pharmacogenetics

Question 1

1. What is the role of Butyrylcholinesterase (pseudoesterase) [BChE]?

Answer 1

Neuromuscular blocker drugs, such as Succinylcholine that acts as a depolarizing NMJ blocker, is used during surgical procedures to cause skeletal muscle paralysis. Succinylcholine is not metabolized effectively at the synapse therefore the membrane remains depolarized and unresponsive to additional impulses resulting in flaccid paralysis. The neuromuscular blocked lasts about 5-10minutes terminating with the rapid hydrolysis by plasma butyrylcholinesterase.

Question 2

2. What is the effect of Butyrylcholinesterase polymorphism?

Answer 2

Patients with an autosomal recessive, genetic variations/defects in BChE have a decreased rate of metabolism of succinylcholine resulting in prolonged paralysis. The normal Dibucaine number for BChE is over 75. Heterozygous atypical enzyme has a DN number b/t 40-70 and Homozygous atypical enzymes have a DN number below 20. The lower the number, the less active the enzyme is therefore the more succinylcholine remains in the cleft and paralysis continues.

Question 3

3. What is the role of N-acetyltransferase 2 (NAT2)?

Answer 3

NAT2 catalyzes the acetylation of isoniazid and other drugs.

Question 4

4. What is the effect of N-acetyltransferase 2 (NAT2) polymorphism?

Answer 4

Slow acetylators → metabolize isoniazid slowly and have high blood drug levels
Fast acetylators → metabolize isoniazid rapidly and have low blood drug levels
The rate of isoniazid acetylation is an autosomal recessive inherited trait. Slow acetylators are homozygous for autosomal recessive allele of the enzyme leading to an enzyme with lower activity. Slow acetylators are prone to toxicity b/c the drug does not get metabolized by acetylation and rather you have increased plasma level of the drug.

Question 5

5. What is the effect of NAT2 polymorphism on Isoniazid, Hydralazine, Procainamide, and sulfonamide?

Answer 5

Isoniazid → neuropathy and hepatotoxicity
Hydralazine and Procainamide → systemic lupus erythematosus
Sulfonamide → HSN reactions, hemolytic anemia and systemic lupus erythematosus

Question 6

6. What is the role of CYP2D6?

Answer 6

CYP2D6 is a member of the cytochrome P450 family of drug-metabolizing enzymes. It metabolizes a large number of drugs including antidepressants, anti-arrhythmics and analgesics.

Question 7

7. What is the effect of the CYP2D6 polymorphism?

Answer 7

CYP2D6 was originally described with Debrisoquine (anti-hypertensive) and Sparteine (oxytotic agent). CYP2D6 polymorphisms can be placed in to different categories…

1. Ultrarapid metabolizers → multiple (up to 13 copies) of the CYP2D6 gene
2. Extensive metabolizers → heterozygous or homozygous for the WT allele
3. Poor metabolizers → pt are homozygous for recessive alleles coding for enzymes with low activity

Question 8

8. What commonly prescribed drugs are metabolized by CYP2D6?

Answer 8

1. B-blocker – Metoprolol
2. Antipsychotic – Haloperidol
3. Opioids – codeine and dextromethorphan
4. Antidepressants – Fluoxetine, imipramine, desipramine

Question 9

9. What is the effect on CYP2D6 with Codeine administration?

Answer 9

Codeine needs to be metabolized to be active in the morphine form. If the pt is a poor metabolizer, then they need a larger dose to increase chance of morphine reaching system. If the pts is a fast metabolizer, then they need a smaller dose to prevent adverse effects of too much morphine such as respiratory depression or even respiratory arrest.

Question 10

10. What is the role of Thiopurine S-methyltransferase (TPMT)?

Answer 10

TPMT catalyzes the S-methylation of the anticancer thiopurines 6-mercaptopurine and azathioprine. Methylation of these drugs inactive them. Thiopurines also have a narrow therapeutic index leading to pts suffering from life-threatening myelosuppression if the incorrect dose is given.

Question 11

11. What is the effect of TPMT polymorphism?

Answer 11

Approximately 1/300 individuals are homozygous for a polymorphism that leads to low TPMT activity. Low activity causes increased amts of active Thiopurine levels within the plasma increasing the risk of myelosuppression when treated with standard doses. These pts with low TPMT activity have to be treated with approximately 1/20 of the standard dose.

Question 12

12. What are the two ways that variations in drug targets can occur with pharmacodynamics?

Answer 12

1. variation in germ-line DNA

2. variation in somatic DNA (in the case of cancer)

Question 13

13. Discuss the mutations in Epidermal growth factor receptor (EGFR) effecting drug function.

Answer 13

EGFR is often overexpressed in non-small cell lung cancer (NSCLC). Drugs have been developed to target this receptor – Gefitinib. Gefitinib is an inhibitor of the tyrosine kinase of EGFR and is an approved treatment for NSCLC. Pts with mutations in the ATP-binding site of the tyrosine kinase domain of the receptor respond better to gefitinib. (why??)

Question 14

14. Discuss the characteristics of Warfarin that make it a dangerous drug.

Answer 14

Warfarin is a commonly prescribed drug that has a narrow therapeutic window and wide interindividual variability leading to problematic dosing. Under-anticoagulation can result in thrombosis and over-anticoagulation can result in bleeding.

1. S-warfarin is 3-5x more potent than R-warfarin
2. S-warfarin is metabolized by ONLY CYP2C9
3. R-warfarin is metabolized by CYP1A1, CYP1A2, CYP3A4 and others
4. CYP2C9 alone is a highly polymorphic gene causing some variants to have lower activity than the WT allele – these pts who have the lower CYP2C9 activity required a decreased dose of warfarin
5. The target for Warfarin – vitamin K epoxide reductase [encoded by the gene vitamin K epoxide reductase complex 1 – VKORC1]
6. VKORC1 has polymorphisms that may also affect warfarin dosing requirement

Question 15

15. What does it mean by the genetic variation associated with idiosyncratic drug effects?

Answer 15

Idiosyncratic drug reactions are not caused by differences in drug metabolism or target bur rather the interactions b/t the drug and certain physiology of the pt. [ex. G6PD deficiency]

Question 16

16. What is the role of G6PD enzyme?

Answer 16

G6PD enzyme protects RBCs from oxidative injury allowing for the regeneration of NADPH.

Question 17

17. What is the effect of a G6PD deficiency?

Answer 17

Diminished G6PD activity impairs the ability of the cell to form NADPH which is essential for the maintenance of the reduced glutathione pool. Decreased NADPH results in a decrease in cellular detox of free radicals and peroxides formed within the cell.

Question 18

18. What is the most common G6PD deficiency polymorphism?

Answer 18

G6PD A- → 90-95% reduction of enzyme function

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

Question 19

19. What drugs cause oxidative stress on RBCs?

Answer 19

1. Sulfonamides
2. Antimalarials
3. Chloramphenicol
   * Individuals with G6PD deficiency who are exposed to these drugs may develop hemolytic anemia