Section 4 - Pharmocodynamics Revised

Click to edit Master title style Click to edit Master text styles Second level Third level Fourth level Fifth level Click to edit Master title style Click to edit Master text styles Second level Third level Fourth level Fifth level Click to edit Master text styles Second level Third level Fourth level Fifth level Principles of Pharmacology and Toxicology (BIOL3020) Section 4 Pharmacodynamics and Toxicology testing Rang et al 2007 (Chapter 2) The term receptor is often used loosely The wrong definition any target molecule with which a drug molecule has to combine in order to elicit its specific effect Can include enzymes carrier molecules ion channels Receptors. P  Receptor-drug interactions D F How do we determine affinity Receptor 0 nmol/L 1 1.5 18 How do we determine affinity A  XA KA 50 KA Drug A Drug B The Binding Capacity  Bmax Affinity Revisited Concentration (objects/field) 50 75 100 150 200 250 300 Amount Bound 10 20 30 35 35 35 Concentration (objects/field) 50 75 100 150 200 250 300 Amount Bound 10 20 30 35 Non-linear Regression is used to calculate KA and Bmax Sigma Plot The binding equation The curve on right is represented by the equation B Bmax.XA/(XA KA) B amount of drug bound XA concentration of drug KA affinity So if we make XA KA then B Bmax/2  XA KA Drug binding kinetics K 1 K-1 Affinity is related to the binding kinetics How do we determine the effect of the drug O O What is the difference between full and partial agonists Differences in efficacy between chemically related agonists These agonists act on the same receptors in a given biological system full agonists can produce a maximal response partial agonists can only produce a sub-maximal response Competitive Antagonism Agonist Antagonist Competitive antagonists compete with agonists for the binding site Example of Competitive Antagonism Pr 0 Pr x1 Pr x2 Pr x3 Non-Competitive Antagonism - - Non-Competitive Antagonism GP Extracellular Intracellular K K K Agonist Antagonist Block Receptor Desensitization The measurement of ion channel opening in response to the agonist glutamate Other types of Receptor Desensitization Receptors linked to second messengers (GPCRs) are often phosphorylated to become inactive Extracellular Intracellular Chemical messenger/drug Activation of downstream protein Protein kinase Other types of Receptor Desensitization Down Regulation Prolonged exposure to agonists often results in a gradual decrease in the number of receptors expressed on the cell surface Removed by endocytosis  Receptor antagonist and physiological antagonism Toxicology Testing w  Dose (mg/kg body weight) Increasing dose Dose Response Function (LD50) 25 50 75 100 10 20 30 40 50 60 70 80 90 100 Response Categories of Toxicity  , , Agent LD50 (mg/kg) Determining Hazard