1.Site of Action Dosage Effects Plasma Concen. Pharmacokinetics Pharmacodynamics

2. Bound Free Free Bound LOCUS OFACTION RECEPTORS TISSUE RESERVOIRS SYSTEMIC CIRCULATION Free Drug Bound Drug ABSORPTION EXCRETION BIOTRANSFORMATION 3. FDAApproved and Unapproved Uses Interactions with Other Drugs Adverse Effects and Contraindications AIDS MEMORIZATION OF: 4. WHY BE CONCERNED ABOUT HOW DRUGS WORK? Better assessment of new modalities for using drugs Better assessment of new indications for drugs Better assessment of new concerns regarding risk-benefit AIDS EVALUATION OF MEDICAL LITERATURE: 5. 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 patients 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 patients disease. 6. WHY BE CONCERNED ABOUT HOW DRUGS WORK? Knowledge of how a drug works increases the therapists confidence that the drug is being used appropriately. PEACE OF MIND! 7. HOW DO DRUGS WORK? Some antagonize, block or inhibit endogenous proteins Some activate endogenous proteins A few have unconventional mechanisms of action 8. HOW DO DRUGS ANTAGONIZE, BLOCK OR INHIBIT ENDOGENOUS PROTEINS? Antagonists/ Agonist of Cell Surface Receptors Antagonists / Agonist of Nuclear Receptors Enzyme Inhibitors/ stimulators Ion Channel Blockers/ Activators Transport Inhibitors/ Stimulators Inhibitors/ stimulator of Signal Transduction Proteins 9. A macromolecular component of the organism that binds the drug and initiates its effect. Definition of RECEPTOR: Most receptors are proteins that have undergone various post-translational modifications such as covalent attachments of carbohydrate, lipid and phosphate. 10. 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: 11. HOW DO DRUGS WORK BY ANTAGONIZING/AGONIZING CELL SURFACE RECEPTORS? KEY CONCEPTS: Cell surface receptors exist to transmit chemical signals from the outside to the inside of the cell. Some compounds bind to cell surface receptors, yet do not activate the receptors to trigger a response. When cell surface receptors bind the molecule, the endogenous chemical cannot bind to the receptor and cannot trigger a response. The compound is said to antagonize or block the receptor and is referred to as a receptor antagonist. 12. HOW DO DRUGS WORK BY ANTAGONIZING/AGONIZING CELL SURFACE RECEPTORS ? Cell Membrane Unbound Endogenous Activator (Agonist) of Receptor Inactive Cell Surface Receptor Extracellular Compartment Intracellular Compartment 13. HOW DO DRUGS WORK BY ANTAGONIZING/AGONIZING CELL SURFACE RECEPTORS Cell Membrane Bound Endogenous Activator (Agonist) of Receptor Active Cell Surface Receptor Extracellular Compartment Intracellular Compartment Cellular Response 14. HOW DO DRUGS WORK BY ANTAGONIZING/AGONIZING CELL SURFACE RECEPTORS Cell Membrane Displaced Endogenous Activator (Agonist) of Receptor Inactive Cell Surface Receptor Upon being Bound Extracellular Compartment Intracellular Compartment Bound Antagonist of Receptor (Drug) 15. Footnote: Most antagonists attach to binding site on receptor for endogenous agonist and sterically prevent endogenous agonist from binding. If binding is reversible - Competitive antagonists If binding is irreversible - Noncompetitive antagonists However, antagonists may bind to remote site on receptor and cause allosteric effects that displace endogenous agonist or prevent endogenous agonist from activating receptor. (Noncompetitive antagonists) HOW DO DRUGS WORK BY ANTAGONIZING/AGONIZING CELL SURFACE RECEPTORS 16. HOW DO DRUGS WORK BY ANTAGONIZING/AGONIZING CELL SURFACE RECEPTORS Cell Membrane Displaced Endogenous Activator (Agonist) of Receptor Inactive Receptor Extracellular Compartment Intracellular Compartment Bound Antagonist of Receptor Allosteric Inhibitor Active Receptor 17. ARE DRUGS THAT ANTAGONIZE CELL SURFACE RECEPTORS CLINICALLY USEFUL? Angiotensin Receptor Blockers (ARBs) for high blood pressure, heart failure, chronic renal insufficiency (losartan ; valsartan) Some important examples: Beta-Adrenoceptor Blockers for angina, myocardial infarction, heart failure, high blood pressure, performance anxiety (propranolol; atenolol) 18. HOW DO DRUGS WORK BY ANTAGONIZING/ AGONIZING 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 19. HOW DO DRUGS WORK BY ANTAGONIZING/ AGONIZING NUCLEAR RECEPTORS? Intracellular Compartment Nucleus DNA Modulation of Transcription Active Nuclear Receptor Bound Endogenous Activator (Agonist) of Nuclear Receptor 20. HOW DO DRUGS WORK BY ANTAGONIZING/ AGONIZING 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 21. ARE DRUGS THAT ANTAGONIZE NUCLEAR RECEPTORS CLINICALLY USEFUL? Mineralocorticoid Receptor Antagonists for edema due to liver cirrhosis and for heart failure (spironolactone) Some important examples: Estrogen Receptor Antagonists for the prevention and treatment of breast cancer (tamoxifen) 22. HOW DO DRUGS ANTAGONIZE, BLOCK OR INHIBIT ENDOGENOUS PROTEINS? Antagonists of Cell Surface Receptors Antagonists of Nuclear Receptors Enzyme Inhibitors Ion Channel Blockers Transport Inhibitors Inhibitors of Signal Transduction Proteins 23. HOW DO DRUGS WORK BY INHIBITING ENZYMES? Active Enzyme Substrate Product Cellular Function Inactive Enzyme Substrate Bound Enzyme Inhibitor (Drug) 24. HOW DO DRUGS WORK BY INHIBITING ENZYMES? KEY CONCEPTS: Enzymes catalyze the biosynthesis of products from substrates. Some drugs bind to enzymes and inhibit enzymatic activity. Loss of product due to enzyme inhibition mediates the effects of enzyme inhibitors. 25. ARE DRUGS THAT INHIBIT ENZYMES CLINICALLY USEFUL? Cyclooxygenase Inhibitors for pain relief, particularly due to arthritis (aspirin; ibuprofen) Some important examples: Angiotensin Converting Enzyme (ACE) Inhibitors for high blood pressure, heart failure, and chronic renal insufficiency (captopril; ramipril) HMG-CoA Reductase Inhibitors for hypercholesterolemia (atorvastatin; pravastatin ) 26. HOW DO DRUGS ANTAGONIZE, BLOCK OR INHIBIT ENDOGENOUS PROTEINS? Antagonists of Cell Surface Receptors Antagonists of Nuclear Receptors Enzyme Inhibitors Ion Channel Blockers Transport Inhibitors Inhibitors of Signal Transduction Proteins 27. ARE DRUGS THAT BLOCK ION CHANNELS CLINICALLY USEFUL? Calcium Channel Blockers (CCBs) for angina and high blood pressure (amlodipine; diltiazem) Some important examples: Sodium Channel Blockers to suppress cardiac arrhythmias (lidocaine; amiodarone) 28. ARE DRUGS THAT INHIBIT TRANSPORTERS CLINICALLY USEFUL? Selective Serotonin Reuptake Inhibitors (SSRIs) for the treatment of depression (fluoxetine ; fluvoxamine) Some important examples: Inhibitors of Na-2Cl-K Symporter (Loop Diuretics) in renal epithelial cells to increase urine and sodium output for the treatment of edema (furosemide ; bumetanide ) 29. Tyrosine Kinase Inhibitors for chronic myelocytic leukemia (imatinib) Some important examples: Type 5 Phosphodiesterase Inhibitors for erectile dysfunction (sildenafil) This is a major focus of drug development ARE DRUGS THAT INHIBIT SIGNAL TRANSDUCTION PROTEINS CLINICALLY USEFUL? 30. HOW DO DRUGS WORK BY ACTIVATING ENDOGENOUS PROTEINS? Agonists of Cell Surface Receptors (e.g. alpha-agonists, morphine agonists) Agonists of Nuclear Receptors (e.g. HRT for menopause, steroids for inflammation) Enzyme Activators (e.g. nitroglycerine (guanylyl cyclase), pralidoxime) Ion Channel Openers (e.g. minoxidil (K) and alprazolam (Cl)) 31. HOW DO CHEMICALS WORK BY ACTIVATING CELL SURFACE RECEPTORS? KEY CONCEPTS: Cell surface receptors exist to transmit chemical signals from the outside to the inside of the cell. Some chemicals bind to cell surface receptors and trigger a response. Chemicals in this group are called receptor agonists. Some agonists are actually the endogenous chemical signal, whereas other agonists mimic endogenous chemical signals. 32. HOW DO CHEMICALS WORK BY UNCONVENTIONAL MECHANISMS OF ACTION? Disrupting of Structural Proteins e.g. vinca alkaloids for cancer, colchicine for gout Being Enzymes e.g. streptokinase for thrombolysis Covalently Linking to Macromolecules e.g. cyclophosphamide for cancer Reacting Chemically with Small Molecules e.g. antacids for increased acidity Binding Free Molecules or Atoms e.g. drugs for heavy metal poisoning, infliximab (anti-TNF) 33. HOW DO DRUGS WORK BY UNCONVENTIONAL MECHANISMS OF ACTION (Continued)? Being Nutrients e.g. vitamins, minerals Exerting Actions Due to Physical Properties e.g. mannitol (osmotic diuretic), laxatives Working Via an Antisense Action e.g. fomivirsen for CMV retininitis in AIDS Being Antigens e.g. vaccines Having Unknown Mechanisms of Action e.g. general anesthetics 34. Receptors: Regulatory proteins that interact with drugs or hormones and initiate a cellular response Ion channels G-protein coupled receptors Receptor-enzymes Cytosolic-nuclear receptors Act as transducer proteins Receptor-effector signal transduction Post-receptor signal transduction provides for amplification of the signal 35. Ligand-gated Ion Channels 36. G-protein coupled receptors 37. G-protein coupled receptors Membrane 38. G-protein coupled receptors 39. Receptor-enzyme Binding site Catalytic site 40. Cytosolic-Nuclear receptors 41. Receptor-mediated Mechanism of Action drugs beneficial effect caused by the drugs ability to interact with the receptor and change physiological or biochemical or pathological processes Then termed mechanism of drug action 42. Intermediate Messengers or Second Messengers Activation of a receptor may initiate a series of events mediated by intermediate messengers. Signal transduction Drug Binding Site Effect intermediate messengers e.g. cyclic AMP 43. Mechanism of action Classical Receptors Drug actions on Classical receptors are based on types of Ligands Agonist -> Stimulation Antagonist -> Inhibition Neurotransmitter noradrenaline (NA) receptor action Hormones angiotensin receptor action Local hormones histamine receptor action 44. Mechanism of action Uptake Carriers Uptake carriers or Transport proteins can have a role in regulation of drug action Example: Norepinephrine (NE) action NE Uptake carrier NE release from nerve Receptors Neurotransmission Reuptake Rapid inactivation Decrease NE action Drug Uptake inactivation More NE Increase NE action X 45. Mechanism of action Ion Channels drug - ion channel enhances /inhibits action e.g. Ca++ channel blocker (verapamil) 46. Mechanism of action Enzymes drug-enzyme interaction inhibition of enzyme activity Neostigmine inhibits acetyl cholinesterase increased acetyl choline Aspirin inhibits cyclooxygenase decreased prostaglandins 47. Inhibition of Enzyme Activity Neostigmine Mechanism of of action: anti-cholinesterase Inhibits activity of acetyl- cholinesterase Effects: increase Acetylcholine (ACh) levels in the synapse. Clinical use: treatment of myasthenia gravis 48. Inhibition of Enzyme Activity Aspirin Mechanism of action: cyclo-oxygenase inhibitor Pharmacological effects: prostaglandin release pain and fever Clinical use: treatment of pain and fever