Introduction to the principles of drug action

1. Introduction to the principles of drug action Dr. M. Yulis Hamidy, M.Kes., M.Pd.Ked

2. Basic Pharmacological Concepts • Pharmacology= The study of the interaction between chemicals and a biological system. • Pharmacodynamics= study of the biochemical and physiological effects of drugs and their mechanisms of action (the effects of the drug on the body) • Pharmacokinetics = deals with absorption, distribution, biotransformation and excretion of drugs (the way the body affects the drug with time)

3. Pharmacodynamics Mechanisms of drug action • Non-specific drug action general anaesthetics, osmotic diuretics, antacids • Alter transport systems Ca antagonists, local anaesthetics, cardiac glycosides • Alter enzyme function COX inhibitors, MAO inhibitors, AChE inhibitors • Act on receptors Synaptic transmitter substances, hormones

4. Receptors Proteins Cell membranes Intracellular 4 main types: • Agonist gated transmembrane channels • G-protein coupled • Nuclear receptors that regulate gene transcription • Linked directly to tyrosine kinase

5. Agonist gated channels receptors

6. G-protein coupled receptors

7. G-protein coupled receptors

8. Nuclear receptors that regulate gene transcription receptors

9. Linked directly to tyrosine kinase Receptor acts as an enzyme receptors

10. Transport Systems • Lipid cell membrane • barrier to hydrophyllic molecules • transport in /out cell • Ion channels • voltage gated • ligand gated • Active transport processes • Na+ pump • Noradrenaline transport

11. Ion channels • Voltage and transmitter gated Ca2+ channels in heart • Voltage gated Na+, K+, Ca2+ - same basic structure Subtypes of each exist Examples: calcium antagonists Ca2+ inVSM & heart local anaesthetics Na+ in nerves anticonvulsants Na+ antiarhythmics Na+ Transport systems

12. Voltage gated channels Transport systems

13. Active transport processes • transport substances against concentration gradient • special carrier molecules • require metabolic energy • Sodium Pump • expel Na+ ions • Na+/K+ ATPase cardiac glycosides some diuretics • Noradrenaline transport tricyclic antidepressants block reuptake Transport systems

14. Enzymes • Catalytic proteins that increase the rate of chemical reactions • Drug examples • Anticholinesterases • Carbonic anhydrase inhibitors • Monoamine oxidase inhibitors • Cyclo-oxygenase inhibitors

15. Speed of responses

17. DRUG RECEPTOR INTERACTIONS Intermolecular forces • Covalent bonds - two atoms share an electron • (40-110kcal/mol) - long lasting - desirable? e.g. Alkylating agents (e.g. anticancer nitrogen mustards) • Ionic bonds- electrostatic attraction between oppositely charged ions • much weaker than covalent bonds (10 kcal/mol) • reversible • Hydrogen bonds- electrostatic attraction between hydrogen atom and electronegative atom • relatively stable (1-7 kcal/mol) - reversible • Van der Waal’s bond- weak bond (0.5 - 1 kcal/mol)

18. Affinity measure of how avidly a drug binds to its receptor • Equilibrium constant KD • KA concentration of drug that produses 50% of response Intrinsic activity Ability of a drug to elicit a response from a receptor

19. Agonist = a drug that is able to alter the conformation of a receptor in such a way that it elicits a response in the system Full Partial Antagonist = a drug that binds to a receptor but does not elicit a response from the system Competitive Irreversible

20. K+1 K-1 Ag Ag + Response K+1 K-1 Ant + Ant Agonist vs antagonist R R

21. Graded dose-responses One tissue/organ can yield the full response range Full agonist Partial agonist Response Agonist concentration [A]

22. Log dose-response curve Full agonist Partial agonist Response Log concentration [A]

23. Emax & ED50 Emax Response ½ Emax I I I I I I I I ED50 ED100 Log concentration [A]

24. Effect of competitive antagonists Agonist alone Response Increasing concentrations of competitive antagonist Log [A]

26. Effect of irreversible antagonists Low dose Agonist alone Response High dose Log [A]