Drug Dosing Regimens

May 29, 2007 — A review published in the May 15 issue of American Family Physician provides various drug dosing regimens and principles for appropriately treating patients with chronic kidney disease.

"Chronic kidney disease affects renal drug elimination and other pharmacokinetic processes involved in drug disposition (e.g., absorption, drug distribution, nonrenal clearance [metabolism])," write Myrna Y. Munar, PharmD, BCPS, and Harleen Singh, PharmD, from the Oregon State University College of Pharmacy in Portland. "Physicians should be familiar with commonly used medications that require dosage adjustments. Resources are available to assist in dosing decisions for patients with chronic kidney disease."

The review notes that drug dosing errors are common in patients with renal impairment, sometimes causing adverse effects and poor outcomes. To avoid these errors, dosages of drugs cleared renally should be adjusted based on creatinine clearance or glomerular filtration rate (GFR) and should be calculated with online or electronic calculators.

For maintenance dosing adjustments, recommended methods are dose reductions, less frequent dosing interval, or both. Loading doses usually do not need to be adjusted in patients with chronic kidney disease.

The National Kidney Foundation's Kidney Disease Outcomes Quality Initiative (K/DOQI) defines chronic kidney disease as the presence of kidney damage or a reduction in the GFR for 3 or more months.

Based on GFR, the K/DOQI classifies chronic kidney disease as stage 1 (kidney damage with normal or increased GFR of 90 mL/minute per 1.73 m ² or greater), stage 2 (kidney damage with a mild decrease in GFR [60 - 89 mL/minute per 1.73 m ²]), stage 3 (moderate decrease in GFR [30 - 59 mL/minute per 1.73 m ²]), stage 4 (severe decrease in GFR [15 - 29 mL/minute per 1.73 m ²]), or stage 5 (kidney failure with GFR less than 15 mL/minute per 1.73 m ² or requiring dialysis).

In patients with chronic kidney disease, inappropriate dosing can cause toxicity or ineffective therapy. Because of age-related decline in renal function and the use of multiple medications to treat comorbid conditions, older patients are particularly at a higher risk of developing advanced disease and related adverse events.

Specific clinical recommendations listed in the current review are as follows:

• Patients with chronic kidney disease should be asked about over-the-counter and herbal medicine use to ensure that medications are in fact indicated.
  
  
• Medications with toxic metabolites should be avoided, the least nephrotoxic agents should be used, and alternative medications should be prescribed if necessary to avoid potential drug interactions.
  
  
• Clinicians should be aware of drugs with active metabolites that can exaggerate pharmacologic effects in patients with impairment of renal function.
  
  
• Dosages of drugs cleared renally should be adjusted based on renal function (calculated as creatinine clearance or GFR). Initial dosages should be determined using published guidelines and adjusted based on patient response. When appropriate, serum drug concentrations should be used to monitor effectiveness and toxicity.

Although dosages of drugs metabolized by the kidney are based on renal function, calculated as GFR or creatinine clearance, these calculations are valid only when renal function is stable and the serum creatinine level is constant. For routine estimation of GFR, the K/DOQI clinical practice guidelines recommend using the traditional Cockcroft-Gault equation or the Modification of Diet in Renal Disease (MDRD) study equation (full or abbreviated).

In patients with GFR less than 60 mL/minute per 1.73 m², the MDRD equation has been shown to be superior to the Cockcroft-Gault equation. The production and excretion of creatinine declines with age, so normal serum creatinine values may not represent normal renal function in older patients. In this age group, the MDRD equation has been shown to be the best method for detecting a GFR less than 90 mL/minute per 1.73 m².

The current review presents specific tables for drug dosing requirements in patients with chronic kidney disease for antihypertensive agents, hypoglycemic agents, antimicrobial agents, analgesic agents, nonsteroidal anti-inflammatory drugs (NSAIDs), statins, and other drugs.

For treating uncomplicated hypertension, thiazide diuretics are first-line agents, but they are not recommended if the serum creatinine level is greater than 2.5 mg/dL (220 µmol/L) or if the creatinine clearance is less than 30 mL/minute. Loop diuretics are most often used to treat uncomplicated hypertension in patients with chronic kidney disease. Adding aldosterone blockers has been shown to reduce mortality in patients with severe heart failure, but potassium-sparing diuretics and aldosterone blockers should be avoided in patients with severe chronic kidney disease because of the rise in serum potassium level that usually accompanies renal dysfunction.

The primary concern about using metformin in patients with renal impairment is that other hypoxemic conditions, such as acute myocardial infarction, severe infection, respiratory disease, and liver disease, increase the risk for lactic acidosis. Rather than completely avoiding metformin in patients with chronic kidney disease, the authors suggest starting with a low dose and titrating, with close monitoring, based on patient response and tolerability. A more frequent practice is to temporarily discontinue metformin therapy in patients at a higher risk for lactic acidosis, such as those who develop sepsis. Sulfonylureas should be avoided in patients with stages 3 to 5 chronic kidney disease.

Many antimicrobial agents are eliminated by the kidney and therefore require dosing adjustments in patients with chronic kidney disease. However, several commonly used agents do not require adjustments. Opioid use is more likely to cause adverse effects in patients with stage 5 kidney disease, and adverse renal effects of NSAIDs include acute renal failure, nephrotic syndrome with interstitial nephritis, and chronic renal failure with or without glomerulopathy, interstitial nephritis, or papillary necrosis.

"Chronic kidney disease