Pharmacodynamics and Pharmacokinetics of Alcohol Pharmacodynamics and Pharmacokinetics of Alcohol 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.
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Pharmacodynamics andPharmacokinetics of Alcohol
Pharmacodynamics andPharmacokinetics of Alcohol
A.W. Jones, PhD, DScDepartment of Forensic Toxicology, University
• 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
0 30 60 90 120 150 180 210 240 270 300
Time After Start of Drinking, min
0
50
100
150
Blo
od E
than
ol, m
g/dl
PeakBAC
Rise inBAC
DrinkingSpree
β-slope
Timeto
Peak
Pharmacokinetic Models
0
0.2
0.4
0.6
0.8
1
1.2
0 1 2 3 4 5 6 7 8
Time, h
Blo
od E
than
ol, g
/L
VC
VC
ko km
Vmax
0
0.2
0.4
0.6
0.8
1
1.2
0 1 2 3 4 5 6 7 8
Time, h
Blo
od E
than
ol, g
/L
DoseDose
Vmax x C-dc/dt =
km + C
-dc/dt = koCt = Co - kot
Response feature analysis of BACprofiles - noncompartmental analysis
0 100 200 300 400 500 600 700
Time After Start of Infusion, min
0
50
100
150
200
Blo
od E
than
ol, m
g/dl
Peak BAC
Co
Mino
β-slope = Co/Mino
Diffusion plunge
First-order kineticsAUC
Typical curve after intravenous Infusion
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)
• Sedation and intoxicating effects• GABA, glycine, glutamate
• No known antagonist of EtOH seemingly exists• RO15-4513 had some potential
Altered synaptic activity caused by ethanol working at multiple molecular sites
* N-methyl-D-aspartate receptor
Receptors involved in some of the actions of ethanol
Effects on ligand-gated ion channels
GABA Receptor
Benzodiazepinereceptor
Barbiturate receptor
Chloride channel
GABAA inhibitory receptor EtOH potentiates the effect of GABA
Effects of Ethanol on the Brain
• Impairment of cognitive and psychomotor functions
• First emotion and decision making e.g. reasoning, thinking, learning and judgement
• Next muscular control e.g.marked impairment of movement, balance, speech, reaction time etc.
• Last affected is respiration and circulation (v. high BAC).
• Degree of impairment depends on dose, rate of drinking and prior experience with alcohol
Alcohol is not evenly distributed in the brain.
Concentrations depend on blood flow and water
content.Tolerance
Acute ToleranceAcute Tolerance
• From studies mainly in dogs, Mellanby foundthat the degree of impairment to alcohol was greater at a given blood-alcohol concentrationon the rising portion of the blood-alcohol curve than it was at the same concentration on thedescending part of the curve.– Some toxicologists considered that the Mellanby effect
was caused by the different alcohol concentration inarterial blood reaching the brain and the venous blood returning from muscle tissue, which was assumed to be the specimen analyzed.
– For a given consumption of alcohol, different blood alcohol concentrations are reached for different individuals.
• This depends on different patterns of absorption, distribution and elimination and body composition.
• Concentration Tolerance– This relates to the concentration of alcohol in blood causing
effects on the individual. The intensity of these symptoms differs between individuals at the same blood-alcohol concentration.
• The mechanism of concentration tolerance relates to the effects of alcohol on the brain – acute and chronic tolerance.
Tolerance• Dispositional Tolerance
– Changes in absorption, distribution, excretion and metabolism of the drug which might lead to a reduction in intensity and duration of the effects on the individual.
• Functional Tolerance– Changes in sensitivity of the brain or other tissue
making it less sensitive to the same degree of exposure to the drug.
Definitions given by Dr. Harald Kalant, Toronto.Pharmacological Reviews 23;1971, pp 135-191.
Alcohol in the Body
• Absorption phase• Distribution phase• Elimination phase
– Metabolism• Oxidation & conjugation
– Excretion
Rate of Absorption Rate of Absorption • Depends on many factors
– Route of administration• Inhalation, sub- and per-cutaneously,
intravenously, rectally, perorally.
– Dosage form• Beer, wine, distilled spirits
• Dilution and CO2 content
• Buffer capacity
– Gastric emptying• Food, time of day, blood-glucose
Esophagus
Rapid absorption fromduodenum
Slow absorption across stomach wall
Pyloric sphincter
0
0.2
0.4
0.6
0.8
1
1.2
0 1 2 3 4 5 6 7 8
Time, h
Blo
od E
than
ol, g
/L
Slow gastric emptying
0
0.2
0.4
0.6
0.8
1
1.2
0 1 2 3 4 5 6 7 8
Time, h
Blo
od E
than
ol, g
/L
Rapid gastric
emptying
Critical Role of Stomach Emptying on Peak BACCritical Role of Stomach Emptying on Peak BAC
• Man 80 kg, drank 190 ml whisky over 60 min, venous BAC at 5.35 p.m. was 0.052 g%
• Man 88 kg, drank 190 ml whisky over 60 min venous BAC at 5.50 p.m. was 0.011 g%
• Man 75 kg, drank 190 ml whisky over 60 min venous BAC at 5.46 p.m. was 0.049 g%
Pyloric Sphincter
Distribution phase Distribution phase • Depends on many factors;
– Water content of the various fluids andtissues
• More H20 more alcohol.
– Importance of ratio of blood flow (F) totissue mass (M).
• Low ratio F/M large A-V difference
– Body water depends on age, gender and the proportion of fat to lean tissue (obesity).
– Widmark’s rho-factor
Measuring Total Body WaterMeasuring Total Body Water! Isotope dilution methods
! Water labelled with deuterium ! Water labelled with tritium ! H2O18
• binding to receptor sites, opening of ion channels
Formate
Acetate
FormaldehydeMethanol
Alcohol-dehydrogenase
Aldehyde-dehydrogenase
Ethanol AcetaldehydeAlcohol-
dehydrogenaseAldehyde-
dehydrogenase
NADHNAD+ NAD+ NADH
Blocked by 4-methyl pyrazole
Blocked byDisulfiram
Antabuse®fomepizole (Antizol®)
Drug alcohol metabolic interactionsat specific enzymes
• Alcohol dehydrogenase– 4-methyl pyrazole, other alcohols,
chloral hydrate• Aldehyde dehydrogenase
– Disulfiram, calcium carbimide, • CYP2E1
– Acetaminophene, chlormethiazole
• Drugs used in treatment of stomach problems – Histamine-H2-antagonists inhibitors of gastric ADH?
• Cimetidine (Tagamet®)• Ranitidine (Zantac®)
– Proton-pump inhibitors• Omeprazole (Losec®)
NNH
H3C
4-methyl pyrazole
Fomepizole Antizol®
N
HNH3C
CH3NHCNHCH2CH2SCH2
NCN
Cimetidine (Tagamet®)
H
N
NNH2CH2CH2
Histamine
A = Cimetidine 7 daysB = Ranitidine 7 daysC = Omeprazole 7 dayscompared with no-drug treatment, EtOH 0.8 g/kg
0 1 2 3 4 5 6
Time (h)
0
5
10
15
20
250
5
10
15
20
250
5
10
15
20
25B
lood
Eth
anol
(mm
ol l-1
)(A)
(B)
(C)
Many studies used very small doses of alcohol e.g. 0.15-0.30 g/kg and found small
increases in peak BAC 0.008-0.015 g/100 mL
Jönsson et al. Eur J Clin Pharmacol 42;209-12, 1992
Drug Drug
Drug Metabolites
Drug Metabolites
Moderate Drinker Heavy Drinker
Prolonged Therapeutic
Effect of the Drug
Diminished Therapeutic
Effect of the Drug
CYP450+ EtOH
ActivatedCYP450X
X
Acetaminophene
N-acetyl-p-benzo-quinone imine
(NAPQI)
Sulfateconjugate
~35%
Glucuronide conjugate
~60%
Glutathione conjugate
Covalent binding to tissues – cell death
CYP2E1 ~5%
Glutathione inactivation
Reactive intermediate
Hepatotoxicity
Induced by alcohol,fasting, protein deficiency
Toxicity of Ethanol Some Factors to Consider
• Age, gender, body mass index• Dose, beverage type, speed of drinking• Route of administration• Hypothermia• Development of chronic tolerance • General state of health
– Malnutrition, metabolic disorders, ketoacidosis• Concomittant use of other drugs
– CNS depressants– Opiates
• Evidence of positional asphyxia or inhalation of vomit.
At what blood-concentration does alcohol kill?
Different authorities cite different concentrations derived presumably from personal experiences but where is the
documentation?
Bernard Knight (UK) >0.30 g%DiMaio & DiMaio (USA) 0.40 g%
53 y0.373 g%164Female
54 y0.355 g%529Male
Mean Age
Blood Alcohol
NGender
Jones and Holmgren, J. Forensic Sciences (USA), July 2003
We recently looked at all deaths in Swedenattributed to acute alcohol poisoning with alcoholas the only drug present in femoral venous blood
Deaths Ascribed to Acute Alcohol Poisoning
0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.70
50
100
150
200
250
0
50
100
150
200
250Acute Alcohol
Poisoning DeathsN = 693
Mean 0.36 g/100 mLMedian 0.36 g/100 mL
Blood-Ethanol Concentration, g/100 mL
Freq
uenc
y
Normal
0.0 1.0 2.0 3.0 4.0 5.0 6.00
10
20
30
0
10
20
30
Blood-Ethanol Concentration, g/L
N = 703Mean 1.70 g/LMedian 1.50 g/LRange 0.1 to 5.6 g/L
Drunk drivers in Sweden with very highblood-ethanol conc., > 0.4 g% (N = 120)*
199 g (570 mL vodka)
159 g (530 mL vodka)
0.43513 (11%)Female (65 kg)
265 g (810 mL vodka)
225 g (710 mL vodka)
0.428107 (89%)Male (75 kg)
5 h** metabolism
EtOH in body, g
Mean BAC g%
N (%)Gender (body weight)
* Swedish records (0.545, 0.544, 0.518, 0.505, g%)
** 8 g/h = 40 g = ~100 mL spirits
Physiological range of ethanolelimination rates from blood
Heavy drinkers such as drunk drivers who reach appreciably high BAC (> 0.12 g/100 mL)
0.016-0.025
Healthy people who drink moderate dose of ethanol under non-fasting conditions.
0.013-0.016
Alcoholics during detoxification or binge drinkers immediately after heavy drinking. Treatment with protein or amino acid rich diets or those suffering from conditions leading to a hypermetabolic state.
0.025-0.035
Healthy people who drink moderate amounts of alcohol after an overnight fast.
0.010-0.013
People with liver dysfunction (e.g. cirrhosis) or those who are malnourished, eat low-protein diets or take a drug that blocks ADH e.g. fomepizole (4-methyl pyrazole)
0.08-0.010
Conditions or treatmentBAC rate of decline g% per h
Rate of ethanol elimination in drinking drivers?
Assuming post-absorptive phase and zero order kinetics J. Forensic Sci. Vol 41, 922-926, 1996.
Time
Blo
od A
lcoh
ol C
onc. t1
t2
TimeB
lood
Alc
ohol
Con
c. t1
Example of calculating elimination rates based on double blood samples
0.0202a_2c0.21006.152b0.183
0.2170.2200.2280.248
BAC g%
2b_2c
2a_2b1b_1c1a_1c1a_1b
Pair of bloods
0.02007.352c
0.02105.552a0.02122.051c0.02021.421b0.01920.391a
BAC rate of decline g%/h
Time of day
Case (blood)
ß-Slope as a Function of Age in Male and Female DWI Suspects
Age
Blo
od-A
lcoh
ol D
ecay
Rat
e,m
g/m
l/h
<20y 20-29y 30-39y 40-49y 50-59y >60y0.00
0.05
0.10
0.15
0.20
0.25
0.30WomenMen
0.00
0.05
0.10
0.15
0.20
0.25
0.30
0.00 0.01 0.02 0.03 0.04 0.050
50
100
150
200
250
0
50
100
150
200
250
Elimination Rate, g/100 mL per h
Freq
uenc
y • Mean 0.019 g% per h
• SD 0.005 g% per h
• Median 0.019 g% per h
• Min 0.00 g% per h
• Max 0.046 g% per h
• 95% range (± 2 SD)
• 0.009 – 0.029 g% per h
Ethanol elimination rate in DWI suspectsDerived from double
blood samples
Gender Differences Kwo et al. Gastroenterology 115;1552-57, 1998
• Different body composition. – Less water/kg in women compared with men lower
volume of distribution in women.• Hormonal differences
– testosterone influences ADH activity?• First-pass metabolism - gastric ADH?• Menstrual cycle in women?• Oral contraceptive steroids?• Liver volume ~same• Alcohol Elimination rate per kg LBM was
higher in women.
Relationship between dose of ethanol and Cmax and AUC of the BAC profile
Time to Reach Peak Concentrations under Social Drinking Conditions
• Wright and Cameron, Alc & Alcoholism 33;495-501, 1998.
– 51 subjects drank 1 mL EtOH/kg as beer (4% v/v) over 90 min (~2 L ) and breath analyzed 5-90 min after end of drinking.
• Peak BrAC at mean time of 16 min (range 5-85 min).
• Ganert and Bowthorpe, Can Soc Forens Sci J. 33;137-43, 2000
– 10 subjects drank 0.37-0.52 g alcohol per kg per hour over 3 hours. Breath was analyzed at 5-10 min intervals for up to 7 hours after start of drinking.
• Peak BrAC at mean time of 12 min (range 4-22 min).
0 200 400 600 800 1000 1200
Time From Start of Drinking, min
0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
4.5B
lood
Eth
anol
, mg/
g
Peak BAC608 min
EOD = 620 min
Ingestion of 364 g ethanol (5.7 g/kg)mainly as 4 vol% Beer
SUBJECT 2
Zink & Reinhardt, Blutalkohol 21;422-433, 1984.
0 200 400 600 800 1000 1200
Time From Start of Drinking, min
0
0.5
1.0
1.5
2.0
2.5
3.0
3.5B
lood
Eth
anol
, mg/
g
Peak BAC575 min
EOD = 580 min
Ingestion of 357 g ethanol (4.7 g/kg)mainly as 4 vol% Beer and spirits
Combined results of experiments with men and women who drank 0.50 g/kg (40% v/v) as a bolus
dose on an empty stomach
Rate of Ethanol Elimination in Alcoholics(induced CYP2E1 activity)
• Male and female alcoholics.• BAC at start of detoxification 0.23 - 0.49 g% w/v.• 6-8 specimens of venous blood taken over 24 h.• Blood-ethanol determined by headspace gas
chromatography.• Rate of ethanol disappearance from blood
calculated as described by Widmark from theslope of the elimination phase.
0 3 6 9 12 15 18 21 24 27
TIME FROM START, h
00.10.20.30.40.5
00.10.20.30.40.5
00.10.20.30.40.5
00.10.20.30.40.5
BLO
OD
ALC
OH
OL
CO
NC
ENTR
ATI
ON
, g%
w/v
β = 0.021 g% per h
β = 0.022 g% per h
β = 0.019 g% per hF
β = 0.024 g% per h
Alcoholics
0 5 10 15 20 25
Time From Start, h
0
100
200
300
400
500
Blo
od E
than
ol, m
g/dl
0
0.5
1.0
1.5
2.0
2.5
3.0
Blo
od M
etha
nol,
mg/
dl
SUBJECT 2
0 5 10 15 20 25
Time From Start, h
0
100
200
300
400
500
Blo
od E
than
ol, m
g/dl
0
0.5
1.0
1.5
2.0
2.5
3.0
Blo
od M
etha
nol,
mg/
dl
Subject 7
EtOH-MeOH metabolic interaction
Faster Elimination Rate in Alcoholics during Detoxification*
• 1 0.443 g% 0.018 g% per h• 2 0.489 g% 0.021 g% per h• 3 0.398 g% 0.028 g% per h• 4 0.454 g% 0.017 g% per h• 5 0.359 g% 0.019 g% per h• 6 0.343 g% 0.016 g% per h• 7 0.337 g% 0.017 g% per h• 8 0.410 g% 0.033 g% per h
Subject BAC at Start ß-slope g% per h
Mean rate (N = 21), 0.023 g% per h (0.013-0.036) *Alcohol & Alcoholism 27;641-647, 1992
0 1 2 3 4 5 6 7Time From Start of Drinking, h
0
25
50
75
100
125
150B
lood
Alc
ohol
, mg/
dlSubject Vomited and Comatose
M 110 kgAlcohol dose 1.02 g/kg
330 ml neat whisky in 25 min
Jones, unpublished work
Retrograde Extrapolation! Position of the BAC profile at the time of driving?! Was alcohol consumed after driving?! Was BAC or BrAC measured?! What allowance if any should be made for absorption
of alcohol contained in the last drink?! Allowance for a rising BAC or BAC plateau? ! Was a urine sample taken?
! Can help to verify post-absorptive state! What elimination rate (ß-slope) should apply?
Exact quantitative results are probably not possible
Retrograde Extrapolation
! Provided that the BAC curve was post-peak at the time of driving and the time of drawing blood then back extrapolation is feasible and simple.
! Ct1 = C0 - ßt1 and Ct2 = C0 - ßt2
! Ct1 = Ct2 + (ß x tdiff)! In criminal cases best to assume a low rate of alcohol
elimination (ß-slope) such as 0.01 g% per hour.
See Stowell and Stowell, JFS, 43;14-21, 1998
Forward Prediction of BAC! This application of Widmark’s equation has been
widely abused and has considerable uncertainty owing to assumptions about the rate of absorption and first-pass metabolism that might occur.
! If alcohol is taken with food then the dose of alcohol available for absorption into the blood is less by 10-20%.
! Drinking heavily over many hours seems to result in larger “losses” of alcohol.
See Zink & Reinhardt , Blutalkohol 21; 422-442, 1984.
Tissue of the ArmTissue of the Arm
High water content of muscle acts as a reservoir for ethanol
High water content of muscle acts as a reservoir for ethanol
Peripheral artery
Peripheral vein
CACV
Arterial-Venous Differences in EtOH Conc. at the Blood Sampling Compartment
0 60 120 180 240 300 360
Time After Start of Drinking, min
-0.2
-0.1
0.0
0.1
0.2
0.3
0.4
0.5A-
V D
iffer
ence
g/L
0 60 120 180 240 300 360
Time
-0.2
-0.1
0.0
0.1
0.2
0.3
0.4
A-V
Diff
eren
ce g
/L Mean ± SDN = 9 Subjects
Male subjects
Arterial-Venous Differences in Blood Ethanol Concentration
Arterial-Venous Differences in Blood Ethanol Concentration
• ABAC > VBAC during the absorption and distribution stages during and shortly afterdrinking– mean 0.019 g% (range 0.008 to 0.043 g%).
• Occurred 10 min after end of drinking.
• ABAC = VBAC at only one time point– 90 min (median) range 45-150 min.– Represents equilibriation in all body water
• ABAC < VBAC at all later times– mean -0.0029 g/L (range -0.0018 to -0.0052).
Studies in Progress• Pharmacokinetics of ethanol in obese subjects
– People with very high BMI > 35– What is volume of distribution of ethanol?– What consequences for Widmark calculatiosn?
• Magnitude and time course of arterial-venous differences in ethanol concentration.– Implications for use of evidential breath-alcohol
analyzers.
• Comparison of glucose and amino acids on rateof alcohol metabolism– Both ethanol and nutrients given intravenously to
sidestep confounding influences of gastric emptying.
”Is this really necessary, your Honor? I’m an expert.”