1. Drug-Receptor Interactions Pharmacodynamics
Joseph De Soto MD, PhD, FAIC

2. Overview Pharmacodynamics refers to the action of a drug on the body.
The actions of drugs on the body are mediated by receptors.
Drug – receptor complexes will alter biochemical processes in the cell by a process called signal transduction.
A threshold level of binding must occur before there is a clinical response.

3. Drug – Receptor Complex
Cells have several types of receptors each of which is specific for a particular agonist.
Most receptors are named by the natural agonist that they bind to. For instance, serotonin binds the serotonin receptor.
An agonist maximally stimulates a receptor and can be either natural or a drug.
The magnitude of the response is proportional to the number of agonist- receptor complexes.
This response can quantified in the dose-response curve.

4. Receptor States
Receptors tend to exist in at least 2 states : inactive (R) and active (R*). At rest, R >>>> R*
Recall that receptors are macromolecules that move into different conformations.
Binding of the receptor with an agonist shifts the equilibrium to the R* conformation.

5. Major Receptor Families
A receptor is any biological molecule binds and produces a measurable response. Receptors are generally large protein macromolecules. Though nucleic acids and other molecules can act as receptors.
Once the receptor has been bound by an agonist the extracellular response must be transduced to an intracellular response. How this is done defines the major receptor families: 1) Ligand – gated ion channels, 2) G – protein coupled receptors, 3) enzyme linked receptors, and 4) Intracellular receptors.

7. Transmembrane Ligand Gated Ion Channels
A ligand gated channel contains an extracellular , transmembrane and intracellular domain forming a potential pore through the membrane.
The extracellular domain will bind the ligand/agonist and cause a conformational change in the channel allowing the channel to be open – usually for a few milliseconds.
As an example, λ aminobutyric acid can bind the GABA receptor allowing for an increase of Cl- influx.

9. Transmembrane G Protein-Coupled Receptors
This receptor also has an extracellular, transmembrane and intracellular domain. The intracellular domain that interacts with a G protein.
Each G- protein has three subunits Gα, Gβ and Gγ. The binding of an agonist to the G protein will allow the Gα subunit to bind GTP and cause the Gα – GTP subunit to disassociate from the Gβ:Gγ subunits.
The Gβ:Gγ subunits will stay associated with the cellular membrane while the Gα – GTP subunit will enter the cytosol.
Both the Gβ:Gγ and Gα – GTP subunits act as second messengers and can interact with effectors.

10. G - Proteins The Gα subunit has Gs, Gi, and Gq subtypes.
Adenylyl cyclase can be activated by Gs or inhibited by Gi in the production of the second messenger cyclic adenosine monophosphate (cAMP). Gi can also cause increased K+ conductance ↓ Ca2+ conductance
Gq can activate phospholipase C which can produce the two second messengers inositol 1,4, 5 – trisphosphate (IP3) and diacylglycerol (DAG). IP3 regulates intracellular free calcium concentrations
DAG can activate protein kinase C.

12. Enzyme Linked Receptors
These receptors may form dimers or other multisubunit complexes when bound with a natural ligand or drug.
These dimers or multisubunit complexes can autophosphorylate different subunits of its own complex and own other protein kinases or enzymes.
Among some of the enzyme linked receptors are the epidermal growth factor , insulin, and atrial natriuretic peptide receptors.

14. Intracellular Receptors
Receptors that lie in the interior of the cell will bind lipid soluble ligands or drugs.
May of the ligand – receptor complexes will dimerize allowing for the dimerized ligand – receptor complex to travel to the cellular nucleus. Where they will bind a transcription factors. Steroids generally act by this mechanism.
Other intracellular ligands are structural proteins , enzymes, RNA and ribosomes. An example is when the antibiotic erythromycin binds the ribosome.

16. Signal Amplification
Signal transduction phenomena have the important characteristics of 1) being able to amplify small signals and 2) mechanisms to protect the cell from overstimulation.
Due to this amplification only a fraction of the total receptors for a specific ligand may need to be bound to elicit a maximal response. The insulin receptor is an example.
These “extra” receptors are called spare receptors. Extra receptors ensure that a small amount of ligand can elicit a maximal response. Sensitivity is increased.

18. Desensitization and Down Regulation of Receptors
Repeated or constant stimulation of a ligand may lead to desensitization of the receptor – in a short period of time. This is called tachyphylaxis. In a long period of time we get the phenomena of tolerance usually do to down regulation of the receptor.
Ion channels for example, once stimulated may undergo a conformational change such that they may be unable to bind or respond to another ligand for a set period of time.
Alternatively, the number of receptors on the membrane surface may be down regulated by having some of the receptors internalized and either sequestered or destroyed within the cell.

21. Dose – Response Relationships
Agonist drugs mimic the action of natural ligands that the body produces.
As the concentration of the drug increases more receptors are activated. Each drug – receptor complex causes a small quantal effect. Several quantal effects together will cause a biological response once threshold is met.
As more drug-receptors complexes are formed the biological effect increases until a maximal amount. At this point , more receptor – complexes will not add to the biological effect.

22. Population Dose Response

23. Potency & Efficacy
The potency is the amount of drug necessary to give 50% of the maximal effect (EC50).
The efficacy is the maximum effect that a drug can cause. The efficacy of a drug is more important than its potency.
As an example assume drug A and B have equal efficacy but drug A is more potent than drug B. One just needs to add more of drug B to meet the effect of drug A at any level.
However, if drug A were more effective than drug B no matter how much of drug B that we added could reach the maximal effect of drug A.

26. Relationship of Drug Binding on Pharmacologic Effect
Let’s make the following assumptions: 1) the biological response is proportional to the number of receptor bound by an agonist 2) that Emax occurs when all the receptors are bound (no spare receptors) and that 3) binding of the receptors does not involve cooperatively.
We can then derive the Michaelis - Menten type equation:
E = (Emax) D____
Kd + D
D = drug concentration , Kd = binding affinity (recall higher the Kd the lower the affinity)

27. Effect vs Drug Concentration
E = (Emax) D____
Kd + D
E = (Emax) D____ high D or low Kd D
E ≈ Emax
E = (Emax) D__ low D or high Kd
Kd Kd
E ≈ D/kd + C ; y = mx + C

29. Full Agonist
If a drug binds to a receptor and produces a maximal biological response that mimics the endogenous ligand , the drug is considered a full agonist , in general we shorten this to agonist.
All full agonists to a specific receptor produce the same maximum biological effect Emax.
We can normalize the maximal effect to lesser effects by giving the maximal intrinsic effect a value of 1

30. Partial Agonists
Partial agonist will bind a receptor but not produce the maximal biological response. Compared to an agonist the partial agonist will have an intrinsic value of between 0 and 1.
A partial agonist may have a binding affinity less than , equal to or greater than the agonist.
In the presence of an agonist a partial agonist will act as an antagonist.

32. Antagonist
Antagonist bind to the receptor without activating the receptor. They usually do so with a greater binding affinity than the agonist.
Antagonist act by preventing the agonist from binding the receptor or blocking the agonists ability to activate the receptor.
There are 1. Competitive 2. Irreversible 3. Allosteric and functional antagonists.

33. Competitive Antagonist
Competitive antagonist bind the receptor reversibly at the same location that an agonist does.
The competitive antagonist prevents the agonist from binding the receptor.
A competitive antagonist can be overcome by increasing the amount of agonist.

35. Allosteric Antagonist
An allosteric antagonist binds to a receptor reversibly to a site different from the agonist.
The binding of the receptor by an allosteric may still allow an agonist from binding to the receptor but will prevent the agonist from activating the receptor.
An allosteric antagonist will also lower Emax and cannot be overcome by adding more agonist.
Like irreversible antagonist an allosteric antagonist is considered irreversible.

37. Irreversible Antagonist
Irreversible antagonist bind irreversibly by covalent binds to a receptor eliminating from the pool of available receptors that an agonist can bind.
This lowers the Emax of the system and adding more agonist will not be able to overcome the binding of the irreversible antagonist to the receptor.
Irreversible antagonist and allosteric antagonist are both noncompetitive antagonist.

39. Inverse Agonists
Receptors tend to be inactive when not bound . However, due to random motion at the molecular level some receptors will spontaneously activate without being bound.
Inverse agonists will bind the inactive form of the receptor R and prevent even the random motion of the receptor to the active form R*.
An inverse agonist will have a intrinsic value of less than 0.

41. Functional Antagonist
A functional antagonist involves the binding of a different receptor by an agonist that causes the opposite effect of the agonist receptor interaction that we are considering.
For example the binding of the α1 receptor by phenylephrine will cause vasoconstriction. While the binding of a β2 receptor by metaproterenol will cause vasodilation.
This is functional antagonism.

42. Therapeutic Index
The therapeutic index (TI) of a drug is the the dose that produces toxicity in 50% of the population TD50 divided by the dose that produces the desired effective response ED50 in 50% of the population.
TI = TD50 / ED50
The TI is a measure of the drugs safety with the larger numbers indicating greater safety.