Every medication can be administered through various means, known as routes of administration;
and various schedules, meaning at a particular frequency and amount, or dose, which is known
as the dosing regimen.
Alright, so routes of administration are broken down into three main categories: enteral,
parenteral, and topical.
In enteral administration, which is the most common form, the medication is administered
through the gastrointestinal tract.
This could mean that it’s swallowed by the mouth, also known as peroral administration;
placed under the tongue, also known as sublingual administration; between the gums and the inner
lining of the cheek, also known as buccal administration; or finally, into the rectum,
also known as rectal administration.
On the other hand, parenteral administration includes any route that bypasses the gastrointestinal
tract, to pump the medication directly into the circulation, such as through an injection
into a vein, intravenously, or IV for short; under the skin, subcutaneously, or SC for
short; or into muscle, intramuscularly, or IM for short.
Finally, there’s topical administration, where the medication is applied directly upon
a particular area of the skin or mucous membrane to achieve a local or systemic effect.
An example of this is an antifungal cream used to treat athlete's foot locally or a
clonidine patch to treat hypertension systemically.
Now, choosing the route of administration depends on many factors.
First of all, these include the chemical properties of the medication itself, such as its stability,
and its ability to cross certain barriers of absorption.
For example, a perorally administered medication needs to be able to resist tough, acidic conditions
within the stomach, and then readily pass through the walls of the intestines into the
blood.
In addition to this, blood coming from the gastrointestinal tract is first directed to
the liver.
And that’s where many medications get broken down or metabolized before gaining their entry
ticket to the systemic circulation.
This means the medications are metabolized before they even get a chance to reach their
target tissues.
This is known as first-pass metabolism or the first-pass effect.
So, medications that get extensively metabolized into inactive forms through that first-pass
shouldn’t be administered perorally as it would decrease their efficacy.
In contrast, IV administration allows medications that are less stable, or less capable of being
absorbed through the gastrointestinal tract, to be directly administered into the bloodstream,
which is also beneficial for medications that have a major first-pass effect.
A practical measure of absorption is bioavailability.
Bioavailability refers to the portion of a medication that reaches the systemic circulation
when administered by non-intravenous routes.
For example, if someone takes 100 mg of aspirin orally, and only 60 mg are absorbed into the
circulation, the bioavailability is 0.6 or 60%.
In contrast, the bioavailability of an intravenously administered medication is always 1 or 100%.
Another factor that should be taken into account for deciding the route of administration is
the urgency of the situation.
So for example, peroral medications take time to get absorbed in the GI tract, so they produce
an effect much slower than intravenous ones.
And for this reason, intravenous administration is usually preferred in emergency settings
and during surgical procedures.
On the flip side, oral preparations are much easier to take at home and don’t need any
special equipment.
Alright, now each medication is given at a specific schedule or dosing regimen, which
determines the frequency of administration, or dosing interval, and the amount administered,
known as dose.
The regimen is important since it affects the onset of action, or the time it takes
for a medication to start working and produce an effect, as well as the duration of action,
which is the total length of time during which a medication produces an effect.
So, there are three main types of dosing regimens.
First, there’s single dosing, meaning that only one dose of a medication is administered.
Let’s plot this into a nice graph with the drug concentration in plasma on the y-axis,
and the time on the x-axis.
So, with single dosing, the plasma concentration of the medication rises steadily as it gets
absorbed into the circulation, until it reaches a peak.
Then the concentration drops again, as the medication is distributed into tissues, gets
metabolized, and is eliminated.
Next, there’s a regimen of continuous infusion.
This is when a medication is infused intravenously at a constant rate.
In this case, the plasma concentration progressively rises and reaches a peak, but, instead of
falling off, it continues at a plateau, also known as a steady state.
The reason why this happens is that as the concentration of the medication increases,
so does the rate of elimination, until eventually the dosing and the elimination rate are equal.
Now, the time required to reach that state is determined by the half-life of the medication,
which is the time needed for the plasma concentration of a medication to be reduced by half or 50%.
So, it usually takes 4 to 5 half-lives to reach steady state.
On the other hand, the concentration of the medication at the steady state depends on
the infusion rate.
So, when the infusion rate is increased or decreased, the plasma concentration will rise
or fall until it reaches a new steady state.
Now, the dose required to maintain the steady state is known as the maintenance dose.
Since at this state the dosing rate must be equal to the rate of elimination, the maintenance
dosing rate can be calculated by multiplying the target plasma concentration, which is
measured in mg/L, by the clearance rate, which refers to the volume of plasma cleared of
that medication per unit of time, and is measured in L/h.
Finally, there’s an intermittent dosing regimen.
This means that a certain dose of a medication is administered at regular time intervals,
through a given route.
If the next dose of a medication is administered before the previous dose has been completely
eliminated, the plasma concentration will once again progressively rise.
In this case, though, it will fluctuate between peaks and troughs, because the rate of elimination
will increase along as well, until it matches the rate of administration.
Just like in continuous infusion, the steady state is usually reached after 4 or 5 half-lives,
and the concentration of the medication at the steady state depends on the dosing interval.
Generally speaking, for most medications, the dosing interval is approximately one half-life.
With intermittent dosing, the maintenance dose is calculated by multiplying the dosing
rate (mg/h) by the dosing interval.
It’s important to note that for medications that are not administered intravenously, the
dosing rate needs to be divided by the bioavailability to account for the portion of medication that
isn’t absorbed into the circulation.
Now, in some cases, like in life-threatening situations or with medications that have long
half-lives, the steady state can be reached more quickly by administering an initial loading
dose.
A loading dose is a large dose given at the beginning of a treatment course to rapidly
reach the peak plasma concentration.
The loading dose is largely determined by the volume of distribution, or Vd, of a medication,
which is used to represent how extensively a medication is distributed throughout the
body.
Therefore, medications with a small volume of distribution will remain mainly in the
plasma; whereas medications with a large volume of distribution will be distributed more extensively
throughout the body.
And this means larger doses will be needed to achieve the desired plasma concentration.
Taking this into account, the loading dose can be calculated by multiplying the target
plasma concentration in the steady state by the volume of distribution of that medication.
And for non-IV medications, this needs to be divided by the bioavailability.
So, in short, maintenance dose and loading dose calculations are mainly dependent on
the clearance rate, bioavailability, and volume of distribution.
Individuals who have decreased clearance, such as those with liver or renal disease,
may require a lower maintenance dose, and possibly, an extended dosing interval or less
frequent dosing to achieve target plasma concentrations.
However, the initial loading dose typically remains the same, since the volume of distribution
is not affected.
All right, as a quick recap, routes of administration include enteral routes: like oral, sublingual,
buccal, and rectal administration.
Parenteral routes: like intramuscular, subcutaneous, and intravenous administration.
And topical or local administration.
The choice between them mainly depends on the properties of the medication and the setting
in which it’s used.
Dosing regimens determine the frequency and dosage of a medication; which include single-dosing,
continuous infusion, and intermittent dosing regimens.
Maintenance and loading dose calculations depend on the bioavailability, clearance,
and volume of distribution of a given medication.