Genetics of Drug Metabolism

Question 1

What is the definition of pharmacogenetics?

Answer 1

The traits that a person has can affect the way drugs are absorbed, distributed, or secreted?

Question 2

What is the definition of pharmacogenomics?

Answer 2

Using genetic information to develop new drugs or targets for drugs

Question 3

What is the definition of pharmacokinetics? What parameters does it use?

Answer 3

-What the body does to a drug (absorption, metabolism, distribution, detoxification, excretion); parameters: dose, half-life, clearance, administration

Question 4

What is the definition of pharmacodynamics?

Answer 4

How a drug affects the body–both undesired and desired effects

Question 5

What is the overall goal of drug administration?

Answer 5

A maximum therapeutic window where there is high efficacy and low toxicity

Question 6

What are the stable and transient factors that can affect how a drug responds to a person or how a person responds to a drug?

Answer 6

Stable: genetics, sex
Transient: compliance, quality of drug, interactions with other drugs, chemicals, or the diet, weight, age

Question 7

What are the main members of the cytochrome P450 family and which is the workhorse of the family?

Answer 7

CYP1A1, CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4 (major one)

Question 8

What is the effect of slow and fast metabolism of drugs in phase I reactions using codeine as an example?

Answer 8

Patients who are slow metabolizers of codeine don’t convert enough of it to morphine to help with pain; fast metabolizers may change so much so quickly that they overdose

Question 9

What is the effect of slow and fast metabolism of drugs in phase II reactions using isoniazid as an example?

Answer 9

People who slowly convert in phase II retain toxic levels of the drug in their system (neuropathy and bone marrow toxicity with isoniazid) and fast metabolizers deal with treatment failure

Question 10

How can genetics lead to improved pharmacodynamic effects in chronic myelogenous leukemia?

Answer 10

The ACL-BCR protein in the translocation can be targeted by Gleevac to knock the protein out and help treat leukemia

Question 11

How does chronic myelogenous leukemia develop?

Answer 11

A translocation of chromosomes 9q and 22q yields a Philadelphia chromosome; an oncogene and BCR gene unite and create a protein product that promotes oncogenesis.

Question 12

What is the genetic cause of neurofibromatosis type II and symptoms are involved?

Answer 12

Mutation in NF2; schwannomas of the vestibular nerve most common, but may include other cranial nerves, meningiomas and astrocytomas also common

Question 13

What are the medical concerns about treating neurofibromatosis surgically? How can it be overcome?

Answer 13

Surgical resection often damages CN VIII and can cause hearing loss and vestibular problems; avastin is a monoclonal antibody that targets VEGF in those cancers

Question 14

What kinds of undesired effects can happen to people with G6PD deficiency and drugs?

Answer 14

Sulfas, anti-malarial drugs, and menthol can induce oxidative stresses that result in hemolytic anemia

Question 15

What kinds of undesired effects can happen to people with malignant hyperthermia and drugs?

Answer 15

Inhaled anesthetics and depolarizing muscle relaxants can induce very high fevers, rhabdomyelysis, and rapid catabolism increases

Question 16

What kinds of undesired effects can happen to people with certain HLA alleles and drugs?

Answer 16

B-1502 allele will induce Steven-Johnson Syndrome where the immune system is activated by carbamazepine via antigen presentation
B-5701 involves adverse reactions to abacavir and floxacillin

Question 17

What is a major concern with warfarin and pregnancy?

Answer 17

It interferes with fetal skeleton development in the first trimester and is teratogenic

Question 18

Why does warfarin require much monitoring?

Answer 18

Warfarin has a narrow therapeutic window and can lead to serious bleeding consequences and needs frequent monitoring of INR and PT

Question 19

What factors are involved in a patient’s pharmacokinetics of warfarin?

Answer 19

Genetic mutations in VKORC1 and CYP2C9 affect the rate of metabolism of the drug; patient’s diet, age, weight, and compliance also play key roles

Question 20

What genetic concerns are present in the administration of plavix?

Answer 20

Between 2 and 14 percent of the US population has a mutation in the CYP that acts on it that increases the risk of non-therapeutic effects

Question 21

What are the four Ps of genomic personalized medicine?

Answer 21

Predictive–can address risks for disorders
Preventative–can address exposures that can change outcomes
Personalized–risks uniquely belong to patient
Participation–patient involved in own care