Drug Administration in Chronic Liver Disease

Abstract

Cirrhosis encompasses a range of pathophysiological changes that may alter drug disposition. Drugs that are dependent primarily on the liver for their systemic clearance are more likely to be subject to reduced elimination and subsequent accumulation. Drug accumulation may lead to excessive plasma drug concentrations and adverse effects, if the adverse effects of the drug are concentration-dependent. The effects of hepatic insufficiency on the pharmacokinetics of drugs are not consistent or predictable. Furthermore, the influence of hepatic disease on the disposition of various drugs can vary, even though those drugs may share the same apparent metabolic pathway. Problems in forecasting drug kinetic behaviour are further enhanced by the additional impairment of kidney function (frequently encountered in patients with advanced liver disease) and by the unpredictability of the glomerular filtration rate using customary methods in patients with cirrhosis. Accordingly, dosages are generally adapted empirically, with the help of serum drug concentrations, when applicable. However, drugs eliminated predominantly by hepatic metabolism are not among those most commonly inducing adverse drug reactions or causing severe complications in patients with cirrhosis. Electrolyte disturbances and the hepatorenal syndrome produced by furosemide (frusemide)-the disposition of which is not substantially modified in liver disease-appear to be the most frequent adverse drug reactions in patients with liver disease. Furthermore, clinically significant alterations in the action of medications at concentrations generally considered to be in the normal therapeutic range are not uncommon. Tissue responsiveness to the pharmacological action of some drugs may be modified, as evidenced by the increased susceptibility of the brain in patients with cirrhosis to the action of many psychoactive agents. Another example is the greater susceptibility of such patients to the nephrotoxic potential of aminogly-cosides, which should not be used in this patient group. Drugs may also interfere with adaptive physiological processes induced by liver disease. ACE inhibitors and nonsteroidal anti-inflammatory drugs counteract the enhanced activity of the renin-angiotensin system in advanced liver disease, thereby generating a high risk of excessive hypotension or acute renal failure, respectively. These drugs are best avoided in patients with cirrhosis. Finally, there may be pharmacological effects that overlap with some pathophysiological modifications related to the process of liver disease, such as increased portal pressure produced by some calcium antagonists, or hypoprothrombinaemia related to the inhibition of synthesis of vitamin K-dependent clotting factors by some beta-lactam antibacterials (especially moxalactam and cefamandole). Accordingly, the use of these drugs should be avoided in advanced liver disease. It is noteworthy that reduced drug metabolism in patients with liver disease does not seem to have a significant impact on the frequency of he...

Drug dosage recommendations in patients with chronic liver disease

“…In four drugs (2.2%) (dacarbazine, leuprorelin, maraviroc and zidovudine) no information in the previously mentioned databases was found nor in further bibliography searches. That is why a theoretical adjustment recommendation based on the proposal defined by Delcò et al (1) From the 191 reviewed drugs, E H was calculated with the Westphal et al formula (13) in 103 drugs (53.9%); in 66 drugs (34.6%) it was not obtained due to lack of data; in 22 drugs (11.5%) E H was obtained through the bibliography.…”

Pharmacokinetics of diclofenac in rats intoxicated with CCL4, and in the regenerating liver

“…Specifically, the liver plays a central role in the pharmacokinetics of many drugs. Liver dysfunction may not only reduce the plasma clearance of a number of drugs eliminated by biotransformation and/or biliary excretion, but it can also affect plasma protein binding which in turn could influence the processes of distribution and elimination [12,13]. Liver disease has major effects on drug response, of which prescribers should be aware to ensure safe and effective therapy [14,15].…”

Efflux Transporter Expression and Acetaminophen Metabolite Excretion Are Altered in Rodent Models of Nonalcoholic Fatty Liver Disease

“…During other liver disease states, such as septic cholestasis, obstructive cholestasis, and alcoholic and viral hepatitis, human and rodent studies have demonstrated alterations in cytochrome P450-mediated drug metabolism, transport, and pharmacokinetics (Forrest et al, 1977;Farrell et al, 1978Farrell et al, , 1979Narang et al, 1981Narang et al, , 1982Narang et al, , 1985Figg et al, 1995;Westphal and Brogard, 1997;Kubitz et al, 1999;Nadai et al, 2001;Congiu et al, 2002). However, there is little information on the effect of NAFLD on these same parameters.…”