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  1. 1. Pharmacokinetic variability<br />
  3. 3. INTRERINDIVIDUAL VARIBILITY<br />The dose required to produce action varies from indvidual to indvidual<br />The doses reflect the various dosage strength in market<br />
  4. 4. Varibility in doses<br />The variability in dose of warfarin required to produce similar prothrombin action in 200 patients varies widely<br />
  5. 5. Interindividual variability<br />Change in plasma concentration of same subject when given in different occasion<br />Causes-<br />Age ,sex,diseases, weight, drug interaction etc<br />High intrasubject variability difficult to prescribe the narrow therapeutic drugs<br />If high intrasubject variability in pharmacokinetic prescribed only if it has wide subject variability <br />
  6. 6. histogram<br />A.The plateau plasma con varies widely in260 patients receiving 25mg of nortryptiline orally three times daily<br />B.The con are log normally distrIbuted as seen in straight line<br />
  7. 7. steps to Indvidlisation <br />
  8. 8. Over view<br />
  9. 9. Describing variability<br />A,B are unimodel but C is bimodal signifying that they are are two major groups with in population With higher and lower clearance<br />
  10. 10. Factors causing varibility<br />
  11. 11. The development and subsequent marketing of drug<br />
  13. 13. OBESITY<br /> a condition that is characterized by excessive accumulation and storage of fat in the body and that in an adult is typically indicated by a body mass index of 30 or greater<br />
  14. 14. Drug administration<br />Drug administration in obese patients is difficult because recommended doses are based on pharmacokinetic data obtained from individuals with normal weights;<br />
  15. 15. Obesity affects<br />pharmacokinetic parameters-<br />volume of distribution (Vd),<br /> clearance (Cl)<br /> protein binding <br />changed for some drugs<br />i.v. anaesthetic drugs<br />inhalational anaesthetics<br />Lipophilic drugs<br />
  16. 16. Body mass index<br />body mass index n a measure of body fat that is the ratio of the weight of the body in kilograms to the square of its height in meters <br />
  17. 17. BMI<br />
  18. 18. Dosage regimen<br />
  19. 19. what ‘weight<br />clinician must appreciate what ‘weight’ should be used to calculate dosage: <br />totalbody weight (TBW),<br /> lean body mass (LBM)<br /> ideal body weight (IBW)?<br />
  20. 20. TBW is actual body weight<br />IBW is estimated by<br /> x =100 for adult males<br />105 for adult females<br />
  21. 21. lbm<br />The percentage of fat and lean body mass<br /> calculated based on<br /> - height(cm)<br /> -Weight(kg)<br /> -girth(inches)<br /> Percentage of fat = 90-2(height-girth)<br />
  22. 22. Lean body mass<br />LBM can be calculated using the formulae<br />
  23. 23. dosage<br />Mostly, dosage recommendations in the package inserts are scaled to TBW<br />For obsity-<br />weight can then be multiplied by the published doses scaled to TBW<br /> = WEIGHT×DOSE ON LABEL<br />
  24. 24. NOMOGRAM(MALE)<br />Nomogram for male patients relating total body weight (kg), height<br />(cm), and gender with lean body mass (LBM) using the formula<br />LBM = 1.1(weight) 128(weight/height)2.<br />
  25. 25. NOMOGRAM (FEMALES)<br />Nomogram for female patients relating total body weight (kg),<br />height (cm), and gender with lean body mass (LBM) using the formula<br />LBM = 1.07(weight) – 148(weight/height)2.<br />
  26. 26. Lipophilic drugs<br />HIGHILY LIPOPHILICDRUGS<br />barbiturates and benzodiazepines show significant increases in Vd for obese individuals. <br />.<br />Less lipophilic DRUGS<br />have little or no change in Vd with obesity<br />Exceptions to this is remifentanil,<br />
  27. 27. Volatile agents<br />Halothane is known to have considerable deposition in adipose tissue<br />hepatic metabolism- halothane hepatitis<br />
  28. 28. Propofol<br />In morbidly obese patients, the induction dose of propofol can be calculated on IBW.<br />Although propofol is highly lipophilic,does not accumulate in obese patients. <br />So the dosage of propofol for maintenance of anaesthesia in obese and lean same<br />
  29. 29.
  30. 30. Drug metabolism<br />Neonates<br />
  31. 31. neonates<br />Invitro studies indicate that variability much greater in first three months of life declines to adult activity<br />New born are higher for contreation toxicity due to development of delay drug metabolism<br />
  32. 32. Enzymatic system required for drug metabolism are higher in neonates and lower in adults <br />Chornic exposure of foetus to epliptic drugs leads to induction of drug metabolism enzymes <br />Sulfate conjugation seems to be efficient in newborn as in adults<br />Conjugation with glucornic acid reduced with increasing age<br />
  33. 33.
  34. 34.
  35. 35. differences<br />
  36. 36. Age groups<br />
  37. 37. PROTEIN BINDING<br /> NEONATES<br />
  38. 38. Protein binding<br />Plasma protein binding is less in newborn than adults <br /> Decrease Plasma protein binding is an increase in apparent volume of distribution in newborn<br />Low plasma binding is due to elevation of bilrubin<br />
  39. 39. competatiion<br /> relative low plasma binding associated with elevated levels of biliubrin<br />Biluburin binds with albumin and many compete with drugs binding <br />
  40. 40. GENDER<br />
  41. 41. sex<br />Sex is an individual factor <br /> lead to interindividual differences in the metabolism of drugs<br />drugs that are metabolized by hepatic oxidation have lower metabolic clearance and longer elimination half-lives in women who are on oral contraceptives<br />
  42. 42. sex differences<br />muscle mass, <br />disposition of muscle tissue, <br />vascular resistance.<br /> gastric motility, <br />secretion,<br /> metabolic rate<br />
  43. 43. PHARMACOKINETIC CHANGES<br />volume of distribition and rate of metabolism changes <br />Volume of distrubution for central compartment is more in males<br />Peripheral compartment of liophilic drug more in females<br />Ex- metablism of few drug in female oxazepam<br /> & metaprolol is slow in female<br />
  44. 44. Pharmacokinetic Properties<br />
  45. 45. references<br />Pharmacokinetics in obese patients by -Lu EC De Baerdemaeker MD<br /> slides of Approaching the In Silico Child<br /> Jeffrey S. Barrett, PhD, FCP<br /><ul><li>Biopharmaceutics and clinical pharmacokinetics</li></ul>milogibaldi ,PhD<br /><ul><li> Clinical Pharmacokinetics Concepts and Applications</li>