Dose Adjustment in Patients with Liver Disease

Abstract

Unfortunately, there is no endogenous marker for hepatic clearance that can be used as a guide for drug dosing. In order to predict the kinetic behaviour of drugs in cirrhotic patients, agents can be grouped according to their extent of hepatic extraction. For drugs with a high hepatic extraction (low bioavailability in healthy subjects), bioavailability increases and hepatic clearance decreases in cirrhotic patients. If such drugs are administered orally to cirrhotic patients, their initial dose has to be reduced according to hepatic extraction. Furthermore, their maintenance dose has to be adapted irrespective of the route of administration, if possible, according to kinetic studies in cirrhotic patients. For drugs with a low hepatic extraction, bioavailability is not affected by liver disease, but hepatic clearance may be affected. For such drugs, only the maintenance dose has to be reduced, according to the estimated decrease in hepatic drug metabolism. For drugs with an intermediate hepatic extraction, initial oral doses should be chosen in the low range of normal in cirrhotic patients and maintenance doses should be reduced as for high extraction drugs. In cholestatic patients, the clearance of drugs with predominant biliary elimination may be impaired. Guidelines for dose reduction in cholestasis exist for many antineoplastic drugs, but are mostly lacking for other drugs with biliary elimination. Dose adaptation of such drugs in cholestatic patients is, therefore, difficult and has to be performed according to pharmacological effect and/or toxicity. Importantly, the dose of drugs with predominant renal elimination may also have to be adapted in patients with liver disease. Cirrhotic patients often have impaired renal function, despite a normal serum creatinine level. In cirrhotic patients, creatinine clearance should, therefore, be measured or estimated to gain a guideline for the dosing of drugs with predominant renal elimination. Since the creatinine clearance tends to overestimate glomerular filtration in cirrhotic patients, the dose of a given drug may still be too high after adaptation to creatinine clearance. Therefore, the clinical monitoring of pharmacological effects and toxicity of such drugs is important. Besides the mentioned kinetic changes, the dynamics of some drugs is also altered in cirrhotic patients. Examples include opiates, benzodiazepines, NSAIDs and diuretics. Such drugs may exhibit unusual adverse effects that clinicians should be aware of for their safe use. However, it is important to realise that the recommendations for dose adaptation remain general and cannot replace accurate clinical monitoring of patients with liver disease treated with critical drugs.

Drug dosage recommendations in patients with chronic liver disease

“…The bulletin written by Shapiro (20) compared the Child-Pugh scores with the Cockcroft-Gault equation used in the adjustment for renal insufficiency. In some studies, the adjustment based on the E H with supplementary information such as plasma protein binding, hepatic cytochrome metabolism or transaminases among others (1,17,19) is proposed. However, general recommendations are proposed for most of the drugs.…”

“…When no information was found, the adjustment recommendations were given according to the process defined by Delcò et al (1), based on the method established by Huet et al (11) and Krähenbühl et al (12). This method classifies each drug according to three parameters: hepatic extraction ratio (E H ) -classified in 3 categories (high ≥ 60%, intermediate 30-60% and low ≤ 30%), bioavailability (F) and plasma protein binding (PB) ( Table I).…”

“…Alterations affecting the kinetics of drugs in chronic liver disease (CLD) are mainly due to three mechanisms: reduction of portal blood flow which affects the pre-systemic elimination of high extraction drugs; decreased synthesis of transport proteins, mainly albumin and alpha-glycoprotein, which affect the bioavailability of drugs highly bound to plasma proteins; reduced drug-metabolizing hepatic enzymes, which affects the amount of plasma active metabolite, thus, the effectiveness and toxicity (1).…”

Pain Management in the Cirrhotic Patient: The Clinical Challenge

“…2 In patients with severe cholestasis, the clearance of drugs with high biliary elimination, such as buprenorphine, may also be compromised because of dysfunction of basolateral and/or apical transmembrane transport systems in hepatocytes, requiring dose reduction or avoidance of use of the drug. 4,6,7 dosing of analgesic drugs with a predominant renal elimination may require adjustment in patients with liver disease (Table 1). Cirrhotic patients often have impaired renal function despite a normal serum creatinine level because of poor nutrition and reduced muscle mass resulting in less creatinine production.…”

Cuidados pré-operatórios em hepatopatas

“…Benzodiazepínicos como midazolam e diazepam apresentam metabolismo lentificado, devendo ser evitados com o risco de precipitar encefalopatia e depressão do sistema nervoso central. 10 O fluxo sanguíneo hepático, especialmente da artéria hepá-tica, é diminuído durante a anestesia geral e cirurgia. Essa redução na oxigenação é crítica e leva a perdas das funções hepáticas mínimas existentes.…”