Lecture 24: Pharmacogenomics

Question 1

Genetic polymorphisms

Answer 1

• Butyrylcholinesterase (Pseudocholinesterase) (BChE)
• N-acetyltransferase 2 (NAT2)
• CYP2D6
• Thiopurine S-methyltransferase (TPMT)

Question 2

Butyrylcholinesterase Polymorphism

Answer 2

Because of its rapid hydrolysis by plasma butyrylcholinesterase, duration of neuromuscular blockade is 5-10 minutes.

Patients with genetic variations in butyrylcholinesterase have a decreased rate of metabolism of succinylcholine (AR).

Fig: percentage of inactivation by dibucaine; higher the number the higher the activity of enzyme

• Normal enzyme: DN ≥ 75
• Heterozygous atypical enzyme: DN ≥ 40-70
• Homozygous atypical enzyme: DN < 20

Question 3

N-acetyltransferase 2 (NAT2) Polymorphism

Answer 3

• N-acetyltransferase 2 (NAT2) catalyzes the acetylation of isoniazid and other drugs.
• Patients treated with isoniazid can be classified as
  
  • Slow acetylators (AR): high blood drug levels
  • Fast acetylators:
• Isoniazid may cause neuropathy and hepatotoxicity.
• Hydralazine and procainamide may cause systemic lupus erythematosus.
• Sulfonamides may cause hypersensitivity reactions, hemolytic anemia and systemic lupus erythematosus.

Question 4

CYP2D6 Polymorphism

Answer 4

• originally described when studying two different drugs, the antihypertensive debrisoquine and the oxytotic agent sparteine.
• metabolizes many commonly prescribed drugs, including:
  
  • The β-blocker metoprolol
  • The antipsychotic haloperidol
  • The opioids codeine & dextromethorphan
  • The antidepressants fluoxetine, imipramine, & desipramine, etc.

Poor metabolizers

• Suffer adverse effects when treated with standard doses of drugs such as metoprolol.
• Codeine is ineffective in poor metabolizers because it requires CYP2D6-catalyzed conversion to morphine.

Ultrarapid Metabolizers

• May require very high doses of drugs that are metabolized by CYP2D6.
• But they can overdose with codeine, suffering respiratory depression or even respiratory arrest in response to standard doses.

Question 5

Thiopurine S-methyltransferase Polymorphism

Answer 5

• TPMT catalyzes the S-methylation of the anticancer thiopurines 6-mercaptopurine and azathioprine.
• Methylation of these drugs inactivates them.
• Thiopurines have a narrow therapeutic index and some patients suffer from life-threatening myelosuppression.

Question 6

Mutations in EGFR

Answer 6

• EGFR is often overexpressed in nonsmall cell lung cancer (NSCLC).
• Gefitinib is an inhibitor of the tyrosine kinase of EGFR; approved for the treatment of NSCLC.
• Patients (Japan, far east) with mutations in the ATP-binding site of the tyrosine kinase domain of the receptor respond better to gefitinib.

Question 7

Warfarin pharmacogenomics

Answer 7

• S-warfarin is 3 - 5 times more potent than R- warfarin.
• The stereoisomers are metabolized by different enzymes.
• CYP2C9 is a highly polymorphic gene.
• Some variant alleles have much lower activity than the wild-type allele.
• 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.

Polymorphism

• vitamin K epoxide reductase complex 1 (VKORC1) gene shows a number of polymorphisms which affect warfarin dose requirement.
• The dose may vary two-fold depending on the polymorphism.

Question 8

G6PD deficiency

Answer 8

G6PD A- polymorphism causes a 90 - 95% reduction of enzyme function.

It is present in 10-20% of Africans and is thought to provide protection against malaria.

Sulfonamides, antimalarials, and cloramphenicol cause oxidative stress on red blood cells.

Question 9

• Clinical case: A 60-year-old man is admitted to the hospital with an ST- elevation myocardial infarction.
• Medical history: hypercholesterolemia and diabetes type 2.
• An occluded LAD was successfully stented.
• The patient developed post-infarction heart failure.

After initial treatment he is discharged on: Simvastatin, Metoprolol Ramipril, Aspirin, Clopidogrel, Glimepiride

• The patient is hospitalized to start warfarin treatment.
• His INR increases abnormally.
• The patient has a slow metabolizer genotype of both CYP2C9 and CYP2D6.

Answer 9

• Warfarin, glimepiride and losartan are metabolized by CYP2C9.
• Metoprolol is metabolized by CYP2D6.
• Slow metabolism of warfarin by CYP2C9 explains the high INR value.
• glimepiride would be increased with increased risk of adverse effects.
• metoprolol would be affected by a slow CYP2D6 metabolism with increased risk of adverse effects.
• Losartan is metabolized by CYP2C9 to a metabolite 10 - 40 times more active.
• The clinical effects of losartan would be affected. This explains the deterioration of heart failure after replacing ramipril with losartan.