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HOW DO DRUGS WORK BY INHIBITING ENZYMES?
KEY CONCEPTS:
• Enzymes catalyze the biosynthesis of products from substrates.
• ...
HOW DO DRUGS WORK BY BLOCKING ION CHANNELS?
KEY CONCEPTS:
• Ion channels allow ions to transverse the cell membrane
throug...
ARE DRUGS THAT BLOCK ION CHANNELS
CLINICALLY USEFUL?
Some important examples:
• Calcium Channel Blockers (CCBs) for angina...
HOW DO DRUGS WORK BY INHIBITING TRANSPORTERS?
Membrane Impermeable Solute
Active Transporter

Membrane Impermeable Solute
...
HOW DO DRUGS WORK BY INHIBITING TRANSPORTERS?
Membrane
Impermeable Solute
Inactive Transporter

Drug that Inhibits Transpo...
HOW DO DRUGS WORK BY INHIBITING TRANSPROTERS?
KEY CONCEPTS:
• Transporters bind to and shuttle membrane impermeable
solute...
ARE DRUGS THAT INHIBIT TRANSPORTERS
CLINICALLY USEFUL?
Some important examples:
• Selective Serotonin Reuptake Inhibitors ...
HOW DO DRUGS WORK BY INHIBITING SIGNAL
TRANSDUCTION PROTEINS?
KEY CONCEPTS:
• Signal transduction proteins transmit a chem...
ARE DRUGS THAT INHIBIT SIGNAL
TRANSDUCTION PROTEINS
CLINICALLY USEFUL?
Some important examples:
• Tyrosine Kinase Inhibito...
HOW DO DRUGS WORK BY ACTIVATING
ENDOGENOUS PROTEINS?
• Agonists of Cell Surface Receptors
• Agonists of Nuclear Receptors
...
HOW DO DRUGS WORK BY ACTIVATING
CELL SURFACE RECEPTORS?

Footnote:
Most agonists attach to binding site on receptor for en...
HOW DO DRUGS WORK BY ACTIVATING CELL
SURFACE RECEPTORS?
KEY CONCEPTS:
• Cell surface receptors exist to transmit chemical ...
ARE DRUGS THAT ACTIVATE
CELL SURFACE RECEPTORS
CLINICALLY USEFUL?
Some important examples:
•Alpha1-Adrenoceptor Agonists f...
HOW DO DRUGS WORK BY ACTIVATING
NUCLEAR RECEPTORS?

Footnote:
Most agonists attach to binding site on receptor for endogen...
HOW DO DRUGS WORK BY ACTIVATING
NUCLEAR RECEPTORS?
KEY CONCEPTS:
• Nuclear receptors exist to mediate the effects of intra...
ARE DRUGS THAT ACTIVATE
NUCLEAR RECEPTORS
CLINICALLY USEFUL?
Some important examples:
• Estrogen Receptor Agonists for hor...
HOW DO DRUGS WORK BY ACTIVATING ENZYMES?
Inactive Enzyme

Substrate
HOW DO DRUGS WORK BY ACTIVATING ENZYMES?
Active Enzyme

Substrate

Product
Enzyme Activator
(Drug)

Cellular Function
HOW DO DRUGS WORK BY ACTIVATING ENZYMES?
KEY CONCEPTS:

• Enzymes catalyze the biosynthesis of products from substrates.
•...
ARE DRUGS THAT ACTIVATE ENZYMES
CLINICALLY USEFUL?
Some important examples:
• Activators of Guanylyl Cyclase for angina
(n...
HOW DO DRUGS WORK BY OPENING ION CHANNELS?
Ions (e.g., Ca++, Na+)
Closed Ion Channel
Binding Site on Ion Channel

Ions (e....
HOW DO DRUGS WORK BY OPENING ION CHANNELS?
Ions (e.g., Ca++, Na+, K+)
Open Ion Channel
Drug That Opens Ion Channel

[Ions]...
HOW DO DRUGS WORK BY OPENING ION CHANNELS?
KEY CONCEPTS:
• Ion channels allow ions to transverse the cell membrane
through...
ARE DRUGS THAT OPEN ION CHANNELS
CLINICALLY USEFUL?
Some important examples:
• Potassium Channel Openers for hair regrowth...
HOW DO DRUGS WORK BY UNCONVENTIONAL
MECHANISMS OF ACTION?

• Disrupters of Structural Proteins
• Drugs that Are Enzymes
• ...
HOW DO DRUGS WORK BY UNCONVENTIONAL
MECHANISMS OF ACTION (Continued)?

• Drugs that Are Nutrients
• Drugs that Exert Actio...
DO SOME DRUGS DISRUPT
STRUCTURAL PROTEINS?
Some important examples:
• Vinca Alkaloids for cancer
(vincristine [Oncovin®]; ...
ARE SOME DRUGS ENZYMES?
Some important examples:
• Thrombolytic therapy for acute myocardial infarction
(alteplase [Activa...
DO SOME DRUGS COVALENTLY LINK
TO MACROMOLECULES?
Some important examples:

• DNA alkylating agents for the treatment of ca...
DO SOME DRUGS REACT CHEMICALLY
WITH SMALL MOLECULES?
Some important examples:
• Antacids that neutralize gastric acid
(var...
DO SOME DRUGS BIND FREE
MOLECULES OR ATOMS?
Some important examples:
• Bile-Acid Sequestrants for hypercholesterolemia
(ch...
ARE SOME DRUGS NUTRIENTS?

Some important examples:
• Vitamins, minerals, lipids, carbohydrates, aminoacids
DO SOME DRUGS EXERT ACTIONS
DUE TO PHYSICAL PROPERTIES?
Some important examples:
• Bulk Laxatives for constipation
(psylli...
DO SOME DRUGS WORK VIA
AN ANTISENSE ACTION?
An important example:
• Antisense Deoxyoligonucleotides for cytomegalovirus re...
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Rational use of drugs part i how do drugs work.ppt33

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

  1. 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. 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. 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. 4. HOW DO DRUGS WORK BY INHIBITING TRANSPORTERS? Membrane Impermeable Solute Active Transporter Membrane Impermeable Solute Cellular Response Intracellular Compartment
  5. 5. HOW DO DRUGS WORK BY INHIBITING TRANSPORTERS? Membrane Impermeable Solute Inactive Transporter Drug that Inhibits Transporters Membrane Impermeable Solute Intracellular Compartment
  6. 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. 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. 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. 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. 10. HOW DO DRUGS WORK BY ACTIVATING ENDOGENOUS PROTEINS? • Agonists of Cell Surface Receptors • Agonists of Nuclear Receptors • Enzyme Activators • Ion Channel Openers
  11. 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. 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. 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. 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. 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. 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. 17. HOW DO DRUGS WORK BY ACTIVATING ENZYMES? Inactive Enzyme Substrate
  18. 18. HOW DO DRUGS WORK BY ACTIVATING ENZYMES? Active Enzyme Substrate Product Enzyme Activator (Drug) Cellular Function
  19. 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. 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. 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. 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. 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. 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. 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. 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. 27. DO SOME DRUGS DISRUPT STRUCTURAL PROTEINS? Some important examples: • Vinca Alkaloids for cancer (vincristine [Oncovin®]; vinblastine [Velban®]) • Colchicine for gout
  28. 28. ARE SOME DRUGS ENZYMES? Some important examples: • Thrombolytic therapy for acute myocardial infarction (alteplase [Activase®])
  29. 29. DO SOME DRUGS COVALENTLY LINK TO MACROMOLECULES? Some important examples: • DNA alkylating agents for the treatment of cancer (cyclophosphamide [Cytoxan®]; chlorambucil [Leukeran®])
  30. 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. 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. 32. ARE SOME DRUGS NUTRIENTS? Some important examples: • Vitamins, minerals, lipids, carbohydrates, aminoacids
  33. 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. 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
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