Pharmacogenetics

Question 1

Butyrylcholinesterase (Pseudocholinesterase)

Answer 1

• Variations in butyrylcholinesterase have a decreased rate of metabolism of succinylcholine, resulting in prolonged paralysis.
• Treated with continued mechanical ventilation until muscle function returns to normal.
• Defects in the BCHE gene, autosomal recessive trait.

Question 2

N-acetyltransferase 2 Polymorphism

Answer 2

• Slow acetylators: metabolize drug slowly and have high blood drug levels
• Fast acetylators: metabolize drug rapidly and have low blood drug levels.

Slow = homozygous for recessive allele, prone to toxicity in drugs inactivated by acetylation

Examples:
Izoniazid - may cause neuropathy and hepatotoxicity
Hydralazine- may result in systemic lupus
Sulfonamides- may result in systemic lupus, hemolytic anemia.

Question 3

cytochrome P450 2D6 Polymorphism (CYP2D6)

Answer 3

Metabolism of a large number of drugs, including antidepressants, antiarrhythmics, and analgesics

• Poor metabolizers are homozygous for recessive allele
• Ultrarapid metabolizers have multiple copies of the CYP2D6 gene.

Question 4

Thiopurine S-Methyl Transferase (TPMT) Polymorphism

Answer 4

Catalyzes the S-methylation of the anticancer thiopurines 6-mercaptopurine and azathioprine.

Homozygotes at increased risk for myelosuppression These patients have to be treated with approximately 1/10 of the standard dose.

Question 5

CYP2C9

Answer 5

Patients who carry the variant alleles require decreased doses of warfarin to achieve an anticoagulant effect, and they have increased risk for hemorrhage during warfarin therapy.

Question 6

VKORC1

Answer 6

vitamin K epoxide reductase complex 1

shows a number of polymorphisms which affect warfarin dose requirement. The dose may vary two-fold depending on the polymorphism.

Question 7

G6PD & pharmacogenetics

Answer 7

Diminished G6PD activity impairs the ability of the cell to form NADPH essential for the maintenance of the reduced glutathione pool.

Patients may develop acute and, at times, severe hemolytic anemia with oxidative drugs (sulfonamides, antimalarials (egprimaquine and chloroquine) and chloramphenicol), and fava beans

ex) Sulfonamides, antimalarials, chloramphenicol

Question 8

Malignant hyperthermia

Answer 8

Autosomal dominant

Defect in the ryanodine receptor gene (RYR1).

Altered Ca2+ release from SR. Triggered by volatile inhalation anesthetics (eg halothane)

Includes tachycardia and hypertension, severe muscle rigidity, hyperthermia, hyperkalemia, and acid-base imbalance with acidosis

Often Fatal