Heme review. My new podcast. I talk about the hydroxychloroquine trial
in depth, link in the description below. A Man Mistakenly Drank Aquarium Cleaner fish medicine. This Is What Happened To His Heart. JD is a 60 year old man, presenting to the
emergency room, unconscious. Paramedics tell the admitting nurse, that
he’s coming in with his wife KD, because she’s unconscious too. You see, JD and his wife were both watching
TV one night in late March 2020. They saw on the news that aquarium cleaner
had been sold out across America and Australia, because there was talk on the internet about
it being a cure for COVID19 disease. They only heard the name chloroquine, connected
it to a medicine for their koi fish to treat parasite infections, and thought that it could
cure them if in case they were infected. “Cure” is the exact word used by that
French doctor in his study that was hyped in the media. “Cure” is not a commonly used word by
doctors. In general, raise a red flag in your mind
when someone throws that word around confidently. Immediately after drinking the chloroquine
aquarium cleaner dissolved in soda, JD and his wife didn’t feel so good. It was just a couple tablets, and hey, this
virus isn’t going to infect us this time, he thought. As the minutes passed JD started feeling some
weakness in his arms and legs. He had trouble talking and walking. He started feeling dizzy and hot and his head
started pounding. He asked his wife, but then she was started
vomiting. JD started breathing quicker and quicker. He wanted to his his wife’s hand before
losing consciousness. KD calls for 911, as they’re brought to
the emergency room where we are now. Given this history of present illness, there’s
a few clues as to what’s happening. Most immediately, JD has hypokalemia. Hypo meaning low. Kal referring to potassium, or more formally
Kalium as shown by its symbol on the periodic table of elements. And emia meaning presence in blood. Low potassium presence in blood. JD and KD clearly took way too much chloroquine
phosphate, which is the active ingredient in the aquarium cleaner, fish parasite medicine.Chloroquine
is a strong base, so it needs to be delivered as a solid salt. The tablet aquarium cleaner that JD dissolved
in soda, was chloroquine phosphate. The medicinal form of chloroquine, is also
chloroquine phosphate. The active ingredient here, chloroquine, is
exactly the same, although the excipients, that is the extra fillers and formulation
parts are likely different. Remove the idea of aquarium cleaner from your
mind now It doesn’t matter if this is an old medicine we’ve had for a hundred years. It doesn’t matter that it’s off patent. People think it’s sticking it to pharmaceutical
companies in using this instead of other therapies, but the reality is this is still made by pharmaceutical
companies. Those are all fallacies. It could work for the disease, but the poorly
designed studies don’t tell us that. If the dose goes just a little higher than
what you take as medicine, it immediately becomes a poison. And in JD and KD, it immediately became a
poison. As doctors perform their physical exam on
JD, they find that his blood pressure is low. He has bradycardia. Brady meaning slow and cardia referring to
heart rate. The interesting thing about chloroquine, is
that it’s based off a natural chemical called Quinine, which is found in Cinchona tree bark. This is a case where someone who says “I
don’t think anything that is natural can be bad for you,” is wrong. Quinine is natural. It’s directly from tree bark. Native Americans and European colonists grounded
the tree bark up, and drank it because what we now know as quinine in that bark, would
treat their fevers. All of this can be really bad for you in a
slightly higher dose than you would take as medicine. And that’s the same for chloroquine and
hydroxychloroquine because the “natural” part of these molecules, all operate the same
way in the body. Chloroquine is lipophilic. Philic meaning affinity for and Lipo meaning
fat. So it preferentially mixes with fat tissue
in the body. This means after ingesting it, it immediately
distributes into the body’s tissues. The brain and nervous tissue are around 60%
fat, meaning chloroquine has likely entered the space, causing him to start seizing and
lose consciousness. But it’s not done here. Because all cells are defined by a bi-lipid
layer, it crosses right in to the cells of other tissues too, bringing us back to hypokalemia. Potassium, like Sodium above it on the periodic
table, is important in signaling in the body. Telling tissues and organs to do things. Potassium is mainly inside cells. Sodium is mostly outside the cells. Exchanging these across the cell membrane,
gives off signals to do things, like release hormones, conduct a nerve impulse or to contract
muscle. On the other hand, potassium promotes muscle
relaxation. A lot of it present outside the cell, means
your muscles would relax for a long time because it can’t exchange with what’s inside the
cell. Too little present means your muscles won’t
stop contracting. We’ve already established that these chemicals
easily enter cells. We know that potassium mainly lives inside
cells. So we can say with some certainty, that chloroquine
does something inside the cells of the body, to keep potassium in, explaining why JD has
hypokalemia. This explains his weakness in his arms and
legs. Those skeletal muscles, would have trouble
with their contractions because of low potassium. This could also explain his nausea and vomiting
because the stomach is a muscle too. And the most important muscle that can immediately
end JD’s life, the heart, is affected too, bringing us back to bradycardia. Chloroquine slows the heart rate. The heart muscles, take in sodium to initiate
a contraction. Calcium goes in to commit to a contraction. Both of these are positively charged, meaning
the muscle cell wants to pump other positive ions out. So it uses potassium, because there’s so
much of it inside the cell. But chloroquine is inside the cell. It doesn’t let potassium out. JD’s heart muscle can’t reset itself to
beat again. This slows his heart down for several minutes,
but as the chloroquine floats around JD’s blood it keeps depositing in his heart. His heart tries again and again to reset itself
for its beats, but the dysrhythmia sets in. The ventricles of his heart starts to flutter. Everything is thrown off sync as ventricular
premature complexes start to appear. The EKG shows JD has torsade de pointes, French
for a twisting of the points, which is a heart rhythm that can cause sudden cardiac death. He enters ventricular fibrillation. JD immediately falls unconscious again because
his heart isn’t actually contracting anymore, it’s just shaking in place and blood can’t
get to his brain. A code is called in the hospital. Doctors rush in to try to resuscitate him. They give chest compressions. They give medicines, and defibrillation. But it’s too late. The rhythm is intractable and terminal. After several minutes, the code was called. But if his wife also consumed the same chloroquine
phosphate, and her heart’s still beating, it may not yet be too late, she may still
be treated and kept alive. Doctors intubate KD. They stick a tube down her throat so that
machine can breathe for her. This protects her airway, because the chloroquine
has started to change her breathing rate. If chloroquine slows the heart rate, then
she should be given a medicine that will speed it up. The medicine should have a short half life
so its levels in the body can be controlled easily. That medicine is epinephrine, or adrenaline,
as it starts to speed up her heart. But epinephrine causes a shift of potassium
in to the cells. If she has hypokalemia too because of chloroquine
overdose, then it means this would worsen it, so she was given potassium IV to reverse
the hypokalemia. But this isn’t the only treatment she needs. If chloroquine is inside her heart cells,
then we need something that will either push or pull it out. Diazepam, also known as Valium, which is an
anti-anxiety medicine looks like it could bind in the heart and push chloroquine out
of the heart muscle and in to the blood. We only happen to know this by chance through
animal studies and human case reports, but it’s been shown in some larger studies. There’s likely many other things going on
in the heart when diazepam is given, and these are not well understood. But what we do know is that diazepam is a
respiratory depressant, so mechanical ventilation is a good choice to keep her oxygenated. The idea of aminoquinoline analogues like
hydroxychloroquine and chloroquine being effective antiviral medicines has been around since
at least the 1960’s. The reality is, even after using the original
quinine, for more than 400 years, we still don’t really know all the different ways
this medicine works. These drugs are bases. Bases cancel out acids. Cells have something called lysosomes, which
breakdown waste through acids. If aminoquinoline can cross into cells easily,
and force the lysosome to be less acidic, then cells can’t dispose waste. They can’t function properly anymore. This is like if you couldn’t take a dump
for 60 days, everything in your body would be broken too. In parasites, chloroquine goes into the food
vacuole instead of a lysosome, raising the pH there, and letting heme lyse the parasitic
membrane. This is how it could treat malaria, which
is caused by a parasite, but also treat koi fish parasite infections too. A cell infected with virus suddenly not functioning
anymore, could be a way this would contain the virus. This could also stop the immune system from
acting violently in the body, which is why hydroxychloroquine can be used to treat rheumatoid
arthritis and lupus. But we also know these medicines can pop open
those acidic organelles. If lysosomes were meant to break things down,
and they break open, they can release enzymes that will dissolve everything inside the cell,
killing it. This is another way it could work on the body. Chloroquine can also shuffle in zinc ions
in the cell. This stops DNA and RNA replication, which
is what viruses hijack in cells to reproduce. In lab experiments, it looks like chloroquine
can add sugars onto the spikes of coronaviruses, and it can interfere with immune cell signaling. Now, some people might say, hydroxychloroquine
is a completely different drug than this chloroquine. That is the medicine that was used in the
French study that in part prompted all of this hype. It is different, kind of. Hydroxy refers to this group, compared to
chloroquine which doesn’t have it. This is one oxygen, bound to one hydrogen. What is water made out of? Hydrogen and oxygen. The point of drug metabolism in the body,
is usually to break down the molecule so that it can be more water soluble and it can dissolve
in the urine, and be excreted from the body. From a very simple level, adding in a hydroxy
group, makes a compound interact with water. So the hydroxy part was used to lessen some
of the side effects that would come from chloroquine. All of these are reasons why it could work
for COVID-19. Keep in mind, when doctors say it’s not
proven to work, as of April 2, 2020, unproven doesn’t mean it doesn’t work. It has a scientific rationale for why it could
work. Unproven means we don’t know if its benefits
outweigh the risks, because we don’t know what the benefits are. Don’t tell me the French study published
on March 20th says that it works. They looked to see if someone tested positive
again at 6 days after treatment. What happens if they tested negative on Day
6, but tested positive again on Day 8? You’re still gonna say it works? Why were the patients who declined therapy,
still included as controls? Did they consent to be included in the study? That’s not clear. If they didn’t consent but were included,
you could make a case to say those people were experimented on, without their consent. The paper said “Untreated patients from
another center and cases refusing the protocol were included as negative controls.“ What’s stopping them from just picking the
worst cases, and finding everyone who tests positive to put on the control arm to make
it look like the medicine is really doing something when it isn’t? Why where some of the controls not tested
from the start? And why is the data different from the initial
posting on IPFS from the one that’s on Medrxiv? Again, cool they did the study, but it doesnt
tell us if it works. They did a second study with 80 patients but
didn’t have a control. But it’s not like the first trial had a
legitimate control arm. Look, I don’t have a stake in this. I want this thing to work. But when someone does a trial like this, it’s
wasting time. Had they designed an actual randomized, controlled
trial, we’d be further along now. Oh, and they added the antibiotic azithromycin
for the possible bacterial superinfection that could come with COVID19. Azithromycin is based off something called
erythromycin, which was discovered from soil samples. These medicines are also known to cause QT
prolongation of the heart. When combined with Quinine derivatives, this
might not be an additive risk, but multiplicative one, possibly mediated through the same potassium
channel blockade. The US FDA approved Hydroxychloroquine only
use for COVID19 inside the hospital on March 30th 2020, because the medical teams can monitor
the heart. Outpatient, it can be dangerous, if you even
do so much as to double up a dose one day accidentally, because it distributes widely
into your body, and stays in your body for several days. Questionable hope isn’t always good hope. There’s other treatments also being tested,
this isn’t the only one, and they should readout data by end April 2020. But to say that this is the only thing that we have for hope, is false because we're doing other studies as well. For KD, as the medicines and her body, run
the course of excess chloroquine in her body, as she was able make a recovery. Take care of yourself. Wash your hands. Be alert, not anxious. And be well.
