Another factor to consider is that the circulating concentration of α1-acid glycoprotein may increase in patients maintained with renal transplant or hemodialysis. The effect may be a decrease in the unbound circulating fraction and diminished biological activity of the drug.
The metabolism or degradation of a medication is probably the area of pharmacokinetics that is least familiar, particularly because the intermediate products of metabolism are difficult to isolate and identify. The rate of renal metabolism by the renal brush border is predicted to decrease as the glomerular filtration rate (GFR) declines. In addition, evidence suggests that metabolism by the liver is variably altered in ESRD. Both the expression and function of cytochrome P-450 (CYP) 2C9 and CYP3A4 are decreased in severe ESRD.5 Although the literature is sometimes contradictory, it appears that in renal failure there is a general slowing of chemical reduction and hydrolysis, but there are normal rates of glucuronidation, microsomal oxidation, and sulfate conjugation.
Excretion takes place through the GI tract and from the kidney to the bladder, and this latter avenue is obviously absent following renal failure. Glomerular filtration, active tubular secretion, and passive tubular reabsorption are the 3 distinct mechanisms of excretion by the kidney, and all of them are affected in ESRD. The artificial substitution by a dialysis machine results in intermittent excretion rather than the continual process performed by healthy kidneys. Drugs are only occasionally metabolized to pharmacologically active compounds that are then normally excreted in urine. Fortunately, most psychotropic medications are metabolized by the liver, eliminated in bile, and excreted in feces.
Prescribing medications for adults
There is a paucity of data documenting the efficacy and pharmacokinetics of psychotropic agents in patients with renal impairment.6,7 Most research is based on a handful of subjects, and well-controlled trials in psychopharmacology are rare. There are very few in vivo studies of pharmacokinetics in persons without kidney disease or patients with ESRD. Accordingly, in the absence of empirical data, clinical experience suggests that the majority of psychotropic medications can be safely used in the ESRD population. Some important considerations and exceptions are noted below.
Most psychotropic medications are fat-soluble and have large volumes of distribution. They are metabolized in the liver and metabo-lites are eliminated in urine and bile. Most of these drugs easily pass the blood-brain barrier, and they are not dialyzable. Attention needs to be paid to medications that have active metabolites—those that are highly plasma protein–bound, and those that have altered pharmacokinetics or pharmacodynamics.8
Lithium is the only known psychotropic medication in which long-term use is associated with nephrotoxicity, renal insufficiency, and even ESRD. Although renal function will often improve if the drug is stopped, some patients require maintenance dialysis or kidney transplant. Attempts should be made to transition to the classic anticonvulsant medications divalproex and carbamazepine(Drug information on carbamazepine), but they may be inadequate mood stabilizers.
For the minority of bipolar patients with ESRD who continue to require lithium(Drug information on lithium), treatment involves administration of a single dose (usually 600 mg) after each dialysis session. Because lithium is a readily dialyzable, small molecule, it is entirely eliminated by dialysis, and a single post-dialysis dose will result in a steady serum level. Serum lithium levels should be measured immediately before dialysis. If lithium is used to augment the therapeutic effects of antidepressants in treatment-resistant unipolar depression, a smaller dose (eg, 300 mg) may be given after dialysis sessions.