Drug Therapy in Renal Failure

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174 Drug Therapy in Renal Failure

Rima A. Mohammad, Gregory A. Eschenauer, Gary R. Matzke

The incidence of acute kidney injury or insufficiency (AKI) in the intensive care unit (ICU) ranges from 5.9% to 25%, depending on how AKI is defined.¹ Renal replacement therapy is required for 4.3% of all critically ill patients and up to 72.5% of patients with AKI.² In-hospital mortality in ICU patients ranges from 5% to 10% in those with no renal dysfunction, 9% to 27% at risk of renal dysfunction, 11% to 30% with AKI, and 26% to 40% with overt kidney failure.³ Critically ill patients with chronic kidney disease (CKD) have poorer outcomes than patients with normal renal function on admission, and the presence of CKD is a significant predictor of hospital mortality in Acute Physiology, Age, and Chronic Health Evaluation (APACHE) III score tools.^4,⁵ Renal insufficiency, whether acute or chronic, alters the absorption, distribution, metabolism, and elimination of many pharmacotherapeutic agents used in the treatment of critically ill patients. In this chapter, the drugs affected are tabulated, and the mechanisms responsible for the changes in disposition are discussed. A general construct for the individualization of drug therapy in patients with CKD or AKI is presented, along with dosage guidelines for the most commonly used ICU medications. Finally, the influence of continuous and intermittent renal replacement therapy on drug clearance is discussed, and dosage guidelines are tabulated for selected drugs for patients with severe CKD or AKI.

Quantitation of Renal Function

Accurate assessment of renal function in critically ill patients is imperative. Serial estimates or measurements of renal function routinely are recommended to guide individualization of drug dosage regimens to optimize clinical outcomes. The calculation of creatinine clearance (CL_cr) from a timed urine collection with creatinine measurement in serum and urine has been the standard clinical measure of renal function for decades. Urine is difficult to collect accurately in the ICU. Furthermore, many commonly used medications interfere with measurement of creatinine, especially when colorimetric assay methods such as the Jaffé method are used. Thus, measurement of CL_cr by this approach is not always the best way to assess glomerular filtration rate (GFR).^6,⁷ The administration of radioactive (¹²⁵I iothalamate, ⁵¹Cr-EDTA, or technetium-99m DTPA) or nonradioactive (aminoglycosides, iohexol, iothalamate, and inulin) markers of GFR, although scientifically sound, is clinically impractical because intravenous (IV) or subcutaneous (SQ) administration of the marker and the collection of multiple timed blood and urine collections make the procedures expensive and difficult to perform.

Estimation of CL_cr or GFR requires only routinely collected laboratory and demographic data and is inexpensive and clinically feasible. The Cockcroft and Gault (C-G) method for estimation of CL_cr ⁸ and the Modification of Diet in Renal Disease (MDRD) method for estimation of GFR⁹ correlate well with CL_cr and GFR measurements in individuals with stable renal function.⁹ These methods lose their predictive performance, however, in patients with liver disease,¹⁰^–¹² unstable renal function,^6,^13,¹⁴ estimated GFR above 60 mL/min,¹⁵ or obesity.^16,¹⁷ In critically ill patients with AKI, both MDRD and C-G overestimate estimated GFR by 33% and 80%, respectively.¹⁸ Finally, although several methods for CL_cr estimation in patients with unstable renal function have been proposed,⁷ as well as equations for “adjusted” weights (for use in the C-G equation) in the obese,^16,¹⁷ the accuracy of these methods has not been rigorously assessed, and at present their use cannot be recommended.

There is considerable controversy at this time regarding whether the C-G or MDRD equation should be utilized to guide drug dosing adjustments in patients with CKD. The MDRD equation was developed to estimate GFR in patients with CKD.¹⁵ However, renal dosing recommendations for currently approved drugs are predominantly (>95%) based on relationships between drug clearance and CL_cr estimated by the C-G equation.¹⁹ The literature now suggests that the two equations cannot be utilized interchangeably, as several studies have shown that the use of the MDRD equation results in discordant dosing recommendations (compared to dosing based on C-G) in up to 40% of patients.¹⁹^–²¹ Complicating these comparisons even further is another problem: several versions of the MDRD equation (and most recently, an equation called Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI]) have been reported since the publication of the original formula.²² As such, clinicians should continue to utilize CL_cr estimated by C-G for drug dosing.²³

Altered Drug Disposition in Critically Ill Patients with Renal Insufficiency

Effect On Drug Absorption

Absorption of drugs from the gastrointestinal (GI) tract is rarely altered in patients with CKD or AKI. Systemic availability of some drugs (i.e., some β-adrenergic blockers, dextropropoxyphene, and dihydrocodeine) is increased in CKD patients as a result of a decrease in metabolism during the drug’s first pass through the GI tract and liver.^24,²⁵ Some orally administered drugs that are extensively metabolized before reaching the systemic circulation may have increased bioavailability, but this phenomenon has been documented for relatively few drugs.^26,²⁷

Effect On Drug Distribution

The volume of distribution of several drugs is increased significantly in patients with AKI or severe CKD.^25,²⁸^–³⁰ Increases may result from fluid overload, decreased protein binding, or altered tissue binding (Table 174-1). The volume of distribution of only a few drugs is decreased in patients with CKD, and the mechanism proposed for this change is a reduction in tissue binding. Digoxin and pindolol are two prime examples, and for both of these drugs, a significant relationship exists between the decrease in distribution volume and CL_cr.^29,³⁰

TABLE 174-1 Effect of End-Stage Renal Disease on Volume of Distribution (L/kg) of Selected Drugs Used in the ICU*

Effect On Drug Metabolism

Preliminary human data suggest a differential effect of CKD on cytochrome P450 (CYP) enzyme activity: the activities of CYP2C19 and CYP3A4 are reduced, whereas the activities of CYP2D6 and CYP2E1 are not affected.^29,³⁰ This differential effect on individual enzymes may help explain some of the conflicting data regarding changes in drug metabolism in the presence of severe CKD.

Reduction of nonrenal clearance of several drugs reported in patients with severe CKD supports the premise that alterations in hepatic cytochrome P450 enzyme expression and/or activity is responsible (Table 174-2).^25,²⁸^–³⁰ Prediction of the effect of CKD on metabolism of a particular drug is difficult even for drugs within the same pharmacologic class.^29,³⁰ Patients with CKD exhibit reductions in nonrenal clearance and alterations in bioavailability of predominantly hepatically metabolized drugs which are generally proportional to the reductions in GFR.

TABLE 174-2 Effect of End-Stage Renal Disease on Nonrenal Clearance of Selected Drugs Used in the ICU

Decreased
Acyclovir	Erythromycin	Nitrendipine
Aztreonam	Imipenem	Procainamide
Bufuralol	Isoniazid	Propranolol
Cefotaxime	Ketorolac	Quinapril
Ceftriaxone	Metoclopramide	Vancomycin
Cilastatin	Morphine	Verapamil
Ciprofloxacin	Nicardipine	Warfarin
Doripenem	Nimodipine
Increased
Bumetanide	Fosinopril	Phenytoin
Cefpiramide	Nifedipine	Sulfadimidine
Unchanged
Acetaminophen	Insulin	Nisoldipine
Chloramphenicol	Lidocaine	Pentobarbital
Clonidine	Metoprolol	Theophylline

Data from references 25, 28–30.

Critically ill patients with AKI have been noted to have higher residual nonrenal clearance for three drugs—imipenem, meropenem, and vancomycin—than patients with CKD who have similar CL_cr.³¹ This difference may be the result of less exposure to or accumulation of uremic waste products that alter hepatic function. Because patients with AKI may have a higher nonrenal clearance than patients with CKD, the resultant plasma concentrations will be lower than expected and possibly subtherapeutic if classic CKD-derived dosage guidelines are followed. Thus for these agents, initial dosing should be adjusted upward, and only after 7 to 10 days of persistent AKI do the dosing guidelines derived from CKD subjects likely become applicable.

Effect On Renal Excretion

Renal clearance is the composite of GFR, renal tubular secretion, and reabsorption: renal clearance = (GFR × f_u) + (renal tubular secretion − renal reabsorption), where f_u is the fraction of the drug unbound to plasma proteins. An acute or chronic progressive reduction in GFR decreases renal clearance; historically, drug dosage guidelines for patients with AKI or CKD have been based on this phenomenon. The contribution of a reduction in renal clearance to the degree of change in the total body clearance of a drug is highly dependent, however, on the fraction of the dose eliminated unchanged by the normal kidney, the intrarenal pathways for drug elimination and transport, and the degree of functional impairment of each of these pathways.^29,³⁰

Drug elimination by GFR occurs by diffusion, but renal tubular secretion and renal reabsorption are bidirectional processes that involve carrier-mediated renal transport systems and passive diffusion. The important renal transport systems involved in the renal tubular excretion of multiple compounds include the organic anionic (i.e., ampicillin, cefazolin, and furosemide), organic cationic (i.e., famotidine, trimethoprim, and dopamine), nucleoside (i.e., zidovudine), and P-glycoprotein transporters (i.e., digoxin and steroids).^32,³³ Accordingly, the clearance of drugs that are extensively renally secreted (renal clearance > 300 mL/min) may be reduced significantly by drug interactions (i.e., probenecid with β-lactam antibiotics) and/or impaired function of one or more of the renal transporter systems. For example, AKI due to ischemia or toxicants results in a significant impairment in the function of renal solute carrier (SLC) 22A organic ion transporters, compounding the effects of decreased GFR on drug clearance.³⁴

Strategies for Drug Therapy Individualization

Secondary references such as the American Hospital Formulary Service Drug Information,³⁵ Drug Prescribing in Renal Failure by Aronoff and colleagues,³⁶ and Goodman and Gilman’s The Pharmacological Basis of Therapeutics³⁷ are excellent sources from which one can acquire information on the pharmacokinetic characteristics of drugs in subjects with normal renal as well as impaired renal function. However, these references often do not provide the explicit relationships of kinetic parameters with CL_cr or GFR. In addition, since the references employ different definitions of renal impairment and utilize varying methodologies for deriving recommendations, drug dosing recommendations occasionally differ significantly.³⁸ This section provides a practical approach for drug dosage individualization in critically ill patients with AKI or CKD and patients receiving continuous renal replacement therapy (CRRT) or intermittent hemodialysis (IHD). Basic pharmacokinetic principles (see Chapter 169) combined with the disposition properties of a particular drug and a quantitative measure of the patient’s degree of renal function enable the clinician to design an individualized therapeutic regimen.

If the relationship of a drug’s total body clearance with CL_cr or GFR is not known, one can estimate the patient’s total body clearance, provided that the fraction of the drug that is eliminated renally unchanged (f_e) in subjects with normal renal function is known. The following approach makes six assumptions: (1) the volume of distribution is unchanged, (2) the change in total body clearance is proportional to CL_cr, (3) renal disease does not alter the drug’s metabolism, (4) metabolites, if formed, are inactive and nontoxic, (5) the drug obeys first-order (linear) kinetic principles, and (6) the drug’s pharmacokinetics can be described adequately by a one-compartment model. If these assumptions are valid, the kinetic parameter/dosage adjustment factor (Q) can be calculated as Q = 1 − (f_e [1 − KF]), where KF is the ratio of the patient’s CL_cr to an assumed normal value of 120 mL/min. The estimated total body clearance (CL_PT) can be calculated as follows: CL_PT = CL_normT × Q, where CL_normT is the value in patients with normal renal function (i.e., patients with a CL_cr of ≥ 120 mL/min). The elimination rate constant of the drug can be calculated as the quotient of the estimated total body clearance and volume of distribution. When these three key kinetic parameters are estimated, the individualized dosage regimen can be calculated as described in Chapter 169.

The optimal dosage regimen for an ICU patient with AKI or CKD depends on the desired goal. If there is a significant relationship between maximal plasma concentration and clinical response ^39,⁴⁰ (i.e., aminoglycosides) or toxicity^40,⁴¹ (i.e., quinidine, phenobarbital, and phenytoin), the dose and dosing interval may have to be modified. If the dosing interval is increased, the maximal plasma concentration and minimal plasma concentration are similar to values in individuals with normal renal function, but the desired target concentrations may not be precisely attained. In this case, consultation with a clinical pharmacist/pharmacologist may be warranted to facilitate the design of a revised dosage regimen. If no specific target values for maximal plasma concentration or minimal plasma concentration have been reported, attaining the same average steady-state concentration may be appropriate (i.e., cephalosporins). This goal can be achieved by decreasing the dose (D_PT = D_NORM × Q) or prolonging the dosing interval (τ) (τ_PT = τ_NORM ÷ Q).* If the dose is reduced while the dosing interval remains unchanged, the maximal plasma concentration becomes lower and the minimal plasma concentration higher (Figure 174-1). This dosage adjustment method, if taken to the extreme, results in maintenance of the desired average steady-state concentration by continuous infusion of a parenteral product. These principles have been used to derive dosage recommendations for commonly used drugs in the ICU for patients with mild, moderate, and severe kidney injury (Table 174-3).

Figure 174-1 Although the average steady-state concentrations (C_ave) are identical, the concentration-time profile would be markedly different if one changes the dose and maintains the dosing interval constant (scenario A) versus changing the dosing interval and maintaining the dose constant (scenario B) or changing both (scenario C). C_max, maximal concentration; C_min, minimal concentration.

(From Matzke GR, Frye RF. Drug therapy individualization for patients with renal insufficiency. Adapted from Dipiro JT, Talbert RL, Yee GC et al., editors. Pharmacotherapy: a pathophysiologic approach. 7th ed. New York: McGraw Hill; 2008, p. 833-44. Copyright McGraw Hill.)

TABLE 174-3 Dosing Guidelines for Drugs Commonly Used in the ICU by Patients with Renal Insufficiency

Impact Of Renal Replacement Therapy

Removal of a drug from the systemic circulation by renal replacement therapy involves several processes: movement from the blood across the dialyzer/hemofilter membrane and into the dialysate/ultrafiltrate and potentially adsorption on the membrane. Passive diffusion (i.e., movement from an area of higher concentration [blood] to one of lower concentration [dialysate]) is the primary mode of drug removal. The renal replacement therapy clearance tends to increase when there is an increase in the surface area of the dialyzer/hemofilter, blood and dialysate/ultrafiltrate flow rate, or duration of the treatment. Convective transport and clearance, which represent the simultaneous movement of drug within ultrafiltered plasma water, must be considered if ultrafiltration is a significant component of the renal replacement therapy prescription. Renal replacement therapy clearance is higher for drugs that are water soluble, have a low molecular weight, have minimal to no binding to plasma proteins, and have a small volume of distribution.

Continuous Renal Replacement Therapy

The three most commonly used forms of CRRT are continuous venovenous hemofiltration (CVVH), continuous venovenous hemodialysis (CVVHD), and continuous venovenous hemodiafiltration (CVVHDF). During CVVH, drugs are removed primarily by convection/ultrafiltration.⁴² The clearance of a drug is a function of the permeability of the hemofilter, which is called the sieving coefficient, and the ultrafiltrate flow rate. The sieving coefficient can be approximated by dividing the concentration of the drug in the ultrafiltrate (C_uf) by the concentration in the plasma entering the hemofilter (C_a): sieving coefficient = C_uf/C_a. The sieving coefficient is often approximated by the fraction unbound to plasma proteins (f_u) because plasma concentrations of the drug of interest may not be readily available. The clearance by CVVH can be estimated as ultrafiltrate flow rate × f_u. Drug clearance by CVVHDF can be estimated, provided that the blood flow rate is over 100 mL/min and dialysate flow rate is less than 33 mL/min, as (ultrafiltrate flow rate + dialysate flow rate) × (f_u or sieving coefficient). If ultrafiltrate flow rate is negligible (<3 mL/min), as is often the case with CVVHD, CVVHD clearance can be estimated as the product of dialysate flow rate and f_u or sieving coefficient.

Individualization of therapy for a patient receiving CRRT depends on the patient’s residual renal function and clearance of the drug by the mode of CRRT the patient is receiving. The patient’s residual drug clearance can be predicted based on the CL_cr and the relationship between total body clearance of the drug and CL_cr as described previously. The CRRT type (CVVH, CVVHD, or CVVHDF) and recommended initial dosage regimens of selected drugs that are used frequently in ICU patients receiving CRRT are listed in Table 174-4.^43,⁴⁴ In cases in which specific data on drug clearance are not available and the patient receiving CRRT is functionally anuric (i.e., urine output is <300 mL/d), drug dosing can be initiated at a level consistent with the individual having a CL_cr of 30 to 50 mL/min, if their ultrafiltration/dialysate or ultrafiltrate flow rate is 2 L/h or greater.

TABLE 174-4 Dosing Guidelines for Drugs Commonly Used in the ICU by Patients Receiving CVVH/CVVHD/CVVHDF/IHD*

Hemodialysis

Drug-related factors that influence hemodialyzability include the molecular weight, protein binding, and volume of distribution of a drug.²⁵ The dialysis prescription factors include the composition of the dialyzer, surface area, and blood and dialysate flow rates. The semisynthetic and synthetic dialyzers used in high-flux hemodialysis have the largest ultrafiltration rates and more closely mimic the filtration characteristics of the human kidney. These dialyzers allow the passage of most drugs that have a molecular weight of ≤15,000 D.⁴⁵ High-molecular-weight drugs such as vancomycin are significantly cleared by this mode of dialysis, and the clearance of many smaller drugs is significantly increased, as reviewed by Matzke.⁴⁶ In order to obtain therapeutic plasma concentrations, patients receiving high-flux dialysis often require larger drug doses than the doses recommended in most references.

Quantification of the impact of hemodialysis on drug disposition can be calculated in several ways, and this contributes to the variability of values in the literature.²⁵ The difference between the half-life during dialysis and the half-life of the drug when the patient is off dialysis provides a crude guide to the impact of dialysis. The half-life during dialysis may not be interpretable in AKI patients because declining plasma drug concentrations during dialysis represent elimination by the patient, which may be considerable. The most accurate means of assessing the effect of hemodialysis is to calculate the dialyzer clearance of the drug.²⁵ Because drug concentrations generally are determined in plasma, the calculation of plasma clearance by the dialyzer (CL^p_D) can be calculated as: CL^p_D = Q_p ([A_p − V_p]/A_p), where A_p is the concentration of drug in plasma going into the dialyzer, V_p is the concentration of drug in the plasma leaving the dialyzer, and Q_p is plasma flow, which equals blood flow through the dialyzer (1 hematocrit). This method accounts for clearance due to diffusion, convection, and adsorption to the dialyzer. The recovery clearance (CL^r_D) approach also has been used for the determination of dialyzer clearance: CL^r_D = R/AUC_0−t, where R is the total amount of drug recovered unchanged in the dialysate and AUC_0−t is the area under the predialyzer plasma concentration-time curve during hemodialysis.²⁵ This method yields lower clearance values than the previous method if there is a significant degree of binding of the drug to the dialyzer. If adsorption contributes minimally to clearance, the two methods are likely to correlate well.