Pharmacogenomics Flashcards
BUTYRYLCHOLINESTERASE POLYMORPHISM
Neuromuscular blockers are drugs used during surgical procedures to cause skeletal muscle
paralysis.
Succinylcholine is a depolarizing neuromuscular blocker. Succinylcholine binds to the nicotinic receptor and acts like acetylcholine to cause depolarization of the end plate. Succinylcholine is not metabolized effectively at the synapse, therefore the membrane remains depolarized and unresponsive to additional impulses. A flaccid paralysis results.
The onset of neuromuscular blockade is very rapid, usually within 1 minute.
Because of its rapid hydrolysis by plasma butyrylcholinesterase (BChE, pseudocholinesterase), duration of neuromuscular blockade is 5-10 minutes.
Patients with genetic variations in butyrylcholinesterase have a decreased rate of metabolism of succinylcholine, resulting in prolonged paralysis.
Prolonged paralysis from succinylcholine caused by abnormal butyrylcholinesterase is treated with continued mechanical ventilation until muscle function returns to normal.
Defects in the BCHE gene are the cause of butyrylcholinesterase deficiency. The hereditary condition is transmitted as an autosomal recessive trait.
Because of the rarity of these genetic variants, butyrylcholinesterase testing is not routine clinical procedure.
N-ACETYLTRANSFERASE 2 POLYMORPHISM
N-acetyltransferase 2, a genetically polymorphic phase II enzyme, catalyzes the acetylation of the antimycobacterial agent 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.
The rate of isoniazid acetylation is inherited. Slow acetylators of isoniazid are homozygous for an autosomal recessive allele of the enzyme, with lower activity levels.
A number of other drugs are also metabolized by N-acetyltransferase 2. Slow acetylators are prone to toxicity of drugs that are inactivated by acetylation. Examples include:
Isoniazid may cause neuropathy and hepatotoxicity.
Hydralazine and procainamide may cause systemic lupus erythematosus.
Sulfonamides may cause hypersensitivity reactions, hemolytic anemia and systemic lupus erythematosus.
CYP2D6 POLYMORPHISM
CYP2D6 is a member of the cytochrome P450 family of microsomal, phase I drug-metabolizing enzymes. CYP2D6 contributes to the metabolism of a large number of drugs, including antidepressants, antiarrhythmics, and analgesics.
Poor metabolizers are homozygous for recessive alleles coding for enzymes with low activity.
Extensive metabolizers are heterozygous or homozygous for the “wild type” allele.
There is a small subset of ultrarapid metabolizers. Some ultrarapid metabolizers have multiple copies of the CYP2D6 gene. Some ultrarapid metabolizers can have up to 13 copies of the gene.
These differences have potentially important medical implications, because CYP2D6 metabolizes many commonly prescribed medications, including the β-adrenergic blocker metoprolol, the neuroleptic haloperidol, the opioids codeine and dextromethorphan, and the antidepressants fluoxetine, imipramine, and desipramine, among many others.
Poor metabolizers may suffer adverse effects when treated with standard doses of drugs such as metoprolol.
Codeine is ineffective in poor metabolizers because it requires CYP2D6-catalyzed conversion to morphine.
Ultrarapid metabolizers may require very high doses of drugs that are metabolized by CYP2D6. But they can overdose with codeine, suffering respiratory depression or even respiratory arrest in response to standard doses.
THIOPURINE S-METHYLTRANSFERASE POLYMORPHISM
TPMT catalyzes the S-methylation of the anticancer thiopurines 6-mercaptopurine and azathioprine. Methylation of these drugs inactivates them. Thiopurines have a narrow therapeutic window and some patients suffer from life-threatening myelosuppression.
Approximately 1/300 individuals are homozygous for a polymorphism that leads to low TPMT activity. Homozygotes for this polymorphism are at increased risk for myelosuppression when treated with standards doses of thiopurine drugs. These patients have to be treated with approximately 1/10 of the standard dose.
MUTATIONS IN THE GENE ENCODING THE EPIDERMAL GROWTH FACTOR RECEPTOR (EGFR)
An example of genetic variation in a drug target in somatic (tumor) DNA involves gain-of- function mutations in the gene encoding the epidermal growth factor receptor (EGFR).
EGFR is often overexpressed in nonsmall cell lung cancer (NSCLC). Several drugs targeting this receptor have been tested clinically.
Gefitinib is an inhibitor of the tyrosine kinase of EGFR. Gefitinib is approved for the treatment of NSCLC. Patients with mutations in the ATP-binding site of the tyrosine kinase domain of the receptor respond better to gefitinib.
WARFARIN
The preceding examples involve pharmacogenetic variations as a result of variation in a single gene. However, there are examples of multiple genes that affect both the pharmacokinetics and pharmacodynamics of a drug. One example is warfarin. Warfarin is one of the most widely prescribed oral anticoagulants. Warfarin has a narrow therapeutic window and wide interindividual variability, making dosing problematic. Under-anticoagulation can result in thrombosis and over-anticoagulation can result in bleeding episodes.
Warfarin is a racemic mixture. S-warfarin is 3 - 5 times more potent than R-warfarin. The stereoisomers are metabolized by different enzymes. Metabolism of the S isomer is mainly via CYP2C9. Metabolism of the R isomer is via CYP3A4 and other CYP isoforms.
CYP2C9 is a highly polymorphic gene. Some variant alleles have much lower activity than the wild-type allele. Patients who carry the variant alleles require decreased doses of warfarin to achieve an anticoagulant effect, and they have increased risk for hemorrhage during warfarin therapy.
However, this pharmacokinetic variation does not explain all of the variance in the therapeutic warfarin dose. There is also a pharmacodynamic component. The molecular target for warfarin is vitamin K epoxide reductase. The gene encoding the enzyme is vitamin K epoxide reductase complex 1, VKORC1. The VKORC1 gene shows a number of polymorphisms which affect warfarin dose requirement. The dose may vary two-fold depending on the polymorphism.
The warfarin drug labeling was revised on August 16, 2007 by the FDA to include genomic information. The new label states that lower initial doses should be considered for patients with genetic variations in CYP2C9 and VKORC1.
GLUCOSE 6-PHOSPHATE DEHYDROGENASE (G6PD) DEFICIENCY
Idiosyncratic drug reactions are not caused by differences in either drug metabolism or drug targets. Idiosyncratic effects seem to result from interactions between the drug and a unique aspect of the physiology of the individual patient. A classic example is the drug reactions associated with functional deficiency of the enzyme glucose 6-phosphate dehydrogenase (G6PD). This enzyme is involved in protecting red blood cells from oxidative injury.
Diminished G6PD activity impairs the ability of the cell to form NADPH that is essential for the maintenance of the reduced glutathione pool. This results in a decrease in the cellular detoxification of free radicals and peroxides formed within the cell.
Glutathione also helps maintain the reduced states of sulfhydryl groups in proteins, including hemoglobin. Oxidation of those sulfhydryl groups leads to the formation of denatured proteins that form insoluble masses (Heinz bodies) that attach to the red cell membranes. Additional oxidation of membrane proteins causes the red cells to be rigid and nondeformable and they are removed from the circulation by macrophages in the spleen and liver.
A number of G6PD polymorphisms have been described. The most common involves a cSNP that causes an amino acid substitution, resulting in a 90% to 95% reduction of G6PD enzyme function. That allele, A-, is present in 10% to 20% of Africans and is thought to provide protection against malaria.
A number of drugs cause oxidative stress on red blood cells as an effect unrelated to their intended targets or their metabolism. These drugs include sulfonamides, antimalarials (eg, primaquine and chloroqune), and chloramphenicol. Individuals with G6PD deficiency who are exposed to these drugs may develop acute and, at times, severe hemolytic anemia.
By definition, idiosyncratic effects are difficult or impossible to predict. However, information emerging from genomic, proteomic, and metabolomic research may prove useful in the future in the development of pharmacogenomic screens for unanticipated drug interactions. At present, unfortunately, idiosyncratic effects cannot be predicted.
