Pharmacogenetics DSA and Waller Lecture Flashcards
Pharmacogenomics:
study of the role of inherited and acquired genetic variation on drug response.
b) Two individuals, of similar weight, receiving the same drug dose may have 1000-fold difference in plasma concentrations.
Factors: age, sex, disease state (e.g., renal impairment), drug-drug interactions, drug-food interactions, pregnancy, and genetics ***.
Pharmacogenetics vs. –genomics
- genetics focuses on individual candidate genes (markers affecting metabolism, distribution, receptor targets, biologic effects)
- genomics: impact of variations of the human genome sequence on pathogenesis of disease and response to drug therapy.
“personalized medicine”
PM, IM, EM and UM
Poor, intermediate, extensive or ultra-rapid metabolizer phenotype (of Phase 1 reactions)
4 categories oof pharmacogenomic influences on drug response
i) Pharmacokinetics – study of the absorption, distribution, metabolism, and elimination of drugs.
ii) Pharmacodynamics – biochemical and physiologic consequences of drug administration.
iii) Idiosyncratic reactions – adverse reaction, cannot be anticipated based upon the known target.
iv) Disease pathogenesis – the underlying severity of disease.
the 2 phases of xenobiotic metabolism
(1) Phase I: addition of a polar group via oxidation, reduction, or hydrolysis; catalyzed predominantly by cytochrome P450 (CYP P450) enzymes.
(2) Phase II: further conjugation (e.g., glucuronidation, methylation, etc.) to more readily excretable, hydrophilic compounds.
CYP2D6 example (codeine)
(a) Example: codeine, prodrug opioid analgesic.
(i) Mechanism of Action (MOA) – codeine and active metabolite morphine bind μ-opioid receptors in central nervous system (CNS). Morphine is x200 more potent than codeine and required for analgesic activity.
(ii) Therapeutic Use – mild to moderately severe pain.
(iii) CYP2D6 responsible for O-demethylation of codeine to morphine.
1. EM: convert sufficient codeine to morphine for desired analgesic effect.
2. PM & IM: may experience insufficient pain relief.
3. UM: increased risk of side effects (e.g., drowsiness and respiratory depression) due to increased morphine concentrations.
(iv) Antitussive properties not affected by CYP2D6 activity.
Thiopurine S-Methyltransferase (TPMT)
a phase II enzyme affected by allelic variation
(a) Example: thiopurine drugs (azathioprine, 6-mercaptopurine, thioguanine)
(i) Therapeutic Use – leukemia and autoimmune diseases.
(ii) TPMT responsible for inactivating drugs.
1. About 90% of white ethnicity inherits high enzyme activity, 10% inherits intermediate activity (heterozygous), and 0.3% inherits low or no activity.
2. Activity phenotypes (high, intermediate, low) applied to polymorphic phase II enzymes as well.
3. Those with defective alleles may accumulate high levels of drug which may result in hematologic toxicity.
Pharmacodynamic genetic variation example of affects at the drug target: Vitamin K Epoxide Reductase Complex (VKORC1) and warfarin
(i) Mechanism of Action (MOA) – inactivates VKORC1. VKORC1 is responsible for conversion of Vitamin K-epoxide to Vitamin K (Vitamin K is essential for activation of clotting factors II, VII, IX, and X, as well as protein C and S). Thus, warfarin depletes functional Vitamin K which results in reduction of activated clotting factors.
(ii) Therapeutic Use – prevention and treatment of thrombosis/embolism.
(iii) VKORC1 is responsible for recycling Vitamin K. A polymorphism (VKORC1-1639G>A) results in reduced expression of VKORC1 in liver; the consequences of which are increased sensitivity to warfarin (necessitating lower doses).
(iv) In addition, warfarin is metabolized via CYP2C9 which is highly polymorphic. Alleles CYP2C9*2 and *3 result in reduced warfarin metabolism. These reduced-function genotypes may further result in increased risk of bleeding due to decreased clearance.
(v) Warfarin illustrates the concept of polygenic influences – combined effect of multiple genes on drug response. Those homozygous for CYP2C9 reduced activity and VKORC1 A alleles require 1/5 to 1/6 the warfarin dose as those who are homozygous for normal functioning alleles.
Pharmacodynamic genetic variation example: (1) Glucose 6-Phosphate Dehydrogenase (G6PD)
Glucose 6-Phosphate Dehydrogenase (G6PD) Deficiency
- Most common disease-producing enzyme defect (400 million worldwide)
- G6PD supplies NADPH which protects RBCs from oxidative damage by regenerating glutathione
- Detoxifies unstable oxygen species
- Drug induced hemolysis occurs when an oxidant drug depletes cell of reduced glutathione
Pharmacodynamic genetic variation effects on Idiosyncratic reactions
i) Unanticipated adverse reaction based on the known drug target.
ii) Drug-Induced Hypersensitivity Reactions
(1) HLA-B*57:01 Polymorphism
(a) Example: abacavir, indicated in the treatment of human immunodeficiency virus (HIV).
(b) Polymorphism found more commonly in European populations. Is associated with abacavir-induced hypersensitivity reactions, in particular Stevens-Johnson syndrome.
(c) Mediated by activation of CD8+ T-lymphocytes release inflammatory cytokines abacavir hypersensitivity reaction.
Pharmacodynamic genetic variation: effects on disease pathogenesis
i) Genetic variations may also alter disease pathogenesis, underlying disease severity, and response to specific drugs.
(1) Example: cystic fibrosis (CF), multisystem autosomal recessive disease.
(a) Caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The CFTR gene is responsible for regulating chloride and water transport in the lungs, digestive tract, and elsewhere.
(b) G551D mutation interferes with activation of the chloride channel.
(c) Ivacaftor, U.S. Food and Drug Administration (FDA) approved in 2012, restores function of the CFTR protein in the 5% of CF patients harboring the G551D mutation.
