TOXICOLOGY & TDM (CC LEC)

Toxicology

Study of the adverse effects of xenobiotics in humans.

Xenobiotics

Chemicals and drugs that are not normally found or produced in the body.

Mechanistic toxicology

Elucidates the cellular, molecular, and biochemical (adverse) effects of xenobiotics.

Descriptive toxicology

Uses the results from animal experiments to predict the level of exposure that will cause harm in human (risk assessment).

Regulatory toxicology

Concerned with the medicolegal consequences of exposure to chemicals or drugs.

Clinical toxicology

Study of interrelationships between xenobiotics and disease states.

Environmental toxicology

Evaluation of environmental chemical pollutants and their impact on human health.

Toxicant

Substance not produced within a living cell or microorganism.

Epidemiology

1. 50% of poisoning cases are suicide attempts (highest mortality rate). 2. 30% are accidental exposure (most frequent in children). Drug overdose in adolescents and adults. 3. Remaining cases are homicidal or occupational (industrial and agricultural) exposure.

Routes of Exposure

1. Ingestion 2. Inhalation 3. Transdermal

Factors that influence absorbance of toxins from the GI tract

1. pH 2. polarity 3. ionization 4. rate of dissolution 5. gastrointestinal motility 6. resistance to degradation 7. interaction with other substances.

Dose-response relationship

1. Poison - Any substance that can cause a harmful effect on exposure. 2. TD50 - Dose that would predict toxic response in 50% of the population.

Poisons

Toxins or toxicant that gets into the body via swallowing, inhaling or absorption.

Toxins

Substances that are biologically synthesized.

LD50

Dose that would predict death in 50% of the population.

ED50

Dose that would predict effective and therapeutic benefit in 50% of the population.

Therapeutic index

Ratio of the TD50 (or LD50) to the ED50.

Specimen of Choice

a. Urine - Random (screening & qualitative detection) - 24-hour b. Blood - Royal Blue top (for most elements) - Tan top (lead)

Individual dose-response relationship

Changes in health effects based on xenobiotic exposure levels.

Quantal dose-response relationships

Changes in health effects of a population based on xenobiotic exposure levels.

Acute Toxicity

Associated with a single short-term exposure to a substance sufficient to cause immediate toxicity.

Chronic Toxicity

Associated with a repeated frequent exposure for extended periods (>3 months), related to an accumulation of the toxicant.

Purpose of Analysis of Toxic Agents

To support the investigation of a known exposure (e.g. spill, suicide attempt).

Screening

Good analytic sensitivity but lack specificity. A negative result can rule out a drug/toxicant. A positive result is presumptive until confirmed by a more specific method.

Example of Screening Method

Tetrahydrocannabinol (THC) is detected using immunoassays, thin-layer chromatography (TLC), and gas chromatography (GC).

Reference Methods

Clinical Chemistry methods used for more specific analysis.

Alcohol

Alcohol dehydrogenase (ALD) is involved in the metabolism of alcohol.

Aldehyde

Aldehyde is analyzed using gas chromatography-mass spectrometry (GC-MS), inductively coupled plasma-mass spectrometry (ICP-MS), and atomic absorption (AA) method.

Symptoms of Alcohol Toxicity

Includes alcoholic hepatitis and cirrhosis.

Sources of Alcohol Exposure

Includes ingestion of liquors.

Ingestion

Routes of Alcohol Exposure

Acetaldehyde.

Metabolic Intermediate of Ethanol

Acetic Acid.

End Products of Ethanol Metabolism

Symptoms of Methanol Toxicity

Includes disorientation and unconsciousness.

Sources of Methanol Exposure

Includes commercial products and homemade liquors.

Ingestion.

Routes of Methanol Exposure

Symptoms of Isopropanol Toxicity

Includes disorientation and unconsciousness.

Sources of Isopropanol Exposure

Includes rubbing alcohol.

Ingestion.

Routes of Isopropanol Exposure

Symptoms of Ethylene Glycol Toxicity

Includes tubular damage and metabolic acidosis.

Sources of Ethylene Glycol Exposure

Includes hydraulic fluid and antifreeze.

Ingestion.

Routes of Ethylene Glycol Exposure

Symptoms of Carbon Monoxide Toxicity

Includes hypoxia (brain and heart) and respiratory depression.

Sources of Carbon Monoxide Exposure

Includes gasoline engines and wood & plastic fires.

Routes of Carbon Monoxide Exposure

Inhalation.

Symptoms of Arsenic Toxicity

Includes non-specific symptoms affecting CNS, renal, and vascular systems.

Sources of Arsenic Exposure

Includes homicide & suicide agent, natural and manmade sources, and occupational exposure.

Routes of Arsenic Exposure

Inhalation and ingestion (water).

Symptoms of Cadmium Toxicity

Includes Itai-itai disease (contaminated rice).

Sources of Cadmium Exposure

Includes mining and industrial processes (electroplating, galvanizing).

Symptoms of Lead Toxicity

Includes tubular dysfunction, basophilic stippling, decreased IQ, and nerve conduction issues.

Sources of Lead Exposure

Includes household paints, gasoline, and pipes.

Symptoms of Mercury Toxicity

Includes bloody diarrhea, hypotension, bradycardia, and renal dysfunction.

Sources of Mercury Exposure

Includes occupational exposure to insecticides and herbicides.

Symptoms of Organophosphate Toxicity

Includes bradycardia, muscular twitching, cramps, and respiratory failure.

Screening for Organophosphate Toxicity

Includes tests for acetylcholinesterase and pseudocholinesterase.

Aspirin

Analgesic, Antipyretic, Anti-inflammatory.

Chromogenic assay

(Trinder's rxn.) spectrophotometer.

Interference with platelet aggregation

Reye's syndrome, Metabolic acidosis (lactic & ketone bodies).

HPLC

High-Performance Liquid Chromatography.

Immunoassay

A biochemical test that measures the presence or concentration of a substance through the use of an antibody.

Salicylate + ferric nitrate

Colored product.

Acetaminophen

Analgesic; Hepatotoxic (liver necrosis).

Glutathione

Eliminated by the liver through conjugation of reactive intermediates (free radicals).

Drugs of Abuse

Substances that are used for non-medical purposes.

Route of Administration

(usage) method by which a drug is delivered to the body.

Amphetamines

Ingestion treats narcolepsy, attention-deficit disorder.

Desired and/or adverse effects of Amphetamines

Ý mental, physical capacity; irritability, psychosis, hypertension, arrythmias.

Methylenedioxy-methamphetamine

Chemically related to OTC medications, ephedrine, and phenylpropanolamine.

Cannabinoids

Found in marijuana.

Cocaine 'crack'

Insufflations, IV injection, Smoking, inhalation (local anesthetic).

Treatment for overdose of Cocaine

Naloxone.

Opiates

Naturally occurring (opium, morphine, codeine), Chemically modified (heroin), Synthetic (fentanyl).

Phencyclidine (PCP)

Ingestion, inhalation of PCP laced tobacco or marijuana (anesthetic).

Barbiturates

(phenobarbital) sedatives.

Benzodiazepines

(Diazepam - Valium, Lorazepam - Ativan).

Therapeutic Drug Monitoring

Involves measuring and monitoring circulating drug levels in serum, plasma, or whole blood.

Factors that may alter absorption

Changes in intestinal motility, pH, and presence of food or other drugs.

Drug distribution

Free fraction of circulating drugs is subject to diffusion out of the vasculature into interstitial & intracellular spaces.

Absorption

The efficiency of absorption of orally administered drugs is dependent on dissociation from its administered form, solubility in gastrointestinal fluids, and diffusion across gastrointestinal membranes.

Hydrophobic (non-polar) drugs

Transverse cell membranes and partition into lipid compartments (e.g. adipose & nerve cells).

Hydrophilic (polar) drugs

May transverse cell membranes but do not partition into lipid compartments.

Vd values

Has small Vd values due to sequestration in the vasculature.

First pass metabolism

All substances absorbed from the intestine enter the hepatic portal system before it enters the circulation.

Free drugs

It is the active (free) fraction that can result in a biologic response.

Serum fraction of free drug

May also be influenced by changes in serum-binding proteins.

Liver metabolism variability

Liver metabolism may vary in every patient as influenced by genetic variation and disease.

Toxic adverse effects

May occur when total serum content is within the therapeutic range but the patient experiences high free fraction.

Absence of therapeutic effects

May occur when total serum content is within the therapeutic range but the patient experiences low free fraction.

Phase I reactions

Produce reactive intermediates.

Phase II reactions

Conjugate parent drug or its metabolites to functional groups.

Glomerular filtration rate (GFR)

GFR directly influences serum half-life and concentration.

Drug elimination rate

For drugs not secreted or reabsorbed, the elimination rate directly relates to the GFR.

Change in concentration (AC)

AC per unit time (AT) is directly related to the concentration of drug (C) and the elimination constant (k).

Pharmacokinetics

The activity of a drug(s) in the body as influenced by absorption, distribution, metabolism and excretion.

Nonresponders

Patients that do not demonstrate the desired therapeutic effect of the drug.

Cytochrome P450 (CYP450) family

The most prominent gene family that affects drug metabolism.

Pharmacogenetic CYP450 profiling

Can be used to personalize drug doses and predict drug-drug interactions.

Multiple-dosage regimen

Most drugs are delivered on a regimen until the serum concentration oscillates between a maximum (peak drug level) and a minimum (trough drug level).

Trough concentrations

Drawn right before the next dose to evaluate established concentrations.