Drugs prescription in patients with chronic liver disease: rules for adjusting doses and beyond

Abstract

The liver is the primary organ where biotransformation processes for drugs and other xenobiotics, necessary to turn originally fat-soluble compounds into more polar substances to facilitate urinary clearance, take place. Therefore, liver disease commonly brings about changes in the metabolism of multiple drugs. In addition to pharmacokinetic changes, chronic liver disease (particularly decompensated liver cirrhosis) induces changes (that is, an abnormal response) in the pharmacodynamics of various drugs and increases the severity of potential adverse events.While the spectrum of liver disease is wide, and hepatic functioning is preserved in many liver conditions, liver disorders are usually associated with physiological and/or structural changes that decrease the liver's metabolic capacity. Firstly, the absorption of a number of drugs may be disrupted by intestinal permeability changes that are characteristic of portal hypertension as well as by altered gastric voiding and bowel motility. Also, necrosis and liver cell dysfunction reduce the levels of liver enzymes responsible for drug metabolism, which affects plasma levels of active principles and hence their effectiveness and potential toxicity. On the other hand, altered liver structure and both intra-and extra-hepatic portosystemic shunts impair presystemic drug clearance for compounds with a high hepatic extraction ratio. Similarly, the synthesis of plasma transport proteins, basically albumin and alfa-glycoprotein, may be reduced, which affects the bioavailability of drugs highly bound to plasma proteins; drug excretion may become disrupted by variable cholestasis and, on occasion, renal impairment. Finally, advanced liver cirrhosis develops with an abnormal (usually exaggerated, deleterious) response to a number of drugs, including benzodiazepines, opiates, and non-steroidal antiinflammatory drugs (1). No wonder then that no single biochemical parameter (albumin, prothrombin activity) or cluster thereof is predictive of drug metabolism. Only general recommendations are issued that rely on a classification of drugs according to their flow-dependent, first-pass extraction ratio, their liver metabolism extent, and -within the latter group-their plasma protein binding degree (2); however, such proposal is a theoretical approach that more often than not is neither based on kinetic studies nor validated in prospective trials. In the present issue of The Spanish Journal of Gastroenterology, Periáñez et al. (3) make an attempt at issuing recommendations for the proper use of drugs in patients with chronic liver disease by using a strategy based on thoroughly reviewing prescribing information sheets, pharmaceutical databases, review articles, and the WHO list of drugs to be excluded or used cautiously in patients with liver disease, adding novel therapies, and adjusting said assessment to hospital medication guidelines. For cases where no relevant information could be found, adjustment recommendations followed the procedure defined by Delcò et al. (2). This strat...

Management of Pharmacologic Adverse Effects in Advanced Liver Disease

“…NSAIDs should be avoided in cirrhotic patients, especially in those with hydrosaline retention, because they inhibit renal prostaglandin synthesis (essential for the maintenance of renal perfusion decreased by the activation of vasoconstrictor systems) and may hasten renal failure [ 7 ]. In a prospective cohort study that included 30 patients with NSAID-associated acute kidney injury, 37% developed persistent renal dysfunction, and the remaining 63% developed reversible renal damage.…”

“…Other drug-related problems in patients with advanced liver disease include lack of adherence, errors due to poor patient understanding, and suboptimal monitoring of treatment and its adverse effects. All these problems lead to increases in adverse events and drug interactions and a higher rate of unscheduled hospital admissions [ 7 , 9 ].…”

“…Unfortunately, there are no tests that accurately determine the degree of impairment of liver metabolic function; therefore, no specific recommendations can be given on the use or dosing of medications in patients with advanced liver disease [ 7 ]. Commonly employed liver function grading systems, such as Child–Pugh, do not correlate efficiently with metabolic alterations of the liver.…”