Pharmacokinetics: Drug elimination and clearance

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Introduction0:00–0:40

Pharmacokinetics refers to the movement and modification of medication inside the body or more simply, it's what the body does to this medication and how it does it.
All right. So once the medication is administered, it first has to be absorbed into the circulation, then distributed to various tissues throughout the body metabolized or broken down and finally eliminated or excreted in the urine or feces.
You can remember this as a DM E absorption distribution, metabolism and excretion. Ok.

Elimination0:40–1:19

Now, let's focus on a process called elimination, which is often confused with the process of excretion. Elimination is the removal of a medication from the body.
Now, this can be accomplished through metabolism where the medication is broken down into inactive metabolites or through excretion, which is when the intact medication is transported out of the body.
This can happen through a number of ways, but the most common route is through urination. So, the major function of the kidneys is to clear metabolic waste material and foreign substances like medications from the body by filtering the blood.
Now zooming in on a nephrons, tubule, each one is lined by cells that have two surfaces. One is the apical surface which faces the tubular lumen.

Urine1:19–5:09

And the other is the basolateral surface which faces the peritubular capillaries which run alongside the nephron. All right.
So first, certain medications in the circulation can be filtered out with the other metabolic wastes when the blood goes through the glomerulus.
Second, as the filtrate makes its way through the proximal convoluted tubule. Certain medications from the peritubular capillaries get secreted into the tubular lumen for polar water soluble medications.
This is mainly done actively through active secretion, meaning that it requires specific carrier proteins on the basolateral membrane of the tubular cells which use ATP for energy, nonpolar lipid soluble drugs.
On the other hand, are secreted into the proximal tubule via passive diffusion, meaning without requiring any energy, that's because they can pass through the cell membranes easily.
So they just move down their concentration gradient from the peritubular blood into the tubular lumen. Now, as the filtrate travels toward the distal convoluted tubule, the level of medication builds up inside the lumen.
So its concentration rises higher than the peritubular capillaries. Now, if the medication is nonpolar and lipid soluble, it may passively diffuse out of the tubular lumen and back into the peritubular circulation.
On the flip side, polar and water soluble medications can't cross the membranes of tubular cells. So they get trapped inside the tubular fluid and are eliminated from the body with the urine.
Next, the acidity of the urine will also affect excretion. Most medications are either weak acids or weak bases.
And they can exist in both an uncharged, nonpolar lipid soluble form as well as a charged polar water soluble form. The ratio between the two forms is determined by the PH of the urine and by the strength of the weak acid or base, which is mainly shown by the ionization constant PK A.
The PK A is the PH at which concentrations of the uncharged and charged forms equal each other. So let's say we place a weak acid H A in alkaline urine with a higher PH than the PK A.
Since there are less hydrogen ions around, it's going to give up its own hydrogen ion and turn into its charged form a minus.
Since it's now polar, it can't pass back through the tubular cells membrane. On the flip side, let's put a weak base B into acidic urine with a PH lower than its PK A with plenty of hydrogen ions around.
It's gonna grab one of them and turn into its charged form BH plus which once again cannot be reabsorbed across the tubular cells membrane.
In other words, weak acidic medications are trapped in alkaline urine. In contrast to weak basic medications which get trapped in acidic urine.
The practical point in this is that an individual presenting with an overdose of a weak acid like aspirin can be given a base like sodium bicarbonate which makes the urine alkaline and helps get rid of aspirin.
Likewise overdose of a weak base like amphetamines can be treated by Acidifying the urine with ammonium chloride. Ok.

Bile and feces5:09–5:49

Now, aside from the kidneys, excretion of medications can also take place through the bile and feces. So, orally administered drugs that don't get absorbed from the gastrointestinal tract are directly passed in feces.
Some drugs that are absorbed in the gastrointestinal tract enter the enterohepatic circulation to get to the liver. Here, they bind to bile, which is excreted back into the intestine and then leaves the body through the feces.
Also, many inhaled anesthetics get eliminated by the lungs through the exhaled air. Aside from these main roots of excretion, small amounts of certain medications can leave the body in breast milk, sweat, saliva and tears.

Other routes5:49–6:01

Clearance6:01–6:45

Ok. Now that we understand excretion, let's look at clearance.
The term clearance of a medication abbreviated as CL refers to the volume of plasma cleared of a medication per unit of time.
Total body clearance or CL total for short is actually a sum of the various clearance roots. So total clearance equals renal clearance, plus hepatic clearance, plus lung clearance plus other clearance.
And it can be calculated by dividing the rate of elimination or how quickly a medication is eliminated by concentration of that medication in the plasma.
And it's usually measured in milliliters per minute or liters per hour. All right, the rate of elimination is determined by the elimination kinetics.

First-order kinetics6:45–8:29

Most medications are eliminated through first order kinetics. What this means is that the rate of elimination is directly proportional to the concentration of that medication in the body.
In other words, the absolute amount or milligrams eliminated per unit of time may change, but the fraction eliminated always remains the same.
So for example, let's say we started with a plasma concentration of 100 mg per liter of drug a and eliminated 50% of it each hour.
Hm Why don't we plot this onto a nice graph with the plasma's concentration of the medication on the Y axis in milligrams and the time in hours on the X axis.
So after the first hour, we'll go from 100 mgs per liter to 50 mgs per liter. So we'll have eliminated 50 mgs per liter.
Then the second hour will eliminate 50% of what's left. So we'll go from 50 mgs per liter to 25 mgs per liter.
And then the third hour, we'll go from 25 to 12.5 mgs per liter. And the fourth hour from 12.5 to 6.25 mgs per liter and so on.
And the curve that's formed shows that there's an exponential decrease in the plasma concentration of that medication. Another cool thing about this graph is that it helps determine the half life of the medication.
This is the time required for the plasma concentration of the medication to be reduced by half. So in this case, it takes one hour for the concentration of the medication to drop from 100 to 50 mgs per deciliter.
Another hour for 50 to become 25 mgs per deciliter. And another hour for 25 to go down to 12.5 mgs per deciliter.

Zero-order kinetics8:29–9:40

This means the half life is one hour and it stays constant as the concentration of the medication decreases. This gives us a reference point when we need to compare the clearance of different medications.
Now, there are a few medications which get eliminated through zero order kinetics like phenytoin warfarin and Aspirin. This means that the rate of elimination is constant independently of the concentration of that medication in the body.
In other words, the absolute amount or milligrams eliminated per unit of time stays the same but the fraction eliminated changes.
So let's say we started with a plasma concentration of 100 mg per liter of drug B and we always eliminate 25 mg per liter each hour.
Why don't we bring back that graph we had before with the plasma's concentration of the medication still on the Y axis and the time still on the X axis during the first hour, we'll go from 100 to 75 mg per liter.
Then after the second hour, we'll go from 75 to 50 then from 50 to 25 and then down to zero. So what we get is a straight line and at first it takes two hours for the concentration of that medication to drop from 100 to 50 mg per liter.

Review9:40–11:14

So its half life is two hours, but it then takes one hour for the concentration to drop from 50 to 25 mg per deciliter and half an hour for 25 to become 12.5 mg per deciliter.
In other words, as the concentration decreases, so does the half life of the medication? All right, is a quick recap.
Elimination refers to the removal of a medication from the body, either through metabolism or excretion. Excretion is done primarily by the kidneys through glomerular filtration, active secretion and passive diffusion and is determined by the chemical properties of the medication and the ph of the urine.
Other routes of excretion include mainly the bile feces and lungs. Clearance of a medication refers to the volume of plasma, cleared of a medication per unit of time.
Elimination kinetics determines the rate of elimination. And it includes the most common type.
First order kinetics where the amount of medication eliminated per unit of time changes, but the fraction stays the same and zero order kinetics where the amount eliminated per unit of time stays the same but the fraction changes.