Barry University PharmD/PhD Drug Receptors Exam Notes PDF

Barry University Christiane Chbib PharmD/PhD Drug Receptors Ion & Channels By the end of the class, you can do the following: Pharmacodynamics Quiz (tulane.edu)...

Barry University Christiane Chbib PharmD/PhD Drug Receptors Ion & Channels By the end of the class, you can do the following: Pharmacodynamics Quiz (tulane.edu) 1 SPM620/ Dr Christiane Chbib Learning objectives 1. Describe the physiology of receptors types 2. Explain the major steps &/or second messenger (as applicable) 3. Understand how a ligand or a drug regulates each receptor type 4. Describe the relation between drug concentration (@receptor) and response (due to action) 5. Explain a drug-response curve as a hyperbolic function or log-transformed 6. Define the following: Agonist, antagonist, partial agonist, right-shift, left-shift and antagonism 7. Differentiate between: potency, maximal efficacy, tolerance and tachyphylaxis, and selectivity SPM620/ Dr Christiane Chbib 2 Drug Receptors Pharmacodynamics describes the actions of a drug on the body and the influence of drug concentrations on the magnitude of the response. Therapeutic and toxic effects of drugs result from their interactions with molecules in the human body called “Receptor”. Receptors are responsible for selectivity of drug action. Drug Receptors largely determine the quantitative relations between dose or concentration of drug and pharmacologic effects. The molecular size, shape, and electrical charge of a drug determine whether and with what affinity it will bind to a particular receptor Recepto r SPM620/ Dr Christiane Chbib 3 Why does a specific drug X exert a certain action? 81 mg (dose) Aspirin can cause blood thinning (response) which can be plotted on a graph termed: dose- response curve. The affinity of a receptor to a specific molecule will determine the concentration needed for this molecule to produce a response. The interaction between a drug and a receptor is specific. Dose-response curve SPM620/ Dr Christiane Chbib 4 Why does a specific drug X exert a certain action? The receptor mediates the action of the agonist or antagonist. Agonist: An agent which activates a receptor to produce an effect similar to that of the physiological signal molecule Antagonist: An agent which prevents the action of an agonist on a receptor, but does not have any effect of its own Antagonists: Antagonists do not activate a signal generation. Antagonists do NOT produce a reverse signal of the agonist. Antagonists occupy the receptor and block the ability of an agonist to activate the receptor. SPM620/ Dr Christiane Chbib 5 Agonist/ Antagonist examples SPM620/ Dr Christiane Chbib 6 Signal transduction 1 2 The binding of drug to its receptor generates signal transduction and elicits a biological response. 3 Second messenger or effector molecules are part of the downstream cascade of events that translates agonist binding into a cellular response. 4 7 SPM620/ Dr Christiane Chbib Drug-receptor interactions: Receptor states Receptors exist in at least two states, inactive (R) and active (R*); R and R* are in reversible equilibrium with each other Binding of agonists causes the equilibrium to shift from R to R* to produce a biologic effect. Antagonists occupy the receptor but do not shift the receptor state to R* Partial agonists shifts receptor state to R*, but the fraction of R* is less than that caused by an agonist. The magnitude of biological effect is directly related to the fraction of R*. 8 SPM620/ Dr Christiane Chbib Dose-response relationship The magnitude of the drug effect depends on the drug concentration at the receptor site determined by both the dose of drug administered and by the drug’s pharmacokinetic profile, such as rate of absorption, distribution, metabolism, and elimination. Kd Drug [ D]  Re ceptor [ R]   [ D  R ]Complex (Re sponse ) As the concentration of a drug increases, its pharmacologic effect also gradually increases until all the receptors are occupied (the maximum effect (Emax)). Two important properties of drugs that can be determined by graded dose–response curves are potency and efficacy. Kd = Dissociation constant of the D-R complex = Concentration of the drug that binds to 50% of the available receptors EC50= Concentration of drug that produces 50% of the maximal response 9 SPM620/ Dr Christiane Chbib Relations between drug concentration and drug effect (A) or receptor-bound drug (B) Maximal response All available receptors EC50= Concentration of drug that produces 50% of the maximal response Kd = Concentration of the drug that binds to 50% of the available receptors 10 SPM620/ Dr Christiane Chbib Copyright © 2016 McGraw-Hill Education. All rights reserved. Potency (EC50) The concentration of drug producing 50% of the maximum effect (EC50) is usually used to determine potency. EC50 for Drugs A and B indicate that drug A is more potent than Drug B, because a lesser amount of Drug A is needed when compared to Drug B to obtain 50-percent effect. SPM620/ Dr Christiane Chbib 11 Question EC50 is used to describe: a) the potency of the drug b) The efficacy of the drug c) The toxicity of the drug d) The affinity of the drug Answer a EC50 is: a) the concentration of drug that exerts 50% of the intrinsic activity b) the concentration of the drug that produces 70% of the intrinsic activity c) the concentration of the drug that produces 25 % of intrinsic activity d) the concentration of the drug that produces no intrinsic activity Answer a SPM620/ Dr Christiane Chbib 12 Efficacy (Emax) Efficacy is the magnitude of response a drug causes when it interacts with a receptor. Efficacy is dependent on the number of drug–receptor complexes formed (its ability to activate the receptors and cause a cellular response). Maximal efficacy of a drug is called Emax; Emax is used to compare the efficacy between different drugs. Emax assumes that all receptors are occupied by the drug, and no increase in response is observed even if a higher concentration of drug is administered. SPM620/ Dr Christiane Chbib 13 Active Learning 14 SPM620/ Dr Christiane Chbib Binding affinity (Kd) A drug's affinity refers to the chemical forces that cause a substance to bind its receptor. It tells us how attracted a drug is to its receptors. It measure the tightness/strength with which a drug binds to the receptor. Kd = the equilibrium dissociation constant for the drug from the receptor. The value of Kd can be used to determine the affinity of a drug for its receptor. The higher the Kd value, the weaker the interaction and the lower the affinity, and vice versa. Kd Kd 50 50 SPM620/ Dr Christiane Chbib 15 Question Kd 50 is used to describe: a) the potency of the drug b) The efficacy of the drug c) The toxicity of the drug d) The affinity of the drug Answer d SPM620/ Dr Christiane Chbib 16  Intrinsic activity (IA) or efficacy Full agonist is a drug that binds to a receptor and produces a maximal biologic response that mimics the response to the endogenous ligand. All full agonists for a receptor population should produce the same Emax. For example, phenylephrine is a full agonist at α1-adrenoceptors, because it produces the same Emax as does the endogenous ligand, norepinephrine (NE). They both cause vasoconstriction upon binding to the receptor. Partial agonists have intrinsic activities greater than zero but less than the full agonist. Even if all the receptors are occupied, partial agonists cannot produce the same Emax as a full agonist. However, a partial agonist may have an affinity that is greater than, less than, or equivalent to that of a full agonist. So, it can bind to the receptor with same affinity as the full agonist, but its pharmacological action is less. Spare receptors is a certain number of receptors that exist in excess of those required to produce a full effect. https://www.youtube.com/watch?v=UKblVJmlQ-I 17 SPM620/ Dr Christiane Chbib Example of the torch FULL AGONIST Strong light beam PARTIAL AGONIST Weak light beam SPM620/ Dr Christiane Chbib 18 Question Which of the following drugs is the MOST or LEAST efficacious? Which of the following drugs is the MOST or LEAST potent? 19 SPM620/ Dr Christiane Chbib Partial agonist Graph : When each of the two drugs is used alone and response is measured, occupancy of all the receptors by the partial agonist produces a lower maximal response (less Emax) than does similar occupancy by the full agonist SPM620/ Dr Christiane Chbib 20 Inverse agonist and Antagonist Inverse agonists exert the opposite pharmacological effects of agonists when they bind to the receptors. Antagonists bind to a receptor with high affinity but possess zero intrinsic activity. An antagonist has no effect in the absence of an agonist but it can decrease the effect of an agonist when present. 21 SPM620/ Dr Christiane Chbib Receptor agonist and antagonists Allosteric site: site at the receptor other than the Active site (usually of the agonist) There are allosteric activator and inhibitors 22 SPM620/ Dr Christiane Chbib Competitive antagonist If both the antagonist and the agonist bind to the SAME site on the receptor in a REVERSIBLE manner, they are said to be competitive The competitive antagonist prevents an agonist from binding to its receptor and maintains the receptor in its inactive state. However, this inhibition can be overcome by increasing the concentration of agonist relative to antagonist. Thus, competitive antagonists characteristically shift the agonist dose–response curve to the right (increased EC50) without affecting Emax. 23 SPM620/ Dr Christiane Chbib Competitive antagonist can be overcome by increasing the concentration of agonist relative to antagonist SPM620/ Dr Christiane Chbib 24 Non-competitive antagonist Non-competitive antagonists bind to a site on the receptor other than the agonist binding site. It causes a downward shift of the Emax, with no shift of EC50 values. In contrast to competitive antagonists, the effect of non-competitive antagonists cannot be overcome by adding more agonist. It can NOT be displaced by increasing concentration of agonist. (They are considered irreversible antagonists) Competitive agonists reduce agonist potency (increase EC50), while non-competitive antagonists reduce agonist efficacy (decrease Emax). Allosteric antagonists are also non-competitive antagonists. https://www.youtube.com/watch?v=nFfPAklivHU SPM620/ Dr Christiane Chbib 25 Major types of receptors Receptors may be classified into four classes: Ligand-gated ion channels: most rapid response to receptor activation/ causes conformational changes of the receptor Transmembrane G protein-coupled receptors (GPCR): most abundant Transmembrane enzyme-linked receptors has catalytic activity and cytosolic domain (linked to the cytosol) Transmembrane tyrosine kinase receptors Intracellular receptors: in cytoplasm or nucleus/ their ligands are the most lipid soluble SPM620/ Dr Christiane Chbib 26 Major Types of Receptors 1. Intracellular 2.Transmembrane 3. Transmembrane 4. Ligand/voltage-gated 5. G protein-coupled receptors enzyme-linked tyrosine kinase ion channels receptors receptors receptors SPM620/ Dr Christiane Chbib Kinase: adds a phosphate that comes from ATP 27 Intracellular receptors: Several biologic ligands are sufficiently lipid- soluble to cross the plasma membrane and Formed of act on intracellular phospholipids receptors. One class of such ligands includes steroids (corticosteroids), and thyroid hormone Ligand lipophilicity SPM620/ Dr Christiane Chbib 28 Transmembrane Receptors (Enzyme linked & Tyrosine Kinase) Examples are receptors mediating the signaling of insulin These receptors consist of an extracellular ligand-binding domain and a cytoplasmic enzyme domain which may be a protein tyrosine kinase. Kinase refers to adding a phosphate atom (phosphorylation) – figure of tyrosine kinase linked Extracellular ligand binding Cytoplasmic enzyme Active state forming a dimer domain SPM620/ Dr Christiane Chbib Inactive state 29 Ligand and voltage-gated ion channels The extracellular portion of ligand-gated ion channels contains the ligand binding site. 2 types of channels exist: a. The first type of the ion-channels opens to allow passage of ion when a ligand binds i.e. Ligand-gated channels. b. The second type opens when a certain voltage change takes place i.e. voltage-gated channels. Usually activated by changes in the electrical membrane (polarization; depolarization…) potential near the channel 30 SPM620/ Dr Christiane Chbib G-protein coupled receptor G-protein means: GTP –binding signal transducer protein. The extracellular domain of this receptor contains the ligand-binding area. When the receptor is activated by binding to a ligand, the intracellular domain interact with a G-protein. There are many kinds of G proteins like, Gs, Gi and Gq. They all are composed of a trimeric three protein subunits. The α subunit binds guanosine triphosphate (GTP), and the β and γ subunits anchor the G protein in the cell membrane. www.youtube.com/watch?v=Glu_T6DQuLU 31 SPM620/ Dr Christiane Chbib G-protein coupled receptor Conformational change When the agonist binds to the receptor, the α subunit binding GTP dissociates from the βγ subunits Sometimes, the activated effectors produce second messengers that further activate other effectors in the cell, causing a signal cascade effect. A common effector, activated by Gs and inhibited by Gi, is adenylyl cyclase, which produces the second messenger cyclic adenosine monophosphate (cAMP). SPM620/ Dr Christiane Chbib 32 G-protein Coupled Receptors (GPCRs) * * G Protein Actions G-stimulatory activates adenylyl cyclase (Gαs) G- inhibitory (Gαi) inhibits adenylyl cyclase Gαq Activates Phospholipase C Signal Transduction Pathways (G-Protein, Receptor Tyrosine Kinase, cGMP) ( 33 youtube.com) SPM620/ Dr Christiane Chbib G-protein Coupled Receptors (GPCRs) 34 SPM620/ Dr Christiane Chbib Question Once a G-protein coupled receptor (GPCR) has bound to its ligand, which of the following steps allows the α subunit to dissociate from the receptor and trigger downstream cascades? a. Exchanging the G-protein’s bound GDP for a GTP b. Exchanging the G-protein bound ADP for an ATP c. Exchanging the G-protein association with a magnesium ion for a calcium ion d. Degradation of the GPCR’s C-termina tail that is bound too the α subunit Answer a SPM620/ Dr Christiane Chbib 35 Desensitization and down-regulation Tachyphylaxis: When a receptor is exposed to repeated administration of an agonist, the receptor becomes desensitized resulting in a diminished effect. This phenomenon, called “Tachyphylaxis”. Tachyphylaxis is defined as diminished response due repeated administration. Down or up-regulation Receptors may be down-regulated such that they sequestered within the cell and become unavailable for further agonist interaction. These receptors may be recycled to the cell surface (in case of up-regulation), restoring sensitivity, or, alternatively, may be further degraded (in case of down-regulation), decreasing the total number of receptors available. During this recovery phase, unresponsive receptors are said to be “refractory.” Repeated exposure of a receptor to an antagonist may result in up-regulation of receptors, in which receptor reserves are inserted into the membrane, increasing the total number of receptors available Tolerance: Tolerance refers to a gradual decreased response to a drug, requiring a higher dose of drug to achieve the same initial response. Tolerance is different from tachyphylaxis because it develops over a long period of time, whereas tachyphylaxis is an acute event. In addition, tolerance can be overcome by increasing the dose, unlike tachyphylaxis. 36 SPM620/ Dr Christiane Chbib Tachyphylaxis vs Tolerance Drug Administration Drug Administration Tolerance Tachyphylaxis Tolerance SPM620/ Dr Christiane Chbib 37 Question What is Tachyphylaxis? a) Increased number of receptors due to upregulation b) increased response to the drug multiple administration c) diminished response to the drug due to repeated administration d) increased response to the drug due to a single administration Answer c SPM620/ Dr Christiane Chbib 38 Question SPM620/ Dr Christiane Chbib 39 KAHOOT SPM620/ Dr Christiane Chbib 40 Question SPM620/ Dr Christiane Chbib 41 Question SPM620/ Dr Christiane Chbib 42 Question SPM620/ Dr Christiane Chbib 43 Question SPM620/ Dr Christiane Chbib 44 SPM620/ Dr Christiane Chbib 45