January 25, 2015 Introduction to Pharmacology Edward Fisher, Ph.D., R.Ph. Professor and Associate Dean for Academic Affairs Director MS Clinical Psychopharmacology University of Hawaii at Hilo College of Pharmacy fishere@hawaii.edu 1
Ligands Ligand: a molecule, or a molecular group that binds to another chemical entity to form a larger complex. In the field of pharmacology, it is a molecule, as a hormone or a drug, which binds to a receptor Molecules that carry signals for cellular communication Endogenous ligands Exogenous ligands Toxins Drugs 2
Introduction to Pharmacology Pharmacology: the study of substances that interact with living systems through chemical processes. Medical pharmacology therapeutic application Toxicology undesirable effects of chemicals on living systems Pharmacodynamics: the actions of the drug on the body. How the drug affects you Biochemical effects, mechanism of action (MOA) Drug classification Pharmacokinetics: the actions of the body on the drug. How you affect the drug Absorption, distribution, metabolism, & excretion Involved with the time course of the drug in the body 3
1. DRUG ADMINISTRATION 2. PHARMACOKINETICS Effects of the body on drugs: Absorption Distribution Elimination Metabolism 3. PHARMACODYNAMICS Effects of drugs on the body: Receptor-mediated responses 4
Introduction to Pharmacology Receptor: part of an organism or cell (macromolecule) that interacts with a ligand (drug, endogenous molecule) causing a chain of biochemical events leading to an observable response. Active states vs. inactive states Inert Binding Site: a component of the biologic system to which a drug binds without changing any function 5
Introduction to Pharmacology Drug: any substance that brings about a change in biologic function through its chemical actions. Endogenous synthesized in the body (hormones) Xenobiotics chemicals not synthesized by the body Drug: Pharmacy definition: Articles intended for use in the diagnosis, cure, mitigation, treatment or prevention of disease in man or other animals. 6
Principles Of Drug-Receptor Interaction Drugs generally exert their effects by: 1) Mimicking the actions of endogenous chemicals at receptors Example: Activation of mu opioid receptors by opioid analgesics ( pain killers ) such as morphine, codeine, and meperidine Endogenous Opioids (enkephalins, endorphins) Mu Opioid Receptor Opioid Drug (e.g., morphine) ANALGESIA 7
Principles Of Drug-Receptor Interaction Drugs generally exert their effects by: 2) By blocking the actions of endogenous chemicals at receptors Example: Blockade of the dopamine receptors by the antipsychotic drug Haloperidol Dopamine D 2 Dopamine Receptor Haloperidol extracellular intracellular Psychotic Symptoms 8
Principles Of Drug-Receptor Interaction Drugs generally exert their effects by: 3)By Inhibiting enzymes Examples Monoamine oxidase inhibitor phenelzine (Nardil ) COX2 (cyclooxygenase-2) inhibitor celecoxib treatment of inflammatory disorders 9
Principles Of Drug-Receptor Interaction Drugs generally exert their effects by: 4) By modulating the function of membrane transporters Examples NE transporter (NET) adrenomimetic drugs (Ephedrine, Amphetamines) Serotonin transporter antidepressants (Paroxetine) 10
Principles Of Drug-Receptor Interaction Activation of the same type of receptor can produce a variety of different physiological effects depending on its location Example: Activation of beta 2 adrenergic receptors in the lungs vs. liver Lungs Epinephrine Liver Beta 2 Adrenergic Receptors Relaxation of bronchial smooth muscle Breakdown of glycogen 11
Principles Of Drug-Receptor Interaction Inhibition of the same type of receptor can produce a variety of different physiological effects depending on its location Example: Haloperidol - Potent D₂ blockade nigrostriatal causes EPS - Dopaminemesolimbic treats positive symptoms 12
Drug-receptor Binding DRUG RECEPTOR chemical structure binding site The Lock and Key Model Receptor Activation = Biochemical Response Estrogen Receptor Estrogen 13
Introduction to Pharmacology Drug targets biomolecules that have a role in the disease process and are considered to be the site of action for drug therapy (receptors, enzymes, DNA, ion channels, transport proteins) 14
Introduction to Pharmacology Agonist: a drug that binds to and activates a receptor which brings about an effect. Albuterol β 2 -selective adrenoceptor agonist 15
Introduction to Pharmacology Antagonist: a drug that binds to a receptor and prevents agonists from binding; do not activate receptor; blockers. No direct effect, the antagonistic effect results from the prevention of agonist binding and activation of the receptor Atropine antagonist for muscarinic cholinoceptors Curare - antagonist for nicotinic cholinoceptors Generally they are structurally bulky to prevent receptors from going back to active confirmation, and so that they have more sites for receptor interaction 16
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Introduction to Pharmacology Partial Agonist: a drug that binds to a receptor and activates it, but the effect is not as great as with a full agonist. Are agonists if no full agonist is present; are antagonists if a full agonist is present Pindolol partial β receptor agonist Many drugs that act as competitive antagonists are really partial agonists Inverse Agonist: a drug that binds to a receptor and stabilizes it in the inactive conformation. Constitutively active receptors active without binding to agonist 18
A Full Agonist An Antagonist A Partial Agonist Receptor X Receptor X Activation State A No Activation Activation State B Maximal Effect No Effect Sub-maximal Effect 19
Introduction to Pharmacology Regulation of the activity of a receptor with conformationselective drugs 20
Two-state Model 21
Rinactive R active
10 R inactive 10 R active
10 R inactive 10 R active Add 8 INVERSE AGONISTS that bind to inactive receptor molecule and stabilize it
2 R inactive 10 R active New equation
6 R inactive 6 R active 4 Active Receptors are converted to 4 inactive
6 R inactive 6 R active Fewer active receptors with constitutive activity
A Little Background on Drugs Sources A drug is a substance that brings about a change in biologic function through its chemical actions. Endogenous Exogenous (xenobiotics) States Solids Liquids Gases Size Drugs do not create effects they modulate function = Chemicals foreign to the biological system in question Vast majority of drugs have a MW between 100 1000 MW 100 helps achieve selective receptor binding MW 1000 inhibits diffusion-mediated distribution 28
Drug Receptors & Pharmacodynamics Receptors: 1.) Determine the quantitative relations between dose or concentration of drug and pharmacologic effects receptor number in various target tissues 2.) Are responsible for selectivity of drug action Affinity determined by chemical forces that cause drug to bind to the receptor Efficacy change in confirmation toward the active state Intrinsic activity ability to evoke maximal effect after binding 3.) Mediate the actions of both pharmacologic agonists and antagonists receptor classes, subtype, and isoforms 29
Receptor: Class α β Subtype α 1 α 2 Isoforms α 1a α 1b 30
A Closer Look at Selectivity Selectivity is a number of receptor types with which a drug will interact Lower selectivity = increased incidence of adverse effects Drug A More Selective Drug B Less Selective Receptor X Receptor X Receptor Y Therapeutic Effect Only A Therapeutic Effect and a Adverse Effect 31
A Closer Look At Affinity The affinity of a drug for a receptor describes how readily and tightly that drug binds to its receptor High affinity = good drug-receptor interaction; LESS drug needed to produce a response Low affinity = poor drug receptor interaction; MORE drug needed to produce a response Example: Affinity for mu opioid receptor: fentanyl > morphine > meperidine Dose typically used for analgesia: fentanyl: 0.1 mg; morphine: 10 mg; meperidine: 100 mg 32
A Closer Look At Intrinsic Activity Intrinsic activity describes the ability of a drug to activate a receptor and produce a physiological response when it binds to a receptor Agonists: bind to the receptor and activate it, producing a physiological response Have intrinsic activity Antagonists: Receptor antagonists bind to the receptor but do not change its function. However, they prevent activation by endogenous chemicals or other drugs Do not have intrinsic activity 33
Some drug s MOA do not involve receptors: antacids, osmotic diuretics 34
Regulatory Proteins: Enzymes: Types of Receptors Mediate actions of most drugs and endogenous chemicals (neurotransmitters, hormones, autocoids) Best characterized Usually through inhibition Methotrexate inhibits dihydrofolate reductase Transport Proteins: Digoxin inhibits Na +, K + ATPase Structural Proteins: Colchicine inhibits tubulin Prevents polymerization of microtubules 35
Aspects of Drug Receptor Function Relationship between drug concentration (dose) & pharmacologic response 36
Relationship Between Dose & Response Concentration Effect curves = Dose Response curves Hyperbolic curve; concentration-effect reflects concentrationreceptor binding From: Basic & Clinical Pharmacology, B.G. Katzung (Ed.), 2007 McGraw-Hill Companies 37
Occupation theory Magnitude of pharmacological effect is proportional to percentage of receptors occupied 38
Relationship Between Dose & Response E MAX maximal response that can be produced by drug EC 50 concentration of drug that produces 50% maximal effect K d concentration of free drug at which there is 50% maximal binding equilibrium dissociation constant; measure of affinity low K d high affinity slow dissociation high K d low affinity rapid dissociation From Receptor From: Basic & Clinical Pharmacology, B.G. Katzung (Ed.), 2007 McGraw-Hill Companies 39
Relationship Between Dose & Response Sigmoidal curve Expands region of low drug concentration Linear mid-portion Compresses higher portion From: Basic & Clinical Pharmacology, B.G. Katzung (Ed.), 2007 McGraw-Hill Companies 40
Relationship Between Dose & Response Receptor-Effector Coupling: Transduction process between occupancy & drug response Coupling efficiency based on 1.) extent of conformational change (full agonist-full response, partial agonist-partial response) and 2.) biochemical events that transduce occupancy into response 41
Relationship Between Dose & Response Competitive Antagonist: Reversibly competes with agonist for receptor binding Antagonism can be overcome by concentration of agonist Effect is influenced by: Concentration of antagonist Concentration of agonist that is competing for binding to receptors Propranolol vs. Norepi Effects vary widely in individuals due to differences in clearance Exercise can overcome effect From: Basic & Clinical Pharmacology, B.G. Katzung (Ed.), 2007 McGraw-Hill Companies 42
Relationship Between Dose & Response Irreversible (noncompetitive) Antagonist: Antagonism cannot be overcome by concentration of agonist Dependent on own rate of elimination Phenoxybenzamine irreversible α adrenoceptor antagonist control hypertension due to pheochromocytoma in case of overdose, cannot competitively activate receptor From: Basic & Clinical Pharmacology, B.G. Katzung (Ed.), 2007 McGraw-Hill Companies 43
Relationship Between Dose & Response Full agonist at single concentration Full agonist at single concentration From: Basic & Clinical Pharmacology, B.G. Katzung (Ed.), 2007 McGraw-Hill Companies 44
Relationship Between Dose & Response Allosteric Antagonist: Binds to another part of the molecule Chemical Antagonist: A drug may bind to and inactivate another drug Protamine used to counteract heparin Desferrioxamine chelates iron Physiological Antagonist: One type of functional antagonism agonists that oppose via action on a different receptor or system Use of a separate endogenous regulatory pathway Glucocorticoids vs. insulin in controlling blood glucose Effects are less specific & more difficult to control 45
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Aspects of Drug Receptor Function Relationship between dose and clinical response 47
Relationship Between Dose & Clinical Response Maximal benefit with minimal toxicity Graded dose-response relationship: Potency EC 50 or ED 50 (dose needed for 50% of drug s maximal effect) Dependent on affinity (K d ) and Efficiency of coupling response Maximal efficacy limit of the dose-response relationship; important for clinical effectiveness Dependent on ability to reach relevant receptors Route of administration, absorption, site of action 48
Relationship Between Dose & Clinical Response Potency = dose needed for 50% of drug s maximal effect Drugs A & B are more potent than drugs C & D The pharmacologic potency of A is less than that of B Drug A has a larger maximal efficacy than drug B Drugs A, C, & D have equal maximum efficacy which is greater than the maximum efficacy of B From: Basic & Clinical Pharmacology, B.G. Katzung (Ed.), 49 2007 McGraw-Hill Companies
Relationship Between Dose & Clinical Response A very steep curve implies: Cooperative actions of different systems Need great majority of receptors to be occupied Narrow therapeutic range 50
Intensity of response A Closer look at Potency Potency: Describes the amount of a drug required to produce a specific effect Represented by the ED 50 The lower the ED 50, the more potent the drug Determines the drug dose that will be used clinically 50% More potent More Less 1 100 Log dose Less potent 51
A Closer Look At Efficacy Intensity of response Efficacy: Describes the maximal effect that a drug can produce Represented by the E max The greater the E MAX, the more efficacious the drug Determines clinical effectiveness 20 10 More 1 Less Log dose More efficacious Less efficacious 52
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Relationship Between Dose & Clinical Response Therapeutic index TD 50 /ED 50 Digoxin narrow Benzodiazepines and antipsychotics - wide 54
Cumulative Quantal Dose-response Curve and Drug Safety Indices Therapeutic window the range of doses of a drug or of its concentration in a bodily system that provides safe and effective therapy Narrow vs. wide therapeutic window 55
The clinically acceptable risk of toxicity depends critically on the severity of the disease being treated 56
Relationship Between Dose & Clinical Response Variation in drug responsiveness: Clinical response in individual patients Idiosyncratic infrequently observed in most patients Genetic differences in metabolism Immunological differences Hypersensitivity true allergy (uncommon) Hyperreactive intensity of effect is increased vs. that in most individuals Hyporeactive intensity of effect is decreased vs. that in most individuals Tolerance responsiveness decreases as a consequence of continued drug administration Tachyphylaxis decreased responsiveness that occurs rapidly after administration of a drug 57
Relationship Between Dose & Clinical Response Four mechanisms contribute to variation in drug responsiveness 1.) Alteration in concentration of drug that reaches receptor 2.) Variation in concentration of endogenous receptor ligand 3.) Alteration in number or function of receptors 4.) Change in responsiveness distal to receptor 58
1.) Alteration in concentration of drug that reaches receptor Dose ADME 59
2.) Variation in concentration of endogenous receptor ligand Saralasin weak partial agonist at angiotensin II receptors Angiotensin II is a potent vasoconstrictor What would be its effect on blood pressure up or down? What would be the effect on blood pressure of giving saralasin to a patient with high levels of angiotensin? What would be the effect on blood pressure of giving saralasin to a patient with low levels of angiotensin? 60
3.) Alteration in number or function of receptors Up-regulation (thyroid hormone increases receptors in heart; antagonists like -blockers also do this) Stop antagonist increase in receptor number - response to endogenous ligand (need to wean) Down-regulation Stop agonist may have too few receptors to get effective stimulation 61
3.) Alteration in number or function of receptors Pharmacogenomics (or pharmacogenetics) is the study of the genetic variations that cause differences in drug response among individuals or populations. Future clinicians may screen every patient for a variety of such differences before prescribing a drug. 62
4.) Change in responsiveness distal to receptor Largest and most important class of mechanisms that cause variation in responsiveness to drug therapy Age General health Severity & pathophysiology of disease Wrong diagnosis Compensatory mechanisms - (baroreceptor reflex after administration of an anti-hypertensive agent) 63
Relationship Between Dose & Clinical Response Clinical selectivity: beneficial vs. toxic effects of drugs: Same receptor-effector mechanism, direct pharmacological extension Same receptor, different effectors / different tissues Different receptor-effector mechanisms 64
Relationship Between Dose & Clinical Response Strategies for lowering adverse effects: Use lowest dose possible Add an adjunctive drug that acts on a different receptor mechanism Anatomical selectivity refine administration to get more drug to site of action 65
No drug causes only a single, specific effect 66
Drugs are selective, not specific 67