Pharmacodynamics: What is the relationship between dose and response?
For a drug to generate an evident physiological response, its concentration at the site of
action needs to be sufficiently high.
However, since direct measurements aren't possible in many tissues, drug concentrations
are monitored in plasma.
The dose of a drug is measured in milligrams or millimoles and is sometimes based on body
weight.
If the dose is plotted on the X-axis of a diagram and the drug’s response on the y-axis,
a dose-response curve is obtained.
Such curves are usually S-shaped.
This indicates two things: that a minimum concentration of a drug is required to achieve
a significant response and that there is a maximum response, which can’t be enhanced
by further increasing the drug’s dose.
To compare different drugs with one another, there are some important pharmacological parameters
that you should know: The efficacy is the maximum effect a drug
is capable of producing based on its therapeutic goal.
The efficacy can be quantified by the effective dose, in short, ED.
It’s the minimal drug amount required to achieve the maximum effect.
Alternatively, the ED50 value can be used, that is, the dose required to produce 50%
of the maximum possible response.
The ED50 value indicates the potency of a drug.
The potency not only depends on the efficacy of a drug but also on its binding affinity
at the target site.
As we saw in part one of our episode on Pharmacodynamics, a drug can only unfold its potential effect
if it’s able to bind to the appropriate sites.
If a drug is highly potent, then a low dose is sufficient to generate a massive response.
If a drug is of low potency, a corresponding higher dose is required.
Having said that, a highly potent drug doesn't automatically cause more side effects than
a drug with low potency.
To understand this, let’s take a look at the toxicological effects of substances:
You’ve probably heard of the saying “The dose makes the poison”.
What it means is that each drug can also exhibit toxic effects if administered in larger amounts.
This effect can be displayed graphically, producing an S-shaped saturation curve as
well, termed the dose-toxicity curve.
Analogous to the effective dose, the lethal dose, in short LD, can be determined from
the curve.
The lethal dose is the amount of drug that is lethal in 100% of the exposed population
as determined through animal experiments.
The LD50 value is the dose that is lethal in 50% of the exposed population.
The ratio of LD50 to ED50 is termed the therapeutic index and differs for each drug.
It’s an important measure of the safety of a drug: The higher the therapeutic index,
the safer the drug, as the risk of a toxic or lethal overdose decrease.
As previously mentioned, depending on the bioavailability, this minimal amount can be
comparably high for a drug to exert its effect.
This implies that the effect of a drug is already reduced before it’s completely eliminated
from the body.
Through renewed drug intake, the drug can accumulate in the body.
In this way, several small individual doses can lead to a cumulative effect in the body
and reach a lethal dose.
This always needs to be considered when determining the dose of drugs, which has a narrow therapeutic
index or a long elimination time.
Let’s go back to the efficacy and look at the various agonists and antagonists that
we introduced in our previous pharmacodynamics episode.
If a competitive antagonist is administered, the drug blocks the target receptor from the
endogenous signaling molecule.
As a result, the dose-response curve for the signaling molecule shifts into the range of
higher concentrations.
So, with an antagonist present, the concentration of the signaling molecule must be significantly
higher to match its sole effect.
This is due to the equilibrium formed by bound and unbound drug and the signaling molecules.
Increasing the concentration of the signaling molecule shifts this equilibrium, ultimately
displacing the competitive antagonist from the receptor.
In contrast, if a non-competitive antagonist is administered to the patient, then the maximum
efficacy of the signaling molecule decreases.
In such cases, antagonist binding doesn’t block the receptor but diminishes the interaction
between the signaling molecule and the receptor.
This results in a therapeutically relevant consequence: The effect of a competitive antagonist
can be completely reversed if the signaling molecule concentration is increased or an
appropriate agonist is administered at a sufficiently high concentration.
This isn’t possible with non-competitive antagonists because they don’t compete directly
with the signaling molecules and, therefore, don’t form an equilibrium.
If a partial agonist is administered to the patient, the maximum efficacy decreases, while
the potency of the signaling molecule increases simultaneously.
The first effect is due to the weaker signal produced by the partial agonist, which displaces
the signaling molecule.
The second effect is the result of the weaker yet additional effect the partial agonist
exhibits, reducing the minimally required concentration of signaling molecules required
to produce a significant response.
Though it can remain difficult to distinguish between different mechanisms of drug action,
you should now be well equipped with the necessary basics on pharmacodynamics and pharmacokinetics
to help you better understand the effect of a drug.
If you’d like to test your knowledge on the dose-response relationship, then don’t
miss our quiz on the next slide.