38 use of drugs in children with impaired renal function


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38 use of drugs in children with impaired renal function

  1. 1. Use of drugs in children with impaired renal function: what is to worry about? Augustina Jankauskien ė , Vilnius university children hospital, Lithuania
  2. 2. Dosing information for pediatric patients: are they really “therapeutic orphans”? <ul><li>Inadequate pediatric dosing information s from 1497 sources were rewieved: </li></ul><ul><li>< 1 month (80.5%) </li></ul><ul><li>1-3 months (79.1%) </li></ul><ul><li>3 months- 2 years (77.5%) </li></ul><ul><li>2-6 years (73.2%) </li></ul><ul><li>6 -12 years (71.6%) </li></ul><ul><li>Tan E, Med J Austr, 2003, 179(4):195-8 </li></ul>
  3. 3. Cochrane reviews <ul><li>Using “ chronic renal failure ” in the Title, Abstract or Keyword and “ drug therapy ” in the Title, Abstract or Keyword and “ children ” in abstract in “ Cochrane database of Systematic Reviews” there were 12 results out of 5416 </li></ul>
  4. 4. There is the reason to worry: <ul><li>Most studies on drug dosage are performed o n adults </li></ul><ul><li>Two thirds of all drugs used in clinical practi c e are totally or partially excreted by the kidney </li></ul><ul><li>Off-label use is common </li></ul><ul><li>Requires multiple considerations, is time consuming and error-prone </li></ul>
  5. 5. Approach to pediatric drug dosing Physiological characteristics of the child: <ul><li>A bsorptive capacity (reaches adult values at 2 years of age) </li></ul><ul><li>Gastric empt y ing delayed, approaches adult values within 6-8 months </li></ul><ul><li>Intramuscular administration of the drugs is unreliable in neonates since blood flow to the muscles varies over the first 2-3 w eeks </li></ul><ul><li>Percutaneous absorption can be faster and higher </li></ul><ul><li>Bartelink I.H et al. Guidelines on Paediatric dosing on the basis of Developmental Physiology and Pharmacokinetic Considerations. Clin Pharmacokin 2006:45(11):1077-1097 </li></ul>
  6. 6. Approach to pediatric drug dosing Pharmacokinetic parameters of the drug <ul><li>Bioavailability of the drug and frequent feeding </li></ul><ul><li>Bioavailability of a rectal solution of paracetamol in infants was shown to be decreased in comparison to suppository formulations </li></ul><ul><li>Bartelink I.H et al. Guidelines on Paediatric dosing on the basis of Developmental Physiology and Pharmacokinetic Considerations. Clin Pharmacokin 2006:45(11):1077-1097 </li></ul>
  7. 7. Goals and limitations of pharmacology <ul><li>Level of active component in the target organ </li></ul><ul><li>Preexisting renal disease </li></ul><ul><li>Variation of body composition </li></ul><ul><li>Diet as a function of age </li></ul>
  8. 8. <ul><li>SORT: KEY RECOMMENDATIONS FOR PRACTICE </li></ul><ul><li>Clinical recommendation Evidence </li></ul><ul><li>rating References </li></ul><ul><li>In patients with chronic kidney disease, over-the-counter and herbal medicine C 17, 21, 25, </li></ul><ul><li>use should be assessed to ensure that medications are indicated; medications 30, 36, 43 </li></ul><ul><li>with toxic metabolites should be avoided, the least nephrotoxic agents </li></ul><ul><li>should be used, and alternative medications should be used if potential drug </li></ul><ul><li>interactions exist. </li></ul><ul><li>Physicians should be aware of drugs with active metabolites that can C 25 </li></ul><ul><li>exaggerate pharmacologic effects in patients with renal impairment. </li></ul><ul><li>Dosages of drugs cleared renally should be adjusted based on the C 1, 4 </li></ul><ul><li>patient’s renal function (calculated as creatinine clearance or glomerular </li></ul><ul><li>filtration rate); initial dosages should be determined using published guidelines </li></ul><ul><li>and adjusted based on patient response; serum drug concentrations should be </li></ul><ul><li>used to monitor effectiveness and toxicity when appropriate. </li></ul><ul><li>C = consensus, disease oriented evidence, usual practice, expert opinion, or case series . </li></ul><ul><li>REFERENCES : </li></ul><ul><li>National Kidney Foundation. K/DOQI clinical practice guidelines for chronic idney disease: evaluation, classification, and stratification. Am J Kidney Dis </li></ul><ul><li>2002;39 (2 suppl 1):S1-266. </li></ul><ul><li>4. Aronoff GR. Drug Prescribing in Renal Failure: Dosing Guidelines for Adults. 4th ed. Philadelphia, Pa.: American College of Physicians, 1999. </li></ul><ul><li>17.Kappel J, Calissi P. Nephrology: 3. Safe drug prescribing for patients with renal insufficiency. CMAJ 2002;166:473-7. </li></ul><ul><li>21.Livornese LL Jr, Slavin D, Gilbert B, Robbins P, Santoro J. Use of antibacterial agents in renal failure. Infect Dis Clin North Am 2004;18:551-79. </li></ul><ul><li>25.Drayer DE. Pharmacologically active drug metabolites: therapeutic and toxic activities, plasma and urine data in man, accumulation in renal failure. Clin </li></ul><ul><li>Pharmacokinet 1976;1:426-43. </li></ul><ul><li>30. Bennett WM, Henrich WL, Stoff JS. The renal effects of nonsteroidal anti-inflammatory drugs: summary and recommendations. Am J Kidney Dis 1996;28 </li></ul><ul><li>(1 suppl 1):S56-62. </li></ul><ul><li>36. Gambaro G, Perazella MA. Adverse renal effects of anti-inflammatory agents: evaluation of selective and nonselective cyclooxygenase inhibitors. J Intern </li></ul><ul><li>Med 2003;253:643-52. </li></ul><ul><li>43. Isnard Bagnis C, Deray G, Baumelou A, Le Quintrec M, Vanherweghem JL. Herbs and the kidney. Am J Kidney Dis 2004;44:1-11. </li></ul>
  9. 9. Factors influencing drug dosage <ul><li>Age </li></ul><ul><li>Specific drugs </li></ul><ul><li>Combination of drugs </li></ul><ul><li>Pharmacogenetics </li></ul><ul><li>Underlying disease </li></ul><ul><li>The dosage of toxins </li></ul><ul><li>Concomitant medications </li></ul><ul><li>Dehydration </li></ul>
  10. 10. Table : Classification of various drugs based on pathophysiologic categories of acute kidney injury deBroe ME et all (2003) Clinical nephrotoxins: Renal injury from drugs and chemicals, 2 edn.Kluwer Academic, Dordrecht Pathophysiology Drugs known to cause acute kidney injury Prerenal failure NSAIDs, ACE inhibitors, cyclosporine A (CyA), norepinephrine, AT2-receptor antagonists, diuretics, interleukins, cocaine, mitomycin C, tacrolimus, estrogen, quinine Acute tubular necrosis Antibiotics: aminoglycosides, cephalosporins, amphotericin B, rifampicin, vancomycin, foscarnet, pentamidine NSAIDs, glaphemin, contrast media, acetaminophen, CyA, cisplatinum, i.v. immunoglobulin, dextran, maltose, sucrose, mannitol, heavy metals Acute interstitial nephritis Antibiotics: ciprofloxacin, methicillin, penicillin G, ampicillin, cephalosporins, oxacillin, rifampicin NSAIDs, glaphenin, acetylsalicylic acid (ASA), fenoprofen, naproxen, phenylbutazone, piroxicam, tolmetin, zomepirac, contrast media, sulfonamides, thiazides, phenytoin, furosemide, allopurinol, cimetidine, omeprazole, phenindione Tubular obstruction Sulfonamides, methotrexate, methoxyflurane, glaphenin, triamterene, acyclovir, ethylene glycol, protease inhibitors Hypersensitivity angiitis Penicillin G, ampicillin, sulfonamides Trombotic microangiopathy Mitomycin C, CyA, oral contraceptives
  11. 11. Dose adjustment <ul><li>Body weight-based dosing regiments </li></ul><ul><li>Body surface area (BSA) based dosing regiments </li></ul><ul><li>Age based dosing regiments </li></ul><ul><li>Physiological parameters: cardiac output, extracellular water volume, resting metabolic rate </li></ul><ul><li>Protein binding characteristics </li></ul>
  12. 12. Dosage guideline based on renal e xcretion . From: Bartelink I.H et al. Guidelines on Paediatric dosing on the basis of Developmental Physiology and Pharmacokinetic Considerations. Clin Pharmacokin 2006:45(11):1077-1097 AS – Active Tubular Secretion. A marker for AS is p -aminohippuric acid
  13. 13. Several basic principles <ul><li>Accumulation of drugs and their metabolites </li></ul><ul><li>Modification of drug doses necessary when GFR< 30 – 40 ml/min/ 1.73m ² </li></ul><ul><li>Dosing interval </li></ul><ul><li>Reducing the size of individual dosage </li></ul><ul><li>Loading dose </li></ul><ul><li>Drug monitoring </li></ul><ul><li>Daschner M, Ped Nephrol(2005)20:1675-1686 </li></ul><ul><li>Trompeter RS, Ped Nephrol, 1987, 1: 183 - 194 </li></ul>
  14. 14. Table: Drug doses for children with normal and reduced kidney function. All doses are given for normal renal function, for a glomerular filtration rate (GFR) of 40 and 10 ml/ min / 1,73 m 2 , and for anuric patients. The doses for reduced renal function are calculated as a percentage of the normal dose and divided into the indicated number of single doses (for example: normal dose 100 mg/ kg / day in two single doses = 2 x 50 mg/ kg daily; dose at a GFR of 10 ml / min / 1,73 m 2 : 30 % in one single dose = 1 x 30 mg/ kg daily) Daschner M. Pediatr Nephrol (2005)20: 1675-1686 Group / subgroup Normal daily dose, number of single doses Dose at GFR (ml/min/1 . 73m 2 ) Dialysis 40 10 Anuric Aldosterone antagonists Spironolactone PO: 1-5 mg / kg in 2 single doses IV: -5mg / kg in 4 single doses 50 % (1 single dose) 25 % (1 single dose) Contraindicated Analgesics / anti-inflammatory agents Acetylsalicylic acid 5(-10) mg / kg as single dose (max. 4x / day) 75 % 50 % (increase dose interval) 50 % (increase d ose interval) Ibuprofen 20-30 mg / kg in 3-4 single doses Max. daily dose 1.2 g Normal dose Normal dose Normal dose Paracetamol 10-20 mg / kg as single dose (max.4x / day) . Max. daily dose 4g Normal dose 50 % (increase dose interval) 50 % increase d ose interval) Antibiotics aminoglycosides Gentamicin 3-5 mg / kg / day in 3 single doses Peak level 5-10 mg / ml Trough level 0.5-2 mg / l Max. daily dose 360 mg 60 % (2 single doses) Reduce loading dose 10 % (1 single doses) Reduce loading dose 5 % (1 single d ose), loading dose 1-2 mg / kg 15 % after hemodialysis; Intraperitonea loading dose 8 mg / l, Maintenance dose 4mg / l Antivirals Ganciclovir IV: initial (14 days) 10 mg / kg / day in 2 single doses, then 5 mg / kg / day in 1 single PO: 100 mg / kg / day in 3 single doses PO dose at GFR < 40: mg / kg = GFR; max. daily dose 3g PO IV: 40 % (2 single doses) 10 % (1 single dose); orally in 2 single doses 1.25mg.kg afte r Each hemodialysis(or 5 % during Peritoneal dialysis); PO in 2 single doses 1.25 mg / kg after each Hemodialysis (or 5 % during Peritoneal dialysis); PO in 2 single doses
  15. 15. Too complicated for crude guidelines <ul><li>Avoid unfamiliar drugs </li></ul><ul><li>Systematically check the recommended dosage in tables </li></ul><ul><li>Check plasma drug level </li></ul><ul><li>Delete any non-essential treatment </li></ul><ul><li>Assess renal function during the entire duration of treatment </li></ul>
  16. 16. Recommendations <ul><li>For preventing amphotericin -induced nephrotoxicity: saline infusion prior to administration (10 – 15 ml/kg body weigh) and use of lipid formulations of amphotericin </li></ul><ul><li>Goldman RD, Koren G. J Pediatr Hematol Oncol (2004)26:421 -426 , </li></ul>
  17. 17. Recommendations <ul><li>Radiocontrast media : preventive measures: intravenous hydration and administration of acetylcysteine </li></ul><ul><li>Tepel M, Zidek W (2004). Curr Opin Nephrol Hypertens13: 649-654 </li></ul><ul><li>Cytostatics : infusion of mannitol and saline </li></ul><ul><li>Liposomal formulation of cisplatin, Lipoplatin </li></ul>
  18. 18. Recommended reading <ul><li>Daschner M (2003) Tabelarium Nephrologicum. Shaker Verlag, Aachen </li></ul><ul><li>Daschner M, Ped Nephrol (2005) 20:1675-1686 </li></ul>
  19. 19. Resources for More Information About Dosing Adjustments in Patients with Chronic Kidney Disease Drug Prescribing in Renal Failure: Dosing Guidelines for Adults Publisher: American College of Physicians PDA download: http://acp.pdaorder.com/pdaorder/-/605920537541/ item?oec-catalog-item-id=1028 FDA Center for Food Safety and Applied Nutrition Web site: http://www.cfsan.fda.gov/ FDA MedWatch Web site: http://www.fda.gov/medwatch/index.html Medline Plus (herbal medicine) Web site: http://www.nlm.nih.gov/medlineplus/herbalmedicine.html National Center for Complementary and Alternative Medicine Web site: http://www.nccam.nih.gov/ National Kidney Disease Education Program Web site: http://www.nkdep.nih.gov National Kidney Foundation Web site: http://www.kidney.org/
  20. 20. Guidelines must run the gaun t let between being too general to be useful and too specific to be excl u sive Baber N.S. Paediatric regulatory guidelines: do they help in optimising dose selection for children? Br J Clin Pharmacol, 2 00 5