Pharmacodynamics – Part 2: Dose-response Relationship

Pharmacodynamics – Part 2: Dose-response Relationship

Pharmacodynamics – Part 2: Dose-response Relationship

By Bryan Wright 0 Comment October 12, 2019


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.

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