Pharmacogenomics

Question 1

Genetic variations in anti epileptic medications

Answer 1

Phenytoin =
HLA-B*1502
CYP2C9
CYP2C19

Carbamezapine =
HLA-B*1502 and HLA-A

Question 2

Genetic variation in anti depressants

Answer 2

SSRI =
CYP2D6
CYP2C19

TCA =
CYP2D6
CYP2C29

Question 3

Example of a silent SNP

Answer 3

Pgp 3435C>T = silent SNP = synonymous SNP

C>T baspair change leads to translational delay
(Ie. Rate of mRNA to protein translation in ribosomes)

This SNP can affect the folding of Pgp

Leads to difference in substrate affinity and overall activity (but not on the amount of protein in the cell)

Question 4

What are the effects of C>T SNP?

Answer 4

CC variant (nirmal) has higher Pgp activity than the TT

THEREOFRE LESS DRUG IS LET ACROSS THE BBB IN CC patients COMPARED to TT

Eg.
C>T SNP = more phenobarbitoje in the brain 🧠 hence patients need lower doses to have an effect

Question 5

Kinetic properties of phenyotin

Answer 5

1. Dose dependant
2. 90% met by CYP2C9
   **3. REST met by CY2C19 **

Question 6

Phenytoin metabolism

CYP2C92
CYP2C93

Answer 6

CYP2C9*2 = 430 C>T
- 29% reduction in phenytoin clearance compared to wild type

CYP2C9*3 = 1075 A>C
- 95% reduction in phenytoin clearance compared to wild type
= INCREASE SERUM PHENYTOIN CONCENTRATIONS

Question 7

Drug labels in relation to HLA-B*15:02 allele and chinese/Asian ethnicity

Answer 7

FDA

PATIENTS WITH ANCESTRY IN AT RISK POPULATIONS SHOULD BE SCREENED FOR THE HLA-B*1502 allele PRIOR TO STARTING CARBAMEZAPINE AND OXCARBAZEPINE

Question 8

Phenytoin dosing for polymorphism in CYP2C9 and HLA-B*15:02

Answer 8

1. Standard for all *2 and *3 allele
2. If 1 x CYP2C9 is *2 or *3 = intermediate = 25% reduction
3. If BOTH are *2 *3 = poor metabolised = 50% reduction in dose
4. If HLA-B*15:02 carrier = DO NO PRESCRIBE

Question 9

Phenytoin and other FOOD, DRUGS, OTC interactions 🚩🚩🚩🚩🚩

Answer 9

1. 🚩St john’s wart
   = Inc. CYP2C9 activity
   = decrease phenytoin plasma levels
2. 🚩Alcohol
   = Increase phenytoin plasma levels
3. 🚩CA containing antacids
   = decrease phenytoin plasma levels

And more!!!! 🚩🚩🚩🚩🚩🚩

Question 10

Paroxetine and CYP2C9

Answer 10

CYP2D6 = POOR METABOLISER

greatly reduced metabolism when compared to extensive metabolises

Higher plasma concentrations may increase probability of side effects

Recommend
Use alternative drug or decrease dose by 50%