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Drug Kinetics and CRRT

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  • Cl, ke. and t1/2: Parameters described for drugs with first order kinetics in one compartment model
  • The smaller the child the more significance of increases in Vd. Example: 4kg * 80mL/kg = ~300mL Blood volume 40kg * 80mL/kg = ~3000mL Blood volume 20kg * 80mL/kg = ~1600mL Blood volume
  • Clearance Reference: Standard HD <500 daltons High-flux HD <5000 daltons Hemoperfusion <3500 daltons CRRT <40,000 daltons Plasmapheresis > 40,000 daltons As reported by Patrick Murray, M.D. Professor of Medicine Section of Nephrology University of Chicago [email_address]
  • Transcript

    • 1. Drug Kinetics and CRRT: Parameters and Principles Morgan R. Cole, Pharm.D., BCPS Manager, HDVCH Pharmacy Services Clinical Pharmacy Specialist, Pediatric Critical Care
    • 2. Objectives
      • Describe CRRT principles
      • Understand basic pharmacokinetic (Pk) parameters
      • Describe CRRT principles and effects on Pk
      • Describe variances in Pk parameters
        • Critically ill
        • Pediatrics & Neonates
      • Understand assumptions to estimate dosing regimens in pediatric CRRT
    • 3. CRRT Principles
    • 4. CRRT Principles
      • Heparin Anticoagulation
      • Citrate Anticoagulation
        • Acid Citrate Dextrose – Anticoagulation (ACD-A)
      • Calcium Chloride Replacement
      • Convective Clearance
        • Hemofiltration ~ Ultrafiltration
        • Filter Replacement Fluid (FRF)
      • Diffusive Clearance
        • Hemodialysis
        • Dialysate
    • 5.  
    • 6. CRRT Principles
      • Usual circuit priming volume ~ 100-150mL
        • Blood, Saline, & Albumin
      • Usual Blood Flow Rate
      • ~ 3-5mL/kg/min
      • Tubing and Membrane Filter impact
        • Adsorption
      Adapted with permission from: Gambro Training Manual 1 and 2 Slides from Gambro Training package Last Update: February, 2008
    • 7.  
    • 8. Ultrafiltration
      • Movement of fluid through a semi-permeable membrane caused by a pressure gradient
      • Positive, negative and osmotic pressure from non-permeable solutes
      Adapted with permission from: Gambro Training Manual 1 and 2 Slides from Gambro Training package Last Update: February, 2008
    • 9. Convective Clearance
      • Movement of solutes with water flow, “solvent drag”.
      • The more fluid moved through a semi-permeable membrane, the more solutes that are removed.
      • Replacement Fluid is used to create convection
      Adapted with permission from: Gambro Training Manual 1 and 2 Slides from Gambro Training package Last Update: February, 2008
    • 10.  
    • 11. Diffusive Clearance
      • Movement of solutes from an area of higher concentration to an area of lower concentration.
      • Dialysate is used to create a concentration gradient across a semi-permeable membrane.
      Adapted with permission from: Gambro Training Manual 1 and 2 Slides from Gambro Training package Last Update: February, 2008
    • 12.  
    • 13. Pharmacokinetic Parameters
    • 14. Pharmacokinetic Parameters
      • Volume of Distribution (Vd) = Volume a drug would occupy if one compartment model exists (conceptual) L / Total Body Weight (TBW) kg
      • Vd L/kg = Volume L / TBW kg
      • Loading Dose (LD) mcg/kg = Vd L/kg * serum concentration mcg/mL
      • Protein Binding (Pb) describes the bound fraction of drug but infers the free fraction of drug available for pharmacological action
        • Albumin is the largest contributor to protein binding, though other proteins contribute
    • 15. Pharmacokinetic Parameters
      • Clearance describes the elimination of drug (volume) mL from the body per unit time min
      • Cl mL/min = Volume mL / Time min
      • Maintenance Dose (MD) mcg = Cl mL/min * serum concentration mcg/mL * dosing interval min
      • Terminal elimination half life (t 1/2 ) is the time hours that it takes for the serum concentration of a drug to be reduced by 50%
      • t 1/2 hours = 0.693 * ke hours -1
      • ke hours -1 = Vd L * Cl mL/min
    • 16. Pharmacokinetic Parameters Hemodialysis Peritoneal dialysis CRRT Oliguric renal failure Anuric renal failure Shock states First order kinetics Zero order kinetics t 1/2 Oliguric renal failure Anuric renal failure Shock states Hemodialysis Peritoneal dialysis CRRT First order kinetics Zero order kinetics Cl Hypoproteinemia Hypoalbuminemia Acidosis / Fever / Uremia Medication competition IVIG administration Albumin administration Adequate nutrition Total protein = 5-7 Albumin = 3-5 Pb Dehydration Volume loss Diarrhea/Vomitting Volume resuscitation Ascites Capillary leak Edema One compartment model Two compartment model Vd Critically ill patient variation Increases Decreases Healthy individual Pk Parameter
    • 17. CRRT Impact on Kinetic Parameters
      • Usual circuit priming volume ~ 100-150mL
        • Increases Volume of Distribution (Vd)
        • Usual adult blood volume ~5000mL (0.07L/kg or 70mL/kg)
        • Usual pediatric blood volume ~80mL/kg
      • Tubing binds drug
        • Increases Vd
        • Adsorption
      • Membrane Filter binds drug by “Gibbs-Donnan Effect”
        • Increases Vd
        • Adsorption
    • 18. CRRT Impact on Kinetic Parameters
      • Usual Blood Flow Rate ~ 3-5mL/kg/min
        • Higher the rate leads to increased Clearance (Cl)
      • Ultrafiltrate Rate ~ Filter Replacement Fluid (FRF) Rate if the patient is kept in even fluid balance ~ 35-40mL/kg/hr (2.5L/m 2 /hr)
        • Higher the rate leads to increased Cl
      • Dialysate Rate ~ 35-40mL/kg/hr (2.5L/m 2 /hr)
        • Higher the rate leads to increased Cl
    • 19. CRRT Impact on Kinetic Parameters
      • Convective Clearance (Filter Replacement Fluid (FRF))
        • Hemofiltration = Ultrafiltration
        • Clearance (Cl f ) depends on the sieving coefficient (S), small molecules (S = 1) and low protein bound drugs pass freely through the membrane filter based on pressure
        • Drug concentration in filtrate (Cf)
        • Drug concentration in plasma (Cp)
        • *Clearance depends on Protein binding (Pb), independent from Molecular weight
        • Cl f mL/min = Q f mL/min * S
      • **Q f is the ultrafiltrate rate mL/min = FRF rate mL/min and depends on membrane surface area and transmembrane pressure
      S =
    • 20. Sample sieving coefficients (S) Adapted from Golper, Dialysis Transpl 1993;22:185-188 DelDot, Br J Clin Pharmacol 2004;58:3,259-268 Malone, Antimicrobial Agents and Chemotherapy 2001;3148-3155 Mariat, Crit Care 2006;10:1,R26 Fuhrmann, Journal of Antimicrobial Chemotherapy 2004;54,780-784 Guenter, Pharmacotherapy 2002;2:175-83 Tegeder, Antimicrobial Agents and Chemotherapy 1997;41(12):2640-2645 Valtonen, Journal of Antimicrobial Chemotherapy 2001;48,881-885 Valtonen, Journal of Antimicrobial Chemotherapy 2000;45,701-704 Kraft, Pharmacotherapy 2003;23(8):1071-1075 Churchwell, Blood Purif 2006;24(5-6):548-554 ~0.8 Meropenem ~0.8 Imipenem ~0.85 Cefepime ~0.85 Ceftazidime ~0.9 Amikacin ~0.8 Tobramycin ~0.8 Gentamicin S Medication ~0.7 Vancomycin S Medication ~0.15 Daptomycin ~0.8 Linezolid ~>1 Pip / Tazo ~0.75 Ciprofloxacin ~0.85 Moxifloxacin ~0.8 Levofloxacin
    • 21. CRRT Impact on Kinetic Parameters
      • Diffusive Clearance (Dialysate)
        • Hemodialysis
        • Clearance (Cl d ) depends on the dialysate saturation (S d ), small molecules including small, low protein bound drugs pass through the membrane filter based on diffusion & pressure
        • Drug concentration in dialysate (C d )
        • Drug concentration in plasma (C p )
        • *Clearance depends on Protein binding (Pb) & Molecular weight <40,000 daltons
        • Cl d mL/min = Q d mL/min * S d
      • **Q d is the dialysate rate mL/min and depends on membrane surface area, pore size, and blood flow rate and dialysate rate
      S d =
    • 22. CRRT Impact on Kinetic Parameters
      • Combined hemofiltration plus dialysis (Cl df )
        • Convective Clearance (Filter Replacement Fluid (FRF))
        • Diffusive Clearance (Dialysate)
        • Cl df = Q f * S + Q d * S d
      • Native clearance must be taken into account if the patient maintains renal function despite CRRT support
    • 23. Convective + Diffusive Clearance
      • Ultrafiltrate Rate ~
      • Filter Replacement Fluid (FRF) Rate
      • ~ 35-40mL/kg/hr
      • (2.5L/m 2 /hr)
      • Dialysate Rate
      • ~ 35-40mL/kg/hr
      • (2.5L/m 2 /hr)
    • 24.  
    • 25. Clinical Pearls
      • Medications unaffected by CRRT
        • Ceftriaxone
        • Metronidazole
        • Clindamycin
        • Lansoprazole
        • Pantoprazole
        • Cyclosporin
        • Phenytoin
    • 26. Clinical Pearls
      • Due to extracorporeal clearance provided by CRRT remember to hold the following if CRRT circuit goes down and consult the primary service /nephrology service
        • Total Parenteral Nutrition / Enteral Nutrition
        • Antibiotics except ceftriaxone, clindamycin, metronidazole
        • Potassium, and Phosphorus supplementation
        • H2 receptor antagonists
    • 27. Clinical Pearls
      • Due to extracorporeal clearance provided by CRRT remember to monitor closely for toxicity + reduce the dose for the following if CRRT circuit goes down and consult the primary service /nephrology service
        • Sedation (Midazolam, Lorazepam, Fentanyl, & Morphine)
        • Pressors (Norepinephrine, Epinephrine, & Dopamine)
        • Inotropes (Milrinone, Dobutamine, & Epinephrine)
      • If a new circuit is initiated, a reloading phase will occur until complete adsorption occurs and a new steady state with the circuit is reached.
    • 28. Summary
      • Understand CRRT principles
        • Ultrafiltration / Convective vs Diffusive Clearance
      • Understand basic pharmacokinetic (Pk) parameters
        • Vd / Pb / Cl / t 1/2
      • Describe variances in Pk parameters
        • Critically ill
        • Pediatrics & Neonates
      • Understand CRRT principles and effects on Pk
        • Adsorption /  Vd /  Cl
      • Understand assumptions to estimate dosing regimens in pediatric CRRT
        • Pb / MW / S / Sd / Clf / Cld / Cldf
    • 29. References
      • Gambro Renal Products, Intensive Care Division, 14143 Denver West Parkway Lakewood, Co.  80401
      • Golper, Dialysis Transpl 1993;22:185-188
      • DelDot, Br J Clin Pharmacol 2004;58:3,259-268
      • Malone, Antimicrobial Agents and Chemotherapy 2001;3148-3155
      • Mariat, Crit Care 2006;10:1,R26
      • Fuhrmann, Journal of Antimicrobial Chemotherapy 2004;54,780-784
      • Guenter, Pharmacotherapy 2002;2:175-83
      • Tegeder, Antimicrobial Agents and Chemotherapy 1997;41(12):2640-2645
      • Valtonen, Journal of Antimicrobial Chemotherapy 2001;48,881-885
      • Valtonen, Journal of Antimicrobial Chemotherapy 2000;45,701-704
      • Kraft, Pharmacotherapy 2003;23(8):1071-1075
      • Churchwell, Blood Purif 2006;24(5-6):548-554