Pharmacogenetics Lecture Flashcards
Define pharmacogenetics
Pharmacogenetics
is defined as the genetic basis for different responses to a particular drug.
Is pharmacogenomics the same thing?
Most use it interchangeably but others regard it as the application of genomic information to identify individuals **who are likely to respond favourably or poorly to a particular drug.
Describe factors contributing to variation in drug response
The factors contributing to variation in drug response are very important.
Some environmental factors will play a role, including age, smoking, sex, pregnancy, exercise, underlying conditions and diet.
- the degree of impact of the environmental factors is modulated by an individual’s genetic makeup
The interaction of environmental factors and genetic makeup determines an individual’s response.
Genetic influence
Genetic influence can inform whether a drug will work, how well it will work, and whether a drug will be toxic or not.
Genetic influence on pharmacokinetics accounts for 75-85% of variability in the half-life (t½) of drugs eliminated by metabolism.
Evidence for this is from twin studies comparing fraternal and identical twins:
- very little difference in half-life between identical twins
- variability among fraternal twins
- underlies the importance of genetics on drug metabolism
Why is pharmacogenetics important?
Adverse Drug Reactions
In the United States in 2014:
- Approximately 2,000,000 adverse drug reactions (ADRs) occurred, with almost half being serious.
- 123,927 ADRs resulted in fatalities. ^[similar proportion in Au]
- ADRs rank among the top 10 causes of hospitalization and death in the US.
- *Serious means: death, hospitalization, life-threatening, disability, congenital anomaly, and/or other serious outcome
Aim of Pharmacogenetics
The goal of pharmacogenetics is personalized pharmacotherapy, aiming to tailor drug treatments to individual genetic profiles in order to pick the drug, the dose, administration at the right time (minimise toxicity and maximise therapeutic effect) ^[i.e. the promise]
Describe the benefits of pharmacogenetics
Pharmacogenetics offers several advantages, including:
- More potent/powerful medicines
- Improved (better), and greater safety with drugs from the first use ^[less trial/error required to see this]
- Enhanced methods for determining appropriate drug dosages (focusing on “how much” instead of “which drug”)
- Streamlined drug discovery and approval processes ^[aka dramatic improvements, less abandonment of drugs in discovery process]
- Reduction in the overall cost of healthcare
Describe the role of genetic variation on pharmacotherapy
Human Genome
- The human genome contains approximately 3,000,000,000 nucleotides.
- It comprises 30,000 - 40,000 genes, with alternative splicing and post-translational modifications generating around 100,000 proteins, many of which are involved in disease. (and metabolism/activation/interaction of drugs)
Genome Variations
- Genomes of any two individuals are 99.9% identical
- Genomes of any two individuals are 99.9% identical, regardless of race, ethnicity, or geographical location.
- However, there are about 3,000,000 genetic differences between individuals, mostly in the form of single nucleotide polymorphisms (SNPs) but also including deletions, insertions, duplications, and reshuffling (ranging from a few nucleotides to whole genes).
- Some of these genetic variations influence an individual’s response to drugs.
Possible location of genetic variation
- Location determines effect of SNP (note intergenes = unknown)
Genetic Variation on Pharmacotherapy
Genetic variation can affect pharmacotherapy in the following ways:
- Variation in the target protein or pathway (i.e. receptor, to exact effect)
- Variation in proteins involved in drug metabolism (or toxicity)
- Idiosyncratic effects (i.e. not due to reasons 1 or 2)
Describe the effects in target protein variation on pharmacolotherapy
Differences in the target protein must affect either:
(i) the amount of protein expressed (relates to SNPs in promoters) or (ii) the function of the protein (SNPs in exons)
Protein quantity or function
See the Michaelis-Menten curves: Km and Vmax
- note that with curve A: Km is increased, i.e. more is needed to reach Vmax, therefore protein has lower affinity for substance. Therefore, SNP is most likely in binding site aka exonic
- with curve B: Km is largely unchanged, but V max is decreased, therefore, mutation is located in promoter, enhancer, or causes instability of RNA, thereby decreasing amount
Use the b2 adrnergic receptor as an example of the effect of protein variation
Respiratory Example: β2 Adrenergic Receptor
The β2-adrenergic receptor is involved in the relaxation of airway smooth muscles and is commonly targeted by β2-adrenergic agonists found in asthma inhalers.
Altered Function of β2 Adrenergic Receptor
Researchers have found that certain mutations in the β2-adrenergic receptor can lead to changes in its expression/ function. Changes at position 16 and 27 are associated with downregulation in response to beta-agonists, while changes at 164 can lead to altered function/decreased response.
This second type of mutation is quite rare (occurs in 2-5% of heterozygotes).
The response and duration of action of the drug in reduced in affected individuals.
Decreased activity, and reduction in maximum amount lads to poorer binding and function, therefore cAMP decreases more rapidly.
Describe the effect of genetic variations in drug metabolism enzymes
Genetic Variations in Drug Metabolism Enzymes
Variations in enzymes are the most important factor with regards to individual variation in drug response.
Enzymes involved in drug metabolism play a crucial role in individual variation in drug response. Phase I enzymes add functional groups, while Phase II enzymes add groups that increase water solubility.
There are significant polymorphisms present in almost all major enzymes involved in phase I and II metabolism, however, most do not produce a clinical effect in the absence of drug therapy.
Recall - how well a drug is metabolised is related to how long it lasts, and how high the therapeutic/toxicity is
Variation in Phase I Pathway - Cytochrome P-450 2D6
Cytochrome P-450 2D6 is responsible for metabolizing various drugs, including codeine, fluoxetine, and metoprolol.
Genetic variations, such as multiple copies of the CYP2D6 gene or (2) copies with poor or no activity, can affect drug metabolism
- ultrarapid in the case of multiple copies
- poor in the case of copies with poor activity (see also [[Pharmacology - B2 Kuracloud 1]])
- ratio of prodrug to metabolite
- more prodrug – poorer metabolism - sustained levels lead to toxicity of drug
- more metabolites – faster metabolism, lessened effects of drugs. Metabolite can cause toxicity
Variation in Phase II Pathway - N-Acetylation
N-acetylation, a phase II pathway, plays a role in metabolizing drugs like isoniazid (an antituberculosis agent) as well as antihypertensives and antiarrhythmics. Slow acetylators are susceptible to isoniazid-induced neurotoxicity. In fast acetylators, metabolites can cause hepatotoxicity.
Describe the effects of idiosyncratic genetic variation
Idiosyncratic Effects
Idiosyncratic effects of drugs are not caused by differences in drug targets or drug-metabolizing enzymes.
Instead, they may be influenced by genetic variations in enzymes like glucose 6-phosphate dehydrogenase (G6PD), which protects erythrocytes from oxidative stress.
Polymorphisms leading to G6PD deficiency can make medications causing oxidative stress dangerous for some individuals (as a result of reduced enzyme activity), could result in death of erythrocytes.
Examples of these drugs include: sulfonamides, some antimalarials and ibuprofen.
Describe the polygenic determinants of drug effect
Polygenic Determinants of Drug Effect
Genetic factors influencing drug effects can be polygenic, involving multiple genes.
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Discuss the pros and cons of pharmacogenetics
Potential Impact of Pharmacogenetics on Dosing Regimens
Pharmacogenetics has the potential to impact dosing regimens, leading to more personalized and effective drug treatments.
There are multiple different regimens because multiple genes and alleles are involved.
Barriers of Pharmacogenetics
The implementation of pharmacogenetics faces various challenges, including
- the complexity of finding gene variations affecting drug response ^[But it is getting better]
- limited drug alternatives
- disincentives for drug companies to develop multiple pharmacogenomic products ^[help fraction of population, not economically viable]
- the need for educating healthcare providers.
Is Pharmacogenetics Possible?
The vast genetic diversity among individuals raises questions about the feasibility of implementing pharmacogenetics. However, thankfully, some genetic differences are common and some may prove significant for drug response, although many of these SNPs, half of which are already known, will be ‘unimportant’ i.e. outside of coding sequence, or will not result in an amino acid change.
Molecular Diagnostics of Pharmacogenomic Traits
Currently, molecular diagnostics for pharmacogenomic traits are limited. Screening for targeted therapies and pharmacogenomics is ongoing but not widely available.
Time between FDA Approval and Detection of a Pharmacogenetic Phenotype
The time lag between FDA drug approvals and the identification of pharmacogenetic phenotypes can impact the availability and adoption of personalized treatments.
