Pharmacogenetics

Question 1

Plasma cholinesterase Deficiency

Answer 1

Chromosome 3

Autosomal recessive

Caucasian pop highest prevalence (4%)

5-60min apnea (1/3000 >1hr apnea)

Question 2

Acute intermittent Porphyria

Answer 2

Autosomal dominant

Mutation in biosynthetic pathway of heme

Symptoms d/t buildup of pre-cursors
-porphyrins

Exacerbation by drug/hormones or spontaneous

Question 3

NAT2 deficiency

N-acetyltransferase

Answer 3

Isoniazid (med for TB)
convert isoniazid to acetylisoniazid

Chromosome 8
Single recessive gene

27 NAT2 alleles

Question 4

Fast vs Slow Acetyllators

Answer 4

Fast: prone to hepatotoxicity

Slow: prone to isoniazid toxicity (peripheral toxicity)
NAT25 and NAT26 account for 90% of slow

Question 5

Meds acetyltransferase important for metabolism of:

Answer 5

hydralazine, procainamide, dapsone, sulfonamides,
(deficiency = lupus type syndrome
autoimmune D of skin/ kidney/ joints)

Question 6

NAT2 Deficiency by race

Answer 6

40-70% white and AA
10-20% Jap and Canadian Eskimo
80+% Egyptians

Question 7

Phase 1 & 2 Metab

Answer 7

Phase 1: [functionalization]
oxidation, reduction, hydrolysis
80% of Metab,
expose functional group = >polarity

Phase 2: [Conjugation rxn]
acetylation, glucuronidation
large polar compound attached 
     via covalent bond
>> Polarity

Question 8

Human Genome Project

Answer 8

genome ~3 billion bases
gene ~3,000 bases
~22,300 total # protein coding genes
>99% of nucleotide bases same in all ppl

Question 9

Wafarin

Answer 9

Anticoagulant for PE, A-fib, artificial heart valves, post ortho surgeries
R & S Warfarin metabolized by diff enzymes

Question 10

CYP2C9 SNPs

& Warfarin

Answer 10

Wild-type variant: 1* 
   Metabolize normally
2 Polymorphic variants  2* and 3*
   2* 30% redcuction in metab
   3*  90% reduction in metab

Question 11

VKORC1:
target enzyme for warfarin
Many Polymorphisms

Answer 11

G1639A causes lower level of VKOR enzyme

so need less warfarin

Question 12

Clopidogrel

Answer 12

anti-platelet drug, PRODRUG
absorbed in intestine, activated in liver
bind to ADP receptor [P2RY12] on plt
-> irreversible blocking of ADP binding
   -> no receptor activation 
         -> inhibit blood clotting

Question 13

Clopidogrel metabolized

Answer 13

by CYP-2C19, variants in -2C19
    2 = no metabolism/effect 
       (most common)
    3, 4 and 5 = no metab/effect 
[^ poor metabolizers]
  17 = >metab -> large effect -> 
     more bleeding

Question 14

Codiene

Answer 14

PRODRUG (< affinity for receptors)
metabolized by CYP-2D6
mutations in ^ change change in morphine response

Question 15

CYP-2D6 Mutations

Answer 15

Poor Metab: no converting -> no morphine
->no pain relief

Intermediate Metab: low enzyme activity
-> low morphine/pain response

Extensive Metab: Normal [most ppl]

Question 16

CYP-2D6 Mutation

Ultra-rapid metabolizer

Answer 16

High CYP-2D6 activity ->

convert to morphine ->

Question 17

Tamoxifen

Answer 17

PRODRUG
Estrogen receptor antagonist
Tx ER+ breast CA
metabolized by CYP-2D6
     ^rate limiting enzyme
Metabolites of have >affinity for estrogen receptor

Question 18

Vemurafenib

Answer 18

Melanoma drug for BRAF V600E mutation only
~80% of melanoma has ^ mutation
If have melanoma want gene testing

Question 19

What also influences drug efficacy?

besides genes?

Answer 19

Age
Environment
Drug Rxns (& food rxns)
BMI
Diet
Smoking

Question 20

Research challenges

Answer 20

Cost to develop tests,
Relatively new
benefit minority of ppl (mutations rare)
cost of test vs monitoring for ADRs
Time to do genetic screen
Stigmatization of ethnic groups
cost to do tests

Question 21

Benefit of Gene screening

Answer 21

Increase efficacy of drugs
less toxicity & ADRs
ADR >hospitalization cause
only have to do once

Question 22

Pharmacogenetics

Answer 22

study of genetically determined variation in how individuals respond to drugs