Toxicology Exam 1

1. Who was the father of toxicology?

Mathew Orfila

2. Who first used autopsy material to prove if someone was poisoned.

Mathew Orfila

3. Toxicology: The study of how natural or man-made poisons cause undesirable effects in living organisms

Poison:

Toxicant: Any chemical that can injure or kill humans, animals, or plants; a poison

Toxic: Poisonous or deadly effects on the body caused by any form of consumption

Toxin: Toxic substances produced naturally

Toxicity: The degree to which a substance is poisonous or can cause injury

Toxic symptoms:Any feeling or sign indicating the presence of poison in the system 

Toxic effects: Health effects that occur due to exposure to a toxic substance

Tolerance: Tolerance is a person's diminished response to a drug, which occurs when the drug is used repeatedly and the body adapts to the continued presence of the drug

Selective toxicity: Means that a chemical will produce injury to one kind of living matter without harming another form of life

NOAEL: No Observed Adverse Effect Level; used in experimental toxicology to perform toxicity risk assessment studies

Adverse Effects: occur when two drugs are competing for the same receptor

Additive adverse effect of a drug: Drug B + C = 8 units → additivity

Potentiate adverse effect of a drug: Drug A + B = 5 units → potentiation

Antagonistic adverse effect of a drug: Drug C + D = 20 units → synergism

4. ED50: Is the dose that would be predicted to be effective or have a therapeutic benefit in 50% of the population

TD50: Is the dose that would be predicted to produce a toxic response in 50% of the population.

 LD50: Is the dose that would predict death in 50% of the population.

Therapeutic dose: The higher it is the more safe a dose is.

5. The disciplines of Toxicology.

1. Mechanistic: elucidates the cellular and biochemical effects of toxins

2. Descriptive: uses results of animal experiments to predict harmful effects to humans

3. Occupational Toxicology: Combines occupational medicine and occupational hygiene

4. Environmental Toxicology: Integrates toxicology with sub-disciplines such as ecology, wildlife and aquatic biology, environmental chemistry.

5. Food Toxicology: Is involved in delivering a safe and edible supply of food to the consumer

6. Regulatory Toxicology: Gathers and evaluates existing toxicological information to establish concentration-based standards of “safe” exposure

7. Clinical: the study of interrelationships between toxin exposure and disease states (diagnosis & therapeutic intervention)

8. Forensic: concerned with medico-legal consequences of exposure to a toxic substance or a toxin.

6. Which are the factors (intrinsic and extrinsic) affecting toxicity.

Intrinsic: Age, Gender, body size, and susceptibility.

Extrinsic: Dose, Route of exposure, Frequency, Duration, Concentration, Absorption, Metabolism, Accumulation, Distribution,  Elimination, Properties of the chemical

7. The types of postmortem toxicological cases.

8. The difference between a coroner and a medical examiner

A coroner is an elected position, and a medical examiner is a medical doctor.

9. The different types of postmortem biological specimens, their advantages and disadvantages. What information are we getting from each type of specimen (impairment, recent use, long term use, suicide/overdose.

• Gastric content

  • Useful after overdoses

• organs/tissues

  • When the body is found after blood has already clotted, this can be useful

• Bile

  • When blood and urine are not available, since we prefer to work with biological fluid instead of tissue, we will use bile

• Vitreous fluid

  • Gold standard sample when testing alcohol

  • Remains for days after death, is in a protected cavity so not affected by any microbes

• Brain

• Hair 

  • Tells us about long-term use of the substance

  • The testing itself requires high expertise and is very vigorous

  • Passive exposure of substance into the hair

10. Which biospecimen is important in the case of the sudden death of a person who has large quantities of a lethal agent in the stomach.

Gastric content.

11. Which specimen correlates the concentration of a drug with the impairment of the person.

Urine/Blood

12. The importance of vitreous fluid in ethanol testing

• Gold standard sample when testing alcohol

13. What does the initials STA mean?

• Systematic Toxicological Analysis

14. Describe the steps of STA for a biological sample.

Screening/General unknown screening. If possible, target MS analysis will be conducted and qualitative/quantitative measures will follow.

15. The meaning of PTS (Proficiency Testing Scheme)

• Proficiency Testing Scheme

16. The meaning of SOPs (Standard Operation procedures)

To standardize a procedure.

17. The classification of drugs Pharmacokinetics/pharmacodynamics

Pharmacokinetics: The study of what the body does to the drug

Pharmacodynamics: The study of what the drug does to the body

19. How to define Tmax, Cmax, AUC, T1/2.

• Cmax is the max concentration

• Tmax is the time taken to reach Cmax

• T1/2 is the time taken to reach the half life elimination of the drug

• AUC: Area Under the Curve

20.How many half-lives are required for a drug to be sequentially administered in order to achieve steady-state concentrations in a patient’s plasma?

Four to five half-lives.

21. What is the difference between one and two compartment systems in pharmacokinetics.

22. What is the difference on the elimination of a drug from the body between a zero order kinetics and a first order kinetics.

23. Know the four steps of how drugs move throughout the body.

24. The different routes of administration.

25. The structure of a cell membrane.

26. How bioavailability is defined.

The actual amount of the drug which enters into the bloodstream

27. The factors which affect bioavailability.

1. Route of administration

2. Formulation

   1. Chemical properties of the substance

   2. Type: chalky powder vs gel capsule

28. The difference between passive and active diffusion during the absorption of drugs through the gastrointestinal tract.

29. The significance of Henderson-Hasselbach equations.

Acidic drug’s pH = pka + log [ionized]/[unionized]

Basic drug’s pH = pka + log [unionized]/[ionized]

A medium with an acidic pH favors the absorption of an organic acidic drug

A medium with a basic pH favors the absorption of an organic base drug

30. How the ionization of drugs affects their absorption in stomach and the gastrointestinal membrane. How the hydrophobicity (lipid solubility) of a drug affects the distribution.

31. Which factors affect bioavailability

• Solubility

• Concentration

• Surface area

• Blood supply

• pH

32. Which route of administration provides 100% bioavailability of a drug.

Intravenous

33. Which factors affect the distribution of a drug in the body’s compartments.

Distribution is movement of a medication from circulation to the body's tissues. The higher the volume of distribution, the more it absorbs into the tissues and the less it absorbs into the blood.

34. How to evaluate the volume of distribution (Vd) in regard to the partition of a drug into blood and the human bodies compartment.

Dose administered/plasma concentration = Vd

35. How the hydrophobicity (lipid solubility) of a drug affects the distribution.

Depending on the hydrophobicity, the drug may absorb more into the tissues (higher lipid solubility) or more into the blood (lower lipid solubility)

36. Which reactions are considered as phase I and as phase II.

Phase I:

Oxidation

O-dealkylation (codeine > morphine)

N-dealkylation (codeine > norcodeine)

O-deamination (amphetamine > phenylacetone)

N-oxidation (amitriptyline > amitriptyline-N-oxide)

Reduction

Nitro reduction (nitrazepam > 7-amino-nitrazepam)

Hydrolysis

Ester hydrolysis (cocaine)

Amide hydrolysis (acetaminophen)

Phase II

Conjugation: with endogenous compounds

Glucuronidation (Oxazepam)

Sulfate formation (morphine)

Glutathione conjugation (paracetamol)

Glycine conjugation (salicylate)

Synthesis

Methylation (Theophylline)

Acetylation (Procainamide)

37. The importance of free and protein binding of a drug in blood.

Drug protein binding in the blood reduces the concentration of free drugs available for diffusion across membranes.

38. The name of the enzyme responsible for drugs’ metabolism.

P450: monooxygenases

39. The significance of CYP450 enzyme inhibition and induction in the metabolism of a drug is.

they can significantly alter the rate at which a drug is broken down by the body

40. The mechanism of action for Monoamine Oxidase and its inhibitors.

Monoamine oxidase inhibitors (MAOIs) work by blocking the activity of the monoamine oxidase enzyme, which is responsible for breaking down neurotransmitters like serotonin, norepinephrine, and dopamine in the brain

41. The Phase I and Phase II metabolic reactions with examples.

Flashcard 1
Q: What is the role of NADPH in Phase I metabolism?
A: NADPH donates electrons in Phase I metabolism, specifically during reactions catalyzed by cytochrome P450 enzymes.

Flashcard 2
Q: What is P450-RH, and what is its function in Phase I metabolism?
A: P450-RH is a reduced form of cytochrome P450 that contains electrons from NADPH and is essential for catalyzing oxidation reactions, often involving O2.

Flashcard 3
Q: How does O2 participate in Phase I metabolism?
A: In Phase I metabolism, O2 acts as a reactant in the oxidation reaction catalyzed by cytochrome P450 enzymes, combining with the substrate and electrons to introduce an oxygen atom.

Flashcard 4
Q: What happens to NADPH during Phase I metabolism?
A: During Phase I, NADPH is oxidized to NADP+, providing the necessary electrons for enzymatic reactions catalyzed by cytochrome P450 enzymes.

Flashcard 5
Q: What does CO (carbon monoxide) do in the context of Phase I metabolism?
A: CO binds to the heme iron in the cytochrome P450 enzyme, preventing its activity. This is used to study the enzyme's function.

Flashcard 6
Q: In Phase I metabolism, what is produced alongside the substrate's oxidation?
A: H2O (water) is often produced as a byproduct when O2 is involved in the oxidation reaction, and the substrate is hydroxylated.

Flashcard 7
Q: What is the general role of 2H in Phase I metabolism?
A: 2H (hydrogen atoms) are transferred during the reaction, contributing to the reduction of the cytochrome P450 enzyme and participating in the hydroxylation of the substrate.

Flashcard 8
Q: What is Phase I metabolism primarily responsible for?
A: Phase I metabolism primarily involves the oxidation of xenobiotics, introducing functional groups (like hydroxyl groups) via cytochrome P450 enzymes, often requiring NADPH, O2, and producing H2O.

Flashcard 9
Q: What are the key steps involved in a cytochrome P450-catalyzed reaction in Phase I?
A: The key steps involve NADPH donating electrons to P450-RH, which then interacts with O2 and the substrate. The product is often oxidized with the release of H2O.

Flashcard 10
Q: How does Phase II metabolism differ from Phase I?
A: Phase II metabolism involves conjugation reactions (e.g., sulfation, glucuronidation), where a functional group is added to the substrate, unlike Phase I, which mainly involves oxidation.

Phase I Metabolism Example:
Substrate: Acetaminophen (Tylenol)
Enzyme: Cytochrome P450 (CYP450)

• Process:
  Acetaminophen undergoes oxidation via cytochrome P450 enzymes in the liver. In this reaction, NADPH donates electrons to the P450-RH enzyme, which interacts with O2. The product is an oxidized form of acetaminophen, which introduces a hydroxyl group (–OH), making the molecule more polar.

• Byproducts:
  H2O (water) is released during the oxidation process, and NADP+ is produced from NADPH.

• Outcome:
  The metabolite is slightly more water-soluble and can undergo further conjugation in Phase II.

Phase II Metabolism Example:
Substrate: Acetaminophen (from Phase I)
Enzyme: Glucuronosyltransferase

• Process:
  After Phase I metabolism, acetaminophen is conjugated with glucuronic acid in Phase II, making it more water-soluble and easier to excrete. The enzyme glucuronosyltransferase facilitates the addition of glucuronic acid to the hydroxyl group (–OH) added during Phase I.

• Byproducts:
  This process produces UDP-glucose as a byproduct, and the conjugated acetaminophen becomes more easily excreted in the urine.

• Outcome:
  The Phase II conjugate of acetaminophen is now a more water-soluble molecule that can be readily eliminated from the body.

42. How phase II glucuronidation affects the excretion of a drug from urine.

converting the drug molecule into a more water-soluble conjugate (glucuronide), which allows for easier filtration and elimination through the kidneys

43. What the first pass effect is.

The amount of drug reaching system circulation is less than the amount absorbed

44. Which is the functional unit of a kidney

The function unit of the kidney is called the nephron

45. The mechanisms of renal excretion of a drug.

glomerular filtration (passive movement of drug molecules from the blood into the forming urine at the glomerulus), tubular secretion (active transport of drugs from the peritubular capillaries into the tubular lumen, mainly in the proximal tubule), and tubular reabsorption (passive diffusion of the drug back from the tubular lumen into the bloodstream, which can be influenced by the drug's properties and urine pH).

46. Which of the urine excretion mechanisms (filtration, secretion, reabsorption) requires a carrier protein

"secretion" and "reabsorption" typically require a carrier protein, as they often involve active transport of specific molecules across the renal tubule cell membrane