Tiêu đề 14. RENAL IMPAIRMENT & PHARMACOKINETIC CONSIDERATIONS.pdf ✅

PHARMD GURU Page 2 PHARMACOKINETIC CONSIDERATIONS:  Uremic patients may exhibit pharmacokinetic changes in bioavailability, volume of distribution, and clearance.  The oral bioavailability of a drug in severe uremia may be decreased as a result of disease-related changes in gastrointestinal motility and pH that are caused by nausea, vomiting, and diarrhea.  Mesenteric blood flow may also be altered. However, the oral bioavailability of a drug such as propranolol (which has a high first-pass effect) may be increased in patients with renal impairment as a result of the decrease in first-pass hepatic metabolism.  The apparent volume of distribution depends largely on drug–protein binding in plasma or tissues and total body water.  Renal impairment may alter the distribution of the drug as a result of changes in fluid balance, drug–protein binding, or other factors that may cause changes in the apparent volume of distribution.  The plasma protein binding of weak acidic drugs in uremic patients is decreased, whereas the protein binding of weak basic drugs is less affected.  A decrease in drug–protein binding results in a larger fraction of free drug and an increase in the volume of distribution.  However, the net elimination half-life is generally increased as a result of the dominant effect of reduced glomerular filtration.
PHARMD GURU Page 3  Protein binding of the drug may be further compromised due to the accumulation of metabolites of the drug and various biochemical metabolites, such as free fatty acids and urea, which may compete for the protein-binding sites for the active drug.  Total body clearance of drugs in uremic patients is also reduced by either a decrease in the glomerular filtration rate (GFR) and possibly active tubular secretion or a reduced hepatic clearance resulting from a decrease in intrinsic hepatic clearance.  In clinical practice, estimation of the appropriate drug dosage regimen in patients with impaired renal function is based on an estimate of the remaining renal function of the patient and a prediction of the total body clearance.  A complete pharmacokinetic analysis of the drug in the uremic patient may not be possible. Moreover, the patient’s uremic condition may not be stable and may be changing too rapidly for pharmacokinetic analysis.  Each of the approaches for the calculation of a dosage regimen has certain assumptions and limitations that must be carefully assessed by the clinician before any approach is taken.