Hepatic Drug Metabolism

Question 1

Describe what active drugs are converted into in the liver and what the purpose of this is.

Answer 1

They are converted to inactive compounds in the liver to promote excretion by the kidneys

Question 2

What is a pro-drug?

Answer 2

Inactive compounds that become active after metabolism

Question 3

Give 2 advantages of using pro-drugs.

Answer 3

The prevention of adverse / side effects

Improved distribution

Question 4

Give an example of an opioid pro-drug and its active form.

Answer 4

Codeine (inactive pro-drug) is converted to morphine (active form)

Question 5

What is first-pass metabolism?

Answer 5

Orally-administered drugs, absorbed by the GI tract, are transported through the liver via the portal system where they are metabolised to an extent before entering the systemic circulation

Question 6

Give the 3 biochemical pathways of drug metabolism in the liver, what is produced or their purpose.

Answer 6

Phase I reactions produce intermediate metabolites. Phase II reactions produce conjugated metabolites. Phase III involves the transport of the drug for excretion via the kidneys or bile

Question 7

What are the 3 main types of Phase I reactions?

Answer 7

Oxidation
Reduction
Hydrolysis

Question 8

What is the purpose of Phase I reactions? Give examples.

Answer 8

To provide a functional group, such as OH or NH2

Question 9

What effect does providing a functional group have on the drug?

Answer 9

It increases the polarity of the drug and provides a site for Phase II reactions

Question 10

What effect do Phase I reactions have on the pharmacological activity of drugs and pro-drugs?

Answer 10

They decrease the pharmacological activity of drugs and increase the pharmacological activity of pro-drugs

Question 11

What are the cytochrome P450 enzymes and where are they located?

Answer 11

A superfamily of enzymes located on the smooth endoplasmic reticulum of hepatocytes

Question 12

What do cytochrome P450 enzymes contain which allows them to capture oxygen?

Answer 12

Haem

Question 13

What 3 things do cytochrome P450 enzymes require the presence of in order to function?

Answer 13

Molecular oxygen

NADPH

NADPH cytochrome P450 reductase

Question 14

Which kind of steps does the process of drug oxidation by cytochrome P450 involve?

Answer 14

Oxidation + reduction steps

Question 15

Describe what cytochrome P450 does to oxygen atoms during oxidation.

Answer 15

It catalyses the transfer of one oxygen atom to the substrate (drug) while the other oxygen atom is reduced to water

Question 16

Describe 2 oxidations that do not involve the CYP450 system.

Answer 16

Ethanol is metabolized by alcohol dehydrogenase (cytosolic enzyme)

Monoamine oxidase enzymes inactivate many biologically active amines (e.g. noradrenaline, serotonin, dopamine)

Question 17

Other than the liver, where else can hydrolytic reactions occur?

Answer 17

Plasma and many tissues

Question 18

Give a common medication which is hydrolysed in the body and what it forms.

Answer 18

Aspirin – hydrolysed to salicylic acid

Question 19

Phase II reactions involve which process and what does this involve?

Answer 19

Conjugation – the attachment of a large chemical group to a functional group on the drug molecule

Question 20

Describe conjugated drugs post Phase II reactions in terms of their pharmacological activity and affinity for water.

Answer 20

Pharmacologically inactive and hydrophilic

Question 21

List 5 chemical groups involved in conjugation.

Answer 21

Glucuronyl
Acetyl
Methyl
Aulphate
Glutathione

Question 22

How are larger drug molecules excreted from the body?

Answer 22

Via the bile

Question 23

What kind of transporters move drugs out of hepatocytes and into the bloodstream? Give 2 examples.

Answer 23

Efflux transporters. Multi-drug resistance (MDR) proteins and P-glycoproteins

Question 24

Why is drug metabolism different in neonates? How does this alter the dosage?

Answer 24

Hepatic drug-metabolizing enzyme systems are immature and renal clearance is also inefficient. Lower doses of all drugs are needed

Question 25

Why is drug metabolism different in children? Where should dosages be obtained from?

Answer 25

Metabolic clearance can be quicker in children than in adults because CYPs are mature and the relative liver mass and hepatic blood flow are higher. Dosages should be obtained from a paediatric dosage handbook

Question 26

Why is drug metabolism different in older adults?

Answer 26

Overall capacity for hepatic drug metabolism, particularly Phase I reactions, is reduced because relative liver mass and hepatic blood flow are lower

Question 27

How will CYP450 enzyme induction affect the rate of drug metabolism?

Answer 27

More rapid metabolism of drugs

Question 28

How will CYP450 enzyme inhibition affect the rate of drug metabolism?

Answer 28

Reduced metabolism of drugs

Question 29

In what way does long-term administration of drugs affect CYP450 enzyme activity and how?

Answer 29

Often induces CYP450 activity by enhancing the rate of synthesis or reducing the rate of degradation of the CYP enzymes

Question 30

In what way does St John’s Wort affect CYP450 enzyme activity?

Answer 30

Induces the activity of many CYP450 enzymes

Question 31

Give 3 drugs which St John’s Wort could interfere with.

Answer 31

Warfarin

Antiepileptic drugs

Oral contraceptives

Question 32

In what way does omeprazole affect the activity of CYP450 enzymes?

Answer 32

Relatively weak inhibitor of many CYP450 enzymes

Question 33

If omeprazole is taken alongside warfarin or phenytoin, in what way will this alter their plasma levels and how?

Answer 33

Plasma levels of warfarin and phenytoin will be increased due to the inhibition of the CYP450 enzymes, resulting in reduce drug metabolism

Question 34

Where can information on drug interactions be found?

Answer 34

British National Formulary

Question 35

What is the term for a mutation that occurs in more than 1% of the population?

Answer 35

Polymorphism

Question 36

What are the categories of polymorphisms in relation to drug metabolism?

Answer 36

Poor metaboliser

Extensive metaboliser

Ultra-rapid metaboliser

Question 37

Give 3 ways in which cirrhosis leads to an increased bioavailability of drugs.

Answer 37

Decreased drug-metabolising capacity

Hypoproteinaemia

Porto-systemic shunting directs drugs away from the liver