Pharmacogenetics

Question 1

CYP2D6 Polymorphism

Answer 1

Debrisoquine effect–> excessive hypotension (increased concentrations and decreased metabolism of drug)
Ultrafast metabolism–> duplication of normal allele
Metabolizes 25% of prescription drugs
Anti-depressants
Metabolize codeine–> morphine

Question 2

CYP2C19 Polymorphism

Answer 2

Poor metabolizer effect–> 3-20% are homozygous poor metab
PPI- omeprazole (poor metabolizer have higher drug levels, higher pH and better control of GERD)
Anti convulsants - Phenytoin (poor metabolizer with low therapeutic window causes more drug levels and side effects)
Anti-platelet–> Clopidogrel (activated by 2C19)
Even one slow allele causes increased outcomes of MI and stroke
By >50%

Question 3

Clopidogrel and PPI

Answer 3

Both are substrates of CYP2C19
Competitive inhibition
Both are given post MI and Omeprazole causes decreased levels of activated Clopidogrel
Increased risk of serious CV event

Question 4

CYP2C9 Polymorphism

Answer 4

Handles about 15% of drugs
Poor metabolizer phenotype *2 and *3 (31% of patients)
*1 is the wild type normal

Question 5

Warfarin

Answer 5

Anticoagulant cleared exclusively by CYP2C9 (narrow therapeutic window)
*3 has a larger impact than *2
If *3 or *2 polymorphism
Significantly reduces warfarin clearance and increases half-life
Lower maintenance dose required
Increased risk of anti-coagulation/bleeding

Question 6

Vitamin K Receptor (VKORC1) Polymorphism

Answer 6

VKORC1 is subunit of Vit K epoxide reductase and needed to take clotting factors for functional forms

Warfarin is antagonist of VKORC1 because competitive inhibitor

Polymorphism
Clade A–> H1 and H2 = lower expression of VKORC1 so lower warfarin dose needed
Clade B–> H7, H8, H9= higher expression of VKORC1 so higher warfarin dose needed

Question 7

N-acetyltransferase-2

Answer 7

Detoxifies isoniazid (anti-tuberculosis drug)
Initial observation was increased neurological side effects
Correlation with plasma concentration and difference in plasma half-life
Autosomal-recessive trait
slow acetylators are homozygous for slow allele
Fast acetylators have one or two copies of fast allele

Question 8

Pseudocholinesterase Polymorphism

Answer 8

Succinylcholine is a surgical muscle relaxant whose effects typically wear off 5 min after dose stopped
Atypical patients experience apnea and paralysis for 2-3 hours
May increase susceptibility to some insecticides and to cocaine toxicity

Question 9

TPMT Polymorphism

Answer 9

Increased risk for life threatening bone marrow suppression when treated with 6-MP
Greater risk when TMPT activity decreases because it is used to clear the excess drug but now more active drug in bone marrow
Low activity allele has 2 SNPs in TPMT gene

Question 10

SLCO1B1 Polymorphism

Answer 10

Organic anion transporter important for uptake of hydrophilic drugs into the liver
Statins decrease cholesterol by inactivating in liver but can’t get into liver so toxicity in blood
Skeletal muscle toxicity is the side effect (rhabdomyolysis, Myalgia, Myopathy)