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      Improving Medication‐Related Outcomes in Chronic Liver Disease

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      1 , 2 , , 3
      Hepatology Communications
      John Wiley and Sons Inc.

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          Abstract

          Patients with chronic liver disease (CLD) are becoming increasingly complex due to the rising prevalence of multimorbidity and polypharmacy. Medications are often essential to manage the underlying liver disease, complications of cirrhosis and portal hypertension, and comorbidities. However, medication‐related problems (MRPs) have been associated with adverse patient outcomes, including hospitalization and mortality. Factors that can contribute to MRPs in people with CLD are variable and often entwined. This narrative literature review discusses key barriers and opportunities to modify risk factors and improve medication‐related outcomes for people with CLD.

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          Hospital readmissions among patients with decompensated cirrhosis.

          Early rehospitalizations have been well characterized in many disease states, but not among patients with cirrhosis. The aims of this study were to identify the frequency, costs, predictors, and preventable causes of hospital readmissions among patients with decompensated cirrhosis. Rates of readmission were calculated for 402 patients discharged after one of the following complications of cirrhosis: ascites, spontaneous bacterial peritonitis, renal failure, hepatic encephalopathy, or variceal hemorrhage. Costs of readmissions were calculated using the hospital accounting system. Predictors of time to first readmission were determined using Cox regression, and predictors of hospitalization rate/person-years were determined using negative binomial regression. The independent association between readmission rate and mortality was determined using Cox regression. Admissions within 30 days of discharge were assessed by two reviewers to determine if preventable. Overall, 276 (69%) subjects had at least one nonelective readmission, with a median time to first readmission of 67 days. By 1 week after discharge, 14% of subjects had been readmitted, and 37% were readmitted within 1 month. The mean costs for readmissions within 1 week and between weeks 1 and 4 were $28,898 and $20,581, respectively. During a median follow-up of 203 days, the median number of readmissions was 2 (range 0-40), with an overall rate of 3 hospitalizations/person-years. Patients with more frequent readmissions had higher risk of subsequent mortality, despite adjustment for confounders including the Model for End-stage Liver Disease (MELD) score. Predictors of time to first readmission included MELD score, serum sodium, and number of medications on discharge; predictors of hospitalization rate included these variables as well as the number of cirrhosis complications and being on the transplant list at discharge. Among 165 readmissions within 30 days, 22% were possibly preventable. Hospital readmissions among patients with decompensated cirrhosis are common, costly, moderately predictable, in some cases, possibly preventable, and independently associated with mortality. These findings support the development of disease management interventions to prevent rehospitalization.
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            An official ATS statement: hepatotoxicity of antituberculosis therapy.

            Drug-induced liver injury (DILI) is a problem of increasing significance, but has been a long-standing concern in the treatment of tuberculosis (TB) infection. The liver has a central role in drug metabolism and detoxification, and is consequently vulnerable to injury. The pathogenesis and types of DILI are presented, ranging from hepatic adaptation to hepatocellular injury. Knowledge of the metabolism of anti-TB medications and of the mechanisms of TB DILI is incomplete. Understanding of TB DILI has been hampered by differences in study populations, definitions of hepatotoxicity, and monitoring and reporting practices. Available data regarding the incidence and severity of TB DILI overall, in selected demographic groups, and in those coinfected with HIV or hepatitis B or C virus are presented. Systematic steps for prevention and management of TB DILI are recommended. These include patient and regimen selection to optimize benefits over risks, effective staff and patient education, ready access to care for patients, good communication among providers, and judicious use of clinical and biochemical monitoring. During treatment of latent TB infection (LTBI) alanine aminotransferase (ALT) monitoring is recommended for those who chronically consume alcohol, take concomitant hepatotoxic drugs, have viral hepatitis or other preexisting liver disease or abnormal baseline ALT, have experienced prior isoniazid hepatitis, are pregnant or are within 3 months postpartum. During treatment of TB disease, in addition to these individuals, patients with HIV infection should have ALT monitoring. Some experts recommend biochemical monitoring for those older than 35 years. Treatment should be interrupted and, generally, a modified or alternative regimen used for those with ALT elevation more than three times the upper limit of normal (ULN) in the presence of hepatitis symptoms and/or jaundice, or five times the ULN in the absence of symptoms. Priorities for future studies to develop safer treatments for LTBI and for TB disease are presented.
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              Clinical pharmacology of tramadol.

              Tramadol, a centrally acting analgesic structurally related to codeine and morphine, consists of two enantiomers, both of which contribute to analgesic activity via different mechanisms. (+)-Tramadol and the metabolite (+)-O-desmethyl-tramadol (M1) are agonists of the mu opioid receptor. (+)-Tramadol inhibits serotonin reuptake and (-)-tramadol inhibits norepinephrine reuptake, enhancing inhibitory effects on pain transmission in the spinal cord. The complementary and synergistic actions of the two enantiomers improve the analgesic efficacy and tolerability profile of the racemate. Tramadol is available as drops, capsules and sustained-release formulations for oral use, suppositories for rectal use and solution for intramuscular, intravenous and subcutaneous injection. After oral administration, tramadol is rapidly and almost completely absorbed. Sustained-release tablets release the active ingredient over a period of 12 hours, reach peak concentrations after 4.9 hours and have a bioavailability of 87-95% compared with capsules. Tramadol is rapidly distributed in the body; plasma protein binding is about 20%. Tramadol is mainly metabolised by O- and N-demethylation and by conjugation reactions forming glucuronides and sulfates. Tramadol and its metabolites are mainly excreted via the kidneys. The mean elimination half-life is about 6 hours. The O-demethylation of tramadol to M1, the main analgesic effective metabolite, is catalysed by cytochrome P450 (CYP) 2D6, whereas N-demethylation to M2 is catalysed by CYP2B6 and CYP3A4. The wide variability in the pharmacokinetic properties of tramadol can partly be ascribed to CYP polymorphism. O- and N-demethylation of tramadol as well as renal elimination are stereoselective. Pharmacokinetic-pharmacodynamic characterisation of tramadol is difficult because of differences between tramadol concentrations in plasma and at the site of action, and because of pharmacodynamic interactions between the two enantiomers of tramadol and its active metabolites. The analgesic potency of tramadol is about 10% of that of morphine following parenteral administration. Tramadol provides postoperative pain relief comparable with that of pethidine, and the analgesic efficacy of tramadol can further be improved by combination with a non-opioid analgesic. Tramadol may prove particularly useful in patients with a risk of poor cardiopulmonary function, after surgery of the thorax or upper abdomen and when non-opioid analgesics are contraindicated. Tramadol is an effective and well tolerated agent to reduce pain resulting from trauma, renal or biliary colic and labour, and also for the management of chronic pain of malignant or nonmalignant origin, particularly neuropathic pain. Tramadol appears to produce less constipation and dependence than equianalgesic doses of strong opioids.
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                Author and article information

                Contributors
                kelly.hayward@uq.edu.au
                Journal
                Hepatol Commun
                Hepatol Commun
                10.1002/(ISSN)2471-254X
                HEP4
                Hepatology Communications
                John Wiley and Sons Inc. (Hoboken )
                2471-254X
                10 October 2020
                November 2020
                : 4
                : 11 ( doiID: 10.1002/hep4.v4.11 )
                : 1562-1577
                Affiliations
                [ 1 ] Centre for Liver Disease Research, Faculty of Medicine The University of Queensland, Translational Research Institute Brisbane QLD Australia
                [ 2 ] Department of Gastroenterology and Hepatology Princess Alexandra Hospital Brisbane QLD Australia
                [ 3 ] Department of Clinical Pharmacy Deventer Hospital Deventer The Netherlands
                Author notes
                [*] [* ] Address Correspondence and Reprint Requests to:

                Kelly L. Hayward, Ph.D.

                Centre for Liver Disease Research, The University of Queensland

                Level 5, West Wing, Translational Research Institute

                37 Kent Street

                Woolloongabba, Brisbane, QLD 4102

                Australia

                E‐mail: kelly.hayward@ 123456uq.edu.au

                Tel.: +61 7 3443 8015

                [†]

                These authors contributed equally to this work.

                Author information
                https://orcid.org/0000-0001-6115-3420
                https://orcid.org/0000-0001-6996-894X
                Article
                HEP41612
                10.1002/hep4.1612
                7603526
                33163829
                2e785109-70d1-42cb-ba65-16f178dea0a4
                © 2020 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

                History
                : 14 May 2020
                : 20 August 2020
                : 08 September 2020
                Page count
                Figures: 1, Tables: 3, Pages: 16, Words: 24089
                Categories
                Review
                Review
                Custom metadata
                2.0
                November 2020
                Converter:WILEY_ML3GV2_TO_JATSPMC version:5.9.3 mode:remove_FC converted:01.11.2020

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