Mechanism of drug action, Relationship between drug conc & effect, Receptors, Structural & families of receptors, Quantitation of drug receptor interaction & elicited effects

1. Presented by,
K.Meghana M.Pharm 1st Year
Department of Pharmacology
K.K College of Pharmacy, Chennai.

3. PHARMACODYNAMICS
Study of the biochemical , cellular and
physical effects of drugs.
The mechanism of action at the organ
level as well as cellular level.
Pharmacon=Drug
Dynamics = Action.
“ What a drug does to the body”.

4. MECHANISM OF DRUG
ACTION
RECEPTO
R
MEDIATO
R
DRUGS
NON-
RECEPTOR
MEDIATOR
DRUGS IN
ACTION

5. MECHANISM OF DRUG
ACTION
 Four major catagories
• Enzymes.
• Ion Channels.
• Transporters.
• Receptors.

6. ENZYMES
 All biological reactions are carried out
under catalytic influence of enzymes.
 Thus, simulation of enzyme by drugs
are unusual.
 Example: Pyridoxine acts as a
cofactor and increases decarboxylase
activity.

7. Ion Channel
 Proteins act as ion selective channels.
 Participates in transmembrane
signalling and regulate intracellular
iconic composition.
 Common target of drug action.
Ligand gated Channels.
G-protein regulated channels.
Voltage operated and stretch sensitive
channels.

8. EXAMPLES
 Quinidine blocks myocardial Na+
channels.
 Mifedipine blocks l-type of voltage
sensitive Ca2+ channels.

9. TRANSPORTERS
 Several substrates are translocated
across membranes by binding to
specific transponters (carriers).
 Facilitate diffusion in the direction of
the concentration gradient.
 Pump the ion against the
concentration gradient using metabolic
energy.

10.  Drugs produce their action by direct
interaction with carrier of transporter
proteins to inhibit the on going
physiological transport.
 Examples:
Furasemide inhibits the Sodium-Pottasium-
Chloride channels cotranporter in the ascending
limb of loop of Henle.

12. RECEPTORS
 It is a macromolecule or binding site
located on cell surface or inside the
effector cell.
 It recogonize the drug and initiate
response to it ,but itself has no other
function.
EXAMPLE: Muscarinic (M type) and Nicotinic (N
type) receptors of cholinergic system.

13. NATURE OF RECEPTORS
 Not hypothesis anymore-proteins and
nuleic acid.
 Isolated,purified,cloned and amino
acid sequencing done.
 Cell surface receptors remain floated
in cell membrane lipids.
 Non-polar hydrophobic portion of the
amino acid remain buried in
membrane while polar hydrophilic
remain on cell surface.

14.  Binding of small ligand-capable of
tripping balance at distance site-brings
conformational changes.
 Major classes of receptors are same
structural motif –individual receptors
differ in amino acid sequence, length of
extra and intracellular loops etc.,
 Most drugs act on Physiological
receptors-nerotransmitters, autacoides,
hormones etc.
 True drug receptors-BZD,
Sulfonylureas(SUR1).

15. RECEPTOR SUBTYPES
 Evaluation of receptors and subtypes-
lead to discovery of various newer
target molecules.
 Example Acetylcholine – Muscarine
and Nicotinie.
◦ M1,M2,M3 etc.
◦ NM and NN.
◦ α(alpha) and β(beta)…..

16.  Criteria of classification
 Pharmacological criteria – potencies of
selective agonist and antagonists-
Muscarinic,nicotinic,alpha and beta
adrenergic etc.
 Tissue distribution- beta 1 and beta 2.
 Lignad binding – Radiological radio-labelled
ligands.
 Transducer pathway: MN and MM
 Molecular cloning-based on cloning, amino
acid sequencing and three dimensional
structure.

17. FUNCTIONS OF
RECEPTORS
 To regulate signals from outside the
cell to inside the effector cell.
 To amplify the signal.
 To integrate various intracellular and
extracellular signals.
 To adapt to short term and long term
changes and maintain homeostasis.

18. PHYSIOLOGICAL
RECEPTORS
Many drug receptors are proteins that
normally serve as receptors for
endogeneous regularly ligands .
These drug targets are termed as
Physiological receptors.
 Agnoist:-
◦ Bind to physiological receptors and mimic
the regulatory effects of the endogenous
signalling compound. Example:-
Muscarine and Nicotine.

19.  Primary Agonist:- The drug binds to he
same recognition site as the
endogenous agonist.
 Allosteric (or allotopic) agonist:- Bind to
a different region on the receptor.
 Antagonist:- An agent which block or
reduce the action of an agonist on a
receptor or the subsequent response ,
but does not have effect on its own.

20.  Inverse agonist:- An agent which
activates receptors to produce an effect
in the opposite direction to that of the
agonist.
Example:-DMCM on benzodiazepine
receptor.
 Partial agonist:- An agent which
activates a receptor to produce
submaximal effect but antagonizes the
action of a full agonist.
Example:- opioids.

21. Theories of Receptors
Most therapeutically useful drugs bind only
transiently to their intended receptor.
The induced – fit theory of enzyme –
substrate interaction.
◦ This theory was proposed by Koshland.
◦ According to this theory the receptor need not
necessarily exists in the approximate
conformation.
◦ As the drug approaches the receptor, a
conformational change is induced. This change
in the receptor could be responsible for the
biological response
◦ Example:- Acetylcholine may interact with
regulaton protein.

22.  The receptor was suggested to be
elastic and it could return to its original
conformation after the drug was
released.
 The drug may undergo conformational
changes.

23. Macromolecular Perturbation Theory:-
 This theory suggest that two types of
conformation change exist and the rate of
their existence determines the observed
biological response.
Agonist produce specific perturbation
required for biological response while
Antagonist produce non-specific
perturbation which fails to yield a biological
response.
This theory can partially account for the
activity of partial agonist.

24. Activation-Aggregation Theory:-
Even in the absence of drug the receptors
are in dynamic equilibrium between the
active and inactive form.
Agonist shifts the equilibrium to active form,
antagonist shifts to inactive form.
This theory can account for the activity of
inverse agonist but produce responses
opposite to agonist.

25. Occupation Theory:-
 This suggests that the magnitude of drug
response depends on the proportion of the
receptors occupied by the drug.
The response will progressively increase till a
steady state is achieved.
Interaction of the agonist with the receptors
bring changes in the receptor which in turn
convey the signal to the effector system.
The final response is brought by the effector
system (second messengers). The agonist
itself is the first messenger.
The transduction process links the binding of
the receptor and the actual response is called
Coupling.

26. Rate Theory:-
The rate theory proposes that the
magnitude of response depends on the rate
of agonist-receptor association and
dissociation.
 the rate of receptor-binding is more initially
but after it reaches the peak, it decreases.
The number of drug receptor interaction per
unit time determines the intensity of the
response.

27. STRUCTURAL AND FUNCTIONAL
FAMILIES OF PHYSIOLOGICAL
RECEPTORS
Ion Channels (or) Receptor Channels:-
 Located at cell membrane.
 Directly related to channels (ligand gated
ion channels).
 Involved in fast synaptic transmission.
 Response occurs in milliseconds.
 Depending on the ion and channel
depolarisation/hyper polarisation occurs.

28.  They can be classified as voltage–
activated,ligand – activated, store-activated,
stretch – activated and temperature –
activated.
 Voltage-gated channels:-
 Voltage sensitive
 Conformal change in response to the potential
gradient.
 Generally ion specific.
 Important for excitable cells like neurons.
 Role in regulation of depolarization and polarization
of neural membrane during an action potential.
 Distributed along the axon and cell body of neurons.

29.  Types :-
◦ Sodium channel:- responsible for
membrane depolarization in action
potential generation.
◦ Calcium channel:- Role in both linking
muscle excitation with concentration as
well as neuronal excitation with transmitter
release.
◦ Potassium channel:- Role in repolarization
of cell membrane.

30.  Ligand Gated channels:-
 Channels activated by the binding of a
ligand to a specific site.
 Major ligand-gated channels in the
nervous system are those that respond to
excitatory neurotransmitters such as
glycine or GABA.
example:- Nicotinic Ach.

31. Ion channel

32. G-protein –coupled receptors:-
 G-protein coupled receptors also known as
seven –transmembrane domain receptors,
TT receptors, Serpentive receptor, and G-
protein –linked receptors.
 Located at cell protein.
 Response occurs in seconds.
 Proteins spanning the plasma membrane
because of intertaction with guanine
nucleotides-GTP and GDP.
 The G-protein consists of three subunits α,β
and γ.

33.  When a ligand binds to the G-protein
coupled receptor, the G-protein gets
activated.
 This in turn activates adenyl cylase or
phosphatipase to generate the
respective second messengers.
 These second messenger system are
called efferent pathways . G-protein
act through second messengers.
 Example:- Muscarinic, adrenergic,
seritonin and others.

34.  Second messengers:-
◦ Cyclic AMP system (CAMP).
◦ Cyclic GMP system (CGMP).
◦ Inosital phosphate system (IP3).
 G-Protein-coupled receptors work are
◦ Adenycyl cylase/ CAMP pathway.
◦ IP3/ Phosphotipase pathway
◦ Ion channel regulation.

35. Adenylyl cylase pathway and
Phospholipase pathway

36.  Enzyme receptors:
 located at cell mambrane.
Involved in response to metabolic signals
and growth regulations.
Response occurs in minutes.
Activation of receptors result in
phosphorylation of tyrosine residue and
activation of many pathway in cell.
Example:- Receptors of Insulin ,lepin.

37.  Nuclear Receptors:-
 Located at nucleus (Intracellularly).
Directly related to DNA.
Response occurs in hours or days and
persist longer
Activation of receptors either increasing or
decreasing protein synthesis.
Example:- Receptors for steroidal
hormones,Vitamin D, thyroid hormones and
retinoids.

38. Quantitative Aspect of Drug
Interactions with Receptors
 The dose response curve depicts the
observed effect of a drug as a function
of its concentration in the receptor
compartments.

39.  The intensity of response increases with
increase in dose and the dose response
curve is rectangular hyperbola. This is
because drug-receptor interaction obeys
law of mass action.
 Where E=observed effect at a dose [D] of
the drug.
Emax = maximal response.
KD= dissociation constant of the drug-
receptor.

40. Advantages of DRC
 A wide range of drub doses can be
easily displayed on a graph.
 Comparision between agonists and
study of antagonists becomes easier.
 Affinity,Efficiacy,Potency:-
Drug –receptor interaction is
characterized by
Binding of drug to receptor

41.  Affinity,Efficiacy,Potency:-
Drug –receptor interaction is
characterized by
Binding of drug to receptor .
Generation of a response in a biological
system.

42. Affinity
 Ability of a drug to combine with
receptor.
 A high affinity drug has a low KD and
will bind or greater number of a
particular receptor at a low
concentration than a low-affinity drug.
 the affinity constant or equilibrium
association constant KA is reciprocal of
the equilibrium constant.

43. Potency
 It is the amount of drug required to
produce a certain response
 Example:-
◦ Highly protein drugs like morphine,
chlorpromazine produced high response
at low concentration.
◦ Low potent drugs like ibuprotein and
acetylsalicylic acid produced low
response at low concentration.

44. Potency

45. Efficacy
 The capacity of a drug to activate a
receptor and generate a cellular
response .

46. Quantifying Antagonism
 Competitive Antagonism:-
 Antagonists is chemically similar to
agonist and binds to same receptor
molecules.
 Affinity (1) but IA(0)=No response.
 Log DRC shifts to the right.
 Antagonism is reversible. Increase in
concentration of agonist overcomes the
block.

48.  Non-Competetive Antagonism:-
 Allosteric site binding altering receptor not
bind with agonist.
No competition between them.
no change of effect
Agonist concentration is incerased,
Flattering of DRC of agonist by increasing
the concetration of antagonist.

50. Pseudo-reversible
Antagonism
 Lesser degree of receptor occupancy
by the antagonist and availability of
spare receptors.
 Increasing concentration of agonist –
shift LDR to right.
 Increasing concentration of
antagonist-reduction in maximal
response.

51. Drug Synergism
 Synergism is facilitation of the effects of
one drug by another when given together
 Two types – Additive, Supra-additive.
 Additive:-
◦ Effect of drugs A+B=Effect of drug A + Effect
of drug B
◦ Final effect is same as the algebraic sum of
the magnitude of individual drugs.
◦ Side effects do not add up.
Example:- Codeine + Acetaminophen =
Increasing action of codeine as a pain
reliever.

52.  Supra-additive :
◦ When two drugs are given together the
final effect is much more than the simple
algebraic sum of the magnitude of
individual drugs.
Example:- sulphamethoxazole and
trimethoprim –sequential blockage of two
steps in synthesis of folic acid in micro
organisms.

53. SUMMARY
Mechanism of drug action and the
relationship between drug
concentration and effect. Receptors,
structural and functional families of
receptors, quantisation of drug
receptors interaction and elicited
effects.