Unit 1 - Pharmacogenetics and Pharmacogenomics

Question 1

difference between pharmacogenetics and pharmacogenomics

Answer 1

genetics: study of genes and their alleles in relationship to drug response in a given patient
genomics: study of genes related to drug metabolism, and use of knowledge to develop new, targeting drugs

Question 2

some facts on adverse drug reactions?

Answer 2

ADR; toxic reactions to rugs are well known

• ADRs are 4th/5th leading cause of death among adults
• overall incidence in US hospitals is 6.7%, fatalities 0.3%
• -over 2 million serious ADRs to FDA approved drugs each year
• 50% of all ADRs are due to genetic anomalies

Question 3

pharmacokinetics VS pharmacodynamics

Answer 3

kinetics: study of time course of drug metabolism, absorption, transport, excretion
dynamics: how drug affects body
- relationship between drug, target, and related receptors/enzymes

Question 4

what are the 6 major cytochrome p450 enzymes that metabolize 90% of drugs?

Answer 4

CYP1A1, 1A2, 2D9, 2D6, 2C19, and 3A4

Question 5

what are the data on CYP2D6? what happens to activity if this gene is spliced, framshifted, missense, or copy number variant?

Answer 5

Xm 22

• involved in metabolism of ~100 drugs
• -antidepressants, neuroleptics, beta-blockers, analgesics
• spliced or frameshift: no activity
• missense: decreased activity
• copy number variant: increased activity

Question 6

what happens if poor or ultra metabolizers are given codeine?

Answer 6

codeine is a prodrug that is converted to active morphine by CYP2D6

• poor metabolizers cannot convert drug, and have limited therapeutic effect
• ultra metabolizers may become intoxicated with even low doses of codeine

Question 7

what does TPMT do?

Answer 7

thiopurine methyltransferase gene that catalyzes s-methylation and inactivates 6-MP and 6-thioguanine

Question 8

G6PD deficiency

Answer 8

X-linked disease that is susceptible to drug-induced hemolysis

• rare in Caucasians, but 10% of Africans and common in Mediterranean
• oxidant drugs deplete cell of reduced glutathione, resulting in oxidative damage and hemolysis

Question 9

can G6PD deficient people still take oxidant drugs?

Answer 9

can take them for a short time, but longer exposure causes jaundice, hemolysis, and possibly death

Question 10

favism

Answer 10

hemolytic anemia caused by ingesting fava beans

-extreme form of G6PD, but not all people with G6PD are affected by fava beans

Question 11

explain malignant hyperthermia

Answer 11

AD disease with mutations in 6 loci (RYR1, CACNL 1A3, 4 more)

• negative response to inhalation anesthetics (high fever, dustained contractions, hypercatabolism) due to elevation of ionized Ca in the muscle
• -easy to undo if caught early enough
• can be diagnosed by muscle biopsy and muscle contracture testing

Question 12

how does coumadin work?

Answer 12

inhibits the enzyme epoxide reductase (Vit K reductase, VKOR)
-this inhibits reduced vit K formation, which is essential for clotting

Question 13

explain the pharmacokinetics of warfarin?

Answer 13

there are 2 alleles that are important

1. VKORC1 allele of VKOR gene
   - 30% of variation
   - low dose (more sensitive to drug; Asians)
   - high dose (more resistant to drug; Africans)
2. CYP2C9 allele of cytochrome p450
   - 10% variability
   - common in Caucasians, rare in others

Question 14

besides genetics, what are further complicating factors of drug metabolism?

Answer 14

1. drug reacts with common medicines and antibiotics (increase risk of bleeding)
2. foods with lots of vit K may reduce effectiveness of drug, while ginger/garlic increase risk of bleeding
3. excessive use of alcohol may also change effect of drug