Drugs and the liver

Question 1

What is the definition of metabolism?

Answer 1

All chemical reactions involved in maintaining the living state of the cells and the organism

Question 2

What is intrinsic clearance?

Answer 2

Theoretical unrestricted maximum clearance of unbound drug by an eliminating organ, in absence of blood flow or plasma protein binding limitations

Question 3

What is conjugation?

Answer 3

Addition of chemical groups to drugs during metabolism

Question 4

What is hydrolysis?

Answer 4

The chemical breakdown of a compound due to reaction with water

Question 5

What is reduction?

Answer 5

The loss of oxygen (gain of electrons) within a chemical reaction

Question 6

What is oxidation?

Answer 6

The gain of oxygen (loss of electrons) within a chemical reaction

Question 7

Which nutrients are metabolised by the liver?

Answer 7

Carbohydrates
Protein
Lipids

Question 8

Which proteins are synthesised by the liver?

Answer 8

1. Albumin
2. Coagulation factors (vit K)
3. Complement factors
4. Haptoglobin
5. Ceruloplasmin
6. Transferrin
7. Protease inhibitors

Question 9

Which molecules are stored in the liver?

Answer 9

1. Iron
2. Copper
3. Vitamins A, D and B12

Question 10

What does the liver secrete?

Answer 10

Bile salts

Bilirubin

Question 11

The sinusoids contain 2 regions, what are they?

Answer 11

Perivenal region (low O2 conc) - glucoronidation occurs here

Periportal region (high O2 conc) - Ox phos and gluconeogenesis occur here

• This creates an oxygen gradient within the sinusoid

Question 12

What are the 2 ways that drugs enter into the hepatocyte?

Answer 12

1. Via the hepatic artery as circulating drugs

2. Via the hepatic portal vein as absorbed drugs

Question 13

How are the metabolites excreted from the hepatocyte?

Answer 13

1. Hepatic vein (to undergo excretion via the kidney)

2. Bile salts

Question 14

What does hepatic clearance of drugs depend on?

Answer 14

1. Liver blood flow
2. Intrinsic clearance
3. Protein binding

Question 15

What is the extraction ratio?

Answer 15

A way to characterise your drugs

- The ratio of hepatic clearance of a drug:flow of hepatic blood

Question 16

There are 3 classes of extraction ratio, what are they?

Answer 16

1. High extraction ratio
2. Low extraction ratio
3. Intermediate extraction ratio

Question 17

High extraction ratio drugs are rapidly cleared from the blood by the liver, true or false?

Answer 17

True

Question 18

For high extraction ratio drugs, what is clearance dependent on?

Answer 18

Primarily dependent on hepatic blood flow

Question 19

Examples of high extraction ratio drugs

Answer 19

1. Verapamil
2. Morphine
3. Propanolol

Question 20

What is clearance of low extraction ratio drugs dependent on?

Answer 20

• It is dependent on the intrinsic metabolising capacity of the liver and by the free drug fraction

Question 21

Examples of low extraction ratio drugs

Answer 21

Warfarin

Phenytoin

Question 22

What is clearance of intermediate extraction ratio drugs dependent on?

Answer 22

Both hepatic blood flor, intrinsic metabolising capacity of the liver an the free drug fraction

Question 23

Examples of intermediate extraction ratio drugs

Answer 23

Aspirin

Codeine

Question 24

Which types of enzyme mediate the phase 1 (hydrolysis/oxidation) reactions in the liver?

Answer 24

Esterases

Oxidoreductases such as CYP450

Question 25

What do the phase 2 conjugation (sulphonation/glucoronidation) reactions do to the drug?

Answer 25

Make the metabolites less reactive, less toxic and more polar - CONJUGATING ENZYMES carry these out

Question 26

The main purpose of drug metabolism is to do what?

Answer 26

Make the drug non-reactive, non-toxic and easy as possible to excrete preferentially via the kidney

Question 27

The phase 2 reaction in the liver involves the addition of which substances to a toxic chemical or drug?

Answer 27

Cysteine, glycine, sulphur molecule

Question 28

What is the most common phase 2 reaction in the liver?

Answer 28

Glucoronidation

Question 29

What are the other conjugation reactions in the liver?

Answer 29

Amino acid conjugation and sulfoconjugation

Question 30

Aspirin is hydrolysed into which substance?

Answer 30

Salicylic acid

Question 31

How does paracetamol cause toxicity in a normal situation?

Answer 31

Paracetamol is metabolised to two metabolites 1) Formation of sulfur/glucaronide metabolites - which are secreted by urine (95% of paracetamol is metabolised via this mechanism) 2) The other 5% is metabolised into an intermediate called NAPQI. This is a toxic metabolite which is removed by addition of glutathione and excreted via the urine. IF THIS IS NOT REMOVED EFFECTIVELY, HEPATOTOXICITY WILL OCCUR

Question 32

What happens during a paracetamol overdose?

Answer 32

The majority of paracetamol is now metabolised into NAPQI due to the levels of glutathione being exhausted by the excess paracetamol - The >NAPQI levels cause liver damage, potentially ending with transplant requirement

Question 33

Paracetamol toxicity cannot be seen for the first how many hours?

Answer 33

48hrs

Question 34

Treatment for paracetamol overdose

Answer 34

IV infusion of acetylcholine