Pharmacogenetics

Question 1

define pharmacogenetics

Answer 1

• the study of the role of inheritance in variation in drug response

Question 2

name the 3 types of genetic variations that can influence pharmacotherapy

Answer 2

• Variation in proteins involved in drug metabolism or transport (pharmacokinetic variation)
• variation in drug targets (pharmacodynamic variation)
• variation in proteins associated with idiosyncratic adverse drug effects

Question 3

describe butyrylcholinesterase polymorphism

Answer 3

• neuromuscular blockers are drugs used during surgical procedures to cause skeletal muscle paraylsis
• succinylcholine is not metabolized effectively at the synapse
  
  • the membrane remains depolarized and unresponsive to additional impulses
  • a flaccid paralysis results
• patients with genetic variation in butyrlcholinesterase have a decreased rate of metabolism of succinylcholine
  
  • prolonged paralysis

Question 4

describe N-acetyltransferase 2 polymorphism

Answer 4

• NAT2 catalyzes the acetylation of isoniazid and other drugs
• patients treated with isoniazid can be classified as:
  
  • slow acetylators: metabolize isoniazid slowly and have high blood drug levels
  • fast acetylators: metabolize isoniazid rapidly and have low blood drug levels
• slow acetylators are prone to toxicity of drugs that are metabolized by acetlyation

Question 5

name examples of NAT2 defects

Answer 5

• isoniazid may cause neuropathy and hepatotoxicity
• hydralazine and procainamide may cause lupus
• sulfonamides may cause hypersensitivity reactions, hemolytic anemia and lupus

Question 6

describe CYP2D6 polymorphism

Answer 6

• poor metabolizers are homozygous for recessive alleles coding for enzymes with low activity
• extensive metabolizers are heterozygous or homozygous for the wile type allele
• some ultratrapid metabolizers have multiple copies of the CYP2D6 gene
  
  • can have up to 13 copies of the gene

Question 7

what does CYP2D6 metabolize

Answer 7

• B-blocker metoprolol
• antipsychotic haloperidol
• opiods codeine and DXM
  
  • CYP2D6 can’t convert codeine into morphine, which is the active drug
    
    • ultrametabolizers may undergo respiratory distress since they convert it too fast
• antidepressants

Question 8

describe thiopurine S-methyltransferase polymorphism

Answer 8

• TPMT catalyzes the S-methylation of the anticancer thiopurines 6-mercaptopurine and azathioprine
  
  • methylation of these drugs inactivates them
• people with low TPMT activity are at an increased risk for myelosuppression when treated with standard doses of thiopurine drugs
  
  • patients have to be treated with 1/10 the standard dose

Question 9

describe the CYP2C9 polymorphic gene

Answer 9

• some variant alleles have much lower activity than normal
• patients who carry these variant alleles require decreased doses of warfarin to achieve an anticoagulant effect
  
  • at an increased risk for hemorrhage

Question 10

describe VKORC1 gene polymorphisms

Answer 10

• The gene encoding the enzyme is vitamin K epoxide reductase complex 1, VKORC1
• the dose may vary depending on the polymorphism

Question 11

describe deficiency of G6PD

Answer 11

• G6PD protects red blood cells from oxidative injury
• diminished G6PD activity impairs the ability of the cell to form NADPH
• decreased NADPH results in a decrease in the cellular detox of free radicals and peroxides formed within the cell

Question 12

why do people with G6PD deficiency develop hemolytic anemia

Answer 12

• A number of drugs cause oxidative stress on red blood cells
  
  • sulfonamids, antimalarials, chloramphenicol, fava beans
• individuals with G6PD deficiency who are exposed to these drugs may develop hemolytic anemia
  
  • red blood cells don’t have mitochondria and don’t have any other source of NADPH

Question 13

describe malignant hypothermia

Answer 13

• potentially fatal genetic disorder of skeletal muscle
• triggered in susceptible individuals by volatile inhalation anesthetics (halothane) and depolarizing skeletal muscle relaxants such as succinylcholine
  
  • one of the main causes of death during anesthesia

Question 14

describe mechanism behind malignant hyperthermia

Answer 14

• malignant hyperthermia results from altered control of Ca2+ release from the SR
• in most cases, the syndrome is caused by a defect in the ryanodine receptor gene
• abnormal ryanodine receptors trigger unregulated release of calcium from the SR, which may lead to an acute malignant hyperthermia crisis
  
  • causes sustained muscle contraction –> generates heat
  • accelerated levels of aerobic metabolism produce CO2 and deplete O2 and ATP
  • switches to anaerobic metabolism
  • energy stores depleted
  • muscle fibers die leading to hyperkalemia and myoglobinuria

Question 15

what is the antidote to malignant hyperthermia

Answer 15

• Dantrolene blocks Ca2+ release from the SR
  
  • measures to reduce body temp. and restore electrolyte and acid-base balance