Pharmacokinetics 2011


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Pharmacokinetics 2011

  1. 1. Pharmacokinetics 2011 Maria Luisa D. Delacruz. MD DLS-HSI College of Medicine Department of Pharmacology
  2. 2. Pharmacokinetics <ul><li>“ What the body does to the drug?” </li></ul><ul><li>“ How the body handles the drug?” </li></ul>
  3. 3. Pharmacokinetic Processes <ul><li>Absorption </li></ul><ul><li>Distribution </li></ul><ul><li>Metabolism / Biotransformation </li></ul><ul><li>Excretion </li></ul>
  4. 4. Routes of Drug Administration <ul><li>Enteral </li></ul><ul><li>Parenteral </li></ul><ul><li>Topical </li></ul>
  5. 5. Routes of Drug Administration <ul><li>Enteral </li></ul><ul><ul><li>Oral </li></ul></ul><ul><ul><li>Sublingual </li></ul></ul><ul><ul><li>Buccal </li></ul></ul><ul><ul><li>Rectal </li></ul></ul>
  6. 6. Routes of Drug Administration <ul><li>2. Parenteral </li></ul><ul><ul><li>Intradermal </li></ul></ul><ul><ul><li>Subcutaneous </li></ul></ul><ul><ul><li>Intramuscular </li></ul></ul><ul><ul><li>Intravenous </li></ul></ul>
  7. 7. Routes of Drug Administration <ul><li>3.Topical </li></ul><ul><ul><li>Dermal </li></ul></ul><ul><ul><li>Inhalational </li></ul></ul><ul><ul><li>Mucous membrane </li></ul></ul><ul><ul><ul><li>Nasal </li></ul></ul></ul><ul><ul><ul><li>Ophthalmic/Otic </li></ul></ul></ul><ul><ul><ul><li>Vaginal </li></ul></ul></ul>
  8. 8. Mechanisms of Drug Passage Across Membranes <ul><li>Passive Diffusion </li></ul><ul><li>Facilitated Diffusion </li></ul><ul><li>3. Active Transport </li></ul><ul><li>4. Pinocytosis </li></ul>
  9. 9. Mechanisms of Passage Across Membranes <ul><li>PASSIVE DIFFUSION </li></ul><ul><ul><ul><li>higher conc  lower conc </li></ul></ul></ul><ul><ul><ul><li>driving force – difference in drug conc </li></ul></ul></ul><ul><ul><ul><li>utilized by majority of drugs </li></ul></ul></ul>
  10. 10. Passive Diffusion
  11. 11. Mechanisms of Passage Across Membranes <ul><li>Facilitated Diffusion </li></ul><ul><li>carrier-mediated transport process </li></ul><ul><li>does not require energy </li></ul><ul><li>carrier enhances movement of the drug down </li></ul><ul><li>an electrochemical gradient </li></ul><ul><li>e.g. GLUT 4 enhances the permeation of glucose across a muscle cell membrane </li></ul>
  12. 13. Mechanisms of Passage Across Membranes <ul><li>ACTIVE TRANSPORT </li></ul><ul><ul><ul><li>requires carrier </li></ul></ul></ul><ul><ul><ul><li>energy consuming </li></ul></ul></ul><ul><ul><ul><li>against a concentration gradient </li></ul></ul></ul><ul><ul><ul><li>saturability </li></ul></ul></ul><ul><ul><ul><li>selectivity </li></ul></ul></ul><ul><ul><ul><li>competitive inhibition by </li></ul></ul></ul><ul><ul><ul><li>co-transported compounds </li></ul></ul></ul>
  13. 15. Mechanisms of Passage Across Membranes <ul><li>PINOCYTOSIS </li></ul><ul><ul><ul><li>folding over the part of </li></ul></ul></ul><ul><ul><ul><li>the cell membrane </li></ul></ul></ul><ul><ul><ul><li>formation of small vesicle </li></ul></ul></ul><ul><ul><ul><li>molecules of extracellular contents are trapped </li></ul></ul></ul>
  14. 16. Factors that Affect the Drug Passage Across Membranes <ul><li>1. molecular size and shape </li></ul><ul><li>2. degree of ionization </li></ul><ul><li>3. relative lipid solubility of its ionized and nonionized forms </li></ul><ul><li>4. binding to serum and tissue proteins </li></ul>
  15. 17. ABSORPTION <ul><li>is the movement of a drug from its site of administration to the systemic circulation and the extent to which this occurs </li></ul>
  16. 18. ABSORPTION <ul><li>For an orally administered drug, Absorption depends on: </li></ul><ul><ul><ul><li>disintegration </li></ul></ul></ul><ul><ul><ul><li>dissolution </li></ul></ul></ul><ul><ul><ul><li>diffusion </li></ul></ul></ul>
  17. 19. Factors that Affect the Rate and Extent of Drug Absorption <ul><ul><li>Dosage form / Drug formulation </li></ul></ul><ul><ul><li>Physicochemical Properties of the Drug </li></ul></ul><ul><ul><ul><ul><li>molecular weight </li></ul></ul></ul></ul><ul><ul><ul><ul><li>pH </li></ul></ul></ul></ul><ul><ul><ul><ul><li>lipophilic vs hydrophilic </li></ul></ul></ul></ul><ul><ul><li> * Partition coefficient </li></ul></ul>
  18. 20. <ul><li>most drugs are weak acids or bases that are present in solution as both the nonionized and ionized forms </li></ul><ul><li>nonionized substances are usually more lipid-soluble and can diffuse readily across the cell membrane </li></ul><ul><li>ionized molecules have low lipid solubility and are unable to penetrate the lipid membrane </li></ul>
  19. 21. Factors that Affect the Rate and Extent of Drug Absorption <ul><li>3. Physiologic variables </li></ul><ul><ul><ul><li>gastric motility </li></ul></ul></ul><ul><ul><ul><li>pH at the absorptive site </li></ul></ul></ul><ul><ul><ul><li>area of absorbing surface </li></ul></ul></ul><ul><ul><ul><li>mesentric blood flow </li></ul></ul></ul><ul><ul><ul><li>presystemic elimination / first pass </li></ul></ul></ul>
  20. 22. <ul><li>Acidic pH </li></ul><ul><li>weak acid – more unioinized – more lipid soluble </li></ul><ul><li>weak base – less unionized – less lipid </li></ul><ul><li> soluble </li></ul><ul><li>Alkaline pH </li></ul><ul><li>weak acid – less unionized – less lipid soluble </li></ul><ul><li>weak base – more unionized – more lipid </li></ul><ul><li> soluble </li></ul>pH at Absorptive site
  21. 23. BIOAVAILABILITY <ul><li>measures the rate and extent by which a drug reaches systemic circulation </li></ul><ul><li>fraction of unchanged drug that reaches systemic circulation </li></ul>
  22. 24. Factors that Affect Bioavailability <ul><li>1. Biopharmaceutical factors </li></ul><ul><ul><li>Dosage form </li></ul></ul><ul><ul><li>Physicochemical properties </li></ul></ul><ul><li>2. Physiologic factors </li></ul><ul><ul><li>Gastric motility </li></ul></ul><ul><ul><li>Presystemic metabolism </li></ul></ul><ul><li>3. GIT contents – Food, drugs, fluid </li></ul><ul><li>4. Disease states </li></ul>
  23. 25. Determinants of Bioavalability 1. Plasma data
  24. 26. Determinants of Bioavalability <ul><li>AUC is the most reliable measure of bioavailability. </li></ul><ul><li>It is directly proportional to the total amount of unchanged drug that reaches the systemic circulation </li></ul>
  25. 27. Determinants of Bioavalability <ul><li>2. Urine data </li></ul><ul><li>maximum urinary excretion rate </li></ul><ul><li>time for maximum excretion rate </li></ul><ul><li>cumulative amount of drug excreted in the </li></ul><ul><li>urine </li></ul><ul><li>3. Pharmacologic effect </li></ul>
  26. 28. Bioavailability <ul><li>Bioequivalence: </li></ul><ul><ul><li>when two related drugs show comparable bioavailability </li></ul></ul><ul><li>Therapeutic Equivalence: </li></ul><ul><ul><li>when two similar drugs have comparable efficacy and safety </li></ul></ul>
  27. 29. Routes of Administration, Bioavailability, and General Characteristics Route Bioavailability (%) Characteristics Intravenous (IV) 100 (by definition) most rapid onset Intramuscular (IM) 75 to ≤ 100 large volumes often feasible; may be painful Subcutaneous (SC) 75 to ≤ 100 smaller volumes than IM; may be painful; slower onset than IV or IM Oral (PO) 5 to < 100 most convenient; first-pass effect may be significant Rectal (PR) 30 to < 100 less first-pass effect than oral Transdermal 80 to ≤ 100 usually very slow absorption; used for lack of first-pass effect; prolonged duration of action
  28. 30. Distribution <ul><li>process by which a drug reversibly leaves the systemic circulation and enters the interstitial space and/or the cells of the tissues </li></ul><ul><li>once in the blood stream, the drug is distributed to the different tissues </li></ul>
  29. 31. DISTRIBUTION <ul><li>Factors that Influence Drug Distribution </li></ul><ul><li>Plasma Protein Binding </li></ul><ul><li>Cardiac Output an Regional Blood Flow </li></ul><ul><li>Permeability and Perfusion of Membranes </li></ul><ul><li>Diseases </li></ul>
  30. 32. Factors that Affect Distribution: <ul><li>1. Plasma protein binding </li></ul><ul><ul><li>drugs bound to proteins are not </li></ul></ul><ul><ul><li>readily distributed </li></ul></ul><ul><ul><li>and are inactive </li></ul></ul><ul><ul><li>high protein binding prolongs onset and duration of action </li></ul></ul>
  31. 33. Factors that Affect Drug Distribution <ul><li>Plasma protein binding </li></ul><ul><ul><li>weakly acidic drugs – albumins </li></ul></ul><ul><ul><li>weakly basic drugs –  -1-acid glycoproteins </li></ul></ul><ul><ul><li>free, unbound drug is the active form of the drug </li></ul></ul>
  32. 34. Factors that Affect Distribution: <ul><li>2. Cardiac output and blood flow to the tissues </li></ul><ul><ul><li>highly vascular organs </li></ul></ul><ul><ul><li>receive more of the drugs </li></ul></ul>
  33. 35. Factors that Affect Distribution: <ul><li>3. Permeability </li></ul><ul><li>and Perfusion </li></ul><ul><li>of Membranes </li></ul>
  34. 36. Factors that Affect Distribution: <ul><li>Natural barriers </li></ul><ul><ul><li>Blood brain barrier </li></ul></ul><ul><ul><li>Placental barrier </li></ul></ul><ul><ul><li>Blood-ocular barrier </li></ul></ul><ul><ul><li>Prevent distribution of drug to areas where their effects may be dangerous </li></ul></ul>
  35. 37. Blood brain barrier Placental barrier
  36. 38. Factors that Affect Drug Distribution <ul><li>4. Diseases </li></ul><ul><ul><li>renal, cardiac failure </li></ul></ul><ul><ul><li>plasma albumin conc: ↓ in malnutrition, hepatic and renal diseases </li></ul></ul><ul><ul><li>alpha-1-acid glycoprotein conc: ↓ in pregnancy and post MI </li></ul></ul>
  37. 39. Volume of Distribution <ul><li>the volume of fluid to which a drug is distributed </li></ul><ul><li>drugs with large volume of distribution will have a longer half-life and duration of action </li></ul>
  38. 40. Volume of Distribution amount of drug administered initial drug concentration VD = <ul><ul><li>relates the amount of a given drug in the body to the concentration of the drug in the blood </li></ul></ul>
  39. 41. Metabolism / Biotransformation <ul><li>process by which a drug is altered chemically into another compound called “metabolites” which may be more active or less active than the parent drug </li></ul><ul><li>primarily occurs in the liver </li></ul><ul><ul><li>can also occur in the stomach, small intestines, plasma, kidney, lung, skin, other tissues </li></ul></ul>
  40. 42. Metabolism / Biotransformation <ul><li>Two Phases: </li></ul><ul><ul><li>1. Phase I reaction </li></ul></ul><ul><ul><ul><li>oxidation, hydrolysis, reduction </li></ul></ul></ul><ul><ul><ul><li>mediated by cytochrome P450 (drug metabolizing enzymes ) </li></ul></ul></ul><ul><ul><li>2. Phase II reaction </li></ul></ul><ul><ul><ul><li>glucuronidation, sulfation, glutathione conjugation, n-acetylation, methylation </li></ul></ul></ul>
  41. 44. Metabolism <ul><li>Significance: </li></ul><ul><ul><li>defensive mechanism </li></ul></ul><ul><ul><li>increases polarity of drug molecules </li></ul></ul><ul><ul><ul><li>restricts penetration thru cellular membrane </li></ul></ul></ul><ul><ul><ul><li>reduces distribution </li></ul></ul></ul><ul><ul><ul><li>promotes elimination </li></ul></ul></ul>
  42. 45. Factors Affecting Drug Metabolism <ul><ul><li>1. Non – Genetic </li></ul></ul><ul><li> Age </li></ul><ul><li>Sex </li></ul><ul><li>Liver size / function </li></ul><ul><li>Diet / Nutrition </li></ul><ul><li>Environmental </li></ul><ul><ul><li>2. Genetic </li></ul></ul>
  43. 47. Factors Affecting Drug Metabolism <ul><li>2. Genetic </li></ul><ul><li>e.g. </li></ul><ul><li>Acetylation – slow and fast </li></ul><ul><li>Oxidation – poor and extensive </li></ul>
  44. 49. Excretion <ul><li>process by which a drug or its metabolites is eliminated from the body </li></ul><ul><li>main organ of elimination is the kidneys </li></ul><ul><li>other organ of excretion include the biliary system, GIT, skin and lungs </li></ul>
  45. 50. Renal Excretion <ul><li>Glomerular </li></ul><ul><li> filtration </li></ul><ul><li>Tubular </li></ul><ul><li>secretion </li></ul>
  46. 52. Half- life (T½) <ul><li>time required to decrease the concentration of the drug in the plasma by 50% </li></ul><ul><li>often used to determine frequency of administration </li></ul><ul><li>determines the time to attain steady-state concentration </li></ul>
  47. 53. Half- life (T½) <ul><li>Drug needs about 4-5 half lives to be completely eliminated from the body </li></ul><ul><li>E.g. Paracetamol (ACET) 500 mg half-life 4 hrs </li></ul><ul><li>after 1 st 4 hrs = 250 mg </li></ul><ul><li>after 2 nd 4 hrs = 125 mg </li></ul><ul><li>after 3 rd 4 hrs = 62.5 mg </li></ul><ul><li>after 4 th 4 hrs = 31.25 </li></ul><ul><li>after 5 th 4 hrs = 15. 635 </li></ul>
  48. 54. Half- life (T½) T ½ = 0.7 x Vd Cl Where: Vd = volume of distribution Cl = clearance
  49. 55. Steady State <ul><li>the point where rate of drug availability equals rate of elimination </li></ul><ul><li>constant drug concentration </li></ul><ul><li>point where expect maximum drug effect </li></ul><ul><li>usually attained after 4-5 half lives </li></ul>
  50. 56. Steady State
  51. 57. Clearance <ul><li>the measure of the ability of the body to eliminate the drug </li></ul><ul><li>the sum of hepatic metabolism and renal excretion </li></ul>
  52. 58. Kinetic Order <ul><li>1. Zero order </li></ul><ul><li>2. First order </li></ul>
  53. 59. Zero Order <ul><li>constant </li></ul><ul><li>independent of the amount of drug </li></ul><ul><li>linear </li></ul><ul><li>active transport </li></ul>
  54. 60. First Order <ul><li>not uniform </li></ul><ul><li>proportional to the amount of drug </li></ul><ul><li>Curvilinear </li></ul><ul><li>passive diffusion </li></ul>
  55. 61. Elimination of Drugs Order of Elimination 1. First Order 2. Zero Order
  56. 62. Zero order Elimination Time after Drug Administration Drug in Body (mg) Amount of Drug Eliminated Fraction of Drug Eliminated 0 1000 ---- ---- 1 850 150 0.15 2 700 150 0.18 3 550 150 0.21 4 400 150 0.27 5 250 150 0.38 6 100 150 0.60
  57. 63. First order Elimination Time after Drug Administration Drug in Body (mg) Amount of Drug Eliminated Fraction of Drug Eliminated 0 1000 ---- ---- 1 850 150 0.15 2 723 127 0.15 3 614 109 0.15 4 522 92 0.15 5 444 78 0.15 6 377 67 0.15
  58. 64. “ The gift of true friendship is that it takes us by the hand and reminds us we are not alone in the journey! “