 Resek, Jayne, MS RN,
Copyright
Quarnstrom
Donaldson
Standards for Conscious Sedation
Level 1 minimal sedation - Anxiolysis
A drug-induced state during which patients respond
normally to verbal commands. Although cognitive function
and coordination may be impaired, ventilatory and
cardiovascular functions are unaffected.
Level 2 Moderate Sedation/Analgesia Conscious Sedation
Level 3 Deep Sedation/Analgesia
Level 4 Anesthesia
Anesthesia
Today
vol.11 No. 2 Fall 2000 p. 2
6/6/05 Resek, Jayne, MS RN,
Copyright
Quarnstrom
Donaldson
Standards for Conscious Sedation
Level 1 minimal sedation - Anxiolysis
Level 2 Moderate Sedation/Analgesia Conscious Sedation
A drug-induced depression of consciousness during which
patients respond purposefully to verbal commands, either
alone or accompanied by light tactile stimulation. No
interventions are required to maintain a patient airway and
spontaneous ventilation is adequate. Cardiovascular
function is usually maintained.
Level 3 Deep Sedation/Analgesia
Level 4 Anesthesia
Anesthesia
Today
vol.11 No. 2 Fall 2000 p. 2
6/6/05 Resek, Jayne, MS RN,
Copyright
Quarnstrom
Donaldson
Standards for Conscious Sedation
Level 1 minimal sedation - Anxiolysis
Level 2 Moderate Sedation/Analgesia Conscious Sedation
Level 3 Deep Sedation/Analgesia
A drug-induced depression of consciousness during which
patients cannot be easily aroused but respond purposefully
following repeated or painful stimulation. The ability to
independently maintain ventilatory function may be
impaired. Patients may require assistance in maintaining a
patent airway, and spontaneous ventilation may be
inadequate. Cardiovascular function is usually maintained.
Level 4 Anesthesia
Anesthesia
Today
vol.11 No. 2 Fall 2000 p. 2
6/6/05 Resek, Jayne, MS RN,
Copyright
Quarnstrom
Donaldson
Standards for Conscious Sedation
Joint Commission on Accreditation of Healthcare
Organizations (JCAHO)
Level 1 - None
Level 2 - conscious sedation - pulse oximeter and
Blood Pressure, ability to resuscitate.
Monitoring YES
Patient assessment - ASA status YES - 1 OR 2
Staff - someone is always with the patient YES
Equipment YES
Informed consent
YES
Competent at least one level greater than where
you6/6/05
normally
if patients
into
level
Resek, Jayne,practice
MS RN,
Anesthesia
Today
vol.11slip
No. 2 Fall
2000next
p. 2
Copyright
Quarnstrom
Donaldson
NORMAL DISTRIBUTION CURVE
mean
freq.
hyper
hypo
11 S.D.=
S.D.= 66%
66%
22 S.D.
S.D. == 95%
95%
33 S.D.
S.D. == 99.7%
99.7%
response
Pallasch, Anes. Prog. 35:87-101,1988
6/6/05
Copyright Quarnstrom Donaldson
Chloral Hydrate
Response
100
ED50
LD50
50
Margin
of
Safety
0
Dose
6/6/05
Copyright Quarnstrom Donaldson
Drug Distribution and Elimination
Compartment models
Volume of distribution
First and zero kinetics
Clearance and extraction ratios
First pass effects
Drug half lives
6/6/05
Copyright Quarnstrom Donaldson
Principals of Pharmacotherapy: Pharmacokinetics Pallasch, T.J. Anes. Progress 35:133-146 1988
Compartment Models
Simple one compartment model
all drugs spread uniformly through the body
Two and three compartment model - better
varying blood flows
changes in pH
plasma protein binding
tissue affinity for certain drugs
Three compartment model is most accurate
But two compartment is OK in most cases.
central compartment- extra cellular fluid and organs
peripheral tissue compartment - muscle and fat
6/6/05
Copyright Quarnstrom Donaldson
Principals of Pharmacotherapy: Pharmacokinetics Pallasch, T.J. Anes. Progress 35:133-146 1988
Volume of Distribution
Apparent volume of distribution (Vd)
If Vd is small - drug is bound to plasma - little drug
will be in tissues - higher blood
concentrations
If Vd is large it will be widely distributed through the
tissues - but lower blood concentrations
6/6/05
Copyright Quarnstrom Donaldson
Principals of Pharmacotherapy: Pharmacokinetics Pallasch, T.J. Anes. Progress 35:133-146 1988
First and Zero Order Kinetics
First-order - a constant percentage crosses a membrane or
is metabolized per unit of time - filtration of is
determined by concentration.
Zero-order - a constant amount of drug is metabolized
per unit of time - independent of drug concentration.
Ethanol metabolism is zero-order. There is a limited
number of receptor cites to metabolize that drug
6/6/05
Copyright Quarnstrom Donaldson
Principals of Pharmacotherapy: Pharmacokinetics Pallasch, T.J. Anes. Progress 35:133-146 1988
Clearance and Extraction Ratios
Clearance is the amount of blood volume from
which the drug is completely removed,
cleared, per unit of time. ml./min.
It is the total of all clearances of all organs.
Extraction ratio is the difference in drug
concentrations from the arterial to the venous
blood of an organ from 0 to 1. If one, all drug
is removed first pass if 0 non is removed by
that organ.
6/6/05
Copyright Quarnstrom Donaldson
Principals of Pharmacotherapy: Pharmacokinetics Pallasch, T.J. Anes. Progress 35:133-146 1988
First Pass Effects
Some drugs have such high Extraction ratios that
virtually all is removed First pass through the
liver. If the drug is taken orally literally none
of it reaches the tissue.
Romazicon, flumazenil, is such a drug. It cannot
be given orally as it is absorbed through the
intestinal wall into the portal circulation and
goes directly to the liver where it is almost
100% deactivated.
6/6/05
Copyright Quarnstrom Donaldson
Principals of Pharmacotherapy: Pharmacokinetics Pallasch, T.J. Anes. Progress 35:133-146 1988
Drug Half Lives, T1/2
This is the time it take any drug concentration to fall
50%. It is based on a two-compartment model,
first-order kinetics (constant % of drug
concentration) and an exponential decline have the concentration for each fixed time
increment. It is generally a reliable indicator
of the rate of removal of a drug from the blood
and body - duration of action.
Exception high fat soluble drug - diazepam, valium
Has a half life of 20 - 50 hours but it is very fat
soluble so blood levels fall like a much shorter
half life
6/6/05
Copyright Quarnstrom Donaldson
Principals of Pharmacotherapy: Pharmacokinetics Pallasch, T.J. Anes. Progress 35:133-146 1988
Drug Half Lives, T1/2
Oral
I.V.
100
Distribution from
blood to tissue
distribution
(alpha phase)
75
Half Lives, T1/2
50
Elimination via
liver and kidneys
Elimination
(beta phase)
25
0
0
6/6/05
2
4
8
10
0
2
Copyright Quarnstrom Donaldson
4
8
10
Principals of Pharmacotherapy: Pharmacokinetics Pallasch, T.J. Anes. Progress 35:133-146 1988
CHLORAL HYDRATE
CL
O H
CL C C H
CL
O H
chloral hydrate
6/6/05
CL
H
CL C C H
CL
O H
trichloroethanol
Copyright Quarnstrom Donaldson
CHLORAL HYDRATE
age
age
sex
sex
15
15
O
O
22
22
O
O
weight
weight
dose
dose
procedure
procedure
reaction
reaction
drugs
drugs
115
115
33 g.
g.
ex
ex 3rd molars
vom
vomit
narcan
narcan
dopamine
dopamine
120
120
2.5g.
2.5g.
ex
ex 3rd molars
problem
problem
outcom
outcome
blood
blood levels
6/6/05
epinephrine
epinephrine
c.a.
c.a.
c.a.
c.a.
revived
died
revived
died
65
71
65 µg/m l
71 µg/m l
(( normal
normal 5 - 15 µg/ml after 1 gm dose)
Copyright Quarnstrom Donaldson
CHLORAL HYDRATE INDUCED ARRHYTHMIAS
age
age
dose
dose
22
99
17
17
19
19
21
21
29
29
32
32
33
33
1.5
1.5
0.6
0.6
14
14
17.5
17.5
20
20
10
10
20
20
40
40
arrhythmia
arrhythmia
c.
c. a.
a.
PVC
PVC
SVT
SVT
PVC,
PVC, VT
VT
PVC,
PVC, Vfib
Vfib
VT
VT
PVC,
PVC, VT
VT
PVC,
PVC, Vfib
Vfib
PVC
PVC
no
no
no
no
no
no
yes
yes
no
no
no
no
yes
yes
yes
yes
antiarrhythmia
antiarrhythmia outcome
outcome
drug
drug resistance
resistance
no
yes
yes
yes
no
yes
survived
survived
survived
survived
survived
survived
survived
survived
survived
survived
survived
survived
survived
survived
died
died
In
In large
large doses,
doses, it
it shortens the cardiac refractory period.
May
May sensitize
sensitize heart to circulating catecholamines.
Jastak, J.A.D.A., vol 116, march 1988
6/6/05
Copyright Quarnstrom Donaldson
Chloral hydrate vs Halcion
Response
100
ED50
LD50
50
Margin
of
Safety
Margin
of
Safety
0
Dose
6/6/05
Copyright Quarnstrom Donaldson
LD50
NORMAL DISTRIBUTION CURVE
mean
freq.
hyper
hypo
11 S.D.=
S.D.= 66%
66%
22 S.D.
S.D. == 95%
95%
33 S.D.
S.D. == 99.7%
99.7%
response
Pallasch, Anes. Prog. 35:87-101,1988
6/6/05
Copyright Quarnstrom Donaldson
APPREHENSION CONTROL
sedation - mildly sleepy people are less
likely to feel fearful
barbiturates
alcohol - trichloroethanol (chloral hydrate)
anti anxiety medication
mephenesin
meprobamate - 1955
benzodiazepine
librium - 1960
valium - 1965
Snyde, Drugs and the Brain, N.Y.,Scientific American Library, 1986
6/6/05
Copyright Quarnstrom Donaldson
TRANQUILIZERS
1945 Frank Berger - While attempting to
discover an antibacterial for penicillin
resistant bacteria, discovered mephenesin
which he noted quieted mice. An effect he
referred to as "tranquilization."
He developed a derivative meprobamate, which
turned out to be a sedative not a tranquilizer.
Snyde, Drugs and the Brain, N.Y.,Scientific American Libr ary, 1986
6/6/05
Copyright Quarnstrom Donaldson
BENZODIAZEPINE DRUGS
Roach was attempting to imitate the nonsedating
nonaddicting antianxiety actions attributed to
meprobamate.
( It turned out meprobamate
was a simple sedative.)
The goal was noble. The rational for the search
was flawed as such an agent did not exist.
to relieve anxiety
Snyde, Drugs and the Brain, N.Y.,Scientific American Library, 1986
6/6/05
Copyright Quarnstrom Donaldson
BENZODIAZEPINE TRANQUILIZERS
Leo Sternbach 1930 - Cracow, Poland developed quinazolines.
evaluated for Roach in 1955 saw no sedationturned chemicals over to Randall
Lowell Randall found an active agent
Sternbach reexamined chemical properties found it was not a quinazoline - named the
new class benzodiazepines
librium - 1960
valium - 1963
by 1975 15% of population
100,000,000 Rx / yr.
Snyde, Drugs and the Brain, N.Y.,Scientific American Libr ary, 1986
6/6/05
Copyright Quarnstrom Donaldson
BENZODIAZEPINE DRUGS
relieve anxiety
produce some drowsiness - patients became
tolerant to this effect in a few days
"vague uneasiness, generalized
fear and associated physical
symptoms of anxiety fade away."
tolerance develops
withdrawal occur
advantage - overdoses are rarely fatal
except with alcohol or barbiturates
Snyde, Drugs and the Brain, N.Y.,Scientific American Libr ary, 1986
6/6/05
Copyright Quarnstrom Donaldson
GABA
NH2 - CH2 - CH2- CH2 - CO2
6/6/05
Copyright Quarnstrom Donaldson
GABA Receptor
Cl
Cl
Cl
Cl
cell
wall
Cl
A
B
Cl
6/6/05
Copyright Quarnstrom Donaldson
Cl
Diazepam Alcohol Gaba Receptors
Sedativeconvulsant
Benzodiazepine
Cl-- ion channel
6/6/05
Copyright Quarnstrom Donaldson
Gaba
Diazepam Alcohol Gaba Actions
Cl
Cl
Cl
Cl
Cl
6/6/05
Cl
Copyright Quarnstrom Donaldson
Pharmacology
Compare
Compare to
to valium
valium
Absorption
Absorption
Half
Half life
life
Active
Active metabolites
metabolites
Structure-activity
Structure-activity relationship
relationship
Nitrogen
Nitrogen atom
atom prevents
prevents water
water solublity.
solublity.
Triazo
Triazo ring
ring alows
alows quick
quick metabolism
metabolism
Chlorine
Chlorine atom
atom is
is responsible
responsible for
for
potency.
potency.
Chlorine
Chlorine atom
atom is
is responsible
responsible for
for
benzodiazepine
benzodiazepine action.
action.
6/6/05
Copyright Quarnstrom Donaldson
Halcion - Triazolam
N
N
H C
3
N
N
Cl
Cl
6/6/05
Copyright Quarnstrom Donaldson
Triazolam Structure-Activity
N
triazo ring is
responsible for
ease of oxidation
N
N
H C
3
nitrogen is responsible for
lack of water solubility
N
N
Cl
Cl is responsible
for potency
Cl
6/6/05
Cl is responsible for
benzodiazapine action
Copyright Quarnstrom Donaldson
Diazepam vs Triazolam
H
O
H C
3
N
N
N
N
Cl
H
H C
3
N
Cl
Cl
Diazepam
6/6/05
N
Triazolam
Copyright Quarnstrom Donaldson
Benzodiazepine Elimination
drug
drug
alprazolam
alprazolam
time
time to peak
plasm
plasma conc.
elim
elimination
ination
half-life
half-life
m ajor active
m etabolites
1-2
1-2 hr.
hr.
12-15
12-15 hr.
hr.
-hydroxyalprazolam
-hydroxyalprazolam
0.5
0.5 -- 4.0
4.0 hr.
hr.
20-70
20-70 hr.
hr.
1-6
1-6 hr.
hr.
10-18
10-18 hr.
hr.
desmethyldiazepam
desmethyldiazepam
(oxepam)
(oxepam)
none
none
**
2-5
2-5 hr.
hr.
none
none
1-4
1-4 hr.
hr.
5-15
5-15 hr.
hr.
none
none
11- 22 hr.
hr. §§
1.5-5.0
1.5-5.0 hr.•
hr.•
-hydroxytriazolm
-hydroxytriazolm
Xanax
Xanax
diazepam
diazepam
Valium
Valium
lorazepam
lorazepam
Ativan
Ativan
midazolam
midazolam
Versed
Versed
oxazepam
oxazepam
Serax
Serax
triazolam
triazolam
Halcion
Halcion
§§ peak
peak concentration
concentration is
is 28%
28% faster
faster ifif given
given sublingually
sublingually
•
half
life
will
be
prolonged
in
the
presence
• half life will be prolonged in the presence of
of erythromycin,
erythromycin, cimethidine
cimethidine (tagamet),
(tagamet), isoniazid
isoniazid
and
and possibly
possibly oral
oral contraceptives
contraceptives
** not
not available
available as
as an
an oral
oral agent
agent
6/6/05
Copyright Quarnstrom Donaldson
Diazepam vs Triazolam
drug
time to peak elim ination
plasm a conc. half-life
triazolam
1 - 2 hr. §
diazepam
0.5 - 4.0 hr. 20 - 50 hr
m ajor active
m etabolites
1.5 -5.0 hr.• -hydroxytriazolm
desm ethyldiazepam
(oxepam )
§ peak concentration is 28% faster if given sublingually
• half life will be prolonged in the presence of erythromycin,
cimethidine (tagamet), isoniazid and possibly oral contraceptives
6/6/05
Copyright Quarnstrom Donaldson
Benzodiazepine Elimination
drug
drug
alprazolam
alprazolam
time
time to peak
plasm
plasma conc.
elim
elimination
ination
half-life
half-life
m ajor active
m etabolites
1-2
1-2 hr.
hr.
12-15
12-15 hr.
hr.
-hydroxyalprazolam
-hydroxyalprazolam
0.5
0.5 -- 4.0
4.0 hr.
hr.
20-70
20-70 hr.
hr.
1-6
1-6 hr.
hr.
10-18
10-18 hr.
hr.
desmethyldiazepam
desmethyldiazepam
(oxepam)
(oxepam)
none
none
**
2-5
2-5 hr.
hr.
none
none
1-4
1-4 hr.
hr.
5-15
5-15 hr.
hr.
none
none
11- 22 hr.
hr. §§
1.5-5.0
1.5-5.0 hr.•
hr.•
-hydroxytriazolm
-hydroxytriazolm
Xanax
Xanax
diazepam
diazepam
Valium
Valium
lorazepam
lorazepam
Ativan
Ativan
midazolam
midazolam
Versed
Versed
oxazepam
oxazepam
Serax
Serax
triazolam
triazolam
Halcion
Halcion
§§ peak
peak concentration
concentration is
is 28%
28% faster
faster ifif given
given sublingually
sublingually
•
half
life
will
be
prolonged
in
the
presence
• half life will be prolonged in the presence of
of erythromycin,
erythromycin, cimethidine
cimethidine (tagamet),
(tagamet), isoniazid
isoniazid
and
and possibly
possibly oral
oral contraceptives
contraceptives
** not
not available
available as
as an
an oral
oral agent
agent
6/6/05
Copyright Quarnstrom Donaldson
Benzodiazepine Elimination
drug
drug
alprazolam
alprazolam
time
time to peak
plasm
plasma conc.
elim
elimination
ination
half-life
half-life
m ajor active
m etabolites
1-2
1-2 hr.
hr.
12-15
12-15 hr.
hr.
-hydroxyalprazolam
-hydroxyalprazolam
0.5
0.5 -- 4.0
4.0 hr.
hr.
20-70
20-70 hr.
hr.
1-6
1-6 hr.
hr.
10-18
10-18 hr.
hr.
desmethyldiazepam
desmethyldiazepam
(oxepam)
(oxepam)
none
none
**
2-5
2-5 hr.
hr.
none
none
1-4
1-4 hr.
hr.
5-15
5-15 hr.
hr.
none
none
11- 22 hr.
hr. §§
1.5-5.0
1.5-5.0 hr.•
hr.•
-hydroxytriazolm
-hydroxytriazolm
Xanax
Xanax
diazepam
diazepam
Valium
Valium
lorazepam
lorazepam
Ativan
Ativan
midazolam
midazolam
Versed
Versed
oxazepam
oxazepam
Serax
Serax
triazolam
triazolam
Halcion
Halcion
§§ peak
peak concentration
concentration is
is 28%
28% faster
faster ifif given
given sublingually
sublingually
•
half
life
will
be
prolonged
in
the
presence
• half life will be prolonged in the presence of
of erythromycin,
erythromycin, cimethidine
cimethidine (tagamet),
(tagamet), isoniazid
isoniazid
and
and possibly
possibly oral
oral contraceptives
contraceptives
** not
not available
available as
as an
an oral
oral agent
agent
6/6/05
Copyright Quarnstrom Donaldson
Benzodiazepine Elimination
drug
drug
alprazolam
alprazolam
time
time to peak
plasm
plasma conc.
elim
elimination
ination
half-life
half-life
m ajor active
m etabolites
1-2
1-2 hr.
hr.
12-15
12-15 hr.
hr.
-hydroxyalprazolam
-hydroxyalprazolam
0.5
0.5 -- 4.0
4.0 hr.
hr.
20-70
20-70 hr.
hr.
1-6
1-6 hr.
hr.
10-18
10-18 hr.
hr.
desmethyldiazepam
desmethyldiazepam
(oxepam)
(oxepam)
none
none
**
2-5
2-5 hr.
hr.
none
none
1-4
1-4 hr.
hr.
5-15
5-15 hr.
hr.
none
none
11- 22 hr.
hr. §§
1.5-5.0
1.5-5.0 hr.•
hr.•
-hydroxytriazolm
-hydroxytriazolm
Xanax
Xanax
diazepam
diazepam
Valium
Valium
lorazepam
lorazepam
Ativan
Ativan
midazolam
midazolam
Versed
Versed
oxazepam
oxazepam
Serax
Serax
triazolam
triazolam
Halcion
Halcion
§§ peak
peak concentration
concentration is
is 28%
28% faster
faster ifif given
given sublingually
sublingually
•
half
life
will
be
prolonged
in
the
presence
• half life will be prolonged in the presence of
of erythromycin,
erythromycin, cimethidine
cimethidine (tagamet),
(tagamet), isoniazid
isoniazid
and
and possibly
possibly oral
oral contraceptives
contraceptives
** not
not available
available as
as an
an oral
oral agent
agent
6/6/05
Copyright Quarnstrom Donaldson
Xanax -Alprazolam
Dosage 0.25-1.0 mg adults
Onset 1 hour
Durration 1-2 hours
2004 SW Dental Conference Joseph Giovannitti JR, DMD
QuickTime™ and a
TIFF (LZW) decompressor
are needed to see this picture.
6/6/05
Copyright Quarnstrom Donaldson
QuickTime™ and a
TIFF (LZW) decompressor
are needed to see this picture.
QuickTime™ and a
TIFF (LZW) decompressor
are needed to see this picture.
6/6/05
Copyright Quarnstrom Donaldson
6/6/05
Copyright Quarnstrom Donaldson
6/6/05
Copyright Quarnstrom Donaldson
6/6/05
Copyright Quarnstrom Donaldson
Effects
Interaction with the Gama Amino Butyric Acid
receptor complex.
Potentiates GABA.
Alters the Chloride ion channel to increase
frequency of their opening.
Interacts with the glycine receptors.
Alters opiate peptide concentrations.
5-HT decreases - a precursor of Seratonin.
6/6/05
Copyright Quarnstrom Donaldson
Effects
Central nervous system
system
Antianxiety, sedative-hypnotic,
sedative-hypnotic,
anticonvulsant and skeletal
skeletal muscle
muscle
relaxant
All depress CNS to some
some degree.
degree. These
These tend
tend
to be more antianxiety as
as compared
compared with
with
barbiturates and other
other sedative-hypnotics.
sedative-hypnotics.
Depress the limbic
limbic system
system and
and areas
areas of
of brain
brain
associated with emotion
emotion and
and behavior
behavior
particularly the hippocampus
hippocampus and
and the
the
amygdaloid nucleus.
6/6/05
Copyright Quarnstrom Donaldson
Cardiovascular system
Benzodiazepines cause few alterations in
cardiac output or blood pressure when
administered intravenously to healthy
persons.
Slightly greater than normal doses cause slight
decreases in blood pressure, cardiac output,
and stroke volume in normal subjects and
patient with cardiac disease, but are not
usually clinically significant.
Triazolam did not affect cardovascular
dymanics in doses 4 to 8 times normal.
6/6/05
Copyright Quarnstrom Donaldson
Absorption
Rapid peak within 2 hours
Faster in elderly and young women
Faster in daytime than at night
due to longer predose fasting period
2 times faster after a 12 hour fast.
85% absorbed 15% passed through.
6/6/05
Copyright Quarnstrom Donaldson
Distribution
No difference in obese and normal patients.
Plasma potient binding at 89%. 49% to
to serum
serum
proteins.
Crosses readily into central nervous system
system
because of high lipid solubility.
solubility.
Crosses the placental barrier and milk of rats.
rats.
6/6/05
Copyright Quarnstrom Donaldson
Metabolism
Halcion is oxidized first pass in liver and lining of gut by
the cytochrome P450 mono-oxygenase system
The P450 is made up of many enzymes. The majority of
drug metabolism is by seven enzymes, 1A2, 3A4, 2c8,
2C9/10, 2C19, 2C19, 2D6, 2F1.
Halcion is metabolized by the 3A4 enzyme.
The presence or absence of an enzyme can be
idiosyncratic or associated with certain patient subsets
6/6/05
Copyright Quarnstrom Donaldson
Metabolism
The absence of an enzyme can be idiosyncratic
or associated with certain patient subsets
CYP 2D6:
2-10% of the total population
5-10% of Caucasians 6% of Afro-Americans
0-1% of Asians
CYP 2C19: 18-25% of Afro-Americans and Asians
2-5% of Caucasians
S.E. Asians may have less 3A4 enzyme
Giving the drug a longer half life
6/6/05
Copyright Quarnstrom Donaldson
Elimination
Half life averages 1.2 to 3.3 hours.
Slower at night.
Longer - elderly - lower liver
oxidixing capacity.
No change with kidney dialysis.
Slower with cirrhosis.
91% eliminated in urine
9% in feces within 72 hr.
6/6/05
Copyright Quarnstrom Donaldson
Benzodiazepine Elimination
CNS.
CNS. conc.
conc.
drug
drug
blood
blood brain
brain
barrier
barrier
plasma
plasma conc.
conc.
plasma
plasma binding
binding
liver
liver
portal
portal circulation
circulation
(metabolism)
(metabolism)
excretion
excretion
6/6/05
fat
fat
stores
fat
partition
fatpartition
stores
time
time
00
1hr.
1hr.
Copyright Quarnstrom Donaldson
66 hr.
hr.
11 d.
d.
66 d.
d.
Bioavailability
Fraction of
unchanged
drug reaching
the systemic
circulation after
administration
by any route
6/6/05
IV Dose
Oral Dose
Target Organ
Systemic
Circulation
Portal
Circulation
Cytochrome
Excretion
Copyright Quarnstrom Donaldson
P450 metabolism
Inhalation
N2O
Side effects .5 mg.
8% sleepiness
4% headach, dizzyness, neuritis,
dry mouth
Reproduction
In rats slightly reduced fertility
but did not affect postnatal
development in rats.
6/6/05
Copyright Quarnstrom Donaldson
Cardiovascular system
Benzodiazepines cause few alterations in
cardiac output or blood pressure when
administered intravenously to healthy persons
Slightly greater than normal doses cause slight
decreases in blood pressure, cardiac output and
stroke volume in normal subjects and patients
with cardiac disease, but are not usually
clinically significant.
Triazolam did not affect cardovascular dynamics
in doses 4 to 8 times normal.
6/6/05
Copyright Quarnstrom Donaldson
Contraindications to Traizolam
absolute
relative
known
known hypersensitivity
hypersensitivity
lack
lack of
of knowledge
knowledge
inability
inability to
to initiate resuscitation
myasthemia
myasthemia gravis
gravis
glaucoma
glaucoma
first
first trimester
trimester
lactation
lactation
concurrent
concurrent CNS
CNS depressants
depressants
Cimethadine
Cimethadine (tagamet)
(tagamet)
Erythromycin
Erythromycin
Isoniazid
Isoniazid
6/6/05
pediatric
pediatric patients
patients
geriatric
geriatric patients
patients
psychiatric
psychiatric patients
patients
no
no FDA
FDA approval
approval for
for
dental
dental sedation
sedation
Copyright Quarnstrom Donaldson
Patient Assessment
ASA Classification American Society of Anesthesiologists
ASA I:
ASA II:
ASA III:
ASA IV:
ASA V:
ASA E:
6/6/05
normal healthy
mild systemic disease – does
not effect the way the live
severe systemic disease –
effects the way they live
incapacitating systemic
disease
moribund, 24 hours to live
emergency
Copyright Quarnstrom Donaldson
Patient Assessment
Much the same as for doing dentistry
Cardiovascular Disease
Pregnancy – benzodiazepines are known
teratogens
Elderly
Patients on Steroids
6/6/05
Copyright Quarnstrom Donaldson
Cardiovascular Disease
Hypertension
Ischemic heart disease
Valvular heart disease
Congestive heart disease
Dysrhythmia
6/6/05
Copyright Quarnstrom Donaldson
Cardiovascular Disease
Hypertension
Systolic
<140
140
160-200
200 &/or
6/6/05
Diastolic
<90
&/or 90-95
Effect on Treatment
none
none: reassess BP next 2
appt.
&/or 95-115 reassess in 5 min.,
refer to MD
>115
reassess in 5 min., refer to
MD immediately
Copyright Quarnstrom Donaldson
Cardiovascular Disease
Hypertension Protocol
Vital signs
Stress reduction
Chairside manner
Profound Local Anesthesia
Conscious sedation
Limit epinephrine to 0.04 mg. – 2
cartridges - 1:100,000 epi.
Retraction cord with epi. ???
6/6/05
Copyright Quarnstrom Donaldson
Cardiovascular Disease
Hypertension
Ischemic heart disease
stable
Treatment?
Yes?
Valvular heart disease
Congestive heart disease
Dysrhythmia
6/6/05
Copyright Quarnstrom Donaldson
unstable
No
Cardiovascular Disease
Hypertension
Ischemic heart disease
stable
unstable
Treatment?
Yes?
No
Valvular heart disease
Consider SBE prophylaxis
Medical consultation
Congestive heart disease
Medical Consultation
Dysrhythmia
6/6/05
Copyright Quarnstrom Donaldson
Cardiovascular Disease
Hypertension
Ischemic heart disease
stable
unstable
Treatment?
Yes?
No
Valvular heart disease
Consider SBE prophylaxis
Medical consultation
Congestive heart disease
Medical Consultation
Dysrhythmia
6/6/05
Copyright Quarnstrom Donaldson
Cardiovascular Disease
Hypertension
Ischemic heart disease
stable
unstable
Treatment?
Yes?
No
Valvular heart disease
Consider SBE prophylaxis
Medical consultation
Congestive heart disease
Medical Consultation
Dysrhythmia
6/6/05
Copyright Quarnstrom Donaldson
Cardiovascular Disease
Dysrhythmia
Vital signs
Stress reduction
Chairside manner
Profound local anesthesia
Conscious sedation
Limit epi to 0.04 mg. – 2 cartridges
1:100,000
No epi. in retraction cord
6/6/05
Copyright Quarnstrom Donaldson
Elderly
Physiologic changes with age
Concomitant disease
Polypharmacy – review medication list
Drug interactions
Decrease initial dose
6/6/05
Copyright Quarnstrom Donaldson
Patients on Steroids
Physiologic release
20-30 mg of cortisol daily
equivalent to:
20-30 mg of hydrocortisone daily
5-7.5 mg. Of prednisone daily
Coverage is required if:
Stressful procedure
On physiologic dose, at least 1 week in
past year
Double daily dose or 100 mg I.M. Hydrocortisone
6/6/05
Copyright Quarnstrom Donaldson
Metabolism
The absence of an enzyme can be idiosyncratic
or associated with certain patient subsets
CYP 2D6:
2-10% of the total population
5-10% of Caucasians 6% of Afro-Americans
0-1% of Asians
CYP 2C19: 18-25% of Afro-Americans and Asians
2-5% of Caucasians
S.E. Asians may have less 3A4 enzyme
Giving the drug a longer half life
6/6/05
Copyright Quarnstrom Donaldson
Drug interactions
Cimethedine - for ulcer treatment
Erythromycin - an antibiotic
Isoniazid - an antitubercular agent
Reduce the first pass liver clearance by
decreased metabolism and reduction in
hapatic blood flow. Due to decrease in
cytochrome P450-mediated oxidatative
system.
6/6/05
Copyright Quarnstrom Donaldson
Halcion Study
6/6/05
Patients
173
Treatments
269
Age
average 31.2 +/- 19.7
range
1.5 - 71
Sex
male
female
Weight
average 135 +/range
23-286
54
119
75
Copyright Quarnstrom Donaldson
Drug Record Forms
6/6/05
Copyright Quarnstrom Donaldson
Patient information and consent forms
6/6/05
Copyright Quarnstrom Donaldson
Medical History and Sedation Record
6/6/05
Copyright Quarnstrom Donaldson
AGE
count
30
20
10
10
6/6/05
20
30
40
Copyright Quarnstrom Donaldson
50
60
70
AGE
count
30
20
10
10
20
30
40
50
60
With new ADA Guidelines
6/6/05
Copyright Quarnstrom Donaldson
70
6/6/05
Copyright Quarnstrom Donaldson
Apprehension Level
terrified
terrified
panicked
panicked
very
very afraid
afraid
afraid
afraid
tense
tense
nervous
nervous
calm
calm
start
start
6/6/05
30
30 min.
min.
60
60 min
min
Copyright Quarnstrom Donaldson
finish
finish
6/6/05
Copyright Quarnstrom Donaldson
6/6/05
Copyright Quarnstrom Donaldson
Amnesia
100%
100%
%
% of
of patients
patients
remembering
remembering
symbol
symbol
80%
80%
60%
60%
40%
40%
20%
20%
pre
pre
med
med
6/6/05
30
30
min
min
60
60
min
min
Copyright Quarnstrom Donaldson
mid
end
mid
end
procedure
procedure
6/6/05
Copyright Quarnstrom Donaldson
6/6/05
Copyright Quarnstrom Donaldson
6/6/05
Copyright Quarnstrom Donaldson
Weight vs. Dose of Halcion
.75
.75
.625
.625
.5
.5
.375
.375
n
n == 100
100
.25
.25
suggested
suggested dose
dose
.125
.125
minimum
minimum dose
dose
00
6/6/05
50
100
150
50
100
150
tended
tended to
to sleep
sleep
good
good sedation
sedation
200
250
300
200
250
300
difficult
difficult but
but possible
possible
uncontrolable
uncontrolable
Copyright Quarnstrom Donaldson
ADA Guidelines
Except for unusual circumstances, the maximum
recommended dose (mrd) shall not be exceded.
Only one dose can be given. You may not titrate for effect.
“In accord with this particular definition, titration of oral medication
for the purposes of sedation is unpredictable. Repeated dosing of
orally administered sedative agents may result in an alteration of the
state of consciousness beyond the intent of the practitioner. Except in
unusual circumstances the Maximum Recommended Dose (MRD) of
an oral mediation should not be exceeded”
The FDA stated there is no mrd for halcion used as an oral
sedative.
6/6/05
Copyright Quarnstrom Donaldson
Weight vs. Dose of Halcion
.75
.75
no sedation
.625
.625
.5
.5
.375
.375
n
n == 100
100
.25
.25
suggested
suggested dose
dose
.125
.125
minimum
minimum dose
dose
00
6/6/05
50
100
150
50
100
150
tended
tended to
to sleep
sleep
good
good sedation
sedation
200
250
300
200
250
300
difficult
difficult but
but possible
possible
uncontrolable
uncontrolable
With new ADA Guidelines
Copyright Quarnstrom Donaldson
Weight vs. Dose of Halcion
no sedation
.75
.75
.625
.625
.5
.5
.375
.375
.25
.25
suggested
suggested dose
dose
.125
.125
minimum
minimum dose
dose
00
6/6/05
50
100
150
50
100
150
tended
tended to
to sleep
sleep
good
good sedation
sedation
200
250
300
200
250
300
difficult
difficult but
but possible
possible
uncontrolable
uncontrolable
With new ADA Guidelines
Copyright Quarnstrom Donaldson
Dose
Dose
of = 0.25mg + 0.125mg
Halcion
(
weight - 40
70
)
(weight in pounds)
If at 30 minutes the patient notices NO
sedation and the dentist observes NO Weight vs. Dose of Halcion
sedation, half the original dose is
administered sublingually.
.75
.75
.625
.625
.5
.5
.375
.375
n
n == 100
100
.25
.25
suggested
suggested dose
dose
.125
.125
minimum
minimum dose
dose
00
6/6/05
Copyright Quarnstrom
50
100
150
50
100
150
tended
tended to
to sleep
sleep
good
Donaldson
good sedation
sedation
200
250
300
200
250
300
difficult
difficult but
but possible
possible
uncontrolable
uncontrolable
Drug Half Lives, T1/2
Oral
I.V.
100
Distribution from
blood to tissue
distribution
(alpha phase)
75
Half Lives, T1/2
50
Elimination via
liver and kidneys
Elimination
(beta phase)
25
0
0
6/6/05
2
4
8
10
0
2
Copyright Quarnstrom Donaldson
4
8
10
Principals of Pharmacotherapy: Pharmacokinetics Pallasch, T.J. Anes. Progress 35:133-146 1988
Titration of Halcion half first dose?
Halcion
Second
1/2 dose
active
conc.
halcion
Population study of triaazolam
pharmacokinetics B.J.Clin.Pharmc (1986)
22, 639-642
Triazolam pharmacodynamics in obesity, J. Clin
Psychopharmacol Vol 15/no3, June 1995
6/6/05
time
1Copyright Quarnstrom
2
3
Donaldson
4
5
Aggressive Titration of Halcion - guess
3rd dose
2nd dose
active
conc.
First dose
n
6/6/05
time
1Copyright Quarnstrom
2
3
Donaldson
4
5
Nitrous Oxide Supplementation
second
second dose
dose at
at 30
30 min
min -- 1/2
1/2 original
original dose
apprehension level
nitrous
nitrous oxide
oxide effect
effect
sedation
sedation
level
level
halcion
halcion effect
effect
sedation
sedation
level
level
11
time
time in
in hours
hours
6/6/05
22
33
Copyright Quarnstrom Donaldson
44
Flumazenol
COOCH CH
3
N
H C
3
N
N
N
C H3
N
H C
3
N
N
Cl
O
Cl
Cl
Flumazenol
6/6/05
Copyright Quarnstrom Donaldson
Triazolam
Flumazenil
ethyl 6 - fluoro - 6, 6 - dihydro - 5 methyl - 6 - oxo - 4h - imidazo
(l,5-a) (1,4) benzodiazepine - 3 carboxylate
6/6/05
Copyright Quarnstrom Donaldson
Dose
.007 and .014 mg/kg.
Lethal dose in mice and rats is 62.5 and
and 125
125 mg
mg
/ kg.
One study suggested lethal dose is 3000
3000 times
times
theraputic dose.
It has been tested up to 200 mg. IV
IV and
and oral.
oral. In
In
the case of oral dosages only 18% is active
active
as it is oxidized in first pass through
through the
the liver
liver
6/6/05
Copyright Quarnstrom Donaldson
Elimination and Side Effects
Eliminated completely in first pass
through liver by P-450 system. Not
effective orally for this reason.
Side effects are infrequent. These include
mild headache, loss of pupil reactivity
to light, mild hypotension.
6/6/05
Copyright Quarnstrom Donaldson
Half life
At 54 minutes (.7 to 1.3 hr.
hr. 50
50 min.
min. average)
average) is
is
less than midazolam and valium
valium so
so you
you may
may
see some rebound.
Worked within 2 to 5 minutes.
minutes.
One author saw no improvment
improvment after
after 15
15
minutes.
Another showed improvment
improvment at
at 15,
15, 30
30 but
but not
not 60
60
minutes.
1 mg. will last for about 2 hours.
6/6/05
Copyright Quarnstrom Donaldson
Flumazenol Reversal of Halcion
flumazenol
active
conc.
6/6/05
time
halcion
without
reversal
1Copyright Quarnstrom
2
3
Donaldson
4
5
Reversal of
Triazolam by
Romazicon,
IV reversal
SL reversal
Flumazenil,
Much effect
An unpublished
from the
needle stick
study
Min.
6/6/05
5 10
Copyright Quarnstrom Donaldson
15
20
Successful Nitrous Oxide / Oxygen
Sedation
apprehension level
sedation
sedation
level
level
nitrous
nitrous oxide
oxide effect
effect
time
time in
in minutes
minutes
6/6/05
Copyright Quarnstrom Donaldson
Inadequate Nitrous Oxide / Oxygen
Sedation
apprehension level
sedation
sedation
level
level
nitrous
nitrous oxide
oxide effect
effect
15
15
time
time in
in minutes
minutes
6/6/05
30
30
45
45
Copyright Quarnstrom Donaldson
60
60
Inadequate Halcion Sedation
second
second dose
dose at
at 30
30 min
min -- 1/2
1/2 original
original dose
dose
apprehension level
sedation
sedation
level
level
halcion
halcion effect
effect
11
time
time in
in hours
hours
6/6/05
22
33
Copyright Quarnstrom Donaldson
44
Nitrous Oxide Supplementation
second
second dose
dose at
at 30
30 min
min -- 1/2
1/2 original
original dose
apprehension level
nitrous
nitrous oxide
oxide effect
effect
sedation
sedation
level
level
halcion
halcion effect
effect
sedation
sedation
level
level
11
time
time in
in hours
hours
6/6/05
22
33
Copyright Quarnstrom Donaldson
44
Deaths from Halcion
Impaired driving
Sexual Assault
Death due to drugs
Death Drug related
Death drug involved
17
4
45
20
8
Cases from 1979-1990 in Canada
of Analytical
Toxicology,
6/6/05 Joynt, Brian, Journal
Copyright
Quarnstrom
Donaldsonvol.17 May/June 1993 p171-177
Deaths from Halcion
Impaired driving
17
9 combination with other drugs
Sexual Assault
4
Death due to drugs
45
Death Drug related
20
Death drug involved
8
Cases from 1979-1990 in Canada
of Analytical
Toxicology,
6/6/05 Joynt, Brian, Journal
Copyright
Quarnstrom
Donaldsonvol.17 May/June 1993 p171-177
Deaths from Halcion
Impaired driving
17
Sexual Assault
4
male and female - “love drug”
Death due to drugs
45
Death Drug related
20
Death drug involved
8
Cases from 1979-1990 in Canada
of Analytical
Toxicology,
6/6/05 Joynt, Brian, Journal
Copyright
Quarnstrom
Donaldsonvol.17 May/June 1993 p171-177
Deaths from Halcion
Impaired driving
Sexual Assault
Death due to drugs
4 were halcion alone
1 10 ng/ml
3 40 ng/ml
Death Drug related
Death Drug involved
17
4
45
20
8
Cases from 1979-1990 in Canada
of Analytical
Toxicology,
6/6/05 Joynt, Brian, Journal
Copyright
Quarnstrom
Donaldsonvol.17 May/June 1993 p171-177
Deaths from Halcion
Death due to drugs
45
4 were halcion alone
1 10 ng/ml
3 40 ng/ml
Peak conc.
0.125 = 1.08 +-0.08 ng/ml
1.67+-0.16 ng/ml elderly
0.25 = 2.02 +-0.15 ng/ml
3.06+-0.22 ng/ml elderly
1.0 = 7.47 +-1.51ng/ml
at .83 hr +-0.32 hr
of Analytical
Toxicology,
6/6/05 Joynt, Brian, Journal
Copyright
Quarnstrom
Donaldsonvol.17 May/June 1993 p171-177
Deaths from Halcion
Death due to drugs
45
41 were halcion + other drugs
9 - 190 ng/ml
Peak conc.
0.125 = 1.08 +-0.08 ng/ml
1.67+-0.16 ng/ml elderly
0.25 = 2.02 +-0.15 ng/ml
3.06+-0.22 ng/ml elderly
1.0 = 7.47 +-1.51ng/ml
at .83 hr +-0.32 hr
of Analytical
Toxicology,
6/6/05 Joynt, Brian, Journal
Copyright
Quarnstrom
Donaldsonvol.17 May/June 1993 p171-177
Deaths from Halcion
Impaired driving
Sexual Assault
Death due to drugs
Death Drug related
Death drug involved
17
4
45
20
8
Most appear to be self inflicted suicide, an error in patient
compliance or the result of foul play
of Analytical
Toxicology,
6/6/05 Joynt, Brian, Journal
Copyright
Quarnstrom
Donaldsonvol.17 May/June 1993 p171-177
Q’s Recommendations
This refers only to the use of halcion
MRD is for use as a sleep aid - elderly with no monitoring
ED60 equals about the LD5 of chloral hydrate.
No use on patients under 40 lbs. (5 years of age).
Titration is possible
It is very slow.
Can be used to adjust initial dose.
Secondary doses should be no more than the
predicted amount that has been
metabolized
(1/2 original dose at 2 hr. intervals)
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Q’s Recommendations
Administered in the office
assistant in the room
Dr. in the office
Monitoring
Pulse oximeter monitoring - constant
BP monitoring (q. 15 min.)
No multiple drugs Single drug plus nitrous oxide OK.
Staff and Dentist must have BLS every year.
The Dentist should be trained and current in
the use of nitrous oxide.
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Solution
Research
Education
Education
Good courses will drive out
Or cause bad courses to be altered.
It is the responsibility of the ADA to educate
and publish when so many are using a drug in
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Copyright Quarnstrom Donaldson
potentially
dangerous
techniques.
Halcion Oral Sedation
Drugs make the world go round.
To get really high
Free online Halcion manual
http://faculty.washington.edu/quarn
select “oral halcion”
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takes a telescope.
Copyright Quarnstrom Donaldson