Clinical pharmaco kinetics 1 bioavailability, 1st pass, renal clearance 2011

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Clinical pharmaco kinetics 1 bioavailability, 1st pass, renal clearance 2011

  1. 1. Clinical Pharmacokinetics-1 Prof. Dr. Talat Ahmed
  2. 2. THEORIES OF DRUG DISTRIBUTION AND ELIMINATION
  3. 3. THEORIES OF DRUG DISTRIBUTION AND ELIMINATION1. Single compartment a) b) theory. central peripheral2. Two compartment blood muscle theory CSF skin3. Multiple lung fat compartment liver bones theory. KidneyF, AUC, CL, Vd, t12, Css
  4. 4. BIOAVAILABILITY
  5. 5. Bioavailability (F) is the fraction of unchanged drug reaching the systemic circulation.I/V administration = 1F (100% bioavailability) AUC= area under curve: It is a measure of the extent of bioavailability given by a particular route. F= AUC after IM or oral dose AUC after I/V dose
  6. 6. F= AUCoral/AUC i/v
  7. 7. FACTORS AFFECYING BIOAVAILABILITY1. EXTENT OF ABSORPTION (= f)2. RATE OF ABSORPTION3. FIRST PASS ELIMINATION
  8. 8. Factors Affecting Bioavailability1. EXTENT OF ABSORPTION (= f) :Bioavailability is the function of absorption=f digoxin, 70% intestinal microflora atenolol, 56% too hydrophilic acyclovir 23% too lipophilicGrape fruit juice:↑ drug absorption1)P-glycoprotein inhibition 2)↓wall metabolism
  9. 9. 2. RATE OF ABSORPTION: it affects rate of availability, determined by:a) Drug formulationb) Amount of given drug.c) Site of Administration.
  10. 10. a) Drug formulation
  11. 11. a) Drug formulation• Disintegration & dissolution time Depends:1.Compression pressure2.Moisture Content3.Nature of additives: excipients - starch, lubricants, disintegrents4.Particle size5.Polymorphism of molecule or ions6.pH
  12. 12. BioequivalencePharmaceutical Equivalent/Generic1. Same active ingredient2. Same strength /concentration3. Same Dosage Form4. Same route of Admn.BioequivalentWhen rate & extent of bioavailability of active ingredient in two products is similar.Therapeutic EquivalenceWhen two products produce same response in same dosage (e.g. aconitine hazard)
  13. 13. b) Amount of given drug• FIRST ORDER ABSORPTION: rate of absorption is proportional to the amount of drug in gut.• ZERO ORDER ABSORPTION: when rate of absorption is not proportionate to the amount of drug in the gut. (when full dose is not absorbed from GI fluids)
  14. 14. c)Site of Administration Oral Topical Transdermal Intramuscular Subcutaneous Sublingual Rectal Inhalation
  15. 15. 3. FIRST PASS ELIMINATION: orally administered drug ↓ gut wall ↓ portal blood ↓ liver bile systemic circulation
  16. 16. The First Pass Effect and Extraction RatioEffect of first pass elimination on bioavailability is expressed as extraction ratio = ERIf a drug is completely absorbed from the gut its systemic bioavailability F = l (100 %)If it passes through liver, it will be decreased by hepatic extraction F = l – ER
  17. 17. Extent Of Absorption = f (predicts systemic bioavailability of drug) F = f x (1- ER) For morphine f =1 ER = 0.67 F = 1 x (1- 0.67) = 33% ( observed value 24%)
  18. 18. Highly Extracted DrugsTherapeutic blood concentration can be reached by high oral dose Lidocaine 20 % Verapamil 20% Propranolol 26% Lidocaine P.O →↑metabolites ↓ CNS toxicity
  19. 19. Poorly Extracted DrugDiazepam 100%Digitoxin 90%Theophylline 96%Shunting of blood past the liver will cause little change in availability. ER = Clliver Q Clliver = Q x Ci – C O Ci
  20. 20. Drug clearance
  21. 21. Clearance (CL) is the measure of removal of drug from body• expressed as: volume of plasma from which all drug is removed in a given time e.g. ml/min or L/h• It is estimated as: Blood Clearance (CLb), Plasma Clearance (CLP), Unbound drug Clearance (CLu)
  22. 22. Drug clearanceIt is similar to creatinine/urea clearance.Creatinine Clereance = UV PRenal Clearance= Conc. in urine x rate of urine formation Conc. in plasmaClearance of a drug = Rate of elimination of all routes Conc. in any body fluidor CL = Rate of elimination or Dose C AUC
  23. 23. Organ clearanceCLorgan = Rate of eliminationORGAN CPTotal systemic clearance:CLsyst = CLrenal + CLliver + CLotherCLorgan = Blood flow x Extraction Ratio = Q x ER = Q x Ci – CO C
  24. 24. DRUG CLEARANCE
  25. 25. Factors related to clearanceA. First Order EliminationB. Capacity Limited EliminationC. Flow DependentD. Plasma Protein binding
  26. 26. A. First Order Elimination Rate of elimination = Cp x CL organFor most drugs elimination is not saturable &is directly proportional to concentrationCan be calculated by AUC CL: Dose AUC
  27. 27. CL= Dose/AUC
  28. 28. B. Capacity Limited EliminationZero Order Elimination, Saturable, Nonlinear,Dose dependent or Michaelis’ Menten Elimination Vmax x C Rate of Elimination= -------------- Km + CThe concentration will keep on rising aslong as dosing continues & steady statecan not be reached.Ethanol, Phenytoin & AspirinAUC can not be used to calculate clearance
  29. 29. C. Flow Dependent Elimination depends on the rate of delivery of drug to the organ of eliminationCLorgan = Blood flow x Extraction Ratio = Q x ER = Q x Ci – CO Ci
  30. 30. D. Plasma Protien binding & Blood Cell partitioning• Plasma Protein binding may be important for extensively bound drugs: Phenytoin 89%, Salicylic acid 85% (Aspirin 49%) When the amount of unbound drug in plasma increases the rate of elimination will increase. When plasma proteins are lower than normal then total drug concentration will be lower but unbound concentration will not be affected.
  31. 31. Factors affecting protein binding• Albumen Concentration In many diseases albumin level is low, resulting in lower total drug concentration (phenytoin, salicylate & disopyramide)• Alpha1-acid glycoprotein concentration It is ↑ed in acute inflammatory disease ↑ing total plasma conc. of propranolol, lidocain & quinidine.• Capacity limited protein binding salicylates & prednisolone
  32. 32. Renal clearance of Benzyl PenicillinFiltration 10 %Tubular secretion 90 %Glomerular filtration rate = 127ml/minRenal clearance = 480 ml/minEstimation of GFRThe most commonly used formula is the"4-variable MDRD," (Modification of Diet in RenalDisease Study Group) which estimates GFR usingFour variables: serum creatinine, age, race, and gender
  33. 33. Cockcroft-Gault formula There is age related decline in renal functions There is decline of muscle mass with age Therefore reduction in production of creatinineCreatinine clearance (mL/min)= 140-age x wt in kg 72 x serum creatinine in mg/dL (x 0.85 for females)
  34. 34. Thank You

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