Intro Drug Biotransformation, Pharmacogenomics, And Clinical Drug Trials-lecture + CIS-Kruse Flashcards

(31 cards)

1
Q

Acetylsalicylic acid (aspirin) –> acetic acid + salicylate

This is an example of ___

A

Inactivation

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2
Q

Diazepam –> Oxazepam

This is an example of ___

A

Active compound –> active compound

-biotransformation into another active compound

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3
Q

L-dopa –> dopamine

This is an example of ___

A

Activation

-prodrug- an inactive drug that undergoes biotransformation to become an active drug (L-dopa in an inactive or pro-drug)

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4
Q

Where does biotransformation mostly occur?

A

In the liver at some point between absorption into the general circulation and renal elimination

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5
Q

__ is the process by which oral drugs undergo extensive biotransformation after absorption prior to entering circulation

A

1st pass effect

Drugs administered parenterally do not undergo 1st pass biotransformation

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6
Q

The 1st pass effect greatly limits the bioavailability of some drugs such that alternative routes of administration must be explored. List a classic example of this

A

Morphine

Ora bioavailability is roughly 25% so parenteral administration is preferred

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7
Q

As a general rule:

__ result in the biological inactivation of the drug

___ produce a metabolite with improved water solubility and increased molecular weight (enhances elimination)

A

Phase 1 rxns

Phase 2 rxns

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8
Q

__ consist of enzymes that convert the parent drug to a more polar metabolite

A

Phase 1 rxns

  • catabolic
  • phase 1 products can be more reactive and sometimes more toxic than the parent drug
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9
Q

___ consist of enzymes that form a conjugate of the substrate

A

Phase 2 rxns

  • conjugation with endogenous substrates to improve water solubility and increase MW
  • anabolic
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10
Q

Phase 1 is usually followed by phase 2. List an exception to this:

A

Isoniazid –> used for TB tx, acetylated 1st by N-acetyltransferase

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11
Q

What types of rxns comprise phase 1 rxns?

A

Oxidations, reductions, and hydrolysis

-products are generally more reactive and may be more toxic than the parent drug

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12
Q

Where are phase 1 enzymes located?

A

In lipophilic ER membranes of the liver (and other tissues)

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13
Q

List some well-characterized enzyme-inducers:

A

Phenobarbital, chronic ethanol (higher CYP450 2E1), benzo[a]pyrene (tobacco smoke), rifampin, st johns wort

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14
Q

List some well-characterized enzyme inhibitors:

A

Grapefruit juice

Compound in juice that inhibits CYP450 enzymes, that will then effect steady state dose of drug you are taking

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15
Q

List ways in which acetaminophen is normally metabolized:

A

95% glucuronidation and sulfation

5% P450-dependent GSH conjugation

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16
Q

Describe glucuronidation and sulfation pathways in acetaminophen toxicity:

A

They are saturated and P450 pathways become increasingly important. Over time, hepatic GSH is depleted faster than is regenerated and toxic metabolites accumulate resulting in hepatotoxicity

17
Q

__ is the study of differences in drug response d/t allelic variation in genes affecting drug metabolism, efficacy, and toxicity at the genomic level

A

Pharmacogenetics

18
Q

__ is the study of the entire genome to assess multigenetic determinants of drug response

A

Pharmacogenomics

19
Q

___ is a variation in the DNA sequence that is present at an allele frequency of 1% or greater in a population

20
Q

Describe drug-response variability & genetics in relation to pharmacokinetics:

A

Variation in the rate at which the body absorbs, transports, metabolizes, or excretes a drug/metabolites

21
Q

Describe drug response variability & genetics as it relates to pharmacodynamics:

A

Allelic variation in a drugs downstream targets, such as receptors, enzymes, or metabolic pathways

22
Q

Polymorphisms in CYP450s can result in absent, decreased, or increased enzyme activity. Describe poor metabolizers vs ultrafast metabolizers:

A

Poor metabolizers are at risk for accumulation of toxic drug levels

Ultrafast metabolizers are at risk for being undertreated with inadequate doses

23
Q

this enzyme deficiency is the most common disease-producing enzyme defect of humans. Deficiencies cause oxidative damage that leads to hemolytic anemia in the presence of oxidants

A

Glucose-6-phosphate DH deficiency

24
Q

What happens with adminstration of succinylcholine in an individual with a polymorphism in butyrcholinesterase?

A

Succinylcholine is a fast acting paralytic. A pt with this polymorphism will take longer to come out of a paralytic state

25
Lead compounds are associated with what type of study?
In vitro
26
What is the transition period for an investigational new drug?
Between animal testing and clinical testing
27
__ is the maximum dose at which a specified toxic effect is not seen
No-effect dose
28
__ is the smallest dose that is observed to kill any experimental animal under a defined set of conditions
Minimum lethal dose (LDmin)
29
__ is the dose that kills approximately 50% of the animals
Medial lethal dose (LD50)
30
__ is measured to assess a drug's effect (e.g., BP for testing an antihypertensive agent
Endpoint
31
The general strategy for eliminating compounds involves biotransformation into ___ derivatives
More polar, and sometimes larger -polar and water-soluble products are more readily excreted by the kidneys