Download Pharmacokinetic & Pharmacodynamic of Ketamine in Pediatric

Pharmacokinetic & Pharmacodynamic
of Ketamine in Pediatric Patients
Prepared by
Nissreen A. Al Thaqafi
M.Sc candidate
Supervised by
Iman Zaghloul Ph.D
Abdulatif Al Dwailie Ph.D
Hala Al Alem Ped. intensive Consultant
Tuesday, June 1,2004
1
Outline
Background
Objective
Methodology
Study design
Inclusion criteria and Exclusion criteria
Procedure
Work plan
2
Background of the study
Pediatric patient frequently require
procedural intervention which are
uncomfortable and emotionally
disturbing for children, and require
substantial immobilization for optimal
performance.
3
Background, cont’d
Ketamine has been used in King
Abdulaziz Medical City/King Fahad
National Guard Hospital/PICU
(KAMC/KFNGH) since June 2002 as a
part of a regimen consisted of AtropineMidazolam and Ketamine (AMK).
4
ketamine
2-(o-chlorophenyl)-2-(methylamino) cyclohexanone
5
Rotatable 3D model
S-(+)-ketamine
R-(-)-ketamine
6
Background
Phencyclidine derivatives
Used as dissociative anesthetic
It is commercially available as racemic
mixture of two enantiomers R(-)ketamine and S(+)-ketamine.
7
1970: Ketamine officially released
for clinical use in U.S.
1999: Ketamine becomes a schedule
III substance under the CSA
8
Background
Disadvantage:
Emergence phenomena
Increased cerebral blood flow
Sympathomimetic cardiovascular effects
Cholinergic salivary and bronchial gland
secretion
Advantage:
No cardio-respiratory depressant effects
produce significant analgesia
9
Background, cont’d
Mechanism of action
 Non competitive NMDA glutamate receptor
antagonism (functional and electro-physiologic
dissociation between thalamus & limbic system)
 It antagonizes acetyl choline receptors
 It has a weak affinity for opioid receptors and
possibly GABA receptors (The analgesic effect)
10
Background (cont.)
It inhibits serotonin and dopamine
reuptake.
Inhibition of nerve growth factor and of
voltage gated Na and K channels.
11
Pharmacokinetics of ketamine
Three compartment open model
t1/2α = 11 - 16 minutes
t1/2β = 2 - 3 hours
Vd ss = 3 L/kg
Therapeutic range 0.7-2.2 ㎍/ml.
Awakening occurs below 0.5 ㎍/ml.
12
Pharmacokinetics of ketamine
Metabolism
Metabolized by the hepatic microsomal system
(CYP3A4, CYP2C9 and CYP2B6).
N-demethylation
ketamine
norketamine
(metabolite I)
13
Norketamine (NK) has 20-30% of the
ketamine activity
NK hydroxlyated to Hydoxynorketamine,
conjugated with glucuronate and excreted
in the urine.
14
Doses, Routes of Administration
15
Objectives
 Evaluation of the Pharmacokinetics and
Pharmacodynamics of Ketamine in pediatric
patients who requires sedation for short procedures
at KAMC/KFNGH.
 Determination of the duration of analgesia which
will be correlated to the measured concentrations in
order to determine the minimum analgesic range.
16
Methodology
17
Study design
Prospective cross sectional study of
pediatric population undergo short
stressful and/or painful procedure
admitted to KAMC/KFNGH
A total of 25 pediatric patients will be
enrolled in the current study
18
Inclusion criteria
1. Age between 3 month and 12 years old.
2. Clinically and hemodynamically stable
patients (ASA Physical Status ClassⅠ&
ClassⅡ)
19
Exclusion criteria
1.
2.
3.
4.
5.
6.
7.
8.
Known increased intracranial pressure
Tumors of the CNS
Severe pre-existing hypertension
Hypersensitivity to any component of sedation
regimen.
Evidence of pulmonary disease
Evidence of heart disease.
ASA Physical Status Class III , Class IV and
Class V
Refuse to consent
20
Procedure
A. Informed consent form
B. NPO 4-6 hours before procedure.
C. IV-access
21
Procedure
D. Base line data
A.
B.
C.
D.
E.
Demographic data
Past and present medical illness
History of previous anesthesia
Procedure indication and physical
assessment
Laboratory data will be collected before
and 24 hours after the procedure: CBC,
AST, ALT, and serum creatinine
22
Procedure
E. Drug dose, administration
F. Collection of blood sample
At 0, 5, 30 minutes, 2, 6,10 hours
following Ketamine administration in
heparinized tube.
23
Procedure
G.Hemodynamic measurement
Cardiorespiratory Monitor, Pulse oxymetry
will be connected to the patient.
•
•
•
•
•
•
•
Systolic blood pressure (SBP)
Diastolic blood pressure (DBP)
Heart rate (HR)
Respiratory rate (RR)
O2 saturation will be measured
Patient responsiveness
Adverse events
(Will be observed and measured in 5 minutes
interval until discharge from PICU, and 30
minutes after upto 24 hrs)
24
Procedure
H. Efficacy end point:
 Onset of sedation
 Observed patient sedation score
1. Patient sedation during the surgery scored
from 0-2 as follows:
 0 = drowsy or sleep but easily to arouse by
verbal stimulus.
 1 = sleep and difficult to arouse or by verbal
stimulus (considered over sedated)
 2 = awake and anxious or disturbed
(considered inadequately sedated)
25
Procedure
H. Efficacy end point:Cont’d
2. Patient movement during procedure scored
from 0-3 as follows:
▰0 = none
▰2 = moderate
▰1 = mild
▰3 = severe
 Recovery time:
1. Time to voice arousal
2. Time to speak
3. Time to sit up
4. Time to meet criteria for removal of
monitoring devices
5. Time to meet criteria for discharge.
26
Procedure
H. Efficacy end point:cont’d
Duration of analgesia will be evaluated
by “FACES PAIN RATING SCALE”
every 30 minute- 1 hour during and
post procedure for 24 hours or until
the 1st dose of any analgesic drug
given.
27
Procedure
I. Ketamine assay
Ketamine will be analyzed by HPLC (high
pressure liquid chromatography)
according to Bolze S et al.
28
Data analysis
1. Pharmacokinetic analysis
Compartmental and Non-Compartmental
analysis of the plasma concentrations of
Ketamine will be conducted using WinNONLIN program.
29
2. Statistical analysis
SPSS program will be used for statistical
evaluation of the data.
Paired t-test will be used to compare the
maximal change in hemodynamic
variables during Ketamine administration
with baseline values.
30
Statistical analysis-cont.
ANOVA test will be used for comparison
of hemodynamic variables at different
time intervals.
The non-parametric Spearman's rank
correlation test to study the correlation
between pharmacokinetic variable and
pathological variables (age, body weight,
creatinine clearance)
31
Work plan
Date
Activity
April 2004
Literatures review
May 2004
Writing the proposal and preparing the data
collection form
KAMC research committee approval
May 2004
June-August Collecting blood samples and patient data
SeptemberOctober
Analysis of Ketamine by HPLC
November
Pharmacokinetic of data and writing the data
32
33