Pharmacogenomics Flashcards
1
Q
Factors that influence drug response phenotype:
A
- age
- gender
- disease
- genetic variation
2
Q
Pharmacogenomics:
A
- the study of role of inheritance in variation in drug response.
- adverse drug rxn are major cause of morbidity and mortality.
- knowledge of pts DNA sequence used to optimize drug efficacy and reduce adverse effects.
3
Q
Genetic variation:
A
- variation in proteins involved in drug metabolism or transport “pharmacokinetic variation”
- variation in drug targets “pharmacodynamic variation”
- variation in proteins assoc. w/ idiosyncratic adverse drug effects.
4
Q
Pharmacokinetics:
A
- most common factor responsible for genetic variation in enzymes that catalyze drug metabolism
- almost all major enzymes in drug metabolism display polymorphisms.
5
Q
Genetic polymorphisms:
A
- Butyrylcholinesterase (psuedocholinesterase) “BChE”
- N-acetyltransferase 2 “NAT2”
- Cytochrome P45O 2D6 “CYP2D6”
- Thiopurine S-methyltransferase “TMPT”
6
Q
BChE polymorphism
A
- neuromuscular blockers: used during surgical procedures to cause SKM paralysis
- Succinylcholine: depolarizing NM blocker. Succ binds to nicotinic rcp; but is not metabolized effectively at the synapse.
- the memb remains depolarized and unresponsive = flaccid paralysis.
- onset of NM blockade is rapid w/i 1 min
7
Q
Pts w/ genetic variation in BChE
A
- have decr. rate of metabolism of succinylcholine = prolonged paralysis
- defects in BChE gene are the cause
- transmitted as an AR trait
8
Q
NAT2 polymorphism
A
- catalyzes the acetylation of isoniazid and other drugs.
- many drugs are metabolized by NAT2
- slow acetylators: metabolize isoniazid slowly w/ high blood drug levels. “homozy rec”. => prone to toxicity of drugs
- fast acetylators: metabolize isoniazid rapidly w/ low blood drug levels.
9
Q
NAT2 drug toxicity in slow acetylators
A
- Isoniazid causes neuropathy and hepatoxicity
- Hydralazine and procainamide cause SLE
- Sulfonamides cause hypersensitivity rxns, hemolytic anemia and SLE
10
Q
CYP2D6 polymorphism
A
- 2: family, D: subfamily, 6: indiv enzyme in subfamily.
- CYP2D6 -> memb of CYP450 family.
- metabolizes a large numb of drugs “antidepressants, antiarrhythmic, analgesics”
- described when studying antiHTN debrisoquine and oxytotic agent sparteine.
- poor metabolizers: homozy rec w/ low enzyme activity
- extensive metabolizers: heterozy or homo for wild type
- ultrarapid metabolizers: have multiple copies of CYP2D6 gene “up to 13 copies”
11
Q
Interindividual differences are important b/c CYP2D6 metabolizes:
A
-β-blocker metoprolol
•The antipsychotic haloperidol
•The opioids codeine & dextromethorphan
•The antidepressants fluoxetine, imipramine, & desipramine
12
Q
Poor metabolizers of CYP2D6
A
- may suffer adverse effects w/ standard dose such as metoprolol.
- Codeine ineffective in PM b/c it requires CYP2D6-catalyzed conversion to morphine
13
Q
Ultrarapid metabolizers of CYP2D6
A
- require high doses of drugs metabolized by CYP2D6
- can overdose w/ codeine, suffering respiratory depression or arrest w/ standard doses.
14
Q
TMPT
A
- catalyzes S-methylation of anticancer thiopurines 6-mercaptopurine and azathioprine.
- methylation inactivates these drugs
- Thiopurines have a narrow therapeutic index and some pts suffer myelosuppresion
- 1/300 homozygous for polymorphism that leads to low TMPT activity = incr. risk for myelosuppresion w/ standard doses of thiopurine drugs; these pts must be treated w/ 1/10 of standard dose.
15
Q
Warfarin
A
- affects both pharmacodynamic/kinetic.
- oral anticoagulant w/ a narrow therapeutic window and wide interindividual variability
- under-anticoagulation = thrombosis and over-anticoagulation = bleeding episodes.
- racemic mixture w/ S-warfarin 3-5x more potent than R-warfarin. (the stereoisomers metabolize diff enzymes)
- molecular targe is vit K epoxide reductate (VKORC1 - shows a no. of polymophism)
