A primer on pharmacology pharmacodynamics

A primer on pharmacology pharmacodynamics Drug binding & effect Universidade do Algarve Faro 2017 by Ferdi Engels, Ph.D. 1 Pharmacodynamics Relation with pharmacokinetics? dosage plasma concentration site of action effect pharmacokinetics pharmacodynamics variable = time variable = drug concentration 2 1

Pharmacodynamics Definition: Study of the action of drugs on living tissue Drug interaction Q: how strong? Receptors Enzymes Ion channels proteins Chemical forces (1)Covalent (2)Electrostatic (3)Hydrophobic Charged ionic molecules Hydrogen bonding Induced dipole interactions (e.g. Van der Waals forces) 9 Drug protein interaction Determinants of binding: Functional groups of drug & amino acids in protein pka values 3 Dimensional structure 10 5

Q: how selective? Different strengths of binding 11 Drug binding an analogy 12 6

Measuring drug protein binding 13 Color Atlas of Pharmacology (3 rd ed.), Lüllmann et al., 2005 Measuring drug protein binding 14 Color Atlas of Pharmacology (3 rd ed.), Lüllmann et al., 2005 7

Measuring drug protein binding C B 1 10 2 20 5 30 10 50 20 70 40 80 Binding Drug concentration (in tube) Need for a (mathematical) model 15 Drug (ligand) interaction with receptors k diss R + L RL k ass Formation of [RL: d[ RL k dt ass [ R[ L association rate constant Dissociation of [RL: d[ RL k dt diss [ RL dissociation rate constant At equilibrium: k ass Direction equilibrium: [ R[ L k [ RL diss [ RL k [ R[ L k ass diss K ass association equilibrium constant 16 8

R + L RL [ RL [ R[ L Kass [ R[ L [ RL K diss dissociation equilibrium constant Kdiss 1 K ass affinity important concept 17 [ R[ L K diss [ RL [ RL [ R tot K diss 1 [ L 18 9

19 y= [ RL x= [ R tot K diss 1 [ L free [RL Binding Drug concentration (in tube?) [L R + L RL free Most often: [RL <<<< [L total [L free [L total 20 10

[ RL [ R tot K diss 1 [ L [R tot Langmuir Saturation curve [L [ RL [ Rtot [L 50 K diss made by WinCurveFit [ L 50 : concentration L where fractional receptor occupation is ½ [ RL [ R tot 1 2 [ L 50 1 K diss 1 [ L 50 K diss Conclusion: K diss is a concentration and expressed as M(olar) or moles/liter 21 Interpretations of K diss R + L RL [ R[ L [ RL Kdiss (1) [ RL [ Rtot Kdiss 1 [ L (2) 22 11

10 20 30 40 50 60 70 80 90 100 23 Concentration (μm) Log(concentration) (M) 24 12

Drug binding Drugs can be: Agonists Antagonist Allosteric modulators Drug effect Agonists induce receptor activation Antagonists inhibit receptor activation Allosteric modulators change agonist/antagonist behaviour But we also have... partial agonists inverse agonists competitive antagonists non competitive antagonists agonists that behave like antagonists antagonists that behave like agonists 25 If effect is directly proportional to the concentration of occupied receptors: E [RL [ Rt Kdiss 1 [ L intrinsic activity important concept 0 1 = 1 full agonist = 0 antagonist 0 < < 1 partial agonist conformational change through binding 26 13

When all receptors are occupied: E [RL becomes E max [ Rt efficacy important concept E [ Rt Kdiss 1 [ L becomes E E Kdiss [ L max 1 [L E K diss E 27 EC 50 : Half maximal effective concentration The molar concentration of an agonist, which produces 50% of the maximum possible response for that agonist If [L = EC 50 [ R [ RL 1 2[ Rt Kdiss [ L[ R [ RL K diss EC 50 Only if assumption slide 26 holds affinity potency important concept Often used (for statistical analyses): pec 50 = log EC 50 a.k.a. pd 2 28 14

Potency vs. efficacy Adams et al Pharmacology for nurses. A pathophysiological approach, 2 nd ed (2008) 29 effect 0 10 20 30 40 50 agonist concentration (M) 30 15

effect Log [agonist (M) 31 Antagonism An antagonist can bind to a receptor, but cannot activate it prevents an agonist from activating a receptor important concept Hitner, Nagle Pharmacology. An introduction, 6 th ed (2012) 32 16

A R AR effect K i I + IR K diss 33 Reversibel = competitive Irreversibel = non-competitive antagonist agonist receptor antagonist Reversibel = non-competitive Irreversibel = non-competitive 34 17

I + A R AR effect K diss K i IR E E Kdiss [ A max 1 competitive non competitive E K diss Emax [ I (1 ) Ki 1 [ A Emax [ I (1 ) Ki E Kdiss 1 [ A 35 important competitive antagonism concept non competitive antagonism EC [ I EC (1 ) K * 50 50 i * E E max max [ I (1 ) K i pk i = log(k i ) a.k.a. pa 2 36 18

Q: competitive or non competitive antagonism? 37 maximal response with only 20% receptor occupation receptor reserve, a.k.a. spare receptors important concept Rang and Dale s Pharmacology, 6 th ed (2007) 38 19

EC 50 0,03 μm K diss 1 μm maximal response with only 20% receptor occupation receptor reserve, a.k.a. spare receptors EC 50 K diss, assumption slide 26 does not hold! Rang and Dale s Pharmacology, 6 th ed (2007) 39 Q: competitive or non competitive antagonism? A: irreversible inhibitor in a tissue with spare receptors 40 20

Agonist and antagonist selectivity important NH 2 Histamine receptor concept G protein COOH histamine receptor subtypes In common: endogenous agonist = histamine H 1 AC, PLC pk i = 5.9 4.7 H 2 AC, PLC 3.8 H 3 AC 8.3 7.1 H 4 PLC 8.3 7.2 41 Agonist and antagonist selectivity H 3 receptor pk i = 8.8 H 4 receptor pk i = 7.6 10 7.6 /10 8.8 or 10 (8.8 7.6) Q: degree of selectivity? 16 fold selectivity thioperamide 10.000 fold selectivity 42 21

Summary Agonist Partial agonist pa 2 Potency Antagonist EC 50 K i K diss Selectivity Efficacy Affinity Receptor subtypes pd 2 43 22