Let's move on to a completely different topic.
Let's move on to colchicine.
Now, colchicine is a selective inhibitor of microtubule assembly.
Now what happens is is that you're inhibiting tubulin
which is necessary for cell division and motality.
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.
Inhibiting tubulin production actually inhibits a lot of
cell function. We call this a general mitotic poison.
So in actual fact, we can use these agents in cancers.
But in our particular discussion today,
we're going to be talking about how it reduces
migration and phagocytosis by macrophages.
This also helps reduce interleukin B4 which I mentioned
to you in the slide before.
This also decreases free radical formation
which is also a mediator of pain and inflammation.
So where do we use colchicine? It's used in acute gout attacks.
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.
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.
Chronic gout prevention is treated with 0.6 mg once a day.
Now, we also use this for pericarditis treatment and prevention.
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.
So, treating a patient for 3 months with colchicine actually reduces
the recurrence of pericarditis in a patient who had pericarditis before.
Interestingly enough, we also use this for disease called
familial Mediteranean fever.
And that treatment dose is 0.6 mg twice a day.
The toxicity of colchicine and overdose can cause
liver, kidney, and other organ failure.
Remember that toxicity can be fatal. 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.
Other drugs used in gout include the uricosurics.
Probenecid is your prototypical agent.
It is a weak acid and it competes with uric acid
for reabsorption at the proximal tubule inside the kidney.
When you give a patient probenecid,
the uric acid is released in the urine.
So here's an example of how uric acid is reabsorbed.
You filter about 100 litres a day of blood into the glomerulus.
90 % of the uric acid is reabsorbed at the proximal convoluted
tubule allowing a small amount of uric acid excretion at the end
This weak acid transporter or WAT is what picks up
these weak acids and brings them back into the blood.
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.
Now at low doses, these uricosuric agents also compete
with uric acid for secretion.
So that causes an increase in uric acid levels as well.
So, a similar phenomenon also occurs with aspirin.
This causes an elevation of uric acid.
So, the bottomline is this. Is that these drugs are
uricosuric, they do promote release of uric acid in the urine.
However, they can also predict or promote an acute gout
attack too, so you have to be very careful using these drugs.
And you don't want to slam people with these medications just
without thinking about them because you can precipitate a gout attack.
The uses of the uricosurics is treatment of chronic gout.
Let's talk about the xanthine oxidase inhibitors.
At one time, these were the mainstay of gout treatment.
Let's look at the physiology behind allopurinol.
Allopurinol is converted to alloxanthine by xanthine oxidase.
This is a suicide inhibitor of xanthine oxidase.
So, uric acid production is cut dramatically because
xanthine oxidase is also needed to produce uric acid.
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.
So, this is an important consideration in cancer chemotherapy.
When we're killing cells, there's all this stuff being generated
as the cells are dying. One of them are purines
and that can cause gout attacks.
That's why you have to be very careful in cancer patients
and that's why we use allopurinol in them.
Other non purine inhibitors of xanthine oxidase are out
on the market now. They are more selective.
They are quite a bit more expensive.
And we're just starting to get the feel for them over time.
In terms of toxicity of allopurinol, I think
the most commonly thing that we see is gastrointestinal upset.
We often see GI upset in low doses of allopurinol usage.
Our rash, vasculitis, and peripheral neuritis are often seen.
I have had many patients who developed rash on allopurinol.
A rare but very feared complication of allopurinol toxicity
is aplastic anemia.
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.
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.