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INTRODUCTION

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Patients with chronic kidney disease (CKD) typically are prescribed an extraordinarily high number of medications compared to individuals without kidney disease. This is due to the presence of numerous comorbidities, including cardiovascular, hematologic, endocrine, psychiatric, and mineral and bone disorders. Notably, patients with end-stage renal disease exhibit the highest medication burden, taking an average of 12 medications (prescribed and over-the-counter) with a median pill burden of 19 per day. All CKD patients are at high risk for developing medication-related problems, including adverse drug effects and drug interactions, leading to suboptimal therapeutic outcomes, and vigilance is required to optimize drug use. Many drugs are predominantly eliminated by the kidney and can accumulate in CKD patients, and even those that are predominantly nonrenally cleared (ie, undergo hepatic metabolism) may require dose adjustment to maximize therapeutic outcomes and to minimize adverse events. As a general rule, if 30% or more of a drug is eliminated unchanged by the kidney, then it will likely require dosage regimen adjustment in CKD patients, especially those with advanced kidney disease (stages 3–5 CKD). A firm knowledge of general principles of pharmacokinetics, and especially of the effects of kidney disease on drug disposition, together with a basic understanding of processes to identify and resolve medication-related problems will facilitate improved drug selection, dosing and safety in all patients with impaired kidney function. This chapter presents clinically relevant pharmacokinetic and pharmacodynamic alterations commonly observed in patients with CKD, provides pragmatic approaches for proactively adjusting drug dosage regimens in these patients, and briefly discusses important medication safety considerations.

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PHARMACOKINETIC CONSIDERATIONS

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The quantitative description of individual parameters that determine drug disposition in the body, including absorption from an extravascular site of administration, distribution to various tissues, and elimination from the body, is termed pharmacokinetics. Decreased kidney function associated with kidney disease results in a reduction in the elimination of renally cleared drugs, which intuitively necessitates a corresponding modification to the dosing regimen to avoid accumulation and potential toxicity. Although renal drug dosage adjustment guidelines are commonly used for this, alterations in drug absorption, distribution, and elimination probably contribute to unpredictable and suboptimal responses.

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Absorption

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The extent of drug absorption from an extravascular site of administration is known as bioavailability. It is presented quantitatively as the percentage of the administered dose that reaches the systemic circulation. Bioavailability may be impacted by several factors, including the route and rate of administration, and pathophysiologic changes at the site of administration. Although little quantitative information is available related to the effect of kidney disease on drug absorption, CKD patients often exhibit pathophysiological changes in the gastrointestinal (GI) tract that can influence bioavailability. For instance, delayed gastric emptying related to gastroparesis may be present in diabetic patients. GI motility may be decreased and can affect the time required to reach the maximal plasma concentration. However, this typically does not affect the maximal plasma concentrations (C...

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