Title 16. DOSE ADJUSTMENT FOR UREMIC PATIENTS.pdf ✅

PHARMD GURU Page 2  The fraction of normal renal function remaining in the uremic patient is estimated from Clcr.  After the remaining total body clearance in the uremic patient is estimated, a dosage regimen may be developed by (1) Decreasing the maintenance dose, (2) Increasing the dosage interval, or (3) Changing both maintenance dose and dosage interval.  Although total body clearance is a more accurate index for drug dosing, the elimination half-life of the drug is more commonly used for dose adjustment because of its convenience.  Clearance allows for the prediction of steady-state drug concentrations, while elimination half-life yields information on the time it takes to reach steady-state concentration. NOMOGRAMS:  Nomograms are charts available for use in estimating dosage regimens in uremic patients.  The nomograms may be based on serum creatinine concentrations, patient data (height, weight, age, gender), and the pharmacokinetics of the drug.  As discussed by Chennavasin and Brater (1981), each nomogram has errors in its assumptions and drug database.  Most methods for dose adjustment in renal disease assume that non-renal elimination of the drug is not affected by renal impairment and that the remaining renal excretion rate constant in the uremic patient is proportional to the product of a constant and the Clcr: Where:  knr is the non-renal elimination rate constant and  α is a constant.  Equation 24.14 is similar to Equation 24.10, where a = 1/VD, and it can be used for the construction of a nomogram.  Figure 24-3 shows a graphical representation of Equation 24.14 for four different drugs, each with a different renal excretion rate constant.
PHARMD GURU Page 3  The fractions of drug excreted unchanged in the urine (fe) for drugs A, B, C, and D are 5%, 50%, 75%, and 90%, respectively.  A Clcr of ≥80 mL/min is considered an adequate GFR in subjects with normal renal function.  The uremic elimination rate constant (ku) is the sum of the non-renal elimination rate constant and the renal elimination rate constant, which is decreased due to renal impairment.  If the patient has complete renal shutdown (ie, Clcr = 0 mL/min), then the intercept on the y axis represents the percent of drug elimination due to non-renal drug elimination routes.  Drug D, which is excreted 90% unchanged in the urine, has the steepest slope (equivalent to α in Equation 24.14) and is most affected by small changes in Clcr. On the other hand, drug A, which is excreted only 5% unchanged in the urine (ie, 95% eliminated by non-renal routes), is least affected by a decrease in creatinine clearance.  The nomogram method of Welling and Craig (1976) provides an estimate of the ratio of the uremic elimination rate constant (ku) to the normal elimination rate constant (kN) on the basis of Clcr (Fig. 23-4).  For this method, Welling and Craig (1976) provided a list of drugs grouped according to the amount of drug excreted unchanged in the urine (Table 24-5).  From the ku/kN ratio, the uremic dose can be estimated according to Equation 24.15:
PHARMD GURU Page 4  When the dosage interval τ is kept constant, the uremic dose is always a smaller fraction of the normal dose.  Instead of reducing the dose for a uremic patient, the usual dose is kept constant and the dosage interval τ is prolonged according to the following equation:  Where τ u is the dosage interval for the dose in uremic patients and τ N is the dosage interval for the dose in patients with normal renal function.