Psychiatrists are often asked to medicate patients with chronic kidney disease (CKD). Currently, there are 350,000 Americans who receive maintenance dialysis for renal failure, and this predominantly elderly population with multiple comorbidities is growing. In selecting psychotropic medications, psychiatrists need to be aware of the effects of renal dysfunction on medication absorption (ie, bioavailability), volume of distribution, metabolism, and excretion of the parent drug and the respective metabolites.
A few psychotropic medications, such as lithium, are primarily excreted by the kidneys, whereas most others are fat-soluble and are metabolized by the liver. Although the Physicians’ Desk Reference routinely recommends the use of partial dosages of psychotropic medications for renal patients, the data that support these recommendations are limited. There are even fewer empirical data available about psychotropic medication use for children. Thus, the clinician will find it necessary to engage in medication trials that are influenced by individual patient tolerability, response, and changes in clinical status.
In 2005, more than 106,000 patients with newly diagnosed end-stage renal disease (ESRD) began dialysis therapy, joining a dialysis population of 341,000 people and a transplant population of 144,000.1 Kidney disease involves people of all ages, including children, but most individuals fall into the adult and geriatric categories.
As shown in Table 1, the National Kidney Foundation Kidney Disease Outcomes Quality Initiative has divided chronic kidney disease into 5 stages. This article emphasizes the management of persons who fall into stages 4 and 5, in which renal function is greatly compromised, necessitating renal replacement therapy. In the nephrology literature, they have traditionally been labeled as having ESRD (the stages of CKD are a more recent taxonomy)—the term we will use throughout this article.
Although the psychiatric epidemiological literature has glaring limitations, clinicians need to familiarize themselves with the prevalence and hazards posed by psychiatric disorders in renal patients.2 For example, precisely quantifying the rate of depression in dialysis patients is limited by heterogeneity in study design, assessment procedures, and sample composition. Reported rates of depression have ranged from 0% to 100%. This variation underscores the need for a more refined and systematic approach to evaluating depression in renal patients. Furthermore, medication-related problems are extraordinarily frequent and were identified in 98% of a sample of 133 hemodialysis patients.3 In this study, patients had a mean of 6 ± 2.3 comorbid illnesses; 11 ± 4.2 different drugs were prescribed per patient, and a total of 475 medication-related problems were detected.
Patients with renal failure may evince alterations in any pharmacokinetic parameter—absorption, volume of distribution, metabolism, or excretion (Table 2).4 Consequently, medication-related problems are frequent occurrences. Two other factors may be of equal or even greater importance, and both influence pharmacokinetics: Many ESRD patients are elderly, and the prevalence of associated severe comorbid disorders (eg, diabetes, hypertension) is high.
Bioavailability is the extent to which a dose of drug enters the systemic circulation. An oral dose is first absorbed from the GI tract; it subsequently passes through the liver, where metabolism and biliary excretion may occur. A decrease in bioavailability for some agents occurs at the level of drug absorption from the GI tract. Alterations in gastric alkalinity (caused by excessive urea generation by the internal urea-ammonia cycle) result in alterations in gastric pH that affect the absorption of psychotropic drugs.
What is already known about psychiatric treatment for patients with renal failure?
? Clinical research and pharmacokinetic data about the psychiatric management of patients with renal failure are lacking. However, experience suggests that in this patient population, competent care may be delivered when the unique physiological, pharmacokinetic, dynamic, and risk/benefit factors are considered.
What new information does this article provide?
? This article reviews the indications and dosing considerations for the most commonly used psychotropic medications. Clinical pearls and practical tips are offered to provide guidance and to assist clinicians as they initiate medication interventions for renal patients with comorbid psychiatric disorders.
What are the implications for psychiatric practice?
? Patients with chronic renal disease may receive timely and effective psychiatric care for their debilitating conditions with psychiatric consultation and the judicious use of psychoactive medications.
Rival mechanisms that affect absorption in patients with renal failure include nausea and vomiting as well as delayed gastric emptying (from diabetic gastroparesis). Diabetes mellitus is a common cause of ESRD and is an important factor to consider when prescribing because of the relationship between atypical neuroleptics and increased serum glucose levels.
Volume of distribution entails the effects of dilution or concentration of medications in the body. The 2 overarching factors that influence distribution are the volume of distribution and protein binding. It is not uncommon in ESRD for elderly patients to become cachectic. These patients have less fluid and less body mass and a decreased volume of distribution. Consequently, a given dose results in a greater concentration of medication in a cachectic patient than in a non-cachectic patient.
The issue of protein binding is especially significant in ESRD. The principle plasma protein responsible for binding to acidic drugs is albumin, while for alkaline drugs, it is α1-acid glycoprotein.3 Proteinuria and hypoalbuminemia are frequently found in renal failure, and there is an accumulation of endogenous binding inhibitors (eg, organic acids, uremic toxins). Binding inhibitors compete with drugs for the carrier protein binding site, and albumin undergoes conformational changes with hypothesized changes in binding properties. The results are diminished protein binding and an increase in the bioactive free fraction of acidic drugs in plasma. All other factors remaining constant, the greater the protein binding of a medication, the lower the dose of the drug required in ESRD, since there is a greater risk of toxicity when increased amounts of the free, unbound forms of acidic drugs are in the plasma.
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