Pharmacogenetics and Personalized Medicine

This set of flashcards covers key vocabulary and concepts in pharmacogenetics and personalized medicine, focusing on genetic impact on drug efficacy and safety.

Pharmacogenetics

The study of how genetic variation affects individual responses to drugs.

Correlates variation in drug response → genetic variation

The influence of heredity on drug response

Therapeutic Window

The range of drug doses at which effective therapy occurs, below which there is little effect and above which toxicity occurs.

Genetic Polymorphism

The occurrence of two or more genetically different forms (alleles) in a population.

Pharmacodynamics

The study of the effects of drugs on the body and the mechanisms of their action.

The effects that the drug has on the targeted tissue, and the effects on the target molecules or signal transduction or receptors

Mendelian Genetics

The study of inheritance traits based on the principles originally set forth by Gregor Mendel.

Biochemical Genetics

The study of the biochemical basis of genetic disorders.

Drug Metabolism

The biochemical modification of pharmaceutical substances by living organisms, usually through specialized enzymatic systems.

Thiopurine

A class of drugs used in chemotherapy, particularly effective against acute lymphoblastic leukemia.

TPMT (Thiopurine Methyltransferase)

An enzyme that metabolizes thiopurine drugs and influences drug efficacy and toxicity.

Acute Lymphoblastic Leukemia (ALL), symptoms, treatment

A type of cancer characterized by the overproduction of lymphoblasts, common in children. Cancer of the white blood cells is characterized by excess lymphoblasts

Symptoms include anemia, sensitivity to infection, and bleeding due to overcrowding of the bone marrow with cancer cells

ALL starts in the bone marrow, leukemia cells invade the blood quickly. Can spread to other parts of the body including lymph nodes, the liver, and the spleen.

treatment of children with ALL has been successful using Thiopurine Chemotherapy

Pharmacogenomics

The study of the genome-wide analysis of genetic determinants of drug efficacy and toxicity.

A shift from focusing on individual candidate genes to genome-wide association studies

Individual Variability

Differences in drug response among individuals due to genetic and environmental factors.

Adverse Drug Reactions

Unwanted effects or side effects occurring after administration of a drug.

Pro-drug

A medication that is administered in an inactive form and is metabolized into an active form within the body.

How do medications work?

1. Drug administration

2. Drug dissolution, absorption distribution and metabolism

3. Drug excretion

4. Delivery to target

What are the different cellular targets?

Receptors, signaling molecules, enzymes, regulatory molecules

What is the therapeutic window, and how is it affected by genetic variation?

The therapeutic window is the range of drug doses that produces therapeutic effects without causing toxicity. Genetic variations can influence drug metabolism and response, potentially narrowing or widening this window, affecting safety and efficacy.

What is the Conventional Model of Drug Treatment

refers to a one-size-fits-all approach to prescribing medications based on average responses in populations, without considering individual genetic differences that may affect drug metabolism and efficacy.

Trail-and-error process: Patient comes in with symptoms → diagnosis is made → proposal of treatment & drug prescription based on age and weight → treatment fails → the case is evaluated again and the process is repeated until an effective treatment is found

Pharmacokinetics

is the study of how drugs are absorbed, distributed, metabolized, and eliminated in the body.

The representation of the body’s action on the drug

• adsorption

• Metabolism

• Excretion

What can influence the individuals drug response?

Genetic variations, environmental factors, age, body weight, and other medications.

How does Thiopurine work?

Thiopurine is a prodrug that gets converted into active metabolites, primarily 6-thioguanine nucleotides (6-TGNs) which inhibit the proliferation of cells by interfering with the synthesis of DNA and RNA, primarily used in treating autoimmune diseases and certain cancers. They cause immunosupression by stoping rapidly growing cells by incorporating into cellular DNA, disrupting lymphocyte function and triggering cell death (apoptosis)

what is the active form of Thiopurine?

6-thioguanine nucleotides (6-TGNs)

What is TPMT?

TPMT (thiopurine S-methyltransferase) is an enzyme that metabolizes thiopurine drugs, influencing their therapeutic efficacy and toxicity by determining the levels of active metabolites in the body.

TPMT is required to regulate the level of the active drug

Why do some patients have strong adverse reactions to the dose of TPMT within the standard therapeutic window?

Some patients have low levels of thiopurine methyltransferase (TPMT), an enzyme responsible for metabolizing thiopurines, leading to toxicity when standard doses are administered.

Allelic variation influences enzyme activity

Different combinations of these alleles → levels of the protein → phenotype

Genetic variation of TPMT, what are the different types to TPMT alleles that have been identified so far?

1. A total of 21 polymorphism (alleles) has been identified. The majority of polymorphism involve a single nucleotide change (SNP variants) in the DNA sequence

2. There is also a polymorphic GC-rich variable number of tandem repeats (VNTR) in the 5’ flanking region of TPMT. The repeats can range from 3-9 repeat elements. This VNTR has been reported to alter TPMT transcription and so its activity.

TPMT Wild Type and Most Common variant alleles

• TPMT*1 (wild type)

• TPMT*3A

• TPMT*3B

• TPMT*3C

How does the 5’ upstream VNTR affect the drug response?

The 5' upstream VNTR affects drug response by influencing the transcription levels of the TPMT gene, which can alter the enzyme's activity and impact the metabolism of thiopurine drugs.

Patients that have a very low TPMT enzyme activity have very (high/low?) of TGN nucleotides at normal drug doses

high levels, leading to increased toxicity. They become sick easily from the effects of the drug.

They are either homozygous for the version of the gene encoding low enzyme activity or heterozygous with a combination of low TPMT activity.

A better drug dose for these patients is 1/10th the level of other patients

Pattients with normal or high TPMT enzyme activity will have _____ or ______ levels of TGN nucleotides

Effective (normal) or low. These patients will do well on the drug or need a higher dose.

These patients are either homozygous for the version of the gene encoding normal enzyme activity or heterozygous

a patient is homozygous for TPMT3A* allele. What level of the drug should they recieve?

They should receive a reduced dose, typically one-tenth of the standard dose, due to very low enzyme activity and increased risk of toxicity.

Pharmacogenomics attempts to explain the variability of drug responses based on _________ between individuals

genetic variability

what are the two drug metabolism factors that can be affected by genetic variations?

Can affect pharmacokinetics & pharmacodynamics of a particular drug:

1. Affects drug efficacy (drug may be less/more potent)

2. Affects drug toxicity (drug may be metabolized at a slower rate: adverse drug reactions)