Drug _receptor interaction

and pharmcodynamic
Pharmcodynamic :
 It The action of drug on the body
and influence of drug
concentration on magnitude of
response.
Most drug exert it effect by
interacting with receptors present
in cell surface or with in cell and
also some drug exert their effect
but not by interacting to receptor
examples antaacids
Signal transduction :
Drug receptor complex
alternations in biochemical or
molecular activity of cell.
When drug binding to it receptor
that will initating series of
reactions that end by specific
intracellular respones.
Agoinst :
Naturally occurring small
molecule or drug that binds to
site on receptor protein and
activate it.
Second messengers or effector
molecules :
Are part of cascade of events
that translate agoinst binding
into cellular response.
Drug receptor complex :
 Cells have many type of receptors each of
which is specific for particular agoinst and
produce specific response. For example cardic
cell memebrane contain beta receptors that
bind and respond to norepinephrine,
epinephrine and also contain muscarinic
receptors for acetylcholine.
 The magnitude of response is proportional to
number of drug receptor complex.
 Most receptors are name for the type of
agoinst that interact best with it. For example
receptor fir histamine is called histamine
receptor.
Receptor states :
Receptor exist in two states :
1- active (R*).
2-inactive (R).
Usually receptor favoring the
inactive state.
Binding of agoinst causes the
equilibrium to shift from R to R*
to produce biological effect.
Antagonist occupy the receptor but
do not increases fraction of R * and
stabilize the receptor in the
inactive state.
Partial agoinsts :
Cause shift in equilibrium from R to
R*but fraction of R* is is less than
that caused by full agoinst.
The magnitude of biological effect
is directly related to the fraction of
R*.
Major receptor family :
The enzyme , proteins, nucleic
acid can act as receptor for
drugs or endogenous agoinsts.
These receptors may be cellular
divided into four families:
1-ligand _gated ion channle s.
2- G protein coupled receptor.
3- enzyme linked receptor.
4-intracellular receptor.
The type if receptor a ligand
interacts depends on the chemical
nature of ligand
Hydrophilic interact with receptor
that is found on cell surface.
Inconstract hydrophobic (lipophilic)
enter cell through the lipid bilayers
of cell membrane to interact with
receptor found inside cells.
G protein coupled receptor
**some characteristics of signal
transduction features :
1-ability
to ampilfy small signals.
2-mechanism to protect the cell
from excessive stimulator.
1-Signal amlification :
Itis characteristics of G protein linked and
enzyme linked receptor.
For example single agoinst receptor
complex can interact with many G protein
there by multiplying the original signal
many fold ans also activated G protein act
for long duration than does original agoinst
receptor complex.
For example :Albuterol exist binding to
receptor for few milliseconds but
subsequent activated in G protein s may
last for hundreds milliseconds.
Because this amplification only
fraction of total receptor for specific
ligand may need to occupied to
formualte maximal response. System
that show this behavior are said to
have spare receptor.
Number of spare receptor different
from ligand to other. For example
insulin show 99% spare receptor.
Inother hand human heart show only
5 to 10% of total beta adrenergic are
spare.
2-desensitization and down
regulation of receptors:
Desensitization :
Repeated or continue adimistration
of agoinst or Antagonist may lead to
change in the responsiveness of the
receptor.
Tachyphylaxis :
Phenomenon which phorphorylation
or similar chemicalevent that make
receptors on the cell surface
unresponsive to ligand.
Down regulation :
Receptors are internalized or sequestered
with cell, that make them unavailable for
further agoint interaction.
Up regulation :
Repeated exposure of receptor to
Antagonist may result up regulation of
receptors in whic receptor reserves are
inserted into membrane that increase total
number of receptors available. Up
regulation of receptors make cell more
sensitive to agoinst and more resistance to
the effect of Antagonist.
Dose _response relationship :
Action of agoinst on it receptor
mimic endogenous ligand
(isoproterenol mimic
norepinephrine in B1 receptors
on heart).
. Magnitude of drug effect
depend drug concentration at
receptor sit which determined by
1-dose of drug adimistered.
2-drug pharmacokinetics profile.
Potency :
Measure of the amount of drug necessary
to produce an effect of given magnitude.
EC 50 is concentration of drug producing
50% of maximum effect.
Drug has low EC50 that mean it more
potent.
For example therapeutic dose of
candesartan range from 4 to 32 mg as
compared to 75 to 300 for irbesartan.
There for candesartan more potent than
irbesartan.
Efficacy :
 Magnitude of response adrug cause when it
interacts with receptor.
 Efficacy depend on number of drug receptor
complex formed and intrinsic activity of drug (it s
ability to activated the receptor and cause
cellular response).
 maximal efficacy of drug(Emax) assumes that all
receptor are occupied by the drug and no
increase in response is observed if high
concentration of drug obtained.
 Emax is zero when antagoinst occipies 100% of
receptors (no receptor activation).
 Efficacy is more clinically useful characteristics
than drug potency.
Intrinsic activity :
Drug categorized according to
their intrinsic activity and Emax
valve into :
A- full agoinsts.
B-partial agoinsts.
C- inverse agoinsts.
D - Antagonist.
A- full agoinsts :

Drugs that bind to receptor and

produce maximal biological
response that mimic the response
of ligand.
For example phenylephrine is full
agoinst at alpha 1 receptor due it
max as Emax as do by
endogenous ligand
norepinephrine.
B- partial agoinst s:
Drugs that bind to all receptor but can
not produce same Emax as full agoinst.
 When receptor exposed to both partial
and full agoinsts the partial agoinst may
act an Antagonist of full agoinsts.
For example aripiprazole it partial
agoinst to dopamine receptor it that act
Antagonist for endogenous dopamine.
Dopamineregic pathway that over active
tend to be inhibited by aripiprazole,
where as underative are stimulated.
C- inverse agoinsts :
Unbound receptor are inactive form and
when binding to agoinsts convert to
active form.
Some receptor show spantaneous
conversion from inactive to active
without present of agoinst.
Inverse agoinst binding to this receptor
and stabilizing then in active form ,
reverse the activity of receptors and
exert the opposite pharmacological
effect of agoinst s.
D-Antagonists:
Antagonist bind to receptor with
high affinity but posses zero
intrinsic activity.
Antagonism may occur either by:
1-blocking the drugs ability to
bind to receptor.
2- by blocking it ability to
activiate receptor.
Type of Antagonist :
1- Competitive :
When agoinst and Antagonist bind to
same site on the receptor in reversible
manner.
Competitive Antagonist prevents agoinst
from binding to receptor and maintain
the receptor in its inactive form.
For example antiHTN terazosin
competes endogenous norepinephrine
at alpha 1 receptor. This type of
inhibition can be over by increase
concentration of agoinst.
2- irreversible
Antagonists:
Itbind covalently to active site of receptor
there by reducing number of receptor
available to agoinst.
In contrast to competitive antagoinst
effect of irreversible Antagonists can not
over by adding more agoinst.
Fundamental differences between
competitive and non competitive
antagoinst is that competitive antagoinst
reduce agoinst potency (increase EC50)
and non competitive antagoinst efficacy
(decrease Emax).
3-Allosteric Antagonist :
Also cause downword shift of Emax with
no change in EC50 valve of agoinst.
This type of antagoinst binds to site
(allosteric site) other than the agoinst
binding site and prevents the receptor
from beging activated by agoinst.
For example : picrotoxin bound into inside
of GABA controlled chloride channel.
When picrotoxin bind inside channel no
chloride enter cell through channel
despite of binding of receptor to GABA.
4- functional Antagonist :
Antagonist may act completely
separate receptors initiating
effects that are functionally
Antagonism by those of agoinst.
For example: epinephrine to
histamine induced
bronchoconstriction.
Functional Antagonist is also
known as physiological
Antagonist.
Therapeutic index (TI) of drug:
Is ratio of dose that produce toxicity
in half population (TD50) to dose
that produces clinically desired or
effective response ((ED50) in half
population .
TI = TD 50 /ED50.
The TI is measure safty of drug
because large value indicates wide
margin between doses that are
effective and doses that are toxic.
Clinical usefulness of
therapeutic index :
Although high TI valves are
required for most drugs, some
drug with low therapeutic indices
are routinely used to treat
serious diseases.
Example of drug with narrow
(low) TI:
Warfarin
The dose of warfarin is adjusted
according INR.
At high dose warfarin cause
hemorrhage (Anticoagulation).
Agent with low TI are those drugs
for which biovailability critically
alters therapeutics effects.
Example of drug with large TI:
Penicillin
Itis safe and common to give
dose in excessive of that which is
mimimally required to achieve
desired response with risk of
adverse side effects. In this case
biovailability not critically alter
therapeutic or clinical effects.