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How do medications work?

Once in the body, medications go through many different changes so that they can be used safely and effectively. Two branches of pharmacology are used to study these processes: one that describes what a medication does to the body (Pharmacodynamics), and one that describes what the body does to a medication (Pharmacokinetics).

What does your body do to a medication (Pharmacokinetics)?

An oral medication, after being swallowed, travels into the stomach where it is broken down into smaller pieces and then absorbed through the walls of the intestines; this is called absorption. The medication then goes through the liver and enters the bloodstream, which acts like a highway allowing medications to travel to different areas in the body; this is called distribution. Medications in inhalers or patches are absorbed through the lungs and skin respectively, and enter directly into the bloodstream. From the bloodstream, most medications need to enter an organ (such as the heart) or tissue (such as a muscle) in order to work. Side effects can occur if the medication acts at a place where it is not supposed to.

Once a medication has been absorbed and distributed, it must be made active; this is called metabolism. Proteins called enzymes are in charge of this process, converting a medication from one form into another mainly in the liver. The active forms are those having an effect on the body, while the inactive forms have no effect. For example, the pain medication codeine is converted into the active form morphine, which helps treat pain in the body. Codeine has little to no effect on pain if it is not converted into morphine. Sometimes your genetics, or other medications, or even certain foods, can influence medication metabolism, for example when enzymes work too quickly or too slowly (see How do genetics affect the way medications work?). Liver damage can also affect how quickly some medications can be metabolized.
Most medications are converted into their inactive form before they can be removed safely from the body, usually in the urine or feces; this is called excretion. If the kidneys are not working properly, medications removed in the urine may be excreted more slowly than normal and generate side effects.

What does a medication do to your body (Pharmacodynamics)?

When medications are in their active form, they can have many different effects on the body. Some medications cure a disease, some slow or stop the progression of a disease, and others help to reduce or eliminate symptoms such as pain.
Medications work when their active forms bind to targets. This binding, between medication and target, is highly specific and should occur in a specific region of the target and in the intended part of the body. When medications bind in parts of the target or parts of the body where they are not intended to, this can result in side effects. For example, some pain medications act on pain receptors but also on receptors in the intestines, which can cause constipation.

How do genetics affect the way medications work?

For medications to act safely and effectively within your body, they go through many different processes. Genetic variants, such as SNPs and CNVs, may alter the amount or level of activity of the proteins processing medications. Your genes can have an effect on how medications are transported (Pharmacokinetics) and how medications actually work within your body (Pharmacodynamics).

Genes and Pharmacokinetics

Your genetic make-up can affect how fast medications are absorbed into the bloodstream and how fast they are distributed into different tissues or organs (for example, from the bloodstream into a muscle), which is known as Pharmacokinetics. One reason for this is that some genes contain directions for how to build enzymes (a type of protein) and some of these enzymes are responsible for breaking down medications. For example, certain genetic make-ups may cause a medication to accumulate within the body resulting in undesirable side effects.
The enzymes that are directly involved in the metabolism of medications, called drug-metabolizing enzymes, act like tiny machines that change and break down medications. Since the instructions to make these enzymes are encoded in DNA, a change in the DNA code (such as a SNP) can cause these enzymes to work faster, slower, or sometimes not at all.
Genetic variation in genes encoding drug-metabolizing enzymes may cause these enzymes to work too slowly, resulting in some medications taking too long to change into their active form and not working very well. Slow acting enzymes may also cause medications to take a long time to change from their active form to an inactive form, making them work for much longer than they should and result in medications to accumulate in the body. When drug-metabolizing enzymes work too quickly, some medications are changed from their active form to their inactive form too rapidly, preventing them to work properly within the body.
Genes encoding enzymes involved in the transport of medications can also affect the way medications are excreted out of your body. Since medications are often excreted in their inactive form, changes in how quickly they are converted from active to inactive forms can affect how fast they are excreted.

Genes and Pharmacodynamics

Another way in which genetics affects metabolism is through medication targets. Medications are directed and/or bind to these targets, making them to change in their behavior or function. Since most targets are proteins encoded by DNA, genetic variation can change the target structure, making it either easier or harder for the medication to do its intended job. If the change in the target makes it harder for the medication to work, the medication might be less effective or even not effective at all. Other DNA variations can create new unintended targets making it easier for a medication to act on parts of the body that can lead to undesirable side effects.
Pharmacogenetic research is an active field of study, continuously uncovering new ways genetics and medications are connected and bringing improvements to healthcare.

How does TreatGx work

TreatGx generates personalized medication options for the management of your condition. It uses your genetic information, together with other information that you supply (age, weight, laboratory results, and current medications) to generate safe, effective medication options. TreatGx provides this information easily and quickly, making it well suited for use in a family practice clinic or pharmacy and in your home.
In TreatGx, the latest top ranking evidence is used to identify personalized medication options that are safe and effective. The medication options are presented in an easy-to-read format with helpful information such as dosing instructions, and medication cost. All of the options offered in TreatGx are personalized for you based on your genetics, health, medications, and other factors that are relevant to the condition and the medications used to treat it.

TreatGx’s unique approach identifies four types of potential interactions: Drug-drug, Drug-Disease, Drug-genetic and Drug-other health information interactions

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Drug-drug interactions: These interactions have a variety of effects on your body that could seriously affect your health. They can cause reduction or enhancement of the effect of another medication you are taking and result in unexpected side effects. To avoid serious drug-drug interactions, TreatGx will generate medication options that do not have known interactions with medications you are currently taking. For example, some medications that are recommended as the first line choice for treating depression have potentially serious interactions with ibuprofen (Advil), making you more likely to have internal bleeding. There are alternative antidepressants that do not have this interaction, so that if you enter into TreatGx that you are taking ibuprofen the safer medication options would be generated.

Drug-disease interactions: These interactions occur when certain diseases or conditions are negatively affected by medications. People can be affected by many diseases at once, and sometimes the medication for one disease makes the others worse. TreatGx takes into account relevant diseases that would be negatively affected by the medication it offers. By doing this, serious drug-disease interactions are avoided. For example a person with Type 2 diabetes and heart failure would not have the medication Pioglitazone appear as an option for treating the diabetes as it could make the heart failure worse.

Drug-genetic interactions: These interactions occur when a medication is metabolized differently depending on a person’s genetic make-up. Drug-gene interactions may cause the medication to be more or less effective and may require a dose adjustment. If the interaction results in a significant negative reaction, an alternative medication may be required. TreatGx incorporates this information to offer dose adjustments or alternative medications when these interactions occur.

Drug-other health information interactions: For medications to act safely and effectively within your body, they go through many different processes, all of which may be altered by your age, weight, liver and kidney function. For example, as we age medications may be excreted more slowly than normal and generate side effects. TreatGx adjusts the dosage and medication options based on your health information.

What is DNA?

What is DNA?
The human body is composed of trillions of cells, each with specific functions and roles. But how are these functions and roles coded? How does each cell know what to do?
Deoxyribonucleic acid (DNA) is a molecule found within the nucleus of all cells, packaged in chromosomes, and holding the information required by a cell to function. DNA is made up of four chemical bases called adenine (A), thymine (T), cytosine (C) and guanine (G) and their order within DNA provides instructions for making proteins. In addition to acting as a set of instructions, DNA also acts as the hereditary material that is passed down from parents to their children and is why children share similar traits with their parents.

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Specific sequences of DNA, called genes, contain directions for how to build a particular protein. Proteins are responsible for nearly everything that happens in the body from determining eye color to breaking down medications. For example, a gene called CYP2D6 encodes for an enzyme called Cytochrome P450 2D6 which is responsible for the metabolism and elimination of approximately 25% of clinically used medications.

Each human cell contains billions of DNA bases and about 20,000 genes, which are collectively referred to as a genome. More than 99% of our genomes are the same, but variations do exist among people. The most common of these variations are called SNPs (Single Nucleotide Polymorphisms).

A SNP is the difference in a single DNA base at a particular location. For example, at a position of a gene the base C is the most common among a group of people, but in some individuals the position is occupied by base A. There are approximately 10 million SNPs in the human genome and most of these SNPs have no effect on the cell or on your health. However, a small number do affect the body and some SNPs affect how individuals respond to certain medications.

Another type of genetic variation is called CNV (Copy Number Variants), which occurs when the number of copies of a particular gene varies from one individual to the next.

What is a SNP

More than 99% of our genomes are the same, but variations do exist among people. The most common of these variations are called SNPs (Single Nucleotide Polymorphisms). A SNP is the difference in a single DNA base at a particular location. For example, at a position of a gene the base A is the most common among a group of people, but in some individuals the position is occupied by base G. A small number of SNPs do affect the body and some SNPs affect how individuals respond to certain medications.

Pharmacogenetic testing

Depending on your genetic makeup, some medications may work more effectively, less effectively or cause side effects for you. Our pharmacogenetic test reports on how your genes affect the way medications work within your body. These results can be used to help you and your health care professional select the best medication and dosing for you.

Can my ancestry be identified
No, myPGx testing has no incidental findings. Unlike other genetic tests, myPGx is designed only to inform your medication choices.

What unexpected things might I learn from pharmacogenetic testing
myPGx uses genotyping not sequencing. myPGx testing has no incidental findings as the analysis is directed at the specific areas of the gene necessary to identify medication/gene interactions. Unlike other genetic tests, myPGx is designed to inform your medication choices. myPGx will not inform you or your physician of diseases that you might get, for example cancer, vascular disease or Alzheimer’s.

What genes are included in the pharmacogenetic test?
Our genetic test reports on genes affecting the way medications work within your body. This type of testing is called pharmacogenetics. Depending on your genetic makeup, some medications may work more effectively, less effectively or produce side effects for you than they do in other people. Your pharmacogenetic results can be used to select personalized medication and dosing. For example, a set of markers on a gene called CYP2D6, which are analyzed using our pharmacogenetic test, can tell how your body will metabolize medications such as codeine.

How are the genes in the pharmacogenetic test selected?
The SNP panel was developed using an evidence-based approach. Firstly, the data from PharmGKB CPIC and the Dutch Guideline Group was reviewed for SNP’s with high level evidence for clinical effect of variants. This list was filtered for drugs used in conditions most commonly managed in primary care. The evidence for SNP’s was then investigated in more detail. The trials for each SNP and drug association were evaluated in detail, a meta-analysis performed, and Forest plots produced. This data was then evaluated and if it confirmed an association with significant clinical outcome indicating a change in dose of a medication, or a change of medication, then the SNP was retained on our panel. This detailed process enabled us to develop and check translation protocols for SNP’s and drug dosage.

How is this different than receiving a Genetic Report from other companies?
• Our pharmacogenetic test has no incidental findings. Unlike other genetic tests, our test is designed only to inform your medication choices
• Unlike other genetic tests, your report is translated into safe, effective and personalized medication options using TreatGx. For each drug option, TreatGx provides the appropriate dose based on your unique genetic profile together with other personal health information including other medications, renal/hepatic function, age, weight, and more.
• For severe ADR’s such as Stevens-Johnson syndrome, the TreatGx software will indicate that drug is not appropriate and provide an alternative.
• Conventional terminology of a patient being an “ultra-rapid metabolizer” may not be helpful. It is important to consider the mechanism of action, metabolism, and excretion of a drug in order to determine the appropriate adjustment.
For example: A CYP2D6 ultra-rapid metabolizer would metabolize codeine into an extremely large dose of morphine. This can result in adverse events including death. Alternatively, the same patient given nortriptyline would excrete most of the drug before reaching circulation. This can result in decreased response and prolong troubling symptoms.

 

Glossary

 

Absorption

The movement of drugs from the site of administration (mouth, skin, etc) into the bloodstream

Adverse Drug Reaction

An undesirable effect of a medication, ranging from minor (a headache) to life-threatening (a heart attack)

Activity (genetics)

In this context, “activity” is used to describe the effect of genetics on the function of the gene. Genetic variations can increase activity, decrease activity, or leave it unchanged. The activity of a gene is also influenced by environmental factors.

Allele

Genes can come in a variety of different forms. Each gene variant is called an allele. Alleles can be used as categories for different patterns of SNPs. Alleles are also used to determine the level of activity of a certain gene.

Arrhythmia

An irregular heartbeat.

Atherosclerosis

A build-up of fat and cholesterol that sticks to the inner walls of the arteries and forms plaques, resulting in the narrowed or blocked blood vessels.

Atherosclerotic Cardiovascular Disease Risk

This is a risk assessment that determines the likelihood of someone developing cardiovascular disease, heart attack or stroke in the future. It takes into account factors like age, gender, race, cholesterol levels, blood pressure, diabetes, and whether or not someone smokes. Patients with higher risk generally need more intensive treatment to help reduce their risk.

Autocaller

Autocaller is the algorithm used by the TaqMan® Genotyper software to generate genotypes from qPCR data.

Autocaller Quality Value

An estimate of the probability that the TaqMan® Genotyper software has made the correct call.

Cardiovascular Disease

Disease of the heart and blood vessels, often related to atherosclerosis (buildup of cholesterol plaques on the inside of blood vessel walls leading to the narrowing and blockage). Types of cardiovascular disease can include heart valve problems, arrhythmias (irregular heartbeats), heart attacks, and strokes.

Cartilage

A flexible conective tissue that is softer than bone and usually found in the joints between bones but also in the lungs, back, ribs, ears and nose.

Child-Pugh Score

This score, ranging from A (mild) to C (severe), is used to assess the severity of chronic liver disease

Cholesterol

Total cholesterol is a measure of all the different types of cholesterol in your body, including HDL cholesterol, LDL cholesterol, and triglycerides.

Clinical Pharmacogenetics Implementation Consortium (CPIC)

A group of scientists, physicians, and others working to develop guidelines for using pharmacogenetic results in the clinic.

CNV Confidence Value

The CNV confidence value is a quality control measure; it is the estimated probability that the copy number is correct.

CNV z-score

The z-score is another quality control measure used in the CNV assay; the technical definition is the number of standard deviations the result is from the mean.

Copy Number Variation (CNV)

If a gene has an increased or decreased number of copies as compared with the usual (2), it is called a CNV.

Coronary Artery Disease

When the arteries that supply blood to your heart are damaged or diseased. This is usually caused atherosclerosis (buildup of cholesterol plaques on the inside of blood vessel walls leading to the narrowing and blockage).

Creatinine Clearance

This calculation describes how well your kidneys are working to filter your blood. The number reflects how much blood is being filtered per minute. As we age, this number slowly declines. It is calculated based on serum creatinine (from a blood test), gender, age, and weight.

Decreased Activity

Indicates that this genotype results in an little to no metabolism; this is the lowest

Deoxyribonucleic acid (DNA)

DNA is a molecule that is used to store the information required to make a living thing. The information is in a code made up of adenine (A), thymine (T), cytosine (C) and guanine (G). For more information, see What is DNA?

Depression Rating Scale

Any rating scale that evaluates the severity of depression based on multiple factors (mood, insomnia, agitation, anxiety, weight loss, etc). Comparing scores on a specific rating scale across time helps determine if the depression is improving.

Distribution

The transfer of drugs from one location in the body to another (for example, from the bloodstream into a muscle)

Drug-metabolizing enzyme

A type of enzyme responsible for the metabolism of medications. See also: Enzyme and Metabolism

eGFR

This is an estimation of creatinine clearance. It describes how well your kidneys are working to filter your blood. The number reflects how much blood is being filtered per minute. As we age, this number slowly declines. It is calculated based on your serum creatinine (from a blood test), age and gender.

Elimination

When a drug leaves the body, usually in the urine (filtered from the bloodstream by the kidneys) or feces. Also called Excretion.

Enzyme

A type of protein that can speed up a chemical reaction. The human body has thousands of different enzymes. See also: Protein (molecule).

Ethnicity

In the case of pharmacogenetics, this refers to a category of people who have a common ancestry. If genetic testing is not available, ethnicity and race can help predict how people will respond to certain medications, based on studies in those particular ethnic groups.

Excretion

When a drug leaves the body, usually in the urine (filtered from the bloodstream by the kidneys) or feces. Also called Elimination.

Extensive Metabolism

Indicates that this genotype results in normal metabolism; this is used as the baseline

External Control (HLA-B*58:01)

A test to ensure that a negative result is due to the absence of HLA-B*58:01 rather than a testing error

Food and Drug Administration (FDA)

The government agency that manages food and drug regulations in the United States.

Gene

A gene is a region of DNA that contains instructions to make a specific protein. The variations of genes that we inherit result in variations of proteins that, in combination with environmental factors, result in variations in phenotypes.

Genotype

In the context of genetic testing, a patient’s genotype is the combination of their alleles.

Genotyping

The process of converting test data into genotypes.

Genotyping Control

A sample from the Coriell repository used to verify that the test is working as intended. Several controls are tested alongside patient samples in each run.

HDL Cholesterol

This is known as the “good” cholesterol because higher levels can reduce your risk for heart disease and stroke. The HDL absorbs cholesterol and takes it back to the liver, which eliminates it from the body.

Health Canada Santé Canada

The government agency that manages federal health regulations in Canada.

Higher Sensitivity

This term is used to indicate that the genotype predicts a risk that is higher than the average.

Human Genome Nomenclature Committee (HGNC)

A non-profit that approves standard names and symbols for components of the human genome such as genes.

Human Genome Variation Society (HGVS)

A society of scientists dealing with the variations in human genetics. The society also defines a standard notation to identify gene variations.

INR

International Normalized Ratio. This is a laboratory measurement of how long it takes blood to form a clot. This is used when people are taking warfarin to make sure the blood is not “too thin” (risk of bleeding) or “too thick” (risk of clotting). Since it is a ratio, if you are not taking warfarin, your INR would be 1. If your INR is 2, this means it takes you twice as long for your blood to clot as someone not on warfarin.

Intermediate Activity

Indicates that this genotype results in an intermediate metabolism; this is lower than baseline

Intermediate Metabolism

Indicates that this genotype results in an intermediate metabolism; this is lower than baseline

LDL Cholesterol

This is known as the “bad” cholesterol because high levels can lead to cholesterol buildup in your arteries and increases your risk of heart disease and stroke.

Medication

A substance used to cure, treat, diagnose, or prevent disease. The terms “medicine”, “pharmaceutical”, “drug”, and many others are also used to describe the same thing.

Metabolism

The breakdown or chemical alteration of substances inside the body. In this context, metabolism specifically refers to the metabolism of medications.

Metabolite

A substance or product produced when a drug is digested or chemically altered during metabolism

MRC Dyspnea Scale

A grading system to assess someone’s severity of shortness of breath. The scale is graded from “0” (only get breathless with strenuous exercise) to “4” (too breatheless to leave the house or breathless when dressing).

Normal Activity

Indicates that this genotype results in normal metabolism; this is used as the baseline

Normal Phenotype

This term is used to indicate that the genotype predicts that the risk or efficacy is not increased above the average.

Personalized medicine (also referred to as precision medicine or molecular medicine)

The use of molecular-based individual information to guide medical decisions, practices, and/or therapies.

Pharmacodynamics

The effect of drugs on the body (how and where drugs work in the body)

Pharmacogenetics

The science behind the relationship between genetics and safety/efficacy of pharmaceuticals.

Pharmacogenomics

A term often used interchangeably with pharmacogenetics. It is can also be used as a broader term to include other fields such as epigenetics.

Pharmacokinetics

The movement of drugs within the body, including absorption, distribution, metabolism, and excretion

Pharmacology

The branch of medicine and biology concerned with the study of drug action.

Phenotype (Predicted)

An individual’s phenotype is their observed traits. Because phenotypes are influenced by both genetics and environment, the results of genetic tests are only predictions.

Polypharmacy

The simultaneous use of multiple drugs by a single patient, for one or more conditions.

Poor Metabolism

Indicates that this genotype results in an little to no metabolism; this is the lowest

Presence/Absence Assay

A test that is done to determine the presence or absence of a specific variant; this test requires an internal or external control

Protein (nutrient)

Protein is one of the three main macronutrients (protein, carbohydrates, and fat). The protein in our diet comes from protein molecules that were made by other living things.

Protein (molecule)

A protein molecule is a structure made from a chain of smaller units called amino acids. Different proteins are responsible for many functions such as speeding up chemical reactions or giving structural support for cells. Proteins are made using instructions stored in DNA.

Quantitative Polymerase Chain Reaction (qPCR) or Real-time PCR

Polymerase chain reaction is a process used to create copies of specific DNA sequences. Real-time PCR is a method to measure the number of copies as they are being created.

QuantStudio™ 12K Flex

A qPCR machine that can handle up to 11,520 individual reactions in one run.

Reference SNP Identification (rsID)

The rs number is an unambiguous way to identify a particular SNP.

Replicate

Samples are included in the test twice or more to improve accuracy.

Self-reported information

Information about yourself, such as your age, ethnicity, kidney function, use of medications, conditions and other health-related information. You will enter this information into forms, or features while signed into your GenXys accounts.

Seizure

Also know as a fit or convulsion, is the result of a surge of abnormal electrical activity in the brain.

Side Effect

A secondary effect of a drug, in addition to its intended effect, that is generally undesirable. However, some side effects of medications are deliberately utilized, such as an antihistamine that causes drowsiness being used as a sleep aid.

Single Nucleotide Polymorphism (SNP)

A SNP is a specific location where one DNA base varies from the reference sequence. The term “SNP” is often used for small deletions and insertions of DNA as well.

Star Allele

Star Alleles are a way to name genetic variations of particular genes. The star alleles can be defined by one or more SNPs.

Stroke

A sudden loss of brain function due to poor blood flow to the brain.

Triglycerides

This is a type of fat found in your blood that your body uses for energy. High levels of triglycerides, combined with low HDL cholesterol or high LDL cholesterol can increase your risk for heart attacks and strokes.

Ultrarapid Metabolism

Indicates that this genotype results in faster metabolism than the baseline

Uric acid

A waste product of the body that naturally occurs and is excreted in the urine.