Pharmacogenetics Flashcards
3 types of genetic variation that can influence pharmacotherapy:
- Variation in proteins involved in drug metabolism or transport (pharmacokinetic variation).
- Variation in drug targets (pharmacodynamic variation)
- Variation in proteins associated with idiosyncratic adverse effects.
Pharmacogenomics
Study of the role of inheritance in drug response
Drug-Metabolizing enzymes: Pharmacokinetics
Genetic Polymorphisms in:
- Butyrylcholinesterase (BChE) (Pseudocholinesterase)
- N-acetyltransferase 2 (NAT2)
- Cytochrome P450 2D6 (CYP2D6)
- Thiopurine S-methyltransferase (TPMT)
Butyrylcholinesterase (BChE)
Succinylcholine is a depolarizing neuromuscular blocker at the end plate. Used in surgical procedures to cause muscle paralysis.
causes flaccid paralysis because it cannot be effectively metabolized in the synapse
acts within 1 minute.
Butyrylcholinesterase Polymorphism
Patients with genetic variations in the butyrylcholinesterase have a decreased rate of metabolism of sucinycholine
- prolonged paralysis
- defects in BCHE gene are the cause
- Autosomal Recessive
N-acetyltransferase 2 (NAT2) Polymorphism
NAT 2 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.
Autosomal recessive
-slow acetylators prone to toxicity with drugs
that are metabolized by acetylation.
Fast acetylators: metabolize isoniazid fast and have low blood levels.
NAT 2 DRUGS and effects:
Isoniazid: causes neuropathy and hepatotoxicity.
Hydralazine and procainamide may cause systemic lupus eythematosus
Sulfonamides: may cause hypersensitivity reactions, hemolytic anemia and systematic lupus eythematosus
CYP2D6 Polymorphism
member of CYP450 family of drug metabolizing enzymes.
first described when studying antihypertensive debrisoquine and oxytotic agent sparteine.
Poor metabolizers are homo. recessive alleles coding for enzymes with low activity
Extensive metabolizers are hetero or homo for wild type. allele
Ultrarapid metabolizers-have multiple copies (upto 13) of the gene.-very easy to overdose these individuals.
Thiopurine S-methyltransferase Polymorphism (TPMT) (anticancer drugs)
Catalyzes the S-methylation of the anticancer thiopurines 6-mercaptopurine and azathiopurine
- methylation inactivates drugs
- thiopurines have a narrow therapeutic index and some patients suffer from life threatening myelosuppression (Bone marrow suppression).
- 1/300 individuals are homozygous for the polymorphism that leads to low TPMT activity.
- increased risk of myelo suppression when treated with standard doses. need to be treated with 1/10 of standard dose.
Warfarin
- Narrow Therapeutic window, and wide inteindividual variability, making dosing problematic.
- under-anticoagulation can result in thrombosis and over-anticoagulation can result in bleeding.
Racemic: S-Warfarin (more potent) and R-Warfarin-metabolized by different enzymes
S-Warfarin: CYP2C9 (highly polymorphic gene)
-lower activity low dosing.
R-Warfarin: Many CYP’s
Vit K epoxide reductase (VKORC1 gene) (pg41)
Malignant Hyperthermia
Abnormal RyR1 receptors trigger unregulated release of calcium from SR.
Autosomal dominant trait -main cause of death in Anesthesia Syndrome includes: Tachycardia Hypertension Severe muscle rigidity Hyperthermia Hyperlipemia Acidosis
Test: caffeine-halothane muscle contracture.
Genetic variation associated with idiosyncratic drug effects
Classic example is G6PD deficiency.
Enzyme protects red blood cells from injury by keeping reducing power going (nadph->gssg->gsh->h2o)
-hemolytic anemia
Drugs that cause oxidative stress on RBCs:
Sulfonamides , antimalarials, and chloramphenicol. Fava beans
Manifesting heterozygous
In carrier females of hemophilia A. Due to skewed x inactivation, leads to a higher percentage of inactivated normal x-chromosome
