Drug-Receptor Concepts 1 PDF

WEEK 11 MPharm Programme Drug-Receptor Concepts 2 Dr G Boachie-Ansah [email protected] Dale 113 ext. 2617 MPharm PHA112 Drug Receptor Concepts WEEK 11 Drug-Receptor Interactions What happens when a drug binds to its receptor? Slide 24 of 76 MPharm PHA112 Drug Recept...

WEEK 11 MPharm Programme Drug-Receptor Concepts 2 Dr G Boachie-Ansah [email protected] Dale 113 ext. 2617 MPharm PHA112 Drug Receptor Concepts WEEK 11 Drug-Receptor Interactions What happens when a drug binds to its receptor? Slide 24 of 76 MPharm PHA112 Drug Receptor Concepts WEEK 11 Consequences of Drug-Receptor Interaction One of four possible things can happen The drug may mimic a natural, endogenous chemical messenger  produce the same effect as the natural chemical messenger (called an ‘Agonist’ drug) The drug may ‘block’ the receptor, i.e. prevent the natural chemical messenger from binding  produce no effect (called an ‘Antagonist’ drug) Slide 25 of 76 MPharm PHA112 Drug Receptor Concepts WEEK 11 Consequences of Drug-Receptor Interaction One of four possible things can happen (cont’d) The drug may bind to a site near the binding site for a natural, endogenous chemical messenger & influence its binding   or  the effect of the natural chemical messenger (called an ‘Allosteric modulator’) The drug may bind to the site normally occupied by a natural, endogenous chemical messenger  produce an opposite effect to the natural chemical messenger (called an ‘Inverse Agonist’ drug) Slide 26 of 76 MPharm PHA112 Drug Receptor Concepts WEEK 11 Types of Drug-receptor Interaction Agonist Antagonist Positive Allosteric Modulator Negative Allosteric Modulator Slide 27 of 76 MPharm PHA112 Drug Receptor Concepts WEEK 11 Drug Agonism & Antagonism What is the basic distinction between ‘Agonist’ & ‘Antagonist’ drugs? Both have ‘affinity’ for their receptors ‘a measure of the ease with which a drug binds to its receptor’ ‘a measure of the probability that a drug molecule will interact with a receptor to form a drug-receptor complex’ ‘Affinity’ expresses the chances of the drug binding to its receptor (By analogy, a key fitting into a lock) affinity is measured by the KD of the drug Affinity = 1/KD Slide 28 of 76 MPharm PHA112 Drug Receptor Concepts WEEK 11 Drug Agonism & Antagonism What is the basic distinction between ‘Agonist’ & ‘Antagonist’ drugs? Agonist drugs have ‘efficacy’, whereas antagonist drugs have no ‘efficacy’ ‘a measure of the ability of the drug-receptor complex to couple or transduce the drug binding into a biological response’ ‘Efficacy’ expresses the ability of the drug to ‘activate’ or cause a conformational change in the receptor that will lead to a biological response. (By analogy, the key turning the lock) ‘efficacy’ (e) may be 0, low or very high Slide 29 of 76 MPharm PHA112 Drug Receptor Concepts WEEK Agonist Drug Action 11 Agonist ‘a drug that binds to its receptor, activates the receptor, and elicits a biological response’ Two types of Agonist Full agonist Partial agonist Slide 30 of 76 MPharm PHA112 Drug Receptor Concepts Agonist Drug Action WEEK 11 Full Agonist binds to its receptor, activates the receptor & is capable of eliciting the maximum possible response has high efficacy (e) e.g. dobutamine, salbutamol Partial Agonist binds to its receptor and activates the receptor, but can only elicit less than the maximum possible response intermediate efficacy (e) reduces the response elicited by the full agonist e.g. buprenorphine, oxymetazoline Slide 31 of 76 MPharm PHA112 Drug Receptor Concepts WEEK 11 Slide 32 of 76 Full vs Partial Agonist MPharm PHA112 Drug Receptor Concepts Antagonist Drug Action WEEK 11 Antagonist (pharmacological) ‘a drug that binds to its receptor but fails to activate the receptor, and so fails to elicit a response’ it has an efficacy (e) of 0 it competes with the agonist drug (or natural chemical messenger) for binding to the receptor its biological ‘effect’ results from preventing the agonist drug (or natural chemical messenger) from binding to its receptor e.g. atenolol, chlorphenamine, naloxone Slide 33 of 76 MPharm PHA112 Drug Receptor Concepts WEEK Drug-Receptor Interactions 11 The 'Spare Receptor' / 'Receptor Reserve' concept exceptions to the ‘receptor occupancy theory’ full agonists may elicit maximum response without full receptor occupancy system is said to have ‘spare receptors’ or a ‘receptor reserve’ enables economy of hormone / transmitter secretion allows low affinity drugs to elicit maximum possible response Slide 34 of 76 MPharm PHA112 Drug Receptor Concepts WEEK 11 Drug-Receptor Interactions Characteristics of the Graded Dose-Response Curve Slide 35 of 76 MPharm PHA112 Drug Receptor Concepts WEEK Intensity of Effect 11 Log Drug Concentration Slide 36 of 76 MPharm PHA112 Drug Receptor Concepts WEEK Characteristics of the Graded Dose-Response Curve 11 Potency A measure of amount of drug needed to elicit a specified response reflected in the location of D-R curve along dose axis experimentally expressed as ED50 or EC50 clinically expressed as absolute or relative potency not a critical characteristic of the drug e.g. morphine vs diamorphine (heroin) Slide 37 of 76 MPharm PHA112 Drug Receptor Concepts WEEK Potency 11 Slide 38 of 76 MPharm PHA112 Drug Receptor Concepts WEEK Characteristics of the Graded Dose-Response Curve 11 Maximal efficacy maximal response / effect produced by the drug reflected as a plateau in the log D-R curve the most important characteristic of drug e.g. paracetamol vs morphine maximal efficacy may be determined or limited in clinical practice by the onset of adverse side effects! Slide 39 of 76 MPharm PHA112 Drug Receptor Concepts WEEK 11 Slide 40 of 76 Maximal Efficacy MPharm PHA112 Drug Receptor Concepts WEEK Characteristics of the Graded Dose-Response Curve 11 Slope slope of curve varies from drug to drug reflects the magnitude of change in response per unit change in dose the slope may be an important consideration in clinical practice under certain circumstances! Slide 41 of 76 MPharm PHA112 Drug Receptor Concepts WEEK Characteristics of the Graded Dose-Response Curve 11 Biological variability different responses to same dose of drug in different individuals different responses to same dose of drug in same individual possible sources of variation in drug response Age Gender Genetic factors Polypharmacy Pathological state Slide 42 of 76 MPharm PHA112 Drug Receptor Concepts WEEK 12 Slide 44 of 76 Drug-Drug Interactions MPharm PHA112 Drug Receptor Concepts WEEK Drug-Drug Interactions 12 Drug Antagonism Summation / Additivity Synergism / Potentiation Slide 45 of 76 MPharm PHA112 Drug Receptor Concepts Drug-Drug Interactions WEEK 12 Drug Antagonism ‘interaction between two drugs such that the effect of one is diminished or completely abolished in the presence of the other’ Types of drug antagonism Competitive antagonism (pharmacological / receptor) Non-competitive antagonism Chemical antagonism Pharmacokinetic antagonism Physiological or Functional antagonism Slide 46 of 76 MPharm PHA112 Drug Receptor Concepts WEEK Drug Antagonism 12 Competitive Antagonism the agonist & antagonist drugs compete for same receptor binding site antagonist drug binding reduces chances of agonist binding   agonist effect 2 subtypes, depending on nature of antagonistreceptor interaction Reversible or surmountable Irreversible or insurmountable Slide 47 of 76 MPharm PHA112 Drug Receptor Concepts Competitive Antagonism WEEK 12 Reversible Competitive Antagonism both the agonist & antagonist drugs bind reversibly to the receptor the fraction of receptors occupied depends on 2 drugs’ relative receptor affinities & concentrations antagonism can be overcome by increasing concentration of agonist drug this leads to two effects on the agonist log D-R curve (in the presence of an effective dose of the antagonist drug) a parallel shift to the right no reduction in the maximal response Slide 48 of 76 MPharm PHA112 Drug Receptor Concepts WEEK Competitive Antagonism 12 100 E Emax 50 0 Agonist Concentration Slide 49 of 76 MPharm PHA112 Drug Receptor Concepts WEEK Competitive Antagonism 12 Irreversible Competitive Antagonism the antagonist drug binds irreversibly to the receptor (due to high affinity or covalent bonding) a fraction of receptors rendered permanently unavailable for agonist drug binding the antagonism cannot be overcome by increasing concentration of agonist drug this leads to two effects on the agonist log D-R curve (in the presence of an effective dose of the antagonist drug) a reduction in the slope of the curve a reduction in the maximal response Slide 50 of 76 MPharm PHA112 Drug Receptor Concepts WEEK 12 Irreversible Competitive Antagonism System Without Spare Receptors 100 E Emax 50 0 Log Agonist Concentration Slide 51 of 76 MPharm PHA112 Drug Receptor Concepts WEEK 12 Irreversible Competitive Antagonism System with Spare Receptors 100 Irreversible Antagonist Log Agonist Concentration Slide 52 of 76 MPharm PHA112 Drug Receptor Concepts WEEK Drug Antagonism 12 Non-competitive Antagonism the antagonist drug does not compete with agonist drug for same receptor binding site the antagonist drug may bind to a different site on the receptor or interfere with response coupling the antagonism cannot be overcome by increasing concentration of agonist drug this leads to two effects on the agonist log D-R curve (in the presence of an effective dose of the antagonist drug) a reduction in the slope of the curve a reduction in maximal response Slide 53 of 76 MPharm PHA112 Drug Receptor Concepts WEEK Non-competitive Antagonism 12 100 E Emax 50 0 Log Agonist Concentration Slide 54 of 76 MPharm PHA112 Drug Receptor Concepts WEEK Drug Antagonism 12 Chemical Antagonism results from direct interaction between the antagonist & agonist drugs the ‘antagonist’ drug binds to / combines with the active drug (‘agonist’) in solution the active drug is rendered inactive or unavailable to interact with its target receptors typical examples protamine vs heparin dimercaprol vs heavy metals (Cd, Pb) Slide 55 of 76 MPharm PHA112 Drug Receptor Concepts Drug Antagonism WEEK 12 Pharmacokinetic Antagonism the ‘antagonist’ drug acts to reduce the effective concentration of the active drug (‘agonist’) at its site of action possible mechanisms reduced absorption from the GIT ferrous salts vs tetracycline antibiotics increased metabolic degradation phenobarbital vs warfarin increased renal excretion NaHCO3 vs aspirin Slide 56 of 76 MPharm PHA112 Drug Receptor Concepts Drug Antagonism WEEK 12 Physiological / Functional Antagonism interaction of two opposing agonist effects in a single biological system  cancelling out of each other’s effect the two drugs elicit opposing responses by acting on different receptors typical examples acetylcholine vs noradrenaline (heart rate) glucocorticoids vs insulin (blood sugar levels) Slide 57 of 76 MPharm PHA112 Drug Receptor Concepts WEEK Summation / Additivity 12 Summation When the combined effect of two drugs which elicit the same overt response, regardless of their mechanism of action, is equal to the algebraic sum of their individual effects Additivity When the combined effect of two drugs, which act by the same mechanism, is equal to that expected by simple addition of their individual effects Slide 58 of 76 MPharm PHA112 Drug Receptor Concepts WEEK Synergism / Potentiation 12 Synergism or Potentiation When the conjoint effect of two drugs is greater than the algebraic sum of their individual effects the synergist may act to increase the concentration of the other drug at its receptor sites tyramine & MAO inhibitors increase the responsiveness of the other drug’s receptor-effector protein benzodiazepines & GABA (GABAA receptor) Slide 59 of 76 MPharm PHA112 Drug Receptor Concepts WEEK 12 Synergism / Potentiation GABAA Receptor Ion channel Slide 60 of 76 MPharm PHA112 Drug Receptor Concepts WEEK 12 Synergism / Potentiation Potentiation By Benzodiazepines Slide 61 of 76 MPharm PHA112 Drug Receptor Concepts WEEK 12 MPharm Programme Drug-Receptor Concepts 4 Dr G Boachie-Ansah [email protected] Dale 113 ext. 2617 MPharm PHA112 Drug Receptor Concepts WEEK 12 Slide 63 of 76 Variation in Drug Responsiveness MPharm PHA112 Drug Receptor Concepts WEEK 12 Variation in Drug Responsiveness Definitions, Types & Mechanisms Drug Tolerance Definitions Mechanisms Slide 64 of 76 MPharm PHA112 Drug Receptor Concepts WEEK 12 Variation in Drug Responsiveness Scope inter-patient variation intra-patient variation Possible consequences lack of efficacy unexpected side effects Possible mechanisms pharmacokinetic pharmacodynamic Slide 65 of 76 MPharm PHA112 Drug Receptor Concepts WEEK 12 Variation in Drug Responsiveness Possible types of variation qualitative variations quantitative variations Quantitative variations Hyper-responsiveness Hypo-responsiveness or tolerance Tolerance Innate vs acquired tolerance Tolerance vs Tachyphylaxis Slide 66 of 76 MPharm PHA112 Drug Receptor Concepts Acquired Tolerance WEEK 12 Definitions ‘An acquired state of progressively decreasing responsiveness to a drug as a result of prior or repeated exposure to the drug or another drug with a similar action’ Mechanisms Pharmacodynamic Metabolic Exhaustion / Depletion of mediators Physiological adaptation Slide 67 of 76 MPharm PHA112 Drug Receptor Concepts WEEK 12 Mechanisms of Acquired Tolerance Pharmacodynamic Receptor ‘down-regulation’ reduction in receptor density e.g. 1-adrenergic receptor Receptor ‘uncoupling’ uncoupling of receptors from their effector systems e.g. 2-adrenergic receptor Metabolic enhanced metabolism of the drug due to induction of metabolising enzymes e.g. alcohol, barbiturates, etc Slide 68 of 76 MPharm PHA112 Drug Receptor Concepts WEEK 12 Mechanisms of Acquired Tolerance Exhaustion / Depletion of mediators common with indirectly-acting drugs due to depletion of endogenous stores of mediators of the drug’s action Amphetamine, nitrates Physiological adaptation evoked compensatory or homeostatic mechanisms blunts or cancels the drug’s effects Diuretics, nitrates Slide 69 of 76 MPharm PHA112 Drug Receptor Concepts WEEK 12 Clinical Selectivity Slide 70 of 76 MPharm PHA112 Drug Receptor Concepts WEEK 12 Clinical Selectivity Absolute vs Relative Selectivity Therapeutic or Desirable effects vs Adverse or Undesirable or Side effects Concept of Therapeutic Index Slide 71 of 76 MPharm PHA112 Drug Receptor Concepts WEEK Clinical Selectivity 12 Absolute vs Relative Selectivity no drug has only one single, specific effect drugs produce a spectrum of effects hence ‘relative’, not ‘absolute’, selectivity of drug action relative selectivity ‘the degree to which a drug acts upon a given site relative to all possible sites of interaction’ Slide 72 of 76 MPharm PHA112 Drug Receptor Concepts WEEK Clinical Selectivity 12 Therapeutic vs Undesirable / Side effects drug effects split into therapeutic & undesirable undesirable effects may be minor or serious how do undesirable effects come about? both effects may be mediated via same receptor-effector mechanism – e.g. nitrates, insulin, warfarin both effects may be mediated via identical receptors located in different tissues – e.g. haloperidol, verapamil both effects may be mediated via different types of receptors – e.g. salbutamol, propranolol Slide 73 of 76 MPharm PHA112 Drug Receptor Concepts WEEK 12 Concept of Therapeutic Index Therapeutic Index Determined by the ratio of toxic to therapeutic dose median toxic dose (TD50) Therapeutic Index = median effective dose (ED50) Provides a useful measure of the margin of safety of the drug the benefit to risk ratio of the drug e.g. penicillin vs warfarin Slide 74 of 76 MPharm PHA112 Drug Receptor Concepts WEEK 12 Slide 75 of 76 Concept of Therapeutic Index MPharm PHA112 Drug Receptor Concepts WEEK Recommended Reading 12 Katzung BG, Trevor AJ. Basic & Clinical Pharmacology, 15th Edition. New York: McGraw-Hill Education, 2021. ISBN: 978-1260452310. Ritter JM et al. Rang & Dale’s Pharmacology, 10th Edition. London: Elsevier, 2023. ISBN: 978-0323873956. Slide 76 of 76 MPharm PHA112 Drug Receptor Concepts WEEK 11 MPharm Programme Drug-Receptor Concepts 1 Dr Gabriel Boachie-Ansah [email protected] Dale 113 ext. 2617 MPharm PHA112 Drug Receptor Concepts WEEK 11 Outline of Lectures What is Pharmacology? Drug-Receptor Concepts Drug-Receptor Interactions Drug-Drug Interactions Variation in Drug Responsiveness Clinical Selectivity Slide 2 of 76 MPharm PHA112 Drug Receptor Concepts WEEK Learning Outcomes 11 At the end of this lecture, you should be able to: Define and distinguish between ‘pharmacology’, ‘pharmacodynamics’ & ‘pharmacokinetics’ Explain how drugs act to produce their effects Describe the various types of drug targets or receptors Define and distinguish between an agonist, a partial agonist & an antagonist Describe how drug-receptor binding translates into a biological effect Define & discuss the importance of therapeutic index Slide 3 of 76 MPharm PHA112 Drug Receptor Concepts WEEK 11 Basic Principles of Drug Action What is Pharmacology? Drugs & The Human Body Drug taking initiates 2 processes action of the drug on the body action of the body on the drug Slide 4 of 76 MPharm PHA112 Drug Receptor Concepts WEEK Drug-Body Interactions 11 “When we have a headache, we take for granted that after taking some aspirin, our headache will probably disappear within 15 to 30 minutes. We also take for granted that, unless we take more aspirin later, the headache may recur within a few hours. This familiar scenario reveals the primary events of pain relief: The first is the administration and absorption of the drug into the body; the second is the distribution of the drug throughout the body; the third is the interaction of the drug with relevant functional components of the body, which are responsible for the drug’s actions; and the fourth is the elimination of the drug from the body”. RM Julien Slide 5 of 76 MPharm PHA112 Drug Receptor Concepts WEEK 11 Basic Principles of Drug Action What is Pharmacology? Drugs & The Human Body Drug taking initiates 2 processes action of the drug on the body action of the body on the drug Study of this ‘drug-body interaction’ called ‘pharmacology’ Slide 6 of 76 MPharm PHA112 Drug Receptor Concepts WEEK 11 Branches of Pharmacology (Traditional) Pharmacology ‘The study of the interaction between drugs & the living body’ Pharmacodynamics Pharmacokinetics ‘The study of the effects of drugs on the living body and how the effects are produced’ ‘The study of how the body deals with or handles drugs’ Pharmacotherapeutics ‘The study of the use of drugs in the treatment & prevention of disease’ Slide 7 of 76 MPharm PHA112 Drug Receptor Concepts WEEK 11 Drug-Receptor Concepts How Do Drugs Act? Slide 8 of 76 MPharm PHA112 Drug Receptor Concepts WEEK How Do Drugs Act? 11 Drugs interact with biological systems in ways that mimic, or otherwise affect, the natural chemical messengers or processes of the body Two types of drug action Non-specific drug action Some drugs act in a simple physical or chemical manner – e.g. antacids, osmotic diuretics, osmotic laxatives lack any specific structure-activity relationship require large doses of drug for effect Slide 9 of 76 MPharm PHA112 Drug Receptor Concepts WEEK How Do Drugs Act? 11 Two types of drug action Specific drug action Most drugs act in a highly specific manner – e.g. phenylephrine, salbutamol, atropine, digoxin they interact with or bind to specific macromolecular or cellular targets in the body, called ‘receptors’ show clear-cut structure-activity relationship produce biological effects at very low doses Slide 10 of 76 MPharm PHA112 Drug Receptor Concepts WEEK 11 The Idea of the Drug ‘Receptor’ The Drug Receptor Concept ‘Most drugs produce their biological effects by interacting with specific macromolecules in the body, called receptors’ The Receptor ‘The specialised component of the cell or organism that interacts with a drug, and initiates the chain of biochemical events leading to the drug's observed biological effects’ Slide 11 of 76 MPharm PHA112 Drug Receptor Concepts WEEK 11 The Drug Target or ‘Receptor’ Drug receptors are protein or glycoprotein molecules Most drug receptors are located on the cell membrane e.g. atenolol, chlorphenamine, cimetidine, codeine Some drug receptors are located inside the cell e.g. oestrogen, testosterone, vitamin D, etc Slide 12 of 76 MPharm PHA112 Drug Receptor Concepts WEEK 11 Drug Targets or Receptors are Protein or Glycoprotein Entities 1-adrenergic Receptor GABAA Receptor Slide 13 of 76 MPharm PHA112 Drug Receptor Concepts WEEK Drug Targets or ‘Receptors’ 11 Multiple Types of Drug Targets or ‘Receptors’ ‘Classical’ receptors – regulatory protein or binding sites for endogenous or natural chemical messengers, such as neurotransmitters & hormones Ion channels – e.g. lidocaine, diazepam, amiodarone Enzymes – e.g. NSAIDs, Statins, ACE inhibitors Carrier or transport proteins – e.g. digoxin, PPIs, SSRIs Slide 14 of 76 MPharm PHA112 Drug Receptor Concepts WEEK 11 Drug-Receptor Interactions How do drugs and receptors interact? Slide 15 of 76 MPharm PHA112 Drug Receptor Concepts Drug-Receptor Interactions WEEK 11 Drugs bind to receptors because the drug’s molecular structure & shape are similar to those of the natural chemical messengers the body produces to target those receptors There must be a complementary fit between the drug molecule & the binding site on the receptor Drug & receptor interact to form a drug-receptor (D-R) complex via a reversible chemical reaction The drug-receptor interaction is governed by the Law of Mass Action We can relate drug concentration & biological effect to the fraction of receptors occupied by the drug Slide 16 of 76 MPharm PHA112 Drug Receptor Concepts WEEK 11 Drug-Receptor Interactions The ‘Lock and Key’ Relationship basis of selectivity of drug action chemical selectivity biological or tissue selectivity Slide 17 of 76 MPharm PHA112 Drug Receptor Concepts WEEK 11 Drug-Receptor Interactions Drug & receptor interact to form a D-R complex via a reversible chemical reaction Drug + Receptor  Drug-receptor complex k1 D + R == DR k2 The fraction of receptors occupied by the drug is a function of: the concentration of drug in the biophase the equilibrium dissociation constant (KD) for drugreceptor complex Slide 18 of 76 MPharm PHA112 Drug Receptor Concepts WEEK Fractional Occupancy 11 Drug Concentration-Receptor Occupancy Curve Concentration of drug Slide 19 of 76 MPharm PHA112 Drug Receptor Concepts Drug-Receptor Interactions WEEK 11 The ‘Receptor Occupancy Theory’ Assumptions drug effect is proportional to the fraction of receptors occupied maximum drug effect (Emax) occurs when all receptors in the system are occupied by the drug Slide 20 of 76 MPharm PHA112 Drug Receptor Concepts Drug Concentration-Effect Curve WEEK 11 E Emax Drug Concentration Slide 21 of 76 MPharm PHA112 Drug Receptor Concepts WEEK 11 Log Drug Concentration-Effect Curve E Emax Log Drug Concentration Slide 22 of 76 MPharm PHA112 Drug Receptor Concepts