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

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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.

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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.

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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.

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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.

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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, aminobutyric acid can bind the GABA receptor allowing for an increase of Cl - influx.

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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 G, G and G. The binding of an agonist to the G protein will allow the G subunit to bind GTP and cause the G GTP subunit to disassociate from the G:G subunits. The G:G subunits will stay associated with the cellular membrane while the G GTP subunit will enter the cytosol. Both the G:G and G GTP subunits act as second messengers and can interact with effectors.

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G - Proteins The G 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 (IP 3 ) and diacylglycerol (DAG). IP 3 regulates intracellular free calcium concentrations DAG can activate protein kinase C.

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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.

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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.

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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.

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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.

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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.

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Population Dose Response

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Potency & Efficacy The potency is the amount of drug necessary to give 50% of the maximal effect (EC 50 ). 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.

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Relationship of Drug Binding on Pharmacologic Effect Lets 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)

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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

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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 E max. We can normalize the maximal effect to lesser effects by giving the maximal intrinsic effect a value of 1

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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.

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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.

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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.

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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.

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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.

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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.

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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 1 receptor by phenylephrine will cause vasoconstriction. While the binding of a 2 receptor by metaproterenol will cause vasodilation. This is functional antagonism.

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

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