Metabolism - Drug Metabolism

Question 0

What are the four steps of pharmacokinetics?

Answer 0

Absorption
Distribution
Metabolism
Elimination

Question 1

What is pharmacology, pharmokinetics and pharmodynamics?

Answer 1

Pharmacology - how chemical agents affect the systems of living things
Pharmacokinetics - what the body does to the drug
Pharmacodynamics - what the drug does to the body

Question 2

What are the exceptions to the rule that drug metabolites are usually inactive?

Answer 2

Pethidine —> norpethidine (toxic)

Codeine —> morphine

Question 3

Way are the main reaction types in phase I of drug metabolism?

Answer 3

Oxidation
Reduction
Hydrolysis

Question 4

Where does phase I metabolism occur?

Answer 4

Liver (microsomes on the ER contain relevant enzymes)
GI tract (broken down and absorbed)
Lungs
Plasma (cholinesterase in the blood breaks ester bonds)
Kidney

Question 5

What is the function of phase I drug metabolism?

Answer 5

To add or expose a reactive group on the drug molecule.

Question 6

How does phase I of drug metabolism metabolise the drug and what is its importance

Answer 6

Uses the CYP system which requires haem containing enzymes and NADPH.
Important in ridding of toxicity.

Question 7

What type of drugs may skip phase I and enter straight into phase II?

Answer 7

Drugs that already have a reactive group exposed

Question 8

Where does phase II drug metabolism occur?

Answer 8

In the liver via cytosolic enzymes

Question 9

What are the types of reaction in phase II metabolism?

Answer 9

Conjugation

• glucoronidation
• sulphate conjugation
• glutathione conjugation

Question 10

What occurs in glucoronidation?

Answer 10

It uses the cofactor UDPGA
Combines metabolites of the drug with glutaronic acid (a metabolite of glucose therefore in high concentration in the liver).

Question 11

What is the function of phase II metabolism?

Answer 11

It takes the altered drug molecule and combines it with a water soluble group so that it can be excreted via kidneys.

Question 12

What are the factors affecting drug metabolism?

Answer 12

Genetic

• polymorphisms/variation in the population
• genetic deletions can cause enzyme deficiencies

Envirnonmental

• some drugs can inhibit the enzymes that work on other drugs = slow their metabolism
• some drugs can stimulate the enzymes that work on other drugs = speed up their metabolism

Question 13

How is paracetamol in normal doses metabolised?

Answer 13

It skips phase I and enters phase II where it is glucoronidated or sulphated.

Question 14

What pathway does paracetamol take in an overdose, and why is this damaging?

Answer 14

It saturates the usual phase II pathway, so enters phase I and produces NAPQI.
NAPQI is toxic to liver cells.
It then undergoes glutathione conjugation in phase II
= uses up all livers glutathione defences against ROS, causing oxidative stress.

Question 15

How and when is a paracetamol overdose treated?

Answer 15

Treated in early stages only.

Treated with N-acetyl cysteine, which can donate a H+ to act as an antioxidant.

Question 16

How is alcohol metabolised and using what enzymes?

Answer 16

1) . Alcohol is converted into acetaldehyde by alcohol dehydrogenase, which also makes NADH.
2) . Acetaldehyde is converted into acetic acid by aldehyde dehydrogenase.
3) . Acetic acid can be converted into acetyl CoA

Question 17

What is the problem with excessive alcohol?

Answer 17

1) . It creates excess NADH = favourable for TAG synthesis or fat deposition
- fatty liver (fatty build up)
- alcoholic hepatitis (inflamed liver)
- alcoholic cirrhosis (scar tissue)

2). Acetaldehyde is toxic to the liver cells.

Question 18

What are the treatments for alcoholism?

Answer 18

1) . Lifestyle
- help/support groups
- rehab

2) . Disulfiram
- inhibits aldehyde dehydrogenase so that if alcohol is consumed, acetaldehyde builds up = severe hangover for weeks.