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Biochemical Pharmacology > Toxicology > Flashcards

Toxicology Flashcards

1
Q

Graded Dose Response

A
  • Measured in a single biological unit
  • Continuous scale
  • Relates dose to intensity of effect
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2
Q

Quantal Dose Response

A
  • Population study
  • All-or-none pharmacological effect
  • Relates dose to frequency of effect
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3
Q

What is the relationship between drug specificity and dose-dependency?

A

The specificity of drug action is usually strictly dose-dependent,
* Increasing the dose of a drug above its therapeutic range may affect molecular targets other than the desired target, causing toxic side effects.
* Off target binding

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4
Q

Is it preferable to have a drug with high or low potency and a lower or higher required dosage?

A
  • It is preferable to have a drug with high potency and a lower required dosage.
  • A drug with a lower potency and higher required dosage is more likely to generate side effects.
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5
Q

What is the purpose of using quantal dose response curves in drug studies?

A
  • Determine the fraction of population that responds to a single dose
  • Describes conc. that produces a given effect in a population.
  • Useful in studying variation among individuals
  • Effects seen over a range of doses, help determine the optimal dose range for a drug.
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6
Q

What does ED50 stand for?

A

Effective dose in 50% of individuals.

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7
Q

In which species are ED50 studies conducted?

A

Both humans and animals

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8
Q

What does TD50 stand for?

A

Dose causing toxic effect in 50% of individuals.

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9
Q

Which species are mostly used for TD50 studies?

A

Humans.

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10
Q

What does LD50 stand for?

A

Dose causing death in 50% of individuals.
Lethal dose

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11
Q

For which type of studies is LD50 mostly reserved?

A

Animal studies

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12
Q

What is a Therapeutic Index (TI)?

A
  • A measure of benefit versus risk,
  • Ratio of the dose required to produce a toxic effect and the dose needed to elicit the desired therapeutic response.
  • The larger the TI, the safer the drug is, and the larger the therapeutic window.
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13
Q

How do you calculate Therapeutic Index in animals?

A

LD50/ED50

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14
Q

How do you calculate Therapeutic Index in humans?

A

TD50/ED50

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15
Q

What is the significance of Therapeutic Index in drug development?

A

Any drug wanting to make it to trial needs to have a therapeutic index as it is an important measure of safety.

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16
Q

What is a Quantal Dose Response Distribution, and what is its shape?

A
  • Describes the concentration of a drug that produces a given effect in a population where responses are present or absent.
  • The shape is a symmetrical normal distribution curve.
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17
Q

How do ED50 and LD50 relate to the Therapeutic Index?

A
  • The Therapeutic Index is calculated as the ratio of LD50 and ED50
  • The larger the difference between LD50 and ED50, the larger the Therapeutic Index, indicating a greater safety margin for the drug.
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18
Q

What is a narrow therapeutic index drug?

A

A medication that requires precise dosing and monitoring due to a small difference between the therapeutic dose and the toxic dose.

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19
Q

How is a narrow therapeutic drug managed?

A
  • Must start with small doses in a hospital setting
  • Patient’s INR (international normalized ratio) is monitored; A coagulation assay (ideal 2.5)
  • High INR levels increase the risk of bleeding (>5.0)
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20
Q

Example of a narrow therapeutic drug

A

Warfarin
* Now banned in ireland
* An oral coagulant
* Deep vein thrombosis, pulmonary embolism

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21
Q

Who was Paracelsus?

A
  • Paracelsus (1493-1541)
  • Swiss physician and alchemist
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22
Q

What is Paracelsus’ contribution to pharmacology?

A

“All substances are poisons, there is none that is not a poison. The right dose differentiates a poison and a remedy.”
The first to apply scientific principles towards medicine and established the precursor of modern-day pharmacology.

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23
Q

What is toxicology?

A

The study of the adverse effects of chemicals on living organisms

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24
Q

What are the divisions of toxicology?

A
  1. Clinical
  2. Occupational
  3. Environmental
  4. Forensic
  5. Developmental
  6. Reproductive
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25
Q

What is clinical toxicology and what does it involve?

A
  • Concerned with disease caused by toxic substances
  • It aims to understand why a person has become sick due to exposure to toxins.
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26
Q

What is occupational toxicology and what does it focus on?

A
  • It explores how different compounds in the workplace can create toxicity in the body.
  • Identifies the toxic properties of such chemicals, defining safe conditions of use, and preventing exposure to harmful levels of such toxins.
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27
Q

What is environmental toxicology?

A

Environmental pollutants and their effects on living organisms

28
Q

What is ecotoxicology?

A
  • Adverse effects of chemicals on living organisms at the population level or on the entire ecosystem.
  • It explores the impacts of different levels of pollutants on organisms and the ecosystem.
29
Q

What is forensic toxicology and what is its primary focus?

A

Focuses primarily on the medico-legal aspects of the harmful effects of chemicals

30
Q

What is developmental toxicology?

A

The study of adverse effects on the developing organism that may result from exposure to chemical agents
* before conception (either parent),
* during prenatal development
* postnatally (until the onset of puberty).

31
Q

What is reproductive toxicology and what does it study?

A
  • The study of the occurrence of adverse effects on the male or female reproductive system that may result from exposure to chemical agents.
  • It is closely linked with developmental toxicology
  • exposure to chemical agents can impact the development of the reproductive system.
32
Q

What factors affect the toxic response to a chemical?

A
  1. Nature of the chemical
  2. Dose size
  3. Duration of exposure
  4. Effects of chemical mixtures
  5. Route of exposure
  6. Life-cycle stage of exposed organism
  7. Susceptibility of chemical to biodegradation and ability to biomagnify in the food chain.
33
Q

What are the two types of toxic effects?

A

Related
e.g. bleeding with coagulants
or
Unrelated
e.g. liver damage with paracetamol
to the principal pharmacological action

34
Q

What causes unrelated toxic effects?

A

Reactive metabolites
and/or
immunological reactions

35
Q

Why is toxicity testing carried out in animals?

A

To identify potential hazards before administering them to humans

36
Q

Why is it important to be aware of interspecies variations?

A

Metabolizing enzymes may differ between species, which can affect how toxins are processed in the body.

37
Q

What is hepatotoxicity?

A

The toxicity of hepatocytes or liver cells

38
Q

What is the role of the liver in drug metabolism?

A
  • It is a detoxifying organ
  • Responsible for metabolizing many therapeutic drugs.
  • Reactive metabolites of drugs are formed by P450 enzymes in the liver. - hepatocytes exposed to them
39
Q

How can hepatotoxicity lead to cirrhosis?

A

If sustained or continuous over time.

40
Q

What are some mechanisms of cell injury that can cause liver damage?

A

Lipid peroxidation
generates further radicals that will damage high-fat cells, including hepatocytes.
and
Oxidative stress

41
Q

Why is paracetamol overdose a common cause of death following self-poisoning?

A
  • Can cause hepatotoxicity
  • Overdose leads to the production of reactive metabolites that damage hepatocytes and cause liver failure.
  • Can be fatal if not treated
42
Q

What is nephrotoxicity?

A

The toxicity of renal cells

43
Q

What are some common drugs that can cause drug-induced nephrotoxicity?

A
  • Non-steroidal anti-inflammatory drugs (NSAIDs)
  • Angiotensin-converting enzyme (ACE) inhibitors
44
Q

How does nephrotoxicity affect renal tubular cells?

A
  • They are exposed to high concentrations of drugs and metabolites as urine is concentrated in the kidney.
  • Renal damage can cause papillary and/or tubular necrosis
45
Q

How do NSAIDs affect the kidney?

A

Inhibit prostaglandin synthesis,
Causes vasoconstriction and lowers the GFR

  • Results in reduced renal perfusion in patients with heart or liver disease.
  • GFR depends critically on vasodilator prostaglandin biosynthesis, so can lead to kidney dysfunction.
46
Q

What are prostaglandins?

A

Important mediators of immune function
(breaks down progesterone in the menstrual cycle)

47
Q

How do prostagladins affect kidney function?

A
  • Regulates renal blood flow and GFR.
  • Helps maintain vasodilation and adequate blood flow to the kidney
48
Q

What is mutagenesis, and how does it relate to carcinogenesis?

A
  • The process of modifying DNA.
  • It is the first step in the process of carcinogenesis
  • Mutation of proto-oncogenes or tumor suppressor genes can lead to carcinogenesis
  • more than one mutation usually required.
49
Q

What are proto-oncogenes and tumor suppressor genes, and how do they contribute to carcinogenesis?

A

Proto-oncogenes are normal genes that can become oncogenes when they are mutated.
Tumor suppressor genes are genes that normally function to prevent the development of cancer.
Mutation of these genes can contribute to the development of cancer.

50
Q

What are carcinogens?

A

Chemical substances that can cause cancer

51
Q

Genotoxic Carcinogens

A

interact directly with DNA

52
Q

Epigenetic carcinogens

A

act at a later stage to increase the likelihood that mutation will result in a tumor

53
Q

What are the advantages and disadvantages of in vitro tests for measuring mutagenicity and carcinogenicity?

A
  • Quick and inexpensive
  • Can sometimes give false positive or false negative results.
54
Q

Why is animal testing (in vivo) required by regulatory authorities before a new drug is licensed for use in humans, and what are some of the limitations of animal testing?

A

It allows for the evaluation of the drug’s safety and efficacy in a living organism.
Limitations:
* expensive
* time-consuming
* species differences

55
Q

What is the Ames test and what is it used for?

A
  • An in vitro test for mutagenicity that measures the rate of back-mutation in Salmonella typhimurium.
  • It is used for screening large numbers of compounds to determine mutagenicity and potential carcinogenicity.
56
Q

What is teratogenesis and when were drugs first implicated as causative agents?

A

The production of structural malformations in the fetus
1960

57
Q

What animals are new drugs usually tested in before being approved for human use?

A

Pregnant females of at least one rodent and one non-rodent species, such as rabbits.

58
Q

What are the three phases of foetal development and what cellular processes are affected by drugs during each phase?

A

Blastocyst formation:
* 0-16 days gestation
* main cellular process is cell division
* affected by cytotoxic drugs and alcohol.

Organogenesis:
* 17-60 days
* division, migration, differentiation, and death,
* affected by teratogens.

Histogenesis and functional maturation:
* 60 days to term
* division, migration, differentiation, and death,
* affected by miscellaneous drugs.

59
Q

During which phase of foetal development can drugs cause malformations?

A

During organogenesis
Can cause malformations in the:
* eyes and brain
* skeleton and limbs
* heart and major vessels
* palate
* genitourinary system

60
Q

What is thalidomide, and what did it lead to?

A
  • Sedative prescribed to control sleep and nausea throughout pregancy - caused fetal defromities
  • Approved in Europe in the late 1950s
  • Not approved in the US by the FDA.
61
Q

What act was passed as a result of thalidomide?
When was it passed?

A

The Kefauver-Harris Amendments to the Food, Drug and Cosmetic Act were passed to ensure drug efficacy and greater safety, requiring drug manufacturers to prove the effectiveness of their products before marketing.
* in 1962

62
Q

How do binding sites in the R form and S form of a drug affect teratogenesis?

A

R form helps you sleep
when turned to S form, binds to feotal cells

63
Q

What is an organoid?
What are they used for?

A

A 3D multicellular in vitro tissue construct that mimics its corresponding in vivo organ.

Created by converting stem cells into organized ‘organoid’ assemblies that can be used to study:
* tissue development
* disease modeling
* predicting treatment response in patients,
* drug screening
* toxicology studies.

64
Q

What is a challenge of an organoid?

A

The lack of a circulatory system and immune cells to sustain further growth and development.

65
Q

What is an organoid-on-a-chip?

A

Designed to sustain the growth and development of organoids in a microfluidic environment.

66
Q

What is a liver-on-a-chip and how has it been used for toxicity screening?

A
  • Uses hydrogels to encapsulate HepG2 cells
  • Used for toxicity screening, such as with alcohol.
  • The administration of alcohol resulted in a dose-dependent decrease in cell viability and function with increasing doses.
67
Q

What is an example of organoid-on-a-chip toxicity testing with paracetamol?

A
  • Involves a liver organoid, where acetaminophen (APAP) toxicity was observed.
  • The toxicity was reduced by N-acetyl-L-cysteine (NAC).

Biochemical Pharmacology (9 decks)

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