Pharmacodynamics and Pharmacokinetics of Alcohol Pharmacodynamics and Pharmacokinetics ...

111 Pages·2003·1.13 MB·English

PPhhaarrmmaaccooddyynnaammiiccss aanndd
PPhhaarrmmaaccookkiinneettiiccss ooff AAllccoohhooll
A.W. Jones, PhD, DSc
Department of Forensic Toxicology, University
Hospital, 581 85 Linköping, Sweden.
[email protected]
Presented at meeting of the California Association of
Toxicologists, Santa Rosa, CA, 1-2 August, 2003.
Pharmacokinetics
Studies of the movement of drugs
into, within and out of the body
What the body does to the drug
CH CH OH
3 2
Pharmacodynamics
Studies of the effect and mechanism
of action of drugs on the body
What the drug does to the body
PPhhaarrmmaaccookkiinneettiiccss
Pharmakon= drug or poison
Kinesis = movement
The discipline known as pharmacokinetics
deals with the way that drugs and their
metabolites are absorbed, distributed, and
eliminated in the body and how these
processes can be described in quantitative
terms.
Pharmacokinetics of ethanol
• Forensic pharmacokinetics
– Widmark’s model
• One-compartment, zero-order elimination
– Michaelis-Menten elimination
• Saturable kinetics – dose dependent
• First-order kinetics
– Operates at very low & perhaps at very high BAC?
• Multicompartment models
– Arterial and venous blood compartments
• Physiologically-based kinetic models
– PB-PK
• Population kinetics
Forensic Pharmacokinetics
Peak
BAC
150
Drinking
Spree
l
d Rise in
/
g BAC
m
100

,
l
o
n
a
h
t
E

d 50
o
Time
o
l to
B
β-slope
Peak
0
0 30 60 90 120 150 180 210 240 270 300
Time After Start of Drinking, min
Pharmacokinetic Models
k k
V o V m
Dose Dose
C V
C
max
1.2
1.2
1
1
L
g/ L
0.8 g/
ol, , 0.8
n ol
a n
h 0.6 a
Et h 0.6
Et
d
o 0.4 d
o o 0.4
Bl o
Bl
0.2
0.2
0
0
0 1 2 3 4 5 6 7 8
0 1 2 3 4 5 6 7 8
Time, h
Time, h
-dc/dt = k
V x C
o
max
-dc/dt =
C = C - k t
t o o k + C
m
Response feature analysis of BAC
profiles - noncompartmental analysis
200
Peak BAC
Typical curve after
intravenous Infusion
l
d
150
/ Diffusion plunge
g
m

,
l
o
n
a 100
h
t β-slope = C /Min
E
o o
C
d
o
o
o
50
l
B
First-order kinetics
AUC
Min
o
0
0 100 200 300 400 500 600 700
Time After Start of Infusion, min
Important articles on EtOH kinetics
• Widmark
– Principles and application of medicolegal alcohol
determination. Biomedical Publications, Foster City, CA,
1981 (tanslation of Widmark’s 1932 German monograph)
• Lundquist & Wolthers
– Acta Pharmacol & Toxicol 1956;14:265-289.
• First application of Michaelis-Menten kinetics, thanks to use of
more sensitive enzymatic ADH method for blood-alcohol analysis
• VonWartburg
– Chapter in ”Human metabolism of alcohol” (vol 1, Crow
and Batt, editors) CRC Press, 1989, pp 9-22.
• Comprehensive review of ethanol pharmacokinetics as well as
applications in forensic casework.
Important articles on EtOH kinetics
• Wilkinson
– Alcohol. Clin. Exp. Res. 1980;4:6-21.
• Comprehensive review of ethanol pharmacokinetics with emphasis
on Michaelis-Menten equation.
• Holford
– Clin. Pharmacokinet. 1987;13:273-292
• Comprehensive review of clinical pharmacokinetics of ethanol
• Kalant
– Chapter in ”Pharmacology of alcohol and alcohol
dependence” (Begleiter & Kissin, editors) Oxford
University Press, 1996, pp 15-58.
• Norberg et al
– Clin. Pharmacokinet. 2003;42:1-31
• Comprehensive review of clinical pharmacokinetics of ethanol
with focus on variability and forensic issues.
PPrrooppeerrttiieess ooff tthhee DDrruugg
EEtthhyyll AAllccoohhooll CCHH CCHH OOHH
33 22
• Small molecule (MW 46.05).
• Unionized at physiological pH and carries
only a weak charge
• Dosage form (beer, wine, spirits).
• Easily passes biological membranes.
– Including blood-brain barrier
• Completely miscible with water.
• Low solubility in lipids and bone.
• Negligible binding to plasma proteins.