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Thursday, May 19, 2016
Design of Deliverable Macrocycles
Session 5 of the 2016 Drug Design and Delivery Symposium
Scott Lokey, Professor of Chemistry & Biochemistry, UC Santa Cruz
Nicholas Meanwell, Executive Director, Bristol-Myers Squibb
Thursday, June 9, 2016
Ice Cream Chemistry
Rich Hartel, Professor of Food Engineering, University of Wisconsin-Madison
Maya Warren, Food Scientist, Cold Stone Creamery
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Forensic Toxicology: Cracking the Case with Chemistry
Dr. Jason E. Schaff Darren Griffin
Forensic Chemist,
Professor of Genetics,
U.S. Government
University of Kent, UK
Slides available now! Recordings will be available to ACS members after one week
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Contact ACS Webinars at acswebinars@[Link] 11
UNCLASSIFIED
FORENSIC TOXICOLOGY:
CRACKING THE CASE WITH CHEMISTRY
Dr. Jason E. Schaff
Forensic Chemist
12 UNCLASSIFIED 05/12/2016
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•5/11/2016
UNCLASSIFIED
DISCLAIMER
All opinions expressed or implied herein
are those of the speaker. None of them
represent, in any way, official positions of
the of the United States Government or
any agency thereof.
13 UNCLASSIFIED 05/12/2016
UNCLASSIFIED
OUTLINE
• What is forensic toxicology?
• Pharmacokinetics / pharmacodynamics
• Analytical methods
• Interpretation of results
• Common drug classes
• Closing thoughts
• Questions
14 UNCLASSIFIED 05/12/2016
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UNCLASSIFIED
WHAT IS TOXICOLOGY?
• From [Link]:
• the science dealing with the effects … of poisons
• “Poison is in everything, and no thing is without poison.
The dosage makes it either a poison or a remedy.”
– Paracelsus
• Interface of pharmacology and analytical chemistry
15 UNCLASSIFIED 05/12/2016
UNCLASSIFIED
COMPLIANCE TESTING
SPECIMENS
• Most often urine
• Sometimes blood, sweat, CHALLENGES
hair, or oral fluid • Fast, cheap testing required
• Setting cutoff levels
• Variable urine density
WHAT IS THE QUESTION? – creatinine normalization
• Using something forbidden? • Conflicting regulations
• Not using something required? • People “beating the test”
16 UNCLASSIFIED 05/12/2016
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•5/11/2016
Audience Survey Question
ANSWER THE QUESTION ON BLUE SCREEN IN ONE MOMENT
Which specimen can be used to PROVE that a person is
intoxicated?
• Urine
• Hair
• Breath
• Blood
• All of the above
17
UNCLASSIFIED
DRIVING UNDER THE INFLUENCE
SPECIMENS
• Blood!!
– only way to prove intoxication CHALLENGES
• Breath (presumptive alcohol) • Accurate quantitation critical
• Urine (exposure only) • Specimen handling / storage
– especially for ethanol
WHAT IS THE QUESTION? • Interpretation absent per se
• Was a per se law violated? • Many specialized attorneys
• Potential impairment from
intoxication?
18 UNCLASSIFIED 05/12/2016
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UNCLASSIFIED
DRUG-FACILITATED ASSAULT
SPECIMENS
• Blood ideal, but often CHALLENGES
collected too late
•Extremely low LODs required
• Urine most common
•Huge (& weird) analyte list
• Hair increasingly useful
•Complex pharmacological
interpretation
WHAT IS THE QUESTION? •Educating contributors
• Was a person chemically
incapacitated?
• Possible chemical impairment of
short-term memory?
19 UNCLASSIFIED 05/12/2016
UNCLASSIFIED
POST-MORTEM TOXICOLOGY
SPECIMENS
• Everything but the kitchen sink!
CHALLENGES
• Blood, urine, bile, vitreous
• Huge target analyte list
humour, liver, brain, etc
• Huge range of concentrations
• Putrefaction
• Post-mortem redistribution
WHAT IS THE QUESTION?
• Pharmacological meaning
• Was there a chemical cause
of, or contribution to, death?
• Could insurance claims or
criminal charges be affected?
20 UNCLASSIFIED 05/12/2016
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UNCLASSIFIED
PHARMACOKINETICS (PK)
• What does the biological system do to the toxicant?
1st Order Kinetics
CONCENTRATION
– Adsorption Zero Order Kinetics
2 Compartment Model
(How does it get in?)
– Distribution
(Where does it go?) TIME
– Metabolism
(How does the system try to detoxify it?)
– Excretion
(How does the system get rid of it?)
21 UNCLASSIFIED 05/12/2016
UNCLASSIFIED
PHARMACODYNAMICS (PD)
• What does the toxicant do to the biological system?
• Desired Effects
– Treat disease or symptom
– Antidote to another toxicant
– Change in mental state
• Undesired Effects
– Damage to healthy tissue
– Functional impairment
– Change in mental state
22 UNCLASSIFIED 05/12/2016
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UNCLASSIFIED
PHARMACOGENOMICS
• How does an individual’s genetic profile affect PK and PD?
• e.g. metabolism of ethyl alcohol
– Ethanol + ADH Acetaldehyde (toxic)
– Acetaldehyde + ALDH Acetate (fuel)
– ALDH underproduction = “Asian flush” response to alcohol
23 UNCLASSIFIED 05/12/2016
Audience Survey Question
ANSWER THE QUESTION ON BLUE SCREEN IN ONE MOMENT
Which of the following analytical techniques is considered
a “rising star” in forensic toxicology?
• Immunoassay
• Gas Chromatography
• Liquid Chromatography
• Gas Chromatography Mass Spectrometry
• Liquid Chromatography Mass Spectrometry
24
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•5/11/2016
UNCLASSIFIED
ANALYTICAL TECHNIQUES
• IMMUNOASSAY
• Antibody binding test with colorometric detection
• Fast, cheap, simple, but very little specificity
GAS CHROMATOGRAPHY LIQUID CHROMATOGRAPHY
•Robust, mature technology •Works for almost all polar compounds
•Very high peak capacity •Tolerant of “dirty” samples
•Limited by analyte thermal •Problems with very non-polar
stability and volatility compounds
•GC-MS is a “Gold Standard” in •LC-MS is a “Rising Star” in forensic
forensic toxicology. toxicology.
25 UNCLASSIFIED 05/12/2016
UNCLASSIFIED
MASS SPECTROMETRY
• Only common detection technique providing unambiguous
identification
• Not a “magic bullet”; know the limitations
– Libraries suggest; standards confirm
– No identification without fragmentation
– Uniform procedures for data interpretation
– Similar spectra within compound classes
– At least two dimensions of overall data required
– High resolution ≠ accurate mass
26 UNCLASSIFIED 05/12/2016
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UNCLASSIFIED
INTERPRETATION
• What is the question?
• What is the scenario?
• Presence / Absence?
– Absence is usually definitive.
– Mere presence less so.
• Concentration
– Per se limits
– Therapeutic vs. toxic vs. fatal
– Measurement uncertainty
• Does the answer make sense?
27 UNCLASSIFIED 05/12/2016
UNCLASSIFIED
TOLERANCE
• Pharmacokinetic
– Increased enzyme activity due to toxicant exposure
– Higher dose needed to obtain a given concentration
• Pharmacodynamic
– Altered receptor / messenger activity due to exposure
– Higher concentration needed to obtain a given effect
• Dependence
– Special case of pharmacodynamic tolerance
– Toxicity or impairment from too low a level
28 UNCLASSIFIED 05/12/2016
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UNCLASSIFIED
DRUG-DRUG INTERACTION
• Pharmacokinetic
– Toxicant competition for available enzymes
– Increased enzyme activity from toxicant exposure
– Effects on renal clearance
• Pharmacodynamic
– (de)Sensitization of receptor systems
– Different receptor systems with the same gross effect
– Additive vs. synergistic vs. antagonistic
• Drug-Food Interactions
– e.g. grapefruit juice
29 UNCLASSIFIED 05/12/2016
UNCLASSIFIED
POST-MORTEM REDISTRIBUTION
• Chemical Potential Gradient
– Biological “pumping” stops
• Gravimetric Gradient
– Fluid redistribution
• Trauma
– Leakage from rupture of the diaphragm, bladder, or GI tract
• Effect Very Compound-Dependant
• Resistant Specimens
– Especially vitreous humour
• Great Care Interpreting Concentrations
30 UNCLASSIFIED 05/12/2016
•15
•5/11/2016
Audience Survey Question
ANSWER THE QUESTION ON BLUE SCREEN IN ONE MOMENT
Which of the following is considered the most common
illicit toxicant of forensic interest today?
• Ethanol like alcohol
• THC like marijuana
• Opioids like morphine
• Hypnotic-Sedatives like benzodiazepines
• Stimulants like cocaine
31
UNCLASSIFIED
ETHANOL
• Most Common Toxicant of Forensic Interest
• CNS Depressant
– No single neurotransmitter target
– Depresses higher functions before lower
– Euphoria / excitation at lower doses
– MANY drug-drug interactions
• Per Se Laws
– Based on studies of “average” population
– Back-extrapolation for determination of violation
• Determination of Impairment and Toxicity
– Complicated by very strong tolerance effects
32 UNCLASSIFIED 05/12/2016
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UNCLASSIFIED
THC
• Most Common Illicit Toxicant of Forensic Interest
• Extremely Lippophillic; Long Detection Half-Life
• Pharmacodynamics difficult to classify
– Cannabinoid-specific receptor systems (CNS and peripheral)
– Dosing rate and route of administration matter
– Hysteresis between effect and blood concentration
• “Synthetic Cannabinoids”
33 UNCLASSIFIED 05/12/2016
UNCLASSIFIED
OPIOIDS
• Clinically as Analgesics, Antitussives, Anesthetic
Aids
• Morphine and Derivatives
– From opium poppies; used for thousands of years
– Complex PK and PD; extensive interconversion
– Severe tolerance and dependence effects
• Synthetic Opioid Agonists
– Fentanyl, tramadol, methadone, etc.
• Opioid Antagonists
– e.g. naloxone; antidote for heroin overdose
34 UNCLASSIFIED 05/12/2016
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•5/11/2016
UNCLASSIFIED
HYPNOTIC-SEDATIVES
• CNS Depressants
– Sleep aids, antidepressants, anti-seizure, anesthetic aids
• Barbiturates (direct)
– No longer common (overdose risk and dependence)
• Benzodiazepines (indirect)
– Extremely common prescription drugs
– Complex metabolism and wide range of effects
• Common in Drug-Facilitated Assault
35 UNCLASSIFIED 05/12/2016
UNCLASSIFIED
STIMULANTS
• Cocaine
– Both enzymatic and non-enzymatic metabolism
– Strong tolerance effects
• Phenethylamines
– Wide range of chemical structures and additional effects
• Pure (almost) stimulant (methamphetamine)
• Decongestant (pseudoephedrine)
• ADHD treatment (methylphenidate)
• Halucinogens (MDMA / “ecstasy”, cathinones / “bath salts”)
36 UNCLASSIFIED 05/12/2016
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UNCLASSIFIED
CLOSING THOUGHTS
• Forensic toxicology operates at the interface of
pharmacology, and analytical chemistry.
• There are many subfields of forensic toxicology, each
with its own focus and requirements.
• The analytical tests must be tailored to answer the
relevant questions.
• Excellent analytical chemistry is no good if the results
aren’t interpreted carefully.
37 UNCLASSIFIED 05/12/2016
Forensic Toxicology: Cracking the Case with Chemistry
Dr. Jason E. Schaff Darren Griffin
Forensic Chemist,
Professor of Genetics,
U.S. Government
University of Kent, UK
Slides available now! Recordings will be available to ACS members after one week
[Link]/acswebinars
Contact ACS Webinars at acswebinars@[Link] 38
•19
•5/11/2016
®
Upcoming ACS Webinars
[Link]/acswebinars
Thursday, May 19, 2016
Design of Deliverable Macrocycles
Session 5 of the 2016 Drug Design and Delivery Symposium
Scott Lokey, Professor of Chemistry & Biochemistry, UC Santa Cruz
Nicholas Meanwell, Executive Director, Bristol-Myers Squibb
Thursday, June 9, 2016
Ice Cream Chemistry
Rich Hartel, Professor of Food Engineering, University of Wisconsin-Madison
Maya Warren, Food Scientist, Cold Stone Creamery
39
Contact ACS Webinars ® at acswebinars@[Link]
Forensic Toxicology: Cracking the Case with Chemistry
Dr. Jason E. Schaff Darren Griffin
Forensic Chemist,
Professor of Genetics,
U.S. Government
University of Kent, UK
Slides available now! Recordings will be available to ACS members after one week
[Link]/acswebinars
Contact ACS Webinars at acswebinars@[Link] 40
•20
•5/11/2016
®
How has ACS Webinars
benefited you?
“ACS Webinars provide great tangible
examples to share with my students. I am so
excited to have this applied case to describe
so that pKa can have real meaning for them,
great timing and great presentation.”
Quote in reference to: [Link]
Amy Naylor, N.D.
Biology & Chemistry Instructor
Mitchell Community College
41
Be a featured fan on an upcoming webinar! Write to us @ acswebinars@[Link]
[Link]/acswebinars
@acswebinars
[Link]/acswebinars
Search for “acswebinars” and connect!
42
•21
•5/11/2016
Benefits of ACS Membership
Chemical & Engineering News (C&EN)
The preeminent weekly news source.
NEW! Free Access to ACS Presentations on Demand®
ACS Member only access to over 1,000 presentation
recordings from recent ACS meetings and select events.
NEW! ACS Career Navigator
Your source for leadership development, professional
education, career services, and much more.
43
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®
ACS Webinars does not endorse any products or
services. The views expressed in this
presentation are those of the presenter and do
not necessarily reflect the views or policies of the
American Chemical Society.
Contact ACS Webinars ® at acswebinars@[Link] 44
•22
•5/11/2016
®
Upcoming ACS Webinars
[Link]/acswebinars
Thursday, May 19, 2016
Design of Deliverable Macrocycles
Session 5 of the 2016 Drug Design and Delivery Symposium
Scott Lokey, Professor of Chemistry & Biochemistry, UC Santa Cruz
Nicholas Meanwell, Executive Director, Bristol-Myers Squibb
Thursday, June 9, 2016
Ice Cream Chemistry
Rich Hartel, Professor of Food Engineering, University of Wisconsin-Madison
Maya Warren, Food Scientist, Cold Stone Creamery
45
Contact ACS Webinars ® at acswebinars@[Link]
•23
