00:02
Let's move on to a
completely different topic.
00:04
Let's move on to colchicine.
00:07
Now, colchicine is a selective
inhibitor of microtubule assembly.
00:13
Now what happens is is that
you're inhibiting tubulin
which is necessary for
cell division and motality.
00:19
So, what is tubulin?
We can think of tubulin as
a combination of a girdle
or something that
holds a building up
and a communication tube that
moves one thing to another
from one part of
the cell to another.
00:32
Inhibiting tubulin production actually
inhibits a lot of cell function.
00:38
We call this a general
mitotic poison.
00:42
So in actual fact,
we can use these agents in cancers.
00:46
But in our particular
discussion today,
we're going to be talking
about how it reduces
migration and phagocytosis
by macrophages.
00:54
This also helps reduce interleukin B4 which
I mentioned to you in the slide before.
01:01
This also decreases
free radical formation
which is also a mediator
of pain and inflammation.
01:08
So where do we use colchicine?
It's used in acute gout attacks.
01:12
It's often associated with
diarrhoea and in fact,
the way that we prescribe this
medication is we tell patients
take 0.1 mg every hour until they
develop diarrhoea, then slow down.
01:24
And it sounds kind of flippen but
it's true it's a very effective agent,
it's very very potent, except for
the fact that it causes diarrhoea,
it would be a perfect
drug for treating gout.
01:38
Chronic gout prevention is
treated with 0.6 mg once a day.
01:43
Now, we also use this for
pericarditis treatment and prevention.
01:47
What we do is we start
off with 0.6 mg a day,
or sometimes even twice a day, then
we go down to once a day for 3 months.
01:55
So, treating a patient for
3 months with colchicine
actually reduces the
recurrence of pericarditis
in a patient who had
pericarditis before.
02:07
Interestingly enough, we also use this for
disease called familial Mediteranean fever.
02:12
And that treatment dose
is 0.6 mg twice a day.
02:16
The toxicity of
colchicine and overdose
can cause liver, kidney,
and other organ failure.
02:24
Remember that
toxicity can be fatal.
02:26
So if you have a patient show up in your
ER who is taking a lot of colchicine,
you have to pay close
attention to these patients.
02:34
Other drugs used in gout
include the uricosurics.
02:38
Probenecid is your
prototypical agent.
02:41
It is a weak acid and it
competes with uric acid
for reabsorption at the proximal
tubule inside the kidney.
02:48
When you give a patient probenecid,
the uric acid is released in the urine.
02:54
So here's an example of how
uric acid is reabsorbed.
02:58
You filter about 100 litres a
day of blood into the glomerulus.
03:04
90 % of the uric acid is reabsorbed
at the proximal convoluted tubule
allowing a small amount of
uric acid excretion at the end.
03:13
This weak acid
transporter or WAT
is what picks up these weak acids
and brings them back into the blood.
03:21
By administering uric acid
agents such as probenecid,
you actually increase the amount of
reabsorption of those drugs like probenecid
and the uric acid is therefore
released into the urine
unchanged and not reabsorbed.
03:43
Now at low doses, these uricosuric agents
also compete with uric acid for secretion.
03:49
So that causes an increase
in uric acid levels as well.
03:54
So, a similar phenomenon
also occurs with aspirin.
03:57
This causes an
elevation of uric acid.
03:59
So, the bottomline is this.
04:02
Is that these drugs are uricosuric, they do
promote release of uric acid in the urine.
04:10
However, they can also predict or
promote an acute gout attack too,
so you have to be very
careful using these drugs.
04:17
And you don't want to slam
people with these medications
just without thinking about them because
you can precipitate a gout attack.
04:25
The uses of the uricosurics
is treatment of chronic gout.
04:33
Let's talk about the
xanthine oxidase inhibitors.
04:36
At one time, these were the
mainstay of gout treatment.
04:40
Let's look at the physiology
behind allopurinol.
04:43
Allopurinol is converted to
alloxanthine by xanthine oxidase.
04:49
This is a suicide inhibitor
of xanthine oxidase.
04:54
So, uric acid production is cut
dramatically because xanthine oxidase
is also needed to
produce uric acid.
05:03
Now, we sometimes use allopurinol
in chemotherapy of cancer patients
to reduce uric acid
production from purines
that are released during the cell
death of all those cancer cells.
05:14
So, this is an important
consideration in cancer chemotherapy.
05:17
When we're killing cells,
there's all this stuff being
generated as the cells are dying.
05:23
This massive cell lysis releases
various intracellular metabolites
into the circulatory system.
05:28
Ultimately,
impacting multiple organ systems
and a process called
tumor lysis syndrome.
05:33
One of the cellular components
released is nucleic acid,
which then causes
elevated peering levels.
05:38
Without treatment,
these are then converted into uric acid
which precipitates in the renal tubules
and causes an acute kidney injury.
05:46
Other non-purine inhibitors of
xanthine oxidase are out on the market.
05:51
Now they are more selective,
they're quite a bit more expensive,
and we're just starting to
get a feel for them over time.
05:59
In terms of toxicity
of allopurinol,
I think the most commonly thing that
we see is gastrointestinal upset.
06:06
We often see GI upset in low
doses of allopurinol usage.
06:12
Our rash, vasculitis,
and peripheral neuritis are often seen.
06:16
I've had many patients who
developed rash on allopurinol.
06:20
A rare but very feared complication of
allopurinol toxicity is aplastic anemia.
06:25
So if you start to see some abnormalities
with your white counts and your red counts,
be very aware that your allopurinol
may be inducing a serious disease.
06:35
With respect to the newer
xanthine oxidase agents,
this agent can cause
gastrointestinal upset
as well as liver
function abnormalities,
and of course you
can get a headache.