PHARMACODYNAMICS-PHARMACODYNAMICS basics.ppt

PHARMACODYNAMICS

1. TAY JU LEE MD
INTI
Pharmacodynamic
s
What the drug does to the
body?

2. Overview
Drug(Ligand) + Receptor ⇋ Drug-receptor
complex  Biologic effect
“A drug doesn’t work unless it is bound”
Drugs only modify underlying biochemical
and physiological processes, they do not
create effects de novo (anew)

3. •DRUG RECEPTOR INTERACTION
•DRUG DOSE-RESPONSE
RELATIONSHIP
•THERAPEUTIC INDEX
Topics of Discussion

4. Chemistry of Receptors and Ligands
Drugs typically exert their effects by interacting with
a receptor
Chemical bonds
Electrostatic
Hydrogen bond
Van der Waals
Binding
Receptor selective
Requires exact fit
Usually reversible
+

5. Types of receptor-effector linkage: E, enzyme; G, G-protein; R, receptor.

6. Major Receptor Families
1.Ligand-Gated Ion Channels
Regulation of flow of ions across cell membranes
Depolarization/Hyperpolarization of membrane
Associated with receptors for fast neurotransmitters
Nicotic receptor - Na
+

8. Major Receptor Families
2.G-Protein coupled receptors – Largest family
3 components
7 membrane-spanning α helices
G protein – α subunit - GTPase & βγ
cAMP / IP3/ Phospholipase A2/ ion Ch
Four Steps
Ligand binding
G protein activation (cytoplasmic side)
Activity of effector (ion channel or enzyme) changed
Intracellular second messenger concentration changes
cAMP: effector enzyme -- adenylyl cyclase, converting ATP to
cAMP – phosphorylates proteins

9. G-Protein Coupled Receptor
Zoya Maslak, Yuri Rashkin - The G Protein Story.flv
http://www.youtube.com/watch?v=K7WSMybZeA8

10. Major Receptor Families
3.Kinase-linked receptors
Cytosolic enzyme activity as integral structure or function
Most common tyrosine kinase activity (Kinase = Phosphate)
Addition of phosphate changes 3D structure of protein
Insulin

11. Insulin Tyrosine Kinase Animation
TK Receptor Animation.flv
http://www.youtube.com/watch?v=-iBb1sH-Eh4
Insulin Signaling (Signal Pathways).flv
http://www.youtube.com/watch?v=FkkK5lTmBYQ

12. Major Receptor Families
4.Nuclear receptors
TWO main categories
Those present in cytoplasm form complex with ligand – migrate
to the nucleus eg. Steroid hormones
Present in nucleus – ligands usually lipids
Binds to specific DNA sequences resulting in regulating gene
sequences – protein synthesis
Longer time course of action
Responsible for 10% of pharmacology and the
pharmacokinetics of 60% of all prescription drugs

13. •DRUG RECEPTOR INTERACTION
•DRUG DOSE-RESPONSE
RELATIONSHIP
•THERAPEUTIC INDEX
Topics of Discussion

14. Drug Dose-Response Relationship
Graded dose-response relations
Drug-Receptor binding
Relationship of binding to effect
Potency
Efficacy
Nature of interactions
Agonists
Antagonists
Functional antagonism
Partial agonists

15. Drug-receptor Binding
Effect of dose on the
magnitude of drug binding
Relationship of binding to
effect assumes
Magnitude proportional to
receptors bound
Maximum efficacy when all
receptors bound
Binding does not show
cooperation
Interactive Pharmacology

16. Potency
Graded dose-response curve shows potency
Determine Effective Concentration 50% EC50
50%

17. Efficacy
Efficiency is dependent on number of drug-receptor
complexes formed and corresponding cellular
response
A drug with more efficacy is better than drug with
more potency
http://www.icp.org.nz/icp_t7.html

18. Nature of Interactions
Agonist
If a drug binds to a receptor and produces a biologic response
that mimics the response to the endogenous ligand
Partial agonist
Has intrinsic activity less than that of a full agonist

19. Theoretical occupancy and response
curves for full vs partial agonists
The occupancy curve is for both drugs, the response curves a and b are for full
and partial agonist, respectively.
 The relationship between response and
occupancy for full and partial agonist, corresponding to the response curves in
A. Note that curve a produces maximal response at about 20% occupancy,
while curve b produces only a submaximal response even at 100% occupancy.

20. Nature of Interactions
Antagonist
Drugs that decrease the actions of the endogenous ligand.
Reversible vs Irreversible
Functional antagonism (physiologic antagonism)
Antagonist binds completely separate receptor initiating
effects functionally opposite of the agonist
Epinephine binding to (β
2 adrenergic receptor )
reversing Histamine-induced bronchoconstriction (H
1

receptor)

21. Reversible vs irreversible competitive
antagonists
A.Reversible competitive
antagonism – log
concentration-effect curve
shifts to right without
change in slope maximum
B.Irreversible competitive
antagonism – Covalent bond
formed with receptor eg.
Aspirin & Omeprazole
1 = 50% occupancy
http://www.icp.org.nz/icp_t14.
html

22. Body adapts to drugs
Change in receptors
Refractory period after effect of first dose - Desensitisation
Loss or addition of receptors
Internalization of receptors due to prolonged exposure to
agonist – and converse.
Exhaustion of mediators
Amphetamine release cathecholamine – stores depleted
Increased metabolic degradation of drug
Tolerance
Physiological adaptation

23. •DRUG RECEPTOR INTERACTION
•DRUG DOSE-RESPONSE
RELATIONSHIP
•THERAPEUTIC INDEX
Topics of Discussion

24. Therapeutic Index
Therapeutic index is the ratio of the dose that
produces toxicity : dose for clinically desired effective
response (50% o f population)
Therapeutic Index = TD50/ ED50
http://www.icp.org.nz/icp_t7.html?htmlCond=3

25. Summary
Drugs only modify underlying biochemical and
physiological processes, they do not create effects
de novo (anew)
4 ways drugs and receptors interact - KING
Dose-Response Curve
Potency vs Efficacy
4 Nature of Interactions
Body adapts to drug
Therapeutic Index

26. References
Howland et al (2006) Lippincott’s Pharmacology 3
rd

Ed.
Rang et al (2007) Rang & Dale’s Pharmacology 6
th

Ed.
Videos and websites in slides