So now let's talk about the renal excretion of drugs
As you remember the kidney is the most important organ for drug excretion.
If the kidney is not working for most drugs, we can assume that the excretion is impaired
and the levels of the drug or its metabolites can build up and cause problems
So, renal excretion is the sum of the drug that is filtered minus the drug that is reabsorbed
plus the drug that is secreted at the level of the nephron
This here is the nephron.
The nephron.
I'm going to write it out here is the functional unit of the kidney.
So let's relate renal physiology to pharmacology
So drug comes in at the afferent arteriole which splits into these glomerular capillaries which are enveloped in Bowman's capsule.
Now, at the bottom of these capillaries at the basement membrane,
there are these slit pores which allow drugs of a certain size to get through and to be filtered.
Drug that is not filtered will leave via the efferent arteriole
and this efferent arteriole branches into another capillary plexus called the peritubular capillaries
Now just as the name implies, peri- around the tubules.
These are surrounding the proximal and distal convoluted tubules of the nephron
and this allows another opportunity for that drug to be secreted if it wasn't filtered.
Also, drug that is filtered has an opportunity to be reabsorbed here
and so the drug that is reabsorbed or the drug that is not secreted can then leave via the renal vein.
So let's spend a moment here and talk about each one of these steps and relate it to pharmacology.
So the first step is filtration.
Now filtration doesn't really care if the drug is metabolized or unmetabolized.
We can filter both types of drug metabolized or unmetabolized.
However what filtration differentiates between is free vs. bound drug.
And really only free drug can be filtered.
So what do I mean when I say free?
Well, remember that some drugs can bind to plasma proteins specifically to albumin.
So drugs that are unbound to albumin can be filtered at the level of the glomerulus.
Albumin itself is too big to get through
and if you see albumin in the urine, that is a problem.
And frequently, we use albumin as a marker to determine the progression of kidney disease in diabetic patients.
Something called microalbuminuria.
So small amounts of albumin in the urine.
If those levels go up, we know this patient might be having kidney problems.
So after filtration we then get to reabsorption.
Now reabsorption is a good thing and a bad thing.
We want to reabsorb a lot of the stuff that is filtered at the glomerulus.
We want to reabsorb salts. We want to reabsorb sugar or glucose.
We want to reabsorb amino acids and a lot of that is happening at the proximal convoluted tubule.
but what we don't want to reabsorb is drugs.
Now, it's important to remember this.
The whole point of metabolism was to prevent reabsorption
and the reason here is that reabsorption, it prefers lipid soluble drugs.
Lipid soluble drugs.
And as we remember, most drugs need to be somewhat lipid soluble to get across the GI tract and be absorbed into our body.
So, once those drugs get to our liver, we have remember, phase I and phase II metabolism
What those do is that they change the drug and make it more polar
and by making it more polar, it prevents reabsorption.
Now that's the way that our body does it.
Fortunately, we can also manipulate the pH of the urine so to add a charge on to uncharged drugs.
So, we can change the pH and charge
and by changing the pH and charge, we can prevent the reabsorption of certain drugs.
This is a concept that we're going to cover in a future video and it's called ion trapping.
By making something charged in the urine, we can then prevent reabsorption.
It has nothing to do with filtration and everything to do with reabsorption.
Remember that and don't be confused by it.
And so, step three is secretion.
And for many drugs, this is the way that we get rid of it into our urine
and finally when we take the sum of all of these, we get our urinary excretion.
So now let's relate this back to clearance which was the topic of the last video.
So clearance itself, the definition of it. It is the volume of plasma that gets filtered of drug per unit time.
It is not telling us how much drug is getting filtered. It's just telling us how much volume of plasma is getting filtered per unit time.
To figure out how much drug is getting filtered, what I'm referring to is the rate of elimination.
And so this rate of elimination, this is an amount. This is the mass over time.
Mass is in the milligrams of drug and this was equal to as we previously discussed, the clearance x the concentration.
Now this is an important concept here.
Anytime we multiply a flow rate by a concentration, we get a mass over time or the amount of drug over time.
and the reason is that the flow rate or the volume over time multiplied by the concentration which you're screaming at me is equal to a mass over volume.
These volumes cancel out and I get a mass or the milligrams of drug that are eliminated per unit time.
Now clearance is specific for elimination whereas, the same concept of clearance is GFR.
GFR is a flow rate but it's a flow rate of drug that is being filtered. It's the glomerular filtration rate.
And we say that the glomerular filtration rate is approximately equal to the clearance of creatinine.
Now remember that creatinine is not creatine.
Creatine is something that is found in your muscles. Once it is broken down, it forms creatinine.
So just take out that in to spell creatine.
So it's imperative that you understand this relationship between the creatinine clearance and the GFR.
Now the glomerular filtration rate is really just a flow rate. It is a volume divided by time.
It does not tell us how much drug is entering or leaving the system.
To figure out how much drug enters or leaves the system over a certain period of time,
really again we're talking about something like the rate of elimination, a mass over time.
That has to do with the drug.
So GFR is just like clearance. It's a volume over time.
Whenever I want to figure out the amount of a drug entering or leaving a system over a certain period of time,
I need to take that flow rate, a volume over time and multiply it by a concentration which has the units of mass over volume.
Volume cancels out and again I'm left with mass over time.
So, let's relate that to this nephron.
So, here I'm just going to draw a little picture and we're just going to assume that this represents the kidney.
So here we have a certain rate of drug entering the kidney
And so that is going to be a volume over time, a certain volume of plasma and that there's a certain concentration of drug in that plasma.
We'll call that C1 and we're going to say that that equals the rate leaving the rate out the kidney or the urinary excretion
and there's a certain volume that we create urine over a certain period of time multiplied by the concentration of drug in the urine.
So this right here, we'll call this the urine excretion rate and there's a concentration of drug in the urine that is C2
and we're going to assume here that up here, we have this flow rate, the glomerular filtration rate
and there's a concentration here in the plasma (Px) which we'll call C1.
And we're going to assume that there is no reabsorption or secretion.
Now under these constraints, we have this picture here.
So we have the GFR multiplied by the plasma concentration of that drug and because there is nowhere else to go,
we assume that that equals the urine excretion rate multiplied by the urine concentration of the drug.
So if I was going to solve this for the glmerular filtration rate, I have this urine excretion rate multiplied by the concentration of this substance that is not reabsorbed or secreted
and I divide this by the plasma concentration of that substance (Px).
When I do that, I get the GFR.
So this little relationship right here, it's kind of like saying C2 over C1.
This has a term. It's called the extraction ratio.
It kind of gives us a sense of how well that organ can get rid of that drug.
And so we use this equation to estimate our glomerular filtration rate. eGFR.
So the substance that I'm referring to, that is freely filtered, it all goes through but is not reabsorbed or secreted is creatinine.
Now I have to kind of add a little note here and that some creatinine is secreted. And so, this kind of slightly overestimates the GFR
but Creatinine is the most convenient measurement that we have.
And so what I want you to notice here is that if the plasma concentration, if we measure the plasma concentration of creatinine,
and we say that it increases, we can then assume that the estimated glomerular filtration rate is decreasing
and that is super important because when you do a basic metabolic panel and you do a little blood test,
you look at their creatinine concentration. If above a certain point, we say hey, that person might have kidney problems.
Now, you know if you wanted to be very specific, you would have the patient collect their urine over 24 hours.
And so, they would have a certain volume of urine over time, giving them their urine excretion rate.
You measure the average concentration of creatinine in their urine, and you divide that by the plasma concentration of creatinine
but that's a little too cumbersome.
So frequently we just measure this plasma concentration of creatinine
and we have population wide studies that say for a person of a certain age with a certain weight,
these creatining concentrations - plasma concentrations are you know correlated to these glomerular filtration rates.
And so for any exam you might have, you might see them refer to this, you might see them use creatinine
but the gold standard and this is a substance that is not secreted or reabsorbed is inulin.
It is freely filtered and that gives us a little bit more precise measurement of GFR
but again, creatinine is the most convenient and is the most commonly used clinically.
So don't take my word for it, let's look at a paper and we'll show you how important this is.
So a couple of examples, there's two examples you should know where patients might have decreased rates of drug excretion.
One is chronic kidney disease and the other is old age.
So what is chronic kidney disease?
Well that is a patient who has kidney problems for more than 3 months.
And so, signs of kidney damage could be you know leaking albumin into the urine, large amounts of it.
It can be urine sediments that we find in there but the easiest way that you know we determine chronic kidney disease is by looking at the glomerular filtration rate.
And if the GFR is less than 60 ml/min, then we can assume that there is and that occurs for 3 months,
then we can assume that patient has chronic kidney disease.
And as we showed in the last slide, this is estimated from the creatinine concentration.
Increase in creatinine means decreased GFR.
You have to know that.
So, just looking at this paper, this is from the American Family Physician.
It is a pure review journal of the American Academy of Family Physicians.
And it says drug dosing adjustments in patients with chronic kidney disease.
So here, let's just read through the abstract.
Chronic kidney disease affects renal drug elimination and other pharmacokinetic processes involved in drug disposition.
Drug disposition is a term you should know. It's really just referring to the ADME of the pharmacokinetics.
Absorption, distribution, metabolism and elimination.
Drug dosing errors are common in patients with renal impairment and can cause adverse effects and poor outcomes.
Dosages of drugs cleared renally should be adjusted according to the creatinine clearance or glomerular filtration rate
and now you understand why
and they should be calculated using online or electronic calculators.
As I was saying, we have those population wide studies. That's how we calculate it.
Recommended methods for maintenance dosing adjustments are dose reductions and lengthening of the dosing interval.
So if we are not eliminating the drug, then we need to decrease the dosage because the concentration of that drug can go up
or the concentration of its metabolites should go up.
Physicians, and here they're referring to family physicians but really, all physicians should be familiar
with commonly used medications that require dosage adjustments.
Resources are available to assist in dosing decisions for patients with chronic kidney disease.
So now you see why this is important.
And like I said one group of patients should be familiar with are patients with chronic kidney disease.
The other is older patients because as you get older, your GFR also decreases and thus, your clearance.
And so, when you're in hospital, you might dose a drug for a patient and get a call back from the pharmacy saying
"Hey, we need to adjust this drug dosage for this patient because they have a low GFR or they have chronic kidney disease."
And so, what we're gonna do in the next video is actually talk about ion trapping which was what can block the reabsorption of drugs.
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