Now, tubular secretion overall, we've talked about this in previous discussions and lectures
in which we discussed physiologic components such as para-aminohippuric acid and creatinine.
We'll quickly walk through clinical correlation of some of our important tubular secretion.
First and foremost, you tell me what's happening. You're secreting the substance into where?
Good, into the urine. These include bile salts and uric acid. Now, substances that are being secreted
and on this picture giving you an overview as to those substances that are secreted and such
but let's just keep things relatively simple in terms of process. First and foremost,
you're going from where? Close your eyes. Peritubular capillary, most likely PCT.
You're passing across the endothelial cell. You're entering the interstitium. Step one.
Next, what are you going to hit, the basolateral membrane of whom? The epithelial cell, right,
basolateral membrane. Here you have your organic transporters. These organic transporters
will then help a substance be secreted into the urine. Next, are transported out of the cell
into tubular lumen by luminal membrane transporters where when I say luminal, apical, facing the urine.
What is the entire objective of this discussion? How do I get a substance from the blood stop there?
Through interstitium, through my cell into the urine, into the urine secretion,
into the organic transporters. Now, the sites of drug action include the following.
Number one, mannitol, with mannitol works primarily on the PCT in which in its abundance
may then bring about diuresis. In general, the classification of drugs that we're dealing here
are your diuretics. When would you think about giving mannitol? Maybe if your patient had increased
intracranial pressure. A mannitol would try to help to decrease that pressure by removing
some of that fluid. Carbonic anhydrase inhibitor, when did we last talk about this? High altitude.
What kind of pH imbalance? Good, respiratory alkalosis because of hyperventilation in high altitude.
Acutely, a couple of days later, the kidney should kick in and get rid of that bicarb. What if it doesn’t?
Maybe perhaps you’d think about giving acetazolamide and carbonic anhydrase inhibitor.
Loop diuretic, number three. Where are you? Thick ascending limb, number one symport
for reabsorption, sodium potassium two chloride. Knock it out, you have massive diuresis
and you’re specifically focusing upon potassium. Thiazides are important. Now, thiazide
as being a drug inhibits your sodium chloride symport. What’s also interesting about thiazide
is that it is PTH receptor sensitive. In other words, it behaves like PTH. Think of it as such
where it’s responsible for, interesting feature, reabsorption of calcium. No other diuretic will do that.
No other diuretic will do that except for thiazide. It reabsorbs calcium, now, to the point
where it causes hypercalcemia? It depends. Usually not but understand that it has a mechanism
of reabsorbing calcium. No other diuretic will do that. Potassium-sparing diuretic,
now there are two classes here. The one that you’re focused should be, at this point, from pathology
is the fact that you are antagonizing the aldosterone. So, it’s an aldosterone antagonistic drug
in which if you antagonized the aldosterone, what are doing? You are now sparing your potassium.
It’s not being secreted. It will be held back in your plasma, hence, a potassium-sparing diuretic.
The second class, let it be triamterene or amiloride, those will work on the sodium channel.
Those are not aldosterone receptor antagonists. Now, the secretion in diuretics, important here.
This will go back to our topic of secretion and you needed organic transporters.
Those were a list of previously diuretics. Let’s put everything together. Most diuretics gain access
by how? Tubular lumen to act. Okay, so far, so good. Most are highly protein bound
and does not freely filter to the glomerulus. That must be understood. When you’re protein-bound,
remember, you’re not going to filter through. So therefore, transported into the tubular lumen
via organic ion transporters. The big one that I had mentioned already was the loop.
The way that it reaches what is its target? The sodium potassium two chloride. How does it get there?
Through your organic ion transporter. Now, what’s my clinical correlate? Now, if you have renal failure,
pay attention please. If there is renal failure, then guess what? Now, you’ll have competition.
Meaning to say that normally speaking, in a renal failure, you can’t get rid of the substances
that you need to, right, because your GFR drops. How can you then confirm this?
Because your plasma creatinine is then going to increase. Your creatinine clearance is going to decrease.
Listen to what I just said. That should make sense. Don’t just breathe through that little fact
that I put out there. Next, with renal failure, the organic ions are going to then accumulate
and they compete, compete with the diuretic. Remember, a lot of times, you want to use a diuretic
in a patient in renal failure to remove that fluid. But with renal failure, you might actually
have to increase the dosage, okay, increase the dosage of your loop diuretic so that you can outcompete
your organic substances that are then competing for that transporter. Large doses of diuretics
must be given to overcome the competition that is being provided by the renal failure substances.
Keep that in mind. Extremely important, once again dose adjustment.