Targets of drug action, transducer mechanisms, dose-response curve and drug-drug interaction

1. Pharmacodynamic Principles
Dr. M. Ahsan (MBBS, MD)

2. Pharmacodynamics
“What the drug does to the body !!”
Pharmacodynamics describes :
The action of the drug on the body
Influence of drug concentrations on the magnitude of response
Modification of the action of one drug by another drug

3. Targets of drug action
Functional proteins are targets of drug action :
• Enzymes
• Ion channels
• Transporters
• Receptors

4. Drug target: enzymes
Drugs can either increase or decrease the rate of enzymatic activity.
Enzyme stimulation is less common than enzyme inhibition
Stimulation is seen with natural substances only.
Enzyme inhibition can be :
Competitive
Noncompetitive

5. Drug target: ion channels
Ion channels are transmembrane proteins :
Regulate intracellular composition
Participate in transmembrane signaling
Ion channels can be :
Ligand –gated
Voltage-gated
 Quinidine blocks myocardial Na
channels
 Phenytoin modulates voltage-
sensitive neuronal Na channels
 Sulfonylureas inhibit pancreatic
ATP-sensitive K channels

6. Drug target: transporters
• Specific proteins act as transporters/carriers and traslocate substrate in the
direction of concentration gradient or against the concentration gradient
Eg. Probenecid inhibits active transport of organic acid (uric acid, penicillin)
in renal tubules by interacting with organic anion transporter

7. Drug target: receptor
• It is defined as a macromolecule or binding site located on the surface or
inside the cell that serves to recognize the signal molecule/drug and
initiate response to it, but itself has no other function

8. Ligand
Any molecule which attaches selectively to particular receptors or sites.
Agonist
Antagonist
Partial agonist
Inverse agonist

9. Ligands
Agonist : an agent which activates the receptor to produce an effect similar
to the physiological signal molecule.
They have :
Affinity
Maximal intrinsic activity (IA=1)

10. Ligands
Antagonist : an agent which prevents the action of an agonist on a receptor,
but does not have any effect of its own.
• They have:
Affinity
No intrinsic activity (IA=0)

11. Ligands
• Partial agonist : an agent which activates the receptor to produce
submaximal effect but antagonizes the action of a full agonist.
• Affinity
• Submaximal intrinsic activity (IA between 0 and 1)

12. Ligands
• Inverse agonist : an agent which activates a receptor to produce an
effect in the opposite direction to that of the agonist
• Affinity
• Intrinsic activity between 0 and -1

13. Regulation of receptors
• Up regulation :
increase in number of receptor
• Down- regulation :
Decrease in number of receptors

14. Up-regulation of receptors
• Increase in number of receptors
• Continued presence of an antagonist or absence of an agonist
results in unmasking of receptors or their proliferation.
• Eg. MI can be precipitated on abrupt withdrawal of beta-blockers

15. Down regulation of receptors
• The number of receptors decrease in the continued presence of an
agonist
It can be brought about by :
• Internalization of the receptor
• Decreased synthesis/increased destruction of the receptor
Eg. Asthma patients treated
continuously with beta-agonist,
become less responsive to them

16. Transducer mechanism
There are 5 major categories:
• GPCRs
• Ion channel receptors
• Transmembrane enzyme-linked receptors
• Transmembrance JAK-STAT binding receptor
• Receptors regulating gene expression

17. G-Protein Coupled Receptors
• Cell membrane receptors
• Consist of 7 alpha helical transmembrane units with 3 intracellular
and 3 extracellular loops
• Linked to the effector through one or more GTP activated proteins (G
proteins) on the cytosolic site
• G-proteins are hetero-trimeric in composition (αβγ subunits)

18. GPCRs
A. In inactive state, GDP is bound to α subunit
GDP is displace by GTP in the active state
α subunit carrying GTP dissociates from other two
subunits
B. The α subunit has GTP-ase activity
The bound GTP hydrolyses to GDP
The α subunit then dissociates from the
effector to rejoin its other subunits

19. GPCRs
Different G proteins based on the α subunit
• Gs : Adenylyl cyclase activation, Ca2+ channel opening
• Gi : Adenylyl cyclase inhibition, K+ channel opening
• Go : Ca2+ channel inhibition
• Gq : Phospholipase C activation

20. GPCRs
• Muscarinic receptor (M2): Gi, Go
• Muscarinic (M1): Gq
• β adrenergic: Gs
• α1 adrenergic : Gq
• α2 adrenergic: Gi

21. Ion channels
• Cell surface receptors
• Ligand gated ion channels
• They enclose ion channels (Na, K, Ca or Cl)
• Agonist binding opens the channel
This leads to change in ion composition….causing
depolarization/hyperpolarization
Eg: Nicotinic cholinergic receptor, GABA receptors

22. Transmembrane enzyme linked receptors
• These receptors have an extracellular ligand binding site
• It is connected through the transmembrance peptide to an
intracellular domain
• The intracellular domain has enzymatic property
• Eg. Insulin receptor

23. Transmembrane JAK-STAT binding receptors
• The intracellular domain does not have intrinsic enzymatic activity
• Binding of ligand induces dimerization which increases affinity for
cytosolic tyrosine protein kinase JAK (Janus Kinase)

24. Transmembrane JAK-STAT binding receptors
• On binding JAK, the tyrosine residues of the receptor are
phosphorylated…….and binds to STAT (another free moving protein)
• Pairs of phosphorylated STAT move to the nucleus to regulate gene
transcription
Eg: Receptors for cytokines, growth factors

25. Receptors regulating gene expressions
• These are intracellular receptors (cytoplasmic/nuclear)
• They bind to lipid soluble ligands which can penetrate the cell
• The receptor-ligand complex then translocates to the nucleus and
binds to gene-regulating elements
Eg: steroid receptor

26. Dose-response curve
• Intensity of response increases with increase in dose
• Dose-response curve is a rectangular hyperbola
E max : maximal response
EC 50 : dose of the drug at which half
maximal response is produced

27. When response is plotted against
log(dose), the curve become
sigmoid
Linear response is seen in the 30-
70% response zone
Wide range of drug doses can be
plotted
Comparison between agonist and
study of antagonists become easier
Dose-response curve

28. Potency
It refers to the amount of drug needed to
produce the same response.
Important for choosing the dose of the drug
The position of the DRC on the dose axis is the
index of drug potency.
DRC positioned rightwards indicates lower
potency

29. Efficacy
It refers to the maximal response that
can be elicited by the drug
The upper limit of the DRC is the
index of drug efficacy
Efficay is more important for choosing
the drug

30. Slope of DRC
• Steep slope indicates that a
small increase in dose will
markedly increase the response
• Flat slope indicates that little
increase in response occurs over
a wide dose range

31. DRC
• Compare Drug A, B, C and D

32. Therapeutic index
• DRCs for different effects of a
drug may be different.
The gap between the therapeutic effect DRC and the
adverse effect DRC defines the therapeutic index of
the drug
TI = LD50 / ED 50

33. Therapeutic window
• Therapeutic window is bounded
by the:
dose which produces minimal
therapeutic effect
and
dose which produces maximal
acceptable adverse effect

34. Combined use of drugs
Drugs can exhibit :
 Synergism
 Antagonism

35. Synergism
• Action of one drug is facilitated or increased by use of another drug
• Both the drugs can have action in the same direction
OR
• One drug is inactive but enhances the action of the other

36. Synergism
• Additive
• Supra-additive / Potentiation

37. Additive Synergism
The effect of two drugs is in the same direction and adds up
A + B = effect of drug A
+
effect of drug B

38. Additive synergism
Advantages :
• Side effects of the combination may not add up
• Combination is better tolerated than higher dose of one drug
Eg : aspirin + paracetamol
glibenclamide + metformin

39. Supra-additive synergism
• Effect of the combination is greater than the individual effect of the
drugs
• Occurs when one drug is inactive, but enhances the effect of the
other
Eg : levodopa + carbidopa
acetylcholine + physostigmine
Effect of drug (A+B) > effect of drug A
+
effect of drug B

40. Antagonism
• One drug decreases or abolishes the action of another drug
Effect of drug (A+B) < effect of drug A
+
effect of drug B

41. Antagonism
• Physical antagonism
• Chemical antagonism
• Physiological / functional antagonism
• Receptor antagonism

42. Receptor antagonism
• One drug blocks the receptor action of the other – it is selective in
nature
Types :
• Competitive antagonism
• Non-competitive antagonism
• Non-equilibrium antagonism

43. Receptor antagonism
Competitive antagonism:
• There is a parallel shift of the DRC
• No suppression of maximal
response
• Extent of shift depends on the
concentration of the antagonist

44. Factors affecting drug action
• Body size
• Age
• Sex
• Species/Race
• Genetics
• Routes of drug administration
• Environmental factors & time of
administration
• Psychological factors
• Pathological states
• Other drugs

45. Thank you