How Drugs Work An introduction to clinical pharmacology

1. Applied Sciences Lecture Course How Drugs WorkAn introduction to clinical pharmacology Dr Ally Duncan SpR In Anaesthesia & Clinical Fellow in Undergraduate Medical Education Manchester Royal Infirmary March 2012

2. Objectives Define the terms “pharmacodynamics” & “pharmacokinetics” Summarise mechanisms of drug action Understand some basic principles of drug-receptor interactions Understand factors affecting drug absorption & distribution Understand processes of drug elimination

3. Which statement best describes pharmacodynamics? • The rate of elimination of a drug • The distribution of the drug within the body • Effects of the drug on the body • Effects of the body on the drug

4. Pharmacodynamics Effect of drugs on the body “How the drug works” “what the drug does to the body”

5. Pharmacokinetics Describes the absorption, distribution and elimination of drugs from the body “what the body does to the drug”

6. How drugs work Physical interactions Enzyme interactions Receptor interactions

7. Physical interactions • Actions dependent on chemical properties • Antacids • Basic salts • Neutralise gastric acidity • Activated charcoal • Absorption of poisons from the GI tract

8. Enzyme interactions Active site Enzyme Molecule Enzymes are biological catalysts

9. Enzyme interactions 1 substrate 2 3 products

10. Enzyme interactions Competitive inhibition Non-competitive inhibition

11. Competitive inhibition Competitive inhibitor substrate Competitive inhibitor interferes with active site & prevents substrate from binding

12. Non-competitive inhibition Non-Competitive inhibitor substrate Non-competitive inhibitor changes shape of enzyme so it cannot bind to substrate

13. Angiotensin converting enzyme converts • Renin to Angiotensinogen • Angiotensinogen to angiotensin I • Angiotensin I to angiotensin II

14. Example of enzyme inhibition Angiotensinogen (liver) ACE Inhibitors Renin (kidney) Bradykinin (active) Angiotensin I (decapeptide) Angiotensin converting enzyme (mostly in lung tissue) Angiotensin II (octapeptide) Bradykinin (degraded) • Angiotensin Converting Enzyme Inhibitors • E.g. Lisinopril, captopril

15. Receptors

16. Receptors - definitions • Receptor • A molecule on the surface or within a cell that recognises and binds with specific molecules (ligand) • Ligand • A molecule that binds to a receptor • Binding site • Specific region on the receptor to which the ligand binds

17. Receptors classed by mechanism of action • Altered Ion permeability • Ligand-gated ion channels • Regulation of gene-transcription • Production of intermediate messenger • G-protein coupled receptors

18. Alter ion permeability Ligand Binding site ions

19. Regulation of gene transcription • Intracellular receptors • require ligand to be lipid soluble and cross cell membrane • E.g steroid hormones, Thyroid hormones

20. Regulation of gene transcription Nucleus Hormone Receptor Anabolic steroid Formation of new protein (e.g. muscle tissue) E.g. anabolic steroids

21. Production of intermediate messengers Activation of intermediate messenger G - Protein G-protein coupled receptors

22. Intermediate messengers Adenyl cyclase Phospholipase c Membrane guanyl cyclase

23. Examples of G-protein coupled receptors • Opioid receptors • Morphine, fentanyl, diamorphine • Adrenoceptors • Adrenaline, noradrenaline, β-blockers, salbutamol • Muscarinic acetylcholine receptors • Atropine

24. Where are 1 adrenoceptors located? • Lungs • Heart • Peripheral blood vessels

25. β1 Adrenoceptor Adrenaline Adenyl cyclase G - Protein Increased heart muscle contractility cAMP ATP

26. Receptor-drug interactions

27. Drug-receptor interactions • 2 properties determine the nature of a drugs pharmacological effect • Affinity • Refers to how well a drug binds to its receptor • Intrinsic activity or efficacy • refers to the magnitude of effect the drug has once bound to the receptor

28. Definitions • Agonist • Affinity for receptor • Intrinsic activity • Antagonist • Affinity for receptor • NO intrinsic activity

29. β1 Adrenoceptor Adrenaline Adenyl cyclase G - Protein Increased heart muscle contractility cAMP ATP

30. β1 Adrenoceptor Atenolol Adenyl cyclase G - Protein Increased heart muscle contractility cAMP ATP

31. Agonists • Full agonist • Drug that generates a maximal response from a receptor (Emax) • Demonstrates high affinity & high intrinsic activity • Partial agonist • Fails to achieve maximal effect even in high dose • Demonstrates reduced intrinsic activity

32. Response Dose Dose-response curve

33. Log-dose response curve Emax Response Log dose Full Agonist Partial Agonist

34. Antagonists • Reversible • Competitive • The effect of the antagonist can be overcome by increasing the concentration of the agonist • The 2 molecules are competing for the same receptor • Non-competitive • Do not bind to the same site on the receptor as the agonist • Effect results from preventing receptor activation through conformational distortion • Effect cannot be overcome by increasing the concentration of agonist

35. Antagonists • Irreversible • Irreversibly bind to the receptor • Increasing agonist concentration will not overcome the blockade

36. Emax Response Log dose Full Agonist Agonist in presence of competitive antagonist

37. Emax Response Log dose Full Agonist Full agonist + non-competitive or irreversible antagonist

38. Other factors affecting pharmacological response • Receptor down-regulation / up-regulation • Receptor desensitisation • Change to affinity / maximal response • Genetic variations

39. Summary of pharmacodynamics • Pharmacodynamics considers the effects of drugs on the body – “How drugs work” • 3 main mechanisms of drug action • Physical interactions • enzyme interactions • Receptor interactions • 3 main receptor categories • Ligand-gated ion channels • Intracellular receptors altering gene transcription • G-protein coupled receptors • Explored principles of drug –receptor interaction All Figures were produced using Servier Medical Art - www.servier.com

40. Pharmacokinetics

41. Pharmacokinetics Describes the absorption, distribution and elimination of drugs from the body “what the body does to the drug”

42. Factors affecting drug absorption

43. Cell membrane Hydrophillic head Hydrophobic tail

44. Which is the commonest way that molecules pass across a cell membrane • Passive diffusion • Facilitated diffusion • Active transport • pinocytosis

45. Passage across the cell membrane Passive diffusion Facilitated diffusion Active transport Pinocytosis

46. Passive diffusion • Passive movement of substances from an area of high concentration to an area of low concentration • Rate of diffusion is dependent on: • Molecular size • Concentration gradient • Lipid solubility • pH & ionisation • Protein binding

47. Passive diffusion • Molecular size • Smaller molecules diffuse more readily than larger ones • Graham’s law • Rate of passive diffusion is inversely proportional to the square root of molecular size

48. Passive diffusion • Concentration gradient • A large concentration gradient across the cell membrane increases the speed of diffusion • Fick’s law • Rate of diffusion across a membrane is proportional to the concentration gradient across the membrane

49. Passive diffusion • Lipid solubility • Highly lipid soluble preparations diffuse easily across the cell membrane

50. Passive diffusion • pH & ionisation • Only un-ionised fraction of a drug is available to cross the cell membrane • Degree of ionisation of a drug in solution depends on molecular structure of drug & the pH of solution