Pharmacogenomics

Question 1

Factors that influence drug response phenotype:

Answer 1

• age
• gender
• disease
• genetic variation

Question 2

Pharmacogenomics:

Answer 2

• 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.

Question 3

Genetic variation:

Answer 3

• 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.

Question 4

Pharmacokinetics:

Answer 4

• most common factor responsible for genetic variation in enzymes that catalyze drug metabolism
• almost all major enzymes in drug metabolism display polymorphisms.

Question 5

Genetic polymorphisms:

Answer 5

• Butyrylcholinesterase (psuedocholinesterase) “BChE”
• N-acetyltransferase 2 “NAT2”
• Cytochrome P45O 2D6 “CYP2D6”
• Thiopurine S-methyltransferase “TMPT”

Question 6

BChE polymorphism

Answer 6

• 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

Question 7

Pts w/ genetic variation in BChE

Answer 7

• have decr. rate of metabolism of succinylcholine = prolonged paralysis
• defects in BChE gene are the cause
• transmitted as an AR trait

Question 8

NAT2 polymorphism

Answer 8

• 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.

Question 9

NAT2 drug toxicity in slow acetylators

Answer 9

• Isoniazid causes neuropathy and hepatoxicity
• Hydralazine and procainamide cause SLE
• Sulfonamides cause hypersensitivity rxns, hemolytic anemia and SLE

Question 10

CYP2D6 polymorphism

Answer 10

• 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”

Question 11

Interindividual differences are important b/c CYP2D6 metabolizes:

Answer 11

-β-blocker metoprolol
•The antipsychotic haloperidol
•The opioids codeine & dextromethorphan
•The antidepressants fluoxetine, imipramine, & desipramine

Question 12

Poor metabolizers of CYP2D6

Answer 12

• may suffer adverse effects w/ standard dose such as metoprolol.
• Codeine ineffective in PM b/c it requires CYP2D6-catalyzed conversion to morphine

Question 13

Ultrarapid metabolizers of CYP2D6

Answer 13

• require high doses of drugs metabolized by CYP2D6

- can overdose w/ codeine, suffering respiratory depression or arrest w/ standard doses.

Question 14

TMPT

Answer 14

• 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.

Question 15

Warfarin

Answer 15

• 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)

Question 16

Warfarin metabolism

Answer 16

• CYP2C9: a highly polymorphic gene.
• some variants have lower activity than wild-type
• pts w/ variant allele require decr. doses of warfarin to achieve an anticoagulant effect and have incr. hemorrhage risk.

Question 17

Idiosyncratic drug effects

Answer 17

• rxns are not caused by differences in drug metabolism or targets
• effects from interactions btwn the drug and physiology of pt “i.e. drug rxn assoc. w/ defic of G6PD”

Question 18

G6PD deficiency

Answer 18

• protects RBCs from oxidative injury and is polymorhic.
• diminished activity = impairs ability to form NADPH; which is essential for glutathione reductase (protects from oxygen radicals)
• decr. NADPH = decr cellular detoxification of free radicals and peroxides w/i cell.
• Sulfa, antimalarials and chloramphenicol “cause oxidative stress” - indivs w/ G6PD defic exposed to these develop hemolytic anemia (also from fava beans ingestion)

Question 19

Malignant Hyperthermia

Answer 19

• fatal genetic disorder of SKM “AD trait”
• results from altered control of Ca2+ release from SR = defect in ryanodine rcp gene “RYR1”
• incr. in Ca2+ generates heat.
• production of CO2 and deplete O2 and ATP “accl levels of aerobic metabolism”
• switch to anaerobic met worsens acidosis w/ lactate production
• energy stores deplete
• muscle fibers die = hyperkalemia and myoglobinuria.
• in susceptible indivs by volatile inhalation of anesthetics (eg halothane) and depol SKM relaxants “succinylcholine”
• tachycardia, HTN, severe muscle rigidity, hyperthermia/kalemia, acidosis.

Question 20

Caffeine-halothane muscle contracture test

Answer 20

• reliable test to establish susceptibility to MH
• muscle sample of thigh is removed and placed in physiological sltn; strength is measured.
• nl muscle will not change its baseline but an MH indiv will contract abnormally.