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