Imagine this: you’re a new mother, having
just given birth to healthy baby boy.
Unfortunately, the delivery has left you with debilitating
post-partum pain.
Your doctor prescribes you a painkiller, which
really helps, but also makes you feel
drowsy, tired, and sometimes constipated.
At the same time, you notice that your son
isn’t breastfeeding very well.
The doctor reassures you that everything's fine and recommends you freeze
and store your excess breastmilk for convenience,
and you go home relieved.
One day, your child doesn’t wake up.
His skin is gray and he’s not breathing.
Frantically, you call 911 but
it’s too late.
Authorities arrive.
An autopsy is done.
Extremely high levels of morphine are found
in your son’s blood.
Infanticide is considered.
Your life is in shambles.
This is a true case study published in the
Lancet back in 2006.
The culprit ended up being codeine, an opioid
analgesic.
Codeine is found in Tylenol No. 3, a painkiller
prescribed to many new mothers to relieve
post-partum pain.
Yet the vast majority of these breastfeeding
mothers have healthy babies.
What happened in this case?
In this episode of Medicurio, we will explore
the concept of pharmacogenomics – how our
genes change how we respond to medications.
When drugs enter our body, they are metabolized
and structurally modified by enzymes which
either activate or deactivate these medications.
The most well-known family of drug-metabolizing
enzymes are the cytochrome P450 enzymes.
There are over 50 different isozymes of CYP450
enzymes, 7 of which are involved in metabolizing
over 80% of medications as shown here.
For this story, let’s focus on CYP2D6.
The CYP2D6 gene sequence varies between people.
These genetic variants, or alleles, result
in slight structural changes in the CYP2D6
enzyme, which alter how effective the enzyme
is at metabolizing drugs.
Broadly, they can be grouped as normal function,
decreased function, and non-functional.
Since we inherit a copy of each gene from
each parent, each person will have two CYP2D6
alleles.
A person can be classified as rapid, intermediate,
or poor metabolizers based on what combination
of CYP2D6 alleles they inherited.
A person who is a rapid metabolizer will have
at least one functional allele.
However, an intermediate metabolizer will
have a decreased function and a non-functional allele,
and a poor metabolizer will have two
non-functional alleles.
You can see all the possible combinations
here –
the majority of people are rapid metabolizers.
In rare cases, a person can be classified
as an ultra-rapid metabolizer.
These people have three normal alleles of
CYP2D6 rather than two due to a gene duplication,
and so they metabolize certain drugs extremely rapidly
and efficiently because they have more enzymes.
Changes in metabolism can alter the effectiveness and toxicity of a drug.
Drugs can either be activated or inactivated
after they are metabolized.
Codeine itself is a weak painkiller but is
still used because CYP2D6 metabolizes around
10% of the codeine into morphine, a potent
opioid analgesic.
Now consider this – if all metabolizer types
were given the same codeine dose, an ultra-rapid
metabolizer would convert way too much codeine
into morphine, and theoretically should be
receiving a lower dose to prevent overdose.
It turned out the mother in the case was an
ultra-rapid metabolizer and the excess morphine
entered her breastmilk and into her son, which
likely caused an overdose.
High levels of morphine were found in her
frozen breastmilk, supporting this explanation.
A year after this was reported, the FDA added
a warning label on codeine use during breastfeeding,
recommending that the lowest dose be used
in nursing mothers.
It later strengthened its warning in 2017
after more reports of opioid overdose from breastfeeding.
The takeaway from this story isn’t to say
that codeine is a bad drug and should be banned
– it’s quite an effective painkiller if
used in the right people.
Unfortunately, we just don’t know who the
right people are unless we do genetic testing,
which is still quite expensive and has implications
on privacy and ethical issues.
But surely this tragedy could have been avoided
if the doctors knew the mother was an ultra-rapid
metabolizer so she would not be prescribed
codeine.
This story isn’t just applicable for codeine
and CYP2D6.
Almost all drugs are metabolized by a combination
of CYP450
and phase II enzymes such as TPMT and UGT.
Many of these enzymes have genetic variations
that change their function, altering the effectiveness
and toxicity of the drug.
We don’t know who has what genetic variation,
so there is the risk of patients prescribed
medications that could harm them.
Genetic variations are a major cause of adverse
drug reactions,
which are a huge burden on the healthcare system.
The solution?
Imagine if we can use pharmacogenomic information
to prescribe each individual patient the most
effective and least harmful medication based
on their genetic makeup – in other words,
precision medicine.
Not only could it prevent a baby dying from
toxic breastmilk, it could also prevent bone
marrow damage in a patient with an autoimmune
disease, reduce the risk of bleeding for people
with bad hearts, and increase the chance a
person is protected from future strokes, just
to name a few.
But this is easier said than done.
The hardest barrier to using pharmacogenomic information in the clinic is relating genes to outcomes.
While the codeine example seems straightforward,
most drugs have such a complex metabolic pathway
involving multiple enzymes that it is difficult
to predict the patient’s response.
Further complicating the situation are genetic
changes in drug transporters and receptors,
as well as non-genetic reasons such as age,
sex, concurrent diseases, drug-drug interactions,
diet, and other environmental factors.
All of these also influence a drug’s effect
on a person.
There’s still a lot more to learn about
pharmacogenomics before it can really help
in the clinic, but new links between genes
and drugs are being discovered every day.
Perhaps in the future, when more research is done and genetic testing becomes more routine,
doctors can also use genetic information when prescribing medicine to maximize benefits
and minimize harms for every patient.
Thanks for watching, and see you next time
on Medicurio.
