Pharmacogenomics

Question 1

What factors can influence the drug response phenotype?

Answer 1

Age
Gender
Underlying disease
Genetic Variation

Question 2

Interindividual differences in the genes that encode ?

Answer 2

Drug Targets
Drug Transporters
Enzymes that catalyze drug metabolism
–can affect the success or failure of pharmacotherapy

Question 3

Pharmacogenetics is important because ?

Answer 3

Adverse drug reactions are a major cause of morbidity and mortality

Question 4

What are single nucleotide polymorphisms or SNPs?

Answer 4

One nucleotide is exchanged for another at a given position

Question 5

Individuality affects the way in which each person?

Answer 5

will respond to drug treatment

Question 6

What three types of interindividual genetic variation can influence pharmacotherapy?

Answer 6

1. Variation in proteins involved in drug metabolism or transport
2. Variation in drug targets or pathways associated with those targets
3. Genetic variation associated with idiosyncratic adverse drug effects

Question 7

The most common factor responsible for pharmacogenetic variation in drug responses is genetic variation in?

Answer 7

Enzymes that catalyze drug metabolism

Question 8

Butyrylcholinesterase polymorphism is the first enzyme variation to discuss. What drugs does this polymorphism effect?

Answer 8

Neuromuscular blockers: used during surgical procedures to cause skeletal paralysis
–Succinylcholine: depolarizing neuromuscular blocker that is not metabolized effectively at the synapse therefore the membrane remains depolarized and unresponsive to impulses. therefore flaccid paralysis

Question 9

Describe the changes in the neuromuscular blockage in a patient with butyrylcholinesterase polymorphsim

Answer 9

Duration usually: 5-1 minutes due to plasma butyrylcholinesterase

• -patients with the variation have a decreased rate of metabolism of succinylcholine therefore prolonged paralysis
• -tx with continued mechanical ventilation until muscle function returns to normal

Question 10

Defects in the BCHE gene are cause of butyrlycholinesterase deficiency. The condition is transmitted as what?

Answer 10

Autosomal recessive trait

Question 11

The next enzyme variation is N-acetyltransferase 2 polymorphism. What is the use of this enzyme?

Answer 11

Catalyzes the acetylation of the antimycobacterial agent Isoniazid, and other drugs. Patients treated with Isoniazid can be classified as:

1. Slow Acetylators: metabolize isoniazid slowly and have high blood drug levels
2. Fast Acetylators: metabolize isoniazid rapidly and have low blood drug levels

Question 12

In addition to Isoniazid a number of other drugs are metabolized by the N-acetyltransferase 2 enzyme. Slow acetylators are prone to toxicity of drugs that are inactivated by acetylation: Examples:

Answer 12

Isoniazid may cause neuropathy and hepatotoxicity
Hydralazine and procainamide may cause Lupus
Sulfonamides may cause hypersensitivty reactions, hemolytic anemia and lupus

Question 13

The next enzyme variation is CYP2D6 polymorphism. It is member of the cytochrome P450 family of microsomal enzymes. Describe the changes seen with this?

Answer 13

Poor metabolizers are homozygous for recessive alleles coding for enzymes with low activity
Extensive metabolizers are heterozygous or homozygous for the wild type allele
Ultrarapid metabolizers: have multiple copies of the CYP2D6 gene

Question 14

CYP2D6 metabolizes what medications?

Answer 14

Beta blockers: metoprolol
Neuroleptic: haloperidol
Opioids: codeine and dextromethorphan
Antidepressants: fluoxetine, imipramine and desipramine

Question 15

Describe the effects of the various metabolizers in CYP2D6 polymorphism

Answer 15

Poor metabolizers: suffer adverse effects when treated with standard doses of drugs such as metoprolol
–codeine is ineffective in poor metabolizers it requires CYP2D6 catalyzed conversion to morphine
Ultrarapid metabolizers: may require very high doses of drugs that are metabolized by CYP2D6
–but can overdose with codeine

Question 16

The last polymorphism is thiopurine S-methyltransferase polymorphism. TPMT catalyzes the S-methylation of the anticancer thiopurines 6-mercaptopurine and azathioprine. Methylation of these drugs inactivates them. Thiopurines have a narrow therapeutic window so what happens?

Answer 16

some patients suffer life threatening myelosuppression

Question 17

Homozygotes for the TPMT polymorphism are at an increased risk for myelosuppression when treated with standard doses of thiopurine drugs. These patents have to be treated with what dose?

Answer 17

1/10th of the standard dose

Question 18

Next variations in drug targets: pharmacodynamics. First under this topic is mutations in the gene encoding the epidermal growth factor receptor (EGFR). Explain this variation

Answer 18

Gain of function mutation in the gene encoding the epidermal growth factor receptor (EGFR)

• -EGFR is overexpresse in nonsmall cell lung cancer (NSCLC).
• -Gefitinib is an inhibitor of the tyrosine kinase of EGFR.
• -patients with mutations in the ATP binding site of the tyrosine kinase domain of the receptor respond better to the drug

Question 19

Warfarin is a drug that involves both the pharmacokinetics and pharmacodynamics variations. explain the pharmacokinetic variation

Answer 19

Warfarin is a racemic mixture
–S warfarin is 3-5times more potent than R warfarin. metabolism of S isomer is mainly via CYP2C9
metabolism of R isomer is via CYP3A4 and other CYP isoforms
CYP2C9 is a highly polymorphic gene.
–patients who carry the variant alleles require decreased doses of warfarin to achieve an anticoagulant effect, and they increased risk for hemorrhage from the therapy.

Question 20

explain the pharmacodynamic component of warfarin

Answer 20

The gene encoding the enzyme is vitamin K epoxide reductase complex 1, VK0RC1

• -this gene shows a number of polymorphisms which affect warfarin dose requirement. The dose may vary two fold depending on the polymorphism
• -need to give a lower dose

Question 21

Next topic is genetic variation associated with idiosyncratic adverse drug effects. What does this mean?

Answer 21

Idiosyncratic effects seem to result from interactions between the drug and a unique aspect of the physiology of the individual patient

Question 22

A classic example of genetic variation associated with idiosyncratic adverse drug effects is the functional deficiency of the enzyme glucose 6 phosphate dehydrogenase (G6PD). This enzyme is involved in protecting red blood cells from oxidative injury. Diminished activity of this enzyme results in what?

Answer 22

Diminished activity

• -impairs the ability of the cell to form NADPH that is essential for the maintenance of the reduced glutathione pool
• -this results in a decrease in the cellular detoxification of free radicals and peroxides formed within the cell.

Question 23

A number of drugs cause oxidative stress on red blood cells as an effect unrelated to their intended targets or their metabolism. These drugs include?

Answer 23

Sulfonamides
Antimalarials
Chloramphenicol
–individuals with G6PD deficiency who are exposed to these drugs may develop acute and at times severe hemolytic anemia