The document discusses how drugs work by interacting with endogenous proteins in the body, including cell surface receptors, nuclear receptors, enzymes, ion channels, and transporters. It provides examples of how drugs can antagonize, activate, inhibit or open these proteins. Antagonists bind receptors and prevent endogenous activators from binding, while agonists activate receptors. Enzyme inhibitors and ion channel blockers change the normal functions of these proteins. The document emphasizes that understanding how drugs work at the molecular level allows for better evaluation and use of drugs to treat diseases.

1. HOW DO DRUGS WORK?

4. WHY BE CONCERNED ABOUT HOW DRUGS WORK? The patient has more respect for and trust in a therapist who can convey to the patient how the drug is affecting the patient’s body. AIDS PATIENT-DOCTOR RELATIONSHIP: A patient who understands his/her therapy is more inclined to become an active participant in the management of the patient’s disease.

5. WHY BE CONCERNED ABOUT HOW DRUGS WORK? Knowledge of how a drug works increases the therapist’s confidence that the drug is being used appropriately. PEACE OF MIND!

8. HOW DO DRUGS WORK BY ANTAGONIZING CELL SURFACE RECEPTORS? A macromolecular component of the organism that binds the drug and initiates the drug’s effect. Definition of RECEPTOR : Most receptors are proteins that have undergone various post-translational modifications such as covalent attachments of carbohydrate, lipid and phosphate.

9. HOW DO DRUGS WORK BY ANTAGONIZING CELL SURFACE RECEPTORS? A receptor that is embedded in the cell membrane and functions to receive chemical information from the extracellular compartment and to transmit that information to the intracellular compartment. Definition of CELL SURFACE RECEPTOR :

10. HOW DO DRUGS WORK BY ANTAGONIZING CELL SURFACE RECEPTORS? Cell Membrane Unbound Endogenous Activator (Agonist) of Receptor Inactive Cell Surface Receptor Extracellular Compartment Intracellular Compartment

11. HOW DO DRUGS WORK BY ANTAGONIZING CELL SURFACE RECEPTORS? Cell Membrane Bound Endogenous Activator (Agonist) of Receptor Active Cell Surface Receptor Extracellular Compartment Intracellular Compartment Cellular Response

12. HOW DO DRUGS WORK BY ANTAGONIZING CELL SURFACE RECEPTORS? Cell Membrane Displaced Endogenous Activator (Agonist) of Receptor Inactive Cell Surface Receptor Extracellular Compartment Intracellular Compartment Bound Antagonist of Receptor (Drug)

13. Footnote: Most antagonists attach to binding site on receptor for endogenous agonist and sterically prevent endogenous agonist from binding. However, antagonists may bind to remote site on receptor and cause allosteric effects that displace endogenous agonist or prevent endogenous agonist from activating receptor. HOW DO DRUGS WORK BY ANTAGONIZING CELL SURFACE RECEPTORS?

16. HOW DO DRUGS WORK BY ANTAGONIZING NUCLEAR RECEPTORS? A receptor that exists in the intracellular compartment and upon activation binds to regulator regions in the DNA and modulates gene expression. Definition of NUCLEAR RECEPTOR :

17. HOW DO DRUGS WORK BY ANTAGONIZING NUCLEAR RECEPTORS? Unbound Endogenous Activator (Agonist) of Nuclear Receptor Inactive Nuclear Receptor In Cytosolic Compartment Intracellular Compartment Nucleus DNA Inactive Nuclear Receptor In Nuclear Compartment

18. HOW DO DRUGS WORK BY ANTAGONIZING NUCLEAR RECEPTORS? Intracellular Compartment Nucleus DNA Modulation of Transcription Active Nuclear Receptor Bound Endogenous Activator (Agonist) of Nuclear Receptor

19. HOW DO DRUGS WORK BY ANTAGONIZING NUCLEAR RECEPTORS? Displaced Endogenous Activator (Agonist) of Nuclear Receptor Intracellular Compartment Nucleus DNA Bound Antagonist of Receptor (Drug) Inactive Nuclear Receptor In Cytosolic Compartment Inactive Nuclear Receptor In Nuclear Compartment

20. HOW DO DRUGS WORK BY ANTAGONIZING NUCLEAR RECEPTORS? Footnote: Most antagonists attach to binding site on receptor for endogenous agonist and sterically prevent endogenous agonist from binding. However, antagonists may bind to remote site on receptor and cause allosteric effects that displace endogenous agonist or prevent endogenous agonist from activating receptor.

23. HOW DO DRUGS WORK BY INHIBITING ENZYMES? Active Enzyme Substrate Product Cellular Function

24. HOW DO DRUGS WORK BY INHIBITING ENZYMES? Inactive Enzyme Substrate Bound Enzyme Inhibitor (Drug)

27. HOW DO DRUGS WORK BY BLOCKING ION CHANNELS? Open Ion Channel Intracellular Compartment Ions (e.g., Ca ++ , Na + , K + ) [Ions] Cellular Response

28. HOW DO DRUGS WORK BY BLOCKING ION CHANNELS? Blocked Ion Channel Intracellular Compartment Ions (e.g., Ca ++ , Na + ) Drug that Blocks Ion Channels Ions (e.g., K + )

31. HOW DO DRUGS WORK BY INHIBITING TRANSPORTERS? Active Transporter Intracellular Compartment Membrane Impermeable Solute Cellular Response Membrane Impermeable Solute

32. HOW DO DRUGS WORK BY INHIBITING TRANSPORTERS? Inactive Transporter Intracellular Compartment Membrane Impermeable Solute Membrane Impermeable Solute Drug that Inhibits Transporters

35. HOW DO DRUGS WORK BY INHIBITING SIGNAL TRANSDUCTION PROTEINS? (Some overlap with enzyme inhibitors) Cell Membrane Bound Endogenous Activator (Agonist) of Receptor Active Cell Surface Receptor Extracellular Compartment Intracellular Compartment Cellular Response Multiple Signal Transduction Proteins (each is a potential drug target)

36. HOW DO DRUGS WORK BY INHIBITING SIGNAL TRANSDUCTION PROTEINS? (Some overlap with enzyme inhibitors) Cell Membrane Bound Endogenous Activator (Agonist) of Receptor Active Cell Surface Receptor Extracellular Compartment Intracellular Compartment Blockade or Augmentation of Signal Transduction Pathway by Drug

40. HOW DO DRUGS WORK BY ACTIVATING CELL SURFACE RECEPTORS? Cell Membrane Inactive Cell Surface Receptor Extracellular Compartment Intracellular Compartment

41. HOW DO DRUGS WORK BY ACTIVATING CELL SURFACE RECEPTORS? Cell Membrane Active Cell Surface Receptor Extracellular Compartment Intracellular Compartment Bound Exogenous Agonist of Receptor (Drug) Cellular Response

42. Footnote: Most agonists attach to binding site on receptor for endogenous agonist and trigger a response. However, agonists may bind to remote site on receptor and cause allosteric effects that increase the ability of an endogenous agonist to bind to or activate the receptor. HOW DO DRUGS WORK BY ACTIVATING CELL SURFACE RECEPTORS?

45. HOW DO DRUGS WORK BY ACTIVATING NUCLEAR RECEPTORS? Inactive Nuclear Receptor In Cytosolic Compartment Intracellular Compartment Nucleus DNA Inactive Nuclear Receptor In Nuclear Compartment

46. HOW DO DRUGS WORK BY ACTIVATING NUCLEAR RECEPTORS? Intracellular Compartment Nucleus DNA Modulation of Transcription Active Nuclear Receptor Bound Exogenous Agonist of Receptor (Drug)

47. HOW DO DRUGS WORK BY ACTIVATING NUCLEAR RECEPTORS? Footnote: Most agonists attach to binding site on receptor for endogenous agonist and trigger a response. However, agonists may bind to remote site on receptor and cause allosteric effects that increase the ability of an endogenous agonist to bind to or activate the receptor.

50. HOW DO DRUGS WORK BY ACTIVATING ENZYMES? Inactive Enzyme Substrate

51. HOW DO DRUGS WORK BY ACTIVATING ENZYMES? Active Enzyme Substrate Product Cellular Function Enzyme Activator (Drug)

54. HOW DO DRUGS WORK BY OPENING ION CHANNELS? Closed Ion Channel Intracellular Compartment Ions (e.g., Ca ++ , Na + ) Ions (e.g., K + ) Binding Site on Ion Channel

55. HOW DO DRUGS WORK BY OPENING ION CHANNELS? Open Ion Channel Intracellular Compartment Ions (e.g., Ca ++ , Na + , K + ) [Ions] Cellular Response Drug That Opens Ion Channel

70. HOW DO DRUGS WORK? Now you know!!