What’s up everyone, it’s Jessica, and welcome to CritIC: the pharmacokinetics series.
In this last video in these introductory series we’ll go through excretion.
If you haven’t seen the rest yet, I do advise you to start with the first one in these series,
but I highly recommend that you at least watch the one on clearance first.
Now for excretion!
Excretion is the process of removing substances from our body.
This is mostly done in the kidney, so we’ll focus on that in this video, but excretion
can also happen through bile or the lungs.
In the context of clearance: if an active drug is excreted, it is therefore then also
cleared through excretion.
If an inactive drug is excreted, it is cleared by metabolism.
But a lot of the time, it is a combination of both.
The functional unit of the kidney is the nephron, which consists of the glomerulus, the proximal
tubule, the loop of Henle, the distal tubule and the collecting ducts.
A drug first encounters the nephron when it travels through the afferent arteriole to
the glomerulus.
The glomerulus functions as a filter: free drug (meaning unbound to plasma protein) of
small molecular size can pass through and will enter the proximal tubule.
Drugs that were not filtered, will leave the glomerulus through the efferent arteriole
and pass the proximal tubule, where they may undergo active secretion.
Note that this applies to a lot of renally cleared drugs!
Secretion is performed by mainly two transporters, either the organic anion transporter for weak acids,
or the organic cation transporter for weak bases.
The third and final step is reabsorption.
Since this is a passive process through diffusion, this mostly applies to uncharged drugs, since
they can cross cell membranes.
So why are these steps important in understanding renal drug clearance?
Well, in common clinical practice we determine renal function and thus renal clearance by
calculating the glomerular filtration rate based off of our serum creatinine levels,
and we adjust our dose based on that.
Leaving aside the obvious drawbacks of using a standardized formula like the CKD-EPI or
the MDRD for the estimation of GFR in our mostly heterogenic population
even if we calculate the GFR by measuring creatinine levels in a 24 hour urine collection, there’s
this one big assumption that we make that I think you need to know:
as stated before, a lot of renally cleared drugs are mainly cleared through through active secretion,
not through filtration.
Is GFR a good representative of all renal function and thus tubular secretion?
I don’t think it is.
Though I don’t have a practical solution for this.
Secondly, the different transporters responsible for active secretion, like p-gp, and the different
types of OAT’s and OCT’s, can be a cause of drug-drug interaction.
These transporters can be induced, inhibited, blocked or saturated.
For example, cimetidine (an H2-receptor blocker used for ulcer treatment) inhibits the organic
cation transporter, reducing tubular secretion of metformin, which could cause an in increase
of plasma levels of up to 40%.
Fortunately, there are only few clinically relevant interactions, but I’m sure more
will surface in time.
By the way, fun fact, though used for the calculation of glomerular filtration rate,
creatinine itself undergoes tubular secretion for about 10-20%, and this amount can increase
up to 50% in people with renal failure.
This is why you see an increase in serum creatinine when you prescribe trimethoprim, without actually
causing a decrease in GFR.
Lastly, remember in the absorption video when we talked about the influence of pH on the
ionization of weak acids and bases?
Well that applies here too!
A trick used in toxicology is to alkalinize the urine with sodium bicarbonate.
This is for instance used for the treatment of an aspirin overdose.
Aspirin, or acetylsalicylic acid, is a weak acid.
Sodium bicarbonate ionizes the drug and makes it more water soluble, keeping it in urine
and out of our body.
The same goes for phenobarbital.
And that sums up what I wanted to share on excretion and renal clearance.
And that brings us to the end of the introductory series on pharmacokinetics.
I’m very curious to hear your thoughts on these series.
Let me know in the comments below, and stay tuned for the more advanced ones coming up.