Professor Dave again, let’s check out some
mechanisms.
We just learned about pharmacokinetics, which
helped us understand how a drug moves through
the body.
Through absorption and then distribution,
a drug will travel through the bloodstream
and eventually arrive at its target cells,
where it can elicit its intended effect, prior
to being metabolized and excreted.
But what is this intended effect?
Once a drug reaches its target, what exactly does it do, and how does this produce a cellular response?
The study of this process is called pharmacodynamics.
So essentially, pharmacokinetics is the study
of how our bodies affect a drug, while pharmacodynamics
is the study of how a drug affects our bodies.
Pharmacodynamics is quite complex, dealing
with many advanced concepts in biochemistry,
but we will do our best to go through the
basics here, so that we will be ready to look
at specific drugs and their mechanisms of action.
Far and away, the vast majority of drugs elicit
a physiological response because of the way
that they interact with a particular protein.
Most often this will be a receptor protein,
which may be embedded in the cell membrane,
or it may be found inside the cell, whether
in the cytoplasm or the nucleus.
As we recall from the biochemistry series,
any receptor will have a ligand, which is
a molecule that fits into the active site
of the receptor, and in essence turns the
receptor on, evoking a conformational change
that then propagates the signal in one of
several ways.
When drugs interact with receptors, there
are two main ways that this could go.
A drug could be an agonist for a particular
receptor, meaning that it fits into the active
site and mimics the native ligand, eliciting
the typical physiological response.
We can call these facilitators.
Or, a drug could be an antagonist for this
receptor, meaning that it binds to the active
site, but does not activate the receptor,
thereby locking it in an inactive state.
We can call these inhibitors, or sometimes
blockers.
Whichever the case may be, we can represent
binding with this very simple equilibrium,
which depicts some ligand, L, referring to
the drug, and R, referring to the receptor,
in equilibrium with LR, which is the receptor-ligand
complex, with the ligand bound to the active site.
With that understood, we must now define two
terms, potency and efficacy.
Potency refers to the strength of a drug at
a particular concentration or dosage, or the
amount of a drug that is required to produce
a particular effect.
And to get more technical, it refers to the
concentration or dosage required to produce
50% of the maximal effect that drug can achieve.
This can be examined on something called a
dose-response curve.
As we can see, drugs of different potencies
will require different doses, or different
amounts of the drug being administered, to
elicit the drug response it is capable of
achieving.
So if a drug is extremely potent, only a very
small amount of it will need to be administered
in order to achieve its maximum effect.
By contrast, efficacy deals with the maximum
effect that can be achieved by a drug, such
that after this is reached, no higher dose
will produce any further effect.
Two different drugs may have similar potencies,
meaning that the response increases over the
same increase in dosage, but one will achieve
a more significant response than the other,
or a more significant effect, due to its higher efficacy.
And similarly, two drugs can have the same
efficacy, but differ in their potency, since
one requires a smaller dosage to achieve its
maximum effect than the other.
So we can clearly see that potency correlates
with the X-axis, while efficacy correlates
with the Y-axis.
So what is it that determines the efficacy of a drug?
To understand this we have to look at how
the drug interacts with its target.
If the purpose of the drug is to bind to the
active site of a receptor or enzyme, how well
does it bind?
What is its binding affinity?
If describing binding using this equilibrium
from before, how heavily is the forward reaction
favored, the one that produces the LR complex?
Well in order to answer this question, we
have to ask a few more.
How well does the drug fit into the active site?
How many electrostatic interactions are being
made, and of what variety?
Are there hydrogen bonds?
Perhaps even covalent interactions?
If the drug is acting as an inhibitor, then
a high binding affinity will be crucial in
order to have reasonable efficacy, because
if the binding affinity is low, then when
the native ligand comes along, which is the
molecule that is supposed to go in the active
site, it will most likely have a higher binding
affinity than the drug, and will displace
it, thus no inhibition can be achieved.
Sometimes inhibitors will bind irreversibly,
meaning that once they’re in, they’re
stuck there, which is often the case if covalent
bonds are formed between the drug and the
protein, although covalent bonds are not necessarily
required for binding to be irreversible.
On the other hand, if the drug is acting as
an agonist, again binding affinity will be
relevant, and it will also have to have the
right functional groups necessary to promote
the same conformational change in the protein
as the native ligand, so that the protein
will produce the same cellular response.
Now that we understand affinity, we can conceptualize
potency and efficacy in a slightly different
way, using receptors as an example.
Potency is the affinity of a drug for a particular
receptor.
If the affinity is very high, most of the
drug will be bound at any given time, and
thus very little of the drug will be needed
to occupy all the receptors.
Efficacy describes the effect the drug has
on the receptor once it is bound, or the degree
of its ability to act as an agonist or antagonist.
So potency is related to affinity, wherease
efficacy is related to the clinical effect
of the drug.
So now that we know a little bit about pharmacokinetics
and pharmacodynamics, we are ready to start
looking at specific examples of drugs.
With each drug, or each class of drugs, we
will try to be as specific as possible regarding
the target of the drug, its effect, and its
precise mechanism of action in producing the
effect, so the concepts that we’ve gone
over so far will be reinforced quite a few
times moving forward.
If you need a little more clarity, watch these
first few tutorials again, otherwise, let’s
move forward and tackle as many drugs as we can.
