Pharmacokinetics: Topical and systemic drugs
Have you heard of the saying: “Pharmacokinetics is what the body does to a drug; pharmacodynamics
is what a drug does to the body”?
This interplay between the body and drug is what we’d like to depict in this Chalk Talk
series.
First, we’ll start with two episodes on pharmacokinetics, looking at what the body
does to a drug when it's absorbed, distributed, metabolized, and excreted.
Five phases can be differentiated in this process.
These are commonly referred to as LADME.
L stands for liberation, the process by which a drug is released from its dosage form.
A represents the absorption of a drug into the body.
D indicates the distribution of a drug through the bloodstream or the lymph system in various
tissues.
M stands for metabolism or biotransformation of the drug.
Finally, E represents excretion, the removal of the substance from the body.
Let’s take a detailed look at these different pharmacokinetic phases.
Liberation differentiates between two administration forms.
These are drugs that can unfold their effect directly after application such as inhaled
or intravenously injected substances.
The second form includes drugs that need to be initially released from their dosage form
through physical or chemical processes in order to be absorbed by the body.
Examples of such dosage forms are ointments, tablets, or pain patches.
As a result, such dosage forms have a delayed effect.
The most important routes of administration are intravenous, intramuscular, subcutaneous,
inhaled, peroral, local, and rectal.
However, from the dosage form alone, it’s impossible to determine whether the drug has
a topical or systemic effect.
Topically administered drugs mainly act locally; in other words, they’re applied at the site
of action.
Some examples that come to mind include glucocorticoid ointments for eczema or orally administered
charcoal tablets for diarrhea.
Systemic drugs, in contrast, are transported to their site of action.
One example are painkillers, which are transported to the central nervous system regardless of
whether they’re administered intravenously, peroral, or as a patch.
Which dosage form is most suitable for a patient depends especially on the desired drug concentration
at the site of action, as the drug’s concentration strongly depends on its absorption and distribution.
Let’s take a more detailed look at this relationship.
The most important aspects of drug absorption are the rate at which the drug is taken up
and the concentration subsequently reached at the site of action.
As topical drugs are released directly at the site of action, their concentration is
high immediately afterward.
In contrast, systemic drugs are distributed throughout the body to be transported to their
site of action.
Therefore, the drug’s concentration at this site depends directly on its concentration
in the circulation.
To monitor this effect, the plasma level of systemic drugs is usually measured and presented
in a diagram.
If a systemic drug is administered intravenously, its maximum concentration is reached once
it’s injected into the bloodstream.
The drug’s plasma concentration then drops continuously because the drug gradually leaves
the circulation.
The decrease can be linked to several processes: distribution of the drug into the tissue as
well as it’s storage, metabolism, and excretion from the body.
If a systemic drug is administered through another dosage form, its plasma concentration
is initially zero and starts to increase once it’s absorbed into the bloodstream.
This is referred to as the absorption rate.
The interaction between the absorption rate and the elimination rate results in a characteristic
time course of the plasma concentration of the drug.
In this diagram, the absorption rate is initially much higher than the elimination rate resulting
in a steep increase and high maximum of the curve.
In comparison, if the ratio between absorption and elimination is shifted towards elimination,
there’s a comparatively lower maximum plasma drug concentration.
Also, the curve rises less steeply initially but flattens quickly towards the end.
Now, let's move on to the relationship between the absorption and elimination rates for the
different routes of administration: The rate of absorption is at its maximum through
intravenous administration.
However, with intramuscular administration, for example, the plasma drug concentration
is zero upon drug release and increases depending on its uptake into the bloodstream.
Intramuscular administration usually leads to rapid absorption into the bloodstream.
The transport route of a drug via subcutaneous administration is somewhat longer and the
absorption rate is, therefore, lower.
Orally administered drugs are absorbed even more slowly.
This effect on the absorption rate can be used clinically to delay the drug’s effect
or keep it constant over a longer period of time.
This is referred to as delayed release or sustained release.
Yet the different phases not only affect the maximum plasma drug concentration but are
also one of the factors influencing drug retention time in the body.
This is best described by the biological half-life.
It indicates the length of time required until the plasma drug concentration reaches half
of its maximum.
The half-life is of therapeutic importance: the shorter the half-life, the faster the
decline in the plasma drug concentration.
After four half-lives, approximately 90% of the drug is eliminated.
The relationship between concentration and the effect of a drug will be discussed in
our Chalk Talk episode on pharmacodynamics.
But for starters: the half-life and the duration of the effect don’t necessarily correlate
with one another!
Let’s finish this first look at pharmacokinetics with a summary: The first part of the plasma
concentration-time curve that is, from administration to its maximum, predominantly depicts the
absorption phase.
Therefore, it represents the bioavailability of the drug.
The second part of the curve is dominated by elimination processes.
These will be the focus of part 2 of our Chalk Talk episode on pharmacokinetics.