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Distribution From A Physiologic Perspective

Distribution From A Physiologic Perspective. Objectives. Problems / Questions Related to Introduction Distribution From A Physiologic Perspective] Five “Distribution Problems” are provided starting at slide 21. Not all of these problems will be completed in class …

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Distribution From A Physiologic Perspective

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  1. Distribution From A Physiologic Perspective Objectives • Problems / Questions Related to Introduction • Distribution From A Physiologic Perspective] • Five “Distribution Problems” are provided starting • at slide 21. Not all of these problems will be completed in class … • but you are expected to work through them on your own.

  2. Opening Question: Mr. JR receives 500 mg of Levofloxacin by intravenous bolus (over 1 minute) and the serum concentration is measured immediately and found to be 5.0 mg/L. What is the apparent volume of distribution? What percent of drug is located in serum?

  3. Distribution Where does drug go? Objective Review Basic Principles related to drug & chemical / metabolite distribution in the body Develop a definition for Volume of Distribution

  4. Where does the drug go? Is it confined to blood or is it mostly in the blood or is it largely confined to tissues?

  5. Facts and Figures Body Weights Actual vs Ideal (IBW) Male: 50 kg + (2.5 kg/inch over 5 ft) Female: 45.5 kg + (2.3 kg / inch over 5 ft) Blood Volume (L) ~ 8% of IBW Body water (L) ~60% of IBW

  6. Barriers to Distribution • 1. GI Tract •  Intestinal wall prevents absorption • … not all drugs are absorbed • Vascular walls • limits “escape” from serum / blood • Cellular walls • limits “free” movement within the body Plasma or Serum ~ 55% RBC’s, ~ 45% of whole blood Extra-cellular Water ~ 15 L Intra-cellular Water ~ 25 L Whole Blood ~ 5 L

  7. Body Water1 Tissue % Water %Weight Water per 70 kg ( L ) Skin 72 18 9.1 Muscle 75 42 22.1 Brain 75 2 1.1 Skelton 22 16 2.5 Adipose 10 ~10 0.7 Other 12 6.5 Total 100 42 1. Skelton, H. Arch Int. Med 1927; 40: 140.

  8. General Principles of Distribution If you add 1000 mg of a drug to 10 L of water, what is the final concentration? 1000 mg Following complete mixing Concentration (C) = 1000 mg/ 10L = 100 mg/L 10 L C = Amount / volume Volume = Amount / C

  9. General Principles of Distribution 1000 mg If you add 1000 mg of a drug to 10 L of water, what is the final concentration? C = Amount / volume Volume = Amount / C 10 L Could the concentration change as a function of time after addition? If you knew that you had added 1000 mg of drug and then drew a sample from a corner of the vessel before complete mixing occurred, what would you conclude?

  10. General Principles of Distribution Again you add 1000 mg of a drug to 10 L of water, but now there is some charcoal in the water that may bind the drug. The observed concentration after complete mixing is 50 mg/L 1000 mg 10 L Since Volume = Amount / C then the apparent volume of distribution is: = 1000 mg/50 mg/L = 20L …??? BUT The real volume is 10L Charcoal

  11. General Principles of Distribution Again you add 1000 mg of a drug but this time in addition to the charcoal and 10L of water there is 1 L of oil. You measure the concentration in the oil (150 mg/L) and in the water (25 mg/L). 1000 mg 1L 10 L Now calculate the volume: Based on the concentration in the water Volume = Amount / C then the apparent volume of distribution is: = 1000 mg/25 mg/L = 40L Charcoal

  12. General Principles of Distribution Again you add 1000 mg of a drug but this time in addition to the charcoal and 10L of water there is 1 L of oil. You measure the concentration in the oil (150 mg/L) and in the water (25 mg/L). 1000 mg 1L 10 L Now calculate the volume: Based on the concentration in the oil Volume = Amount / C then the apparent volume of distribution is: = 1000 mg/150 mg/L = 6.66 L Charcoal

  13. General Principles of Distribution Mass Balance Water: Concentration 25 mg/L True Volume: 10L Amount of Drug = 250 mg Apparent Volume = 40L Oil: Concentration 150 mg/L True Volume: 1L Amount of Drug = 150 mg Apparent Volume = 6.66 L Charcoal: (therefore) Amount = 600 mg 1000 mg 1L 10 L Charcoal

  14. General Principles of Distribution 1000 mg • Conclusions • The calculated Apparent Volume • depends on the fluid being • sampled. • 2. The volume depends on the host, and the physical/chemical properties of the drug or metabolite • 3. The calculated Apparent Volume • rarely reflects a real physiologic • volume. 1L 10 L Charcoal

  15. General Principles of Distribution …so what is the Apparent Volume of Distribution? … it is the volume of sampled fluid need to account for the total amount of drug in the body … at distribution equilibrium … (following complete mixing). The volume is not associated with a particular space or anatomical area or tissue. It is a proportionality constant relating concentration and amount in the body. 1000 mg 1L 10 L Charcoal

  16. General Principles of Distribution • …so, if it is not real, how useful is it? • Uses: • It tells us how much drug must be added to the body so as to achieve a specified concentration in the sampled fluid. • In a general way it tells us where the drug is stored in the body or where it might be found. 1000 mg 1L 10 L Charcoal

  17. General Principles of Distribution L/70 kg 50,000 20,000 10,000 5,000 1,000 500 100 50 10 5 Quinacrine Chloroquine Nortriptyline Digoxin Propranolol Quinidine Quinolones (1- 2 L/kg), Tetracycline Phenobarbital Phenytoin Theophylline (0.45 L/kg) Aminoglycodises (0.25 L/kg) ASA Warfarin

  18. General Principles of Distribution Question: If the drug is distributing to total body water, why are there large differences in the volume for different drugs? Physical Chemical properties of the drug High molecular weight (mabs) and even ICG (MW = 775) are confined to plasma volume. Ions (Cl-, Br-) rapidly distribute throughout extra-cellular fluid but do not easily cross cell membranes. Other Ions (K+, Ca2+) are actively transported across membranes. Potassium is predominately intra-cellular. Protein Binding

  19. General Principles of Distribution Protein Binding: Unless a drug is actively transported into cells, it is generally assumed that only free drug can distribute to tissues. In blood, drugs often bind to albumin. The unbound (free) drug can diffuse out of the blood, into the extra-cellular water and often into cells (intra-cellular water). Equilibrium is established

  20. General Principles of Distribution Protein Binding: Unless a drug is actively transported into cells, it is generally assumed that only free drug can distribute to tissues. The equilibrium between Bound & Free remains in place. It is also assumed that at equilibrium the free concentration is equal in all tissues

  21. General Principles of Distribution Protein Binding: Unless a drug is actively transported into cells, it is generally assumed that only free drug can distribute to tissues. If a drug is highly bound within tissues, the equilibrium established between bound and free will find the majority of the drug in tissues, (based on binding and mass).

  22. General Principles of Distribution Protein Binding: Unless a drug is actively transported into cells, it is generally assumed that only free drug can distribute to tissues. Protein binding in blood will <effectively> keep drug in blood. However, since tissue mass exceeds blood volume, any binding in tissues will shift the equilibrium toward drug in tissues.

  23. General Principles of Distribution Protein Binding: Unless a drug is actively transported into cells, it is generally assumed that only free drug can distribute to tissues. The volume of distribution of a drug can be viewed as a relationship between tissue binding and binding to protein within the blood. If a drug is highly protein bound within blood but has little tissue binding, the volume of distribution will be small (~10L – e.g. warfarin).

  24. General Principles of Distribution Protein Binding: Unless a drug is actively transported into cells, it is generally assumed that only free drug can distribute to tissues. Even if a drug is highly protein bound within blood but also has high tissue binding, the volume of distribution will be large.

  25. General Principles of Distribution Protein Binding: Unless a drug is actively transported into cells, it is generally assumed that only free drug can distribute to tissues. The volume of distribution of a drug can be viewed as a relationship between tissue binding and binding to protein within the blood. VdTOTAL = VB + VT (fB/fT) Where VB is blood volume ~ 5L and VT is body water (between 30-50 L). fB and fT is the fraction unbound in tissue and in blood

  26. General Principles of Distribution Protein Binding: Unless a drug is actively transported into cells, it is generally assumed that only free drug can distribute to tissues. VdTOTAL = VB + VT (fB/fT) Where VB is blood volume ~ 5L and VT is body water (between 30-50 L). If fB is 5% (free in blood or plasma) and fT is 100% (free in issues – no binding) The final volume is 5L of blood volume plus ~2.5L of tissue volume. 7.5L total. The volume of distribution of a drug can be viewed as a relationship between tissue binding and binding to protein within the blood.

  27. General Principles of Distribution Protein Binding: Unless a drug is actively transported into cells, it is generally assumed that only free drug can distribute to tissues. VdTOTAL = VB + VT (fB/fT) Where VB is blood volume ~ 5L and VT is body water (between 30-50 L). If fB is 5% (free in blood or plasma) But fT is 1% (free in issues – 99% binding) The final volume is 5L of blood volume plus ~250 L of tissue volume. 255L total. The volume of distribution of a drug can be viewed as a relationship between tissue binding and binding to protein within the blood.

  28. General Principles of Distribution Effect of Protein Binding on Volume of Distribution VdTOTAL = VB + VT (fB/fT) This makes the assumption that the drug may distribute to all places in the body where water exists and this may not be true if there is active transport in or out of a particular tissue. eg. BBB etc.

  29. General Principles of Distribution Observe the Effect of Protein Binding on Volume of Distribution of Propranolol For propranolol as the free fraction increases from ~5% to ~30% Volume (Vd) increases from ~125 L to ~800 L. 6-fold increases in both FF and Vd. Open circles – Liver disease patients

  30. General Principles of Distribution L/70 kg 50,000 20,000 10,000 5,000 1,000 500 100 50 10 5 Quinacrine Chloroquine Nortriptyline Digoxin Propranolol Quinidine Quinolones (1- 2 L/kg), Tetracycline Phenobarbital Phenytoin Theophylline (0.45 L/kg) Aminoglycodises (0.25 L/kg) ASA Warfarin Five Examples: Example 5: Cyclosporin … 3000L Example 2: Ciprofloxacin … 120L Example 1: Levofloxacin … 100L Example 4: Levofloxacin … 83.3L Example 3: Theophylline … 36L Notice that the Volume of distribution is different for all drugs and will also be different for each patient (levo).

  31. Male Acute Community Acquired Pneumonia Distribution Problems Five Examples: Example 1: Levofloxacin Calculate Volume Example 2: Ciprofloxacin Given Volume, Calculate Concentration Example 3: Theophylline Calculate Volume …then predict new dose Example 4: Levofloxacin Example 5: Cyclosporin

  32. General Principles of Distribution • Summary • The calculated apparent Volume depends on the fluid being sampled. • Drugs can go anywhere (phys.-chem. prop.) leaving extra-cellular water to distribute into bone, fat or … anywhere, any tissue. • 3. The apparent Volume depends on the host, and the physical/chemical properties of the drug or metabolite. • 4. The calculated apparent Volume rarely reflects a real physiologic volume. • The minimum volume* of distribution is vascular volume (8% IBW: 6’ ♂ = 6.4L). • 6. There is no maximum volume*.

  33. First Example: Levofloxacin Volume of Distribution IV Dose Blood Kidney Liver Oral Dose GI Tract

  34. Male Acute Community Acquired Pneumonia Distribution Problem 1 Calculate Volume Male with Pneumonia Age: 45 yr Weight: 80 kg Drug: Levofloxacin Observe: Serum levofloxacin concentration following i.v. bolus of 500 mg 5 g/mL (mg/L) Additional Information: Blood Volume: 8% of body weight Hematocrit: 0.45

  35. Male Acute Community Acquired Pneumonia Distribution Problem 1 • Questions • What is the Volume of distribution of levo? • 2. Where in the body does levo appear • to be located? What percent is located • in the Serum? • 3. If the serum levo concentration • is at the mid-point of target…3 g/mL • how much drug is in the serum? • what is the total amount of drug in • your patient (MAC)?

  36. Male Acute Community Acquired Pneumonia Distribution Problem 1 Equations Conc = Dose / V V = Dose/Conc Answers. 1. What is the Volume of distribution of levo? Dose = Initial [ ] = Levo Volume: = 2. Proportion in Serum: =

  37. Male Acute Community Acquired Pneumonia Distribution Problem 1 Equations Conc = Dose / V V = Dose/Conc Answers. 1. What is the Volume of distribution of levo? Dose = 500 mg Initial [ ] = 5 g/mL (mg/L) Levo Volume: = Dose / Conc = 500 / 5 = 100 L 2. Proportion in Serum: =

  38. Male Acute Community Acquired Pneumonia Distribution Problem 1 Equations Conc = Dose / V V = Dose/Conc Answers. 2. Proportion in Serum: Weight : 80 kg Levo Volume: 500 mg/ 5 mg/L Blood Volume: 8% of body weight Hematocrit: 0.45 Blood volume: = Serum (55%): = Levo Volume: = Proportion in Serum: =

  39. Male Acute Community Acquired Pneumonia Distribution Problem 1 Equations Conc = Dose / V V = Dose/Conc Answers. 2. Proportion in Serum: Weight : 80 kg Levo Volume: 500 mg/ 5 mg/L Blood Volume: 8% of body weight Hematocrit: 0.45 Blood volume: = 0.08 x 80 kg = 6.4 L Serum (55%): =6.4 x 0.55 = 3.5 L Levo Volume: = 500 mg/ 5 mg/L = 100 L Proportion in Serum: =

  40. Male Acute Community Acquired Pneumonia Distribution Problem 1 Equations Conc = Dose / V V = Dose/Conc Answers. 2. Proportion in Serum: Weight : 80 kg Levo Volume: 500 mg/ 5 mg/L Blood Volume: 8% of body weight Hematocrit: 0.45 Blood volume: = 0.8 x 80 kg = 6.4 L Serum (55%): =6.4 x 0.55 = 3.5 L Levo Volume: = 500 mg/ 5 mg/L = 100 L Proportion in Serum: = 3.5 L/100.0 L = 3.5%

  41. Male Acute Community Acquired Pneumonia Distribution Problem 1 Equations Conc = Dose / V V = Dose/Conc • Answers. • 3. If the serum levofloxacin concentration • is at the mid-point of target … ~ 3mg/L … • how much drug is in the serum? • what is the total amount of drug in MAC? • Therapeutic Range: 5 - 1 g/mL = mg/L • mid point: 3 mg/L • Amount in body at equilibrium: • = • Amount in serum: • =

  42. Male Acute Community Acquired Pneumonia Distribution Problem 1 Equations Conc = Dose / V V = Dose/Conc • Answers. • 3. If the serum levofloxacin concentration • is at the mid-point of target … ~ 3mg/L … • how much drug is in the serum? • what is the total amount of drug in MAC? • Therapeutic Range: 5 - 1 g/mL = mg/L • mid point: 3 mg/L • Amount in body at equilibrium: • = 3 mg/L x 100.0 L = 300 mg • Amount in serum: • = 3 mg/L x 3.5 L = 10.5 mg • Percent in serum: = 10.5 mg/ 300 mg • = 3.5%

  43. Levofloxacin Distribution Problem 1 Review Answers. Body Weight: 80 kg Blood Volume: 8% of body weight Serum is 55% of Blood Serum = (0.08) x (0.55) x (80) = 3.52 L Serum conc. = 3 g/mL = 3 mg/L Amount in Serum: = (3.5 L) x 3 mg/L) = 10.5 mg Amount in Body, based on volume of 100 L = (3) x (100) = 300 mg Percent in Serum: 10.5 mg / 300 mg = 3.5% Volume 100 L 100 L/80kg = 1.2 L/kg Recall Levo monograph indicated volume was between 74 & 112 L.

  44. Second Example: Ciprofloxacin Volume of Distribution IV Dose Blood Kidney Liver Oral Dose GI Tract

  45. Male Acute Community Acquired Pneumonia Distribution Problem 2 This time … given Volume Male with Pneumonia Age: 45 yr Weight: 80 kg Drug: Ciprofloxacin Goal: Serum ciprofloxacin concentrations ranging 3 - 4 g/mL (target) Additional Information: Cipro Volume: 1.5 L/kg Blood Volume: 8% of body weight Hematocrit: 0.45

  46. Male Acute Community Acquired Pneumonia Distribution Problem 2 • Questions • What dose should be given to MAC to • achieve a peak concentration of between • 3 and 4 g/mL? • What percent is located in the Serum? • If the serum cipro concentration • is at the mid-point of target…3.5 g/mL • how much drug is in the serum? • what is the total amount of drug in MAC?

  47. Male Acute Community Acquired Pneumonia Distribution Problem 2 Equations Conc = Dose / V V = Dose/Conc • Answers. • What dose should be given to MAC to • achieve a peak concentration of between • 3 and 4 g/mL? • Cipro Volume: 1.5 L/kg • Pt weight: 80 kg • 6.4 x 0.55 = 3.5 L • Cipro Volume (L): =

  48. Male Acute Community Acquired Pneumonia Distribution Problem 2 Equations Conc = Dose / V V = Dose/Conc • Answers. • What dose should be given to MAC to • achieve a peak concentration of between • 3 and 4 g/mL? • Cipro Volume: 1.5 L/kg • Pt weight: 80 kg • 6.4 x 0.55 = 3.5 L • Cipro Volume (L): = 1.5 L/kg x 80 kg • = 120.0 L • Peak target [ ] mg/L = 3 g/mL • Req. Cipro Dose =

  49. Male Acute Community Acquired Pneumonia Distribution Problem 2 Equations Conc = Dose / V V = Dose/Conc • Answers. • What dose should be given to MAC to • achieve a peak concentration of between • 3 and 4 g/mL? • Cipro Volume: 1.5 L/kg • Pt weight: 80 kg • 6.4 x 0.55 = 3.5 L • Cipro Volume (L): = 1.5 L/kg x 80 kg • = 120.0 L • Peak target [ ] mg/L = 3 g/mL (mg/L) • Req. Cipro Dose = 3 mg/L x 120 L • = 360 mg

  50. Male Acute Community Acquired Pneumonia Distribution Problem 2 Equations Conc = Dose / V V = Dose/Conc • Answers. • What dose should be given to MAC to • achieve a peak concentration of between • 3 and 4 g/mL? • Cipro Volume: 1.5 L/kg • Pt weight: 80 kg • 6.4 x 0.55 = 3.5 L • Cipro Volume (L): = 1.5 L/kg x 80 kg • = 120.0 L • Peak target [ ] mg/L = 4 g/mL (mg/L) • Req. Cipro Dose = 4 mg/L x 120 L • = 480 mg

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