Pharmacokinetic Changes in Liver Failure and Impact on Drug Therapy

Pharmacokinetics is a term that describes the time course and fate of a drug in the body. The term encompasses drug absorption, distribution, metabolism, and elimination and is often referred to as drug disposition.1Absorption is defined as the process by which a drug enters the systemic circulation, distribution is the movement of the drug between body compartments, and metabolism encompasses the activation or inactivation of the drug through biotransformation reactions. Elimination is the removal of the drug from the body through different routes, including in urine, feces, and bile.2Critically ill patients pose several challenges to health care providers that are related to medication pharmacokinetics. These challenges are due to the complex interactions of the patient’s multiple disease states and often are due to the presence of multiorgan dysfunction. Organ dysfunction affects the safety and effectiveness of medications because many organs are involved in drug disposition.1 Metabolism occurs in multiple areas of the body; however, the liver plays a central role in drug metabolism because of the high concentrations of multifunctional enzymes. The liver has hepatocytes that contain the necessary enzymes for metabolic pathways that activate or inactivate the drug.1The disposition of many medications relies on hepatic function for metabolism and elimination, and these processes may be hampered when physiological factors impair liver function.3 Common drug classes that are highly dependent on the liver for metabolism include analgesics, sedatives, antibiotics, and anticoagulants. In order to better predict the impact of hepatic dysfunction on medication pharmacokinetics, it is important to understand the factors affecting hepatic metabolism. The liver’s ability to eliminate drugs from the body is dependent on blood flow to the liver and its enzymes’ ability to metabolize drugs. Medications are classified as those whose metabolism is dependent on hepatic blood flow (eg, morphine) and those whose metabolism is dependent on liver enzyme activity (eg, diazepam). Drugs that are dependent on blood flow for metabolism are very sensitive to changes in perfusion such as episodes of hypotension, hypovolemia, or shock.3–6 In the setting of hypotension or shock, hepatic blood flow is decreased, resulting in reduced metabolism and increased systemic concentrations of these medications.6 In addition, when medications that are dependent on hepatic blood flow for metabolism are given orally, their initial metabolism during the absorption process (ie, first-pass metabolism) is reduced in shock states, increasing the oral bioavailability and systemic concentrations of these agents. Oral medications should be avoided in patients with shock, and the medications should be administered parenterally.Alternatively, drugs dependent on liver enzymes for metabolism are susceptible to changes in liver enzyme activity and protein binding; therefore, changes in activity of the metabolic enzymes or protein binding will greatly affect the hepatic clearance of the drug.2–6 Metabolic enzymes may be further classified as phase I (ie, oxidation) or phase II (ie, glucuronidation, sulfation). Certain medications are metabolized through either phase I or phase II enzymes and are affected to various degrees.2–6 Albumin is the primary drug-binding protein, and its systemic concentration is reduced during critical illness, resulting in an increase in the pharmacologically active free concentration of the drug and potentially an enhanced pharmacologic effect. Factors that reduce liver enzyme activity include shock and other medications that inhibit the metabolizing ability of the liver. Both of these conditions may result in increased systemic drug concentrations.This article provides an overview of the pharmacokinetic alterations in acute and chronic liver failure while highlighting key points to guide agent selection, dosing, and monitoring.The liver is a complex organ with a wide array of functions: carbohydrate, protein, and lipid metabolism; clearance of toxins; and synthesis of clotting factors. Liver failure is considered the loss of normal liver function and can be classified as acute or chronic.7 Both acute and chronic liver failure will alter the pharmacokinetic parameters of many medications and may result in various changes in drug disposition, ultimately resulting in altered pharmacologic effect.7–10Acute liver failure is defined as evidence of coagulation abnormalities (prolonged prothrombin times and elevated international normalized ratios [INRs]) and any degree of mental alteration in patients without preexisting cirrhosis and with a duration of illness of less than 26 weeks.11 In addition to coagulopathies, acute liver failure is commonly associated with elevated levels of aspartate aminotransferase, alanine aminotransferase, and bilirubin.12 It is a rare but life-threatening disease that occurs after a triggering event. Common triggering events include viral infection (specifically hepatitis A, B, E), autoimmune liver disease, acute ischemic hepatocellular injury (shock liver), or drug-induced liver injury (eg, acetaminophen toxicity).9 Acute liver failure is characterized by free radical damage, oxidative stress, and hepatocellular necrosis.13 Clinical manifestations of acute liver failure may include coagulopathies, encephalopathy, hypotension, and renal insufficiency.13–15In patients with chronic liver failure, the extent of hepatic injury is usually more significant and has occurred for more than 26 weeks.11 Common causes include long-term alcohol abuse or chronic viral hepatitis.3 The continuous cycle of damage, inflammation, and healing of the liver results in fibrotic tissue, decreased perfusion, and various degrees of hepatocyte dysfunction.3,16–19 Advanced liver disease is termed cirrhosis and is divided into compensated (early stages) and decompensated (later stages) cirrhosis. In compensated cirrhosis, the liver can still carry out most functions, and the disease manifests as nonspecific signs and symptoms such as weight loss and weakness.7 In decompensated cirrhosis, liver function is altered by fibrosis that leads to ascites, encephalopathy, and gastrointestinal and variceal bleeding.19 Fibrosis also leads to hemostatic abnormalities that increase the risk of bleeding and thrombosis.7 Cardinal features of coagulopathies include thrombocytopenia, excessive fibrinolysis, platelet dysfunction, and disseminated intravascular coagulopathy.3,7,16–19Acute liver failure may have variable effects on pharmacokinetic processes. Although diffuse necrosis is present, hepatocyte dysfunction is generally mild and does not significantly affect drug disposition.10,20,21 During times of acute injury, blood levels of aminotransferases are often elevated.3 Despite these changes, the pharmacokinetic parameters of hepatically metabolized medications do not change much in patients with liver failure due to active viral hepatitis or acute ischemic liver injury.3,20,21Cirrhosis has a marked effect on the pharmacokinetics of a drug because of the irreversible liver damage. Cirrhosis affects drugs that are dependent on hepatic blood flow and liver enzyme activity for metabolism because of the decreased hepatic blood flow and the reduction in total functional enzymes. Cirrhosis is associated with notable pharmacokinetic alterations, including increased bioavailability of oral drugs that depend on hepatic blood flow for metabolism, increased volume of distribution due to decreased protein binding, decreased drug metabolism due to reduced liver enzyme activity, and decreased elimination.3Additionally, these alterations are dependent on the severity of hepatic impairment. The Child-Pugh score and the Model for End-Stage Liver Disease (MELD) are validated scoring systems used in liver failure. The Child-Pugh score (Table 1)4 represents the severity of hepatic insufficiency and can be used to determine the need for dosing adjustments for drugs metabolized by the liver in patients with hepatic dysfunction.3 The MELD scoring system is used to determine prognosis in patients with liver failure. Alterations in pharmacokinetic properties in acute and chronic liver failure are summarized in Table 2.1–16The management of acute and chronic pain in patients admitted to the intensive care unit is key to appropriate patient care and facilitation of optimal clinical outcomes.22 Most analgesics, including acetaminophen, most nonsteroidal anti-inflammatory drugs (NSAIDS), and opioids rely heavily on the liver for metabolism and elimination.21,22 Drug accumulation and adverse effects may occur as a consequence of liver failure.16,21,22 Specific guidelines for analgesic dosing or agent selection for critically ill patients with liver failure are lacking. However, daily monitoring of general markers used to monitor liver function such as INRs, prothrombin times, transaminase levels, and total bilirubin levels will guide whether a dose decrease or discontinuation is warranted.16,21,22 Notably, these markers of liver function may not correlate with the severity of injury like serum creatinine level and creatinine clearance correlate with the degree of renal dysfunction. Thus, dose adjustments in liver injury are made empirically because these markers reflect hepatocellular damage rather than hepatocellular function. This situation is unlike dose adjustments with renal dysfunction, which are based on creatinine clearance.3–6Acetaminophen is used both as monotherapy and in combination with opioids for acute and chronic pain management.18,23 Typical dosing of acetaminophen is 650 mg every 4 to 6 hours up to a maximum daily dosage of 4 g in patients without liver dysfunction. In patients with chronic liver failure, decreased metabolism leads to prolongation of the normal drug half-life and higher plasma concentrations compared with healthy persons, increasing the potential for adverse effects.18 In addition, a small portion of acetaminophen is metabolized by the cytochrome P450 isoenzyme CYP2E1 to N-acetyl-p-benzoquinone imine (NAPQI), which is hepatotoxic and must be conjugated to glutathione to be made nontoxic. It has been suggested that patients with liver failure may have lower levels of glutathione and therefore an impaired ability to detoxify NAPQI. However, the evidence suggesting that low glutathione stores are linked with adverse effects from acetaminophen use is limited.24 Owing to the prolongation of the drug’s half-life, it is reasonable to avoid acetaminophen administration in patients with severe hepatic dysfunction, and, if use is necessary, restrict the maximum daily dose to 2 g.23NSAIDs as a drug class are ideal agents for pain management because of their anti-inflammatory properties; however, most NSAIDs are metabolized by the liver.18,22,23 The impact of liver failure on drug disposition for NSAIDs is variable and highly dependent on the individual agent. Specific recommendations for dosing adjustments and monitoring with NSAIDs are lacking. Chronic liver failure is often accompanied by impaired renal function, which may further increase concentrations of NSAIDs. In addition, for patients who have varices due to cirrhosis, increased concentrations of NSAIDs may further increase the risk of a bleeding episode.21 NSAIDs should be dosed cautiously in patients with liver dysfunction, and there should be close daily monitoring of increased fluid retention, increased blood pressure, and reductions in hemoglobin level, hematocrit, and platelet count.18,22,23Last, opioids are a class of analgesics used for moderate to severe pain. Opioid agents undergo metabolism through the liver, and some require activation by the liver to produce their analgesic effects.20 Morphine and hydromorphone are dependent on hepatic blood flow for metabolism. Although the metabolism of parenteral forms may not be impaired in patients with cirrhosis, first-pass metabolism may be impaired in patients with chronic liver disease, leading to increased bioavailability and risks for adverse effects following administration of oral morphine and hydromorphone.22 Initial dose reductions should be applied in patients with hepatic dysfunction who require opioid therapy, and doses should be titrated slowly to achieve adequate pain control. In addition, continuous monitoring of signs and symptoms of toxic effects of opioids should be emphasized.Common adverse effects associated with accumulation of opoids include oversedation and respiratory depression.18,22–24 Conversely, preventing inadequate pain control in patients receiving specific opioid agents that depend on the liver for activation is also important.22 Oxycodone and codeine are primary examples of agents that require this biotransformation. Oxycodone is metabolized in the liver into its active form, oxymorphone, whereas a small fraction of codeine is activated to morphine. As a result of decreased enzymatic activity in patients with liver failure, analgesic effects from oxycodone and codeine may be reduced.24 However, because only a small fraction of codeine is converted to morphine, this agent may be used with caution in patients with liver failure. In contrast, oxycodone’s metabolite, oxymorphone, has minimal analgesic effects compared with oxycodone. Because of the reduced biotransformation of oxycodone to oxymorphone, concentrations of oxycodone are increased, which may increase risk for adverse effects. Thus it is recommended to initiate oxycodone at lower doses in patients with liver failure.24Often, when one is considering both the need to provide appropriate care in critical illness and the fear of adverse effects of analgesic medications, the result may inadvertently be undertreatment of pain in critically ill patients. However, the best approach to optimal pain management involves careful selection of an analgesic agent, starting with low doses, and use of short-acting opioids (eg, fentanyl) with doses titrated to provide adequate pain control.22,23Appropriate sedation management is a key component of care for many critically ill patients to help achieve optimal levels of both comfort and safety. Ideal sedatives have a rapid onset of action and are readily cleared from the body without accumulation. The most commonly prescribed sedatives are propofol, dexmedetomidine, and benzodiazepines.2Propofol metabolism does not appear to be significantly altered by hepatic disease; therefore, dose adjustments are often not necessary in this population. In general, propofol clearance may be slower in critically ill patients because of reduced hepatic blood flow even though this does not correlate with an increase in propofol accumulation in clinical studies, and dose adjustments are most likely not needed.23 Dexmedetomidine is extensively metabolized by the liver, and clearance may be decreased by as much as 50% in patients with severe hepatic dysfunction. Lower doses should be initiated in patients with severe hepatic dysfunction and titrated to achieve sedation goals.23All benzodiazepines are low-extraction drugs that are dependent on hepatic enzymes for metabolism and are eliminated in the urine. Midazolam is extensively metabolized by the liver, and decreased metabolism is responsible for accumulation of midazolam in patients with liver failure.22 In contrast, lorazepam metabolism is reported to be less altered by liver failure. Last, diazepam has active metabolites that contribute to its prolonged sedative actions and the potential for accumulation leading to worsening encephalopathy in patients with cirrhosis. In patients with liver dysfunction, metabolism of diazepam is decreased and thus it has a prolonged half-life.2,22,24 Therefore, lorazepam is preferred in patients with acute or chronic liver failure, but if diazepam is necessary, lower doses should be used.Accumulation of sedative agents in patients with liver dysfunction results in deeper sedation and the potential for adverse effects. To ensure optimal dosing of sedatives and promote good clinical outcomes, sedation should be assessed regularly and repeatedly by using validated clinical assessment tools. Several bedside assessment tools can be used to assess the adequacy of sedation, including the Richmond Agitation-Sedation Scale and the Sedation-Agitation Scale (Tables 3 and 4).25 Frequent assessments every 1 to 2 hours allow for appropriate dose adjustments to maintain optimal sedation and achieve sedation goals for intensive care patients.2,24,26The most notable pharmacokinetic changes in patients with liver failure that affect the efficacy of antibiotics are reductions in protein binding. Antibiotics are considered low-extraction drugs that are not affected by changes in hepatic blood flow; however, they may be affected by a decrease in protein binding. Several antibiotics are highly protein bound; examples include penicillin, ceftriaxone, aztreonam, vancomycin, and daptomycin. Increased concentrations of unbound drug increase the availability of the drug for metabolism or elimination.5 Interpreting ramifications of these changes is difficult in the absence of validated pharmacokinetic data on unbound concentrations of specific antibiotics in the serum and tissues. In addition, predicting how these alterations affect each antimicrobial agent’s effectiveness is challenging because efficacy is heavily dependent on the specific pathogen and the therapeutic concentrations needed for eradication or growth suppression.5,27Serum concentrations of vancomycin and aminoglycosides (tobramycin, gentamicin, and amikacin) can be altered in patients with chronic liver failure when underlying renal dysfunction is present.27–29 Compensatory mechanisms in patients with advanced liver failure lead to intrarenal vasoconstriction, hypoperfusion, and fluid shifts, resulting in the formation of ascites, which may lead to renal failure.27 Often, renal failure translates to reductions in maximum drug concentrations, whereas drug accumulation occurs in ascites secondary to prolonged half-life.28,29 In general, in patients with ascites, the individual dose may need to be increased and the dosing interval prolonged to compensate for the increase in volume of distribution due to the ascites. Adjustments in dosages and dosing intervals are needed in drugs that are highly protein bound to albumin.29 Monitoring strategies and careful clinical assessment are key to optimizing therapy with these agents. Monitoring should involve evaluating for signs of clinical improvement and changes in renal function (ie, urine output and serum level of creatinine) in order to make appropriate dose adjustments.Because of the lack of data needed to provide specific dosing adjustments for each antibiotic, the best practical recommendation is to place a greater emphasis on monitoring the patient’s clinical response to therapy and the toxic effects of specific antimicrobial agents.Heparin, enoxaparin, warfarin, and argatroban are anticoagulants used in the intensive care unit for a variety of indications but most commonly for prophylaxis and treatment of venous thromboembolism. These anticoagulants are metabolized by the liver to various extents, and therefore the effects of hepatic impairment on their pharmacokinetics are variable.30–32 Current recommendations for dosage adjustments for heparin and enoxaparin in patients with liver disease are lacking. However, factor Xa level or prothrombin time may be used to monitor for efficacy and the need for dose adjustments. Other hematologic parameters, such as platelet count and hemoglobin level, are used to monitor for bleeding.30–32Warfarin has a complex pharmacokinetic profile and undergoes extensive hepatic metabolism, primarily through cytochrome P450 enzymes, and is highly bound to albumin. Warfarin must be converted to its active metabolite by hepatic enzymes to exert its desired anticoagulant effect.30 Liver failure can reduce the rate of drug conversion and attenuate warfarin’s effects. Also, liver failure alters clotting pathways, clotting factor production, and platelet count, potentially increasing the risk for bleeding in patients taking warfarin.30,32 Lower doses should be used and warfarin’s effects may be delayed in patients with severe liver dysfunction. The INR is a useful tool to monitor safety and efficacy of warfarin, and warfarin doses are adjusted daily on the basis of INR results.33Argatroban is an alternative anticoagulant used in patients with heparin-induced thrombocytopenia.33 It is a direct thrombin inhibitor that is hepatically metabolized with minimal renal elimination. In patients with liver failure, argatroban’s metabolism and clearance are impaired, leading to a prolonged half-life.33 Therefore, it is recommended that argatroban infusions be started at a lower dose of 0.5 μg/kg per minute. This infusion is monitored via activated partial thromboplastin time (aPTT) and is dose adjusted to achieve an aPTT 1.5 to 3 times the initial baseline value for optimal anticoagulation.33 The different pharmacokinetic changes in liver failure for the anticoagulants and other agents discussed in this article and the clinical implications of those changes are summarized in Table 5.6,12,17–31Many factors play a role in drug disposition in critically ill patients. Alterations in pharmacokinetics are multifactorial. The liver is a major site of metabolism for many drugs administered to critically ill patients; thus, liver failure often results in alterations of the drugs’ pharmacokinetics. Because pharmacokinetic changes vary from agent to agent, clinicians must be aware of the potential for negative consequences related to these pharmacokinetic changes. Increased drug concentrations may lead to significant toxic effects, an increased risk of adverse effects, and negative clinical outcomes. with the pharmacokinetic changes in patients with acute and chronic liver failure to adverse effects. of these pharmacokinetic changes have clinical implications but specific on how to these changes is however, monitoring of adverse effects and signs of treatment failure therapy to be in patients with liver failure.