Principles of Drug Usage in Dialysis Patients

Introduction

The evolution of the field of dialysis and the advances in surgical procedures and access placement have made it possible to treat patients with end-stage kidney disease (ESKD) with dialysis therapy for more than 60 years. Improvements in pharmacotherapy management prior to and after dialysis initiation have contributed to these remarkable advancements. However, uremia may directly or indirectly affect different aspects of drug pharmacokinetics or pharmacodynamics. Most pharmacotherapeutic agents or their active/inactive metabolites are completely or partially eliminated by the kidneys.

The movement of drugs through different body compartments is known as pharmacokinetics, which defines drug absorption and bioavailability, tissue distribution, metabolism, and elimination. Patients with chronic kidney disease (CKD) have altered pharmacokinetic properties in addition to having a number of clinical comorbidities, which require close monitoring to avoid adverse drug reactions while correcting or preventing complications of these comorbid conditions. In patients with CKD, many aspects of pharmacokinetics, in particular drug elimination, are significantly different from those of patients with normal kidney function. For drugs that are excreted unchanged through the kidney, the dosage should be adjusted to avoid toxicities ( Table 58.1 ). In addition, uremia may alter extra-kidney drug metabolism. Depending on various factors (e.g., the size of the drug molecule and degree of protein binding), a significant amount of drug removal may occur during dialysis. To prevent toxicity and optimize efficacy, it is critical that these factors be taken into account and appropriate dosage adjustments made when prescribing drugs for dialysis patients. Finally, many pharmacotherapeutic and diagnostic agents, such as antimicrobial and iodinated contrast that are known nephrotoxins, make kidneys susceptible to future acute kidney injuries and consequently CKD. Discounting the intrinsic nephrotoxicity of these agents may predispose patients with early stages of kidney disease to develop late-stage CKD and eventually require dialysis. A number of studies have indicated that patients with CKD are prescribed drugs almost four times more than those without kidney disease. Additionally, exposure to potential nephrotoxins is significantly higher in this population.

This chapter discusses pharmacologic principles for prescribing drugs in CKD and provides a number of measures to reduce iatrogenic morbidities from drug dosing in this population. In addition, this chapter provides specific dosage recommendations for commonly used pharmacotherapeutic agents at different stages of kidney impairment for patients with CKD.

Pharmacologic Principles and Alterations in Uremia

Dosage modification in dialysis patients must take into account the effects of the uremic milieu on a variety of pharmacokinetic parameters, such as drug absorption, volume of distribution, protein binding, and drug metabolism. Bioavailability is defined as the percentage of administrated dose that reaches the systemic circulation. Drug bioavailability may be impaired because of delayed gastric emptying or edema of the gastrointestinal (GI) tract, particularly in diabetic patients with gastroparesis. Medications commonly prescribed in dialysis patients may alter drug bioavailability. For example, furosemide is used commonly in CKD patients, but bioavailability is reduced to less than 20% in this population. Gastric pH is frequently high because of the use of antacids or H ₂ blockers, which may result in decreased absorption of medications requiring an acid milieu. Aluminum- or calcium-containing phosphate-binding antacids may form nonabsorbable chelation products with certain drugs, such as digoxin or tetracycline, with impairment of their absorption. Many oral antibiotics, such as fluoroquinolones, have decreased absorption when given in combination with multivalent metal cations such as iron or calcium carbonate/phosphate binders leading to therapeutic failure and requiring hospitalization in some patients.

After drug absorption and equilibration, individual drugs distribute throughout the body in a characteristic manner. The apparent volume of distribution (V _d ) is the quantity of drug in the body (L/kg body weight) divided by the plasma concentration at equilibrium. The scientific model of this relationship is the following equation:

V _d represents that amount of volume (in liters) in which the drug must have been dissolved to render the observed plasma concentration. Drug distribution is complex and can be influenced by protein binding, pKa, pH, tissue perfusion, and lipophilicity. Drugs that are highly tissue bound or lipid soluble usually have a large V _d , while drugs that are highly bound to circulating proteins are largely confined to the vascular space and therefore usually have a V _d of less than 0.2 L/kg. In a variety of disease states, including uremia and proteinuria, other drugs may alter the V _d of therapeutic agents. From a practical standpoint, the changes in V _d are usually not clinically significant except for those drugs that have a small V _d (< 0.7 L/kg) and are not highly protein bound under normal circumstances.

The degree of drug-protein binding is altered in uremic patients with potentially important pharmacologic consequences. The unbound or free drug is pharmacologically active and available for pharmacologic effects. Decreased binding of various drugs has been demonstrated in patients with kidney impairment. As a result, for any given drug level (bound plus unbound), the proportion of free or active drug is increased. The increased free drug concentrations may lead to an increased risk of drug toxicity. For example, patients with CKD and significant proteinuria are at a greater risk of phenytoin and procainamide toxicity. Although the plasma concentrations of these agents could be low, the elevated free fraction confers a risk of serious toxicity. Close follow-up and more frequent monitoring of serum concentrations are required to optimize clinical outcomes. For most drugs, because both drug elimination and pharmacologic activity are increased for any given dose, the clinical consequences are difficult to predict. Prescribing medications in patients with CKD requires a sophisticated understanding of the pharmacokinetic parameters of each agent.

When a medication reaches the systemic circulation, it is metabolized by the smooth endoplasmic reticulum in the liver, GI tract, and other tissues. Drug metabolism is a complex set of sequences that involves many organs and pathways in the body. The metabolism of a drug by the liver before entering the systemic circulation is known as first-pass metabolism . With first-pass metabolism, a drug is absorbed into the intestines and enters the portal vein before it reaches the liver for metabolism. After it is metabolized by the liver, the drug then enters the systemic circulation, where it produces an effect on the body. Generally, first-pass metabolism reduces the bioavailability of a given drug, thus decreasing the plasma concentration. In patients with CKD, the addition of phosphate binders, calcium, and iron may interfere with first-pass metabolism and reduce the drug exposure significantly.

In phase 1 metabolism, the oxidase class of enzymes is involved with drug metabolism. This oxidase group is more commonly known as CYP 450 enzymes. Oxidation metabolism leads to increased water solubility of most drugs. For all of this to occur, active CYP 450 enzymes are required. The most common CYP 450 enzyme is CYP 3A4, which metabolizes 50% of all drugs. With CYP 2D6, polymorphisms can affect the rate of drug metabolism. Uremia and kidney disease might affect expression of many of these enzymatic pathways.

With phase II metabolism, the enzymes involved with metabolism are transferases. The enzymes help transfer polar molecules to a drug to make them more soluble. Examples of these enzymes include glucuronate, glutathione, and nitration and sulfonation electrophilic aromatic substitution. The product of this reaction is known as a conjugate , thus the term “the conjugation reaction.” One of the most well-known medications that use phase II metabolism is acetaminophen. The most common process for phase II metabolism is glucuronidation conjugation.

The kidneys are the most common route of drug excretion. The drug removal rate is typically expressed as elimination half-life (t _½ ), the time required for the plasma concentration to decrease by 50%. The half-life is dependent on V _d and clearance (kidney, hepatic, or other) as expressed by the following formula:

As the kidney clearance decreases, t _½ will increase (assuming that V _d is unchanged). It should be noted that active drug metabolites may also be excreted by the kidney and therefore have a prolonged half-life in kidney failure.