+
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§ionid=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§ionid=134127206. Accessed May 18, 2017.
++
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.
+++
EFFECT OF CKD ON DRUG DISPOSITION
++
Drug absorption.
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.
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.
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.
++