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Drug actions /certified fixed orthodontic courses by Indian dental academy
- 2. INDIAN DENTAL ACADEMY Leader in continuing dental education www.indiandentalacademy.com
- 3. Pharmacokinetics Pharmacokinetics •• Time course of drug absorption, Time course of drug absorption, distribution, metabolism, excretion distribution, metabolism, excretion How the drug How the drug comes and goes. comes and goes.
- 4. Pharmacokinetic Processes Pharmacokinetic Processes “LADME” is key Liberation Liberation Absorption Absorption Distribution Distribution Metabolism Metabolism Excretion Excretion
- 5. Liberation Liberation •• •• Applies to drugs given orally Applies to drugs given orally Components Components – Release of drug from pill, tablet, capsule – Release of drug from pill, tablet, capsule – Dissolving of active drug in GI fluids – Dissolving of active drug in GI fluids Ex: Enteric coated Ex: Enteric coated aspirin slows absorption in aspirin slows absorption in stomach vs non-coated stomach vs non-coated
- 6. Absorption Absorption •• Movement from administration site into Movement from administration site into circulation circulation
- 7. Factors Affecting Factors Affecting Liberation/Absorption Liberation/Absorption •• Formulation factors Formulation factors – Tablet disintegration – Tablet disintegration – Inert ingredient // – Inert ingredient solvent effects solvent effects – Solubility – Solubility – Drug pH – Drug pH – Concentration – Concentration •• Patient factors Patient factors – Absorbing surface – Absorbing surface – Blood flow – Blood flow – Environmental pH – Environmental pH – Disease states – Disease states – Interactions with food, – Interactions with food, other drugs other drugs
- 8. Membranes and Absorption Membranes and Absorption Hydrophilic Hydrophilic Heads Heads Lipid Bilayer Hydrophobic Hydrophobic Tails Tails Small, uncharged H2O, urea, CO2, O2, N2 Swoosh! Large, uncharged Glucose Sucrose DENIED! Small charged ions H+, Na+, K+, Ca2+, Cl-, HCO3- DENIED!
- 9. LaChatlier’s Principle LaChatlier’s Principle a.k.a. Mass Action a.k.a. Mass Action System System at at Equilibrium Equilibrium 4 Na+ + 4 Cl_ A reaction at equilibrium A reaction at equilibrium responds to stress in a responds to stress in a way to best return to way to best return to equilibrium equilibrium 4 NaCl
- 10. 4. System returnsequilibrium System responds system 4. 3.2. Stress responds to stress System returnsequilibrium 3.1. Stress applied equilibrium! 2.1. System at to toto stress System applied equilibrium! System at to to system ⇑ by 4 8 4 4 Na+ System not at System not at An example of equilibrium! equilibrium! LaChatlier’s Principle + 4 NaCl dissociate 8 4 Cl- ⇑ 8 ⇓ by 4 12NaCl 8 4 NaCl
- 11. Ionization Ionization Acids Acids HA Bases Bases H+ + B- Release/Donate H++ Release/Donate H H+ + A - Ionized Ionized form form Bind/Accept H++ Bind/Accept H HB Non-ionized Non-ionized form form
- 12. Environmental pH and Environmental pH and Ionization Ionization If we put an acidic drug in an If we put an acidic drug in an environment with a lot of H++ (low pH) environment with a lot of H (low pH) what will this equilibrium do? what will this equilibrium do? HA HA HA HA HA H+ + A - ⇑ System atformenvironment H++ from formenvironment Non-ionizedat Equilibrium ⇑ System acid predominates! H from Equilibrium Non-ionized acid predominates!
- 13. A real live, actual clinical A real live, actual clinical question... question... Aspirin is an acidic drug. In the Aspirin is an acidic drug. In the stomach will it exist mostly in ionized stomach will it exist mostly in ionized or non-ionized form? or non-ionized form? NON-IONIZED Why? Why?
- 14. How will this affect aspirin How will this affect aspirin absorption? absorption? Lipid Bilayer Ionized form Ionized form (charged) (charged) A- Ionized form Ionized form (uncharged) (uncharged) HA HA
- 15. Moral of the story... Moral of the story... Acidic drugs are best absorbed from Acidic drugs are best absorbed from acidic environments acidic environments Basic drugs are best absorbed from Basic drugs are best absorbed from basic environments basic environments
- 16. So... So... To ⇑ absorption of an acidic drug… To ⇑ absorption of an acidic drug… acidify the environment acidify the environment To ⇓ absorption of an acidic drug… To ⇓ absorption of an acidic drug… alkalanize the environment... alkalanize the environment...
- 17. Distribution Distribution •• •• •• •• Rate of perfusion Rate of perfusion Plasma protein (albumin) binding Plasma protein (albumin) binding Accumulation in tissues Accumulation in tissues Ability to cross membranes Ability to cross membranes – Blood-brain barrier – Blood-brain barrier – Placental barrier – Placental barrier
- 18. Plasma Protein Binding Plasma Protein Binding warfarin (Coumadin) is highly protein warfarin (Coumadin) is highly protein bound (99%). Aspirin binds to the same bound (99%). Aspirin binds to the same site on serum proteins as does site on serum proteins as does Coumadin. If a patient on Coumadin Coumadin. If a patient on Coumadin also takes aspirin, what will happen? also takes aspirin, what will happen? 1) Why? 1) Why? The available Coumadin will 2) Why do we care? 2) Why do we care? increase.
- 19. Blood-Brain Barrier Blood-Brain Barrier The blood brain barrier consists of The blood brain barrier consists of cell tightly packed around the cell tightly packed around the capillaries of the CNS. What capillaries of the CNS. What characteristics must a drug possess characteristics must a drug possess to easily cross this barrier? to easily cross this barrier? Non-protein bound, non-ionized, Why? Why? soluble and highly lipid
- 20. Metabolism Metabolism (Biotransformation) (Biotransformation) •• Two effects Two effects – Transformation to less active metabolite – Transformation to less active metabolite – Enhancement of solubility – Enhancement of solubility •• •• Liver = primary site Liver = primary site Liver disease Liver disease – Slows metabolism – Slows metabolism – Prolongs effects – Prolongs effects
- 21. Hepatic ‘First-Pass’ Hepatic ‘First-Pass’ Metabolism Metabolism •• •• •• •• Affects orally administered drugs Affects orally administered drugs Metabolism of drug by liver before drug Metabolism of drug by liver before drug reaches systemic circulation reaches systemic circulation Drug absorbed into portal circulation, must Drug absorbed into portal circulation, must pass through liver to reach systemic pass through liver to reach systemic circulation circulation May reduce availability of drug May reduce availability of drug
- 22. Elimination Elimination •• Kidneys = primary site Kidneys = primary site – Mechanisms dependent upon: – Mechanisms dependent upon: •• Passive glomerular filtration Passive glomerular filtration •• Active tubular transport Active tubular transport – Partial reabsorption – Partial reabsorption – Hemodialysis – Hemodialysis •• Renal disease Renal disease – Slows excretion – Slows excretion – Prolongs effects – Prolongs effects
- 23. Active Tubular Transport Active Tubular Transport Probenecid is moved into the urine by Probenecid is moved into the urine by the same transport pump that moves the same transport pump that moves many antibiotics. Why is probenecid many antibiotics. Why is probenecid sometimes given as an adjunct to sometimes given as an adjunct to antibiotic therapy? antibiotic therapy? It competes with the antibiotic at the pump and slows its excretion.
- 24. Urine pH and Elimination Urine pH and Elimination A patient has overdosed on A patient has overdosed on phenobartital. Phenobarbital is an acid. phenobartital. Phenobarbital is an acid. If we ‘alkalinalize’ the urine by giving If we ‘alkalinalize’ the urine by giving bicarbonate what will happen to the bicarbonate what will happen to the phenobarbital molecules as they are phenobarbital molecules as they are filtered through the renal tubules? filtered through the renal tubules? They will ionize...
- 25. How will this affect phenobarbital How will this affect phenobarbital reabsorption by the kidney? reabsorption by the kidney? Non-ionized HA Ionized H+ + A - Decreased reabsorption Decreased reabsorption Increased elimination Increased elimination
- 26. Elimination Elimination •• Other sources Other sources – Feces – Feces – Exhaled air – Exhaled air – Breast milk – Breast milk – Sweat – Sweat
- 27. Biological Half-life (t 1/2)) Biological Half-life (t 1/2 •• Amount of time to eliminate 1/2 of total Amount of time to eliminate 1/2 of total drug amount drug amount •• Shorter tt 1/2 may need more frequent doses Shorter 1/2 may need more frequent doses •• Hepatic disease may increase tt1/2 Hepatic disease may increase 1/2
- 28. A drug has a half life of 10 seconds. You A drug has a half life of 10 seconds. You give a patient a dose of 6mg. After 30 give a patient a dose of 6mg. After 30 seconds how much of the drug remains? seconds how much of the drug remains? Time Time Amount Amount 0 sec 0 sec 6 mg 6 mg 10 sec 10 sec 3 mg 3 mg 20 sec 20 sec 1.5 mg 1.5 mg 30 sec 30 sec 0.75 mg 0.75 mg
- 29. Administration Routes Administration Routes •• Intravenous Intravenous – Fastest, Most dangerous – Fastest, Most dangerous •• Endotracheal Endotracheal – Lidocaine, atropine, narcan, epinephrine – Lidocaine, atropine, narcan, epinephrine •• Inhalation Inhalation – Bronchodilators via nebulizers – Bronchodilators via nebulizers •• Transmucosal Transmucosal – Rectal or sublingual – Rectal or sublingual
- 30. Administration Routes Administration Routes •• Intramuscular Intramuscular – Depends on perfusion quality – Depends on perfusion quality •• Subcutaneous Subcutaneous – Depends on perfusion quality – Depends on perfusion quality •• Oral Oral – Slow, unpredictable – Slow, unpredictable – Little prehospital use – Little prehospital use
- 31. Pharmacodynamics Pharmacodynamics •• The biochemical and physiologic The biochemical and physiologic mechanisms of drug action mechanisms of drug action What the drug What the drug does when it gets there. does when it gets there.
- 32. Drug Mechanisms Drug Mechanisms •• •• Receptor interactions Receptor interactions Non-receptor mechanisms Non-receptor mechanisms
- 33. Receptor Interactions Receptor Interactions Lock and key mechanism Agonist Receptor Agonist-Receptor Interaction
- 34. Receptor Interactions Receptor Interactions Induced Fit Receptor Perfect Fit!
- 37. Non-receptor Mechanisms Non-receptor Mechanisms •• Actions on Enzymes Actions on Enzymes – Enzymes = Biological catalysts – Enzymes = Biological catalysts •• Speed chemical reactions Speed chemical reactions •• Are not changed themselves Are not changed themselves – Drugs altering enzyme activity alter processes – Drugs altering enzyme activity alter processes catalyzed by the enzymes catalyzed by the enzymes – Examples – Examples •• Cholinesterase inhibitors Cholinesterase inhibitors •• Monoamine oxidase inhibitors Monoamine oxidase inhibitors
- 38. Non-receptor Mechanisms Non-receptor Mechanisms •• Changing Physical Properties Changing Physical Properties – Mannitol – Mannitol – Changes osmotic balance across membranes – Changes osmotic balance across membranes – Causes urine production (osmotic diuresis) – Causes urine production (osmotic diuresis)
- 39. Non-receptor Mechanisms Non-receptor Mechanisms •• Changing Cell Membrane Permeability Changing Cell Membrane Permeability – Lidocaine – Lidocaine •• Blocks sodium channels Blocks sodium channels – Verapamil, nefedipine – Verapamil, nefedipine •• Block calcium channels Block calcium channels – Bretylium – Bretylium •• Blocks potassium channels Blocks potassium channels – Adenosine – Adenosine •• Opens potassium channels Opens potassium channels
- 40. Non-receptor Mechanisms Non-receptor Mechanisms •• Combining With Other Chemicals Combining With Other Chemicals – Antacids – Antacids – Antiseptic effects of alcohol, phenol – Antiseptic effects of alcohol, phenol – Chelation of heavy metals – Chelation of heavy metals
- 41. Non-receptor Mechanisms Non-receptor Mechanisms •• Anti-metabolites Anti-metabolites – Enter biochemical reactions in place of normal – Enter biochemical reactions in place of normal substrate “competitors” substrate “competitors” – Result in biologically inactive product – Result in biologically inactive product – Examples – Examples •• Some anti-neoplastics Some anti-neoplastics •• Some anti-infectives Some anti-infectives
- 42. Drug Response Relationships Drug Response Relationships •• •• Time Response Time Response Dose Response Dose Response
- 43. Time Response Relationships Time Response Relationships Maximal (Peak) Effect Effect/ Response Latency Duration of Response Time
- 44. Time Response Relationships Time Response Relationships IV IM SC Effect/ Response Time
- 45. Dose Response Relationships Dose Response Relationships •• Potency Potency – Absolute amount of drug required to produce – Absolute amount of drug required to produce an effect an effect – More potent drug is the one that requires lower – More potent drug is the one that requires lower dose to cause same effect dose to cause same effect
- 47. Dose Response Relationships Dose Response Relationships •• Threshold (minimal) dose Threshold (minimal) dose – Least amount needed to produce desired effects – Least amount needed to produce desired effects •• Maximum effect Maximum effect – Greatest response produced regardless of dose – Greatest response produced regardless of dose used used
- 48. Dose Response Relationships B A Therapeutic Effect Effect Dose Which drug has the lower threshold dose? Which has the greater maximum effect? A A B B
- 49. Dose Response Relationships Dose Response Relationships •• Loading dose Loading dose – Bolus of drug given initially to rapidly reach – Bolus of drug given initially to rapidly reach therapeutic levels therapeutic levels •• Maintenance dose Maintenance dose – Lower dose of drug given continuously or at – Lower dose of drug given continuously or at regular intervals to maintain therapeutic levels regular intervals to maintain therapeutic levels
- 50. Therapeutic Index Therapeutic Index •• •• •• •• Drug’s safety margin Drug’s safety margin Must be >1 for drug to be usable Must be >1 for drug to be usable Digitalis has a TI of 2 Digitalis has a TI of 2 Penicillin has TI of >100 Penicillin has TI of >100 LD50 TI = ED50
- 51. Therapeutic Index Therapeutic Index Why don’t we use a Why don’t we use a drug with a TI <1? drug with a TI <1? ED50 < LD50 = Very Bad! ED50 < LD50 = Very Bad!
- 52. Factors Altering Drug Factors Altering Drug Responses Responses •• Age Age – Pediatric or geriatric – Pediatric or geriatric – Immature or decreased hepatic, renal function – Immature or decreased hepatic, renal function •• Weight Weight – Big patients “spread” drug over larger volume – Big patients “spread” drug over larger volume •• Gender Gender – Difference in sizes – Difference in sizes – Difference in fat/water distribution – Difference in fat/water distribution
- 53. Factors Altering Drug Factors Altering Drug Responses Responses •• Environment Environment – Heat or cold – Heat or cold – Presence or real or perceived threats – Presence or real or perceived threats •• •• Fever Fever Shock Shock
- 54. Factors Altering Drug Factors Altering Drug Responses Responses •• Pathology Pathology – Drug may aggravate underlying pathology – Drug may aggravate underlying pathology – Hepatic disease may slow drug metabolism – Hepatic disease may slow drug metabolism – Renal disease may slow drug elimination – Renal disease may slow drug elimination – Acid/base abnormalities may change drug – Acid/base abnormalities may change drug absorption or elimination absorption or elimination
- 55. Influencing factors Influencing factors •• Genetic effects Genetic effects – Lack of specific enzymes – Lack of specific enzymes – Lower metabolic rate – Lower metabolic rate •• Psychological factors Psychological factors – Placebo effect – Placebo effect
- 56. Pediatric Patients Pediatric Patients •• •• Higher proportion of water Higher proportion of water Lower plasma protein levels Lower plasma protein levels – More available drug – More available drug •• Immature liver/kidneys Immature liver/kidneys – Liver often metabolizes more slowly – Liver often metabolizes more slowly – Kidneys may excrete more slowly – Kidneys may excrete more slowly
- 57. Geriatric Patients Geriatric Patients •• •• •• •• Chronic disease states Chronic disease states Decreased plasma Decreased plasma protein binding protein binding Slower metabolism Slower metabolism Slower excretion Slower excretion •• •• Dietary deficiencies Dietary deficiencies Use of multiple Use of multiple medications medications •• Lack of compliance Lack of compliance
- 58. Web Resources Web Resources •• Basic Pharmacokinetics on the Web Basic Pharmacokinetics on the Web – http://pharmacy.creighton.edu/pha443/pdf/Defa – http://pharmacy.creighton.edu/pha443/pdf/Defa ult.asp ult.asp •• Merk Manual: Overview of Drugs Merk Manual: Overview of Drugs – http://www.merck.com/pubs/mmanual_home/se – http://www.merck.com/pubs/mmanual_home/se c2/5.htm c2/5.htm
- 59. Web Resources Web Resources •• Merk Manual: Factors Affecting Drug Merk Manual: Factors Affecting Drug Response Response – http://www.merck.com/pubs/mmanual_home/se – http://www.merck.com/pubs/mmanual_home/se c2/8.htm c2/8.htm •• Merk Manual: Pharmacodynamics Merk Manual: Pharmacodynamics – http://www.merck.com/pubs/mmanual_home/se – http://www.merck.com/pubs/mmanual_home/se c2/7.htm c2/7.htm
- 60. www.indiandentalacademy.com Leader in continuing dental education