in this lesson we'll cover the concept of pharmacodynamics so while
pharmacokinetics describes the actions of body on the drug pharmacodynamics
describes the opposite in other words in the study of pharmacodynamics we look at
what a drug does to a body so when a drug enters your body it then starts
interacting with cell receptors which in turn leads to a formation of signal and
this signal through series of different reactions ultimately results in some
biological effect so for example the signal can tell DNA to stop replicating
cells in our body have lots and lots of different receptors which when stimulated
can produce very unique responses the receptors that have the most therapeutic
relevance can be divided into four types number one ligand-gated ion channels
number two G protein-coupled receptors number three enzyme-linked receptors and
number four intracellular receptors so now let's talk about them in more
details let's start with ligand-gated ion channel which is probably the
easiest one to describe out of the four and just a quick reminder ligand
generally refers to some molecule or an ion so this channel has a ligand
binding site and when the ligand binds to it the channel opens very briefly
which allows ions such as sodium potassium chloride calcium etc to pass
through the membrane and that's all it is to it next we have G protein-coupled
receptor also known as seven-transmembrane receptor and this is
because it passes through the cell membrane seven times so these receptors
are composed of three subunits alpha beta and gamma all together known as
G protein in its inactive form the alpha subunit has
GDP attached to it however when ligand binds to the receptor the affinity for
GTP increases so then GTP replaces GDP this in turn causes the alpha subunit to
dissociate from beta-gamma complex and then both of these complexes go to
interact with other enzymes or proteins which they can alter and regulate
ultimately leading to some kind of response now there are three kinds of
G proteins that are important to remember these are Gs Gi and Gq first Gs is a
stimulative g-protein that activates enzyme called adenylyl cyclase which
produces cyclic AMP from ATP cyclic AMP is a very important second
messenger the second kind the Gi is an inhibitory G protein which inhibits
adenylyl cyclase thus lowers levels of cAMP in the cell
the last one is Gq which activates class of enzymes called phospholipases C
we will refer to them as PLC now PLC produces two second messengers first
diacylglycerol which we will refer to as DAG and the second one inositol
triphosphate which will refer to as IP3 now DAG just like cAMP leads to
different responses through activation of protein kinases however IP3
produces various responses by mediating intracellular release of calcium it's
also important to remember that G protein-coupled receptors as well as most
enzyme-linked receptors have ability to amplify signals that they receive so for
example just one stimulated G protein receptor can activate many adenylyl
cyclases which will result in more cyclic AMP molecules produced and ultimately
amplified response now let's move on to enzyme-linked receptors
these receptors just like G protein receptors have extracellular binding
site where ligand typically hormone or growth factor can attach and thus
stimulate enzymatic activity inside the cell
most enzyme-linked receptors are of tyrosine kinase type which simply means that they
display kinase activity and that there is a amino acid tyrosine involved in
that so the way it works is that when ligand binds to two of these receptors
it causes conformational change that results in aggregation of both
receptors once the dimer is formed the tyrosine regions get activated and cause
ATP to become ADP which results in auto phosphorylation of the receptors now
once each tyrosine picks up phosphate group different inactive intracellular
proteins come up and attach themselves to phosphorylated tyrosine this in turn
causes conformational change in the attached protein ultimately leading to
cascade of activations that produces cellular response next and the last type
of receptor that I want to talk about is intracellular receptor unlike the other
three this receptor is located entirely inside the cell rather than on cells
membrane therefore the ligand has to first cross lipid membrane and then once
it's inside it can then bind to the receptor now the activated ligand
receptor complex can move into the nucleus bind to DNA and regulate gene
expression ultimately leading to synthesis of specific proteins now let's
briefly talk about life cycle of receptors so each cell's DNA contains
code that's used to synthesize proteins from which different receptors are
assembled once assembled the receptors get embedded into the cell membrane and
can receive and respond to signaling molecules but now let me ask you what
happens if cells receive too much stimulation which can potentially damage
the cell well fortunately for us cells have the ability to downregulate
receptors meaning they can take them out of the
membrane and recycle them which leads to fewer number of expressed receptors and
thus decreased sensitivity to signaling molecules on the other hand let me ask
you what happens if most of cell's receptors get blocked and cell receives
very weak signals well in that case cells have the ability to upregulate
their receptors which means that more receptors can get inserted into the
membrane thus increasing cell sensitivity to signaling molecules now
let's look at the example where our signaling molecule is actually some kind
of a drug so as the concentration of that drug increases its pharmacologic
effect also increases until we reach the point at which all the receptors are
occupied if we plot this we can determine EC50 from the graph EC50 is
simply the concentration of a drug that produces 50% of the maximal
effect and it tells us how potent the drug is so let's call this curve drug "A"
now if we can graph dose response for a different drug let's say drug "B" which
yields different curve we can now easily tell that of the two drug "A" is more
potent because it has lower EC50 simply less drug is needed to get half of the
max response now what else can we see on this graph it looks like drug "B" doesn't
even reach the same level of pharmacological effect as drug "A" and
this is due to its efficacy so maximum efficacy of each drug is represented by
Emax at which we assume that all the receptors are occupied by the drug and
higher concentrations of it don't produce larger effect so in this example
drug "A" is not only more potent but also more efficacious now let's talk about
intrinsic activity of drugs so intrinsic activity refers to ability of a drug to
produce maximal effect so if a drug binds to a receptor and is able to
produce maximum effect that is comparable to
effect produced by our bodies own endogenous ligand we call it a full
agonist now let's say about 15% of receptors show some kind of activity
when there is no agonist around this is what we call basal activity so again in
presence of full agonist we would see maximal effect next if we have agonist
that is unable to produce maximal effect even if it occupies all the receptors we
call partial agonist lastly if we have an agent that binds to the receptors and
instead of activating them it stabilizes receptors in their inactive form we call it
inverse agonist and this is because it simply eliminates basal activity on the
other side of the spectrum we have antagonist which refers to a ligand that
can bind to receptor and block it thus reducing agonist activity so if we have
both agonist and antagonist that can bind to the same side on the receptor
they will compete for that side therefore antagonist
that binds and prevents agonist from binding it's called competitive
antagonist the characteristic of competitive antagonist is that it shifts
dose response curve of the agonist to the right so for example if agonist is some
drug in the presence of competitive antagonists we need higher
concentrations of that drug to get half of the max effect which is EC50 so
potency is reduced now some antagonists can form covalent bonds with active site
on the receptor and thus irreversibly block it
this is non-competitive process because irreversible antagonists can't be
displaced by agonist which leads to reduction in maximal effect which is
Emax and thus reduction in agonist efficacy another type of antagonist is
called allosteric antagonist unlike the other ones these bind to the site
different from agonist binding site and induce
conformational change which prevents agonist from activating the receptor and
just like with irreversible antagonist the allosteric ones also cause reduction
in Emax but no change in EC50 the last important concept in pharmacodynamics
that would like to talk about is therapeutic index our bodies are very
complex therefore not everyone will experience the same exact effect from
the same dose of a drug this is why we came up with therapeutic index as it
helps us to measure the relative safety of a drug for a particular treatment so
therapeutic index is simply the ratio of the dose of a drug that produces
toxicity in 50% of the population to the dose of a drug that produces effective
response in 50% of the population so if we were to graph it we would need to
determine the curve that represents positive therapeutic response and the
curve that represents negative toxic response so in this example after
obtaining data from the population we can determine dose of a drug at which
we observed effective response in half of the population which is our ED50
and we can also determine dose of a drug at which we observed toxic response in
half of the population which is our TD50 now having all that on the graph we
can easily determine therapeutic index which is this range of doses at which a
drug provides benefits without causing major toxicity and with that I wanted to
thank you for watching and I hope you enjoyed this video