Toxicology Terms And Concepts

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Toxicology

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The study of the adverse effects of chemical or physical agents on living organisms.

Alternate: the study of poisons

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Toxicologist

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Person trained to examine and communicate the nature of toxicological effects on human, animal, and environmental health

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Mechanistic toxicologist

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Individual concerned with identifying and understanding the cellular, biochemical, and molecular mechanisms by which chemicals exert toxic effects on living organisms

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Descriptive toxicologist

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Individual concerned directly with toxicity testing, which provides information for safety evaluation and regulatory requirements

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Regulatory toxicologist

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Individual responsible for deciding, on the basis of data provided by descriptive and mechanistic toxicologists, whether a drug or chemical poses a sufficiently low risk to be marketed for a stated purpose or subsequent human or environmental exposure resulting from its use.

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Forensic toxicology

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A hybrid of analytical chemistry and fundamental toxicological principles concerned primarily with the medicolegal aspects of the harmful effects of chemicals on humans and animals.

Alternate: application of toxicology to the chemical analysis of material, usually human body fluids and/or tissues, the results of which are intended to be introduced as evidence in documents or legal proceedings

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Clinical toxicology

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An area of professional emphasis in the realm of medical science that is concerned with disease caused by or uniquely associated with toxic substances.

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Environmental toxicology

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Focuses on the impacts of chemical pollutants in the environment on biological organisms.

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Ecotoxicology

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Specialized area within environmental toxicology that focuses more specifically on the impacts of toxic substances on population dynamics in an ecosystem.

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Poison

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Any substance which, when introduced into the body by any method, occasions disease or death; and this as an ordinary result, in a state of health, and not by a mechanical action.

Usually associated with a substance that kills by rapid action even in a small quantity.

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Toxin

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Toxic substances that are produced by biological systems such as plants, animals, fungi or bacteria.

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Toxicant

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Used in speaking of toxic substances that are produced by or are a by-product of anthropogenic (human made) activities.

Alternate: any poisonous agent, an alcohol or other poison, causing symptoms of what is popularly called intoxication.

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Chemical allergy

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An immunologically mediated adverse reaction to a chemical resulting from previous sensitization to that chemical or to a structurally similar one. Manifested only after a second or subsequent exposure-drug.

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Hapten

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A molecule that must combine with an endogenous protein to elicit an allergic reaction.

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Chemical idiosyncrasy

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Genetically determined abnormal reactivity to a chemical.

Extreme sensitivity to low doses or extreme insensitivity to high doses of the chemical.

Unusual or unexpected responses to drugs.

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Local effect

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Effects that occur at the site of the first contact between the biological system and the toxicant.

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Systemic effect

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Effects that require absorption and distribution of a toxicant from its entry point to a distant site at which deleterious effects are produced.

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Target organs

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Target organ of toxicity most frequently involved in systemic toxicity is the CNS (brain and spinal cord).

Muscle and bone are least often the target tissues for systemic effects.

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Intoxicant

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Synonymous with poison, usually as an inorganic chemical or synthetic chemical.

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Examples of deadly toxins

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Bacillus anthracis (Anthrax)

Clostridium botullinum (Botulism)

Corynebacterium diptheriae (Diphtheria)

Shellfish (Saxitoxin)

Clostridium tetani (Tetanus)

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Venom

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Poisonous animal secretions forming fluid mixtures of many different enzymes, toxins and other substances.

Produced in specialized glands

Actively delivered through specialized delivery systems (fangs, stingers, etc.)

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Acute toxicity

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The effects of a single dose/multiple dose exposure during 24 hour period.

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Sub-acute toxicity

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The effects of multiple doses exposure during 14 day period.

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Sub-chronic toxicity

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The effects of multiple doses exposure during 90 day period.

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Chronic toxicity

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The effects of multiple doses during more than 90 days. Two years in rodents; one year in non-rodents.

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Carcinogenicity

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Process involving chemicals that induces neoplasms that are:

-Usually not observed

-The earlier induction of neoplasms than are commonly observed

-and/or the induction of more neoplasms that are usually found

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Carcinogen

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Chemical that induces neoplasm

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Neoplasm

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TBD

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Mutagenicity

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Mutations are heritable changes produced in the genetic information stored in the DNA of living cells

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Mutagenesis

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The process of causing mutations

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Mutagens

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Chemicals capable of causing mutations

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Teratogenicity/Teratogenesis

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The production of defects in the reproductive process resulting in either reduced productivity due to fetal or embryonic mortality or the birth of offspring with physical, mental, behavioral, or developmental defects

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Teratogen

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Compounds causing reproductive (birth) defects

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Relative toxicity: Extremely toxic

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<1 mg/Kg

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Relative toxicity: Highly toxic

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1-50 mg/Kg

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Relative toxicity: Moderately toxic

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50-500 mg/Kg

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Relative toxicity: Slightly toxic

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0.5-5 g/Kg

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Relative toxicity: Practically non-toxic

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5-15 g/Kg

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Relative toxicity: Relatively harmless

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>15 g/Kg

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Potency

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Sensitivity of an organ or tissues to a drug; measure of a dose

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Efficacy

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The maximum effect of a drug; measure of quantified drug response

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Drug tolerance

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After chronic use, the same amount of drug is insufficient to cause the desired effect, thus more drug is needed to produce the desired effect.

A compensatory response.

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Normal value

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Concentration of a substance found in the general population that has no toxic effects

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Therapeutic value

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Concentration of a drug sufficient to treat a medical disorder and not cause toxicity.

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Toxic value

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Concentration of a chemical associated with harmful effects that may or may not be life threatening.

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Lethal value

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Concentration of an intoxicant that is consistent with death.

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Peak value

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Concentration of a drug obtained following a single dose.

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Steady state value

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Concentration of a drug obtained with continuous administration sufficient to treat a medical disorder and not cause toxicity.

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Bioavailability

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The fraction of the administered dose reaching the systemic circulation.

i.e.: IV delivered = 100%

non-IV ranges from 0 to 100%

i.e.: lidocaine oral bioavailability 35% due to destruction in gastric acid and liver metabolism

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Apparent volume of distribution (Vd)

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Vd = Dose/C

or

Vd = Amount of drug in body/Concentration in plasma

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Clearance

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Volume of plasma cleared of drug per unit time

Clearance = rate of elimination/plasma concentration

Used to determine IV infusion rates

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Multiple dosing

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Continuous steady administration of a drug; plasma concentration rises fast at first then more slowly to reach a plateau where:

rate of administration = rate of elimination

Steady state is then achieved

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Reference material

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A substance with one or more properties of which are established sufficiently well enough to be used for a calibration apparatus, assessing a measurement or assigning values to a material.

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Certified reference material

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A reference material, with one or more property values that are certified by a valid procedure, or accompanied by or traceable to a certificate or other documentation which is issued for a certifying body.

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Calibrators

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Prepared from reference material or purchased, are used to calibrate an assay.

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Additive effect

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Occurs when the combined effect of two chemicals is equal to the sum of effects of each agent given alone (2 + 3 =5)

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Synergistic effect

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Occurs when the combined effects of two chemicals are much greater than the sum of the effects of each agent given alone (2 + 2 = 20)

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Potentiation

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Occurs when one substance does not have a toxic effect on a certain organ or system but when added to another chemical makes that chemical much more toxic (0 + 2 = 10)

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Antagonism

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Occurs when two chemicals administered together interfere with each other's actions or one interferes with the action of the other (4 + 6 =8); (4 + (-4) = 0); (4 + 0 =1)

Antagonists are very desirable in toxicology and are often the basis of antidotes.

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Functional antagonism

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When two chemicals counterbalance each other by producing opposite effects on the same physiologic function

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Chemical antagonism/inactivation

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A chemical reaction between two compounds that produces a less toxic product.

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Dispositional antagonism

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When the disposition (absorption, distribution, biotransformation, or excretion) of a chemical is altered so that the concentration and/or duration of the chemical at the target organ are diminished.

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Receptor antagonism

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Occurs when two chemicals that bind to the same receptor produce less of an effect when given together than the addition of their separate effects. (4 + 6 = 8) or when one chemical antagonizes the effect of the second chemical. Often referred to as blockers.

Advantageous in the clinical treatment of poisons. (i.e. naloxone to treat the respiratory depressive effects of morphine)

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Tolerance

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State of decreased responsiveness to a toxic effect of a chemical resulting from prior exposure to that chemical or structurally related chemical.

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Major routes/pathways

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1) Gastrointestinal (ingestion)

2) Lungs (inhalation)

3) Skin (topical, percutaneous, dermal)

4) Parenteral (other than intestinal)

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Dose-response relationship

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The characteristics of exposure and the spectrum of toxic effects that come together in a correlative relationship

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Threshold dose

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The minimally effective dose of any chemical that evokes a stated "all or none" response

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Allometry

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The field of study that examines the relationships between body weight and other biological and physical parameters

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Therapeutic index (TI)

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The ratio of the dose required to produce a toxic effect and the dose needed to elicit the desired therapeutic response

TI = TD50/ED50

TD= toxic dose

ED=effective dose

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Selective toxicity

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Chemical that produces injury to one kind of living matter without harming another form of life even though the two may exist in intimate contact

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Ultimate toxicant

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Chemical species that reacts with the endogenous target molecule (e.g. receptor, enzyme, DNA, lipid, etc.)

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Toxication/Metabolic activation

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Biotransformation to harmful products (formation of a toxic metabolite)

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Modes of toxication

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1) Conversion into electrophiles

2) Conversion into free radicals

3) Conversion into nucleophiles

4) Conversion into redox-active reactants

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Stages in the development of toxicity after chemical exposure

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1) Delivery of toxicant

2) Interaction with target molecule/alteration of biological environment

3) Cellular dysfunction, injury

4) Inappropriate repair and adaptation

5) Toxicity

*Toxicity can occur after step 3 as well as step 4

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Apoptosis

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Programmed cell death

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Absorption

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The process by which toxicants cross body membranes and enter the bloodstream.

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Distribution

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The process by which a toxicant is distributed to tissues throughout the body after after absorption into the bloodstream.

Rate of distribution to organs or tissues is determined primarily by blood flow and the rate of diffusion out of the capillary bed into the cells of a particular organ or tissue.

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Volume of distribution (Vd)

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The volume in which the amount of drug would need to be uniformly dissolved in order to produce the observed blood concentration.

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Excretion

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The elimination of toxicants from the body. The kidney is the most important organ for excretion of xenobiotics. The main principle is the biotransformation to more water-soluble products as a prerequisite to excretion through urine.

Other routes of excretion are through the feces (biliary), and lungs (for gases).

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Other modes of elimination

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Cerebospinal fluid

Milk

Sweat and saliva

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Xenobiotic biotransformation

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A series of enzyme-catalyzed processes that alters the physiochemical properties of foreign chemical (xenobiotics) from those that favor absorption across biological membranes (namely, lipophilicity) to those favoring elimination in urine or bile (namely, hydrophilicity).

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Four categories of xenobiotic catalysis reactions

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1) Hydrolysis (e.g. carboxylesterase)

2) Reduction (e.g. carbonyl reductase)

3) Oxidation (e.g. cytochrome P450)

4) Conjugation (e.g. UDP-glucuronsyltransferase)

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Phase I reactions

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1) Hydrolysis

2) Reduction

3) Oxidation

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Phase II reaction

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Conjugation

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Major hydrolytic enzymes

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1) Carboxylesterases (serine esterase)

2) Cholinesterases (serine esterase)

3) Paraoxonases (Lactonases)

Major but not the only types of hydrolytic enzymes

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Examples of drugs metabolized by hydrolysis

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TBD

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Examples of drugs metabolized by reduction

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TBD

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Examples of drugs metabolized by oxidation

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TBD

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Examples of drugs metabolized by conjugation

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TBD

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Types of conjugation reactions

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1) Glucuronidation

2) Sulfonation (sulfation)

3) Acetylation

4) Methylation

5) Conjugation with glutathione (mercapturic acid synthesis)

6) Conjugation with amino acids

7) Thiosulfate sulfurtransferase

8) Phosphorylation

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Toxicokinetics

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The quantitative study of the movement of an exogenous chemical from its entry into the body, through its distribution to organs and tissues via the blood circulation, and to its final disposition by way of biotransformation and excretion.

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Classic toxicokinetic model

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Typically consists of a central compartment representing blood and tissues that the toxicant has ready access to, along with one or more peripheral compartments that represent tissues in slow equilibration with the blood.

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One-compartment toxicokinetic model

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Quantification of the blood or more commonly plasma concentrations of a toxicant at several time points after a bolus IV injection.

The data often falls on a straight line.

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First order kinetics

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Occur at toxicant concentrations that are not sufficiently high to saturate either metabolic or transport processes.

Rate of elimination at any time is proportional to the amount of toxicant remaining in the body at that time.

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Two-compartment toxicokinetic model

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After rapid IV administration of some toxicants, the semi-logarithmic plot of plasma concentration versus time does not yield a straight line; but a curve implies more than one dispositional phase.

Time is required for the toxicant to be taken up into certain tissue groupings, and to then reach an equilibration with the concentration in the plasma; hence a multi-compartment model.

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Compartment

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A definable anatomical site or tissue type in the body that acts as a unit in effecting a measurable kinetic process.

e.g. functional portion of an organ, segment of blood vessel with surrounding tissue, an entire organ such as the liver, or a widely distributed tissue type such as fat or skin.

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Genetic toxicology

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Field of toxicology that assesses the effects of chemical and physical agents on the hereditary material (DNA) and on the genetic processes of living cells.

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Developmental toxicology

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The study of pharmacokinetics, mechanisms, pathogenesis, and outcome following exposure to agents or conditions potentially leading to abnormal development.

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Hematotoxicology

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Study of the adverse effects of drugs, non-therapeutic chemicals and other agents in our environment on blood and blood-forming tissues.

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Mechanisms/Types of toxin-induced liver injury

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1) Cell death

2) Canalicular cholestasis

3) Bile duct damage

4) Sinusoidal damage

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Necrosis

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Form of cell dying that is characterized by cell swelling, leakage of cellular components, nuclear disintegration (karyolysis) and an influx of inflammatory cells.

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Types of pesticides

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1) Insecticides

2) Herbicides

3) Fungicides

4) Rodenticides

5) Fumigants

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Three major subfields of forensic toxicology

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1) Postmortem forensic toxicology

2) Human performance toxicology

3) Forensic drug testing

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Human performance toxicology

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Also known as behavioral toxicology, relies on the toxicologist elucidate and quantify the dose-effect relationship between drugs that elicit behavioral changes and those changes.

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DUI arrest decision process (3 steps)

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1) Initial observation of the vehicle in motion and how the driver stops the vehicle

2) Officer's first contact with the driver

3) After the driver exits the vehicle and the administration of psychomotor tests/PAS.

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Walk and turn clues and failure criteria

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1) Can't maintain balance during instructions

2) Starts test too soon

3) Stops while walking

4) Does not touch heel to toe

5) Steps off line

6) Uses arms to balance

7) Loses balance on turn/incorrect turn

8) Incorrect number of steps

9) Cannot do test

2 or more clues or inability to complete test, probability is 68% that the suspect's BAC> 0.10%

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One leg stand clues and failure criteria

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1) Puts foot down

2) Uses arms to balance

3) Sways while balancing

4) Hops

5) Cannot do test

2 or more clues or the inability to perform the test, 65% probability BAC >0.10%

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HGN clues and failure criteria

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Six clues total (3 per eye)

1) Lack of smooth pursuit

2) Nystagmus at maximum deviation

3) Onset of nystagmus prior to 45 degrees

4 or more clues, 77% probability BAC >0.10%

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12 steps of the DRE exam

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1) Breath alcohol test

2) Interview of the arresting officer

3) Preliminary exam of the suspect

4) Examination of the eyes

5) Divided-attention psychophysical tests (FST's)

6) Vital signs

7) Dark room examination

8) Examination of muscle tone

9) Examination for injection sites

10) Suspect's statements and other observations

11) Opinion of the evaluator

12) Toxicological examination

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%CV

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Measure of precision

%CV= (Standard deviation/Mean) x 100

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Generally accepted accuracy range in forensic urine drug testing

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+/- 20%

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Generally accepted %CV values in forensic urine drug testing

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<15%

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Limit of detection (LOD)

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The lowest concentration of drug that produces a detectable response

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Limit of quantitation (LOQ)

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The lowest concentration of analyte that can be accurately and precisely measured

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Specificity

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The ability of the method the measure an analyte in the presence of all potential analytes

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Carryover

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Contamination of a sample by the preceding sample

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Compounds used to adulterate urine samples

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Alcohol, ammonia, ascorbic acid, Visine, lemon juice, salt, peroxide, vinegar, detergent, golden seal root, bleach.

Adulterants may affect urine pH, specific gravity and chloride levels.

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Passive diffusion

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The movement of a substance from an area of high concentration to an area of low concentration.

Initially at the site of absorption, no drug is present in the blood proximal to that site. The the drug will diffuse from the site into the blood.

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Facilitated diffusion

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Diffusion that occurs with the assistance of membrane proteins along a concentration gradient.

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Factors affecting drug bioavailability

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1) Solubility

2) Concentration

3) Surface area

4) Blood supply

5) pH

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Phase I metabolism

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Reactions characterized by enzymatic transformation of functional groups.

Most widely studied group of enzymes are the cytochrome P450 mono-oxygenases which exist in several forms called isozymes.

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Examples of Phase I metabolism

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N-dealkylation--amitriptyline

O-dealkylation--codeine

Desulfuration--parathion

Sulfoxide formation--cimetidine

Ester hydrolysis--cocaine

Amide hydrolysis-lidocaine

Deacylation--heroin

Aliphatic hydroxylation--pentobarbital

Aromatic hydroxylation--propranolol

Deamination--chlordiazepoxide

Nitro reduction--flunitrazepam

N-oxide formation--atropine

Epoxide formation--carbamazepine

Reduction--chloral hydrate

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Enzyme induction

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Occurs when a xenobiotic increases the metabolic activity of an enzyme. Can potentially reduce the efficacy of a drug.

Examples: barbiturates, antiepileptics, rifampin.

Example: taking carbamazepine concurrently with haloperidol or birth control pills increases metabolism of those drugs, thereby reducing the efficacy.

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Enzyme inhibition

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Occurs when a xenobiotic binds to an enzyme decreasing its activity.

Usually results from a competition for the active site between the drug and the inhibitor.

Decreases the ability of a Phase I metabolic enzyme to function by assisting with the metabolism of a particular drug. Can lead to accumulation of a drug in the body.

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Types of hydrolytic enzymes

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1) Cholinesterase

2) Acetylcholinesterase: also known as true or red blood cell cholinesterase, found in erythrocytes, lung, spleen, nerve endings and gray matter. Hydrolyzes acetylcholine and acetylbetamethylcholine

3) Pseudocholinesterase: produced in the liver, but also located in the plasma, heart, pancreas, and white matter. Lacks the substrate specificity of acetylcholinesterase. Hydrolyzes acetylcholine, butrylcholine and benzoylcholine.

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Phase II metabolism

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Conjugation reactions that involve the derivitization of a drug or Phase I metabolite with an endogenous substance.

The main purpose is to increase the water solubility of compounds to facilitate elimination.

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First pass effect

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For orally administered drugs; enzymes in the GI tract can metabolize drugs before they enter the bloodstream.

Drugs with a significant first-pass effect may require administration by other routes.

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Excretion

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The final removal of xenobiotics or their byproducts from the body. Most common route is through the kidneys.

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Types of excretion

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1) Hepatic (liver)

2) Renal (kidneys)

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Factors affecting hepatic excretion

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-Blood flow to the liver, affected by physiological, pathological and pharmacological factors.

-Ability of the liver to remove or extract the drug from the blood.

-Measurement of drugs/metabolites in feces may indicate poor absorption rather than hepatic excretion.

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Enterohepatic circulation

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Drugs/byproducts excreted into the bile that then enters the intestine and is re-absorbed into the blood. Subsequent elimination by the kidney may occur.

May account for an increase in the time it takes to clear a drug from the body.

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Chemicals used in protein precipitation extractions

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-Organic solvents (acetone, ACN, MeOH)

-Zinc sulfate in MeOH

-5-sulfosalicylic acid

-Perchloric acid

-Trichloroacetic acid

-Sodium tungstate

-Ammonium sulfate

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Examples of strongly acidic drugs

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-Salicylic acid

-Phenylbutazone

-2,4-Dinitrophenol

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Examples of weakly acidic drugs

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-Acetaminophen

-Phenobarbital

-Chlorothiazide

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Examples of amphoteric basic drugs

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-Morphine

-Gabapentin

-Benzoylecgonine

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Examples of strongly basic drugs

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-Amphetamine

-Chlorcyclizine

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Sedative-hypnotic toxidromes

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-Hypothermia

-Bradypnea or hypopnea

-Lethargy

-Stupor, obtundation

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Sympathomimetic toxidromes

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-Hyperthermia

-Tachycardia

-Hypertension

-Agitation, delirium, seizures

-Mydriasis

-Diaphoresis

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Steps for the treatment of poisons

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-Prevent poison absorption

-Hasten poison elimination

-Administration of specific antidotes

-Supportive therapy

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Prevention of poison absorption

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-Protect the airway

-Activated charcoal

-Specific gastric lavage solutions

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Methods to hasten elimination in poisoning

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-Biliary excretion (prevents entrahepatic redistribution)

-Urinary excretion (diuresis, ion trapping)

-Dialysis

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Dialysis indications for poisoning

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-Immediately for methanol or ethylene glycol

-Dependent on serum concentrations (barbs, theophylline, salicylates)

-Key indicators of additional use (renal failure, CNS disturbances, worsening overall condition)

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Dialysis methods

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-Peritoneal

-Hemodialysis

-Hemoperfusion

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Classic poisons and antidotes

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Arsenic--BAL

Carbon monoxide--Oxygen

Cyanide--Nitrites/thiosulfate

Ethylene glycol--Ethanol/fomepizole

Iron--Desferoxamine

Lead--Succimer

Methanol--Ethanol

Organophosphate pesticides-Atropine/PAM

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Chelating agents that are poison antidotes

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-BAL

-DMPS

-DMSA (succimer)

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Target organs of lead toxicity

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-Hematopoietic system

-Central and peripheral nervous system

-Kidneys

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Pathophysiology of CO poisoning

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-Tissue hypoxia from binding to hemoglobin molecule

-Binding to cytochrome oxidase, myoglobin and other hemoproteins inhibits utilization of oxygen

-Acute mortality due to ventricular dysrhythmias from hypoxic stress

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Toxidromes of CO

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-Neurologic impairment (seizure, confusion)

-Systemic impairment (dysrhythmias, metabolic acidosis)

-%HbCO values: 25% or 15% in pregnant women

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Carboxyhemoglobin Levels vs Symptoms

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<10%--Asymptomatic, headache

10-20%--Headache, nausea, dizziness, tachycardia

20-30%--Vomiting, fatigue, fainting, chest pain, blurred vision, weakness, tachycardia, dyspnea, ataxia

40-50%--Seizures, coma, hypotension, myocardial ischemia, pulmonary edema

>50%--death

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CO Pharmacokinetics

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-Hb affinity 200-300 times > than oxygen

-HbCO doesn't carry O2 or CO2

-HbCO = %CO (air) x kT

Where k=min vol factor, 0.018 at 6L/min

T=duration of exposure in hours

-HbCO formation constant at minute volume up to 20L

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CO elimination and treatment

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-99% elimination by lungs

-1% oxidized to CO2

-Room air (t 1/2=320 min)

-Treatment with 100% O2 (t 1/2=80 min)

-Hypobaric O2 @ 2-3 atm (t 1/2=20 min)

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Properties of hydrogen cyanide (HCN) gas

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-HCN can be fatal at low levels of 150-200 ppm (50-100 mg)

-Easily absorbed through the skin, lungs and GI tract (workplace PEL = 4.7 ppm)

-Concentration >50 ppm considered life threatening

-Urinary excretion of CN and CNS

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Mechanisms of toxicity of CN

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-Combines with ferric ion Fe3+ cytochrome oxidase to inhibit cellular respiration

-Cells can't use oxygen from the blood producing cytotoxic anoxia

-Cytochrome oxidase present in most cells, therefore many organs are simultaneously affected (sudden death, heart, brain/brain stem)

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Treatment of cyanide poisoning

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-Admin of amyl nitrite ampules and/or sodium nitrite IV

-Sodium thiosulfate IV

-100% oxygen

-Possible gastric lavage

-Cyanide antidote kit if available

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Properties of CN antidote kit

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-Nitrite converts hemoglobin to methemoglobin

-CN binds to methemoglobin;

Methemoglobin --> cyanmethemoglobin

-CN transferred from cyanmethemoglobin by sodium thiosulfate

-Sodium thiosulfate increases substrate for rhodenase; CN --> sodium thiosulfate

-Hydroxycobalamin (Cyanokit)

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Methanol poisoning

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-Onset of symptoms: 30-48 hr

-Gastrointestinal distress (nausea, vomiting, pancreatitis)

-Eye distress (blurred vision, constricted field of vision, photophobia, blindness)

-Metabolic acidosis (tachycardia, shock/hypotension, multi-organ failure)

-CNS (EtOH like intoxication, tremor, hypokinesis, Parkinson-like syndrome)

-Metabolism: MeOH-->Formaldehyde-->Formic acid

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Treatment of MeOH/ethylene glycol poisoning

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-For metabolic acidosis: administer bicarbonate

-Competitive inhibition of alcohol dehydrogenase (100 mg/dL of ethanol infusion)

-Administration of Fomepizole

-Hemodialysis

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Drugs and specific antidotes

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Acetaminophen--N-acetylcysteine

Anti-cholinergics (atropine, scopolamine)--Phystigmine

Benzos--Flumazenil

Digoxin--Digabind

Opiates--Naloxone

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Affinity

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In immunology, the strength of binding between an antibody and its antigenic determinant.

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Analyte

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A substance of interest that is being identified and measured in an assay

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Antibody

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A protein synthesized by animal lymphocytes in response to a foreign substance that specifically binds the foreign substance. The molecular weight of the monomeric form of an antibody is about 150,000 Da.

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Antigen

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Any substance that stimulates an animal lymphocyte to produce an antibody that specifically binds it.

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Antigenic determinant

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The portion of an immunogenic molecule that binds to an antibody-binding site.

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Avidity

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In immunology, the strength of binding between antiserum, or an antibody mixture, and an antigen.

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CEDIA

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Cloned enzyme donor immunoassay

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Competitive binding process

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The process of two different substances competing for the same antibody-binding sites. In immunoassays, the competing substances are an antigen and a labeled antigen.

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Cross-reactivity

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Qualitative definition: The degree of response in an immunoassay to a substance other than the analyte of interest.

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Cutoff

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A concentration of an analyte established for a screening assay below which all measured values are identified as negative for the analyte.

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ELISA

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Enzyme linked immunosorbent assay

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EMIT

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Enzyme multiplied immunoassay technique

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FPIA

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Fluorescence polarization immunoassay

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Hapten

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A small, non-immunogenic molecule that is attached to a larger immunogenic substance, forming a new antigen that stimulates production of antibodies specific for the small molecule.

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Heterogeneous immunoassay

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An immunoassay that requires bound and free antigen to be separated before labeled antigen is measured.

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Homogeneous immunoassay

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An immunoassay that allows measurement of labeled antigen without separating bound and free antigen.

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Immunoassay

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Any assay using antibodies that specifically bind an analyte to identify and measure the amount of the analyte.

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Immunogen

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A substance injected into an animal, causing production of antibodies to the injected substance.

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KIMS

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Immunoassay: kinetic interaction of microparticles in solution

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Logit B/B0

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In immunoassay: a mathematical function used to linearize standard plots

B=bound counts per minute (cpm)

B0=bound cpm of drug free sample

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Monoclonal antiserum

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Antiserum containing antibodies that each have identical binding properties.

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Polyclonal antiserum

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Antiserum containing antibodies with a spectrum of affinities/specificities toward an antigen. Animals produce polyclonal antiserum.

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Sensitivity

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An assay characteristic that denotes the assay's ability to detect an analyte in samples

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Specificity

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An assay characteristic that denotes the assay's ability to correctly identify an analyte in a sample.

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Titer

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A measure of an antiserum's antibody concentration, usually expressed as the antiserum dilution that gives 50% binding of labeled antigen.

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3 major classes of opiate receptors

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-Mu

-Kappa

-Delta

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Locations of opiate receptors

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-Limbic system

-Thalamus

-Striatum

-Hypothalamus

-Midbrain and spinal cord

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Acute toxicity of opiates

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-Miosis

-Coma

-Respiratory depression (mu receptors)

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Mechanism of acetaminophen (APAP) hepatoxicity

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-Saturates the glucuronidase & sulfatase enzymes that conjugate APAP

-Most of the dose of APAP is metabolized by p450 enzymes which produce an intermediate that is conjugated by glutathione

-OD of APAP depletes glutathione stores

-Nucleophilic APAP intermediate metabolite (NAPQI) of p450 oxidation attacks cellular structural molecules rich in thiol groups, disrupting hepatic function

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Phases of APAP poisoning

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-Phase I: within 24 hrs of ingestion. Nausea, vomiting, diaphoresis, pallor

-Phase II: 24-72 hrs post ingestion. Elevation in serum hepatic enzymes, right upper quadrant pain.

-Phase III: 3-5 days post ingestion. Signs of hepatic necrosis, hepatic encephalopathy, possible renal failure

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Treatment of APAP overdose

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-N-acetylcysteine (Mucomyst) supplies thiol nucleophile to bind to toxic intermediate

-Most likelihood of success if patient is treated within 10 hrs of OD ingestion

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Anti-cholinergic (Muscarinic) Poisoning

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-Hot as a hare (hyperthermia)

-Blind as a bat (mydriasis)

-Dry as a bone (blocked secretions)

-Red as a beet (hypertension)

-Mad as a hatter (agitation, delirium)

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Drugs with anti-cholinergic activity

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-Belladonna alkaloids (atropine, scopolamine)

-Diphenhydramine, hydroxyzine

-TCA's

-Benztropine

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Toxidrome of Organophosphate pesticides cholinesterase inhibitors

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-Salivation

-Lacrimation

-Urination

-Defecation

-Gastric motility

-Emesis

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Drugs with cholinergic activity

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-Cocaine

-Amphetamine

-Organophosphates

-Carbamate pesticides

-Physostigmine

-Pilocarpine

-Betel nut (Areca catechu)

-Mushrooms

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Flumazenil

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Benzo antagonist

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Digoxin toxicity

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-Nausea, vomiting, diarrhea

-Blurred vision

-Tachycardia, premature contractions

-Hallucinations

-Toxicity increased by: hypokalemia, hypercalcemia, hypomagnesmia, hypoxia, hypothyroidism, quinidine and Ca2+ channel blockers

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Supportive therapy of digoxin toxicity

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-Maintain blood pH and electrolytes

-Maintain normal respiration

-Maintain normal BP and cardiac fxn

-Maintain tissue perfusion

-Maintain renal fxn

-Prevent secondary infections

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Types of workplace testing

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-Pre-employment

-Random

-Reasonable suspicion

-Post accident

-Return to duty

-Follow up testing

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Reasons for an observed urine collection

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-Positive sample

-Adulterated sample

-Substituted samples

-Problem w/initial sample collection

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Amphetamine rule for urine SAMHSA specimens

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In order to report a sample positive for methamphetamine, the sample must also have amphetamine present at equal to or greater than 100 ng/mL

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Urine specimen validity testing

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-Creatinine (concentration/dilution)

-Specific gravity (concentration/dilution)

-pH (Acids and bases)

-Oxidants (adulterants)

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Urine HHS reported as "diluted" criteria

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-Meets both criteria:

1) Creatinine 2.0 mg/dL to 20.0 mg/dL

2) Specific gravity is 1.0010 to 1.0030

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Urine HHS reported as "substituted" criteria

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-Meets both criteria:

1) Creatinine is <2.0 mg/dL

2) Specific gravity is <1.0010 or >1.0200

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Urine HHS reported as "invalid" criteria

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-Creatinine is <2.0 mg/dL and specific gravity is >1.0010 but <1.0200 (normal)

-Creatinine is >2.0 mg/dL and specific gravity is <1.0010

-pH 3-4.5 or 9-11

-Oxidant test is positive on 2 screen tests

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Urine HHS reported as "adulterated" criteria

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-pH <3 or >11

-Nitrite >500 ug/mL

-Chromium VI >50 ug/mL

-Bleach, iodine or fluoride detected

-Glutaraldehyde detected

-Surfactant detected >100 ug/mL dodecylbenzene

-Other specific adulterant using an initial confirmation test

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Three types of pain patients

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-Group I: Primary pain patients. No history of substance abuse

-Group II: Pain patients with past substance abuse

-Group III: Pain patients with concurrent opioid addiction

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BAC conversions (0.15)

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-0.15 g/210 L breath

-0.15 g/100 mL blood

-0.15 g/dL blood

-0.15% by weight by volume

-150 mg/100 mL blood

-150 mg/dL blood

-1500 mg/L blood

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Peripheral blood locations

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-External iliac vein

-Femoral vein

-Subclavian vein

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Postmortem redistribution

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-Underlying mechanisms are complex and of different types

-Passive drug release from drug reservoirs such as the gastrointestinal tract, liver, lungs, and myocardium may occur immediately after death

-Cell autolysis and the putrefactive process participate in redistribution

-Basic lipophilic drugs with a large distribution volume are particularly susceptible to PMR

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Factors affecting absorption

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-Biological (how drugs move across membranes)

-Physico-chemical

-Dosage form

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Bathochromic shift

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AKA "red" shift. In UV-VIS, the shift to a longer wavelength

i.e.: With phenolic compounds, making the solution more alkaline leads to an absorption shift to a longer wavelength. Used with barbiturates...in acidic or neutral solution, barbs show little absorption above 230 nm, but at pH 9.2, ionization results in strong conjugated chromophore with absorption near 240 nm. At pH 13, a second ionization occurs, extending the ionization further.

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Hyperchromic effect

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In UV-VIS, the loss of fine structure and an increase in molar absorptivity. Can occur during a bathochromic shift.

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Hypsochromic shift

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AKA "blue" shift. In UV-VIS, the shifting to a shorter wavelength; solvent effect.

i.e: In aromatic amines, when acidified the protonated quaternary group is no longer part of the chromophore, shifting the spectrum to a lower wavelength with a sharp fall in absorptivity (hypochromic effect).

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Hypochromic effect

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In UV-VIS, a sharp fall in absorptivity, usually associated with a hypsochromic or blue shift; solvent effect.

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Chromophore

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A molecular group responsible for energy absorption (UV-VIS). Usually a conjugated system with a delocalization of electrons.

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Auxochrome

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Any saturated chemical group that has little or no intrinsic absorption, but modifies the absorption spectrum when attached or conjugated directly to a chromophore via its polarizable lone pair of electrons.

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Ultraviolet wavelength range

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200-400 nm

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Visible light wavelength range

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400-800 nm

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Visible light ranges (short to long)

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violet380–450 nm

blue450–495 nm

green495–570 nm

yellow570–590 nm

orange590–620 nm

red620–750 nm

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Beer-Lambert Law

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A combination of the two laws of absorption that describe the extent of absorption of radiation by a system at a single wavelength.

A=Ebc

A= Absorbance (no units)

E= molar absorbtivity (L/mol cm)

b= path length of sample/cuvette (cm)

c= concentration of the compound in the solution (mol/L)

Absorbance is directly proportional to the other parameters provided all aspects of the law are fulfilled/obeyed.

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Drugs with good UV absorbance

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-Barbs (Phenobarbital)

-Benzos (Diazepam)

-Phenothiazines

-Tricyclic antidepressants

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Limitations of UV-VIS

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-Low specificity

-Therapeutic concentrations of drugs may be too low to detect

-Preferred as a screening technique vs. confirmatory

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Drugs with natural fluorescence

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-Chlorquine

-Dantroline

-LSD

-Propranolol

-Quinidine

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Fluorescence Spectrophotometry

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The emission of light from molecules that have been excited to higher energy levels after absorption of electromagnetic radiation.

The emitted light originates from the lowest excited state of the molecule and is usually at a different wavelength than the light that causes excitation of the molecule.

Compounds need to have a flat, rigid molecular structure with high concentrations of delocalized electrons.

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Factors affecting fluorescence

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-Aromatic functional groups with low energy transition levels fluoresce intensely

-Aliphatic and alicyclic carbonyl groups or highly conjugated double bond structures may exhibit fluorescence

-Large number of aromatic systems fluoresce

-Solvents containing bromine or iodine will decrease fluorescence

-Ionized and non-ionized forms of a compound will have a different wavelength and emission intensity

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IR Spectrophotometry

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The study of reflected, absorbed or transmitted electromagnetic radiation of wavelength 0.8um to 500 um (longer than visible light).

Based on the principle that molecules have specific frequencies of internal vibration.

The total energy of molecule (molecular energy) is the total sum of its translational, vibrational, rotational and electronic energies.

Absorption only takes place when there is a change in the dipole moment of a molecule.

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Regions of the IR spectrum

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-Near IR: 0.8-2.5 um

-Mid IR: 2.5-25 um (the range that is most useful for info about pesticides and drugs)

-Far IR: 25-500 um

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Three types of IR absorption

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-Fundamental

-Overtone

-Combination

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FTIR (Fourier Transform IR)

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FTIR uses a interferometer (beam splitter and two perpendicular mirrors) instead of a monochromator used in traditional dispersive IR spectrophotometers.

An interferogram is produced as the result of two beams of light that recombine at the detector. The data is then transformed mathematically by Fourier transform to provide a traditional IR spectrum.

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GC split mode

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The septum purge remains open, minimizing extraneous peaks resulting from septum bleed. A typical split ratio (ratio of split vent flow to column flow) is 50:1.

Using the 50:1 ratio, with a flow of 1 mL/min through a capillary column, 0.02 uL of a 1 uL injection would go on the column.

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GC splitless mode

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The split vent valve remains closed. This allows as much of the sample as possible to get onto the column (low concentration samples).

The sample vaporizes after injection and the total flow goes to the column which is typically at a temp 30 degrees below the boiling point of the injection solvent.

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GC derivitization

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GC requires that the analyte be volatilized at an elevated temperature which may break down many heat labile compounds; some compounds lack volatility.

Producing a chemical derivative of the drug of interest using a suitable derivatizing agent, the above problems are overcome.

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Derivatizing agents

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-Silylating agents

-Acetylating agents

-Methylating agents

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Silylating agents (GC derivatization)

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-One of the most widely used means for derivatizing drugs

-BSTFA or BSA

-Compounds containing a carboxylic acid, amide, phenolic or alcohol group react well.

-Are highly volatile. Silylated drugs are readily hydrolyzed back to the parent compound and therefore should be kept free from any water.

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Acetylating agents (GC derivatization)

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-Acetic anhydride, propionic anhydride, trifluoroacetic anhydrides most common.

-The acetylated drugs are more stable than silyl derivatives and is applicable to many classes of drugs

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Methylating agents (GC derivatization)

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-Used primarily for the derivatization of barbs and some carboxylic acids.

-Achieved using HCl in methanol or diazomethane.

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Types of GC detectors

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-Electron capture

-Flame ionization

-Thermal conductivity

-Mass spectrometer

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HPLC columns

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-Normal phase (adsorption): usually silica. Mainly used for the separation of non-polar or moderately polar compounds. Polar stationary phase; non-polar mobile phase. Elution order: non-polar first, polar more strongly bound.

-Reversed phase (partition): silica support with a non-polar phase bonded to it. Elution order: polar first, non-polar more strongly bound. Reducing the polarity of the eluent increases the eluting strength of the mobile phase.

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Types of HPLC detectors

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-UV-VIS

-Diode array

-Fluorescence

-Electrochemical

-Refractive index

-Mass spectrometer

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Mass Spectrometry

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A sample usually in vapor form is bombarded with electrons, which convert it to an ionic state consisting of the parent ion and several ionic fragments of the original molecule.

The ions are then separated according to their mass/charge ratio (m/e; m/z).

The mass spectrum records the amounts (abundance) of each ion. The MW of the compound can generally be determined from the mass spectrum.

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Advantages of MS

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-Specific

-Sensitive to ng/mL

-Qualitative and Quantitative

-Compatible with separation techniques (GC, LC, CE)

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Disadvantages of MS

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-Expensive

-High maintenance

-Skilled analysts

-Not as sensitive as some detectors (Fluorescence, LIF)

-More suited to "low" MW compounds (<500)

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General operation of an MS

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-Create gas-phase ions

-Separate the ions in space or time based on their mass-charge ratio

-Measure the quantity of ions of each mass-charge ratio

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MS Ion source

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-Heated filament that produces a beam of electrons that is accelerated to an energy level of about 70 eV.

-Interaction between electrons and the analyte molecules result in the latter reaching the excited state.

-If the energy of the molecule exceeds its ionization potential then a molecular ion (M+) is produced by the loss of an electron from the molecule.

-Further excitation of the molecule can result in breaking of chemical bonds and the formation of molecular fragments.

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MS Ionization methods

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-Electron Impact (EI)

-Chemical ionization (CI)

-Electrospray ionization (ESI)

-Fast atom bombardment (FAB)

-Matrix-assisted laser desorption ionization (MALDI)

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Electron impact (EI) MS

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Uses an electron beam, usually generated from a tungsten filament to ionize gas-phase atoms or molecules.

An electron from the beam knocks an electron off the analyte atoms or molecules to create ions.

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Chemical ionization (CI) MS

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Uses a reagent ion to react with the analyte molecules to form ions by either a proton or hydride transfer.

Reagent ions are produced by introducing a large excess of methane (relative to the analyte) into an electron impact (EI) source.

Electron collisions produce CH4+ and CH3+ which further react with methane to form CH5+ and C2H5+

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Electrospray ionization (ESI) MS

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Very fine needle and a series of skimmers. A sample solution is sprayed into the source chamber to form droplets. The droplets carry charge when they exit the capillary and, as the solvent evaporates, the droplets disappear leaving highly charged analyte molecules.

Particularly useful for large biological molecules that are difficult to vaporize or ionize.

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Fast atom bombardment (FAB) MS

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High energy beam of neutral atoms, typically Xe or Ar, strikes a solid sample causing desorption and ionization.

Used for large biological molecules that are difficult to get into the gas phase.

Causes little fragmentation and usually gives a large molecular ion peak, making it useful for MW determination.

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Matrix assisted laser desorption ionization (MALDI) MS

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LIMS method of vaporing and ionizing large biological molecules such as proteins or DNA fragments.

The biological molecules are dispersed in a solid matrix such as nicotinic acid.

A UV laser pulse severs the matrix that carries some of the large molecules into the gas phase in an ionized form so they can be extracted into an MS.

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Mass analyzer (MS)

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Quadrapole mass filter consists of four parallel rods with different applied electrical potentials and a superimposed Rf field that affect the trajectory of ions travelling down the flight path centered between the four rods.

Only ions of a certain mass-to-charge ratio pass through the quadrapole filter, all other ions are thrown out of their original path.

A mass spectrum is obtained by monitoring the ions passing through the quadrapole filter as the voltages and Rf conditions on the rods are varied.

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Ion-trap MS

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Uses three electrodes to trap ions in a small volume.

The mass analyzer consists of a ring electrode separating two hemispherical electrodes. A mass spectrum is obtained by changing the electrode voltages to eject the ions from the trap.

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MS data presentation

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Data is presented as a graph of abundance vs. m/z, with m/z representing the MW of each of the molecular fragments and is expressed in atomic mass units (amu).

The most abundant ion (the base peak) is usually assigned a relative abundance of 100% and all other ions are assigned values relative to the abundance of the base peak (normalized spectrum).