Drug-related problems and dosage adjustment in patients with liver disease

The liver is essential for the metabolism of medicinal substances. Liver disease, especially liver cirrhosis, may lead to various pharmacokinetic and pharmacodynamic changes, predisposing patients with liver cirrhosis to adverse drug events (ADEs). In contrast to patients with renal failure, where dose adjustment can be performed by means of creatinine clearance, no such surrogate parameter exists for patients with liver disease. Specific dosage recommendations for patients with liver cirrhosis are often not available in the product information. We contributed to the development of a database that categorizes drugs according to their pharmacokinetic characteristics and allows for specific dosage recommendations for patients with liver disease. In the first study, we summarized this database for all anti-infective drugs on the Swiss market in 2012. Forty-seven % (N = 49) and 44% (N = 46) of the 104 anti-infectives on the market were primarily eliminated by the liver and the kidney, respectively. For 9 drugs, the elimination pathway could not be elucidated. One fifth of all drugs was eliminated ≥50% by bile. CYP P450 enzymes were involved in the metabolism of 27% of the drugs. For 48% of the anti-infectives, studies on pharmacokinetic alterations in liver disease were found. The Swiss product information provides specific recommendations for patients with liver disease for only 50% of anti-infective drugs. The aim of the second study was the assessment of diagnoses, medication patterns, adverse drug reactions (ADRs), and potential drug-drug interactions (pDDIs) in cirrhotic patients at hospital admission. For this purpose, we performed a cross-sectional retrospective study including 400 patients with liver cirrhosis. At hospital admission, the 400 patients had 2415 diagnoses (median 6 per patient) and 1999 drugs (median 5 per patient), whereof 68% were predominantly eliminated by the liver. In total, 200 ADRs and 132 pDDIs were detected in 112 (28%) and 86 (21.5%) patients, respectively. Fifteen ADRs were directly caused by 17 DDIs, whereof three resulted in hospital admission. Patients with ADRs were older, had more comorbidities, were treated with more drugs, and had a worse renal function and more pDDIs than patients without ADRs. In the third study, the medication at hospital admission of the same population described in the second study was analyzed in greater detail with the goal to determine the prevalence of incorrectly dosed drugs (IDDs) and their association with ADRs. The adequacy of the drugs with respect to dosing or prescribing was investigated retrospectively by means of previous publications or the above-mentioned database. Additionally, we calculated potential cost savings associated with IDDs and additional hospital stay due to IDD-induced ADRs. In contrast to the second study, we excluded vitamins and minerals for the analyses. Of the remaining 1653 drugs prescribed (median 4 per patient), 336 (20%) were IDDs in 184 patients. Overall, 198 ADRs (83% preventable) occurred in 110 patients. Sixty-one (31% of all ADRs) were associated with IDDs in 40 patients, whereof 77% were considered to be preventable. Especially non-steroidal anti-inflammatory drugs and psycholeptics were a frequent cause of preventable ADRs. Overall, IDDs were more frequently associated with ADRs than correctly dosed drugs and patients with IDDs were more frequently admitted to the hospital due to ADRs. Hospitalizations due to IDD-induced ADRs resulted in 94 additional hospital days. Potential drug-cost savings as a result of mere dose adjustment in patients with liver cirrhosis was minor, but considerable when taking into account hospitalizations due to preventable ADRs caused by IDDs. Pharmacotherapy in patients with liver cirrhosis is complex and specific recommendations for dosage adjustment frequently not available. Prescribing physicians should be aware of problematic drugs and the principles of dosage adjustment in patients with liver cirrhosis. Prevention of IDDs and associated ADRs potentially leading to hospital admission can contribute to the reduction of healthcare costs. By developing a database allowing for specific dosage recommendations in patients with liver disease, we are contributing to a safer drug treatment in patients with liver cirrhosis.