PHARMACODYNAMICS

Dr.B.M.PUROHIT
Assistant Professor (Pharmacology)
P.D.U.MEDICAL COLLEGE,
Rajkot (GUJARAT). 360001
purohitbhargav@rediffmail.com
 DYNAM

PHARMACO DYNAMICS
DRUG O=
POWER

STUDY OF THE ACTION OF THE DRUG.

Consequences of binding of drug with its
target.
Study of drugs POWER (CAPABILITY) of
producing action.
Study of biological and therapeutic effects of
drugs.

what drug does to the

body
 First think of
all the physical
properties
 Binds with Binds with
the SAME the
SITE and is DIFFERENT
REVERSIBLE SITE and is
.. IRREVERSIB
LE ..
Adrenalin
stimulates
adenyl
cyclase
activity
Like heavy
metals,
strong
acids,
Phenobarbit alkalies, Binds with
one, alcholo etc.. the SAME
rifampicin, NO SITE and is
alcohol THERAPEU IRREVERSIB
induces CYP TIC LE ..
EXAMPLES OF ENZYME
INHIBITION
 TRANSPORTERS
Cocaine blocks NET increases the
availability of NE.
SSRI blocks SERT increases the
availability of 5-HT.
Amphetamine blocks DAT increases
the availability of DA.
Tiagabine blocks GAT increases the
availability of GABA.
Probenecid blocks OAT decreases the
tubular secretion of penicillin.
 Now comes the most important/difficult aspect of the
discussion

Receptors

This section involves a lot of molecular complexities.

When you go to faculty to understand this

They will say, take interest in it.

They dont know that if you take too much interest in

this molecular confusion.

.You will loose interest in life

 What are receptors ?
Macromolecules
Present in cells ( in the membrane, cytosol
or nucleus)
Which on binding with a molecule
Transmits the information
To effecter molecule
Which triggers subsequent reaction..
it just RECEIVES and TRANSMITS
information it has no
activity of its own
 NEED A REVISION ?
 What are receptors ?
Macromolecules
Present in cells ( in the membrane, cytosol
or nucleus)
Which on binding with a molecule
Transmits the information
To effecter molecule
Which triggers subsequent reaction..
it just RECEIVES and TRANSMITS
information it has no
activity of its own
 Like u
Like u
Like u Like u propose
propose
propose propose some one
some one
some one some one and reaction
and get we
and get and without is sharp
are just good
instant YES saying OPPOSITE
friends not
with a smile. anything she how dare
more than
!! goes away you think like
that
that !!!

Binding Binding
Binding Binding
FULL PARTIAL NO OPPOSITE
RESPONS RESPONS RESPONS RESPONS
E E
 EXAMPLES
Agonist Ach on muscurinic and
nicotinic receptor
Partial agonist pentazocine at
delta receptor.
Antagonist phentolamine at
receptors.
Inverse agonist DMCM at
benzodiazepine receptors.
Two important terminologies
AFFINITY :
Ability to combine with receptor
EFFICACY /INTRINSIC ACTIVITY :
Ability to trigger subsequent reactions.
IA for agonists is 1
IA for partial agonist is between 0 to 1.
IA for antagonist is 0
IA for inverse agonist is -1.
 Two state receptor model
Receptors exist in two
INTERCHANGEBLE forms :
Active (Ra)
Inactive (Ri.)
At rest, two states are in equilibrium
with each other.
 Under resting conditions

Ra Ri

Following AGONIST(A)
binding
A

RESPONSE Ra Ri

Following PARTIAL
AGONIST (PA) binding
PA

PARTIAL Ra Ri
RESPONSE
Following
ANTAGONIST(AN) A
A
binding
N N

Ra Ri

NO RESPONSE
Following
INVERSEAGONIST (IA)
binding

I OPPOSITE
Ra Ri A
RESPONSE
 RECEPTOR CLASSIFICATION
BASED ON TRANSDUCER
Nn receptors
GABA
MECHANISM Insulin
receptors receptors
Glycine
receptors
Beta
receptors Cytokine ,
ACTH GH
receptors

receptors
M1
receptors

Steroid
1 receptors receptors
Difference between the two
in heart
is that 1st have inbuilt
channel while GPCR
modulates separate
 Need a revision?
 RECEPTOR CLASSIFICATION
BASED ON TRANSDUCER
Nn receptors
GABA
MECHANISM Insulin
receptors receptors
Glycine
receptors
Beta
receptors Cytokine ,
ACTH GH
receptors

receptors
M1
receptors

Steroid
1 receptors receptors
Difference between the two
in heart
is that 1st have inbuilt
channel while GPCR
modulates separate
 1.RECEPTORS LINKED TO
ION CHANNELS
Nicotinic cholinergic receptor,
(GABAA) receptor, and
Receptors for glutamate, aspartate, and glycine
In response to agonist binding various types of ion channel
opens. (Na,Cl.Ca,K etc.)
Function is modified based on cell types and ion channels
involved.

http://www.youtube.com/watch?v=4zzedEDQ6AU
http://www.youtube.com/watch?
v=ygiKfIs3P3Y&feature=related
2.GPCR
 Need a revision ?
2.GPCR
Adenylyl cyclase pathway
Gs
stimulates it
Gi inhibits it
 http://www.youtube.com/watch?
v=iGb93jCKVXs&feature=related
http://www.youtube.com/watch?
v=ukUFG_xpNRk
PLC PATHWAY
Do you feel like crying ?
G-PROTEIN COUPLED CHANNEL
REGULATION
G proteins BY THEMSELVES modulates
SEPERATELY LOCATED ion channels.
In other ionchannel linked receptors, ion
channels were INBUILT.
NO INTERMEDIARY MOLECULES.
Gs opens Calcium channel
Gi or Go opens K channel and close Ca
channel.
Depending upon ion channels and cell
type, function will be modified.
 http://www.youtube.com/watch?
v=NB7YfAvez3o
http://www.youtube.com/watch?
v=V_0EcUr_txk&feature=related
http://www.youtube.com/watch?
v=DOPM2YC1Mlc&feature=related
http://www.youtube.com/watch?
v=0qGNuAUy-Dc&feature=related
http://www.youtube.com/watch?
v=bU4955rLv_8
 3.ENZYME LINKED
RECEPTORS
Two types of mechanisms :
Receptors inner membrane site have
intrinsic enzyme activity.
Receptors inner membrane site doesnt
have intrinsic enzyme activity but binds
Janus Kinase on activation.
 INTRINSIC ENZYME RECEPTORS :
Enzymes are ..
Protein kinase
Guanylyl cyclase.
Which binds mostly tyrosine, but can be
serine or threonine on substrate
molecule.

Example : Insulin
 JAK-STAT KINASE BINDING RECEPTORS :
Cascade is same as that of intrinsic tyrosine
kinase linked receptor.
Difference is that here tyrosine kinase is
CYTOSOLIC.
In previous discussion it was linked to
CYTOSOLIC END OF RECEPTOR.
On binding JAK will be activated and
phosphorylate tyrosine residues of the
receptor which phosphorylates and binds
STAT.
STAT dimer is tranlocated to the nucleus to
regulate gene transcription of cytokines,
GH.
 http://www.youtube.com/watch?
v=G4K6IQZGHJc
 4.RECEPTORS REGULATING
GENE EXPRESSION.
Location :
Cytosolic
Nuclear

Examples :
Steroid hormones
Thyroxine
Vit D,A.
 http://www.youtube.com/watch?
v=YUv9PFQper4&playnext=1&list=P
LEEE5A627695E1E4A
http://www.youtube.com/watch?
v=Dxyq8GAWbpo
 RECEPTOR REGULATION
Up regulation & super sensitivity
following prolonged deprivation.
Upregulation increased number of receptors.
Supersensitivity increased activity of
transducer mechanisms.
Down regulation & desensitization.
following prolonged exposure .
Downregulation decreased number of
receptors
Desensitization decreased activity of
transducer mechanisms
 What these receptors do ?
They transmit signal from outside to
inside the cells.
Maintain balance between
extracellular and intracellular
environment
They drive medical students crazy
Through structural proteins
Colchicin gets bound to tubulin
protein
Cyclosporin gets bound to
immunophilins protein.
 Through nucleic acid
Anticancer drugs like
Cyclophosphamide,
Methotrexate
 Through protoplasmic
poison
Alcohol
Heavy metals.
Antiseptics
Disinfectants
 Similarities to endogenous
substance
Sulfonamides are similar to Folic
Acid.
It deranges the metabolic cycle.
 Modification of immune
system.
Vaccines upregulates immunity and
protects against infections
Immunosuppressant knocks down the
immune system and protects against
autoimmune diseases.( where bodys
immune system is damaging native
cells)
 By antimicrobial action
They halt the multiplication/ kill the
organism while having minimum
effect on host cells.
Like streptomycin, penicillins
 By replacement
By replacing the deficient substance.
Like iron in iron deficiency anaemia.
Thyroxin in hypothyroidism.
Glucocorticoids in Addisons disease.
 By placebo action
Placebo is inert substance by itself.
But it gives psychological satisfaction to the patient that
SOMETHING is being done.
It can have profound therapeutic effect.
It is of greatest value for pain and psychoactive remedies.
Like placebo induced analgesia is reversed by naloxane,
which means placebo causes release of endogenenous
opioids.
Depend upon confidence of doctor and faith of the patient.
Injection produces more profound effect than tablets.
 DOSE RESPONSE
RELATIONSHIP
Dose plasma concentration relationship.
How much DOSE is administered and how much CONCENTRATION is obtained .
It is studied under the purview of pharmacokinetics
Because concentration available at a point of time is the sum total of
absorption, distribution, metabolism and excretion of the drug.
Plasma concentration effect relationship.
It is studied under the purview of pharmacodynamics.
Concentration available at the site of action govern the ultimate EFFECT.
So consequence of binding of drug with target cells.
For majority of drugs, this relation ship is linear(i.e. more conc., more response)
But at times there can be discrepancies
Some allergic reactions are independent of the dose of the drug.
 This relationship is plotted on .
Notches in this
DRC line are
unintentional , so DRC is
Log DRC kindly ignore it. hyperbolic or
Presume they parabolic
dont exist
DRC Log DRC is
sigmoid
shape
RESPONSE

Log DRC

DOSE
 DRC :
If conc. Increase from 1,2,3,4,5, .after some time there will
be physical limitations of graph paper.(i.e. after 10-20 units
you cant place concentration further)
Steep DRC means smaller increase in dose greater increase
in response.
Flat DRC means larger increase in dose less increase in
response
Log DRC :
Broader concentration range can be covered.
Because if one conc. Is 10 mg and next 100 mg, when log dose
is taken ..
They become 1 & 2 only.
So one can cover wider range of reading.
In 30-70 % middle part of graph you can obtain linear
relationship.
So judging in between reading is less liable to cause error.
 Therapeutic window
phenomenon
TOXIC EFFECT
MAXIMUM SAFE
CONCENTRATION.

Concentration
THERAPEUTIC
WINDOW
MINIMUM EFFECTIVE
CONCENTRATION

NO
THEREAPEUTIC
EFFECT

Time
 Maintaing drug within therapeutic window
is necessary for drugs like ..
Antiepileptic drugs
Anticoagulants
Lithium
because in these drugs
Higher concentration will produce
unacceptable toxicity
Lower concentration will produce
therapeutic failure.
Both are unacceptable.
 Drug potency and efficacy
Potency means comparison of 2 drugs
on wt to wt basis.
2 mg drug A produces 10 % response
2 mg drug B produces 30 % response
So drug B is more potent.
Efficacy means MAXIMUM RESPONSE
that can be elicited by a drug.
Maximum response by drug A is 40 %
Maximum response by drug B is 10 %
Drug A is more efficacious.
 Clinicians are concerned about
efficacy.
Example :
Thiazide diuretics given in maximal
doses, produces less diuresis activity
than furosemide.
Aspirin given in maximal doses,
produces less analgesic activity than
morphine.
 Effect of (A+B) >
Effect of (A+B) =
Effect of A + effect
Effect of A + effect
of B
of B
Imipenam + cilastin
Nsaid+ opioids
potentiation of
analgesia
action of imipenam
Amoxycillin +
Levodopa +
cloxacillin
carbidopa
Broader microbial
increased efficacy of
coverage
levodopa.
 Two drugs act by two
different pathways.
NO CROSS TALK.
End results are OPPOSITE.
e.g. adrenaline &
Binds with histamine Binds with the
the SAME Insulin & glucagon on
DIFFERENT
SITE and is blood glucose levels
SITE and is
REVERSIBLE
IRREVERSIBLE
.. Like Ach &
..diazepam &
Atropine
bicuculline

Charcoal adsorbsAcids neutralizes

alkaloids alkalies
KMnO4 oxidizes
alkaloids
Binds with the SAME
SITE and is
IRREVERSIBLE ..
Adrenaline &
phenoxybenzamine
 NEED A REVISION ?
 Two drugs act by two
different pathways.
NO CROSS TALK.
End results are OPPOSITE.
e.g. adrenaline &
Binds with histamine Binds with the
the SAME Insulin & glucagon on
DIFFERENT
SITE and is blood glucose levels
SITE and is
REVERSIBLE
IRREVERSIBLE
.. Like Ach &
..diazepam &
Atropine
bicuculline

Charcoal adsorbsAcids neutralizes

alkaloids alkalies
KMnO4 oxidizes
alkaloids
Binds with the SAME
SITE and is
IRREVERSIBLE ..
Adrenaline &
phenoxybenzamine
 Get ready for self
assement.
What is pharmacodynamic ?
How a drug may act?
Give a few examples of drug producing action by physical property ?
Give a few examples of drug producing action by chemical property ?
Give examples of drugs acting by modifying enzymatic mechanisms .
Give examples of drugs acting by modifying transporters.
What are receptors ?
How will classify them based on transducer mechanisms.
What are agonists, partial agonists, antagonist and inverse agonist ? give examples.
What is affinity ? what is intrinsic activity?
Give examples of receptors linked to ion channels ?
How many types of GPCR exist ? which are the second messengers linked to each of
them.
Which are enzyme linked receptors ? Give examples.
How receptors regulate gene expression ? Give examples.
What is upregulation and super sensitivity ?
What is downregulation and desensitization ?
What are the functions of the receptors ?
 Give examples of drug acting by structural proteins
Give examples of d rug acting by binding with nucleic acid
Give examples of drug acting by protoplasmic poisons.
Give examples of drug acting like endogeneous substance.
Give examples of drug acting by modifying immune system.
Give examples of drug acting by placebo action.
Give examples of d rug acting by antimicrobial action.
Give examples of d rug acting by replacement.
What are the differences between DRC and log DRC ?
What is therapeutic window phenomenon ? For which drug becomes significant.
What is drug potency and drug efficacy ? What is more important for clinician ?
What is synergism ? give examples.
What is antagonism ? Give examples.