Pharm 2060B Module 4

Front 1

Define metabolism/biotransformation

Back 1

enzyme mediated alteration of a drug's structure

Front 2

Name 5 sites of drug metabolism

Back 2

1. Liver (Primary Site)

2. Intestine (Enterocytes can metabolize)

3. Stomach (especially alcohol)

4. Kidney (contains many drug metabolizing enzymes)

5. Intestinal bacteria (in the lumen)

Front 3

What are two roles of drug metabolism?

Back 3

to protect us from environmental toxins, and synthesize essential endogenous molecules

Front 4

T/F - the same family of enzymes that synthesize exogenous molecules, metabolize endogenous molecules

Back 4

False. - the same family of enzymes that metabolize exogenous molecules, synthesize endogenous molecules

Front 5

Name 5 consequences of drug metabolism on the drug.

Back 5

1. The Water solubility of the drug may be increased to promote excretion. (This is the most important consequence of drug metabolism)

2. Drug Inactivation

3. Increase in drug effectiveness

4. Drug activation (prodrugs are inactive until metabolized)

5. Increase drug toxicity

Front 6

Explain first order kinetics

Back 6

In situations where the amount of free drug is less than the metabolic capacity, first order kinetics is displayed. This is when the rate of metabolism is directly proportional to the concentration of the free drug, so a constant fraction of free drug is getting metabolized per unit time (i.e. 1% per second)

Front 7

Is first order kinetic independent, or dependent of drug concentration?

Back 7

Dependent. Rate of metabolism is directly proportional to drug concentration.

Front 8

Do most drugs exhibit first, or zero order kinetics?

Back 8

First! :)

Front 9

Explain zero order kinetics

Back 9

In zero order kinetics, the concentration of the free drug is much higher than the metabolic capacity of the body. Rate of drug metabolism is constant over time. A constant amount of drug is metabolized per unit time.

Front 10

Is zero order kinetics independent, or dependent of drug concentration?

Back 10

independent. A constant amount of drug is metabolized per unit of time.

Front 11

What is a classic example of a drug that displays zero order kinetics?

Back 11

Alcohol

Front 12

What are 4 areas of first pass metabolism?

Back 12

Hepatocytes, intestinal enterocytes, stomach, intestinal bacteria

Front 13

What is the primary result of first pass metabolism

Back 13

a decreased amount of parent drug in the systemic circulation

Front 14

name 4 characteristics of high ER drugs

Back 14

Front 15

Name 4 characteristics of low ER drugs

Back 15

Front 16

What is the function of phase 1 metabolism?

Back 16

To convert lipophilic drugs to more polar molecules, facilitating excretion, by introducing or unmasking polar functional groups such as hydroxyls or amines

Front 17

What three reactions are involved in phase 1 metabolism?

Back 17

oxidation, reduction, hydrolysis

Front 18

What is the function of phase II metabolism?

Back 18

To make lipophilic drugs more polar via conjugation reactions, that is, the addition of large, water soluble molecules

Front 19

In which phase, 1 or 2, are the metabolites always less active than the parent drug?

Back 19

Phase 2. In phase 1, metabolites may be more, less, or equally as active as the parent drug

Front 20

Name 4 examples of Phase II conjugates added to drugs

Back 20

glucuronic acid, sulfate, acetate, amino acids

Front 21

What is the only phase II metabolite that is more active than its parent drug

Back 21

Morphine 6-glucuronide. It is a more potent analgesic than morphine unmetabolized.

Front 22

T/F some drugs can directly enter phase II metabolism

Back 22

True

Front 23

Where are phase I metabolic enzymes localized within cells?

Back 23

Smooth Endoplasmic Reticulum

Front 24

Where are most Phase II metabolic enzymes localized within cells? What is an exception to this?

Back 24

Most phase II metabolic enzymes are localized within the cytosol. The exception to this is glucuronidation, which is localized to the smooth ER

Front 25

CYPs are the predominant Phase ___ metabolizing enzyme. Majority of drug metabolism is performed by _______ CYP enzymes.

Back 25

CYPs are the predominant Phase I metabolizing enzyme. Majority of drug metabolism is performed by hepatic CYP enzymes.

Front 26

Describe the mechanism of action of CYP.

Back 26

CYPs oxidize drugs by inserting a molecule of oxygen onto the drug and producing water as a product

Front 27

What condition can decrease CYP activity?

Back 27

Malnutrition

Front 28

Which enzyme metabolizes that largest fraction of marketed drugs? Describe its nomenclature.

Back 28

CYP3A4. 3 is the family. A is the sub-family. 4 is the isozyme

Front 29

Name the 5 Phase II drug metabolizing enzymes.

Back 29

1. UGTs

2. SULTs

3. NATs

4. GSTs

5. TPMT

Front 30

Which Phase II metabolizing enzyme metabolizes the most drugs?

Back 30

Trick question. They're all relatively split in their metabolizing activity.

Front 31

Describe the location and mechanism of action of UGTs.

Back 31

1. They are found in the smooth ER

2. They catalyze the transfer of a glucuronic acid to a drug, making it more polar, facilitating excretion

Front 32

Describe the location and mechanism of action of SULTs.

Back 32

1. They are found in the cytosol of cells

2. Catalyze the transfer of a sulfate group to the hydroxyl group of drugs. This makes the drug more polar, facilitating excretion

Front 33

Describe the location and mechanism of action of NATs.

Back 33

1. Found in the cytosol

2. Catalyze the transfer of an acetyl group from acetyl CoA to a drug

Front 34

Describe the location and mechanism of action of GSTs.

Back 34

1. Found either in the cytosol or microsomes

2. Catalyze the transfer of a glutathione molecule to a drug, an intracellular anti-oxidant, rendering the metabolite less toxic.

Front 35

Describe the location and mechanism of action of TPMT.

Back 35

1. Found in the cytosol

2. catalyze the transfer of a methyl group to a drug.

Front 36

What are the 4 factors that affect drug metabolism?

Back 36

1. Age

2. Drug Interactions (enzyme induction and inhibition)

3. Disease State

4. Genetic Polymorphisms

Front 37

By what age do humans reach adult-levels of drug metabolizing enzymes?

Back 37

2 years old

Front 38

________ can induce CYP enzymes

Back 38

Smoking

Front 39

Name 3 consequences of enzyme induction/increased drug metabolism

Back 39

1. Decreased drug plasma concentration

2. decreased drug activity (if metabolite is inactive)

3. increased drug activity (if metabolite is active)

Front 40

Name 3 consequences of enzyme inhibition/decreased drug metabolism

Back 40

1. higher drug plasma concentration

2. increased therapeutic effects of drugs

3. Increased toxicity of drugs

Front 41

Name 4 diseases that decrease CYP activity

Back 41

1. Liver Disease

2. Kidney Disease

3. Inflammatory Disease

4. Infection

Front 42

Name the two enzymes affected by phase I SNPs

Back 42

1. CYP2C9

2. CYP2D6

Front 43

Name the effect of SNPs on CYP2C9

Back 43

CYP2C9 metabolizes the anticoagulant Warfarin. Polymorphisms decrease CYP2C9 activity. If Warfarin dose is not lowered, then patients may experience extensive bleeding

Front 44

Name the effects of SNPs on CYP2D6

Back 44

This enzyme metabolizes codeine to morphine, which is a more potent analgesic. 4 phenotypes can arise from the polymorphisms.

1. Poor metabolizer. No analgesic effect.

2. Intermediate metabolizer. Reduced metabolic activity

3. Extensive metabolizer. Normal metabolic activity.

4. Ultra-rapid metabolizer. Significantly higher metabolic activity. More potent analgesic effects, but more susceptible to side effects.

Front 45

Name 2 Phase II enzymes SNPs can affect

Back 45

1. UGT1A1

2. NAT2

Front 46

Describe the effect of SNPs on UGT1A1

Back 46

UGT1A1 glucuronidates the anti-cancer drug SN 38. Polymorphisms decrease enzyme activity, causing the patient to experience possible side effects of the drug, that is diarrhea and bone marrow suppression

Front 47

Describe the effect of SNPs on NAT2

Back 47

Polymorphisms can cause individuals to become rapid acetylators or slow acetylators to isoniazid. Slow acetylators are susceptible to increased drug toxicity, and certain cancers.