2.01 - Pharmacogenetics Flashcards
What is pharmacogenetics?
The genetic basis for the different patient responses to a particular drug
How does pharmacogenomics differ to pharmacogenetics?
Pharmacogenomics is the application of genomic information to identify individuals who are likely to respond favourably or poorly to a particular drug
What are the benefits of pharmacogenetics?
Better, safer drugs the first time
More accurate methods of determining appropriate drug doses
Decrease in overall cost of health care
How do genetic variations affect pharmacotherapy?
There can be variations in the target protein that can either make the drug more or less efficacious, by increasing activity of the receptor to the agonist, increasing the binding the agonist to the receptor, altering the number of active target proteins etc.
Variations in the drug metabolising proteins can increase or decrease the half life of the drug
Describe the beta2 adrenergic example of protein variation in pharmacogenetics
A large number of known mutations affect the way the receptor is downregulated after exposure to a beta2 agonist.
Before exposure 100% of the receptor should be expressed. Upon exposure normal individuals will downregulate the beta2 receptor over time.
However, Gly16 mutations result in increased downregulation of the receptor leading to a decreased response to the drug
On the other hand Glu27 mutations result in decreased receptor downregulation so will therefore have a greater respone to the agonist
What are the two phases of drug metabolism
Phase I: adds hydroxyls, thiols etc. This inactivates the compounds
Phase II: Adds group (e.g. glucaronic acid) which increases water solubility –> excretion
Describe the variation in CYP450 2D6 and its effect on drug metabolism
Part of Phase I metabolism
Responsible for metabolism many drugs (e.g. codein, fluoxetine, metoprolol)
Having multiple copes of the CYP2D6 gene resulting in ultrarapid metabolism and therefore decreased effectiveness of the above drugs
On the other hand, having two copies of variant with poor activity or one with no activity results in poor metabolism and therefore increased drug concentrations
Describe an example of idiosyncratic effects of pharmacotherapy
These effects are not causes by differences in target drug or drug metabolising enzymes
An example if G6PD deficiency. G6PD normaly protects RBCs from oxidative stress. Medications that put oxidative stress on RBCs may therefore be dangerous in G6PD deficient individuals (ibuprofen)
Describe the RAAS mutations that can affect pharmacotherapy
A particular mutation in the enzyme renin (covnerts angiotensinogen to Ang I) results in higher levels of expression.
These individuals were found to be on several antihypertensives (increased production of AngII and therefore greater CV risk)
These individuals respond better than non-carriers to ACE inhibitors as this class of drug directly effects the problematic pathway
What are some barriers to pharmacogenetics?
The complexity of finding gene variations that affect drug response
Limited drug alternatives
Disincentives for drug companies to make multiple pharmacogenomic products
Educating health care providers
