Rational use of drugs part i how do drugs work.ppt33

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  • 1. 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.
  • 2. HOW DO DRUGS WORK BY BLOCKING ION CHANNELS? KEY CONCEPTS: • Ion channels allow ions to transverse the cell membrane through a pore and down an electrochemical gradient. • Some drugs bind to ion channels and physically block the pore or cause an allosteric change that closes the pore. • Changes in the intracellular concentration of ions mediates the effects of inhibitors of ion channels.
  • 3. ARE DRUGS THAT BLOCK ION CHANNELS CLINICALLY USEFUL? Some important examples: • Calcium Channel Blockers (CCBs) for angina and high blood pressure (amlodipine [Norvasc®]; diltiazem [Cardizem®]) • Sodium Channel Blockers to suppress cardiac arrhythmias (lidocaine [Xylocaine®]; amiodarone [Cordarone®])
  • 4. HOW DO DRUGS WORK BY INHIBITING TRANSPORTERS? Membrane Impermeable Solute Active Transporter Membrane Impermeable Solute Cellular Response Intracellular Compartment
  • 5. HOW DO DRUGS WORK BY INHIBITING TRANSPORTERS? Membrane Impermeable Solute Inactive Transporter Drug that Inhibits Transporters Membrane Impermeable Solute Intracellular Compartment
  • 6. HOW DO DRUGS WORK BY INHIBITING TRANSPROTERS? KEY CONCEPTS: • Transporters bind to and shuttle membrane impermeable solutes across the cell membrane. • Some drugs bind to transporters and cause allosteric changes that prevent proper functioning of the transporters. • Changes in the intracellular concentration of specific solutes mediates the effects of inhibitors of transporters.
  • 7. ARE DRUGS THAT INHIBIT TRANSPORTERS CLINICALLY USEFUL? Some important examples: • Selective Serotonin Reuptake Inhibitors (SSRIs) for the treatment of depression (fluoxetine [Prozac®]; fluvoxamine [Luvox®]) • Inhibitors of Na-2Cl-K Symporter (Loop Diuretics) in renal epithelial cells to increase urine and sodium output for the treatment of edema (furosemide [Lasix®]; bumetanide [Bumex®])
  • 8. HOW DO DRUGS WORK BY INHIBITING SIGNAL TRANSDUCTION PROTEINS? KEY CONCEPTS: • Signal transduction proteins transmit a chemical signal from a receptor to the final biological target. • Some drugs bind to and inhibit key signal transduction proteins. • Inhibition of key signal transduction proteins may block or augment the signal transduction pathway and this mediates the effects of the drug.
  • 9. ARE DRUGS THAT INHIBIT SIGNAL TRANSDUCTION PROTEINS CLINICALLY USEFUL? Some important examples: • Tyrosine Kinase Inhibitors for chronic myelocytic leukemia (imatinib [Gleevec®]) • Type 5 Phosphodiesterase Inhibitors for erectile dysfunction (sildenafil [Viagra®]) • This is a major focus of drug development
  • 10. HOW DO DRUGS WORK BY ACTIVATING ENDOGENOUS PROTEINS? • Agonists of Cell Surface Receptors • Agonists of Nuclear Receptors • Enzyme Activators • Ion Channel Openers
  • 11. HOW DO DRUGS WORK BY ACTIVATING CELL SURFACE 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.
  • 12. HOW DO DRUGS 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 drugs bind to cell surface receptors and trigger a response. • Drugs in this group are called receptor agonists. • Some drug agonists are actually the endogenous chemical signal, whereas other drug agonists mimic endogenous chemical signals.
  • 13. ARE DRUGS THAT ACTIVATE CELL SURFACE RECEPTORS CLINICALLY USEFUL? Some important examples: •Alpha1-Adrenoceptor Agonists for nasal congestion (oxymetazoline [Afrin®]; phenylephrine [Neosynephrine®]) • Opioid Receptor Agonists for analgesia (morphine; meperidine [Demerol®])
  • 14. 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.
  • 15. HOW DO DRUGS WORK BY ACTIVATING NUCLEAR RECEPTORS? KEY CONCEPTS: • Nuclear receptors exist to mediate the effects of intracellular, endogenous chemicals on gene expression. • Some drugs bind to nuclear receptors and trigger a response. • Drugs in this group are called receptor agonists. • Some drug agonists are actually an endogenous chemical, whereas other drug agonists mimic an endogenous chemical.
  • 16. ARE DRUGS THAT ACTIVATE NUCLEAR RECEPTORS CLINICALLY USEFUL? Some important examples: • Estrogen Receptor Agonists for hormone replacement therapy in postmenopausal women (conjugated equine estrogens [Premarin®]) • Glucocorticoid Receptor Agonist for inflammation (hydrocortisone[Cortef®]; dexamethasone [Decadron®])
  • 17. HOW DO DRUGS WORK BY ACTIVATING ENZYMES? Inactive Enzyme Substrate
  • 18. HOW DO DRUGS WORK BY ACTIVATING ENZYMES? Active Enzyme Substrate Product Enzyme Activator (Drug) Cellular Function
  • 19. HOW DO DRUGS WORK BY ACTIVATING ENZYMES? KEY CONCEPTS: • Enzymes catalyze the biosynthesis of products from substrates. • Some drugs bind to enzymes and increase their enzymatic activity. • Increased biosynthesis of product mediates the effects of enzyme activators.
  • 20. ARE DRUGS THAT ACTIVATE ENZYMES CLINICALLY USEFUL? Some important examples: • Activators of Guanylyl Cyclase for angina (nitroglycerin; isosorbide dinitrate [Isordil®]) • Reactivators of Cholinesterase after poisoning with nerve gas or organophosphate pesticide (pralidoxime [Protopam®])
  • 21. HOW DO DRUGS WORK BY OPENING ION CHANNELS? Ions (e.g., Ca++, Na+) Closed Ion Channel Binding Site on Ion Channel Ions (e.g., K+) Intracellular Compartment
  • 22. HOW DO DRUGS WORK BY OPENING ION CHANNELS? Ions (e.g., Ca++, Na+, K+) Open Ion Channel Drug That Opens Ion Channel [Ions] Cellular Response Intracellular Compartment
  • 23. HOW DO DRUGS WORK BY OPENING ION CHANNELS? KEY CONCEPTS: • Ion channels allow ions to transverse the cell membrane through a pore and down an electrochemical gradient. • Some drugs bind to ion channels and allosterically open the ion channel or allosterically render the channel more readily opened by other endogenous chemicals. • Changes in the intracellular concentration of ions mediates the effects of drugs that open ion channels.
  • 24. ARE DRUGS THAT OPEN ION CHANNELS CLINICALLY USEFUL? Some important examples: • Potassium Channel Openers for hair regrowth (minoxidil [Rogaine®]) • GABAAChloride Channel Openers for anxiety (alprazolam[Xanax®]; midazolam [Versed®])
  • 25. HOW DO DRUGS WORK BY UNCONVENTIONAL MECHANISMS OF ACTION? • Disrupters of Structural Proteins • Drugs that Are Enzymes • Drugs that Covalently Link to Macromolecules • Drugs that React Chemically with Small Molecules • Drugs that Bind Free Molecules or Atoms
  • 26. HOW DO DRUGS WORK BY UNCONVENTIONAL MECHANISMS OF ACTION (Continued)? • Drugs that Are Nutrients • Drugs that Exert Actions Due to Physical Properties • Drugs that Work Via an Antisense Action • Drugs that Are Antigens • Drugs with Unknown Mechanisms of Action
  • 27. DO SOME DRUGS DISRUPT STRUCTURAL PROTEINS? Some important examples: • Vinca Alkaloids for cancer (vincristine [Oncovin®]; vinblastine [Velban®]) • Colchicine for gout
  • 28. ARE SOME DRUGS ENZYMES? Some important examples: • Thrombolytic therapy for acute myocardial infarction (alteplase [Activase®])
  • 29. DO SOME DRUGS COVALENTLY LINK TO MACROMOLECULES? Some important examples: • DNA alkylating agents for the treatment of cancer (cyclophosphamide [Cytoxan®]; chlorambucil [Leukeran®])
  • 30. DO SOME DRUGS REACT CHEMICALLY WITH SMALL MOLECULES? Some important examples: • Antacids that neutralize gastric acid (various preparations containing Al(OH)3, Mg(OH)2 or CaCO3)
  • 31. DO SOME DRUGS BIND FREE MOLECULES OR ATOMS? Some important examples: • Bile-Acid Sequestrants for hypercholesterolemia (cholestyramine [Questran®]) • Chelating Agents for heavy metal poisoning (dimercaprol; penicillamine) • Proteins that bind TNF-α for rheumatoid arthritis (infliximab [Remicade®]; etanercept [Enbrel®])
  • 32. ARE SOME DRUGS NUTRIENTS? Some important examples: • Vitamins, minerals, lipids, carbohydrates, aminoacids
  • 33. DO SOME DRUGS EXERT ACTIONS DUE TO PHYSICAL PROPERTIES? Some important examples: • Bulk Laxatives for constipation (psyllium [Metamucil®]; polycarbophil [Fibercon®] • Osmotic Diuretics for edema (mannitol)
  • 34. DO SOME DRUGS WORK VIA AN ANTISENSE ACTION? An important example: • Antisense Deoxyoligonucleotides for cytomegalovirus retinitis in patients with AIDS (fomivirsen [Vitravene®] • This is a major focus of drug development