Pharm Pharmacogenetics (11)

• the study of how genetic variations between individuals affect drug dispositions & responses
• driven mainly by advances in technology, tools have become available to assess multigenic determinants of drug response across the entire genome
• in the past it meant the study of the genetic basis for varieties in drug response, but it only dealt with a few genes at a time

• medication optimization at the individual level
• understanding how genetic polymorphisms affect drug response will allow clinicians to select the right drug at the right dose at the outset of therapy, optimizing therapeutic efficacy while minimizing toxicity
• a possibility as the science of pharmacogenomics advances

in most people only about 10% of the drug distributes to the NMJ b/c the remainder of the drug is metabolized to inactive metabolites by butyrylcholinesterase (BChE)

HOWEVER people who have a genetic deficiency in the expression of BChE are more sensitive to succinylcholine

• an antimyocobacterial agent commonly used as a prophylactic agent in people carrying latent tuberculosis
• N-acetyltransferase metabolizes it to inactive metabolites (via acetylation)
• SOME people have a genetic deficiency in the expression of this enzyme or their enzyme doesn't acetylate efficiently, making them more sensitive to isoniazid
• these people have a heightened risk of toxicity (specifically neurotoxity) from isoniazid

• an antimalarial therapy that increases oxidative stress in RBCs
• G6PD (glucose-6-phosphate dehydrogenase) protects most people from this effect

SOME people have a genetic deficiency in G6PD, leading to an increased risk of hemolysis & hemolytic anemia when primaquine is taken

severe acute hemolytic anemia

glucose-6-phosphate dehydrogenase (G6PD)

• variations in DNA sequence present at an allele frequency of 1% or greater in a population
• 2 main types of sequence variations are associated w/ phenotype alterations:

• 1. single nucleotide polymorphisms (SNPs)
• 2. insertions/deletions (indels)

• single base pair substitutions
• 1 is present in the human genome for every few hundred to thousand base pairs (depending on the gene region)
• SNPs account for the majority of observed sequence variations between individuals
• cSNPs = SNPs in a gene's coding region
• a SNPs location in relation to a gene determines the effect it will have on said gene

infrequent, especially in coding regions, but are more likely to produce a functional effect b/c bases are added or removed instead of substituted

when it is determined that a genetic polymorphism exists and is relevant to a paradigm when it actually ISN'T

the effect of a polymorphism on a drug response must be replicated (through research) before applied clinically to avoid a type I error

• 1. pharmacokinetically
• 2. pharmacodynamically
• 3. Other

polymorphisms in metabolizing enzymes or transporters alter the way the body handles a medication

eg. over or under-expression of cytochrome P450 enzymes lead to increased or decreased metabolism of substrate drugs

polymorphisms can affect drug receptors & targets, therefore changing a drugs effectiveness

• eg.
• vitamin K epoxide reductase for warfarin

angiotensin converting enzyme for ACE inhibitors

HMG-CoA reductase for statins (lipid modifying agents)

• patients who have a genetic polymorphism in a gene that makes them MORE likely to form coagulation factors in the blood
• eg. a mutation in the prothrombin gene
• if they're already predisposed to blood clots, something like the estrogen in birth control might further increase their risk

• a potassium channel blocking anti-arrhythmic agent, such as quinidine
• such a drug in a predisposed individual may increase the risk for a side effect like QT prolongation (a biomarker for ventricular tachyarrhythmias & a risk factor for sudden death)

• a mutated (of normal proteins) peptide made by breast tumor cells
• if the tumor expresses HER2/neu, a monoclonal antibody called Herceptin can treat the cancer by binding to the surface peptide & killing cells that produce the mutated protein

• Warfarin
• CYP2C9 polymorphisms affects its pharmacokinetics (drug metabolism)
• vitamin K epoxide reductase (VKOR) polymorphisms affect its pharmacodynamics
• VKOR is an enzymes that activates clotting factors
• there also tend to be non-genetic factors that also account for variability in drug response such as age, weight, gender, diet, co-morbidities, & other drug interactions

• enzyme that metabolizes warfarin to hydroxywarfarin, its inactive metabolite
• if a polymorphism causes this enzyme to be missing or less effective warfarin may accumulate & cause excessive bleeding → lower dose needed
• if a polymorphism causes this enzyme to rapidly metabolize warfarin a larger dose might be needed for the drug to take effect

• reduces vitamin K to its active form so it may act in the blood coagulation cascade
• warfarin inhibits VKOR, preventing blood from clotting → thinning the blood
• underactive/missing: less warfarin needed to exert a desired effect OR warfarin won't work at all because it has nothing to inhibit
• overactive: a larger dose of warfarin needed to exert a desired effect

those encoding transporter, enzyme, & receptor proteins

• Enzymes:
• Cytochrome P450 (eg. 2C9, 2C19, 2D6, 3A)
• UGP-glucuronosyltransferase
• Sulfotransferase
• N-actetyltransferase

Transporters: P-glycoprotein (MDR1)

• 2-5% of Europeans & 18-23% of East Asians are poor metabolizers as a result of 2C19*3 polymorphisms
• polymorphism → non-functioning 2C19*3 enzyme → drugs don't work

clopidogrel (Plavix) an antiplatelet prodrug metabolized by 2C19*3 that inhibits the formation of blood clots to prevent stroke & MI

omeprazole (Prilosec) is a proton pump inhibitor that treats reflux disease by inhibiting the 2C19*3 enzyme

• polymorphisms of CYP2D6 tend to produce enzymes that ultra rapidly metabolize certain drugs such as antidepressants, antipsychotics, codeine, & tamoxifen
• such polymorphisms can be found in 29% of Ethiopians, 1-5% of Europeans, & less than 2% of African American

• a CYP2D6 polymorphism that turns someone into a rapid metabolizer results in conversion of more than the usual ~10% of codeine into morphine
• giving a normal dose to a rapid metabolizer can result in morphine toxicity because they've converted more than a normal person would using their polymorphed CYP2D6 enzyme

• there's resistance to abandon the “trial and error” approach most clinicians are comfortable with
• concerns about genetic discrimination
• unfamiliarity with the principles of genetics
• a lack of outcomes data
• it's not affordable

hypocrites: it is acceptable for clinicians to make drug dose adjustments based on changes in organ function (eg. liver or kidney) even in the absence of clinical outcomes data

• FDA approved medication labels are including more information on the use of pharmacogenetic testing
• however few drugs are required or recommended for testing
• pharmacogenomic biomarkers in drug labels are most often there for informational purposes, like for codeine, warfarin, or clopidogrel

a nuceloside reverse transcriptase inhibitor used to treat HIV/AIDS

patients who have a HLA-B*5701 gene polymorphism are more likely to suffer a hypersensitivity reaction to abacavir

a chimeric monoclonal antibody designed to treat certain types of cancers such as metastatic colon cancer or head & neck cancers

• whether the Epidermal Growth Factor Receptor (EGFR) gene is expressed
• if it is Cetuximab can target the receptor & kill the cell on which its located

an immusupressant used for leukemia, inflammatory bowel disease, & other immunologic conditions

if the TPMT*2 & *3 gene (a conjugating enzyme responsible for metabolism of azathioprine) polymorphism makes the enzymes less effective, toxicity may result due to production of a metabolite via an alternative metabolism pathway

a chemotherapy agent used to treat metastatic colon cancer

a UGT1A1*28 gene polymorphism (a conjugating enzyme responsible for metabolism of ironotecan) may result in accumulation of a toxic metabolite (SN38)