1 / 61

Bound

LOCUS OF ACTION “RECEPTORS ”. TISSUE RESERVOIRS. Bound. Free. Free. Bound. ABSORPTION. EXCRETION. Free Drug. SYSTEMIC CIRCULATION. Bound Drug. BIOTRANSFORMATION. WHY BE CONCERNED ABOUT HOW DRUGS WORK?. AIDS MEMORIZATION OF:. FDA Approved and Unapproved Uses

dyllis
Download Presentation

Bound

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. LOCUS OF ACTION “RECEPTORS” TISSUE RESERVOIRS Bound Free Free Bound ABSORPTION EXCRETION Free Drug SYSTEMIC CIRCULATION Bound Drug BIOTRANSFORMATION

  2. WHY BE CONCERNED ABOUT HOW DRUGS WORK? AIDS MEMORIZATION OF: • FDA Approved and Unapproved Uses • Interactions with Other Drugs • Adverse Effects and Contraindications

  3. WHY BE CONCERNED ABOUT HOW DRUGS WORK? AIDS EVALUATION OF MEDICAL LITERATURE: • Better assessment of new modalities for using drugs • Better assessment of new indications for drugs • Better assessment of new concerns regarding risk-benefit

  4. WHY BE CONCERNED ABOUT HOW DRUGS WORK? AIDS PATIENT-DOCTOR RELATIONSHIP: 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. 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? PEACE OF MIND! Knowledge of how a drug works increases the therapist’s confidence that the drug is being used appropriately.

  6. HOW DO DRUGS WORK? Most work by interacting with endogenous proteins: • Some antagonize, block or inhibit endogenous proteins • Some activate endogenous proteins • A few have unconventional mechanisms of action

  7. 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

  8. Definition of RECEPTOR: A macromolecular component of the organism that binds the drug and initiates its effect. Most receptors are proteins that have undergone various post-translational modifications such as covalent attachments of carbohydrate, lipid and phosphate.

  9. Definition of CELL SURFACE RECEPTOR: 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.

  10. HOW DO DRUGS WORK BY ANTAGONIZING 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.

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

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

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

  14. HOW DO DRUGS WORK BY ANTAGONIZING CELL SURFACE RECEPTORS? 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)

  15. HOW DO DRUGS WORK BY ANTAGONIZING CELL SURFACE RECEPTORS? Displaced Endogenous Activator (Agonist) of Receptor Extracellular Compartment Bound Antagonist of Receptor Cell Membrane Active Receptor Inactive Receptor Intracellular Compartment Allosteric Inhibitor

  16. ARE DRUGS THAT ANTAGONIZE CELL SURFACE RECEPTORS CLINICALLY USEFUL? Some important examples: • Angiotensin Receptor Blockers (ARBs) for high blood pressure, • heart failure, chronic renal insufficiency • (losartan [Cozaar®]; valsartan [Diovan®]) • Beta-Adrenoceptor Blockers for angina, myocardial infarction, • heart failure, high blood pressure, performance anxiety • (propranolol [Inderal®]; atenolol [Tenormin®])

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

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

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

  20. ARE DRUGS THAT ANTAGONIZE NUCLEAR RECEPTORS CLINICALLY USEFUL? Some important examples: • Mineralocorticoid Receptor Antagonists for edema due to • liver cirrhosis and for heart failure • (spironolactone [Aldactone®]) • Estrogen Receptor Antagonists for the prevention and treatment • of breast cancer (tamoxifen [Nolvadex®])

  21. 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

  22. HOW DO DRUGS WORK BY INHIBITING ENZYMES? Active Enzyme Substrate Product Cellular Function Inactive Enzyme Substrate Bound Enzyme Inhibitor (Drug)

  23. 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.

  24. ARE DRUGS THAT INHIBIT ENZYMES CLINICALLY USEFUL? Some important examples: • Cyclooxygenase Inhibitors for pain relief, • particularly due to arthritis (aspirin; ibuprofen [Motrin®]) • HMG-CoA Reductase Inhibitors for hypercholesterolemia • (atorvastatin [Lipitor®]; pravastatin [Pravachol®]) • Angiotensin Converting Enzyme (ACE) Inhibitors for • high blood pressure, heart failure, and • chronic renal insufficiency • (captopril [Capoten®]; ramipril [Altace®])

  25. 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

  26. 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®])

  27. 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®])

  28. 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

  29. 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)

  30. 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.

  31. 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)

  32. 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

  33. Characteristics of Drug-Receptor Interactions • Chemical Bond: ionic, hydrogen, hydrophobic, Van der Waals, and covalent. • Saturable • Competitive • Specific and Selective • Structure-activity relationships • Transduction mechanisms

  34. NH4+-CH2(n)-NH4+

  35. Receptor Transduction Mechanisms • Ion channel linked receptors e.g. Ach nicotinic (Na+) and GABA (Cl-) • Second messenger generation, adenylate cyclase stimulation or inhibition - cAMP, guanylate cyclase - cGMP, phospholipase C - IP3, DAG • Some receptors are themselves protein kinases • Intracellular receptors (e.g. corticosteroids, thyroid hormone)

  36. OCCUPATION THEORY OF DRUG-RECEPTOR INTERACTIONS k1 D + R <=> DR k2 By Law of Mass Action: [D]•[R]•K1= [DR]•K2 Therefore K2 /K1= Kd = [D]•[R]/[DR] If RT = total # of receptors, then RT = [R] + [DR] Replace [R] by (RT-[DR]) and rearrange: EFFECT [DR] [D] RT Kd + [D] effect = = Max. effect

  37. effect [DR] [D] Max. effect RT Kd + [D] When [D] = Kd [DR] RT = = = 0.5 1.00 0.75 T [DR]/R 0.50 0.25 0.00 0 5 10 15 20 [D] Kd

  38. Receptor Binding % Bound Kd Concentration of Ligand The dose-response relationship (from C.D. Klaassen, Casarett and Doull’s Toxicology, 5th ed., New York: McGraw-Hill, 1996).

  39. Compounds Have Different Affinities for the Same Receptor 1.00 Kd=0.5 Kd=1 kd=5 0.75 T [DR]/R 0.50 0.25 0.00 0.01 0.10 1.00 10.00 100.00 [D] (concentration units)

  40. Types of Receptor Antagonists Competitive Noncompetitive

  41. PARTIAL AGONISTS - EFFICACY Even though drugs may occupy the same # of receptors, the magnitude of their effects may differ. Full Agonist 1.0 Partial agonist 0.8 0.6 Partial agonist % Maximal Effect 0.4 0.2 0.0 0.01 0.10 1.00 10.00 100.00 1000.00 [D] (concentration units)

  42. HOW TO EXPLAIN EFFICACY? Drug (D) The relative affinity Of the drug to either conformation will determine the effect of the drug Ri Ra DRi DRa CONFORMATIONAL SELECTION

  43. R R2* R1* R3* R2* R1* R R R2* R1* R3* R3* From Kenakin, T. Receptor conformational induction versus selection: all part of the same energy landscape. TiPS 1996;17:190-191.

  44. Spare Receptors

  45. Receptor Regulation • Sensitization or Up-regulation 1. Prolonged/continuous use of receptor blocker 2. Inhibition of synthesis or release of hormone/neurotransmitter - Denervation • Desensitization or Down-regulation 1. Prolonged/continuous use of agonist 2. Inhibition of degradation or uptake of agonist Homologous vs. Heterologous Uncoupling vs. Decreased Numbers

More Related