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Pharmaceutical Sciences > PharmSci IV Exam 4 > Flashcards

PharmSci IV Exam 4 Flashcards

1
Q

What about the structure of DNA/RNA makes it susceptible to damage by electrophiles?

A

The purine and pyrimidine bases are nucleophilic.

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2
Q

Where in the central dogma does DNA damage lead to carcinogenesis?

A

Replication

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3
Q

What are the three (3) stages in the Multistage model of carcinogenesis?

A
  1. Initiation
  2. Promotion
  3. Progression
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4
Q

What are the three (3) critical targets in the initiation stage?

A
  1. Proto-oncogenes
  2. Tumor suppressing genes
  3. DNA Repair enzymes
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5
Q

What is a complete carcinogen? (3 components)

A

A chemical that is able to act at all stages:

  1. damage DNA (initiation)
  2. promote clonal expansion (promotion)
  3. cause chromosome disarrangement [clastogenesis], polyclonal growth and angiogenesis (progression)
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6
Q

What are the four (4) metabolic forms of a carcinogen?

A
  1. Pre-carcinogen [not electrophile]
  2. Proximate carcinogen [may or may not be electrophile]
  3. Ultimate carcinogen [electrophile, free radical, ROS]
  4. Non-carcinogenic metabolites
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7
Q

What three (3) amino acid residues are susceptible to electrophilic binding?

A
  1. Cysteine
  2. Lysine
  3. Histamine
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8
Q

What are three (3) modes of DNA damage?

A
  1. Inter-strand crosslink (2 electrophiles)
  2. Intra-strand crosslink (2 electrophiles)
  3. Adduct (1 electrophile)
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9
Q

What are four (4) protection mechanisms against DNA damage?

A
  1. Glutathione and Glutathione-S-Transferase
  2. Superoxide Dismutase and Catalase
  3. Dietary and endogenous antioxidants
  4. DNA repair mechanisms
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10
Q

What is the process of bioactivation of benzo[a]pyrene?

A

Ultimate carcinogen contains epoxide and dihydrodiol:

  1. CYP-catalyzed alkyl oxidation forms epoxide.
  2. Epoxide hydrolase forms dihydrodiol.
  3. Alkyl oxidations forms an epoxide.
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11
Q

What are three (3) classes of deleterious or toxic drug effects?

A
  1. Pharmacological [overactivation]
  2. Pathological [cell/tissue damage]
  3. Genotoxic [can lead to cancer]
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12
Q

Define toxicology

A

study of adverse effects o living organism

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13
Q

Define hazard

A

Possible source of danger

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14
Q

Define toxin

A

Biological hazard

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15
Q

Define toxicant

A

Human made hazard

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16
Q

Poison

A

Capable of adverse response in biological systems

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17
Q

What is an idiosyncratic reaction?

A

An undesired effect that can occur at any dose

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18
Q

What is the distinction between immediate and delayed undesired effects?

A
  1. Immediate is quickly seen

2. Delayed has a latent period; may be carcinogenic or teratogenic.

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19
Q

What is the distinction between reversible and irreversible?

A

For a reversible effect, removing the toxicant will reduce the adverse effects.

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20
Q

What are two (2) mechanisms of chemical interactions?

A
  1. Pharmacokinetic [alter ADME]

2. Pharmacodynamic [compete for target]

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21
Q

What are four (4) classifications of chemical interactions?

A
  1. Additivity
  2. Synergy
  3. Potentiation
  4. Antagonism
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22
Q

Define additivity

A

Response is the sum of two agents

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23
Q

Define synergy

A

Combined effect is greater than the sum

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24
Q

Define potentiation

A

An agent does not have a response until a second agent is present.

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25
Q

Define antagonism

A

Interference between two agents decreases total response

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26
Q

What are four (4) classifications of antagonism?

A
  1. Functional
  2. Chemical
  3. Dispositional
  4. Receptor
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27
Q

What is functional antagonism?

A

Two agents balance opposite effects.

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28
Q

What is chemical antagonism?

A

Two agents inactivate one another.

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29
Q

What is dispositional antagonism?

A

One another alters the ADME of another.

30
Q

What is receptor antagonism?

A

Receptors compete with another for a target.

31
Q

What are three (3) assumptions in dose response?

A
  1. The response is due to the chemical administered.
  2. The magnitude of the response is related to the dose.
  3. There is a means of measuring and expressing toxicity.
32
Q

When quantifying dose-response, what is the distinction between individual/graded and quantal?

A
  1. Individual/graded looks at the magnitude of response in an individual.
  2. Quantal looks at an all-or-nothing threshold response in a population.
33
Q

What does the slope of the probit plot tell you about the population?

A
  1. A steep slope indicates greater variability

2. A shallow slope indicates less variability

34
Q

What are EC50 and ED50?

A

Concentration or dose when 50% of test group responds.

35
Q

What are LC50 and LD50?

A

Concentration or dose when 50% of the test group dies.

36
Q

What is NOAEL?

A

No Observed Adverse Effect Level

37
Q

Define the Therapeutic Index

A

TI = TD50/ED50

38
Q

Define Margin of Safety

A

MS = TD1/ED99

39
Q

Define potency

A

The range of doses overwhich the chemical causes an increasing response.

40
Q

Define maximal efficacy

A

The limit of the response given an increasing dose. (horizontal asymptote)

41
Q

What are four (4) steps in the development of toxicity?

A
  1. Delivery
  2. Interaction with Target Molecule
  3. Cellular dysfunction/injury
  4. Inappropriate repair and adaption
42
Q

What are four (4) examples of Ultimate Toxicants?

A
  1. Parent xenobiotics
  2. Metabolite (e.g. reactive electrophiles)
  3. Reactive Oxygen Species
  4. Endogenous (altered biomolecules)
43
Q

What are two (2) pathways involved in the delivery of a toxicant?

A
  1. Bioactivation

2. Detoxification

44
Q

What are three (3) outcomes of toxicant reactions with a target molecule?

A
  1. Dysfunction [inactivation]
  2. Destruction [adduct; breakdown]
  3. Neoantigen formation [immune system]
45
Q

What are four (4) types of reaction between a toxicant and a target molecule?

A
  1. Noncovalent [reversible]
    2 . Covalent [adduct formation; irreversible]
  2. H-Abstraction [ROS]
  3. Electron transfer [redox; heme groups]
46
Q

Describe HSAB Theory

A
  1. Soft Electrophiles prefer Soft Nucleophiles

2. Hard electrophiles prefer hard nucleophiles

47
Q

Using HSAB theory, describe the susceptibility of cysteine residues.

A

The soft cysteine bases are susceptible to soft =O.

48
Q

Using HSAB theory, describe the susceptibility of histamine residues.

A

The medium-soft histamine residues are susceptible to epoxides.

49
Q

Using HSAB theory, describe the susceptibility of lysine residues.

A

The medium-soft histamine residues are susceptible to epoxides.

50
Q

Using HSAB theory, describe the susceptibility of DNA/RNA bases.

A

The hard DNA/RNA bases are susceptible to carbocations and nitrenium ions.

51
Q

What determines the injury that develops upon binding of the toxicant to the target molecule?

A

The role of the target molecule

52
Q

What are two categories of target molecule roles?

A
  1. Cell regulation

2. Cell maintenance

53
Q

What injury can develop when a toxicant affects a target molecule involved with regulation?

A
  1. Dysregulation of gene expression

2. Dysregulation of ongoing cell function

54
Q

What injury can develop when a toxicant affects a target molecule involved with cell maintenance?

A
  1. Impaired internal maintenance

2. Impaired external maintenance (e.g. bleeding)

55
Q

What are three (3) outcomes that occur when there is dysrepair from cellular injury?

A
  1. Oragn ailure
  2. Fibrosis
  3. Carcinogenesis
56
Q

What are four (4) types of toxicity?

A
  1. Cell death/tissue injury
  2. Altered phenotype/function
  3. Immunological hypersensitivity
  4. Cancer
57
Q

What are two (4) mechanisms of drug toxicity?

A
  1. On-target (mechanism based) toxicity
  2. Off-target (unintended receptor) toxicity
  3. Immunological (hypersensitivity)
  4. Biological activation
58
Q

What are two (2) drug examples of on-target toxicities?

A
  1. Statins

2. Diphenhydramine

59
Q

What is a drug example of an off-target toxicity?

A

Thalidomide

60
Q

What are three (3) broad considerations when determining toxicity?

A
  1. Overdose
  2. Drug-drug interactions
  3. Adverse effects (of the drug)
61
Q

What are two (2) key anatomical parts of the liver?

A
  1. Portal triad [blood enters liver]

2. Terminal hepatic vein [blood exits liver]

62
Q

What are the three (3) parts of the Portal triad?

A
  1. Portal vein
  2. Hepatic artery
  3. Bile duct
63
Q

What is the difference between the orientations of the lobule and the acinus of the liver? (2 components)

A
  1. The lobule is oriented with the Terminal Hepatic Vein in the center.
  2. The Acinus is oriented with the Portal triad in the center.
64
Q

Describe the acinus (2 components)

A
  1. Centered at the portal triad,

2. Three zones of metabolic regions that are increasingly distant from blood supply.

65
Q

What are notable component gradients in Zone 1 of the acinus?

A
  1. Higher O2

2. Higher Glutathione (GSH)

66
Q

What are notable component gradients in Zone 3 of the acinus?

A
  1. Higher CYP

2. Higher Epoxide Hydrolase

67
Q

What are four (4) notable liver injuries?

A
  1. Fatty liver [steatosis]
  2. Immune-mediated response
  3. Canalicular cholestasis
  4. Fibrosis and Cirrhosis
68
Q

What are two (2) serum biomarkers for liver injury?

A
  1. ALT [alanine transaminase]

2. AST [aspartate transaminase]

69
Q

What is a biomarker for biliary duct obstruction (cholestasis)?

A

ALP [alkaline phosphatase]

70
Q

In the bioactivation of ultimate carcinogens, what are three (2) ways to yield the nitrenium ion?

A
  1. Oxidation of amine (CYP, NADPH, O2, H+)
  2. Acetylation (NAT, Acetyl CoA) on N-OH followed by leaving of acetic acid.
  3. Sulfation (SULT/PAPS) on N-OH followed by leaving of HOSO3-
71
Q

In the metabolism of DNA-reactive metabolites, what is a detoxification mechanism?

A

Glutathione (GSH) + Glutathione-S-Transferase (GST)

72
Q

Describe a probit plot (3 components)

A
  1. Generated from population data where the response is all-or-none.
  2. Constructing using standard deviations, with 1 standard deviation from the mean representing 68% of the population.
  3. Provides information on how a population responds to a drug at varying doses.

Pharmaceutical Sciences (9 decks)

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