Drug metabolism and excretion

Question 1

What is metabolism

Answer 1

Removal of lipid-soluble drug molecules to prevent reabsorption by kidneys

Question 2

How is metabolism achieved

Answer 2

Converting drugs into water-soluble molecules

Question 3

Where does metabolism occur

Answer 3

Mostly in the liver, but also in plasma, lung and intestinal epithelium

Question 4

What is excretion

Answer 4

Removal of drug/metabolites form the body

Question 5

How does excretion occur

Answer 5

Mostly in urine, but also via bile/faeces, sweat, tears, saliva, exhaled air and breast milk

Question 6

What is clearance

Answer 6

The volume of plasma cleared of drug per unit time

Question 7

What drug has a constant clearance

Answer 7

A drug that obeys first order kinetics

Question 8

What is the plasma clearance for a drug that is removed by liver metabolism and kidney excretion

Answer 8

Plasma CL = Hepatic CL + Renal CL

Question 9

What determines the amount of drug available at the site of action

Answer 9

Metabolism and clearance

Question 10

What are safety issues when it comes to drug metabolism

Answer 10

1. Metabolism produces new chemical entities that may have their own effect
2. Components of racemic molecules (D/L isomers) may be handled differently

Question 11

Why do most drugs undergo metabolism prior to removal

Answer 11

To increase excretion

Question 12

What are prodrugs and give an example

Answer 12

Drugs that are activated by metabolism

e.g. enalapril into active form enalaprilat by esterases

Question 13

Some drugs are eliminated unchanged, give an example

Answer 13

Digoxin

Question 14

Phase 1 of drug metabolism

Answer 14

• Main process is oxidation within the liver

- Addition of oxygen molecules to carbon, nitrogen and sulphur molecules in drug structure

Question 15

What is phase 1 of drug metabolism carried out by and how

Answer 15

Carried out by cytochrome p450 enzymes
It binds the drug to an O2 molecule
One oxygen is used to oxidise the drug, one is used to reduce water

Question 16

Why is it a problem that phase 1 only used one type of enzyme

Answer 16

Since either the enzymes will be saturated or the rate at which the body can metabolise the drug will be slowed down since they are competing for active sites

Question 17

Phase 2 of drug metabolism

Answer 17

Increases water solubility of drug excretion

Question 18

How is phase 2 of drug

metabolism carried out and give an example

Answer 18

Joins the phase 1 product with an endogenous substance, normally a large molecule, through the production of stable covalent bonds
e.g. glucuronidation (reaction with glucose)

Question 19

Which drug is an exception to this metabolism process and how

Answer 19

Paracetamol
Goes straight to phase 2 by undergoing either glucuronidation or sulphate conjugation creating one of two safe products
These are excreted quite readily by the kidney

Question 20

What happens when you overdose on paracetamol

Answer 20

The phase 2 enzyme will be saturated making the body to undergo phase 1 metabolism, this produces a toxic intermediate (NAPQI) that covalently binds to proteins changing their structure
Phase 2 of this pathway is glutathione conjugation which is a safe molecule

Question 21

Why are alcoholics more likely to have the toxic metabolite accumulated

Answer 21

There is an up regulation of cytochrome p450 therefore they are more likely to go down the phase 1 pathway

Question 22

What does glomerulus filtration depend on

Answer 22

The amount of drug bound to plasma proteins

Question 23

Why is it key to make drugs water-soluble

Answer 23

Since when molecules pass through tubules they are concentrated, creating a large concentration gradient for reabsorption

Question 24

What is tubular secretion

Answer 24

Acid/base molecule carriers transporting molecules into tubular fluid, lower levels of unbound drug in plasma

Question 25

What does excretion =

Answer 25

Filtration - reabsorption + secretion

Question 26

What is renal clearance

Answer 26

The volume of plasma cleared of drug per unit time in one pass through the kidey

Question 27

How does age affect drug metabolism and excretion

Answer 27

Cyto p450 activity reduced in neonates/elderly
glomerular filtration rate is reduced greatly in neonates/elderly
increased fat % in elderly

Question 28

How does genetics affect drug metabolism and excretion

Answer 28

45% in Europe and USA and 80-90% of asians have fast acetylators

Question 29

How does disease affect drug metabolism and excretion

Answer 29

Liver diseases impairs drug metabolism

Renal diseases may alter pharmokinetics