This discussion covers components of Pharmacodynamics like: Drug-enzyme interaction Drug receptor interaction Intracellular signalling pathways Therapeutic index, Therapeutic window

1. Pharmacodynamics-II
Dr. Pravin Prasad
M.B.B.S., MD Clinical Pharmacology
Lecturer, Lumbini Medical College & TH
12 December, 2018 (26 Mangsir, 2075),
Wednesday

2. Questions from yesterday…
What do you understand by the term
pharmacodynamics?
Name five principles of drug action.
What are common drug targets?
Define receptor.

3. By the end of the class, MBBS
Ist year students will be able to:
Appraise the different types of:
Drug enzyme interaction
Drug receptor interaction
Explain the Intracellular signaling mechanism
Interpret the Dose Response Curve
Explain the difference between therapeutic
index and therapeutic Window

4. Drug – Enzyme Interaction
Enzyme
Normal
Substrate
Product

5. Drug – Enzyme Interaction
Enzyme
Competitive Inhibition
Inhibitor
No Product
Substrate
Competition
for the binding
site
Non functional

6. Drug – Enzyme Interaction
Enzyme
Competitive Inhibition: Equilibrium Type
Inhibitor
No Product
Substrate
Product
Inhibitor can
be displaced Non functional

7. Drug – Enzyme Interaction
Enzyme Endogenous
substrate
Inhibitor
Bacterial
folate
synthase
Para-amino
benzoic acid
Sulfadiazine
Cholinesteras
e
Acetylcholine Physostigmin
e
 Competitive enzyme inhibition (equilibrium type)

8. Drug Target- Enzymes
Enzyme
Competitive Inhibition: Non equilibrium Type
Inhibitor
No Product
Substrate
Inhibitor cannot
be displaced

9. Drug – Enzyme Interaction
 Competitive enzyme inhibition (nonequilibrium ty
Enzyme Endogenous
substrate
Inhibitor
Cholinesteras
e
Acetylcholine Malathion, OPs
Dihydrofolate
reductase
DHF Methotrexate

10. Enzyme
Drug – Enzyme Interaction
Enzyme
Non-competitive Inhibition
Inhibitor
No Product
Substrate
• Substrate
cannot bind to
enzyme
• No
competition
between
substrate and
inhibitor

11. Drug – Enzyme Interaction
 Non-Competitive enzyme inhibition
Enzyme
Endogenous
substrate
Inhibitor
Carbonic
anhydrase
H2O and CO2 Acetazolamide
H+-K+ ATPase H+ and K+ Omeprazole
Cyclooxygena
se
Arachidonic
acid
Aspirin

12. Drug Receptor Interaction
Agonist
Binds to a receptor, and
Produces an effect similar to that of the
physiological signal molecule
Antagonist
Binds to a receptor, but
Prevents the action of an agonist on a receptor
or a subsequent response
Does not have any effect on its own

13. Drug-Receptor Interactions
Log [drug]
LevelofResponse
Full agonist
Partial agonist
Baseline activity
Inverse agonis
Antagonist

14. Drug-Receptor Interaction:
Agonists
Full agonist:
Activates the receptor maximally
Partial agonist:
Activates the receptor sub-maximally
Inverse agonist:
Activates the receptor, but in opposite
direction

15. GPCRs: Intra-cellular signaling
Mechanism (cAMP pathway)
β Gsα
Gγ
Adenyl
yl
Cyclase
GD
P
GT
P
ATP
cAM
P
PKA

16. GPCRs: Intra-cellular signaling
Mechanism (PLC-IP3-DAG
pathway)
β Gqα
Gγ
PLC
GD
P
GT
P
IP3
Ca2+
PIP2
DAG
PKc
Effects
Effects
Ca2+

17. GPCRs: Intra-cellular signaling
Mechanism (channel
regulation)
Directly opens or inhibits ion channels
Mainly mediated through βγ subunits of Gi and
Gq proteins
Controls opening of K+ and Ca2+ channels
Example: mAChR (M2):
Cardiac K+ channels opening 
hyperpolarization
Decreased activity of cells

18. Dose Response Curve
Dose
Response
Is a hyperbolic curve
• Low concentration of drug,
response increases
significantly
• High concentration of drug,
response increases slightly
• Comparison of responses
becomes difficult

19. Dose Response Curve
Log[Dose]
Response
Sigmoid curve
• Wider range can be
plotted
• Intermediate
portion essentially
linear
• Comparison of
responses can
be made

20. Dose Response Curve
Log[Dose]
Response
Maximal Response
50% response
Efficacy
Potency
EC50
Slope

21. Dose Response Curve
Potency on DRC:
Depicted by position of DRC on Log[dose]
axis
• More left- more potent
Comparison of potency of two drugs done at
EC50
• Drug Concentration at which 50%
response is obtained

22. Dose Response Curve
Efficacy on DRC:
Maximal response that can be elicited by a
drug
• Upper limit of DRC
Dictates the choice of drug
Efficacy and Potency: independent of each
other

23. Dose Response Curve
Slope of DRC:
Steep graph:
• Response changes rapidly with change in
dose
• Dose needs to be individualised
Flat graph:
• Response changes slowly with change in
dose

24. Therapeutic index
Calculated in experimental animals
2 DRC plotted:
Effective dose DRC
Lethal dose DRC
Separation of these DRC: Therapeutic index
Calculated as:
𝑇ℎ𝑒𝑟𝑎𝑝𝑒𝑢𝑡𝑖𝑐 𝑖𝑛𝑑𝑒𝑥 =
𝐿𝑒𝑡ℎ𝑎𝑙 𝐷𝑜𝑠𝑒 50
𝐸𝑓𝑓𝑒𝑐𝑡𝑖𝑣𝑒 𝐷𝑜𝑠𝑒 50

25. Dose Response Curve
Log[Dose]
Response(numberofanimals)
50% response
ED50
LD50
Effective dose
DRC Lethal dose
DRC
TI= LD50/ED50

26. Therapeutic Window
Also known as therapeutic range
More relevant in clinical set up
Two DRCs:
Effective dose DRC
Adverse effect DRC
Minimal therapeutic effect to Maximal
acceptable adverse effect

27. Dose Response Curve
Log[Dose]
Response(%)
Maximal
acceptable
adverse
effect
Therapeuti
c Window/
range
Effective dose
DRC Adverse
effect DRC
Minimal
therapeutic
effect

28. Drug – Enzyme Interaction
Vmax
½ Vmax
½ Vmax
Vmax
Km KmKmKm
Vmax
ReactionVelocity
Substrate concentratio
Normal
Non Eq. type
Eq. type
Non-competitive
Enzyme induction
Enzyme stimulatio

29. Drug – Enzyme Interaction
km Vmax
Competitive (Equilibrium) Increased
Not
changed
Competitive (Non-
equilibrium)
Increased Decreased
Non-competitive
Not
changed
Decreased
Enzyme induction
Not
changed
Increased

30. Post-Test
Log[Dose]
Response
Identify the drug
with highest:
• Potency
• Efficacy
A
B
C

31. Conclusion
Competitive enzyme inhibition (equilibrium type)
can be reversed by increasing the concentration of
substrate
Agonists have affinity to receptors, but differ in
their intrinsic activity
Depending on the G-protein of GPCRs, signalling
pathway may include cAMP, IP3-DAG or ion
channels themselves
Log[dose] response curve is used for comparing
drugs
Therapeutic window is more clinically applicable

32. Next class…
Tomorrow (9-10 am)
Topics:
Factors modifying drug action
Any queries?
Thank you!