A 58-year-old man with type 2 diabetes mellitus comes to the emergency department with fever, malaise, lower abdominal discomfort, and left flank pain. The patient has a history of diabetic autonomic neuropathy with bladder dysfunction and has been hospitalized multiple times for recurrent urinary tract infections. His temperature is 39.4 C (103 F), blood pressure is 94/50 mm Hg, and pulse is 118/min. Height is 180 cm (5 ft 11 in), weight is 150 kg (331 lb), and BMI is 46 kg/m². On examination, there is suprapubic and left costovertebral angle tenderness. After review of culture and sensitivity tests from his prior hospitalization, the patient is started on an empiric antibiotic regimen that includes an aminoglycoside. While calculating the appropriate dosage, the hospital pharmacy uses an adjusted body weight that is lower than the patient's actual body weight. Which of the following best explains the use of this adjusted parameter?

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11ec160b_3c3a_2f12_9249_4d93f3fd60f7_MD0001_00 Drugs are typically dosed to maintain plasma drug concentrations within a target range. Although fixed drug dosing is convenient for providers and patients, dosing based on body weight (eg, mg/kg) is often used to improve safety and efficacy, particularly for medications with a narrow therapeutic window (eg, heparins, aminoglycosides, anesthetics). Body weight affects both the rate of drug clearance and the volume of distribution. Drug clearance rates correlate closely with lean body weight (ie, the weight of all nonadipose tissues, including muscle, liver, kidneys). Likewise, the volume of distribution for most drugs also gets larger as lean body mass increases. However, obesity causes a disproportional increase in adipose mass, which can have a variable effect on the volume of distribution depending on the solubility of the drug (eg, hydrophilic, hydrophobic). Aminoglycosides are large, charged molecules that cannot cross cell membranes; their volume of distribution is limited to the extracellular space, which increases only marginally in obese individuals. As a result, dosing in obese patients is based on an adjusted body weight that takes into account only a portion (~40%) of the excess adipose mass. (Choice B) The route of elimination does not directly impact weight-based drug dosing, aside from the fact that lipophilic drugs more often undergo hepatic elimination. Furthermore, aminoglycosides are not metabolized by the liver; they are freely filtered by the glomerulus and excreted unchanged in the urine. (Choice C) The vast majority of drugs, including aminoglycosides, undergo first- (not zero-) order metabolism. In addition, body weight adjustments with regard to medication dosing are usually made according to the way a drug distributes within the body's tissues. (Choice D) Acidic drugs with a high degree of plasma protein binding (eg, warfarin) are retained in the intravascular space and have a limited volume of distribution that is less affected by body weight. In contrast, aminoglycosides have minimal plasma protein binding and can distribute extensively into the interstitial compartment. (Choice E) Lipophilic drugs partition extensively into adipose tissues; their volume of distribution is better correlated with total body weight than with lean or adjusted body weight. Highly lipophilic drugs (eg, phenytoin) are tightly sequestered within adipose tissue and often require an initial loading dose to saturate fat stores and achieve adequate serum levels. Educational objective: Many drugs are dosed based on total body weight to improve safety and efficacy. In obese individuals, use of lean body weight or an adjusted body weight may be necessary when dosing hydrophilic drugs (eg, aminoglycosides) that do not distribute into adipose tissue. __________ References: Drug dosing in obese adults. (http://www.ncbi.nlm.nih.gov/pubmed/29109603)

A 58-Year-Old Man with Type 2 Diabetes Mellitus Comes to the Emergency