Pharmacokinetics – Part 1: Topical and Systemic Drugs

By Adem Lewis / in , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , /

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.

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