1. Pharmacodynamics What the drug does to the body?
Tay Ju Lee MD
INTI

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)
“A drug doesn’t work unless it is bound”

3. Topics of Discussion Drug receptor interaction
Drug Dose-response relationship
Therapeutic INdex

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 +
Handful are covalent bonds
VDW is the sum of the attractive or repulsive forces between molecules (or between parts of the same molecule)
Synonym of totality of intermolecular forces. Van der Waals forces are relatively weak compared to normal chemical bonds,

5. Mnemonic KING
Kinase-linked receptors
ligand gated Ion channels
Nuclear receptors
G-protein-coupled receptors
Types of receptor-effector linkage: E, enzyme; G, G-protein; R, receptor.

6. Major Receptor Families
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
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
Guanine - Go between
These are sometimes called metabotropic receptors.
Structures comprise seven membrane-spanning α-helices, often linked as dimeric structures.
One of the intracellular loops is larger than the others and interacts with the G-protein.
The G-protein is a membrane protein comprising three subunits (α, β, γ), the α subunit possessing GTPase activity.
When the trimer binds to an agonist-occupied receptor, the α subunit dissociates and is then free to activate an effector (a membrane enzyme or ion channel). In some cases, the βγ subunit is the activator species.
Activation of the effector is terminated when the bound GTP molecule is hydrolysed, which allows the α subunit to recombine with βγ.
There are several types of G-protein, which interact with different receptors and control different effectors.
Examples include muscarinic acetylcholine receptors, adrenoceptors, neuropeptide and chemokine receptors, and protease-activated receptors.
receptor – Gets the job done once authorised by hormone

9. G-Protein Coupled Receptor
The function of the G-protein. The G-protein consists of three subunits (α, β, γ), which are anchored to the membrane through attached lipid residues. Coupling of the α subunit to an agonist-occupied receptor causes the bound GDP to exchange with intracellular GTP; the α-GTP complex then dissociates from the receptor and from the βγ complex, and interacts with a target protein (target 1, which may be an enzyme, such as adenylate cyclase, or an ion channel). The βγ complex may also activate a target protein (target 2). The GTPase activity of the α subunit is increased when the target protein is bound, leading to hydrolysis of the bound GTP to GDP, whereupon the α subunit reunites with βγ.
Zoya Maslak, Yuri Rashkin - The G Protein Story.flv

10. Major Receptor Families
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
Insulin Signaling (Signal Pathways).flv

12. Major Receptor Families
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
A family of 48 soluble receptors that sense lipid and hormonal signals and modulate gene transcription.
Two main categories:
those that are present in the cytoplasm, form homodimers in the presence of their partner, and migrate to the nucleus. Their ligands are mainly endocrine in nature (e.g. steroid hormones).
those that are generally constitutively present in the nucleus and form heterodimers with the retinoid X receptor. Their ligands are usually lipids (e.g. the fatty acids).
A third subgroup transduce mainly endocrine signals but function as heterodimers with retinoid X receptor (e.g. the thyroid hormone).
The liganded receptor complexes initiate changes in gene transcription by binding to hormone response elements in gene promoters and recruiting coactivator or corepressor factors.
The receptor family is responsible for the pharmacology of approximately 10%, and the pharmacokinetics of some 60%, of all prescription drugs.

13. Topics of Discussion Drug receptor interaction
Drug Dose-response relationship
Therapeutic INdex

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

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 (β2 adrenergic receptor ) reversing Histamine-induced bronchoconstriction (H1 receptor)

21. Reversible vs irreversible competitive antagonists
Reversible competitive antagonism – log concentration-effect curve shifts to right without change in slope maximum
Irreversible competitive antagonism – Covalent bond formed with receptor eg. Aspirin & Omeprazole
1 = 50% occupancy

22. Body adapts to drugs Change in receptors Loss or addition of 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. Topics of Discussion Drug receptor interaction
Drug Dose-response relationship
Therapeutic INdex

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

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 3rd Ed.
Rang et al (2007) Rang & Dale’s Pharmacology 6th Ed.
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