Chapter 7: Genetic and Genomic Considerations in Pharmacotherapeutics

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Okay, so picture this.

You're in clinic.

You write a perfectly standard guideline -directed prescription.

Right, exactly by the book.

Exactly by the book.

You double check the dosing.

You send the patient on their way.

I mean, you did everything right, you know, but then that exact prescription, the one you pulled straight from the standard of care, it results in a life -threatening emergency.

It's a terrifying scenario.

It really is.

And today we're looking at why standard medicine is failing, like up to 40 % of your patients.

So welcome to the deep dive.

Glad to be here.

Consider this your pharmacotherapeutics tutoring session.

We are digging deep into Chapter 7 of Lynn's Pharmacotherapeutics, and our mission today is to master pharmacogenomics so you can safely prescribe tailored treatments.

Because honestly, adverse drug reactions are currently the fourth leading cause of death in the U .S.

Yeah, that statistic always gets me.

Fourth leading cause.

Right.

I mean, driving over a hundred thousand deaths and two million serious adverse events every single year, it's wild.

It completely reframes the entire concept of prescribing.

I mean, it is no longer sufficient to just match a clinical diagnosis to a specific drug.

That's old school.

Yeah, the one size fits all approach.

Exactly.

The new standard of care requires matching a drug to a specific patient's biological and genetic makeup, which is why major health care organizations like the National Academy of Medicine, the ANA, the AAPA, they have all essentially mandated genomics education for advanced practice providers.

We have to stop these adverse events.

Which makes total sense.

But before we get into the specific drugs, we hear terms like genetics and genomics thrown around constantly, right?

Are we talking about the same thing, or is there like a functional difference in practice?

There is a really significant functional difference.

So genetics is the older, much narrower field.

Like Gregor Mendel's pea plants.

Yes, exactly.

Going all the way back to the peas.

Genetics is specifically the study of how individual traits are passed from one generation to another through individual genes.

OK, got it.

But genomics is much broader.

The genome is the entirety of a person's genetic material.

So genomics studies how all of those genes interact with one another and crucially how they interact with the person's environment, their diet, their lifestyle.

So it's the whole picture.

And if we apply that to the medications you're going to prescribe, we arrive at pharmacogenomics.

We are looking at how a patient's entire genetic makeup influences their response to a pharmacological treatment.

Which falls under the broader umbrella of precision medicine.

Precision medicine.

Because I still hear people call it personalized medicine.

Yeah.

You might still hear older practitioners use that term, but the scientific community is they're moving away from it.

It creates this false expectation.

Like you're getting a bespoke suit, but for drugs.

Exactly.

Personalized implies some lab is out there custom brewing a brand new unique drug for every single individual on the planet.

And we just don't do that.

Precision medicine is really about identifying effective treatment strategies for groups of patients who share specific genetic lifestyle and environmental characteristics.

Let me try to visualize how we actually identify those groups.

So for the students listening, if your patient's genome is this massive millions of pages instruction manual, we need a way to find the relevant information, right?

Right.

Is a biomarker essentially like, I don't know, a brightly colored sticky note poking out of those pages, just indicating that a specific genetic variation is present?

That is a highly accurate way to look at it, actually.

A biomarker is just a measurable indicator.

And the FDA now has over 250 medications that actually list these specific biomarkers right on the package insert.

That's a lot.

It is.

But simply identifying that a biomarker is present, finding that sticky note that's only the first step.

The critical question for you as a clinician is what is that genetic variation actually doing to the drug inside the body?

Which naturally brings up the most common interference, right?

Altered drug metabolism.

The pharmacokinetics.

Exactly.

Pharmacokinetics.

So if a genetic mutation happens in the liver,

how does that physically change the way a drug is processed?

Well, think of a metabolizing enzyme in the liver as a highly specialized piece of machinery.

It has a very specific slot, a binding pocket.

The drug molecule is supposed to slide perfectly into that slot to either be broken down or activated.

But a genetic mutation alters the physical three -dimensional shape of that enzyme.

So the slot gets warped.

Right.

The slot becomes warped.

So when the drug tries to enter, it might bounce off entirely, meaning it doesn't get metabolized at all.

Or it might get pulled in and processed at a super accelerated rate.

It speeds it up or slows it down.

Okay.

Let's map that onto the therapeutic index or the TI, because this is crucial for the listener to grasp.

It really is.

So if a drug has a wide TI,

altered metabolism is like parallel parking a compact car in a massive driveway.

I like that analogy.

Lots of room for error.

Exactly.

You could be a little fast or a little slow, and you're still safely in the driveway.

But a narrow TI is like parking a bus in an alleyway.

Small shifts mean you are crashing straight into toxicity or therapeutic failure.

That is exactly what happens.

For drugs with a narrow therapeutic index, hitting outside that safe zone means immediate danger.

Let's look at therapeutic failure first, because that often occurs with prodrugs.

Oh, prodrugs are tricky.

Very.

Because a prodrug enters the body in a totally inactive form.

It relies entirely on a specific enzyme to convert it into its active therapeutic state.

So if a patient has that warped version of the enzyme, the drug simply passes through their system doing absolutely nothing.

Wow.

I'm thinking about tamoxifen here.

It's a huge one in oncology prescribed to prevent breast cancer recurrence.

Yeah, tamoxifen is a classic example.

It's a prodrug.

It requires the enzyme CYP2D6 to be converted into its active form, which is called endoxifen.

And if a patient has a variant that prevents that enzyme from functioning?

They are taking a pill every single day that is offering zero protection against their cancer coming back.

That is terrifying.

The clinical data really backs up how dangerous that is, too.

In women who are categorized as poor metabolizers of tamoxifen, the breast cancer recurrence rate is nine and a half times higher than in normal metabolizers.

Nine and a half times.

Wait, how common is this variant?

It's not rare at all.

Between eight and 10 % of patients of European descent,

and get this up to 40 % of patients of Asian descent,

lack this functioning enzyme.

40%.

That is a staggering number.

But wait, the FDA does not explicitly mandate testing for this variant before prescribing tamoxifen, do they?

They do not, even though the testing kits are readily available.

That's such a controversial clinical nuance.

I mean, 40 % of a demographic could be taking a useless drug.

It's a massive issue.

However, for other prodrugs, the FDA takes a much stronger stance, like clopidogrel or plavix.

Right, the antiplatelet drug.

Exactly.

It's used to stave off heart attacks and strokes.

Also a prodrug.

It requires the enzyme CYP2C19,

and roughly 25 % of patients produce a variant form of this enzyme, usually the star 2 variant.

And so they get a severely weakened antiplatelet response.

Right, leaving them highly vulnerable to a cardiovascular event.

So for clopidogrel, the FDA actually does recommend testing, and alternative therapies are advised for poor metabolizers.

Good to know.

And we see this exact same mechanism cause issues in standard pain management, too.

Oh, absolutely.

Coding.

It has to be converted into morphine by CYP2D6.

And what is it?

About 1 in 14 people of European heritage lack a functional version of this enzyme.

Yep.

So if they are prescribed coding post -surgery, they literally receive zero pain relief.

And as a clinician, it's incredibly easy to mislabel that patient as drug -seeking, right?

They're saying, I'm still in pain, I need more.

And you're thinking they're just an addict.

That's when in reality, their liver physically cannot process the medication.

It's a huge bias blind spot.

But let's look at the other side of that equation.

What happens when the variant enzymes are moving too slowly and standard doses become highly toxic?

Right, because instead of failing to activate a drug, the liver is failing to clear an already active drug.

Exactly.

The active drug simply backs up and accumulates in the blood.

For example, isoniazid, which is a standard tuberculosis treatment.

It's processed by the enzyme N -acetyltransferase 2.

The population split on this one is just wild to me.

It really is.

Among Americans of European heritage, about 52 % are slow metabolizers and 48 % are rapid metabolizers.

It's almost a 30 -50 split.

So without adjusting the dose based on genetics,

half your patients might experience severe drug toxicity and the other half might experience treatment failure because their bodies clear it way too fast.

You're just flipping a coin if you don't know their genetics.

Thiocurians follow the same dangerous curve.

Like thioguanine or mercaptopurine?

Exactly, those anti -cancer drugs.

They are inactivated by the enzyme TPMT.

So an inherited TPMT deficiency means those standard doses just accumulate to highly toxic levels, which leads to severe, potentially fatal bone marrow damage.

And the FDA strongly recommends testing for TPMT variants, right?

Yes.

They require a drastic dosage reduction if the patient is deficient.

Another one is fluorosil.

All right, another anti -cancer drug.

About 1 % of the US population produces a poor form of the enzyme dihydropyramidine dehydrogenase.

So standard doses in these patients lead to fatal central nervous system injury.

Wow.

Fatal CNS injury from a standard dose.

But let's bring it back to a medication you'll see constantly in primary care, warfarin or coumadin.

Oh, warfarin.

Yeah.

A classic narrow therapeutic index drug.

Notoriously narrow.

It is inactivated by CYP2C9.

So patients with an altered CYP2C9 gene metabolize warfarin very slowly.

The drug accumulates.

Exactly.

Drastically increasing their risk for severe, life -threatening bleeding.

The FDA recommends testing for CYP2C9 variants.

But there is a really interesting clinical pearl here for the students, though.

Even with the FDA recommending these relatively expensive genetic tests for warfarin, traditional cheap coagulation tests actually work just as well here.

Yeah, that's true.

Like your standard INR blood draws.

Because the INR directly measures the drug's actual effect on the blood's ability to clot.

It's a solid reminder that the newest, flashiest genetic test isn't always clinically superior to basic monitoring.

That is a very necessary reminder for new prescribers.

Basic labs still save lives.

Okay, so we've established how genetics alter the drug's journey through the liver.

We covered the pharmacokinetics.

Let's say the drug has been metabolized properly and the exact right amount of active medication reaches the destination, the target cell.

Are we totally in the clear?

Not necessarily.

Because what if the lock on the cell door has fundamentally changed shape?

Now we're moving into pharmacodynamics altered drug targets.

Because a drug can only exert its effect if it can actually bind to its intended receptor.

If a genetic variant changes the physical shape or the sensitivity of that receptor, the drug's effect is drastically altered.

Let's look at normal human cell targets like ADRB1.

This gene codes for beta -1 receptors, and a specific variant can make these receptors hyper -responsive to activation.

So this is a massive double -edged sword.

I mean, if a patient has hypertension and these hyper -responsive receptors are activated by stress or adrenaline,

they experience this exaggerated, super -dangerous spike in blood pressure.

But if you block those exact same receptors with a beta blocker… They experience an exaggerated, highly effective decrease in blood pressure.

And population studies actually showed this specific ADRB1 variant occurs more frequently in people of European ancestry compared to people of African ancestry.

Which helps explain the racial differences we see in the clinical efficacy of beta blockers.

Exactly.

It's genetics, not just race.

Before we look at other targets, I want to clarify something for anyone following along in Chapter 7 or reading these package inserts.

You'll see terms like star 2 or star 3 alleles.

Can we break down what an allele actually is in this context?

Absolutely.

An allele is simply a different version or a different flavor of the same gene.

We all have the gene that codes for certain enzymes, but you might have the star 1 version, which is considered standard, while someone else has the star 2 version, which might have a slight mutation that changes how it functions.

That makes reading the actual warfarin package insert so much clearer.

Like if you look at figure 7 .1 in the text section 12 .5 of the insert,

it warns prescribers about both the metabolism side and the target side.

Right.

It lists CYP2C9, star 2, and star 3 in Caucasians, and star 5, 6, and 11 in Africans for metabolism.

But the actual target for warfarin is the VKRC1 enzyme.

Right.

Because warfarin works by inhibiting this enzyme to stop blood from clotting.

And certain variant alleles, specifically the NACNC1639GA variant, produce a form of the VKRC1 enzyme that is incredibly easy to inhibit.

Oh.

Meaning the patient achieves full anticoagulation with a drastically lower dose of warfarin.

Exactly.

Giving them a normal standard dose will almost certainly cause them to bleed out.

The insert explicitly states that the combination of the metabolism variants and this target variant explains the largest proportion of variability in warfarin dosing.

It's just wild how complex it is.

And altered targets don't just happen on normal human cells though, right?

They happen on cancer cells and viruses too.

Yes.

And in these cases, the FDA often requires testing because the drug won't work without the target.

Because if the target isn't there, the drug is entirely useless.

Like Trastuzumab or Herceptin, it's a breast cancer treatment.

It is a monoclonal antibody physically designed to bind to HER2, which is a protein that stimulates tumor growth.

But if the tumor doesn't overexpress HER2.

Which is the case for about 75 % of breast cancer patients, by the way.

Wow.

75%.

Yeah.

So for them, the drug has absolutely nowhere to latch on.

It would be like trying to turn a lock on a door that has no keyhole.

The FDA mandates a positive HER2 test before you can even prescribe it.

Makes sense.

And Cetuximab works on the exact same principle for colorectal cancer, right?

Yep.

Erbitux.

It's built to target the epidermal growth factor receptor, or EGFR.

No EGFR expression on the tumor means the drug does nothing.

So the FDA requires evidence of that expression.

Exactly.

And this concept extends to virology, too.

Meriviroc or Celzentry is an HIV medication.

It works by blocking a viral surface doorway called CCR5.

Which specific strains of HIV use to break into the patient's immune cells.

Right.

But it only works if the patient's specific strain of HIV is CCR5 -tropic.

Meaning, it actually relies on that specific doorway.

If the virus uses a different doorway, blocking CCR5 accomplishes nothing.

So testing to confirm the strain's tropism is totally required.

Exactly.

Alright, so we've covered how genes alter the drug's journey, the pharmacokinetics.

Yeah.

And we've covered the lock on the cell door, the pharmacodynamics.

But there's a third, far more explosive scenario.

The immune system.

Right.

What if a gene variant tricks the body into viewing a life -saving drug as a deadly invader?

This is where we see severe, life -threatening hypersensitivity reactions.

We see this prominently with carbamazepine, also known as Tegradol.

Used for epilepsy and bipolar disorder.

Exactly.

Patients of Asian descent who carry a specific variant allele called HLA -B1502 are at a severe risk here.

How does that variant actually trigger the immune system, though?

What's the mechanism of action?

Think of the HLA system as the body's security alarm.

Its job is to recognize foreign invaders and tag them for destruction by the immune system.

The HLA -B1502 variant acts like a faulty, hypersensitive security system.

So when carbamazepine enters the body, this variant misidentifies the drug's basic chemical structure as a highly dangerous pathogen.

Oh, wow.

So it sounds a massive alarm.

A huge alarm.

Triggering the patient's T cells to aggressively attack their own skin, resulting in life -threatening skin reactions.

The FDA heavily recommends screening patients of Asian descent for this allele.

And a positive result means you must avoid the drug entirely.

Totally.

Avoid it.

AbaCavir, the HIV medication, triggers a similar immune catastrophe, right?

Yes.

Zyugin.

Patients carrying the variant gene HLA -B5701 have a faulty security system that reacts to AbaCavir.

It puts them at massive risk for fatal hypersensitivity reactions.

Sadal.

So the FDA recommends screening, and a positive result is an absolute contraindication for AbaCavir.

Absolute contraindication.

The clinical responsibility here is just immense for the prescriber.

Really is.

But, I mean, knowing these alleles is completely useless if the patient can't get tested or is too afraid of the results to consent to testing.

And that is the real -world barrier.

Understanding the mechanisms is only half the battle.

You are going to practice in a landscape where there are over 70 ,000 genetic testing products on the market.

70 ,000.

Yeah.

Utilizing blood, saliva, hair, amniotic fluid.

It can be totally overwhelming for both the provider and the patient.

Which leads to a very realistic clinic scenario for our listeners.

What happens when a patient walks in with a printed direct -to -consumer genetic report they just bought online?

Oh, the 23andMe conversation.

Right.

Can't patients just use their 23andMe results to dictate their clinical care?

I mean, it's their DNA.

That requires a very critical safety conversation.

Back in 2018, the FDA approved the first direct -to -consumer genetic test kit for breast cancer risk from 23andMe.

It tests for BRCA1 and BRCA2 gene mutations using a saliva sample.

But while the FDA approved the test, they strictly caution against using it as a definitive guide for medical decisions.

Why is that?

Because the BRCA genes have more than 1 ,000 known mutations that can increase cancer risk.

The 23andMe kit only tests for three specific founder mutations.

Only three.

Out of over 1 ,000.

Let's clarify why those three founder mutations are even singled out.

They are tested because they are highly prevalent in specific populations, like individuals of Ashkenazi Jewish descent, right?

Right.

But if a patient gets a negative result on their at -home kit, they might experience this massive sense of relief, thinking they are perfectly safe.

But in reality, they could easily be harboring one of the other 997 mutations that cause breast cancer.

That false sense of security is incredibly dangerous.

It's so dangerous.

And navigating that conversation with a patient requires a depth of pharmacogenomic education that is honestly still lacking in a lot of graduate programs.

And beyond education, there are steep financial barriers to getting the real tests.

Very steep.

Clinical grade genetic tests cost anywhere from $100 to $2 ,000.

And a lot of insurance plans refuse to cover them as a preventative measure.

Right.

They only pay for them after a standard drug has already failed, which defeats the purpose of prevention.

It totally does.

And even if the cost is covered, patients often hesitate to consent to testing because they fear the results will be used against them.

Like if a genetic test reveals a predisposition to a costly chronic disease,

could their insurance drop them?

Could they be fired?

It is a totally valid concern.

To provide some protection, the Genetic Information Nondiscrimination Act, or GINA, was passed in 2008.

Okay, GINA.

GINA prohibits discrimination by employers and health insurance providers based on genetic information.

But, and this is a massive, but there are significant loopholes in GINA that you, as the clinician, must make your patients aware of before they consent to testing.

Yes.

Because GINA does not protect patients receiving care in the military or through the Veterans Administration or through Indian Health Services.

And furthermore, it provides absolutely zero protection when a patient applies for life insurance or long -term care insurance.

That's the big one.

An individual can absolutely be denied coverage for a life insurance policy based on the results of a clinical genetic test you ordered.

Ensuring the patient understands those risks is a core part of informed consent.

It's not just about the medical science, it's the ethics.

Absolutely.

So, to help clinicians navigate this incredibly complex, evolving landscape,

the Clinical Pharmacogenetics Implementation Consortium, or CPIC.

CPIC, right.

They serve as the gold standard resource.

They currently provide 26 detailed guidelines for drugs like codeine, warfarin, and clopidogrel, offering exact therapy recommendations based on specific genetic variations.

That's so helpful to have a centralized resource.

It is.

And resources like PharmGKB also compile international guidelines alongside specialty resources from oncology networks like NCCN and nephrology networks like ASN.

So the resources are out there.

They are.

You just have to know how to use them.

Exactly.

So I want to leave you with a final thought.

Think about your first week in clinical practice.

When a patient walks into your exam room, visibly relieved, and hands you that printed direct -to -consumer genetic report they bought online,

how will you bridge the gap between their excitement and the serious clinical limitations we just discussed?

It's conversation you will definitely have.

Applying these frameworks,

really understanding the underlying path of physiology, and having those difficult ethical conversations, that is what will keep your future patients safe.

From all of us on the Deep Dive's Last Minute Lecture Team, thank you so much for joining us.

We will see you next time.