Pharmacology - Introduction to Pharmacology and Pharmacodynamics - Pharmacodynamics Lecture PDF

PHARMACODYNAMICS Robert Theobald, Jr. Ph.D. Department of Pharmacology [email protected] I. KNOWLEDGE OBJECTIVES Students should be able to: 1. apply the concepts of pharmacodynamics to clinical problems. 2. define and discuss the various terms used in describing drug...

PHARMACODYNAMICS Robert Theobald, Jr. Ph.D. Department of Pharmacology [email protected] I. KNOWLEDGE OBJECTIVES Students should be able to: 1. apply the concepts of pharmacodynamics to clinical problems. 2. define and discuss the various terms used in describing drug-receptor interactions 3. describe drug-receptor interactions based on the ability of drugs to evoke or block physiological responses 4. explain simple dose-response curves that illustrate drug-receptor interactions 5. describe the superfamilies of receptors and the signal transduction mechanism coupled to these receptors Overview of Pharmacodynamics ►Terminology ►Receptors ►Drug Concentration and Response ►Antagonists ►Signaling Mechanisms  PHARMACODYNAMICS The study of the biochemical and physiological effects of drugs, their mechanisms of action, and how the drugs interact with the body.  Clinical Case 1 ► Billy Smith, a 24. y.o. office worker, comes into your clinic for his 6-month checkup. You note that he is a bit lethargic. Mr. Smith says that he has been taking over-the-counter medications for the treatment of seasonal allergies. He also says that he has been tired and groggy for the past 3 days. In examining his oral cavity, you note that the tissue is dry and red. ► Remember - Pharmacodynamics deals with what drugs do to the body. ► What are some of the relevant facts that are important here? ► What other information would be important?  My answers 1. Mechanism of Action of the drug. 2. Receptors affected by over-the-counter medications taken 1. Is this a receptor stimulation or blockade? 2. Is the blockade competitive? 3. Drug selectivity 4. Adverse effects of the drug 5. Potential drug-drug interactions 1. Does patient consume alcohol or other drugs on a regular basis?) 6. Patient’s age, co-morbidities, etc. Components of Pharmacology Pharmacogenetics and Pharmacogenomics Influences on Other Components  II. Definition of Terms A. PHARMACODYNAMICS The study of the biochemical and physiological effects of drugs and their mechanisms of action. for example: In the case of Billy Smith, the physiological effects of the drugs he was taking caused him to be tired. Do these drugs cause that effect? Which receptors would be involved? What is the site of action, central or peripheral? Would this be a problem for him? What if he were a construction worker or heavy machine operator? Receptors for Physiological Regulatory Molecules: Endogenous Ligands Receptors that are targets for drugs are generally also the targets for endogenous substances also, such as neurotransmitters and hormones. The majority of drugs have their pharmacodynamic effect mediated through receptors. ► Receptor Identification and Classification 1. PHARMACOLOGY 1. Specificity and Selectivity of Agonist and Antagonist Molecules 2. Endogenous vs Exogenous Ligands 1. Exogenous ligands more selectivity 2. LIGAND BINDING 1. Molecular biology studies can measure 3. MOLECULAR CLONING  Receptors As targets for drug actions, receptors can be broadly defined as: 1) Components of the organism with which a chemical agent, a drug or ligand, is presumed to interact. 2) Any cellular macromolecule to which a drug or ligand binds to initiate its effect Receptors have two essential functions: 1. Recognition of specific ligand molecule (Ligand binding domain) 2. Transduction of signal into response (Effector domain)  Drug Binding ► Drugs are chemicals that bind with specificity and selectivity to certain receptors. ► A selective drug would have the ability to discriminate between different cell populations to affect only one population, and thereby produce an event only in that population. ► A drug with specificity has the capacity to cause a particular action in a specific cell population. ► Drugs also possess certain characteristics or properties. ► Important Terminology ► Affinity: is the measure of how tightly or strongly a drug (ligand) binds to a receptor. ► Intrinsic Activity: is the ability of a drug to evoke a response or effect in a target by altering some activity in the target, such as stimulating G-protein activity. ► Efficacy: reflects the capacity of a drug to activate a receptor and generate a cellular response. Efficacy of a Drug ► Efficacy of a drug is the strength of a single drug- receptor interaction that evokes a response. ► Responses evoked by drugs can do several things: 1) Alter the rate at which bodily functions occur 1) Modulate intrinsic physiological functions 1) Cannot change the function of cells Caveat: With genetic interventions, that may be changing in the future of clinical application  More Terminology ► Agonists ► Drugs that bind to receptors and produce some effect similar to the response produced by endogenous agents, that is, ► they possess intrinsic activity (IA). ► Antagonists ► Drugs that bind to receptors but do NOT produce an effect, that is, ► they possess NO intrinsic activity (IA). Response No response Agonist: Has both high affinity as well as intrinsic activity such that IA=1. Full agonists trigger the maximal biological response or mimic maximally the effect of the endogenous substance. Ex:- Bethanechol is a cholinomimetic drug which mimics the effect of Ach on cholinergic receptors.  Types of antagonism Antagonism: Effect of two drugs is less than sum of the effects of the individual drugs. 1. Chemical antagonism Eg: Antacids, Chelating agents 2. Physiological /Functional antagonism A drug evokes a physiological/functional effect that interferes with the effect of another drug. Eg. propranolol alters epinephrine’s effect on blood pressure 3. Pharmacokinetic antagonism A drug affects the absorption, metabolism, and/or excretion of another drug to reduce the effect of the second drug. Eg. rifampin alters CYP metabolism of some drugs. 4. Pharmacological antagonism Competitive (Reversible)  Partial agonist :These drugs may have full affinity to bind to a receptor but with low intrinsic activity such that IA=0 to 1. They are only partly as effective as an agonist  Inverse agonist: These drugs have full affinity towards the receptor but their intrinsic activity is such that the drug produces an effect is just opposite to that of agonist such that IA= 0 to -1. ß-carboline is an inverse agonist for benzodiazepines receptors. III. Targets for Drug Action ► Receptors ► Ion Channels ► Enzymes ► Carrier Molecules TARGETS FOR DRUG ACTION Drug Target - Receptors Drug Target - Ion Channels Drug Target - Enzymes Drug Target - Transporters IV. FACTORS THAT AFFECT DRUG-RECEPTOR INTERACTIONS A. BINDING FORCES B. STRUCTURE ACTIVITY RELATIONSHIPS A. BINDING FORCES 1. IONIC 2. HYDROGEN 3. HYDROPHOBIC – from attraction that occurs between the hydrophobic chains of fatty acids or amino acids 4. VAN DER WAALS – WEAKEST ? 5. COVALENT - STRONGEST  B. STRUCTURE ACTIVITY RELATIONSHIPS The chemical structure of a drug affects its properties: 1. Affinity Selectivity and Specificity 2. Intrinsic Activity Efficacy V. Drug – Receptor Interactions A distinction between affinity and intrinsic activity Quantification of Drug Responses provides meaningful information about the effects of a drug and its usefulness Dose-Response (D-R) Curves quantify responses 1. Measurement of the physiological response. 2. Plotting the response in a D-R relationship. 3. The D-R curve cannot measure affinity of the drug for the receptor. A drug can bind tightly to a receptor with high affinity but have little efficacy, therefore, evoking only a small response. Another drug can bind weakly to a receptor, with low affinity, but can evoke a large response, having great efficacy.  QUANTIFICATION OF DRUG- RECEPTOR INTERACTIONS Drug Concentration at Receptor is not known. However, this concentration can be altered by several factors: 1) Metabolism/Degradation 2) Uptake into tissue 3) Diffusion from the site of action. This relationship can be graphically represented in two formats: 1. Quantal D-R Curve 2. Graded D-R Curve B. Dose – Response Curves ► 1. Quantal Relationships ► Based on All or None Responses ► Provides estimate of percent of subjects who will respond to any given dose ► 2. Graded Responses ► Based on data from single subjects ► Provides information about potency and efficacy QUANTAL DOSE RESPONSE CURVE: ALL-OR-NONE RESPONSE QUANTAL DOSE RESPONSE CURVE: ALL-OR-NONE RESPONSE  GRADED DOSE-RESPONSE CURVE Continuous Responses from a single subject  QUANTIFICATION OF DRUG-RECEPTOR INTERACTIONS All receptors don’t have to be occupied to evoke the maximum response. The maximum response of a receptor system is often evoked at a low percent of receptor occupancy. This fact leads to the conclusion of the presence of spare receptors.  SPARE RECEPTORS Spare receptors exist when the maximum drug response is achieved prior to binding saturation of all receptors. When occupied, spare receptors are coupled to the cellular response. Spare receptors are fully functional receptors, the same as all other receptors. They are only termed ‘spare’ because they don’t need to be bound to have a maximum response manifested. This means that you cannot directly correlate physiological responses to binding. ???? Questions ????  Antagonists ► Antagonists exhibit affinity for the receptor but do not have intrinsic activity at the receptor. ► An antagonist that binds to the receptor in a reversible mass- action manner is referred to as a competitive antagonist. ► Because the antagonist does not have intrinsic activity, once it binds to the receptor, it blocks binding of agonists to the receptor. ► A key point about competitive antagonists is that like agonists, they bind in a reversible manner.  Mechanisms of receptor antagonism Antagonists have specific characteristics: Competitive versus Non-competitive can the antagonist be displaced by an agonist? Reversible versus Irreversible or Pseudo-irreversible is the antagonism reversible? what is the nature of the binding of the antagonist to the receptor? Allosteric Nature does the antagonist bind to the same site at the agonist? Physiologic antagonism does the antagonist evoke its response through the same receptor system? Mechanisms of receptor antagonism Competitive antagonism occurs when the agonist A and antagonist I compete for the same binding site on the receptor. Response curves for the agonist are shifted to the right in a concentration-related manner by the antagonist such that the EC50 for the agonist increases (e.g., L versus L′, L′′, and L′′′) with the concentration of the antagonist. Mechanisms of receptor antagonism If the antagonist binds to the same site as the agonist but does so irreversibly (usually with a covalent bond) or pseudo-irreversibly (usually a slow dissociation but no covalent bond), it causes a shift of the dose- response curve to the right, with further depression of the maximal response. Mechanisms of receptor antagonism or P Allosteric effects occur when an allosteric ligand I or P binds to a different site on the receptor to either inhibit (I) the response (see panel C) or potentiate (P) the response (see panel D). This effect is saturable; inhibition or potentiation reaches a limiting value when the allosteric site is fully occupied.  Mechanisms of receptor antagonism Physiologic antagonism. When a response to an agonist drug is altered by a change, a physiological action produced by another drug that does NOT change the agonist drug-receptor interaction. It really causes a pertubation in the cellular response some way, usually through a different receptor system, this is a physiologic antagonism. For example, norepinephrine will cause a rise in heart rate because of stimulation of β1 receptors. If acetylcholine is administered at that time, the rise in heart rate will be obtunded because of stimulation of muscarinic receptors. Both receptors can alter phase 4 depolarization in the S-A node cells, but through different receptors systems. They physiologically antagonize the effect of the other drug. Key features of a competitive antagonist ► Important because most antagonists are competitive in nature. ► Reversible binding to the receptor. ► The blockade can be overcome by increasing the agonist concentration. (Remember the importance of spare receptors). ► The maximal response (efficacy) of the agonist is not decreased. ► The agonist dose-response curve in the presence of a competitive antagonist is displaced to the right, parallel to the curve in the absence of agonist. Partial Agonists/Antagonists Partial antagonists (or agonists) evoke a response that is less than maximal. These agents produce a response that is similar in characteristics of a full agonist, however, the maximum response is decreased. Partial Agonists/Antagonists Partial antagonists also can diminish the response of full agonists when administered prior to administration of the full agonist. Partial Agonists/Antagonists The interaction between full agonists and partial agonist/antagonist drugs is understood because of their binding at the same receptor site. Since they both bind to the same receptor site, they compete with each other for binding which is then reflected in the manifested response. Summary Normal Function Inverse Agonist Effects There are certain receptors that remain inherently in the R* state, even in the absence of an endogenous ligand or and exogenous agonist. These drugs, Inverse Agonists, inactivate these constitutively active receptors (R*) and prevent the basal physiological response that is manifested. The resulting effect of Inverse Agonist binding to this type of receptor places the receptor into the inactive state (R), and the effect is manifested as an opposite response of that to the expected agonist/drug response. Traditionally, G-protein coupled receptors were thought to be inactive and that agonist occupation was required to allow the receptor to assume an active conformation. Recently, though, it has been suggested that some receptors can be constitutively active without the presence of agonist. Constitutively active receptors are thought to be coupled to second messenger pathways in the absence of agonists. These receptors exist in a constitutively active state Agonist Responses  REGULATION OF RECEPTORS ► Changes in receptor sensitivity can occur: 1. Desensitization will diminish the response to a given dose of a drug. 1. Usually due to increased receptor exposure to the drug. 1. Altered binding of the drug to the receptor 2. Decreased coupling of the drug-receptor complex to the signaling mechanism 2. Supersensitivity will enhance the response to a given dose of a drug. 1. Usually due to decreased receptor exposure to the drug. 2. Can be drug induced 1. Can be pathophysiological Sensitivity Changes TACHYPHYLAXIS Phenylephrine Dose The same dose each time RECEPTOR DOWN-REGULATION  Targets for Drug Action Versus Receptor Superfamilies ► Receptors can respond to drug binding in several different ways. ► Targets ► Receptors ► Ion Channels ► Enzymes ► Transporters ► Receptor Superfamilies respond to drug binding in similar fashion. ► Channel-linked ► G-protein linked ► Kinase linked ► Nuclear receptors Receptor Superfamilies  Summary ► 1. Most drugs form reversible, stereo-selective bonds with receptors. ► 2. Both competitive and noncompetitive antagonists will shift D-R curve to the right. Only an irreversible antagonist will reduce maximum effect. ► 3. Graded D-R curves show relationship between dose and magnitude of effect. ► 4. Quantal D-R curves show relationship between dose and cumulative percent of subjects responding. ► 5. Since most drugs act at multiple receptor types, the clinical relevance of these concepts involves the fact that dose, affinity, intrinsic activity, and efficacy at different receptors determine whether a drug is beneficial or toxic.  Reading Assignments available online at AT Still Library ► In Access Medicine: ► Blumenthal D.K. (2017). Pharmacodynamics: molecular mechanisms of drug action. Brunton L.L., & Hilal- Dandan R, & Knollmann B.C.(Eds.), Goodman & Gilman's: The Pharmacological Basis of Therapeutics, 13e. McGraw Hill. https://accessmedicine.mhmedical.com/content.aspx?bookid=2189&sectionid=170349571. ► Zastrow M (2021). Drug receptors & pharmacodynamics. Katzung B.G., & Vanderah T.W.(Eds.), Basic & Clinical Pharmacology, 15e. McGraw Hill. https://accessmedicine.mhmedical.com/content.aspx?bookid=2988&sectionid=250594122 ► In Clinical Key: ► Pharmacology and Therapeutics for Dentistry / [edited by] Frank J. Dowd, Barton S. Johnson, Angelo J. Mariotti. 7th edition, 2017. Elsevier, St. Louis. ► L. Wecker, L. M. Taylor, D.A. and Theobald, R. J., eds. Chapter 1, Pharmacodynamics: Receptors and Concentration-Response Relationships, pp 4-19, In: Brody's Human Pharmacology: Molecular to Clinical, SIXTH EDITION, Copyright © 2019 Elsevier Inc.