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SOURCE

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Source: Battistella M, Matzke GR. Drug therapy individualization for patients with chronic kidney disease. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM, eds. Pharmacotherapy: A Pathophysiologic Approach. 10th ed. New York, NY: McGraw-Hill; 2017. http://accesspharmacy.mhmedical.com/content.aspx?bookid=1861&sectionid=146061579. Halilovic J, Dager W. Acute kidney injury. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM, eds. Pharmacotherapy: A Pathophysiologic Approach. 10th ed. New York, NY: McGraw-Hill; 2017. http://accesspharmacy.mhmedical.com/content.aspx?bookid=1861&sectionid=134127206. Accessed May 18, 2017.

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GENERAL PRINCIPLES

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  • Chronic kidney disease (CKD) causes changes in disposition of some drugs as result of changes in bioavailability, distribution volume, and metabolic activity.

  • Drug therapy individualization (DTI) may involve:

    • Simple proportional dose adjustment based on creatinine clearance (CLcr) or glomerular filtration rate (GFR).

    • Complex adjustments for drugs extensively metabolized or undergoing dramatic changes in protein binding and distribution volume.

  • Patient response to given drug may differ because of physiologic and biochemical changes associated with CKD.

  • Goals of DTI: design drug regimens to optimize therapeutic outcomes and minimize adverse effects.

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EFFECT OF CKD ON DRUG DISPOSITION

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  • Drug absorption.

    • Little quantitative information available.

    • Bioavailability theoretically affected by:

      • Drug interactions.

      • Delayed gastric emptying.

      • Reduced gastric acidity.

      • Edema of GI tract.

      • Concomitant drug therapy, especially antacid, H2-antagonist, and phosphate binder administration.

  • Drug distribution.

    • CKD significantly increases or decreases volume of distribution.

    • Plasma protein binding of acidic drugs (eg, penicillins, cephalosporins, furosemide, phenytoin) is decreased due to hypoalbuminemia, qualitative changes in the conformation of the protein binding site, and/or competition for binding sites by other drugs, metabolites, and endogenous substances.

      • Monitor drug concentrations of free (unbound) drug.

    • Binding of basic drugs (eg, bepridil, disopyramide) is usually normal or slightly increased or decreased.

    • Method to calculate volume of distribution (VD) can be influenced by renal disease.

      • Use distribution at steady state (VSS) to compare patients with renal insufficiency to others with normal renal function.

      • VSS is independent of drug elimination.

  • Metabolism.

    • CKD may decrease nonrenal clearance of drugs to greater degree than seen in AKI (Table 1).

    • Severe renal insufficiency can cause accumulation of metabolites that contributes to pharmacologic activity or toxicity.

  • Excretion.

    • Renal clearance of drug is composite of GFR, tubular secretion, and reabsorption.

    • Importance of altered renal function on drug elimination depends on fraction of drug normally eliminated unchanged by kidneys and degree of renal insufficiency.

    • Difficult to quantify contribution of tubular function to renal drug clearance.

    • Clinical measurement or estimation of CLcr or GFR remains guiding factor for drug dosage regimen design.

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Table Graphic Jump Location
TABLE 1.Impact of ESRD on CLNR of Selected Drugs

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