In this post we talk about two things in the context of ADHD gene-testing, Pharmacokinetics and Pharmacodynamics. Two very technical-sounding words. But don’t worry, we break it down for you.
Welcome to the next post in my 7-part series: Genetic Testing for Choosing ADHD Medications. In this series, we address this question: What’s the best ADHD medication? Simple answer: The medication that works best for the individual.
Don’t you hate that? Are there any easy answers when it comes to ADHD? If you’ve found some, drop me a note below. I’d love to know.
Trouble is, ADHD affects individuals—not clones. It’s easier to market stereotypes but much harder to convey the potential complexity, individual to individual. Relying on simplistic stereotypes means missing the boat. For example, “I can’t have ADHD. I’m always on time!” Some people with ADHD are very punctual; ADHD affects them in other ways.
It’s the same with genetic factors. There is no “ADHD gene” — or even a set of genes. Instead, this highly variable syndrome called ADHD involves potentially hundreds of genes.
No Slam Dunk
All this is why the genetic tests for ADHD medications do not provide the slam-dunk answers that many patients and doctors believe they do. Without knowing this, you risk depriving yourself or your loved one—or your patients—of the optimal medication treatment. Over 7 posts, we explain what you and your prescribers need to know.
But, yes, genetic testing for ADHD medications can provide some useful information. Specifically, you can learn more about how your genes affect your medication response—and how medications respond to you! This gets technical. We’ll take it bit-by-bit. If I can understand it, you can, too!
This ADHD Genetic Testing Blog Series
My scientist husband (“Dr. Goat”) and I pooled our neurons to bring you this series. The goal: more accurate information for the layperson (and medical professionals) with little background in molecular biology or genetics.
Our collaboration required much tedious editing and back-and-forth. My twofold goal with all my books and blog posts: accuracy, clarity, and practical application.
By the way: Ten years ago, no one could have imagined Dr. Goat and me working together so harmoniously on a project. Instead, picture miscommunications galore, chronic conflict, tempers raising the roof, and few epithets tossed around before we both said, “I give up! You’re impossible!”
Thank goodness, we are past those days. Working together is fun and productive. The fact that we can now team up to produce information designed to elevate the lives of our readers? Doubly rewarding.
Note: This post is a little longer than the previous ones. We thought it best, however, not to break up the concepts. So, settle back, take it slowly, and enjoy! This is fascinating stuff, with applications that extend beyond ADHD medications.
The “Best” ADHD Medication? Wrong Question
By Dr. Goat & Gina
Genetic testing for ADHD medications offers one clear benefit: It can help to identify whether you metabolize medications slowly, normally, or very quickly. That’s the focus of this post.
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Now, what is the first very important point to understand about medications? That’s right: Dosing matters. Assuming that the diagnosis is correct and the medications being considered are recommended for it, beneficial effects depend upon identifying the dosage that works best for the individual.
Too low a dose? You don’t get a therapeutic benefit (nothing happens).
Too high? You might start encountering unacceptable side effects—despite that medication being an excellent choice for you.
So, just like Goldilocks, it is crucial to reach a “sweet spot” of dosage. In that sweet spot, you will get the full benefit of the drug with minimal side effects. [Gina does an excellent job of explaining this vis a vis ADHD medications in her first book, Is It You, Me, or Adult A.D.D.?]
Gene Variants Dictate Drug Response
One factor to consider when aiming for that sweet spot of medication effectiveness: how your specific gene variants affect drug response.
We discussed “gene variants” in Defining genotyping, or genetic testing
To recap: Genetic variation (or variants, sometimes called mutations) describe the tiny variations in the DNA sequence in each of our genomes. Genetic variation is what makes us all unique—of hair color, skin color, height, or even the shape of our faces. (Learn more at Genomics 101: What is a variant?)
That’s where genetic tests come in. They identify these gene variants—that is, variations on a common gene. In turn, this information helps you to:
- Determine what dosage you should start with, and
- Decide the order in which drugs should be evaluated.
This information can be especially valuable if you are
- Beginning drug treatment for ADHD,
- Considering changing to a different drug, or
- Introducing an additional drug to your regimen.
It’s worth re-emphasizing: Genetic testing for ADHD medications will not be a “silver bullet.” It is simply a starting point. The last post in this series will examine how I might use my personal results.
Pharmacokinetics (PK) and Pharmacodynamics (PD)
If we want to learn more about how our genes affect ADHD drug response, we need to talk about pharmacogenetics.
Briefly defined, pharmacogenetics is the study of genetic variations that can influence individual responses to pharmaceuticals. Pharma. Genetics.
An earlier post gave an overview of pharmacogenetics. Now we go into more detail on two key aspects:
- Pharmacokinetics (PK): “What the Body Does to the Medication”
- Pharmacodynamics: “What the Medication Does to the Body”
1. Pharmacokinetics (PK): “What the Body Does to the Medication”
We’ve all seen those TV commercials for laundry stain-removers with enzymes. These “scrubbing” enzymes find their targeted stains, latch on, and break down the stain.
Guess what? We also have enzymes in our bodies—but not to break down stains. Instead, our enzymes break down certain substances and convert them into other substances. For example, stomach enzymes break down the food you ingest into tiny bits that can be converted into energy.
Among their many functions, enzymes convert inactive drugs into the active form. Once that conversion happens—and only after it happens—we can actually benefit from the medicine.
(We’ll explain examples of an active and inactive ADHD medication below.)
Enzymes are produced by—you guessed it!—our genes. Genes are the “instruction manuals of life.” As such, they specify how to make proteins. Proteins include enzymes and various other molecules. (To learn more, visit “How Genes Work.”)
The small variations in the instructions coded in our genes end up influencing how enzymes are produced and how they operate. In turn, some of these enzymes (and other types of proteins) affect your body’s response to a medication.
Tiny differences in your genes—and thus your enzymes and other proteins—can affect how your body can metabolize (convert) a drug. This also can affect how long the drug stays your body.
In other words, these genetic variants affect pharmacokinetics (PK).
Deconstructing this word’s Greek roots, we have pharmaco (medication) and kinetics (moving, putting in motion).
Think of pharmacokinetics as the physiological mechanisms by which the body absorbs, distributes, metabolizes, and removes a drug from the body.
A Major Player Among Drug-Response Genes: CYP2D6
We humans have lots of enzymes., but here’s a particularly significant one when it comes to drug-response: Cytochrome P450 2D6, an enzyme encoded by the CYP2D6 gene. It breaks down about a quarter of all drugs, including:
- Antidepressants such as Prozac
- Breast Cancer (Tamoxifen)
- Antipsychotics (e.g. Risperdal, Abilify,)
- Pain Killers (e.g. Codeine)
One Size Does Not Fit All
You’ve probably heard people say, “I’m very sensitive to medication.”
What they typically mean is: anything larger than a very small dose knocks them for a loop. By contrast, there are the “nothing phases me” types— and of course plenty of people in between. This in part due to their drug-response gene variants.
For example, there are generally three categories that describe the rate at which humans metabolize drugs, based on the enzymes produced by their gene variants:
- Slow, or poor, metabolizers: These folks don’t break down medications well at all. Their genetic differences make them slower than average at converting the drug.
- Extensive, or normal, metabolizers: These folks metabolize drugs normally. This is the most common class, representing the type of people for which most drugs are designed.
- Rapid metabolizers: This is the opposite extreme to slow metabolizers. These people may require a higher-than-average dose of a medication.
Sometimes these categories are further broken down into smaller gradients, such as ultra-rapid metabolizers and intermediate metabolizers.
Why Does Metabolizer-Type Matter?
Why is it important to know what type of metabolizer you are? If your body metabolizes a drug too quickly, it can decrease the drug’s efficacy. At the other extreme, if your body metabolizes the drug too slowly, unacceptable side effects may result.
Knowledge is power. If you know that you are a slow metabolizer, you can insist on being started at a lower-than-average dosage. That way, you’ll get a better idea if the drug is a good choice for you—rather than stopping it prematurely due to a too-high dose.
(You don’t absolutely need genetic testing for this purpose, though. Instead, you can follow the wise practice of “start low, titrate slow.” That is, increase the dose slowly.)
Two Types of Drugs: Inactive and Active
Yes, let’s throw in another factor in medication response: whether the drug is inactive or active
Typically, a drug is taken in its active form; it goes to work “as is.” Think of it as the protein equivalent of “ready to wear”.
Other drugs, however, enter the body in an inactive form and require some additional … alterations. These drugs rely on bodily organs such as the liver for conversion to the active form in order to take effect. Genetic variants play a role here, too!
1. An Inactive Form of ADHD Medication: Vyvanse
Consider the ADHD medication Vyvanse. It starts out in an inactive state.
For this reason, it has been marketed as being less easily abused than other medications in the amphetamine class of stimulants (e.g., Adderall, Dexedrine).
The medication in the Vyvanse capsule becomes active only when it reaches a certain point in the gut. At that point, specific gut enzymes convert it into the active form of the drug (lisdexamfetamine). Inactive medications are also called “pro-drugs.”
2. An Active Type of ADHD Medication: Strattera
Now let’s consider an ADHD medication in its active form: Strattera. This non-stimulant was the first drug to receive an FDA-certified indication for adult ADHD.
Below is an excerpt from the drug label for Strattera regarding genes that affect its metabolism. By the way, this is FDA-controlled text. That means it is carefully validated and evidence-backed.
Note in the text the aforementioned CYP2D6. This gene influences the metabolism of many drugs in addition to Strattera and is known to have many variants:
CYP2D6 metabolism — Poor metabolizers (PMs) of CYP2D6 [-metabolized drugs] have a 10-fold higher AUC and a 5-fold higher peak concentration to a given dose of STRATTERA compared with extensive metabolizers (EMs). Approximately 7% of a Caucasian population are PMs. (…) The higher blood levels in PMs lead to a higher rate of some adverse effects of STRATTERA (see ADVERSE REACTIONS).
Poor metabolizers of Strattera reach a much higher peak blood concentration (5 times higher) than extensive metabolizers. Therefore, they are more likely to manifest “adverse reactions” (side effects). These range from constipation to dizziness, as stated in the drug label.
If you are Caucasian, your chances of having the poor metabolizer form of CYP2D6 are pretty high (7%). The drug label says nothing about other racial groups, but that doesn’t mean these groups don’t have poor metabolizers. It may simply mean there is no data available for them, or the data are simply not listed here.
As you can see, it is very useful to know which variant of a gene you have, whatever the type of drug (active or inactive). This is especially true for CYP2D6 because it metabolizes a huge number of drugs.
Conversely, some drugs are metabolized by only very few genes. So in practice, drug-response genotyping typically involves several genes so as to get the whole picture. (In Part 2 of this series, we list the four genes involved in the genotyping tests we took for ADHD medications: CYP2B6, CYP2D6, ADRA2A, and COMT.)
Two Scenarios for Slow (Poor) Metabolizers
If you are a poor metabolizer, there are two very different scenarios to consider. Each scenario rests on whether the drug in the bottle is 1) active (ready to go) or 2) inactive (the body must metabolize it into an active form):
1. If the drug is taken in its active form, the poor metabolizer might require a lower-than-average dosage.
If you are a poor metabolizer, you are slower at removing the drug from the bloodstream than the average person. As a result, you could reach a blood concentration that is too high even if given an “average” dose. That potentially triggers side effects.
The outstanding question then becomes: how much lower of a dose should you take? Unfortunately, there is no ready answer to that question (more below).
2. If the drug is taken in its inactive form—that is, the drug must be metabolized to become active—a standard dose might not be enough.
What?! How can that be?
We just said poor metabolizers risk having too much medication in their system, even with an average dose. How is it that poor metabolizers now suddenly do not get enough from an average dose?
Here’s why. If you’re a poor metabolizer, you are slow at converting the inactive drug into its active form. Therefore, you are failing to reach the dose necessary for beneficial effects, and the drug gets cleared from your system before having had a chance to be converted.
To recap, the slow metabolizer risks two primary effects:
- An over-concentration of active medication
- An under-concentration of inactive medication
2. Pharmacodynamics: “What the Medication Does to the Body”
Again, pharmacodynamics refers to the manner in which the drug affects a cell. Pharmacodynamics is all about how the drug does its work.
For example, consider the “lock and key” nature of the way a drug typically works with a cell. The “lock” is the receptor, a structure on the cell’s surface that selectively receives and binds a specific substance. (Like enzymes, receptors are proteins made according to genetic instructions.)
In this illustration, Drug A fits the receptor perfectly. Drug B doesn’t come close. Substance A can bind to the receptor and an action results.
A stimulant such as Adderall or Ritalin interacts with certain receptors with great specificity. That is, it interacts only with those receptors.
This lock-and-key” interaction is imperative for the drug to do its job. By interaction, we mean that Adderall molecules literally slot into those specific receptors in the same way as, well….as your Big Gulp fits snugly in your car’s cup holder.
The snugness of the stimulant with its receptor, however, can vary. Much depends on—yes, that’s right— the variant of the gene that produces this receptor.
Some forms of the gene will produce a receptor with good snugness. That means less stimulant is required to reach a given effect.
Yet, other variants may produce a receptor form with more … looseness. That requires piling more drug (higher dosage) into the “cup holder” to reach the same snug-fitting effect.
Your Comments and Questions Welcome
- Are you with us so far?
- Are you gaining a better idea of how genes can affect ADHD drug response?
- Do you see how the simple three-column listing of medications in genetic testing barely skims the surface—and can sometimes steer you away from medications that would work very well for you?
- Have we begun to make it clear: There is no best medication for ADHD—only the medication that works best for you, at the appropriate dose.
- With the last post (7), we’ll provide a list of takeaway points.
Coming up next: ADHD Gene-Testing Benefits and Limitations
All 7 Posts in this Series:
1. Explains genetic testing as it relates to ADHD medication-response
2. Dr. Goat and I share our ADHD genetic test results—and reactions
3. Defining the term genotyping, or genetic test
4. This Post: Explains how, when, and why this data might prove helpful
5. Genotyping data provides only one piece of the puzzle
6. A closer look at Gina’s ADHD genetic testing results
7. Drilling down into Dr. Goat’s Results — to explain more about the data
We welcome your comments.
—Gina Pera and Dr. Goat