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.

Clinical Pharmacology & TherapeuticsVolume 30, Issue 2 p. 239-245 Original Article A method for estimating the probability of adverse drug reactions C A Naranjo MD, Corresponding Author C A Naranjo MD Clinical Pharmacology Program, Addiction Research Foundation Clinical Institute Departments of Medicine and Pharmacology, University of TorontoC A Naranjo, MD, Clinical Pharmacology Program, Addiction Research Foundation Clinical Institute, 33 Russell St., Toronto, Ontario M5S 2S1, Canada.Search for more papers by this authorU Busto PharmD, U Busto PharmD Clinical Pharmacology Program, Addiction Research Foundation Clinical Institute Departments of Medicine and Pharmacology, University of TorontoSearch for more papers by this authorE M Sellers MD, PhD, E M Sellers MD, PhD Clinical Pharmacology Program, Addiction Research Foundation Clinical Institute Departments of Medicine and Pharmacology, University of TorontoSearch for more papers by this authorP Sandor MD, P Sandor MD Clinical Pharmacology Program, Addiction Research Foundation Clinical Institute Departments of Medicine and Pharmacology, University of TorontoSearch for more papers by this authorI Ruiz PharmD, I Ruiz PharmD Clinical Pharmacology Program, Addiction Research Foundation Clinical Institute Departments of Medicine and Pharmacology, University of TorontoSearch for more papers by this authorE A Roberts MD, E A Roberts MD Clinical Pharmacology Program, Addiction Research Foundation Clinical Institute Departments of Medicine and Pharmacology, University of TorontoSearch for more papers by this authorE Janecek BSc, Phm, E Janecek BSc, Phm Clinical Pharmacology Program, Addiction Research Foundation Clinical Institute Departments of Medicine and Pharmacology, University of TorontoSearch for more papers by this authorC Domecq PharmD, C Domecq PharmD Clinical Pharmacology Program, Addiction Research Foundation Clinical Institute Departments of Medicine and Pharmacology, University of TorontoClinical Pharmacy Group, Faculty of Chemical Sciences, Universidad de Chile, Santiago, Chile.Search for more papers by this authorD J Greenblatt MD, D J Greenblatt MD Clinical Pharmacology Program, Addiction Research Foundation Clinical Institute Departments of Medicine and Pharmacology, University of TorontoDivision of Clinical Pharmacology, New England Medical Centre Hospital, Boston, MA.Search for more papers by this author C A Naranjo MD, Corresponding Author C A Naranjo MD Clinical Pharmacology Program, Addiction Research Foundation Clinical Institute Departments of Medicine and Pharmacology, University of TorontoC A Naranjo, MD, Clinical Pharmacology Program, Addiction Research Foundation Clinical Institute, 33 Russell St., Toronto, Ontario M5S 2S1, Canada.Search for more papers by this authorU Busto PharmD, U Busto PharmD Clinical Pharmacology Program, Addiction Research Foundation Clinical Institute Departments of Medicine and Pharmacology, University of TorontoSearch for more papers by this authorE M Sellers MD, PhD, E M Sellers MD, PhD Clinical Pharmacology Program, Addiction Research Foundation Clinical Institute Departments of Medicine and Pharmacology, University of TorontoSearch for more papers by this authorP Sandor MD, P Sandor MD Clinical Pharmacology Program, Addiction Research Foundation Clinical Institute Departments of Medicine and Pharmacology, University of TorontoSearch for more papers by this authorI Ruiz PharmD, I Ruiz PharmD Clinical Pharmacology Program, Addiction Research Foundation Clinical Institute Departments of Medicine and Pharmacology, University of TorontoSearch for more papers by this authorE A Roberts MD, E A Roberts MD Clinical Pharmacology Program, Addiction Research Foundation Clinical Institute Departments of Medicine and Pharmacology, University of TorontoSearch for more papers by this authorE Janecek BSc, Phm, E Janecek BSc, Phm Clinical Pharmacology Program, Addiction Research Foundation Clinical Institute Departments of Medicine and Pharmacology, University of TorontoSearch for more papers by this authorC Domecq PharmD, C Domecq PharmD Clinical Pharmacology Program, Addiction Research Foundation Clinical Institute Departments of Medicine and Pharmacology, University of TorontoClinical Pharmacy Group, Faculty of Chemical Sciences, Universidad de Chile, Santiago, Chile.Search for more papers by this authorD J Greenblatt MD, D J Greenblatt MD Clinical Pharmacology Program, Addiction Research Foundation Clinical Institute Departments of Medicine and Pharmacology, University of TorontoDivision of Clinical Pharmacology, New England Medical Centre Hospital, Boston, MA.Search for more papers by this author First published: August 1981 https://doi.org/10.1038/clpt.1981.154Citations: 1,097 AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat Abstract The estimation of the probability that a drug caused an adverse clinical event is usually based on clinical judgment. Lack of a method for establishing causality generates large between-raters and within-raters variability in assessment. Using the conventional categories and definitions of definite, probable, possible, and doubtful adverse drug reactions (ADRs), the between-raters agreement of two physicians and four pharmacists who independently assessed 63 randomly selected alleged ADRs was 38% to 63%, kappa (k, a chance-corrected index of agreement) varied from 0.21 to 0.40, and the intraclass correlation coefficient of reliability (R[est]) was 0.49. Six (testing) and 22 wk (retesting) later the same observers independently reanalyzed the 63 cases by assigning a weighted score (ADR probability scale) to each of the components that must be considered in establishing causal associations between drug(s) and adverse events (e.g., temporal sequence). The cases were randomized to minimize the influence of learning. The event was assigned a probability category from the total score. The between-raters reliability (range: percent agreement = 83% to 92%; κ = 0.69 to 0.86; r = 0.91 to 0.95; R(est) = 0.92) and within-raters reliability (range: percent agreement = 80% to 97%; κ = 0.64 to 0.95; r = 0.91 to 0.98) improved (p < 0.001). The between-raters reliability was maintained on retesting (range: r = 0.84 to 0.94; R(est) = 0.87). The between-raters reliability of three attending physicians who independently assessed 28 other prospectively collected cases of alleged ADRs was very high (range: r = 0.76 to 0.87; R(est) = 0.80). It was also shown that the ADR probability scale has consensual, content, and concurrent validity. This systematic method offers a sensitive way to monitor ADRs and may be applicable to postmarketing drug surveillance. Clinical Pharmacology and Therapeutics (1981) 30, 239–245; doi:10.1038/clpt.1981.154 Citing Literature Volume30, Issue2August 1981Pages 239-245 RelatedInformation

Sex-related variations in the clinical effects of drugs may be observed. In an intensive prospective drug surveillance study of 1920 patients hospitalized at the Department of Medicine of the J. J. Aguirre Hospital in Santiago, Chile, the frequency of adverse drug reactions (ADR) was significantly higher in females than in males (p < 0.0005). Women presented more commonly gastrointestinal and cutaneous allergic reactions. In males electrolyte disturbances were more frequent. Drugs inducing ADR were very similar in both sexes. Eighty-three per cent of ADR in males and 93% in females were dose-related effects. Hospitalization was lengthened by a significantly higher proportion of ADR in men than in women. Other ADR's risk fators such as age, number of drugs administered and duration of hospitalization did not account for the differences observed. In males with ADR there was a higher proportion of patients with cirrhosis and renal insufficiency. These findings suggest that sex is a determinant of the frequency and characteristics of ADR.