L15: Personalized Medicine Flashcards
what is personalized medicine? and why is it a thing
Personalized medicine is the tailoring of medical treatment to the individual characteristics, needs, and preferences of the patient
Clinicians past/present observed that:
- Patients with similar symptoms may have different illnesses
- Medical interventions may work well in some patients with a disease, but not in others with apparently the same disease (i.e. non- responders)
- thats why personalized medicine exists
what are SNPs? How similar and different are humans genetically? what can the variations in genes coding for drug target proteins result in?
- Single nucleotide polymorphisms (SNPs) are the most common form of genetic variability
- Recall that SNPs are single base changes in the DNA: ex. instead of T its A
- Humans are 99.9% genetically identical; the remaining 0.1% is what makes us different from one another
–> Different physical attributes
–> Different predispositions to health conditions - Variation in genes coding for drug target proteins may result in differences in drug efficacy and side effects for different people
what is pharmacogenomics: also Pharmacodynamics and Pharmacokinetics
Pharmacogenomics is study of drug response based on genetic makeup and variability
Pharmacodynamics - What does the drug do to the body?
- Involve biochemical pathway and physiological effects
Affect drug efficacy, toxicity (e.g. side effects), and choice of treatment
Pharmacokinetics - What does the body do to the drug?
- Involve ADME
- Affect dose, delivery, and dosage regimen
what are the various sources that correspond with variations in drug responses
genetic and environmental factors effect the way the drug is processed after taken to yield a response.
they effect the absorption, distribution, metabolism, and excretion of the drug (ADME)
what are the pharmacological and toxicological consequences of drug metabolism
Inactivation: active drug to inactive product
Activation: inactive pro-drug to active product
- Maintenance/no change of activity
- Increased chemical reactivity – ex. protein, lipid, DNA binding
what do hepatic enzymes do
they act on drugs to help eliminate them
Part of evolutionary system to eliminate foreign compounds
Usually, the enzymatic reaction results in a more water-soluble product so it can be secreted
what are two examples of enzymatic reactions that result in a more water soluble product?
inactive –> active
active –> inactive
metabolic reactions
inactive/partially active drug (ex. codiene (pro-drug))
–> Drug-metabolizing enzyme (CYP2D6)
–> Active metabolite (e.g. morphine) ANALGESIA
or for ex.
Active drug (e.g. nicotine) PSYCHOSTIMULANT EFFECTS
–> Drug-metabolizing enzyme (CYP2A6)
–> Inactive/partially active drug (e.g. cotinine)
what can variability in drug metabolizing enzymes do?
Variability in drug-metabolizing enzymes can alter metabolite (small molecules that are intermediates or end products of metabolic processes) concentration levels, which can assist physicians in prescribing the right treatment dosage
for ex. if an enzyme creates little metabolites, we can increase the concentration of the enzyme to create more products.
What are three examples of perscribing different dosages of metabolizers (enzymes) and their ratio of starting material to product
use ex. of codiene, enzyme, product
Variability in drug-metabolizing enzymes can alter metabolite levels, which can assist physicians in prescribing the right treatment dosage
ex. with CYP2D6 enzymes
there can be….
- poor (slow) metabolizers
–> lots of initial codiene, little morphine
extensive (normal) metabolizers
–> little codeine, same amount of morphine
ulta-rapid metabolizers
–> little codeine, more morphine
therefore enzyme potency is positively correlated with product formation
what is a case study of morphine poisoning in a breast-fed infant and CYP2D6 metabolism
- In April 2005, a full-term healthy male infant: intermittent periods of difficulty in breathing and lethargy starting on day 7
- Regaining weight, by day 11, he had grey skin and lower milk consumption. He was found dead by day 13
- His blood concentration of morphine was 70 ng/mL
- The mother had been prescribed a combination preparation of codeine and paracetamol after birth for episiotomy pain
- After genotyping analysis of CYP2D6, they found that the mother was an ultra-rapid metabolizer (made a lot of morphine product) and was breast feeding the child
what are Diagnostic Tests & Personalized Therapeutics
can they be codeveloped
yes.
Diagnostic Test
- Medical test performed to aid in the diagnosis of a disease
personalized therapeutic
- A treatment, therapy or drug that is personalized
- Moving towards developing (and FDA-approving) both test and drug therapy in combination
Case study: Testing for HER2 overexpression in patients with breast cancer to improve treatment success
explain the case study
- what percent of breast cancers are HER2-positive
- what do normal breast cells and HER2 positive breast cancer cells look like in terms of the HER2 receptors in them?
- how does herceptin (medication used in the treatment of certain types of breast cancer) interact with HER2 receptors
- About 20% of breast cancers are HER2-positive
- Drug can slow or stop the growth of the breast cancer
in normal breast cells
- HER2 receptors send signals telling cells to grow and divide
in HER2 Positive breast cancer cells
- there are too many HER2 receptors, which may make the cancer cells grow and divide faster
- Herceptin works by attaching itself to the HER2 receptors and blocking them from receiving growth signals (antagonist)
what are benefits of personalized medicine (6)
- Better tailoring of medication to the patient instead of trial and error
- Shift emphasis in medicine from reaction to prevention
–> Enhanced patient adherence to treatment
–> Safer drug profile (i.e. minimize the occurrence of adverse events) - Reductions in costs of trials
–> Identifying those populations that are responsive to treatment - improves health outcomes (like for heart, leukemia, and colorectal cancer patients)
- make the health system more efficient (strokes are prevented, chemotherapy use goes down, so does costs for colorectal cancer)
Smoking cessation treatments exist with different efficacy.
how many people does tobacco kill yearly and what are three FDA approved smoking cessation treatments?
Tobacco use kills around >8 million individuals yearly worldwide
Three FDA-approved smoking cessation treatments exist:
- Varenicline (Champix)
- Nicotine replacement therapy
- Bupropion (Welbutrin)
How can you optimize smoking cessation treatments based on a smokers nicotine metabolism: a case study
- how is NMR calculated
- how is the liver enzyme CYP2A6 related to the NMR number
Nicotine Metabolite Ratio (NMR) = assess how efficiently ones body metabolizes nicotine. Calculated by dividing the concentration of a nicotine metabolite called 3’-hydroxycotinine (3’-HC) by the concentration of another nicotine metabolite called cotinine (COT) in a person’s urine or blood sample.
- Activity level of liver enzyme CYP2A6 (enzyme which metabolizes nicotine) reflects the NMR value.
- A higher NMR indicates faster metabolism of nicotine (makes more faster ‘3-HC), while a lower NMR indicates slower metabolism (makes less slowly ‘3-HC).
