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Medicinal Chemistry > Drug Metabolism Pt 1 > Flashcards

Drug Metabolism Pt 1 Flashcards

Importance of Drug Metabolism

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1
Q

Importance of Studying Drug Metabolism List A-F

A
  • A. Termination of Drug Action
  • B. Bioactivation
  • C. Drug Interactions
  • D. Stereochemical Implications
  • E. Control of Metabolism
  • F Metabolism Concept Map
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2
Q

List Phase 1 Reactions. Oxidations (1-6)

A
    1. Cytochrome P450
    1. Aromatic Hydroxylation
    1. Olefin OxidListation (Epoxidation)
    1. Aliphatic Hydroxylation
    1. Heteroatom Oxidations
    1. Oxidation of Alcohols-Aldehydes-Acids
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3
Q

List Phase 1 Reactions.

Reductions (1-2)

A
  1. Aldehyde Reductions
  2. Ketone Reductions
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4
Q

List Phase 1 Reactions.

Hydrolysis (1-2)

A
  1. Ester Hydrolysis
  2. Amide Hydrolysis
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5
Q

List Phase 2 Reactions. A-C

A
  • A. Glucuronidation
  • B. Sulfate Formation
  • C. Glutathione Conjugation
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6
Q

List Factors affecting Drug Metabolism

A-J

A
  • A. Cytochrome P450 Multiplicity (isoforms)
  • B. Age
  • C. Species
  • D. Gender
  • E. Pregnancy
  • F. Environmental Considerations (smoking)
  • G. Disease
  • H. Enzyme Induction
  • I. Enzyme Inhibition
  • J. Heredity/Genetics (pharmacogenomics)
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7
Q

Metabolism can terminate drug action by ___(1-3).

A
  1. Bio-inactivation
  2. De-toxification
  3. E-limination
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8
Q

Example of Bio-inactivation.

A

Esterase breaks drug molecule into 2 cmpds.

Ex Procaine

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9
Q

Example of Detoxification pathway used in Med Chem.

A

Antabuse–a planned poison, alcoholic drinks ethanol and he gets sick, due to build-up of aldehyde that is no longer converted to acid.

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10
Q

Example of Elimination.

A

Acetominophen is converted to sulfate (more polar), then a sugar is added, to make it water soluble and easily excreted.

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11
Q

Expect 90% of Drug Metabolism to lead to …

A

Termination of Drug Action via:

  • Bio-inactivation
  • Detoxification
  • Elimination
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12
Q

Expect 10% of Drug Metabolism to lead to …

A

Bioactivation via:

  • Active Metabolites
  • Prodrugs
  • Toxification
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13
Q

Example of Bioactivation.

A

Imipramine (patented drug) had surprise active metabolite. Imipramine to Desipramine.

2nd company came along and patented Desipramine

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14
Q

Common train of Bioactivation:

A

Drug Activity goes up and stays up due to active metabolites.

Discover active metabolites via monitoring–PK

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15
Q

Bioactivation can be used to reduce side effects.

Prodrugs are designed to be activated by Metabolism.

A

Example NSAID. Sulindac (prodrug/less GI upset) a sulfoxide Metabolism reduces to a sulfide, Sulindac Sulfide (active)

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16
Q

Bioactivation can lead to toxicity. Toxigenic Metabolism. Give an example.

A

MPTP–>MPDP–>MPP+ (neurotoxin. -contaminant in illegal drugs was metabolized into neurotoxin that kills dopaminergic neurons and causes parkinsonism.

17
Q

Metabolism can also be the cause of Drug Interactions. Give an example involving Warfarin.

A

Warfarin, blood thinner, can build up if the patient is simultaneously treated with Chloramphenicol (antibiotic) Chloramphenicol blocks CYP450 from breaking down Warfarin (so it stays in system).

18
Q

What is an example of a stereochemical implication of drug metabolism?

A

Racemic mixture of Ibuprofen. S-Ibuprofen is active, R-Ibuprofen is inactive. Body inverts R–>S form and you get a kind of prodrug effect. all is good.

19
Q

Give an example where stereochemical implications lead to toxic effect.

A

Benoxaprofen is active in S- and inactive in R-. R–>S conversion occurs here. But the elderly do not perform the R-S conversion so R-isoform builds up and becomes toxic.

  • This ex. shows that pure S-stereo-isoforms are the best design.
20
Q

If you can predict metabolic pathways you can:

A
  • avoid toxigenic pathways
  • speed up metabolism
  • slow down metabolism
21
Q

Knowledge of the Drug Metabolism is absolutely required by the FDA because:

A

It clearly affects “efficacy” and “toxicity”

22
Q

Remember that Chronic Therapy =

A

Chronic Exposure

Medicinal Chemistry (8 decks)

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