00:01
Let's move on in our discussion
of antiviral agents.
00:04
Let's focus now on those agents
that are active against herpes.
00:08
Now, these agents are important
in the nucleic acid synthesis
portion of antiviral therapy.
00:17
These thymidine kinase
dependent agents
include acyclovir and ganciclovir.
00:22
They're active against
HSV-1 and HSV-2,
as well as varicella-zoster.
00:28
They have a
very short half life
and they're often administered
three to five times a day.
00:34
Now, their renal,
they excreted as well.
00:36
So we do adjust the dose
in renal failure.
00:39
Let's have a look at where they work
on our slide here.
00:43
Now as we're going through
the production of DNA,
we have several steps.
00:49
Now the host kinase
is are acted upon
by acyclovir and ganciclovir
to prevent the diphosphate form
of these agents from being produced.
00:59
They're a competitive substrate
for DNA polymerase,
and they lead to chain termination
after incorporation into the DNA.
01:07
Because they are
defective agents,
because they cause a defect
in the actual DNA,
you're unable to continue production
of the DNA chain itself.
01:18
That's why we call it
chain termination.
01:22
Now, valacyclovir or Valtrex
is a prodrug of acyclovir.
01:26
So you can see here that
I've placed it in a little pink box
above acyclovir and ganciclovir.
01:32
Now, valacyclovir
is able to achieve
three to five times greater
concentration levels.
01:38
And it also lasts a lot longer.
01:40
So, for the most part, it's replaced
acyclovir as a means of therapy
for certain types of disease.
01:49
Penciclovir actually works at
the level of the DNA polymerase.
01:53
So it doesn't cause
chain termination.
01:56
But what it does is it inhibits
the production of DNA.
02:00
Now, famciclovir is converted
to penciclovir by the liver.
02:05
So once again,
I've put this prodrug form
in a little pink box
just under the penciclovir.
02:12
Ganciclovir is a
guanine derivative.
02:16
Acyclovir is a
guanosine derivative.
02:19
So you can see how they're
acting at slightly different agents
within the DNA molecule.
02:25
Now, when we're
looking at these agents,
we know that they're inhibiting
DNA polymerase
and cytomegalovirus,
and HSV alike.
02:32
They're used in CMV retinitis
and other CMV infections
in patients who are
immunocompromised as well.
02:40
The toxicity of
these agents include
leukopenia, thrombocytopenia,
and mucositis.
02:48
Now, there is another agent
that's a prodrug
that I just want
to mention quickly.
02:52
Valganciclovir is a
prodrug of ganciclovir.
02:55
It has a very high bioavailability
and a longer half life.
02:59
So, I anticipate that
this is going to be something
that will come onto the market
quite strongly
and start to replace
the ganciclovir.
03:09
Now, when you take a look
at all of these drugs,
and just sort of throw them
into a class as a whole,
the toxicities
that we are concerned about
is GI distress
and nephrotoxicity.
03:18
So these are present
in significant numbers,
enough that we have to
keep a very close eye on them.
03:24
With most antiviral agents,
you're going to have some kind
of neurological side effects.
03:29
So we talk about
headache, tremor, seizure,
sometimes delirium as well.
03:36
In terms of bone,
there was a concern that there
would be an effect on bone marrow,
but we're actually not seeing that
play out in real life.
03:45
How do agents develop resistance
to drugs like acyclovir?
It will occur in
two different ways.
03:51
The first way is a change
in the viral DNA polymerase.
03:55
So obviously, if there's a
change in the target molecule,
the drug won't work as well
on that target molecule.
04:01
The other way that it'll work
is that some strains of virus
actually lack the thymidine kinase
that it's active upon.
04:09
So, this can be a viral specific
phosphorylation of acyclovir
and these agents will be crossed
resistant to each other.
04:16
So, you have to be aware
that there's multiple ways of
resistance and these are the two.
04:23
Let's move on to
Host kinase agents.
04:25
Now, host kinase agents are going to
work on several areas of function,
but mostly we're
going to be focusing on
the late protein synthesis,
and processing of the virus.
04:37
So cidofovir is activated
by host cell kinases.
04:42
It's active in
herpes simplex virus infections,
cytomegalovirus,
adenovirus, and others.
04:49
Now, it does not
require viral kinase.
04:52
It's active against
many resistant viruses.
04:58
The activity we use it against
CMV retinitis
and mucocutaneous
herpes simplex virus,
and sometimes we'll use it
against genital warts as well.
05:08
The toxicity that we're most
concerned about
is really nephrotoxicity.
05:13
So this is important to monitor
renal function
in patients on these agents.