neur1670 ppt2.pdf - Principles​ ​of​ ​Pharmacology...

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Unformatted text preview: Principles​ ​of​ ​Pharmacology Drug​ ​action​ ​in​ ​the​ ​body Depends​ ​on​ ​drug​ ​concentration​ ​at​ ​site​ ​of​ ​action. This​ ​depends​ ​on A.​ ​Route​ ​of​ ​administration B.​ ​Absorption​ ​and​ ​distribution C.​ ​Binding D.​ ​Inactivation E.​ ​Excretion Dose-Response​ ​Curves Potency​ ​vs​ ​Efficacy - Potency:​ ​ED​50​​ ​ie​ ​dose​ ​causing​ ​50%​ ​of​ ​maximal​ ​response - Efficacy:​ ​The​ ​maximal​ ​response e.g.​ ​Analgesic​ ​Dose-Response​ ​Curve Highest​ ​potency:​ ​Hydromorphine Lowest​ ​efficacy:​ ​Aspirin Therapeutic​ ​Index​ ​TI​ ​=​ ​Toxic​ ​Dose​50​ ​/​ ​Effective​ ​Dose​50 ​ ​ ​ ​ ​ ​ ​ ​TI​ ​=​ ​TD​50​​ ​/​ ​ED​50 Higher​ ​TI​ ​means​ ​safer​ ​drug. Lithium​ ​for​ ​manic-depression​ ​has​ ​TI​ ​<4,​ ​requiring​ ​frequent monitoring. Receptor​ ​Effects Ligand:​ ​Agent​ ​which​ ​binds​ ​to​ ​receptor Agonist:​ ​Agent​ ​which​ ​activates​ ​receptor - Partial​ ​agonist:​ ​Agent​ ​which​ ​activates​ ​receptor,​ ​not​ ​as​ ​great​ ​efficacy​ ​as​ ​full​ ​agonist Antagonist:​ ​Agent​ ​which​ ​interferes​ ​with​ ​agonist​ ​action - Competitive​ ​agonist:​ ​Binds​ ​to​ ​receptor​ ​at​ ​agonist​ ​site​ ​-​ ​same​ ​efficacy​ ​but​ ​↑​ ​ED​50 - Noncompetitive​ ​agonist:​ ​Binds​ ​elsewhere​ ​on​ ​receptor​ ​-​ ​same​ ​ED​50​​ ​but​ ​↑​ ​efficacy Drug​ ​Interactions Receptor​ ​Plasticity - Constant​ ​blockade​ ​→​ ​receptor​ ​upregulation​ ​via​ ​↑​ ​no.​ ​of​ ​receptors - Constant​ ​stimulation​ ​→​ ​receptor​ ​downregulation​ ​via​ ​↓​ ​no.​ ​of​ ​receptors Drug​ ​Delivery Absorption:​ ​Passage​ ​of​ ​drug​ ​from​ ​site​ ​of​ ​administration​ ​→​ ​blood Distribution:​ ​Delivery​ ​of​ ​drug​ ​→​ ​tissues Types​ ​of​ ​Drug​ ​Administration - Intravenous​:​ ​Rapid,​ ​complete​ ​absorption;​ ​must​ ​be​ ​soluble - Oral​:​ ​Stomach​ ​acid​ ​and/or​ ​enzymes​ ​affect​ ​drug. - Absorbed​ ​via​ ​stomach/small​ ​intestine - First-pass​ ​metabolism​ ​by​ ​liver - Intraperitoneal​ ​(i.p.)​:​ ​Into​ ​peritoneal​ ​cavity;​ ​rapid​ ​absorption - Subcutaneous​ ​(s.c.)​:​ ​Placed​ ​under​ ​skin​ ​for​ ​chronic​ ​drug​ ​administration - Intramuscular​:​ ​Drug​ ​can​ ​be​ ​in​ ​a​ ​suspension - Sublingual​:​ ​Under​ ​tongue - Inhalation​:​ ​Rapid;​ ​good​ ​for​ ​local​ ​treatment​ ​of​ ​asthma - Topical​:​ ​Patches​ ​→​ ​passage​ ​through​ ​skin - Direct​ ​application​ ​to​ ​CNS​:​ ​Bypasses​ ​blood-brain​ ​barrier Blood-brain​ ​barrier​ ​(BBB) BBB​ ​prevents​ ​drug​ ​entry​ ​into​ ​the​ ​brain​ ​from​ ​peripheral​ ​blood. Overcoming​ ​the​ ​Blood-brain​ ​Barrier The​ ​area​ ​postrema​ ​and​ ​subfornical​ ​organ​ ​have​ ​a​ ​diminished​ ​barrier. A.​ ​Area​ ​Postrema - In​ ​the​ ​brainstem;​ ​on​ ​dorsal​ ​surface​ ​of​ ​medulla​ ​oblongata - Responds​ ​to​ ​noxious​ ​compounds​ ​in​ ​blood​ ​by​ ​triggering​ ​emesis​ ​(vomiting) - Increased​ ​exposure​ ​to​ ​blood​ ​contents B.​ ​Subfornical​ ​organs - Responds​ ​to​ ​angiotensin​ ​II​ ​by​ ​ ​↑​ ​thirst​ ​response - Blood​ ​volume​ ​↓​ ​→​ ​angiotensin​ ​II​ ​↑ For​ ​a​ ​drug​ ​to​ ​enter​ ​CNS​ ​from​ ​periphery: 1. Lipid​ ​solubility​ ​i.e.​ ​able​ ​to​ ​pass​ ​through​ ​membranes​ ​(high​ ​oil/water​ ​partition​ ​coefficient) e.g.​ ​psychoactive​ ​drugs​ ​such​ ​as​ ​amphetamine,​ ​cocaine,​ ​LSD,​ ​morphine 2. Utilise​ ​transport​ ​mechanisms e.g.​ ​L-DOPA​ ​uses​ ​same​ ​transport​ ​system​ ​which​ ​takes​ ​tyrosine​ ​into​ ​brain ​ ​ ​ ​ ​ ​ ​ ​Converted​ ​in​ ​brain​ ​→​ ​dopamine,​ ​relieve​ ​motor​ ​symptoms​ ​of​ ​Parkinson’s Stereotaxis​ ​apparatus​ ​is​ ​used​ ​for​ ​administering​ ​drugs​ ​directly​ ​into​ ​CNS - The​ ​bregma​ ​(sagittal/coronal​ ​suture​ ​intersection)​ ​is​ ​used​ ​as​ ​a​ ​spatial​ ​reference​ ​point Microdialysis​ ​collects​ ​released​ ​transmitters;​ ​reverse​ ​microdialysis​ ​delivers​ ​drugs. Effect​ ​of​ ​ionization​ ​on​ ​drug​ ​absorption Non-ionised​ ​form​ ​absorbed​ ​better,​ ​e.g.​ ​aspirin pK​a​​ ​=​ ​pH​ ​at​ ​which​ ​50%​ ​of​ ​drug​ ​molecules​ ​are​ ​ionised/unionised Aspirin’s​ ​pKa​ ​=​ ​3.5 - At​ ​pH​ ​2.5,​ ​90%​ ​would​ ​be​ ​unionised - At​ ​pH​ ​4.5,​ ​90%​ ​would​ ​be​ ​ionised - If​ ​an​ ​antacid​ ​is​ ​taken​ ​→​ ​less​ ​aspirin​ ​absorption​ ​since​ ​pH​ ​increases,​ ​more​ ​aspirin​ ​ionised Drug​ ​distribution Drug​ ​distribution​ ​depends​ ​on - Cell​ ​solubility - Molecular​ ​weight - Cell​ ​transport​ ​systems Ethanol​​ ​has​ ​uniform​ ​distribution​ ​throughout​ ​body​ ​due​ ​to​ ​good​ ​lipid​ ​and​ ​water​ ​solubility Some​ ​drugs​ ​e.g.​ ​heparin​​ ​stay​ ​in​ ​blood​ ​after​ ​iv​ ​administration​ ​due​ ​to​ ​large​ ​molecular​ ​weight Drug​ ​inactivation Half-life:​ ​amount​ ​of​ ​time​ ​it​ ​takes​ ​to​ ​reduce​ ​drug​ ​concentration​ ​in​ ​blood​ ​by​ ​one-half e.g.​ ​after​ ​4-half​ ​lives,​ ​original​ ​→​ ​50%​ ​→​ ​12.5%​ ​→​ ​6.25% Drugs​ ​disappear​ ​via… A. Metabolism:​ ​Many​ ​tissues​ ​metabolise​ ​drugs,​ ​especially​ ​liver B. Metabolising​ ​enzymes​ ​concentration​ ​in​ ​smooth​ ​ER a. Some​ ​such​ ​enzymes,​ ​ie​ ​cytochrome​ ​P​450​​ ​enzymes,​ ​can​ ​be​ ​induced​ ​(increased) after​ ​chronic​ ​drug​ ​exposure,​ ​e.g.​ ​to​ ​barbiturates​ ​→​ ​shortens​ ​half-life Drug-food​ ​interactions - Anti-cholesterol​ ​drugs​ ​e.g.​ ​Zocor​​ ​and​​ ​Lipitor​ ​have​ ​metabolism​ ​inhibited​ ​by​ ​grapefruit juice​ ​→​ ​prolong​ ​half-life Drug​ ​elimination Elimination​ ​via​ ​kidney​ ​into​ ​urine - Some​ ​ethanol​ ​eliminated​ ​via​ ​lunges,​ ​hence​ ​breathalyser​ ​tests Metabolic​ ​reactions​ ​→​ ​drugs​ ​more​ ​polar,​ ​won’t​ ​get​ ​reabsorbed​ ​by​ ​kidney​ ​into​ ​bloodstream Drug​ ​tolerance Tolerance:​ ​With​ ​chronic​ ​usage,​ ​need​ ​more​ ​of​ ​drug​ ​to​ ​get​ ​same​ ​effect e.g.​ ​ethanol​ ​tolerance​ ​in​ ​dogs​ ​→​ ​chronic​ ​dogs​ ​less​ ​affected​ ​at​ ​same​ ​alcohol​ ​blood​ ​levels Mechanisms: - Metabolic​ ​tolerance:​ ​Shorter​ ​half-life​ ​e.g.​ ​bariturates - Altered​ ​cellular​ ​response Cross​ ​tolerance:​ ​if​ ​tolerance​ ​exists​ ​for​ ​one​ ​drug,​ ​will​ ​also​ ​exist​ ​for​ ​other - e.g.​ ​morphine​ ​and​ ​heroin,​ ​LSD​ ​and​ ​psilocybin Sensitisation Sensitisation/reverse​ ​tolerance:​ ​Increased​ ​response​ ​with​ ​chronic​ ​administration e.g.​ ​behavioural​ ​sensitisation​ ​to​ ​amphetamine - Can​ ​be​ ​seen​ ​with​ ​stereotyped​ ​and​ ​motor​ ​activity​ ​response​ ​to​ ​amphetamine - Compared​ ​to​ ​drug​ ​craving​ ​state​ ​→​ ​could​ ​aid​ ​in​ ​treating​ ​drug​ ​addiction ...
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