Chapter 15 Marini Pharmacotherapy

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CHAPTER 15 • Pharmacotherapy

frequently or with smaller doses with renal and/or liver dysfunction. Renal function can be assessed and tracked by serum creatinine, used in conjunction with equa- tions that approximate creatinine clearance (most often using the Cockcroft–Gault equation). There are several good guides for dosing adjustments for almost any medication in renal dysfunction, but it is important to remember two vital things: first, serum creatinine usually lags behind actual declines in renal function by 1 to 3 days, and second, the cal- culated creatinine clearance is not valid until renal function plateaus. Therefore, it is advisable to follow trends in renal function, calculating an estimated creatinine clearance on a daily basis, and follow- ing urine output. A defensible strategy for adjust- ing drugs eliminated by the kidney is to assume that once the urine output is less than 0.5 mL/kg/h, the glomerular filtration rate is effectively zero. Just as there are times when doses must be reduced, occa- sionally drug requirements increase. Pregnancy and fully resuscitated major burn patients will have very high volumes of distribution and will likely require higher drug doses to have the same effect. Likewise, extensively traumatized and head-injured patients are often hypermetabolic in the first 2 weeks after injury and will, therefore, need more drug to accom- plish the same effect during this period. Dosing adjustments in liver dysfunction are more difficult (very few references exist on how to make them) because there is no in vivo surrogate (like serum creatinine for renal dysfunction) to predict their drug clearance. Patients at risk for impaired liver function include those who are malnourished or are on low-protein diets and those patients who exhibit clinical signs of hepatotoxicity (nausea, vom- iting, jaundice, hepatomegaly). Liver tests can also be helpful and are used to determine the level of liver dysfunction. These include serum bilirubin (levels above 4 to 5 mg/dL), prothrombin time (>1.5 times control), serum albumin (below 2.0 g/dL), and elevated alanine aminotransferase (ALT) and aspar- tate aminotransferase (AST) (usually three times the upper limit of normal). The reduction in clearance associated with liver disease can also be calculated by the Child–Pugh score, which assigns a score from 5 to 15 based on levels of encephalopathy, ascites, bilirubin, albumin, and prothrombin time. Using that score, patients are then categorized into Child– Pugh A (5 to 6 points, least severe liver disease), B (7 to 9 points, moderately severe liver disease), or C (10 to 15 points, most severe liver disease). Dose

adjustments for drugs with a high hepatic extraction ratio can be made based on Child–Pugh scores if no drug studies are available. For patients in class A Child–Pugh, doses should be about 50% of normal, for patients in class B doses should be about 25% of normal, and for patients in class C it is generally recommended that a drug that is not affected by liver disease be used instead. Unfortunately, there are no convincing studies that affirm this dosing strategy. In general, drugs having a low hepatic extraction ratio are less problematic, because fluctuations in the unbound drug fraction will be rather small and will not significantly alter blood/plasma clearance of the drug. Dose adjustments for low hepatic ratio drugs should be aimed at maintaining normal total (i.e., bound plus unbound) plasma concentrations. “Pro”-drugs for which the metabolite is more biologi- cally active (e.g., erythromycin, enalaprilat, codeine) should be avoided. Although there are limited data on dosing drugs in hepatic dysfunction, more infor- mation continues to surface on specific drugs and, if available, should be consulted. Contrary to conventional wisdom, organ failure does not always mean thankless difficulty for phar- macotherapy. For example, many antibiotics have longer dosing intervals in renal dysfunction, thereby reducing cost and nursing time. Meropenem, for example, is normally dosed every 8 hours but is reduced to once daily in end-stage kidney disease. Another instance would be intentionally using a medication that is cleared by a failing organ to get a prolonged therapeutic effect (e.g., vancomycin in end-stage renal disease). Stopping Ineffective/Unnecessary Treatments Another method to improve safety while reducing costs is to eliminate ineffective prescribing habits. An example is provided by the use of dilute UFH to prevent clotting of most intravenous catheters. It is clear that this process is rarely necessary (saline works just as well), increases cost, and can lead to heparin-induced thrombocytopenia. Another exam- ple is repeated dosing of serotonin (5-HT) antago- nists for nausea and vomiting. Even though 5-HT antagonists are effective when single doses are given to prevent postoperative nausea and vomiting, there are little data to suggest that redosing of these agents adds benefit. Cost savings can also be achieved by addressing stop dates for medications. The most frequent exam- ple of this is seen with antibiotics. Broad-spectrum antibiotics should be tailored once culture data