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Impairment of renal clearance
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Inadequate hepatic metabolism
Increased metabolism by CYP3A4
Increased volume of distribution
Low bioavailability
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This patient with painful ulcerative lesions after hunting rabbits in Arkansas likely has tularemia. This infection can be treated by gentamicin, a highly water-soluble, non-serum protein-bound, renally cleared antibiotic. This patient with end-stage liver disease and ascites likely has increased total body water, which would cause initial measurements of the levels of a highly hydrophilic medication (i.e., gentamicin) after infusion to be lower than expected due to an increased volume of distribution. Volume of distribution (Vd) relates the amount of drug in the body to the plasma concentration and is calculated as: Vd = (amount of drug in the body) / (plasma drug concentration). Drugs that are highly hydrophilic but not bound to serum proteins distribute to water throughout the body. These drugs (e.g., ethanol, gentamicin, and theophylline) will have a significantly increased volume of distribution in conditions that increase body water content such as ascites. For gentamicin, in particular, increases in the volume of distribution necessitate monitoring drug levels to ensure adequate peak concentrations, as gentamicin exhibits concentration-dependent activity. Triginer et al. describe a case series of an increased volume of distribution of gentamicin in patients with sepsis. They found significant differences in peak concentration and half-life of gentamicin in these patients. They recommend increasing the initial drug dosage in these patients. Incorrect Answers: Answer 1: Impairment of renal clearance is incorrect as this would lead to higher than expected levels of gentamicin, not a lower than expected concentration. Renal function may be decreased in patients with end-stage liver disease due to poor prerenal perfusion or hepatorenal syndrome. Answer 2: Inadequate hepatic metabolism is incorrect as gentamicin is renally cleared, not hepatically metabolized. In addition, inadequate metabolism of a drug would be expected to lead to a higher than expected concentration of that drug at a given time after infusion, not a lower than expected concentration. Answer 3: Increased metabolism by CYP3A4 is incorrect as gentamicin is renally cleared, not hepatically metabolized. Cytochrome P450 enzymes such as CYP3A4 are a family of enzymes that oxidize a variety of drugs, which aids in the clearance of various compounds. These enzymes are extensively expressed in the liver, and levels of these enzymes are generally decreased, not increased in patients with end-stage liver disease. Answer 5: Low bioavailability is incorrect as bioavailability is 1 by definition for all drugs given intravenously. Bioavailability is defined as the time integral of the concentration of a drug given orally divided by the time integral of the concentration of a drug given intravenously. Bullet Summary: High body water content increases the volume of distribution and lowers the plasma concentration of water-soluble drugs.
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