00:01
Let's move on to
the next section.
00:03
So you remember that molecule
called the reverse transcriptase.
00:07
We have targets at the
reverse transcriptase.
00:10
Remember that DNA is made up
of nucleosides and nucleotides.
00:16
We're going to look at them
based on what they're targeting.
00:18
So there's the nucleoside
and the nucleotide
reverse transcriptase
inhibitors are either called
NSRTIs
NtRTis
and then we have another
category called the
non-nucleoside reverse transcriptase
inhibitors or the NNRTIs.
00:36
Now these are divided in
our pharmacology lecture
into first and second generation
more for you so that you can
keep a track of these medications
out in clinical practice.
00:46
It's not commonly
divided up this way.
00:49
Okay, let's focus on the NSRTIs.
00:53
So there's a huge list here.
00:55
And I don't expect you
to know all of the drugs.
00:58
It's impossible.
01:00
But I think if you take a look
at the ones that are in boldface,
these are the ones that you are
probably going to come across
in clinical practice.
01:08
You do not need to know that
this particular drug is NSRTIs
or NNRTI, I think that that's
an unreasonable request.
01:15
But if you know how the
drugs work in general,
I think that that
will work you well.
01:20
Now the NSRTIs are mostly
anti metabolic drugs.
01:25
What what that means is that an
interferes with the metabolism
and development of
the DNA particle
or the RNA transcription.
01:34
Now we use three or more drugs at
the same time for HIV treatment
kind of like we do with
tuberculosis and we try to do
these different drugs or use these
different drugs from different classes
so we don't use two
NSRTs at the same time.
01:53
HAART stands for highly
active antiretroviral therapy.
02:00
So this is generally
multi drug regimen
and these regimens are
shown to reduce or reverse
the decrease of the CD4 counts.
02:10
We also, which is our target is
to reduce morbidity and mortality
from the HIV illness.
02:19
Now the NSRTIs act on the
viral reverse transcriptase.
02:24
Remember that the viral reverse
transcriptase is much different
from the mammalian
reverse transcriptase.
02:30
So it made sense that we could
target this very different enzyme
and have fewer side
effects for the human host.
02:39
The NSRTIs lack a 3' Prime
hydroxyl group on the ribose ring,
so that the next nucleotide
can't bind to that chain
the NSRTIS are converted
by the host cell kinase
to triphosphates that block
the binding of the nucleotides
to the D site of the
reverse transcriptase
and they act as a
chain terminator.
03:03
So the chain is no
longer being produced.
03:07
Now all NSRTIs may cause lactic
acidosis and can cause hepatomegaly.
03:13
So watch your amino transferase levels
closely when you're administering this drug
from an exam point of view,
you want to remember that they
can cause a mild hepatitis
and can cause
severe hepatomegaly
and you know,
you may be asked to watch
you may be asked
which enzyme to watch.
03:31
I doubt they would particularly
target ALT as your choice on the exam
at the USMLE level,
but they certainly will
if you're writing your
Internal Medicine boards.
03:42
The next on our
list is abacavir,
so it's a it's actually
quite a good drug.
03:48
Has very good
aural availability.
03:50
It has a half-life
of 12 to 24 hours
and resistance is also unlikely because
it requires several point mutations
on the part of the HIV virus
to be resistant to this drug.
04:02
Side effects include
hypersensitivity reactions.
04:06
And occasionally, these can be
so severe that can become fatal.
04:11
Up to 5% of HIV patients
had fatal reactions in the
initial deployment of this drug.
04:19
Next on our list
is emtricitabine.
04:21
Emtricitabine has good
oral availability.
04:24
It is excreted by the kidneys
and the dosage is once a day.
04:30
So it's actually a fairly
convenient medication.
04:33
It is contraindicated in
pregnancy in small children
and patients who have
underlying hepatic dysfunction.
04:40
Iamivudine is another NSRTI
It's often used in heart
therapy for HIV patients.
04:46
We also use this medication
actually in hepatitis
the toxicity and Adverse
Events are certainly present,
GI/GU symptoms which include
mild gastric distress.
04:59
You can also get
neurological side effects
which include some
mild headaches,
you'll often get fatigued
in these patients.
05:06
In fact, I see that quite often
in the patients coming
from the HIV Clinic
and of course you can have insomnia
the cause of which would be unknown.
05:15
Finally on our list.
We have zalcitabine.
05:17
It is distributed
to most tissues
including into the
central nervous system.
05:21
So you can see where this
particular drug would be useful.
05:24
It is also regionally excreted.
05:26
We adjust the dose in
in renal failure again,
it is metabolized
through cytochrome p450.
05:32
So this is a bit of a
disadvantage because a lot of time
patients who are on this
medication are also on Rifampin.
05:38
So if the patient has
tuberculosis as well as HIV
and they're on Rifampin,
remember that this particular drug
can be affected by the Rifampin.
05:47
In terms of toxicity,
again, we have pancreatitis.
05:51
We can also get ulcerations
of the esophagus
neurological side effects.
05:56
You can get in
peripheral neuropathy.
05:59
It depends on what dose
you're on but certainly
it's something that
we need to consider.
06:04
Zidovudine is used to
come under another name
that's utterly unpronounceable.
06:09
It's distributed
to most tissues.
06:11
It's a limited via
both the kidney
and via the liver,
toxicities of this medication
include bone marrow suppression.
06:20
And this is a particular
concern in patients with HIV.
06:23
Anemia is also seen in
patients on this drug,
and of course neutropenia.
06:28
In terms of your side effects,
usually gastric distress is something
that we are concerned about.
06:33
One thing I want to mention is a
disease called Fanconi syndrome.
06:38
If you can burn this into your
memory the fanconi syndrome
and this particular drug,
you will get at least
one question right
on your exams
neuro includes headache,
insomnia and fatigue.