Lecture 2 - Pharmacokinetics

Question 1

What is the overall function of metabolism?

Answer 1

To make a compound more hydrophilic/water soluble so that it can be more easily filtered and excreted by the kidneys

Question 2

Examples of phase 1 reactions

Answer 2

Oxidation (most common)
Hydrolysis
Reduction
Hydroxylation

Question 3

What is the purpose of phase 1 reactions?

Answer 3

The unmasking or addition of a polar group

Question 4

What enzymes carry out phase 1 reactions? Where are these enzymes found?

Answer 4

Cytochrome p450 enzymes

Found in the ER and mitochondria of liver cells

Question 5

What kind of enzyme normally carries out phase 2 reactions?

Name the most common

Answer 5

Transferases

N-acetyl transferase

Question 6

What is the outcome of phase 2 reactions?

Answer 6

Conjugation of a group onto the exposed polar group

Makes the compound a LOT more soluble/hydrophilic

Question 7

Name 2 drugs that the CYP2D6 is involved in the metabolism of

Answer 7

Codeine
Tramadol  
Beta-blockers
Tricyclic antidepressants 
Hydrocodone
Oxycodone

Question 8

How do opioids exert their analgesic effect?

Answer 8

Bind to the pre and postsynaptic mu opioid receptors
Which is a GPCR coupled to Gi/o
Decrease cAMP
Inactivates calcium channels, reduce neurotransmitter release
Open K+ channels, allowing efflux, hyperpolarisation

Question 9

Describe the metabolism of codeine

Answer 9

Prodrug: 5-10% is converted into morphine
The reaction is O-demethylation by CYP2D6
CYP2D6 is highly polymorphic therefore there are different types of metabolisers

Question 10

What effect will codeine have on an

• ultra rapid metaboliser?
• poor metaboliser?

Answer 10

Ultra rapid: at risk of overdose, respiratory depression and death
Poor: inadequate analgesic effect

Both should consider alternative pain killers that are not metabolised by CYP2D6

Question 11

What are the effects of tramadol?

Answer 11

Mu-opioid receptor agonist
Lower affinity than codeine
Also inhibits reuptake of serotonin and norepinephrine in the spinal cord

Question 12

Describe the metabolism of tramadol

Answer 12

CYP2D6 catalyses production of major metabolite M1, which has high affinity for opioid receptors
CYP3A4 and CYP2B6 form the inactive metabolite M2

Question 13

What are thiopurines used for?

Name an example of one

Answer 13

Treatment of inflammatory and autoimmune diseases
Prevention of organ transplant rejection
Treatment of leukaemia
e.g. Azathioprine

Question 14

Describe the metabolism of thiopurines

Answer 14

Conjugation of a methyl group by thiopurine methyl transferases (TPMTs) (phase 2 reaction) to form an inactive, non-toxic metabolite

Question 15

Side effects of thiopurines

Answer 15

Bone marrow suppression (life threatening)
Nausea
Vomiting
Hepatotoxicity
Pancreatitis

Question 16

When is PGx testing used instead of an enzyme assay?

Answer 16

1. When the enzyme assay indicates poor enzyme activity
2. Recent blood transfusion
3. Previous severe reaction to the drug
4. Enzyme assay results change on repeated testing

Question 17

What effect will Azathioprine have on a person with

• high TPMT activity?
• low TPMT activity?

Answer 17

Ultra rapid (high TPMT): reduced therapeutic effect
Poor (low TPMT): at higher risk for more severe side effects

Question 18

What are the 3 possible outcomes of phase I reactions?

Answer 18

Pharmacologically inactive metabolites formed
Metabolites are pharmacologically active, but less so than the original drug
The original drug is not pharmacologically active, but the metabolite is (pro drug)

Question 19

What is first pass metabolism?

Answer 19

An orally administered drug is metabolised by the liver before reaching systemic circulation
Can be avoided by administering the drug intravenously

Question 20

Name two drugs by which genetic variation affects the pharmacokinetics of the drug, and therefore PGx testing would be useful before prescribing

Answer 20

1. Codeine

2. Thiopurines

Question 21

Name two limitations of PGx testing for genotype-specific dosing

Answer 21

1. Genotyping one gene cannot predict all adverse reactions to a drug. Variants of other genes involved in the metabolism mechanism will contribute
2. Can miss certain variants entirely if you don’t know what you are looking for when you do the assay