W3.Pharmcodynamic 2 update.pdf

Pharmacodynamic-II LEILA ALBLOWI  Lecture objectives ❑ Understand the types of drug-receptor interactions product ❑ Explain the law of mass action in pharmacodynamics ❑ Differentiate between graded and quantal dose-response curves ❑ Examine the therapeutic index and therapeutic window ❑...

Pharmacodynamic-II LEILA ALBLOWI  Lecture objectives ❑ Understand the types of drug-receptor interactions product ❑ Explain the law of mass action in pharmacodynamics ❑ Differentiate between graded and quantal dose-response curves ❑ Examine the therapeutic index and therapeutic window ❑ Differentiate between agonists and antagonists ❑ Explore pharmacodynamic drug interaction  What are the binding forces between drugs and receptors? Types of chemical force in drug receptor interaction Types of chemical bonds: 1. Covalent bond 2. Ionic bond 3. Hydrogen bond 4. Hydrophobic interactions Types of chemical force in drug receptor interaction Bond name Description Strength Covalent bond Involves sharing a pair of electrons between Very strong and often irreversible. two atoms. ( drugs & receptor ) Creates a stable and long-lasting drug-receptor complex. Ionic bond Occurs between atoms with opposite Stronger than hydrogen bonds but weaker than charges. covalent bonds. Its strength is insufficient to prevent dissociation of drug with its receptor Hydrogen bond forms when a partially positively charged Moderate, providing substantial strength to the hydrogen atom, which is covalently bonded drug-receptor interaction. to a highly electronegative atom (like nitrogen, oxygen, or fluorine), is attracted to another nearby electronegative atom. Hydrophobic Called van der Wall’s forces Very weak interactions Occurs between non-polar functional groups Pharmacological models for drug-receptor interaction Pharmacodynamic modelling is based on the occupational theory of drug action which apply the law of mass action on drug-receptor interaction. What is the law of mass action? What is the receptor occupation theory? Pharmacological models for drug-receptor interaction Law of Mass Action ❑ Describe the : The overall reaction b/w drug and protein or receptor The association and dissociation b/w drug and its receptor The rate at which a drug binds to a receptor is proportional Kd= dissociation rate constant to the concentration of the drug and the concentration of D= drug conc. the receptors. R= conc. of protein/receptor ✓ ( ↑ Conc. → ↑ Rate ) DR = conc. of drug-receptor complex The larger the conc. of the reactants the faster will be the reaction rate, and vice versa Pharmacological models for drug-receptor interaction Association Rate: Association: The process where a drug (D) binds to a receptor (R) to form a drug-receptor complex (DR). Proportional to the concentrations of both the drug and the receptor. Dissociation Rate : Dissociation: The breakdown of the drug-receptor (DR) complex back into the drug and receptor Proportional to the concentration of the drug-receptor complex. Pharmacological models for drug-receptor interaction ❑ Equilibrium: At equilibrium, the rate of association equals the rate of dissociation. ❑ Implication of 𝐾𝑑: A lower 𝐾𝑑 value indicates a higher affinity of the drug for the receptor, meaning that the drug binds more tightly to the receptor. Compounds have Different Affinities for the Same Receptor  Receptor Occupation Theory ✓ J. Clark was the 1st to apply the law of mass action in drug-receptor interaction ✓ The Theory states that the intensity of pharmacological effect is directly proportional to the number of receptors occupied by the drug ✓ Termination of response occurs when drug dissociate from the receptor ✓ The greater the number of drug molecules bound to receptors the greater physiological effect or response.  Receptor Occupation Theory and the dose-response curve ❖ The dose-response curve: is a graphical representation that shows the relationship between the dose of a drug and the magnitude of the response it produces ❑ According to the Receptor Occupation Theory: ✓ At low drug concentrations, only a few receptors are occupied, so the response is small. ✓ As the drug concentration increases, more receptors become occupied, and the response increases. ✓ The dose-response curve reflects this relationship, showing a gradual increase in effect with increasing dose until it plateaus at the maximum effect (E-max), corresponding to the point where all available receptors are occupied.  Receptor Occupation Theory and the dose-response curve ❖ The dose-response curve : There are two main types: 1. Graded dose-response relationship A drug effect which increases as dose or concentration is increased In an individual Graded dose-response graphs plot the response to a drug against its concentration 2. Quantal dose-response relationship Plots the fraction of the population that responds to a given dose of drug as a function of the drug dose. A drug effect which is binary (either present or absent) Observed in a population Quantal dose-response graphs plot the rate of an outcome occurrence in a population against the drug dose The dose-response curve Important concept in PD Modelling Potency Potency is a measure of the amount of drug necessary to produce an effect. The concentration of drug producing 50% of the maximum effect (EC50) is often used to determine potency Efficacy Efficacy is the maximum response a drug causes when it interacts with a receptor (E-max) Efficacy is more important than potency. Which drug has more efficacy? Which drug has more potency? Why? Which drug has more efficacy? Which drug has more potency? Why? Which drug has more efficacy? Which drug has more potency? Why? Quantal Dose-Response Relationships Quantal Dose-Response Relationship: Types of responses (that can be examined using Describes the concentrations of a drug the quantal dose-response relationship) that produce a given effect in a include: population. 1. Effectiveness (therapeutic effect) Due to biological differences among 2. Toxicity (adverse effect) 3. Lethality (lethal effect) individuals, drug effects are observed over a range of doses. The doses that produce these responses in 50% of a population are known as: Median effective dose (ED50) Median toxic dose (TD50) Median lethal dose (LD50) Quantal Dose-Response Relationships Therapeutic Index and Therapeutic Window Definition: The range of doses (or concentrations) of a drug that produces a therapeutic response without unacceptable adverse effects (toxicity) in a population of patients. Narrow Therapeutic Window: Requires close monitoring of plasma drug levels to maintain effective dosing without causing toxicity. Therapeutic Index and Therapeutic Window Therapeutic Index (TI) http://cdn.pharmacologycorner.com/wp-content/uploads/2011/01/therapeutic-index1.gif Ratio of the dose that produces toxicity to the dose that produces effective response in a population of individuals. Formula: TI = TD50 / ED50 TD50: Dose that produces toxicity in 50% of the population. ED50: Dose that produces therapeutic response in 50% of the population. Therapeutic Index and Therapeutic Window Interpretations of TI Large TI: Wide Therapeutic Window: Indicates a large difference between therapeutic and toxic doses (e.g., a thousand-fold difference). ❖ It is a measure of drug safety ❖ Wider therapeutic window >> ????. Small TI: Narrow Therapeutic Window: Indicates a small difference between therapeutic and toxic doses (e.g., a twofold difference). Therapeutic Index and Therapeutic Window Warfarin: (example of a drug with a small or low therapeutic index) Penicillin: (example of a drug with a large therapeutic index) Drug-receptor interaction Kd Biological response Drug + Receptor Drug-receptor complex (efficacy) (affinity) o Selectivity: the degree to which a drug binds to a given receptor relative to other receptors. ​ o E.g. Adrenaline selective for α, ß receptor​ o Affinity: to which extent the drug is capable to bind and remained bound to receptor. o High affinity (low kd)=ligand binds well and remained bound long enough to activate the receptor. o Efficacy: ability of a drug to elicit a biological response (intrinsic activity) when it interacts with a receptor. Measured by Emax, value 0-1. Ligands Agonist Antagonist o Binds to receptor but produces NO o Binds to receptor and produces response. biological response o Has affinity o Has affinity o Has no intrinsic activity (zero efficacy) o Has efficacy (intrinsic activity) o Blocks or inhibits the effect on the receptor. The major pharmacodynamic relationships between drugs and their targets Agonists A compound that stimulates a response by binding to a receptor, often mimicking the action of an endogenous compound on the same receptor.  The major pharmacodynamic relationships between drugs and their targets Types of Agonists : Full Agonist: Partial Agonist: Invers Agonist: Produces a maximal Binds to its target receptor Binds to the same receptor as biological response that but produces only a an agonist but induces a mimics the response to submaximal response, even pharmacological response endogenous ligand when all receptors are opposite to that of the agonist. Intrinsic Activity: occupied. Intrinsic Activity: Negative (-1 1 (maximum efficacy). Intrinsic Activity: Less than for full inverse agonist). Example: Morphine on µ- 1 (