The liver is the principal organ of metabolism in the body although other sites are involved such as the gut wall, kidney, skin and lungs. Drug metabolism, by means of enzyme reactions in the liver, is the body's main method of metabolizing drugs. Drug molecules are converted into more polar compounds, which aid their elimination. Generally, metabolism results in the loss of pharmacological activity because transport to the site of action is limited due to reduced lipid solubility, or because the molecule is no longer able to attach to its receptor site. However, in some circumstances drugs are metabolized to more active forms, for example the conversion of codeine to morphine, primidone to phenobarbitone and amitriptyline to nortriptyline.
Concentrations of enzymes involved in both phase I and II reactions vary significantly between individuals with normal hepatic function and even more so between the healthy population and those with hepatic impairment.
Chronic liver disease is more predictably associated with impaired metabolism of drugs than acute liver dysfunction. However, in cases of severe acute liver failure, the capacity to metabolize the drug may be significantly impaired.
In the chronic state, cirrhosis of any aetiology, viral hepatitis and hepatoma can decrease drug metabolism. In moderate to severe liver dysfunction, rates of drug metabolism may be reduced by as much as 50%. The mechanism is thought to be due to spatial separation of blood from the hepatocyte by fibrosis along the hepatic sinusoids.
The use of certain drugs in patients with cirrhosis occasionally increases the risk of hepatic decompensation. An example of this is the increased risk of hepatic encephalopathy in some patients who receive pegylated interferon alfa-2a in combination with ribavirin for the treatment of chronic active hepatitis related to the hepatitis C virus. In addition, co-infection with hepatitis B or C virus, even in the absence of cirrhosis, increases the risk of hepatotoxicity from antiretroviral therapy in patients with coexistent HIV infection.
In the presence of chronic liver disease, there is potential for changing the systemic availability of high extraction drugs, thereby affecting plasma concentrations. A potential consequence of liver disease is the development of portosystemic shunts that may carry a drug absorbed from the gut through the mesenteric veins directly into the systemic circulation. As such, oral treatment with high hepatic clearance drugs such as morphine or propranolol can lead to high plasma concentrations and an increased risk of adverse effects.
Liver damage can also affect drugs with low hepatic clearance. For instance, the effect of warfarin, which has a low extraction ratio, is increased due to the reduced production of vitamin K-dependent clotting factors.
The pharmacokinetic interaction between alcohol and drugs is more complex. An acute ingestion of alcohol may inhibit a drug's metabolism by competing with the drug for the same set of metabolising enzymes. Conversely, hepatic enzyme induction may occur with chronic excessive alcohol ingestion via CYP2E1 resulting in increased clearance of certain drugs (for example phenytoin, benzodiazepines). After these enzymes have been induced, they remain so in the absence of alcohol for several weeks after cessation of drinking. In addition, some enzymes induced by chronic alcohol consumption transform some drugs (for example paracetamol) into toxic compounds that can damage the liver.
In the presence of cholestatic jaundice, drugs and their active metabolites that are dependent on biliary excretion for clearance will have impaired elimination. Further impairment will occur if the compound is excreted as a glucuronide and is subject to enterohepatic circulation.
High extraction ratio
Low extraction ratio
Calcium channel blockers
Non-steroidal anti-inflammatory drugs
Evaluating Hepatic Function
It is also important to look for signs of acute or chronic liver disease such as the presence of jaundice, spider naevi, palmar erythema, ascites, abdominal distention, hepatomegaly, splenomegaly and caput medusa. If there is clinical evidence of liver disease, further investigation is required. This includes liver function tests and an ultrasound of the abdomen. A portal vein Doppler study is also recommended to assess for the presence of portal hypertension. A slowing or reversal of portal vein blood flow indicates portal hypertension which may be related to either liver cirrhosis or portal vein thrombosis.
In renal disease, serum creatinine concentration and the glomerular filtration rate provide a reasonable guide to drug dosage requirements. In contrast, there is no single test that measures liver function so a reliable prediction of pharmacokinetics is not possible. Some evaluation of hepatic function is possible by assessing serum albumin and bilirubin, and prothrombin time. However, these parameters are not directly related to drug clearance. Although not directly correlated with liver dysfunction, elevated liver enzymes may raise the suspicion of hepatic impairment requiring further investigation.
The Child-Turcotte score was designed to estimate the operative risk of an alcoholic patient with cirrhosis. The parameters used include serum concentrations of bilirubin and albumin, prothrombin time, nutritional status and ascites. These parameters were modified to substitute degree of encephalopathy for nutritional status and then became known as the Child-Pugh classification.The grades A, B and C may also be a useful indicator of an individual's ability to effectively metabolize a drug. An alternative method for assessing liver dysfunction is the Model for End-Stage Liver Disease (MELD) score. This may be a more accurate method but is less accessible to most clinicians because it involves calculating the score.
Points assigned = 1
Points assigned = 2
Points assigned = 3
Prothrombin time – seconds over control
Total score of 5–6 is grade A or well compensated disease (1 and 2 year survivals are 100% and 85%)
Total score of 7–9 is grade B or disease with significant functional compromise (1 and 2 year survivals are 80% and 60%)
Total score of 10–15 is grade C or decompensated liver disease (1 and 2 year survivals are 45% and 35%)
Depending on hepatic clearance and the therapeutic index of the drug, dose adjustments or drug avoidance may be required in grades B or C chronic liver disease.
Evaluating the drug in question
Drugs with a narrow therapeutic range that are extensively metabolised by the liver (that is, greater than 20% of their total elimination) should either be avoided altogether (e.g. pethidine) or used with extreme caution (e.g. morphine, theophylline) in patients with significant liver disease.
Drugs with a wide therapeutic range which also undergo extensive hepatic metabolism should be used with caution. In particular, the dosing interval should be increased or the total dose reduced (e.g. carvedilol).
If hepatic elimination is limited (that is, accounting for less than 20% of total elimination), then the therapeutic range of the compound should be reviewed. If the drug has a wide therapeutic index, then the likelihood of an adverse effect related to hepatic impairment is low. However, if the drug has a narrow therapeutic index, then caution should be exercised as significant hepatic impairment may have a clinically relevant effect on the pharmacokinetics (e.g. lamotrigine).
If greater than 90% of the compound is excreted unchanged in the urine, then hepatic impairment is unlikely to play a significant role in the accumulation of the drug and therefore toxicity.
Factors to consider when prescribing drugs dependent on hepatic elimination
- Ascertain how much the drug depends on hepatic metabolism for its elimination from the body.
- Determine the degree of hepatic impairment using the Child-Pugh classification, hepatic enzyme levels and possibly an ultrasound of the liver with portal vein Doppler study.
- If there is doubt about the degree of hepatic impairment or the drug has a narrow therapeutic index (that is, the upper dose range for efficacy is close to the lower concentration range of toxicity), then lower the recommended starting dose by approximately 50%, and titrate to effect under careful supervision – 'start low and go slow'.
- Determine possible interactions between the new drug and any drugs the patient is already taking.
Reference: Sloss A, KublerP. Prescribing in liver disease; Aust Prescr 2009: 32:32-5