I read with interest the article on safe drug prescribing for patients with renal insufficiency.1 The authors have succinctly summarized various medications that require adjustment in dosage in renal failure and others that do not require such adjustments, but I take issue with certain recommendations in Table 4 of the paper.
First, the authors describe morphine as a medication not requiring dosage adjustment in renal failure unless given in a palliative care setting. Although morphine is rapidly metabolized by the liver, it is excreted mainly in the urine as its active metabolites, morphine-3-glucuronide (M-3G) and morphine-6-glucuronide (M-6G). Both M-3G and M-6G readily cross the blood–brain barrier and bind with strong affinity to opiate receptors, exerting strong analgesic effects. In patients with renal failure or in the elderly, the ratios of M-3G and M-6G to morphine increase, making opioid toxicity, prolonged narcosis and respiratory depression more likely.2,3 Morphine dosage must therefore be carefully controlled and adjusted in patients with renal failure.
The authors also state that angiotensin-converting enzyme (ACE) inhibitors require dosage adjustment in renal failure whereas angiotensin receptor blockers (ARBs) do not. Although these generalizations are mostly accurate, subtle pharmacokinetic differences in some agents may make them exceptions to the rule. For example, although most ACE inhibitors require dosage adjustment because they are exclusively eliminated through the kidney, fosinopril has both a renal and hepatobiliary route of elimination and thus may not require dosage adjustment in chronic renal insufficiency.4 Similarly, most ARBs do not require dosage adjustment in renal failure because of their hepatobiliary route of elimination, but 60% of candesartan cilexetil is mainly excreted in the urine as candesartan. In patients with renal insufficiency it may be prudent to employ lower starting doses of this medication.5
Malvinder S. Parmar Internal Medicine and Nephrology Timmins and District Hospital Timmins, Ont.
References
- 1.Kappel J, Calissi P. Nephrology: 3. Safe drug prescribing for patients with renal insufficiency. CMAJ 2002;166(4):473-7. [PMC free article] [PubMed]
- 2.Osborne R, Joel S, Grebenik K, Trew D, Slevin M. The pharmacokinetics of morphine and morphine glucuronides in kidney failure. Clin Pharmacol Ther 1993;54(2):158-67. [DOI] [PubMed]
- 3.D'Honneur G, Gilton A, Sandouk P, Scherrmann JM, Duvaldestin P. Plasma and cerebrospinal fluid concentrations of morphine and morphine glucuronides after oral morphine. The influence of renal failure. Anesthesiology 1994;81 (1): 87-93. [DOI] [PubMed]
- 4.Hui KK, Duchin KL, Kripalani K, et al. Pharmacokinetics of fosinopril in patients with various degrees of renal function. Clin Pharmacol Ther 1991;49:457-67. [DOI] [PubMed]
- 5.de Zeeuw D, Remuzzi G, Kirch W. Pharmacokinetics of candesartan cilexetil in patients with renal or hepatic impairment. J Hum Hypertens 1997; 11(2 Suppl):37S-42S. [PubMed]