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  1. 1. Clinical Pharmacokinetics and Pharmacodynamics Janice E. Sullivan, M.D. Brian Yarberry, Pharm.D.
  2. 2. Why Study Pharmacokinetics (PK) and Pharmacodynamics (PD)? <ul><li>Individualize patient drug therapy </li></ul><ul><li>Monitor medications with a narrow therapeutic index </li></ul><ul><li>Decrease the risk of adverse effects while maximizing pharmacologic response of medications </li></ul><ul><li>Evaluate PK/PD as a diagnostic tool for underlying disease states </li></ul>
  3. 3. Clinical Pharmacokinetics <ul><li>The science of the rate of movement of drugs within biological systems, as affected by the absorption, distribution, metabolism, and elimination of medications </li></ul>
  4. 4. Absorption <ul><li>Must be able to get medications into the patient’s body </li></ul><ul><li>Drug characteristics that affect absorption: </li></ul><ul><ul><li>Molecular weight, ionization, solubility, & formulation </li></ul></ul><ul><li>Factors affecting drug absorption related to patients: </li></ul><ul><ul><li>Route of administration, gastric pH, contents of GI tract </li></ul></ul>
  5. 5. Absorption in the Pediatric Patient <ul><li>Gastrointestinal pH changes </li></ul><ul><li>Gastric emptying </li></ul><ul><li>Gastric enzymes </li></ul><ul><li>Bile acids & biliary function </li></ul><ul><li>Gastrointestinal flora </li></ul><ul><li>Formula/food interaction </li></ul>
  6. 6. Time to Peak Concentration
  7. 7. Distribution <ul><li>Membrane permeability </li></ul><ul><ul><li>cross membranes to site of action </li></ul></ul><ul><li>Plasma protein binding </li></ul><ul><ul><li>bound drugs do not cross membranes </li></ul></ul><ul><ul><li>malnutrition =  albumin =  free drug </li></ul></ul><ul><li>Lipophilicity of drug </li></ul><ul><ul><li>lipophilic drugs accumulate in adipose tissue </li></ul></ul><ul><li>Volume of distribution </li></ul>
  8. 8. Pediatric Distribution <ul><li>Body Composition </li></ul><ul><ul><li> total body water & extracellular fluid </li></ul></ul><ul><ul><li> adipose tissue & skeletal muscle </li></ul></ul><ul><li>Protein Binding </li></ul><ul><ul><li>albumin, bilirubin,  1 -acid glycoprotein </li></ul></ul><ul><li>Tissue Binding </li></ul><ul><ul><li>compositional changes </li></ul></ul>
  9. 9. Metabolism <ul><li>Drugs and toxins are seen as foreign to patients bodies </li></ul><ul><li>Drugs can undergo metabolism in the lungs, blood, and liver </li></ul><ul><li>Body works to convert drugs to less active forms and increase water solubility to enhance elimination </li></ul>
  10. 10. Metabolism <ul><li>Liver - primary route of drug metabolism </li></ul><ul><li>Liver may be used to convert pro-drugs (inactive) to an active state </li></ul><ul><li>Types of reactions </li></ul><ul><ul><li>Phase I (Cytochrome P450 system) </li></ul></ul><ul><ul><li>Phase II </li></ul></ul>
  11. 11. Phase I reactions <ul><li>Cytochrome P450 system </li></ul><ul><li>Located within the endoplasmic reticulum of hepatocytes </li></ul><ul><li>Through electron transport chain, a drug bound to the CYP450 system undergoes oxidation or reduction </li></ul><ul><li>Enzyme induction </li></ul><ul><li>Drug interactions </li></ul>
  12. 12. Phase I reactions types <ul><li>Hydrolysis </li></ul><ul><li>Oxidation </li></ul><ul><li>Reduction </li></ul><ul><li>Demethylation </li></ul><ul><li>Methylation </li></ul><ul><li>Alcohol dehydrogenase metabolism </li></ul>
  13. 13. Phase II reactions <ul><li>Polar group is conjugated to the drug </li></ul><ul><li>Results in increased polarity of the drug </li></ul><ul><li>Types of reactions </li></ul><ul><ul><li>Glycine conjugation </li></ul></ul><ul><ul><li>Glucuronide conjugation </li></ul></ul><ul><ul><li>Sulfate conjugation </li></ul></ul>
  14. 14. Elimination <ul><li>Pulmonary = expired in the air </li></ul><ul><li>Bile = excreted in feces </li></ul><ul><ul><li>enterohepatic circulation </li></ul></ul><ul><li>Renal </li></ul><ul><ul><li>glomerular filtration </li></ul></ul><ul><ul><li>tubular reabsorption </li></ul></ul><ul><ul><li>tubular secretion </li></ul></ul>
  15. 15. Pediatric Elimination <ul><li>Glomerular filtration matures in relation to age, adult values reached by 3 yrs of age </li></ul><ul><li>Neonate = decreased renal blood flow, glomerular filtration, & tubular function yields prolonged elimination of medications </li></ul><ul><li>Aminoglycosides, cephalosporins, penicillins = longer dosing interval </li></ul>
  16. 16. Pharmacokinetic Principles <ul><li>Steady State: the amount of drug administered is equal to the amount of drug eliminated within one dosing interval resulting in a plateau or constant serum drug level </li></ul><ul><li>Drugs with short half-life reach steady state rapidly; drugs with long half-life take days to weeks to reach steady state </li></ul>
  17. 17. Steady State Pharmacokinetics <ul><li>Half-life = time required for serum plasma concentrations to decrease by one-half (50%) </li></ul><ul><li>4-5 half-lives to reach steady state </li></ul>
  18. 18. Loading Doses <ul><li>Loading doses allow rapid achievement of therapeutic serum levels </li></ul><ul><li>Same loading dose used regardless of metabolism/elimination dysfunction </li></ul>
  19. 19. Linear Pharmacokinetics <ul><li>Linear = rate of elimination is proportional to amount of drug present </li></ul><ul><li>Dosage increases result in proportional increase in plasma drug levels </li></ul>
  20. 20. Nonlinear Pharmacokinetics <ul><li>Nonlinear = rate of elimination is constant regardless of amount of drug present </li></ul><ul><li>Dosage increases saturate binding sites and result in non- proportional increase/decrease in drug levels </li></ul>
  21. 21. Michaelis-Menten Kinetics <ul><li>Follows linear kinetics until enzymes become saturated </li></ul><ul><li>Enzymes responsible for metabolism /elimination become saturated resulting in non-proportional increase in drug levels </li></ul>
  22. 22. Special Patient Populations <ul><li>Renal Disease: same hepatic metabolism, same/increased volume of distribution and prolonged elimination   dosing interval </li></ul><ul><li>Hepatic Disease: same renal elimination, same/increased volume of distribution, slower rate of enzyme metabolism   dosage,  dosing interval </li></ul><ul><li>Cystic Fibrosis Patients: increased metabolism/ elimination, and larger volume of distribution   dosage,  dosage interval </li></ul>
  23. 23. Pharmacogenetics <ul><li>Science of assessing genetically determined variations in patients and the resulting affect on drug pharmacokinetics and pharmacodynamics </li></ul><ul><li>Useful to identify therapeutic failures and unanticipated toxicity </li></ul>
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