Pharmacogenetics

Question 1

What are the two sources of variability in response to drugs at optimal dosing?

Answer 1

• Genetic variations
• Environmental factors

Question 2

Describe how genetic variations influence pharmacology

Answer 2

Genes influence both pharmacokinetics and pharmacodynamics:
- genes influence pharmacokinetics by altering expression of proteins involved in ADME
- genes influence pharmacodynamics with differences in enzyme or immune mechanisms

Genetic variation in humans can occur as a result of mutations that either occur in our own cells OR are inherited.

Genetic polymorphisms are changes in the DNA sequence that occurs at an allele frequency of at least 1% of the population.
Genetic polymorphisms are increasingly used to optimise treatment.

Question 3

What can be tested to optimise treatment?

Answer 3

Testing for genetic polymorphisms

Question 4

Provide some examples of drug metabolising enzymes with genetic polymorphisms

Answer 4

• the main:CYP (CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A5)
• N-acetyltransferase (NAT2)
• Glutathione-S-transferases (GSTM1, GSTT1, GSTP1)
• Thiopurine methyltransferase (TPMT)
• UDP-glucuronosyltransferases (UGT1A1, UGT1A4, UGT1A9, UGT2B15, UGT2B17)

Question 5

What are some potential consequences of polymorphic drug metabolising enzymes?

Answer 5

• increased plasma drug concentration and thus duration of action
• decreased plasma drug concentration and therapeutic failure(?)
• Adverse drug reactions/toxicity
• Failure to activate a prodrug
• Drug metabolism via alternative pathways
• Exacerbation of drug interactions

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Question 6

Provide some examples of variation in drug response

Answer 6

CYP
CYP2D6 has many genetic variations.

CYP enzymes are clinically important as they are responsible for metabolising many medications e.g. codeine.

Notably, some of these drugs have narrow therapeutic indices. Thus a pertuebation fo enzymes can lead to toxicity,

Approximately 10% of the codeine dose is converted by CYP2D6.
Analgesic effects of codeine are a result from its conversion to morphine.
- CYP2D6 ‘poor metaboliser phenotype’ variations are found in 7-10% of Caucasians, and 1-2% of North Asian populations (poor drug response)
- CYP2D6 ultra-rapid metaboliser phenotype variations are found in 2-3% of Caucasians, and up to 25% in North African populations (opioid toxicity and respiratory depression)

Question 7

Provide some examples of variation in drug response (2)

Answer 7

HLA
for revision see [[Immunology Lecture 5]]

Abacavir is a reverse transcriptase inhibitor which is highly effective in treating HIV infection, although it has limited clinical use due to severe rashes.
Susceptibility to rash is associated with HLA variant HLAAB5701. Testing is done for this variant

BRAF
Mutations in BRAF proteins are seen in 50% of patients with advanced melanoma.
Dabrafenib and vemurafenib are used to treat metastatic melanoma presenting with BRAF V600(E?) mutations.

HER2
Expression of HER2 important in guiding treatment decisions for patients with breast cancer.
The drug trastuzumab targets HER2, therefore efficacy is based on HER2 expression.

TPMT
Thiopurines are immunosuppressive agents.
TPMT detoxifies thiopurines.
There are large inherited variations in TPMT activity.
Low TPMT activity increases toxicity risk, while high TPMT activity reduces efficacy.

Before the start of treatment, genotype and phenotype test can be done to test TMPT activity, and to identify TMPT alleles TMPT3A, and TMPT

Question 8

Which of the following is NOT a potential consequence of polymorphic drug-metabolising enzymes:
A. Increased concentration and duration of ation
B. decreased concentration and therapeutic failure
C. Reduced oral bioavailability
D. aDVERSE drug reactions
E. drug toxicity

Answer 8

C

Question 9

A TMPT variant resulting in reduced activity is associated with:
A. Higher incidence of thiopurine toxicity
B. increased warfarin efficacy
C. reduced efficacy of opioid analgesics
D. reduced tamoxifen outcomes
E. reduced codeine clearance

Answer 9

A

Question 10

Codeine is metabolised to its active form via CYP2D6 therefore phenotype variations can effect the response of some patients to codeine. Up to 25% of North Africans carry the ultra metaboliser phenotype variation and therefore require special consideration when prescribing codeine because:

A. Rapid metabolism can lead to increased renal clearance
B. Rapid metabolism to an active substance can result in in increased risk of toxicity
C. Rapid metabolism can lead to increased clearance of codeine and lack of efficacy
D. Rapid metabolism can lead to reduced volume of distribution
E. Rapid metabolism causes a bypass of first-pass metabolism

Answer 10

B