Phuong-Thu T. Pham

Phuong-Mai T. Pham

Erik Lawrence Lum

Theodore M. Sievers


Key Concepts

Bioavailability, volume of distribution, plasma clearance, half-life


  • Bioavailability is the percentage or portion of administered drug that reaches systemic circulation.

    • Intravenous (IV) route: Bioavailability is 100%.

    • Non-IV route: Bioavailability depends on:

      • Ease of absorption (i.e., through gut, skin, or mucosal membrane)

      • First-pass metabolism (i.e., hepatic metabolism prior to release into systemic circulation)

Factors that can alter bioavailability in reduced GFR

  • Increased salivary urea in uremia increases salivary pH, which reduces absorption of drugs that are better absorbed in acidic pH.

  • Nausea/vomiting causes loss of oral drugs.

  • Gastroparesis/reduced peristalsis slow drug absorption and delay attainment of plasma peak concentration.

  • The use of antacids and proton-pump inhibitors (PPIs) can increase stomach pH, which reduces absorption of drugs that are better absorbed in acidic pH (e.g., iron, mycophenolate mofetil [MMF; Cellcept], but not mycophenolate sodium [Myfortic]).

  • Phosphate binders can form nonabsorbable complexes with some drugs (e.g., quinolones).

  • Bowel wall edema (e.g., nephrosis) reduces gut absorption.

Volume of Distribution

  • The total amount of drug in the body, expressed as an imaginary volume with a uniform drug plasma concentration:

    • Volume of distribution (Vd) = Total amount of drug in the body ÷ Plasma concentration of drug.

    • Vd is traditionally expressed as L/kg of ideal body weight.

    • Vd is large for drugs with a high degree of lipid solubility, compartmentalization, and low plasma protein binding.

Plasma protein binding

  • Plasma protein binding is a key determinant of Vd (Fig. 10.1).

  • Drugs that are highly protein bound stay in the vascular compartment and have a limited Vd.

  • Vd is low for drugs with high water solubility and high plasma protein binding.

  • Primary drug-binding proteins include albumin and α1-acid glycoproteins:

    • Organic acids generally bind to albumin.

    • Organic bases generally bind to glycoproteins. Increased synthesis of α1-acid glycoproteins may occur in inflammatory states and may alter free drug levels.

Factors that alter plasma protein binding in patients with reduced GFR

  • Reduced serum proteins due to renal loss (e.g., nephrotic syndrome), malnutrition, and/or reduced synthesis

  • Competitive binding of uremic toxins to plasma proteins displaces protein-bound drugs into plasma, resulting in increased free (unbound) drug concentrations.

  • Organic acids that accumulate in renal failure compete with acidic drugs for protein binding. Therefore, a larger fraction of acidic drugs will exist in the unbound active state (e.g., salicylates, warfarin, sulfonamides, phenytoin).

  • Basic drugs bind more readily to nonalbumin proteins.

  • Alteration in blood pH

  • Predicting the effect of changes in protein binding on the kinetic parameters of drugs may be difficult. Although higher free drug concentrations are available at the site of action/toxicity, more is also available for metabolism or renal excretion.

FIGURE 10.1 Volume of distribution (Vd). A. Vd is low for drugs with high plasma protein binding and high water solubility. B. Vd is large for drugs with low plasma protein binding, high lipid solubility, and compartmentalization.

Factors that can alter Vd in renal patients:

  • Increased Vd: edema, ascites/effusions, adsorption onto apparatus (dialysis filters, extracorporeal membrane oxygenation [ECMO] circuits), volume expansion due to extracorporeal machinery (an extra 2,000 to 2,500 mL)

  • Reduced Vd: older age, muscle wasting, amputations, loss of body fat, volume depletion

  • Effect of reduced plasma protein binding on Vd: Predicting the effect of reduced plasma protein binding on the Vd may be difficult. Although more free drug is available for redistribution into other extravascular compartments that can result in increased Vd, more is also available for metabolism or renal excretion. The latter can result in reduced Vd.

    Loading dose is directly proportional to Vd:

    where bioavailability = 1 for IV drug infusion.

  • In the absence of a loading dose, maintenance doses alone will not achieve steady-state level until five drug half-lives later. Thus, for some drugs, a loading dose is given to reduce the time to steady state when it is critical to rapidly achieve therapeutic concentrations (e.g., antibiotics in the setting of sepsis or septic shock).

Plasma Clearance

  • Most drugs are cleared/metabolized by the liver and/or kidneys. Plasma clearance is the sum of clearance of a drug by both renal and nonrenal routes.

  • There is evidence that renal impairment may also reduce nonrenal (i.e., hepatic) metabolism of drugs, presumably via an increase in a circulating inhibitor of hepatic metabolic pathways (cytochrome P450). This factor is thought to be dialyzable.

  • Drug clearance determines maintenance dose.

  • Dose adjustment based on altered drug clearance in a patient with kidney failure:

    Example 1: A drug is 100% excreted by the kidneys. Normal maintenance dose is 100 mg. If kidney function is now 30% of normal, what should be the new maintenance dose?

    Maintenance dose should be reduced to 30% of normal dose, 30 mg.

    Example 2: A drug is 40% cleared by liver and 60% by kidneys. Normal maintenance dose is 100 mg. If kidney function is now 40% of normal and assuming liver clearance is preserved, what should be the new maintenance dose?

    Clearance of the drug is still 40% by liver, but now clearance by kidneys is only 40% of 60%, which is 24%. Total drug clearance would now be 40% by liver plus 24% by kidneys, or 64% total clearance. Maintenance dose should be reduced to 64% of normal dose, 64 mg.

Half-Life (t½)

  • A drug is the time needed for the plasma level of the drug to decrease by 50%.

  • Generally, for an oral drug, 4 to 5 half-life duration are needed to reach steady state. Example: For a drug with of 12 hours, it takes up to 5 × 12 hours = 60 hours (2½ days) to reach steady state. If an immediate therapeutic level is needed, a loading dose must be given.

  • Half-life determines dosing frequency.

Principles of Dialytic Drug Removal

  • Dialysis drug clearance may occur via both diffusion and convection.

  • Clearance is dependent on the characteristics of the drug and dialysis.

    • Drug characteristics: molecular size (<500 Da for hemodialysis [HD], up to 5,000 Da for continuous renal replacement therapy [CRRT]), water solubility, protein binding, Vd, plasma clearance.

    • Dialysis characteristics: membrane pore size, blood and dialysate flow rates, dialysis frequency and duration, ultrafiltration rate, replacement solution location in CRRT (predialysis vs. postdialysis)

  • Drug clearance by dialysis is considered clinically significant if drug clearance is increased by ≥30% with dialysis.

  • Whenever feasible, close therapeutic drug monitoring is recommended.

Special considerations for different modes of dialysis

Hemodialysis (HD)

  • Drug clearance is dependent on dialysis membrane characteristics, blood and dialysate flow rates, and dialysis frequency and duration.

    • Clearance = drug extraction ratio × blood flow, where extraction ratio = (predialysis concentration – postdialysis concentration) ÷ predialysis concentration

  • “High-efficiency,” “high-flux,” and “high-permeability” dialysis membranes can lead to significantly higher drug clearance, particularly for highly water-soluble drug. Example: Vancomycin clearance is significantly increased with high-flux membranes. “High-permeability” membrane is defined as having an ultrafiltration coefficient Kuf > 12 mL/mm Hg/h.

Peritoneal dialysis (PD)

  • Protein-bound drugs may be better cleared with PD compared with HD due to larger peritoneal membrane pore size.

  • Drug clearance by PD is typically approximated at 10 mL/min.

  • Drug clearance by PD may increase with the following:

    • Peritonitis due to increased blood flow

    • Increase number of daily exchanges

Continuous renal replacement therapy (CRRT)

See Chapter 12, Drug Dosing with CRRT


  • Literature on drug removal with plasmapheresis is lacking.

  • Plasmapheresis may significantly remove drugs with high plasma protein binding and/or low Vd.

  • Intravenous immunoglobulin (IVIG), rituximab, and antithymocyte globulin (used for the treatment of acute antibody-mediated and acute vascular rejection) are removed by plasmapheresis. Although the extent of drug removal by such procedure is unknown, as much as a 50% dose loss during plasmapheresis has been described. These agents should be administered immediately after plasmapheresis if possible.


Antimicrobials Agents

Many agents are small (<500 Da), water soluble, not highly protein bound, and appear unchanged in the urine. Dosage reduction is thus usually necessary in patients with CKD and dialysis dependency.

Aminoglycosides (AGs)

  • AGs are mostly excreted unaltered by glomerular filtration and, to a much lesser extent, by tubular secretion. Tubular reabsorption can lead to high renal cortical tissue concentrations even in advanced renal impairment.

  • AGs can cause nephrotoxicity and ototoxicity due to intracellular accumulation and associated injury to lysosomes, Golgi apparatus, mitochondria, and endoplasmic reticulum in proximal tubular cells and inner ear hair cells, respectively. AG nephrotoxicity is typically evidenced by a rise in serum creatinine within 7 to 10 days of exposure.

  • Electron microscopy reveals “myeloid bodies” in proximal tubular cells. Myeloid bodies are thought to arise from drug trapping, followed by a gradual accumulation of drug-phospholipid complexes within the internal lysosomal membranes. The increase in undigested materials interferes with normal membrane activity
    and results in the accumulation of concentric multilamellar lipid layers known as myeloid bodies, which may have similar appearance as those seen in Fabry disease (see Chapter 7 Glomerular and Vascular Diseases).

  • Nephrotoxicity risks: older age, underlying CKD, diuretics, concurrent use of nephrotoxic agents or IV radiocontrast agents, hypokalemia, hypovolemia

  • Bactericidal activity of AG is dependent on the initial rapid intracellular accumulation, followed by significant tissue release postantibiotic administration. The latter is termed “postantibiotic effect.” Drugs with “postantibiotic effect” depend on the loading dose but require less frequent dosing.

  • In general, daily dosing or even q36h to q48h dosing of AG is thought to minimize nephrotoxicity in patients with GFR less than 60 mL/min.

  • Dosing for all AGs is based on ideal body weight and adjusted body weight for obese patients. Serum levels should be measured to ensure therapeutic levels and avoidance of toxicity.

  • In HD, predialysis dosing of AG allows for higher maximal concentration and theoretically better efficacy. Postdialysis dosing of half dose has also been suggested, but potential for higher toxicity must be noted.

  • AG drug removal is thought to be greatest with CVVHDF (significant solute removal by both diffusion and convection), followed by continuous venovenous hemofiltration (CVVH) (significant solute removal by convection) and intermittent HD (predominantly diffusion).

  • In peritonitis, AG should be given intraperitoneally.

Glycopeptides (vancomycin and teicoplanin)

  • Both are predominantly excreted by kidneys.

  • When given IV, both agents are nephrotoxic and ototoxic, but teicoplanin is less nephrotoxic.

  • Nephrotoxicity is thought to involve oxidative stress. Use of vitamin E and N-acetyl cysteine has been suggested to ameliorate vancomycin-induced nephrotoxicity.

  • Nephrotoxic risks include underlying kidney injury, concurrent use of nephrotoxic drugs, prolonged therapy, and high plasma levels.

  • Dialysis vancomycin dosing of 1 g can maintain plasma level above minimum inhibitory concentration (>15 µg/mL) for 3 to 5 days. Of note, trough levels >15 µg/mL are associated with greater nephrotoxicity. Random level monitoring may be used to determine the timing of subsequent doses among patients with renal replacement therapy or advanced kidney disease not on scheduled dosing.


  • Most (penicillins, cephalosporins, carbapenems, monobactams) require dose reduction in CKD. β-Lactams are commonly combined with β-lactamase inhibitors (e.g., clavulanate, sulbactam, tazobactam, avibactam) to minimize antibiotic resistance and improve activity spectrum. Dose adjustment for combination drugs must take into account different metabolism rates of both agents. Whereas rates of metabolism of both agents in ampicillin/sulbactam and piperacillin/tazobactam
    are similar, clavulanate metabolism is much faster than that for ticarcillin in the ticarcillin/clavulanate combination.

  • Unlike AG, most β-lactams have short half-life and no postantibiotic effect. Dose reduction is generally preferred over frequency reduction.

  • Central nervous system (CNS) toxicity leading to lower seizure threshold is not uncommon with β-lactams (e.g., penicillins, imipenem) when used in high unadjusted dose in patients with advanced CKD.

Sulfonamides and trimethoprim

  • Sulfonamides are typically combined with trimethoprim.

    • Both are renally excreted. However, alkaline urine enhances the excretion of sulfamethoxazole, whereas acidic urine promotes trimethoprim excretion.

    • Both accumulate in patients with reduced GFR and dosage adjustment is recommended.

  • Sulfonamides are excreted following acetylation. Acetylated sulfonamides may crystallize in tubular lumen and cause kidney injury, particularly with cumulative dose >84 g. Good hydration and alkalinization may be both preventive and therapeutic.

  • Sulfonamides may also cause tubulointerstitial nephritis.

  • Trimethoprim may inhibit tubular secretion of creatinine and may cause a rise in serum creatinine without actually causing kidney injury.

  • Trimethoprim may block the epithelial sodium channel (ENaC) and cause both hyperkalemia and metabolic acidosis.


  • Rifamycins are predominantly hepatically metabolized and do not require renal dose adjustments..

  • Rifamycins may cause orange-reddish discoloration of body fluids, such as urine, effusions, and PD fluids.

  • Rifampin may cause various renal lesions, including acute tubular necrosis (ATN), acute tubulointerstitial nephritis (ATIN), light-chain proteinuria, and even rapidly progressive glomerulonephritis (RPGN). Intermittent use (e.g., noncompliant patient) is associated with ATN, with or without interstitial infiltrations, hemolysis, and thrombocytopenia. Continuous use is associated with light-chain proteinuria and RPGN.

  • Rifampin is a potent CYP3A4 inducer and can cause subtherapeutic concentrations and treatment failure of various drugs, including calcineurin inhibitors (CNIs) (cyclosporine [CsA], tacrolimus [Tac]), mammalian target of rapamycin (mTOR) inhibitors (sirolimus, everolimus), corticosteroids, and statins. Significant dose increase of affected drugs is generally required.


  • Ciprofloxacin, norfloxacin, and gatifloxacin are significantly cleared by the kidneys and must be dose reduced for GFR below 30 mL/min.

  • Moxifloxacin is only 20% renally excreted and does not require dose adjustment.

  • Quinolones may cause nonspecific CNS symptoms, including headaches, dizziness, restlessness, tremors, and kidney injury from interstitial nephritis, crystalluria.

  • Quinolones absorption is reduced with metal-containing compounds and phosphate binders.


  • There are concerns for toxic accumulation in patients with advanced CKD and potential for pulmonary and hepatic toxicity and peripheral neuropathy. The Food and Administration (FDA)-approved labeling states that the use of nitrofurantoin is contraindicated in patients with a CrCl less than 60 mL/min. Nonetheless, data are lacking to support this recommendation. Retrospective studies have shown that short-term nitrofurantoin use is effective and generally well tolerated in patients with a CrCl of 30 mL/min or more, although higher adverse events have been noted in patients with renal impairment. However, the use of nitrofurantoin in the treatment of urinary tract infection in patients with low GFR is not recommended because the drug cannot accumulate to reach bactericidal concentrations in the urine, thus increasing the chance of treatment failure.

Other antibiotics

  • Doxycycline, tigecycline, and standard-dose minocycline: No dose adjustment needed. For CrCl <80 mL/min, minocycline maximum dose is 200 mg/d.

  • Linezolid: No dose adjustment needed.

  • Linezolid and tetracyclines can lead to type B lactic acidosis. See Chapter 2.

  • Metronidazole: Only 15% of the parent drug is renally cleared. Reduce to twice-daily dosing in dialysis patients.

  • Macrolides:

    • Azithromycin, clarithromycin, roxithromycin (hepatically cleared): No dose adjustment needed.

    • Erythromycin (renally cleared): Dose reduction is required.



  • Kidney failure may occur after 2 weeks of therapy and is associated with the cumulative dose received. Lipid formulations can allow additional doses to be given by delaying the onset of nephrotoxicity.

  • Risks: older age, underlying CKD, hypovolemia, hypokalemia

  • Amphotericin may induce distal tubular injury, distal RTA, magnesium and potassium loss, nephrogenic diabetes insipidus, and arteriolar vasoconstriction (afferent greater than efferent arterioles).

  • Other noted adverse effects: anemia with or without thrombocytopenia presumably due to high inorganic content in liposomal formulations and, possibly, measurement interference/error

  • Liposomal or lipid-based formulations confer lower electrolyte disturbances and are preferred in patients with any degree of residual kidney function. Acute allergic reaction may be seen with lipid-based formulations. Pseudohyperphosphatemia may be seen with liposomal amphotericin (see Chapter 3).

  • Amphotericin is highly protein bound (˜90% to 95%) with a large Vd and is thus not well dialyzable. The large Vd is thought to be due to uptake by tissues.

  • Management of IV amphotericin B-induced nephrotoxicity:

    • Routine preventive measures: normal saline, use of lipid formulations of amphotericin B, reduce administration frequency if possible

    • Continuous infusion may be less nephrotoxic compared with infusions given over 4 hours.

    • Theoretical benefits of low-dose calcium channel blockers (e.g., diltiazem) to reduce renal vasoconstriction may be considered if safely tolerated.


  • With the exception of fluconazole, most agents (keto-, itra-, vori-, posa-, and isavuconazole) are metabolized by the liver and do not require dose reduction.

  • Fluconazole is significantly excreted in the urine and is preferred for the treatment of UTIs. After an adequate loading dose, maintenance dose should be reduced in in patients with reduced GFR.

  • Most azoles are potent inhibitors of CYP3A4 and P-glycoproteins that are involved in the metabolism and absorption of various drugs, including CNIs (CsA, Tac), mTOR inhibitors (sirolimus, everolimus), and statins. Significant dose reduction of the affected drug is generally required.

  • Itraconazoles, voriconazole, and posaconazole are mixed with cyclodextrin in IV formulations. Accumulation of cyclodextrin in renal patients can lead to increased serum creatinine and CNS toxicity (e.g., agitation, myoclonus, visual and auditory hallucinations, colored or flashing light). IV formulations should be avoided for GFR <50 mL/min).

  • Flucytosine is predominantly excreted in the urine and requires dose adjustment for patients with CKD. Flucytosine has a high rate of fungal resistance and is typically not used as a sole agent, but in combination with amphotericin for severe fungal infections.

Echinocandins (caspofungin, micafungin, anidulafungin)

  • Echinocandins are inhibitors of the synthesis of β-D-glucan, a fungal cell wall component. These agents are effective against Candida species and azole-resistant Aspergillus.

  • No dose adjustment is necessary in patients with kidney failure.

  • Unlike azoles, echinocandins typically do not affect CNI levels. However, caspofungin has been shown to reduce Tac levels.

Other antifungals

  • Terbinafine, an agent used to treat onychomycosis, is metabolized by CYP3A4, and 70% is renally excreted. Plasma clearance is reduced by 50% in patients with CrCl <50 mL/min. There are no safety data for terbinafine in CKD: 50% dose reduction is suggested in moderate-to-severe renal impairment.

  • Topical azoles, including clotrimazole, econazole, ketoconazole, miconazole, bifonazole, and tinidazole, are minimally absorbed and have no drug interaction.

  • Topical and oral nystatin is minimally absorbed. Their use in patients with renal impairment is safe.

  • Griseofulvin: No dose adjustment needed.

Antiviral Agents

Herpes simplex virus: famciclovir, acyclovir and its prodrug valacyclovir

  • Renally excreted and may crystallize in tubules, leading to obstructive uropathy and acute kidney injury (AKI), especially when given in high dose via rapid infusion. Slow IV administration (1 to 2 hours) and hydration is critical if given in high doses IV.

  • Associated with leukopenia, neurotoxicity

  • Dose reduction based on kidney function is necessary.

  • Approximately 60% dialyzable.

Cytomegalovirus: Ganciclovir and its prodrug valganciclovir

  • Renally excreted, accumulation may lead to severe bone marrow toxicity.

  • Dose reduction based on GFR is necessary.

  • Highly dialyzable

Antiretroviral Agents (Table 10.1)

Drug classes that do not generally require dose reduction

  • Integrase inhibitors (raltegravir, elvitegravir, dolutegravir)

  • Fusion inhibitors (enfuvirtide)—Enfuvirtide may be associated with membranoproliferative glomerulonephropathy (MPGN).

  • CCR5 antagonists (maraviroc)

    • Dose adjustment not required for mild-to-moderate CKD.

    • For CrCl < 30 mL/min or dialysis dependent: Avoid

  • Protease inhibitors (atazanavir, darunavir, indinavir, nelfinavir, ritonavir, saquinavir, and tipranavir)

  • Non-nucleoside (or nucleotide) reverse transcriptase inhibitors (NRTIs) (delavirdine, efavirenz, etravirine, nevirapine)

Table 10.1 HIV drugs and the kidney

Mechanism of Action

Common Drugs

Dose Adjustments

Renal Effects

Nucleoside reverse transcriptase inhibitors (NRTIs)

NRTI incorporates itself into the DNA during reverse transcription of the viral genome and effectively terminates DNA polymerization.

Abacavir (ABC)

Didanosine (ddI)

Emtricitabine (FTC)

Lamivudine (3TC)

Tenofovir (TDF)

Zidovudine (AZT, ZDV)


Fanconi syndrome has been reported with the use of ABC, ddI, 3TC, and both formulations of tenofovir (tenofovir disoproxil fumarate [TDF] and tenofovir alafenamide).

Nephrogenic DI may occur with ABC, ddI, TDF.

Type B lactic acidosis may occur with all NRTIs.

Non-nucleoside reverse transcriptase inhibitors (NNRTIs)

NNRTIs are small hydrophobic chemical compounds that bind to a pocket near the active site of HIV reverse transcriptase, thereby reducing its ability to optimally catalyze DNA polymerization.

Efavirenz (EFV)

Etravirine (ETR)

Nevirapine (NVP)

Rilpivirine (RPV)


Protease inhibitors (PIs)

PIs bind to and inhibit the HIV aspartyl protease, an enzyme involved in the processing of viral proteins. This inhibits viral maturation, thus formation of a functional virion.

Atazanavir (ATV)

Darunavir (DRV)

Lopinavir (LPV)

Ritonavir (RTV)

Indinavir (IDV)

Saquinavir (SQV)


SQV use is not recommended in severe CKD.

PIs may crystallize in renal tubules and cause urolithiasis.

IDV has been largely replaced by ATV and DRV.

SQV is also associated with hypocalcemia and lactic acidosis.

Integrase inhibitors

Integrase inhibitors block the integration of HIV DNA into human DNA by the HIV integrase enzyme.

Raltegravir (RAL)

Elvitegravir (EVG)

Dolutegravir (DTG)


Elvitegravir is metabolized by CYP3A4 and may have potential CNI and drug-drug interaction. Dolutegravir may increase SCr via inhibition of renal tubular secretion of creatinine.

Fusion inhibitor

Fusion inhibitors inhibit the fusion of the HIV envelope with human cell membranes.

Enfuvirtide (ENF, T-20)


Enfuvirtide may be associated with MPGN.

CCR5 inhibitor

CCR5 inhibitor binds to the external portion of the transmembrane receptor CCR5 that serves as the coreceptor for virus entry.

Maraviroc (MVC)


Avoid use in patients requiring dialysis or with CrCl <30 mL/min

Pharmacokinetic (PK) enhancer

PK enhancers are inhibitors of cytochrome P450 (CYP) 3A enzymes that act as a drug level booster for the protease inhibitors atazanavir and darunavir.

Cobicistat (COBI)


Cobicistat is a strong CYP3A4 inhibitor. Dose reduction is generally required for CNI, mTOR inhibitors, and statins when used with COBI.

Cobicistat may increase SCr via inhibition of renal tubular secretion of creatinine.

Abbreviations: CKD, chronic kidney disease; CNI, calcineurin inhibitor; CrCl, creatinine clearance; MPGN, membranoproliferative glomerulonephropathy; SCr, serum creatinine.

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Jul 21, 2021 | Posted by in NEPHROLOGY | Comments Off on Pharmacology

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