PK3 - Metabolism

Question 1

What are the two main outcomes of drug metabolism

Answer 1

1) Drug becomes more water soluble = better renal excretion
2) Drug may become inactivated

Question 2

What is a prodrug? Example?

Answer 2

Its an inactive drug that must be metabolized to its active form once given

ex; enalapril is metabolized into enalaprilat

Question 3

Are lipid soluble drugs readily excreted? Why or why not?

Answer 3

They are not readily excreted because they can easily diffuse out of the renal tubules through the membranes

Question 4

What type of drug solubility does the collecting duct favour?

Answer 4

Most water soluble drug molecules are excreted in the CD

Question 5

What type of drug solubility does the loop of henle favour?

Answer 5

Most lipid soluble drug molecules are reabsorbed into circulation in the LoH

Question 6

What is the main location of drug metabolism?

Answer 6

Liver

Question 7

What are the two main types of metabolic reactions?

Answer 7

• Phase 1 = non-synthetic functionalization
• Phase 2 = Biosynthetic CONJUGATION reactions

Question 8

How does phase 1 metabolism inactive drugs?

Answer 8

-By creating or uncovering reactive groups like -OH, -COOH, -NH2, -SH

-Achieved mainly through oxidation

Question 9

What is the solubility of phase 1 metabolites

Answer 9

-Usually more water soluble than the parent molecule and usually more chemically reactive

Question 10

What happens during phase 2 metabolism? What state are they in?

Answer 10

-Attach drug molecule (phase 1 metabolite) to a substance from the diet (ex; AAs)
-This produces drug conjugates that are usully polar, inactive and readily excreted

Question 11

Where are conjugation enzymes located?

Answer 11

In the cytoplasm

Question 12

What is the risk of toxic intermediates if a drug only undergoes phase 2 metabolism?

Answer 12

None

Question 13

What are the dietary components usually used for phase 2 metabolism?

Answer 13

-Glucuronic acid and glutathione are the most common

-Acetic acid, sulfate and AAs are other options

Question 14

What is special about cats and phase 2 metabolism?

Answer 14

Cats are deficient in conjugating enzymes so drugs have a longer duration of action and achieve higher concentrations

Question 15

What NORMALLY happens with metabolism of acetaminophen

Answer 15

Normally only a very small amount of it undergoes phase 1 metabolism, and most of it is simply conjugated either to glucuronic acid or sulfate

Question 16

What happens when there is an overdose of acetaminophen

Answer 16

It overwhelms the conjugation pathways. There is excess drug oxidized by P450 enzymes (phase 1) into highly reactive/toxic intermediate metabolites that damages anything it touches —> leads to liver failure if dose is high enough

Question 17

What is the intermediate metabolites oxidized in overdose situations?

Answer 17

NAPQI

Normally its conjugated to glutathione to inactivate it which makes it harmless, but when the system is overwhelmed the glutathion stores are depleted

Question 18

What can you give in an acetaminophen overdose situation?

Answer 18

Administer a source of glutathione (n-acetylcysteine) = minimizes hepatic damage

Question 19

Do all drugs go through phase 1 and 2 metabolism?

Answer 19

No, they are many different variations of drugs using both/none or one

Question 20

What factors affect the rate of drug metabolism? (6)

Answer 20

-Enzyme induction and inhibition
-Multidrug therapy
-Distribution
-Age
-Genetics
-Disease

Question 21

What can induction of metabolic enzymes lead to?

Answer 21

can also cause drug related toxicity depending on whether phase 1 or 2 enzymes are induced

Question 22

What happens to drug action when you increase rate of metabolism?

Answer 22

It usually decreases drug action

Question 23

What happens when there is induction of metabolic enzymes? (Specifically related to hepatic enzymes)

Answer 23

Many hepatic metabolic enzymes can increase in number and activity to certain chemical constituents of food; can also happen with some drugs

Question 24

What happens with inhibition of drug metabolism?

Answer 24

Certain drugs can inhibit P450 activity, mainly by competing for the same enzyme

Can result in elevated circulating levels of concurrently administered drugs

Question 25

What might happen with multidrug therapy? When is it most common?

Answer 25

-There are a finite number of hepatic enzyme molecules so some enzyme pathways can be saturated

-This is most common when multiple drugs requiring the same metabolic enzyme are administered at the same time. They compete for or inhibit the enzymes.

Question 26

How does distribution affect drug metabolism?

Answer 26

Drugs bound to plasma proteins/stored in fat arent available for metabolism

Question 27

What is the effect of age on drug metabolism?

Answer 27

-Neonates/geriatric patients can be relatively deficiency in metabolic capacity
-Hepatic blood flow might be reduced in heart failure which inhibits drug metabolism

Question 28

What effect can genetics have on drug metabolism?

Answer 28

Levels of drug metabolizing enzymes can very between individuals due to genetic polymorphisms

Question 29

How does health and disease affect drug metabolism? (3)

Answer 29

-Poor nutrition can cause deficiency in dietary substances needed for conjugation
-Endocrine dz, liver dz, infectious/inflamm dz = inhibition of drug metabolism
-Heart dz can impair blood flow to liver