By Kevin Shanks, D-ABFT-FT

Pharmacodynamics (PD) is the study of the effect of substances on the body.  The word is derived from Greek – Pharmakon and dynamikos which means “force” or “power”. PD includes concepts such as receptor affinity, receptor activity, and potency. 

“Whelp” by NoelMichelle. Licensed under CC BY-SA 4.0.

Receptor affinity is the measure of how well a substance binds to a receptor. As an example, let’s look at the opioids, morphine and fentanyl. Both substances bind to the mu (µ) opioid receptor. Morphine binds to the receptor with an affinity (Ki) equal to 1.8 nM, whereas fentanyl binds to the receptor with an affinity (Ki) equal to 0.39 nM. This essentially means that fentanyl has a 4-5 stronger hold at the receptor than morphine does. 

Once a substance binds to a receptor, it will produce a response or effect. A substance can bind to the receptor a produce an effect – this is called agonism. A substance can also bind to the receptor and block a response from occurring – this is called antagonism. A drug such as morphine or fentanyl binds to mu opioid receptors and acts as an agonist – it produces analgesia and central nervous system depression. Naloxone, on the other hand, is a receptor antagonist as it binds to mu opioid receptors and does not produce a biological response – it blocks other opioids from binding to the same receptors. 

Potency refers to the amount of a substance that is needed to produce a desired effect. To compare drug potencies, we look at the EC50, or the concentration of drug at which 50% of the maximum effect is achieved. When two substances are tested in the same person, the drug with the lower EC50 would be considered more potent. A lesser amount of a more potent drug is needed to achieve the same effect as a less potent drug. 

Within the study of the pharmacodynamics of drugs, we are also concerned with the route of administration, onset of action, and duration of action.  

The route of administration is the path by which a substance is taken into the body. Common routes of administration include oral (by mouth), dermal absorption, mouth inhalation, nasal inhalation, nasal insufflation, smoking, vaping, intravenous injection, intramuscular injection, intrathecal injection, sublingual absorption, buccal absorption, and rectal absorption. Tablets such as Xanax (alprazolam) and Vicodin (hydrocodone) are to be consumed orally. Cocaine can be nasally insufflated or snorted. Heroin may be injected intravenously. Methamphetamine may be smoked. Nicotine can be vaped. 

The onset of action of a drug is the amount of time it takes for a drug’s effects to occur after administration.  The onset is dependent on the route of administration, but there are other factors including drug formulation, dosage, and the individual consuming the substance. Substances that are orally consumed typically have an onset of action 30-90 minutes and those substances that are smoked or inhaled have onset of action typically within minutes. Substances that are injected directing into the blood stream have effects that occur within seconds to minutes of administration. As an example, when someone smokes or vapes cannabis, the effects normally occur within minutes, but when someone consumes a THC-infused edible foodstuff by mouth, the onset of action is normally 30-90 minutes after ingestion. 

The duration of action of a drug is the length of time that a substance is effective or how long effects are felt. As an example of duration, morphine’s effects are typically felt for 4-5 hours after administration, while fentanyl’s effects are felt for 1-2 hours after use. As with onset of action, the duration of action can also be influenced by route of administration and formulation of drug used. Substances such as Oxycontin (extended release oxycodone) will have a duration approximately 12 hours. 

The branch of pharmacology known as pharmacokinetics can help to answer questions such as ‘Are drugs involved in the incident?’ or ‘How much substance did a living individual consume?’ or ‘When was the substance taken?’, but the knowledge of pharmacodynamics can help to answer questions such as ‘During the incident, was an individual impaired?’ or ‘Was the person suffering from toxic drug effects?’ or “Did this substance play a role in the death of the individual?’.  

If you have any questions or concerns regarding the role of pharmacodynamics in your toxicology case, please reach out to our Axis Forensic Toxicology subject matter experts at [email protected]. 

References 

Guidelines for the Interpretation of Analytical Toxicology Results. Disposition of Toxic Drugs and Chemicals in Man. Twelfth Edition. Randall C. Baselt. Biomedical Publications. Pages xxx-xlii. (2020).  

Pharmacokinetics and Pharmacodynamics. Principles of Forensic Toxicology. Fourth Edition. Barry Levine. American Association for Clinical Chemistry (AACC). 2017. 77-93. 

Introduction to Forensic Toxicology. Clarke’s Analytical Forensic Toxicology. Sue Jickells and Adam Negrusz. Pharmaceutical Press. Pages 1-12. (2008).  

Postmortem Toxicology. Clarke’s Analytical Forensic Toxicology. Sue Jickells and Adam Negrusz. Pharmaceutical Press. Pages 191-218. (2008).  

Postmortem Forensic Toxicology. Principles of Forensic Toxicology. Fourth Edition. Barry Levine. AACC, Inc. Pages 3-14. (2017). 

By Kevin Shanks, D-ABFT-FT

Many forensic toxicology tests are qualitative and provide a positive-negative or present-not detected result. The interpretation of those results is relatively simple. A substance is there or it is not. But, a quantitative test with a numerical result must be put into context of the case to aid in determining its overall meaning. Is the concentration of drug measured significant to the investigation or is it an incidental finding? Forensic toxicologists do this by compiling reference ranges, or sets of blood, serum, or plasma drug or metabolite concentrations which are used as a baseline for interpretation of results.  

A therapeutic blood concentration is a concentration or level of drug or its active metabolite which is present in the blood, serum, or plasma following a therapeutically effective dosage. Most therapeutic ranges originate from data amassed during pharmaceutical medication clinical trials or controlled dosing studies. More often than not, the individuals tested to determine a therapeutic blood range consist of a healthy, non-disease stricken population. A toxic blood concentration is a concentration or level of drug or its active metabolite present in the blood, serum, or plasma that is associated with serious adverse or toxic symptoms. A lethal blood concentration is an amount of drug or its active metabolite present in the blood, serum, or plasma that has been reported to cause fatality, or is so far above reported therapeutic or toxic concentrations, that one may judge it might cause fatality. 

Test tubes and other recipients in chemistry lab by Horia Varlan (CC BY 2.0)

Any value given for a therapeutic, toxic, or lethal blood concentration is not considered absolute, but is to be used as a frame of reference or guideline in evaluating a specific case in its context. Blood concentrations can be affected by dose of the substance used, route of administration, drug absorption differences, age and sex of the individual, potential tolerance to the substance, underlying pathology or observed disease states, postmortem redistribution (PMR), substance protein binding, and the accumulation of active metabolites. 

Some substances have distinct therapeutic, toxic, and lethal blood reference ranges. This can be shown by looking at acetaminophen (Tylenol). Acetaminophen’s therapeutic reference range is 10-30 mcg/mL while it’s toxic and lethal reference ranges are greater than 150 mcg/mL. As you can see, there is a definite difference observed in the reference ranges. 

On the other hand, some substances have overlapping therapeutic, toxic, and lethal blood reference ranges. The reported therapeutic reference range for fentanyl in blood is 1-3 ng/mL. But toxicity may occur at blood concentrations lower than 3 ng/mL. People using fentanyl as a therapeutic medication under the supervision of a physician may also regularly have blood concentration exceeding 3 ng/mL. Another example of this overlap in therapeutic and toxic/lethal ranges is methadone. Acute oral therapeutic dosing of methadone in treatment settings has resulted in blood concentrations 75-860 ng/mL and chronic oral dosing of methadone in medical treatment settings has led to blood concentrations 570-1,006 ng/mL. But, blood concentrations found in the postmortem blood of people who have died from methadone toxicity were 20-5,300 ng/mL. 

There is no one size fits all type of reference range for forensic toxicology testing – the interpretation hinges on the context and circumstances of the case. Axis Forensic Toxicology understands that one should never practice toxicology strictly by the numbers and we are able to help with interpretation of the relevant toxicology in your casework.  

Axis is making changes to its final toxicology reports to align with and provide a single source of values for the reported reference ranges. If you have any questions or concerns regarding a substance’s reference range or its role in your medical-legal death investigation, please reach out to our subject matter experts at [email protected]. 

References 

Disposition of Toxic Drugs and Chemicals in Man. Twelfth Edition. Randall C. Baselt. Biomedical Publications. (2020).  

Pharmacokinetics and Pharmacodynamics. Principles of Forensic Toxicology. Fourth Edition. Barry Levine. American Association for Clinical Chemistry (AACC). 2017. 77-93. 

Introduction to Forensic Toxicology. Clarke’s Analytical Forensic Toxicology. Sue Jickells and Adam Negrusz. Pharmaceutical Press. Pages 1-12. (2008).  

Postmortem Toxicology. Clarke’s Analytical Forensic Toxicology. Sue Jickells and Adam Negrusz. Pharmaceutical Press. Pages 191-218. (2008).  

Postmortem Forensic Toxicology. Principles of Forensic Toxicology. Fourth Edition. Barry Levine. AACC, Inc. Pages 3-14. (2017). 

By Matt Zollman, Director of Operations and Product Management

From time to time, circumstances such as weather or pandemics can cause shipment delays.  Here are some Best Practices to keep in mind as you prepare and track your packages:

Submissions:

• Submit smaller, more frequent shipments. If delays do occur, smaller, more frequent shipments minimize the overall impact to your cases.
• Review your Axis Case Management Portal. Cases are posted to your Case Management Portal once they are logged into our system, where you have visibility into when they are received.
• Record your outbound tracking numbers. We’re not able to see all of them in the system and recording them on your end aids in troubleshooting delays.

Supplies:

• You should receive outbound notification. You should receive an e-mail notification when outbound supplies are ready to be sent. If you do not receive a notification in a timely manner after supplies are requested, please notify Axis.
• Please reach out if you do not receive your order. You should receive your shipment in a timely manner. If you do not, please notify Axis for quick resolution.

Axis is committed to providing the same level of service to which you have become accustomed and, to that end, will continue to communicate any additional delays. As always, if you have any questions about your cases or supplies, please reach out to [email protected] or [email protected].

We look forward to serving you.

By Kevin Shanks, D-ABFT-FT

Pharmacokinetics (PK) is the study of what the body does to a substance. The word is derived from Greek – Pharmakon which means “drug” and kinetikos which means “moving”. PK consists of four areas – absorption, distribution, metabolism, and excretion. This is also known as ADME.  

Instrumentation in the Drug Metabolism and Pharmacokinetics Lab  “Equipment used in the DMPK Lab” by NIH-NCATS is licensed under CC PDM 1.0.

Absorption (A) is the process by which substances enter the bloodstream. Substances can enter the bloodstream through a wide variety of routes, including oral (by mouth), inhalation (lungs), intravenous (injected into a vein), intramuscular (injected into muscle), rectal (suppository), oral mucosa (under the tongue), intrathecal (spinal fluid), dermal (skin), ocular (eye), and intranasal (nose).  

Distribution (D) refers to the transfer of a substance form one part of the body to another. When discussing PK, this usually refers to the movement of substance from the blood into the tissues of the body (liver, heart, kidney, brain, muscle, and fat). Some factors that influence distribution are lipophilicity, pH, and plasma protein binding. 

Metabolism of Heroin (Diacetylmorphine)  Chemical structures drawn by Kevin G. Shanks (2018)

Metabolism (M) is the process by which the substance is altered to facilitate the removal of it from the body. Most metabolism occurs in the liver, but it can also occur in the kidneys, lung, gastrointestinal tract, and blood.  Examples of metabolism include deacetylation (heroin to 6-acetylmorphine to morphine), nitro reduction (clonazepam to 7-aminoclonazepam), N-dealkylation (amitriptyline to nortriptyline), deamination (chlordiazepoxide to demoxepam to nordiazepam), and ester hydrolysis (cocaine to benzoylecgonine), as well as glucuronidation (oxazepam to oxazepam glucuronide), sulfate formation (morphine to morphine sulfate), and glycine conjugation (salicylate to salicyluric acid) 

Excretion (E) is the final removal of the substance or by products from the body. Excretion is most commonly done via the liver and kidneys, but can occur via the lungs, breast milk, feces, sweat, sebum, and semen. 

PK can help answer questions such as ‘Are drugs involved in this incident?’, ‘How much substance did a living individual consume?’, or ‘When was a substance taken by an individual?’.  

The larger question at hand in many cases regarding impairment, drug toxicity, or a substance’s role in cause of death involves a related area of pharmacology called pharmacodynamics (PD), which will be explored in a later blog post. 

If you have any questions or concerns regarding the role of pharmacokinetics in your toxicology case, please reach out to our Axis Forensic Toxicology subject matter experts at [email protected]. 

References 

Guidelines for the Interpretation of Analytical Toxicology Results. Disposition of Toxic Drugs and Chemicals in Man. Twelfth Edition. Randall C. Baselt. Biomedical Publications. Pages xxx-xlii. (2020).  

Pharmacokinetics and Pharmacodynamics. Principles of Forensic Toxicology. Fourth Edition. Barry Levine. American Association for Clinical Chemistry (AACC). 2017. 77-93. 

Introduction to Forensic Toxicology. Clarke’s Analytical Forensic Toxicology. Sue Jickells and Adam Negrusz. Pharmaceutical Press. Pages 1-12. (2008).  

Postmortem Toxicology. Clarke’s Analytical Forensic Toxicology. Sue Jickells and Adam Negrusz. Pharmaceutical Press. Pages 191-218. (2008).  

Postmortem Forensic Toxicology. Principles of Forensic Toxicology. Fourth Edition. Barry Levine. AACC, Inc. Pages 3-14. (2017). 

Alcohol, Drugs, and Driving. Clarke’s Analytical Forensic Toxicology. Sue Jickells and Adam Negrusz. Pharmaceutical Press. Pages 299-322. (2008).  

Human Performance Toxicology. Principles of Forensic Toxicology. Fourth Edition. Barry Levine. AACC, Inc. Pages 15-30. (2017).