DRUG ACTION & PHARMACODYNAMIC M. Imad Damaj, Ph.D. Associate Professor Pharmacology and Toxicology Smith 652B, 828-1676, mdamaj@hsc.vcu.edu Life History of A Drug
Non-Specific Mechanims Drug-Receptor Interaction
Drug-Receptor Interaction Drug (D) Drug- Receptor Complex Ligand- binding domain Effector domain Receptor (R) k 1 k 2 D + R K d = k 2 /k 1 Affinity DR Efficacy Effect Drug-Receptor Interaction Affinity Measure of propensity of a drug to bind receptor; the attractiveness of drug and receptor Efficacy (or Intrinsic Activity) Ability of a bound drug to change the receptor in a way that produces an effect; some drugs possess affinity but NOT efficacy
Simple Occupancy Theory k 3 RECEPTOR THEORY MASS ACTION LAW R + D k 1 k 2 DR effect 25% 50% 75% 100% Simple Occupancy Theory Simple occupancy theory: Intensity of response to a drug is proportional to the number of receptors occupied by that drug Maximal response occurs when all available receptors have been occupied This theory is not able to explain why one drug is more potent than another if they bind to the same receptor and both bind maximally to all receptors? (Example: Demerol vs Talwin)
Drug-Receptor Bonds Drug receptor interactions may involve many different types of chemical bonds, some irreversible but usually weak non-covalent interactions that are reversible: Covalent: almost irreversible Electrostatic: Van der Waals and Hydrogen Ionic: Ionic: opposite charges Structure-Activity Relationship Affinity & efficacy are determined by chemical structure Stringent Relationship
Drug-Receptor Interaction: Receptor Specificity How can a drug interact with one receptor type and not others? Selectivity does not guarantee safety! Structure-Activity Relationship Exploitation of SAR could lead to new drug design Structural modification of Librium leads to the generation of other tranquilizers
Theories of Drug-Receptor Interaction What are receptors? Traditional model was a rigid one: Lock and Key Lock Receptor surface Key Drug or Ligand Drug Receptor Theories of Drug-Receptor Interaction Receptors fluid, flexible surfaces or pockets Can change 3-D structure as ligand docks Occupy small portion or surface of a macromolecule Ligand - Receptor docking structure changes Inactive Active
Theories of Drug-Receptor Interaction Modified Occupancy Theory a. Affinity binding- strength of the attraction between drug and receptor. The > affinity the > potency: Drugs with low affinity require higher concentrations to bind to receptor b. Intrinsic activity- ability of a drug to activate its receptor. High intrinsic activity relates to high maximal efficacy Receptor Theory: Agonists & Antagonists Agonist: Molecules that activate receptors - a drug with affinity and efficacy Antagonist: Molecules that prevent receptor activation by endogenous regulatory molecules and drugs - a drug that has affinity but not efficacy Antagonist Inactive Active Agonist
Agonist Antagonist Receptor Receptor Activated Receptor Inactive Receptor HOW TO EXPLAIN EFFICACY? Drug (D) Ri DRi Ra DRa The relative affinity Of the drug to either conformation will determine the effect of the drug CONFORMATIONAL SELECTION
SPARE RECEPTORS The receptor theory assumes that all receptors should be occupied to produce a maximal response. In that case at half maximal effect EC 50 =K d. Sometimes, full effect is seen at a fractional receptor occupation Spare receptors Allow maximal response without total receptor occupancy increase sensitivity of the system The number of receptors may exceed the number of effector-molecules available Receptor remains activated after agonist departs: more than one receptor is activated Drugs & Signal Transduction Mechanisms Receptor-effector coupling: Transduction process between receptor occupancy and drug response
Main Receptor Classes
1. G protein-coupled Receptors Structure: Single polypeptide chain threaded back and forth resulting in 7 transmembrane α-helices There s a G protein attached to the cytoplasmic side of the membrane (functions as a switch).
2. Ion Channel Receptors Structure: Protein pores in the plasma membrane 3. Tyrosine-Kinase Receptors Structure: Receptors exist as individual polypeptides Each has an extracellular signalbinding site An intracellular tail with a number of tyrosines and a single α- helix spanning the membrane
4. Intracellular Receptors Nuclear proteins Consist a DNA-binding domain attached to a ligandbinding and transcriptional control domains Effects are produced as a result of increased protein sysnthesis - slow onset
Second Messengers & Signal Transduction Second Messengers & Signal Transduction
DOSE-RESPONSE RELATIONSHIPS To determine the quantitative relation between drug concentration and response DOSE EFFECT RELATIONSHIP
Dose-Response Curve Type of Dose-Response Curves Graded Measured in a single biologic unit Continuous scale ( dose( effect) Relates dose to intensity of effect Quantal Population studies All-or or-none pharmacologic effect Relates dose to frequency of effect
Types of Dose-Response Curves: Graded 100 80 Relaxation % Control 60 40 20 0 PDE Inhibition 1 10 100 1000 Theophylline [µm] Graded: Dose related to magnitude on a graded scale Types of Dose-Response Curves: Quantal # of Subjects 50 40 30 20 10 Dose related to % of subjects showing a specified all-or-non response Cumulative % of Subjects 100 80 60 40 20 0 1 3 5 7 9 11 13 15 Dose 0 1 3 5 7 9 11 13 15 Dose
Characteristics of A Dose-Response Curve Variability POTENCY Amount of a drug needed to produce a given effect Determined mainly by the affinity of the receptor for the drug Potency affects drug dosage Relatively unimportant in clinical use of drugs Are more potent drugs superior therapeutic agents? Expressed as EC50 (µm) or ED50 (mg/kg) Graded= 50% of the maximal effect Quantal = 50% population studied (LD50, TD50)
Potency: Graded Responses % of Maximal Effect EC 50 [Drug] ED50 or EC50 = Dose needed to produce 50% of the maximal effect. Potency: Quantal Responses 100 % Achieving Complete Analgesia 80 60 40 ED 90 = 490 mg ED 90 ED 50 = 400 mg ED 50 20 Ferrante et al. Anesth Analg 82:91-7, 1996 0 100 1000 Total Lidocaine Dose (mg)
Potency: Quantal Responses EFFICACY The maximal effect that can be produced by a drug Determined mainly by the properties of the drug and its receptor-effector system Important clinical measure Partial agonist have lower maximal efficacy than full agonists
Dose-Response Curves and Efficacy Dose-Response Curves Showing Efficacy & Potency
SLOPE The shape of the curve describe drug binding to receptors Indicator of useful dosage range (steepness of the curve) The slope have more theoretical than practical use Slopes of Dose-Response Curves
VARIABILITY Curves usually represent the mean response of a sample of population Effect may vary considerably Start Low, Go Slow Expressed as 95% Confidence limits Confidence Limits of Dose-Response Curves
Value of Dose-Response Curves Determining if a drug produces a certain desired effect Determining potency or dose required in producing effect Comparing one drug with others: 1. Efficacy 2. Potency 3. Safety Comparing Dose-Response Curves 100 80 Drug A Drug B % of Maximal Effect 60 40 Drug C 20 0 1 10 100 1000 [Drug]
Relative Safety of A Drug Dose-response curves help estimating the safety of a drug Therapeutic Index: TI= LD50/ED50 * LD50= the median lethal dose of a drug in animals * Statement on selectivity of desired effects vs toxic More general concept: The Median Toxic Dose (TD50) * No drug produce a single effect: example of Codeine * Severity of the disease * Concentration vs dose Therapeutic Index
Examples of TI Substance safety margin Alcohol 1:4-1:10 Aspirin 1:50 Caffeine 1:100 Marijuana 1:400-1:1800 Certain Safety Factor Problems with TI: o Comparison of the mid-points of DRC o Overlap of DRC Determination of Certain Safety Factor: o Compare the extremes of the DRC o Important concept: used to determine a Therapeutic Window o 99% and 1% are not absolutes Certain Safety Factor = LD1 ED99
Therapeutic and Toxic Effects 100 80 Therapeutic Toxic % Responding 60 40 20 0 ED 99 ED TD 1 50 TD 50 50 70 80 90100 200 300 Dose Drug Interaction & Dose-Response Curves Agonist Partial agonist Effect Antagonist Inverse Agonist Log [Drug]
Receptors, Agonists & Antagonists A) Competitive Antagonists Receptors, Agonists & Antagonists A) Non-Competitive Antagonists
Antagonist Effects on Dose-Response Curves A) Competitive Antagonists Antagonist Effects on Dose-Response Curves A) Competitive Antagonists Acetylcholine (µg/ml)
Antagonist Effects on Dose-Response Curves C) Non-Competitive Antagonists Antagonist Effects on Dose-Response Curves C) Non-Competitive Antagonists Percentage Maximum Contraction 100 50 Epinephrine Epinephrine + 2 x 10-7 Dibenamine Epinephrine + 4 x 10-7 Dibenamine 0 0.6 4.8 38.4 [Epinephrine] (µm)
Non-Competitive Antagonist Effects on Dose-Response Curves Thank you for your attention