Hey guys, Jessica here, and welcome to Critic, the tox series.
In this video you’ll learn some practical differences between pharmacokinetic and toxicokinetic principles,
specifically when patients take an overdose of prescription drugs.
For this video, I’m going to assume that you have basic understanding
of the pharmacokinetic principles (i.e. ADME).
If you don’t, watch my introductory series on pharmacokinetics first.
It’s only 6 videos of about 5 minutes each.
Ok, let’s break this down.
When patients take an overdose of a prescription drug, the normal pharmacokinetic properties
don’t apply anymore.
This is because these were derived from therapeutic doses, not from toxic doses.
As you know, a certain drug dose corresponds with a certain plasma level, i.e. drug concentration.
How you get there is the kinetic part.
Now let me throw in some pharmacodynamics here: the drug concentration at which a drug
exerts 50% of its desired therapeutic effect, is called the ED50.
The concentration at which the drug exerts 50% of its toxic effects is called the TD50.
If the ED50 and TD50 are close to one another, it doesn’t take much for a patient to OD on this drug.
Examples of drugs with small therapeutic indexes like this are lithium, paracetamol and digoxin.
When dealing with poisoned patients, it’s important that you know these drugs.
When dealing with toxicokinetics of prescription drugs, I need you to remember two words:
saturable kinetics.
This is more commonly known as nonlinear kinetics or zero-order kinetics, but that confuses me,
so let’s go with saturable.
This means that the rate of elimination is constant and does not depend on the drug concentration.
Whereas in “normal” pharmacokinetics (i.e. first-order kinetics, i.e. linear kinetics)
the fraction of the drug eliminated is constant, but the amount changes with drug concentration,
as explained in my video on clearance and half-life.
And yes, there are drugs with zero-order kinetics at therapeutic doses, but that’s not for
this video.
Now what happens when a patient takes an overdose of a prescription drug.
Well first it needs to be absorbed through the gastro-intestinal tract.
You can imagine that if there are physically a lot of tablets in your stomach and small intestine,
solubility will be decreased and it will take a lot longer for the entire amount
to be absorbed.
This is furthermore enhanced by the fact that the transporters responsible for absorption
would be saturated.
So time to full absorption, or Tmax, is increased.
Same goes for some of the metabolic enzymes that cause the first pass effect,
meaning that bioavailability could be higher than expected.
Changes in distribution also occur.
Protein binding can be saturated as well, leading to higher free drug concentrations.
Higher free drug concentrations equal higher toxicity.
As you’ve learned, metabolism (i.e. hepatic clearance) has two phases.
Phase II, the conjugation phase, can be saturated as well.
This has as effect that it takes longer to metabolize all of the drug, and thus
half-life is increased.
Excretion through the kidney (or bile for that matter) is governed by several transporters,
that also can be saturated.
Renal clearance is therefore slower, and thus, half-life is increased.
All these changes lead to higher total exposure of drug, due to not only a higher ingested dose,
but also due to saturable kinetics, resulting in an increase in Tmax and half-life.
General treatment of the poisoned patient is designed to counter this.
Watch my introductory video for more information.
That’s all I wanted to share on kinetic changes that occur when patients overdose
on prescription drugs, or toxicokinetics.
Let me know what you think!