Metabolism Of Drugs

Question 1

What are the 3 types of metabolism of drugs?

Answer 1

1) drug metabolism as a mechanism of termination of drug action
2) drug metabolism as a mechanism of drug activation
3) drug elimination without metabolism

Question 2

How does drug metabolism as a mechanism of termination of drug action work?

Answer 2

Action of drug is terminated before excreted b/c they are metabolized to biologically inactive derivatives, resulting in more polar, less lipid-soluble drugs, making for less renal reabsorption and more drug excreted

Question 3

How does drug metabolism as a mechanism of drug activation work?

Answer 3

• Some drugs are inactive as they are administered (prodrugs), having to be metabolized in the body to become active
• Many drugs are active as administered and have active metabolites as well
• other drugs have toxic metabolites

Question 4

How does drug elimination without metabolism work?

Answer 4

Some drugs such as lithium are not modified by the body, and continue to act until they are excreted

Question 5

How is phase 1 of metabolism accomplished?

Answer 5

By enzymes (cytochrome P450) found in smooth endoplasmic reticulum; these enzymes make slight modification to the drug to make it more water-soluble, making it easier to get rid of

Question 6

What type of reactions do phase 2 types of metabolism involve?

Answer 6

Conjugation reactions, where an endogenous substrate is conjugated to the drug via the actions of a transferase enzyme (attach another substance with similar high molecular weight = transferase enzyme)

Question 7

In phase 2 types of metabolism, what is the relative size of the drug-conjugate in order to facilitate elimination?

Answer 7

The drug-conjugate has increased size

Question 8

Who is the phase 2 metabolism system lacking in?

Answer 8

Neonates (little kids and babies)

Question 9

The phase 2 type of metabolism is lacking in neonates, which makes them susceptible to what?

Answer 9

To drugs metabolized in this manner

Question 10

What is the most important organ for drug metabolism?

Answer 10

Liver

Question 11

Metabolism occurs via enzymes located in or on what?

Answer 11

• Smooth endoplasmic reticulum = SER (Phase 1 reactions)
• Cytoplasm (Phase 2 reactions)
• mitochondria, cell membrane

Question 12

What phase reaction occurs in the smooth ER?

Answer 12

Phase 1 reactions

Question 13

What phase reaction occurs in the cytoplasm?

Answer 13

Phase 2 reactions

Question 14

Starting with the endoplasmic reticulum, explain how you see heme

Answer 14

ER –> oxidoreductase-CYP complex (enzymes) –> CYP-oxidoreducatase complex (heme complex) –> iron-protoporphryrin IX (Heme)

Question 15

What enzymes are named with the root CYP?

Answer 15

Cytochrome p450 enzymes

Question 16

Cytochrome p450 enzymes are named with a root ____ followed by a number designating the family, letter denoting the subfamily, and another number designating the form.

Answer 16

CYP (“sip”)

Question 17

What is the family, subfamily, and gene number for CYP3A4?

Answer 17

Family = 3
Subfamily = A
Gene number = 4

Question 18

How many CYPs are there that metabolize drugs in humans?

Answer 18

12

Question 19

What are the most active CYPs for drug metabolism?

Answer 19

CYP2C
CYP2D
CYP3A (which CYP3A4/5 metabolizes about 50% of all drugs)

Question 20

Which phase of metabolism reactions involves oxidation, reduction, and hydrolysis?

Answer 20

Phase 1 reactions

Question 21

Phase 1 reactions utilize what type of oxidation?

Answer 21

Cytochrome P450-dependent oxidation

Question 22

Drugs which increase the expression of p450 enzymes (induce liver to make more enzymes)

Answer 22

CYP Inducers

Question 23

Drugs which will reduce the plasma level and therefore the effectiveness of the substrate drug (assuming metabolism inactivates the substrate)

Answer 23

CYP inducers

Question 24

What does reducing the effectiveness of the substrate drug do for the drug?

Answer 24

It reduces the drug, metabolizing more of them

Question 25

Examples of CYP Inducers:

Answer 25

-Benzopyrenes (induce liver to make more enzymes) in cigarette smoke -Chronic ethanol -Barbiturates -Carbamazepine (seizure drug) -Rifampin (antibiotic used for Tuberculosis) "Smoking and drinking in Barb's Car Rif's her Fin"

Question 26

Example: In a patient taking oral contraceptives who is later prescribe rifampin for a bacterial infection, predict what happens next:

Answer 26

- induce more liver enzymes --> decreases BC drug's effectiveness --> PREGGO!!! - instead, use different antibiotic or use other contraceptives

Question 27

Drugs which decrease the expression of p450 enzymes

Answer 27

CYP Inhibitors

Question 28

Drugs which will increase the plasma level, and therefore increase the toxicity risk of the substrate drug (assuming metabolism inactivates the substrate)

Answer 28

CYP Inhibitors

Question 29

When does watching taking CYP inhibitors matter most?

Answer 29

When the other drug you're taking has a really low therapeutic index

Question 30

Examples of CYP inhibitors:

Answer 30

- Cimetidine - Erythromycin (popular antibiotic) - Grapefruit juice (NOT GRAPE JUICE!!!!)

Question 31

Example: In a patient taking warfarin as an anticoagulant who is later prescribed cimetidine for peptic ulcers, predict what happens next:

Answer 31

Pt is more susceptible for bleeding out (blood in urine and bruising easily)

Question 32

For CYP inhibitors and CYP inducers, can one exposure change the enzymes too much?

Answer 32

Not really; you have to have regular exposure to change the enzymes

Question 33

What are the 3 main phase 2 reactions of metabolism?

Answer 33

1) glucoronidation 2) sulfation 3) acetylation

Question 34

What enzyme is associated with the phase 2 reaction of glucuronidation?

Answer 34

Glucuronosyl transferase

Question 35

Why do neonates have problems with phase 2 reactions?

Answer 35

They have reduced glucuronosyl transferase activity, not allowing them to add glucuronosyl transferase to the drug

Question 36

What enzyme is associated with the phase 2 reaction of sulfation?

Answer 36

Sulfotransferase

Question 37

What's an example of an addition of a sulfate group to the drug in a sulfation phase 2 reaction?

Answer 37

Minoxidil

Question 38

What enzyme is associated with the phase 2 reaction of acetylation?

Answer 38

Acetyltransferase

Question 39

Acetylation has genotype count variation. What does this mean?

Answer 39

Slow or fast acetylators (Slow = don't have a lot of enzymes = long 1/2 life = slow metabolism --> can cause drug-induced lupus)

Question 40

What can cause drug-induced lupus?

Answer 40

Too much administration of the slow acetylator in the phase 2 reaction, acetylation

Question 41

What do all of the examples of acetyl drugs for phase 2 reactions cause?

Answer 41

SLE

Question 42

When you administer UDP-glucuronosyl transferase to salicylic acid, which is UDP-glucuronic acid +, what happens to the size of the drug?

Answer 42

It pretty much doubles in size because you're adding more +UDP, allowing you to more readily get rid of the drug

Question 43

The first step in aspirin metabolism is in what phase?

Answer 43

Phase 1

Question 44

The second step in aspirin metabolism is in what phase?

Answer 44

Phase 2

Question 45

What phases are being used when aspirin goes through hydrolysis and then oxidation?

Answer 45

``` Phase 1 (hydrolysis) Phase 1 (oxidation) ```

Question 46

What phases are being used when aspirin goes through hydrolysis and then glucuronide (salicyl acyl)?

Answer 46

``` Phase 1 (hydrolysis) Phase 2 (glucuronide = salicyl acyl) ```

Question 47

What phases are being used when aspirin goes through hydrolysis and then glycine (salicyluric acid)?

Answer 47

``` Phase 1 (hydrolysis) Phase 2 (glycine = salicyluric acid) ```