Therapeutic Drug Monitoring (TDM) and Toxicology Introduction

Define the following terminology

• Toxicology

  • study of poisons, which are agents capable of producing morbid, noxious, or deadly effect

• Pharmacodynamics

  • interaction between a drug and its target cell or tissue

• Pharmacokinetics

  • movement of a drug through the body

• Steady State

  • to describe a predictable level of drug peaks and troughs in a patient's system

    • scheduled basis drug administration

• Half-life (t1/2)

  • the time required for the drug concentration in the blood to decline by one-half

• Therapeutic range

  • blood concentration of a drug that produces the desired medicinal effect while minimizing systemic toxic impact

• Peak and trough

  • the highest and lowest concentrations of a drug in a patient's bloodstream during a dosing cycle

• Poison

  • any agent capable of producing morbid, noxious, or deadly effects

• Effective Dose

  • amount of a substance required to produce a specific, desired effect

• Toxic Dose

  • amount of a substance that produces harmful or adverse effects in an individual

• Lethal Dose

  • specific amount of a substance that is capable of producing deadly effects in an individual

• Chain of custody

  • an essential component of the legal framework surrounding the handling and analysis of toxins

Discuss pharmacokinetics and the factors affecting drug absorption

The movement of drugs across cell membranes

• Absorption

• Distribution

• Metabolsim

• Excretion

Factors affecting

• Route of Administration

• First-Pass Metabolsim

• Physicochemical Properties

• Physiological Surface Factors

• Circulation

Define first-pass effect

Describes whether a drug is metabolized by the liver before it reaches its intended target site in the body

Understanding the first-pass effect is crucial for establishing dosage regimens

• Oral Ingestion

  • They are "first exposed" to hepatic metabolism, which can reduce the amount of active drug that eventually reaches the rest of the body

• Intravenous (IV) Injection

  • bypass the initial trip through the liver, they are not metabolized as quickly as orally administered drugs

Discuss factor influencing drug distribution in the body

The free fraction of a drug diffuses out of the vasculature and into the interstitial and intracellular spaces of various tissues

• only the unbound, or "free," form of a drug is biologically active and able to reach its target site

Explain basic metabolic processes or biotransformation of a drug within in the body

This process primarily occurs in the liver, though it also takes place in the GI tract, kidneys, and lungs

• Phase I

  • expose drug to organic functional groups

  • oxidation, reduction, or hydrolysis

  • Cytochrome P450

• Phase II (Conjugation)

  • a covalent bond is formed between the functional group added during Phase I and an endogenous chemical group

  • The primary goal of Phase II is to create a polar molecule that is inactivated and ready for excretion from the body

Explain the process of elimination and factors that influence the rate of elimination

pharmacokinetic process of removing a drug and its metabolites from the body

• Organ function

• Renal blood flow

• drug-drug interactions

• steady state dynamics

Identify the use of each of the following medications

Digoxin

Quinidine

Procainamide

Aminoglycosides

Vancomycin

Phenobarbital

Phenytoin

Valproic Acid/Depakene

Carbamazepine/Tegretol

Gabapentin

Lithium

Tricyclic antidepressants

Theophylline

Cyclosporine

Tacrolimus

Sirolimus

Cyclosporine

Methotrexate

List route of exposure and absorption of toxins

Exposure:

• Ingestion: Swallowing the substance

• Inhalation: Breathing the substance in

• Transdermal absorption: The substance is absorbed through the skin

• Injection: Toxins can also enter the body via intravenous (IV) injection

Absorption

The majority of toxins are absorbed into the bloodstream through passive diffusion, which involves the substance following a concentration gradient across cell membrane

List the three most frequent causes of toxic exposures

Intentional (suicide): Account for 50% of all exposures

Accidental: Account for 30% of all exposures

Homicide/Occupational exposure: Account for 20% of all exposures

State the lethal oral dose for the six ratings of toxicity

Super Toxic: Less than 5 mg/kg

Extremely Toxic: 5–50 mg/kg

Very Toxic: 50–500 mg/kg

Moderately Toxic: 0.5–5.0 g/kg

Slightly Toxic: 5–15 g/kg

Practically Nontoxic: Greater than 15 g/kg

Differentiate between acute and chronic toxicity

Acute Toxicity

• a single, short-term exposure to a substance

  . The hallmark of acute toxicity is that immediate toxic effects are observed following the exposure

Chronic Toxicity

• frequent re-exposure to a substance over extended periods of time

  . Unlike acute toxicity, the individual doses in chronic exposure do not cause an immediate response

  . Instead, damage or toxic effects accumulate over time.

State the medico-legal implications of toxicology testing and specimen collection requirements for blood alcohol determinations

• Chain of custody: A formal process must be in place to document the handling of the specimen from collection through analysis.

• Drug confirmation: All results must be confirmed using a specific reference method.

• No autoverification: Laboratory results in toxicology are not permitted to be automatically verified by computer systems.

• Specialized permitting: Confirmatory assays, which are highly specific and can separate metabolites from parent compounds, must be performed at facilities that hold a specialized forensic permit

• The phlebotomist must NOT use an alcohol-based cleaner to prepare the site for venipuncture.

• There must be clear documentation stating that a non-alcohol-based cleaner was used during the collection procedure

Convert between units of measure for blood alcohol levels.

Describe the differentiate screening and confirmatory testing methods used in toxicology

the analysis of agents is a two-step process consisting of a screening phase followed by a confirmatory phase

• Sensitivity and Specificity: These tests are highly sensitive (able to detect small amounts) but not specific.

• Methodology: Screening typically utilizes immunoassay or colorimetric methodology.

• Result Type: They are most often qualitative, providing a simple "Positive" or "Negative" result based on established cutoff values.

• Key Limitation: Because they lack specificity, there is a high chance for false positives because the test may react to drug metabolites rather than the parent compound itself

Confirmatory

• Specificity: These assays are highly specific and are often referred to as reference methods.

• Methodology: They utilize advanced techniques such as Gas Chromatography (GC), Mass Spectrometry (MS), or other chromatographic procedures.

• Capabilities: Unlike screening, confirmatory methods can separate metabolites from parent compounds, allowing for a precise identification of the substance.

• Result Type: Depending on the methodology used, these results can be quantitated (providing an exact numerical concentration).

• Regulatory Requirement: Due to their medico-legal implications, confirmatory assays must be performed at facilities that hold a specialized forensic permit

Describe the toxic impact of

Acetaminophen, Salicylate, Ethanol, Carbon Monoxide, amphetamines, barbiturates, benzodiazepines, cannabinoids, tricyclic antidepressants, and cocaine

Identify drugs that are classified as opiates or phencyclidines

opiates

• Opium

• Heroin (Diacetylmorphine)

• Morphine (Duramorph)

• Codeine

• Methadone (Dolophine, Amidone)

• Meperidine (Demerol, Pethidine)

• Propoxyphene (Darvon, Darvocet-N)

• Oxycodone (Oxycontin, Percocet)

• Hydrocodone (Vicodin, Lortab)

• Hydromorphone (Dilaudid)

Phencyclidine

• PCP

• LSD

Recall the following objectives from MLS 4625 related to Chromatographic techniques and Mass Spectroscopy:

Describe and differentiate the following chromatography techniques: Thin Layer Chromatography, Gas Chromatography

Identify the mobile phase and stationary phase of a given chromatographic system

Calculate retention factor for a substance eluted through a TLC procedure

Identify a substance using known retention factor/time data when given a case study

List the steps involved in mass spectroscopy

Define mass/charge ratio (m/z ratio) as it relates to mass spectroscopy

Identify a substance using known m/z ratio data when given a case studyy