1. How can chronic kidney disease (CKD) alter the pharmacokinetic behavior of most drugs?
CKD directly and indirectly affects the pharmacokinetic properties of most drugs. Alterations of drug pharmacokinetics in patients with kidney failure are based on changes in absorption, distribution, metabolism, and elimination.
2. How can changes in absorption resulting from CKD alter the pharmacokinetic behavior of drugs?
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Alkaline saliva. As CKD progresses, saliva becomes more alkaline. This compromises absorption of drugs that need an acid milieu (e.g., iron supplements) and contributes to a higher gastric pH.
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Nausea and vomiting may reduce drug ingestion and absorption.
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Volume overload states: Edema of the gastrointestinal tract limits absorption.
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Drug interactions: Many drugs used in the management of CKD limit drug absorption by forming nonabsorbable complexes (e.g., iron, phosphate-binding agents).
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Gastrointestinal neuropathy: Uremia may delay gastric emptying time, particularly in patients with diabetes.
3. How can changes in distribution from CKD alter the pharmacokinetic behavior of drugs?
The volume of distribution (V D ) represents the ratio of administered dose to the resulting plasma drug concentration. The calculated V D is a theoretic representation of the size of the anatomic space occupied by the drug if it were present throughout the body in the same concentration as that in the plasma. Drugs with a large V D , such as digoxin, are distributed widely throughout the tissues and are present in relatively small amounts in the blood. In patients with CKD, changes in drug distribution may arise from either fluid retention or reductions in the extent of protein binding in tissue and plasma. CKD has very limited effects on drugs with large volume distribution. Conversely, drugs that are less lipid soluble and highly protein bound will tend to have a lower V D because they are more restricted to the vascular compartment. Kidney impairment and hemodialysis has a significant effect on drugs with small V D . For example, in critically ill patients with CKD, for a drug like vancomycin with a small V D , higher than recommended loading and daily doses are needed to rapidly achieve therapeutic serum concentrations.
Malnutrition and proteinuria reduce the amount of protein available for protein binding, and uremic stage may alter the affinity of many drugs to albumin. Thus the concentration of free drug will increase in these settings, which can result in increased free fraction and potential adverse drug reactions. Therapeutic drug monitoring (TDM) for free or unbound drug concentrations in patients with kidney insufficiency or heavy proteinuria (e.g., free phenytoin levels) is an important consideration.
4. How can changes in metabolism as a result of CKD alter the pharmacokinetic behavior of drugs?
Even drugs without or with only minimal kidney elimination can have altered pharmacokinetics in advanced CKD. CKD may increase, decrease, or have no effect on nonkidney clearance. Some drugs are metabolized to active metabolites that are insignificant with normal kidney function but accumulate in CKD. For example, morphine metabolizes to 6- and 3-morphine-gluconate with respiratory depression and seizure properties. In CKD the clearance of the parent compound (morphine) is not significantly affected; however, morphine metabolizes to 6- and 3-morphine-gluconate, which accumulate and place patients at risk for serious adverse drug reactions. Therefore it is recommended that morphine be used cautiously in patients with CKD or avoided completely if high doses or a prolonged use is indicated.
5. How can changes in elimination as a result of CKD alter the pharmacokinetic behavior of drugs?
A reduction in the glomerular filtration rate (GFR) will generally lead to an increased half-life of a drug that is eliminated primarily by the kidney. Clearance is a measure of the efficiency of the kidney at excreting a specific compound. The clearance of a drug is the amount of plasma from which the drug is completely removed from over unit time. For example, a furosemide clearance of 20 mL/min means that every minute enough furosemide is excreted in the urine to completely clear out all of the furosemide from 20 mL of plasma.
6. What characteristics determine whether a drug is removed by dialysis?
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Molecular weight. As a general rule, smaller molecular weight substances pass through the dialyzer membrane much more easily than larger weight molecules. In general, free drug molecules with a molecular weight of less than 500 Daltons (D) are removed efficiently by hemodialysis.
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Protein binding. Decreased protein binding may increase the amount of free drug available for removal during dialysis. In the setting of an overdose, the amount of ingested drug may exceed the normal protein-binding capacity. This would allow removal of the excess drug by hemodialysis, even though dialysis has a minimal effect when the drug is used at normal doses.
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V D . Drugs with large volumes of distribution are not removed effectively by dialysis. Lipid-soluble drugs usually have large volumes of distribution, making significant removal of the drug difficult because the plasma volume is rapidly replenished from other tissues (e.g., cyclosporine and digoxin).
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Water solubility. Drugs with high water solubility will be dialyzed to a greater extent than those with high lipid solubility.
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Dialyzer membrane. The pore size, surface area, and geometry are the primary factors in determining whether a dialysis membrane will clear a specific drug. Historically, standard dialysis membranes did not effectively remove vancomycin (molecular weight, 3300 D) given its size. Currently, high-flux membranes that remove larger-molecular-weight molecules have become standard of care in dialysis practice. Therefore vancomycin and many other antibiotics are removed by these membranes. Dosing of these medications should be held until after dialysis on those days.
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Blood and dialysate flow rates. Increased flow rates during hemodialysis will increase drug clearance. Patients who cannot tolerate standard blood flow rates will require less replacement dosing of a drug after hemodialysis.
7. How is kidney function assessed for drug dosing determination?
The best way is to estimate the GFR. The gold standard is measurement of the clearance of inulin; however, this is cumbersome and impractical for clinical use. Measurement of the 24-hour creatinine clearance (CrCl) is no longer recommended for similar reasoning. This has led to the development of equations to estimate GFR such as the Cockcroft-Gault (CG) and Modification of Diet in Renal Disease (MDRD) study. These equations use serum creatinine as one of the variables and both generally provide similar dosing recommendations. Adverse events such as drug accumulations are relatively uncommon when the GFR remains >50 mL/min.
It is still important to consider potential analytic interferences in these calculations based on the concurrent drug therapy. Some drugs may artifactually increase or decrease the measured serum creatinine concentration without directly influencing GFR. Drugs that inhibit the tubular secretion of creatinine will raise the serum level (e.g., trimethoprim, cimetidine, and probenecid).
8. What the best method to estimate kidney function for drug dosing in CKD?
Most approved drugs advice to use CG method by the way to estimated kidney function for medication dosage adjustment in patients with kidney disease. Recently, it has been questioned that other methods of estimating kidney function perhaps are more accurate than CG method for estimating kidney function. It is important to remember that CG formula, MDRD, and Chronic Kidney Disease-Epidemiology (CKD-EPI) Collaboration equation are only an “estimation” and “approximation” of kidney function. Neither of these methods provides accurate “measurement” or “calculation” of kidney function. In addition, there are many other changes in the kidney that might affect drug handling than just filtration rate such tubular function and organic acid accumulations. Health care providers should also consider drug safety and efficacy for dosage adjustment. In general, a number of recent studies comparing the equations for their influence on drug dosage adjustment have shown that the MDRD perhaps is a better method with a greater concordance with measured GFR compared with other methods.
9. What commonly prescribed drugs cause hyperkalemia in patients with CKD and receiving dialysis?
Many drugs used as therapy for CKD and associated conditions, such as heart failure and hypertension, can cause or worse hyperkalemia. Often, it is combinations of these medications that lead to hyperkalemia. Potassium (K+) supplements are used frequently in combination with diuretic therapy. K+-sparing diuretics (spironolactone, amiloride) inhibit kidney elimination of K+. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) are common causes via alterations in the renin-angiotensin-aldosterone system (RAAS). Digoxin inhibits the basolateral Na-K ATPase in cardiac myocytes. Because of a narrow therapeutic window, overdose states are not uncommon and can result in elevated K+. Acute and/or chronic reductions in GFR in association with the previously mentioned medications can tip a patient into hyperkalemia by compromising K+ excretion by the kidneys. Nonsteroidal antiinflammatory drugs (NSAIDs) and beta blockers also impair kidney K+ excretion mainly through inhibition of RASS system leading to hyperkalemia. Digoxin inhibits the basolateral Na-K ATPase in cardiac myocytes. Penicillin infusion solutions contain a high amount of K+ for drug stability.
Calcineurin inhibitors (CNIs) such as tacrolimus or cyclosporine are the backbone of immunosuppression in kidney transplant and are additionally used in the treatment of some glomerulonephritis. Both of these are associated with various electrolyte abnormalities including hyperkalemia.
10. Which antimicrobials should be avoided prior to hemodialysis on scheduled dialysis days?
Many antibacterial agents are water-soluble, small molecules, and not highly protein bound; thus they are well dialyzed and will require supplementation post-dialysis. Many of these agents are already administered in a reduced dose or frequency given the reduced kidney clearance. Beta-Lactam agents such as penicillins, cephalosporins, carbapenems, and monobactams are examples of such compounds. Aminoglycosides also exhibit similar properties. Carbapenem and imipenem can lower the seizure threshold and should be avoided altogether in patients receiving dialysis; meropenem in a reduced dose is a therapeutic alternative. Antifungals such as fluconazole may require supplemental dosing; however, the echinocandins (caspofungin, micafungin) and the amphotericin family do not. Antiviral agents should receive individual consideration given their varying properties. Entecavir and telbivudine appear to be removed by hemodialysis, whereas lamivudine does not.
11. When is re-dosing or a supplemental dose required following hemodialysis?
Dialysis clearance must increase total clearance by at least 30% to be considered clinically significant and to require a replacement dose after hemodialysis. The physicochemical characteristics as discussed previously determine the extent that a drug may be affected by dialysis.
12. How does kidney failure effect drug metabolism?
Although the kidney is largely thought to be responsible for drug elimination, the kidney plays an important role in drug metabolism, thus contributing to need for dose adjustments. Current drug dosing guidelines are based on CKD, but both CKD and acute kidney injury (AKI) have been associated with decreased metabolism, specifically via cytochrome P450 (CYP) enzymes. The proposed mechanism is through increased circulating levels of urea, PTH, and cytokines, all of which are thought to downregulate both hepatic and intestinal CYP activity. In addition, individuals in kidney failure have been noted to have decreased drug transport (organic anion transporters and P-glycoprotein) capacity, further decreasing metabolism. Although the exact mechanism is not fully understood, improvement in drug metabolism has been noted in patients on dialysis.
13. How should aminoglycosides be adjusted for hemodialysis?
First, the patient’s dosing weight should be determined. Use ideal body weight (IBW) unless total body weight (TBW) is less.
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Nonobese is: TBW < 130% of IBW
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IBW (males) = 50 kg + (2.3 × height in inches >60 inches)
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IBW (females) = 45 kg + (2.3 × height in inches >60 inches)
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In patients who are obese, adjust IBW: ABW (kg) = IBW + 0.4 (TBW − IBW), where ABW is actual body weight.
Second, select the appropriate loading and maintenance doses:
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Loading dose should be considered in life-threatening infection (for gentamicin and tobramycin, give 2.5 mg/kg; for amikacin give 7.5 mg/kg as a loading dose).
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Select appropriate maintenance dose according to indications ( Table 25.1 ).
Table 25.1.
Aminoglycoside Dosing in Patients Undergoing Dialysis
Dose and Frequency in Patients Undergoing Dialysis
DRUG
HEMODIALYSIS (DOSE POSTDIALYSIS)
PERITONEAL DIALYSIS (EVERY 48 H)*
CONTINUOUS RENAL REPLACEMENT THERAPY (EVERY 24 H)
Gentamicin
Serious infection
Urinary tract infection
Synergy
1.5–2 mg/kg
1 mg/kg
1 mg/kg
1.5–2 mg/kg
1 mg/kg
1 mg/kg
1.5–2 mg/kg
1 mg/kg
1 mg/kg
Tobramycin
Urinary tract infection
1.5–2 mg/kg
1 mg/kg
1.5–2 mg/kg
1 mg/kg
1.5–2 mg/kg
1 mg/kg
Amikacin
7.5 mg/kg
7.5 mg/kg
7.5 mg/kg
14. What adjustments should be made for administering vancomycin to patients receiving hemodialysis?
It is important to load patients receiving dialysis with 15 to 20 mg/kg based on ABW. Maintenance doses will depend on the dialysis membrane used during hemodialysis ( Table 25.2 ).
| HEMODIALYSIS (HD) (HIGH FLUX) | CONTINUOUS VENOVENOUS HEMOFILTRATION (HD, HEMODIAFILTRATION) | PERITONEAL | |
|---|---|---|---|
| Loading dose | 15–20 mg/kg dose based on actual body weight (ABW) Note: Not to exceed 1500 mg May consider 20 mg/kg in severe infections (i.e., meningitis, severe sepsis, endocarditis, osteomyelitis, and hospital-acquired pneumonia [HAP]) | 15–20 mg/kg dose based on ABW Note: Not to exceed 1500 mg May consider 20 mg/kg in severe infections (i.e., meningitis, severe sepsis, endocarditis, osteomyelitis, HAP) | Not necessary |
| Maintenance dose (postdialysis) | <75 kg: 500 mg after HD for predialysis level <20 >75 kg: 1000 mg after HD for predialysis level <20 | 10–15 mg/kg every 24 h Note: May consider higher doses in patients who are obese not to exceed 1500 mg Intravenous (IV) q24h | IP (intraperitoneal): 30 mg/kg loading dose 15 mg/kg every 3–5 days Note: Patients that are not anuric may need to adjust dosing frequency because there is residual kidney function IV: 15–20 mg/kg per dose |
| Serum level monitoring | Draw serum level prior to the second HD session, then get random levels with am labs on HD days only (or q48 h) Note: Subsequent serum levels should be drawn prior to every or every other HD session | Draw serum level prior to the second or third dose (approximately 24 h after last dose) Note: May draw random daily levels with am labs | IP: Draw serum trough level 72 h after loading dose IV: Draw serum trough level 48–72 h after initial dose |
| Dosing based on serum levels | If pre-HD level is: >20: hold dose 10–20: give dose after HD (based on weight) <10: administer another loading dose after HD | If serum level is: >20: hold dose 10–20: continue with q24h dosing <10: 15–20 mg/kg loading dose → consider more frequent dosing or increasing the dose | If level is: >20: hold dose <20: administer another dose |
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