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Pharmacology > Metabolism > Flashcards

Metabolism Flashcards

1
Q

How is being lipophilic both a negative and a positive in terms of drugs?

A

Positive: allows for molecule to diffuse across cell membranes and access target tissues

Negative: makes it hard for the body to eliminate the drugs after their use; because kidney reabsorption back into systemic circulation

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2
Q

Importance of biotransformation

A

The metabolism of drugs by enzymes to more water-soluble metabolites allows them to be excreted (urine, bile, feces)

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3
Q

What does a drug’s duration of action depend on?

A

duration of action is inversely proportional to the rate at which they are metabolically inactivated

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4
Q

What is the main determinant of a drugs half life?

A

Biotransformation of the drug

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5
Q

How are biotransformation reactions categorized?

A
  1. Phase 1
  2. Phase 2
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6
Q

Phase I biotransformation rxn

A

-Biotransformation enzymes modify the lipophilic drug molecule mainly by oxidation (adding an OH group, or exposing COOH and NH2) to make them more water soluble

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7
Q

Phase II biotransformation rxn

A

Synthetic rxns that conjugate the drug with a highly polar endogenous compound in the cell (eg. carbohydrate, sulphate, acetate) greatly increasing their water solubility

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8
Q

Which organ is the most important for drug biotranformation?

A

Liver!

Followed by lung, kidney, intestines. Then skin, testes, placenta, adrenals.

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9
Q

Why does the nervous system have very low metabolizing enzymes for drug biotransformation?

A

Because metabolizing enzymes can become dangerous molecules (such as ROS) so don’t want this to occur in nervous system

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10
Q

Most important Phase I biotransformation rxn

A

Oxidation

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11
Q

Important phase II biotransformation rxns

A
  • Sulphation
  • Glucuronidation
  • Glutathione conjugation
  • Acetylation
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12
Q

Cytochrome P450-dependent monooxygenases (CYPs)

A

-major phase I oxidative enzymes

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13
Q

Where are CYP enzymes located?

A

smooth ER

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14
Q

Simple example of Phase I biotransformation rxn (hydroxylation)

A

Drug (RH) + O2 + NADPH –> Metabolite (ROH) +H2O + NADP+

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15
Q

Other than biotransformation rxns, what else are CYPs used for?

A

Used in many catabolic and anabolic reactions involving endogenous compounds (eg. steroid hormones originally derived by cholesterol)

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16
Q

CYP enzyme family

A

-more than 100 different CYP enzymes
-have broad and overlapping substrate specificities

17
Q

Define broad and overlapping in terms of substrate specificities

A

Broad: one enzyme can biotransform many drugs

Overlapping: one drug can be biotransformed by several enzymes

18
Q

CYP causing bioactivation of a drug instead of inactivation

A

CYP enzymes can sometimes bioactivate a drug making them more pharmacologically or toxicologically active

19
Q

Phenacetin and acetaminophen examples

A

CYP enzymes can bioactivate phenacetin, snipping the molecule forming an OH group= Acetaminophen

20
Q

Parathion and paraoxon example

A

CYP enzymes can bioactivate parathion, adding an S group = Paraoxon

**Paraoxon is a strong inhibitor of acetylcholinesterase (stop signal for cholinergic pathways)

21
Q

Hepatic portal venous system

A

-strategy to intercept and detoxify substances ingested (oral route)

-all substances are absorbed from the gut to the liver for biotransformation before they reach systemic circulation

22
Q

First pass effect

A

Results in nearly complete inactivation (more than 90%) of certain drugs after oral ingestion

**Reason why certain drugs are not given orally and are administered via different routes

23
Q

Oral bioavailability

A

The fraction of an orally administered drug that reaches the systemic circulation in an unchanged form

24
Q

Bioavailability eqn

A

Bioavailability= AUC (oral) / AUC (IV)

AUC=area under curve
Curve= concentration of drug in blood over time

25
Q

What molecules are being looked for during a blood test?

A

Phase II biotransformation molecules

26
Q

Glucuronidation

A

-major phase II biotransformation pathyway in mammals
-enzymes for it located on smooth ER

27
Q

Glucuronidation enzyme and cofactor

A

Enzyme: UDP-glucuronosyl transferase (UDP-GT or UGT)

Cofactor: UDP-glucuronic acid

28
Q

Why should acetaminophen not be given to cats?

A

Cats have low levels of UDP-GT so they are unable to biotransform acetaminophen and rid it from the body

29
Q

Sulfation enzyme and cofactor

A

Enzyme: sulfotransferase (ST)

Cofactor: PAPS

30
Q

Acetylation enzyme and cofactor

A

Enzyme: N-acetyltransferase (NAT)

Cofactor: acetyl coenzyme A

31
Q

Glutathione conjugation

A

-extremely important defense against ROS and epoxides

**1:100 O2 molecules are converted to superoxide radical

32
Q

Glutathione conjugation enzyme and cofactor

A

Enzyme: Glutathione S transferase

Cofactor: Glutathione (GSH)

33
Q

Factors influencing biotransformation

A

1.Enzyme induction and inhibition
2. Intraspecific differences
3. Interspecific differences
4. Sex and Age
5. Diet
6. Disease

34
Q

Enzyme induction and inhibition

A

-CYP enzymes and phase 2 enzymes can all be induced and inhibited
- affects duration of drug action and inhibitions
-can also be affected by depletion of cofactors

35
Q

Intraspecific differences

A

-genetic differences in the expression of enzymes= can lead to poor metabolizers or rapid metabolizers in the population

Ex. Alcohol dehydrogenase (ADH) in humans

36
Q

Interspecific differences

A

-Difference animals have differences in biotransformations

-Cats poor glucuronidators (UDP-GT)
-Dogs poor acetylators (NAT)
-pigs poor sulfators (ST)

37
Q

Sex and Age

A

-sex specific differences in certain CYP enzymes… often young and old individuals have lower enzyme activities

38
Q

Diet

A

-certain dietary ingredients can induce or inhibit phase I or phase II enzymes

ex. grapefruit juice inhibits CYP3A4 in humans

39
Q

Disease

A

-impaired liver or kidney function can decrease biotransformation and therefore excretion of drugs

Pharmacology (33 decks)

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