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PHARMACOLOGY - 1 > 4 – Metabolism > Flashcards

4 – Metabolism Flashcards

1
Q

Biotransformation

A
  • The lipophilic nature of drugs that allow them to diffuse across cell membranes is also a HINDRANCE to their elimination from the body
    o *it’s essential to biotransformation drugs to more water-soluble metabolites
  • Main determinant of a drugs half-life
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2
Q

Biotransformation enzymes

A
  • Convert lipophilic drugs into highly water-soluble metabolites that are easily excreted from the body
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3
Q

Categorization of biotransformation reactions

A

-phase 1
-phase 2

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4
Q

Phase 1

A

o Enzymes modify drugs mainly by OXIDATION
 Ex. add an hydroxyl group
o Cytochrome P450-dependent monooxygenases (CYPs)

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5
Q

Phase 2

A

o CONJUGATE the drug with a high polar endogenous compound in the cell
 Ex. CHO, sulphate, acetate

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6
Q

Sites of drug biotransformation

A
  • Liver: high (MOST IMPORTANT)
  • Lung, kidney, intestine: medium
  • Skin, testes, placenta, adrenals: low
  • NS: very low
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7
Q

Cytochrome P450-dependent monooxygenases (CYPs)

A
  • Add or expose a polar functional group to lipophilic drug molecule
  • Located on smooth endoplasmic reticulum
  • Monooxygenase: catalyze the insertion of an oxygen atom
  • *also involved in a wide variety of catabolic and anabolic reactions involving endogenous compounds (ex. steroid hormones)
  • *usually INACTIVATE and drug, but sometimes can BIOACTIVATE a drug
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8
Q

Cytochrome P450-dependent monooxygenases (CYPs): BROAD

A

o One enzyme can bio transform many drugs

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9
Q

Cytochrome P450-dependent monooxygenases (CYPs): OVERLAPPING

A

o One drug can be biotransformed by several enzymes

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10
Q

Hepatic portal venous system

A
  • Delivers all substances absorbed from the gut to the liver BEFORE they reach systemic circulation
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11
Q

“First-pass effect”

A
  • Can result in nearly complete INACTIVATION (>90%) of certain drugs after oral ingestion
    o Why certain drugs are NOT given orally
     Intravenous administration will bypass the ‘first-pass effect’
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12
Q

Oral bioavailability

A
  • Fraction of an orally administered drug that reaches the systemic circulation in an unchanged form
  • Bioavailability = area under the curve oral / area under the curve IV
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13
Q

Phase 2: examples

A
  • Glucuronidation
  • Sulfation
  • Acetylation
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14
Q
  • Glucuronidation
A

o Enzyme: UDP-glucuronosyl transferase (UDP-GT or UGT)
o Cofactor: UDP-glucuronic acid
o Location: smooth ER membrane
 Probably why it is a major phase II enzyme as it is located by CYP
o *cats can’t do it
 Ex. don’t give them acetaminophen

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15
Q
  • Sulfation
A

o Enzyme: sulfotransferase (ST)
o Cofactor: PAPS
o *pigs are poor sulfators

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16
Q

Glutathione conjugation

A
  • One of our most important defenses against electrophiles (ex. ROS and epoxides)
  • Enzyme: Glutathione S-transferase (GST)
    o Abundant
    o Approximately 5% of cytosolic protein in liver cells
  • Cofactor: Glutathione (GSH)
    o mM concentrations in most cells (LARGE)
  • *THIS IS YOUR BESTY
16
Q
  • Acetylation
A

o Enzyme: N-acetyltransferase (NAT)
o Cofactor: acetyl coenzyme A
o *dogs are poor acetylators

17
Q

Genetic and environmental factors influencing biotransformation

A
  1. Enzyme induction and inhibition
  2. Intraspecific differences
  3. Interspecific differences
  4. Sex and age
  5. Diet (nutritional factors)
  6. Disease (underlying pathology)
18
Q

Enzyme induction and inhibition

A
  • CYP enzymes and phase 2 enzymes
  • Very clinically relevant w/respect to duration of drug action and drug interactions
  • Depletion of cofactors (ex. glutathione) can be important
19
Q

‘suicide’ inhibition

A
  • Kills the enzymes(will NEVER work again)
20
Q

Intraspecies differences

A
  • Genetic differences in expression of enzymes
  • Can result in subset of population being ‘poor metabolizers’ or even ‘rapid metabolizes
    o Ex. rapid=need to give more of a drug to get a response
  • Ex. alcohol dehydrogenase in humans
21
Q

Interspecific differences

A
  • Hexobarbital sleeping time after same dose
22
Q

Sex and age

A
  • Sex-specific differences in certain CYP enzymes
    o Why males produce more T and females produce more estradiol
  • In general, young and very old individuals have LOWER enzyme activities
23
Q

Diet (nutritional factors)

A
  • Certain ingredients can induce or inhibit phase 1 or phase 2 enzymes
  • Ex. grapefruit juice inhibits CYP3A4 in humans)
24
Q

Disease (underlying pathology)

A
  • Impaired liver or kidney function can decrease biotransformation (and excretion) of drugs

PHARMACOLOGY - 1 (12 decks)

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