An intensive drug monitoring study suggesting possible clinical irrelevance of impaired drug disposition in liver disease.

Abstract

1 Liver disease can alter the disposition and clinical effects of drugs. However, even though altered drug disposition occurs, there is no clinical evidence relating it to an increased susceptibility to adverse drug reactions (ADRs). 2 An intensive prospective drug monitoring study of 2,582 hospitalized patients was conducted. The adverse drug reactions probability scale (APS) was used to assess ADRs. Only non‐mild, definite or probable ADRs (APS greater than or equal to 5) were included. Severity of liver dysfunction was assessed by a composite clinical and laboratory index (CCLI). 3 The frequency of ADRs was higher in 402 patients with cirrhosis (27.4%) than in 661 with renal dysfunction (22.8%) and in 249 with other parenchymatous liver diseases (13.7%) or in 1,270 patients with neither liver diseases nor renal dysfunction (10.9%) (chi 2 3 = 85.53, P less than 0.001). The frequency of ADRs in cirrhotics was highly correlated with the severity of the liver dysfunction measured by CCLI (r = 0.82, P less than 0.001). 4 Drugs predominantly eliminated by liver metabolism were not among those most commonly inducing ADRs or those causing severe reactions in cirrhotics. Thus, frusemide caused the most common and the most severe ADRs, whereas reactions induced by sedatives were uncommon. Drug‐induced hepatic encephalopathy was more common in cirrhotics receiving diuretics (13.3%) than in those receiving sedatives (1.8%) (chi 2 y.c. = 5.29, P less than 0.025). Patients with alcoholic liver disease had more drug‐induced hepatic encephalopathy (7.7%) than those with non‐alcoholic liver disease (1.2%) (chi 2 y.c. = 11.86, P less than 0.001). 5 These results indicate that susceptibility to ADRs is increased only in severe cirrhosis and that the most common and severe ADRs seem more likely related to enhanced pharmacodynamic action than to impaired drug disposition.

Medicine use and medicine-related problems in patients with liver cirrhosis: a systematic review of quantitative and qualitative studies

“…A total of 16 quantitative studies with 5636 participants were included in the review [15, 27-30, 32, 33, 36-43]. Of these 16 studies, three were conducted in Australia [36][37][38] and the USA [15,39,40], two each in Chile [41,42] and Indonesia [33,43], and one each from Switzerland [27], India [28], UK [30], Pakistan [29] and Netherlands [32]. All included studies used an observational study design ( Table 1).…”

“…Nine studies reported the incidence of the MRPs [12,27,29,32,33,38,[41][42][43]. Seven of the nine studies reported the incidence using total patients as a denominator.…”

“…In addition, risk factors contributed to MRPs' incidence without having a direct causal relationship with MRPs. Polypharmacy was the most commonly reported risk factor for liver cirrhosis [27,41,42] where MRPs were more prevalent in patients taking a median of seven to nine medicines. This was followed by associated comorbidities such as ascites, portal hypertension and prior hepatic encephalopathy [27,42].…”

Drug-Induced Hepatic Disorders

“…Interestingly, reduced drug metabolism in patients with liver disease seems to have an insignificant impact on the frequency of hepatotoxicity in patients with liver disease (Naranjo et al 1983). Electrolyte disturbances induced by furosemide (frusemide) prescribed for ascites was highest on the list of adverse drug reactions (Naranjo et al 1983).…”

Is there increased cerebral sensitivity to benzodiazepines in chronic liver disease?

“…Data to support this concept are singularly lacking. In an intensive prospective study of ADRs in 2,582 consecutive patients admitted to medical wards in two hospitals, 402 had evidence of liver disease (20). This group had a 27% incidence of ADRs, which was an even higher incidence than occurred in patients with renal disease, confirming that cirrhotic patients are susceptible to ADRs.…”