Version May 2024
INTRODUCTION — The liver is responsible for the selective uptake, concentration, metabolism, and excretion of most drugs. Both prescription and over-the-counter medications can cause hepatotoxicity through a variety of mechanisms. Measures such as drug dose adjustment can help prevent adverse drug reactions (eg, acute kidney injury) in patients with cirrhosis.
This topic will discuss the impact of cirrhosis on pharmacokinetics and medication adjustments for patients with cirrhosis.
The hepatic metabolism of drugs and the mechanisms by which drugs might injure a normal liver are discussed separately. (See "Drugs and the liver: Metabolism and mechanisms of injury".)
The clinical patterns of drug-induced hepatotoxicity are discussed separately. (See "Drug-induced liver injury".)
An overview of complications and general management of patients with cirrhosis is discussed separately. (See "Cirrhosis in adults: Overview of complications, general management, and prognosis".)
IMPACT OF CIRRHOSIS ON PHARMACOKINETICS — Cirrhosis may result in hemodynamic changes and complications (eg, ascites) that may impact drug pharmacokinetics; however, the effect of these factors is variable depending on patient characteristics (eg, severity of cirrhosis) and the specific drug [1,2].
Risk factors for adverse drug reactions in patients with cirrhosis include [3]:
●Alterations in hepatic blood flow – Alterations in hepatic blood flow resulting in lower first-pass drug extraction may be due to decreased portal blood flow, increased hepatic arterial resistance, and/or portosystemic shunting [2,4]. In addition, patients with cirrhosis may develop capillarization of the hepatic sinusoids, and this impedes the transfer of substrates to the hepatocytes for metabolism [5]. This may lead to increased bioavailability and higher serum concentrations of some drugs.
●Portosystemic shunting – In addition to decreasing first-pass drug metabolism, portosystemic shunts may permit cardioactive substances to bypass the liver, resulting in altered electrophysiology of the heart (eg, prolongation of the QTc interval) [6,7]. (See "Acquired long QT syndrome: Definitions, pathophysiology, and causes".)
●Changes in cytochrome P450 activity – Cytochrome P450 metabolic activity is altered in patients with cirrhosis, and the effect depends on the severity of liver disease and the specific cytochrome P450 enzyme [8,9]. The loss of function from some cytochrome P450 enzymes results in lower first-pass drug extraction, and this leads to increased serum drug levels of selected medications (eg, clarithromycin) [3,9-11]. The mechanisms of hepatic metabolism of exogenous products are discussed in more detail separately. (See "Drugs and the liver: Metabolism and mechanisms of injury", section on 'Role of the liver in drug metabolism' and "Overview of pharmacogenomics", section on 'CYP isoenzymes and drug metabolism'.)
●Hypoalbuminemia – Patients with cirrhosis may have decreased albumin as the result of a combination of impaired production and dilution from fluid retention [12]. Drugs with a high-binding profile to albumin can therefore have more unbound drug in the serum, which may impact the clearance of and toxicity risk from these medications [3,13].
●Cholestasis – Impaired bilirubin secretion and bile formation can impact drug clearance and subsequently increase serum drug levels, resulting in toxicity [3,11].
●Portal hypertension – Portal hypertension indirectly affects drug metabolism by the following mechanisms (see "Portal hypertension in adults"):
•Ascites – Ascites can impact the volume of distribution for some drugs [3,11,14]. Ascites can also contribute to intestinal edema and impaired permeability, which impacts bioavailability of oral medications [3,11].
•Portal gastropathy – Portal gastropathy can impact absorption of oral medications and impact the drug's bioavailability [3,11].
•Renal blood flow – Hemodynamic changes related to portal hypertension can impact renal blood flow, leading to decreased renal clearance of medications, particularly for patients with decompensated cirrhosis [11]. (See "Hepatorenal syndrome" and 'Factors that guide decision-making' below.)
GENERAL PRINCIPLES
Factors that guide decision-making — Drug selection and dose adjustments are guided by the following factors:
●Indication for drug therapy (ie, underlying diagnosis, need for long-term therapy)
●Pharmacokinetics of the medication (eg, hepatic metabolism, excretion)
●Safety of alternative medications
●Coexisting conditions (eg, renal impairment)
●Concurrent medications (ie, risk of drug-drug interaction)
●Severity of liver disease, which may be categorized using a clinical definition (ie, compensated or decompensated cirrhosis) or a predictive model (ie, Model for End-stage Liver Disease score or Child-Pugh classification). For example, patients who have not developed a major complication are classified as having compensated cirrhosis, whereas patients who have a complication (eg, variceal bleeding, new onset ascites, spontaneous bacterial peritonitis, hepatic encephalopathy) are classified as having decompensated cirrhosis. Prognostic classifications are discussed in more detail separately. (See "Cirrhosis in adults: Overview of complications, general management, and prognosis", section on 'Prognosis'.)
In general, drug and herbal medication use should be minimized in patients with cirrhosis. For example, some patients are taking medications without a clear indication (eg, proton pump inhibitors). In addition, some drugs are initiated during an inpatient hospitalization and continued after hospital discharge but without an indication for long-term use [15].
Rationale for dose modification — Data on drug dose modification for patients with cirrhosis are limited, although empiric dose reduction combined with clinical monitoring (eg, liver biochemical and function tests) is a commonly used strategy to reduce the risk of adverse drug reactions (ADRs) [11,14]. (See "Approach to the patient with abnormal liver biochemical and function tests", section on 'Common liver biochemical and function tests'.) Historically, dosing adjustments were largely based on expert opinion.
Suggestions to guide dose adjustment include grouping drugs based on the degree of hepatic extraction (ie, first-pass metabolism) and grouping patients based on severity of cirrhosis [3,11,14]. For example, drugs with higher rates of hepatic extraction would be expected to have higher serum drug levels as liver disease progresses, thus requiring dose reduction [3,11]. Conversely, a drug that does not undergo first-pass metabolism may not need initial dose adjustment on the basis of hepatic impairment.
Predictive models for drug metabolism based on severity of liver disease show promise [4,16]. One such model predicted an increase in the serum concentrations of 45 medications in patients with either Child-Pugh classes A or B disease [17]. (See "Cirrhosis in adults: Overview of complications, general management, and prognosis", section on 'Prognosis'.)
Monitoring — When a patient with cirrhosis begins a medication, we monitor the patient for signs of decompensation (eg, ascites, hepatic encephalopathy) or extrahepatic ADRs (eg, rash), in addition to advising the patient to report any side effects (eg, anorexia, nausea) [18]. The monitoring plan is individualized based on the risk of drug toxicity, the severity of cirrhosis, and the patient's coexisting conditions.
Many medications can be used safely in patients with cirrhosis, provided that clinicians are observing for ADRs, drug-drug interactions, and the need for dose adjustment if liver disease progresses or comorbid conditions (eg, renal impairment) develop [3,11,19].
Multidisciplinary team — Medication selection, dose adjustments, and monitoring for patients with cirrhosis typically involve a multidisciplinary approach (hepatology, primary care, pharmacy, and other medical subspecialties [eg, nephrology]).
DRUGS FOR CIRRHOSIS-RELATED CONDITIONS — For specific drug prescribing information, please refer to the Lexicomp database and drug label information.
Portal hypertension and varices — Nonselective beta blockers are used for treating portal hypertension complicated by varices to reduce the risk of variceal hemorrhage. Most beta blockers (except nadolol) primarily undergo first-pass metabolism; therefore, increased plasma concentrations can be expected. Therefore, dosing strategy typically includes initiating a low dose and titrating the dose based on blood pressure (ie, maintaining mean arterial pressure >82 mmHg (calculator 1)) and based on heart rate response while observing for adverse effects (eg, fatigue, acute kidney injury) [3,20]:
●For primary prevention of esophageal variceal hemorrhage, the dosing and safety of beta blockers are discussed separately. (See "Primary prevention of bleeding from esophageal varices in patients with cirrhosis", section on 'Preventive strategies'.)
●For prevention of recurrent variceal bleeding in patients with esophageal varices, the dosing and safety of beta blockers are discussed separately. (See "Prevention of recurrent bleeding from esophageal varices in patients with cirrhosis".)
However, we avoid the following beta blockers for patients with cirrhosis:
●Labetalol: Labetalol, a beta and alpha blocker, has been associated with fatal drug-induced liver injury [21].
●Nebivolol: Nebivolol, a beta 1 selective blocker, has been shown to increase portal pressures [22,23].
Adverse effects of beta blockers, including issues related to patients with ascites or hyponatremia, are discussed separately:
●(See "Major side effects of beta blockers".)
Ascites — Ascites is the most common complication of cirrhosis, and splanchnic arterial vasodilation contributes to ascites formation. The pathogenesis of ascites is discussed separately. (See "Pathogenesis of ascites in patients with cirrhosis".)
Diuretic therapy for ascites typically consists of spironolactone and furosemide (see "Ascites in adults with cirrhosis: Initial therapy", section on 'Diuretic therapy'):
●Potassium sparing diuretics – Spironolactone, a potassium sparing diuretic, is safe for use in patients with cirrhosis, and other drugs in this class (eg, eplerenone) also appear to be safe [22]. However, additional efficacy data on eplerenone are required before this drug can be routinely used for managing ascites. In addition, we avoid triamterene because of the risk of extrahepatic adverse drug reactions (ADRs) (eg, megaloblastic anemia) [22].
●Loop diuretics – For patients with cirrhosis, loop diuretics (eg, furosemide) can be used to help potentiate diuresis and avoid hyperkalemia in the setting of spironolactone use [24,25]. Monitoring patients for adverse effects (eg, hyponatremia, hypo- or hyperkalemia, acute kidney injury) is discussed separately. (See "Ascites in adults with cirrhosis: Initial therapy", section on 'Patient monitoring'.)
●Other diuretics – Vasopressin receptor antagonists are selective antagonists of vasopressin V2 receptors that cause hypotonic diuresis, which can raise serum sodium in patients with hyponatremia due to cirrhosis. However, data do not show a benefit over potassium sparing and loop diuretics for patients with ascites [24,25]. In addition, the vasopressin receptor antagonist tolvaptan is not approved for use in patients with cirrhosis based on US Food and Drug Administration labeling. The use of vasopressin receptor antagonists for patients with hyponatremia is discussed in detail separately. (See "Hyponatremia in patients with cirrhosis", section on 'Vasopressin receptor antagonists'.)
Hepatic encephalopathy — Drug therapy for hepatic encephalopathy includes medications such as lactulose (a nonabsorbable disaccharide) and rifaximin (a nonabsorbable antibiotic) [26]. The risk of ADRs is limited to gastrointestinal side effects, and no dose adjustments are needed to reduce the risk of worsening liver disease [24]. The management of patients with hepatic encephalopathy is discussed separately. (See "Hepatic encephalopathy in adults: Treatment".)
DRUGS FOR COEXISTING CONDITIONS — Patients with cirrhosis may have coexisting conditions (eg, diabetes mellitus) that may require drug therapy.
For specific drug-prescribing information, please refer to the Lexicomp database and drug label information.
The Health Base Foundation (The Netherlands Organization for Health Research and Development) maintains a searchable database on drug safety for patients with cirrhosis [22,27].
Lipid lowering agents — We avoid atorvastatin for patients with cirrhosis because of higher serum drug concentrations that may increase the risk of rhabdomyolysis [22,28,29]. In addition, statins are not used for patients with decompensated cirrhosis or significant cholestasis (ie, total bilirubin >1.75 mg/dL [30 microm/L]) because of increased risk of toxicity. Some patients with decompensated cirrhosis may die from liver failure before experiencing benefits from a lipid lowering agent. (See "Hypercholesterolemia in primary biliary cholangitis (primary biliary cirrhosis)", section on 'Candidates for lipid lowering agents'.)
Statins that are not extensively metabolized by the liver (eg, pravastatin) may be used for patients with compensated cirrhosis because the risk of liver injury is low [30,31]. Initial dosing, monitoring, and dose titration are discussed separately. (See "Statins: Actions, side effects, and administration", section on 'Chronic liver disease'.)
For patients with compensated cirrhosis, statins are associated with beneficial effects, including decreased portal pressures (simvastatin) and lower risk for hepatocellular carcinoma [30,32]. (See "Epidemiology and risk factors for hepatocellular carcinoma", section on 'Statins'.)
Antihypertensives — Patients with cirrhosis who are treated for hypertension are closely monitored because baseline blood pressure can decline without the onset of symptoms. Antihypertensive agents are tapered or stopped for patients with low blood pressure (ie, mean arterial pressure (MAP) ≤82 mmHg). The approach to ambulatory and home blood pressure monitoring is discussed separately. (See "Out-of-office blood pressure measurement: Ambulatory and self-measured blood pressure monitoring".)
●Angiotensin inhibition – For patients with decompensated cirrhosis and/or ascites, angiotensin converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) are avoided because of the risk of renal impairment, and this is discussed separately. (See "Ascites in adults with cirrhosis: Initial therapy", section on 'Avoidance of angiotensin inhibition'.)
For patients with compensated cirrhosis and no ascites, ACEIs and ARBs are started at a low dose and dose adjustments are based on monitoring of blood pressure (ie, maintaining MAP >82 mmHg), electrolytes, and kidney function, which is discussed separately. (See "Treatment of hypertension in patients with diabetes mellitus" and "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults" and "Overview of hypertension in adults".)
Both ACEIs and ARBs are effective for treating arterial hypertension, but they do not lower portal pressures [3,33,34].
●Thiazide diuretics – Available data suggest that thiazide diuretics do not increase risk of adverse drug reactions in patients with cirrhosis; however thiazide diuretics are rarely used in this setting [35]. They have minimal impact on ascites and are associated with electrolyte abnormalities (eg, hyponatremia, hypokalemia) that can precipitate hepatic encephalopathy [22]. (See "Hepatic encephalopathy: Pathogenesis" and "Hyponatremia in patients with cirrhosis".)
Adverse effects of thiazide diuretics are discussed separately. (See "Use of thiazide diuretics in patients with primary (essential) hypertension", section on 'Side effects'.)
●Calcium channel blockers (CCBs) – We avoid CCBs that do not have modifiable doses [22]. For CCBs with various dosing options, we reduce the initial dose and maintain the lowest effective total daily dose. CCBs, including the dihydropyridines (eg, nifedipine) and nondihydropyridines (eg, diltiazem), are extensively cleared by the liver, which results in high serum drug levels due to impaired liver function and extrahepatic shunting, particularly for patients with decompensated cirrhosis [3,22].
Hypoglycemic agents — Patients with cirrhosis may also have diabetes mellitus, which is common in patients with nonalcoholic fatty liver disease [36]. (See "Epidemiology, clinical features, and diagnosis of nonalcoholic fatty liver disease in adults", section on 'Association with other disorders'.)
●Insulin – Insulin is generally regarded as safe for patients with cirrhosis, while dose titration should be done cautiously because of possible coexisting conditions or symptoms (eg, early satiety, poor appetite) [37-39]. (See "Insulin therapy in type 2 diabetes mellitus", section on 'Designing an insulin regimen'.)
The pharmacokinetics of insulin are largely unchanged in the setting of cirrhosis [39].
●Metformin – An alternative to metformin is typically used for patients with diabetes mellitus who have decompensated cirrhosis and additional risk factor(s) for lactic acidosis (eg, alcohol use, impaired renal function). The use of and contraindications to metformin for patients with diabetes mellitus are discussed separately. (See "Metformin in the treatment of adults with type 2 diabetes mellitus".)
●Sulfonylureas – We generally use an alternative drug rather than a sulfonylurea for patients with diabetes mellitus and cirrhosis because sulfonylureas are predominantly metabolized in the liver and are highly protein bound [22,39]. As a result, serum drug levels may be increased, and this may lead to higher risk of hypoglycemia. (See "Sulfonylureas and meglitinides in the treatment of type 2 diabetes mellitus", section on 'Sulfonylureas'.)
●Meglitinides – Repaglinide is avoided in patients with cirrhosis, because the pharmacokinetics of repaglinide are significantly altered in patients with hepatic impairment [39]. (See "Sulfonylureas and meglitinides in the treatment of type 2 diabetes mellitus", section on 'Meglitinides'.)
●Pioglitazone – Pioglitazone is avoided in patients with decompensated cirrhosis or peripheral edema, however, it can be used for patients with compensated cirrhosis without peripheral edema [22,37,39,40]. The use of pioglitazone for treating diabetes mellitus is discussed separately. (See "Thiazolidinediones in the treatment of type 2 diabetes mellitus", section on 'Hepatotoxicity'.)
●Sodium-glucose co-transporter 2 (SGLT2) inhibitors – SGLT2 inhibitors, such as canagliflozin, dapagliflozin, and empagliflozin, promote increased urinary excretion of both sodium and glucose. These drugs appear to be safe for use in patients with cirrhosis and are being studied for treating ascites and portal hypertension [41-43]. It is important to note the risk of urinary tract infections with SGLT2 inhibitor use because infection has been associated with decompensation in patients with cirrhosis. (See "Sodium-glucose cotransporter 2 inhibitors for the treatment of hyperglycemia in type 2 diabetes mellitus".)
Contraindications to and dosing adjustments for other drugs used for treating diabetes mellitus can be found in the Lexicomp drug database and in topics on management of diabetes mellitus:
●(See "Alpha-glucosidase inhibitors for treatment of diabetes mellitus".)
●(See "Dipeptidyl peptidase 4 (DPP-4) inhibitors for the treatment of type 2 diabetes mellitus".)
●(See "Glucagon-like peptide 1-based therapies for the treatment of type 2 diabetes mellitus".)
Acid reducers
Proton pump inhibitors (PPIs) — For patients with cirrhosis and an indication for PPIs, we typically use esomeprazole, when available, based on pharmacokinetic data [22,44,45]. For patients with decompensated cirrhosis, omeprazole, lansoprazole, and rabeprazole are generally avoided [22,24]. The indications for and adverse effects of PPIs are discussed separately. (See "Proton pump inhibitors: Overview of use and adverse effects in the treatment of acid related disorders".)
Long-term safety data for PPIs in patients with cirrhosis are uncertain because some studies suggest an increased risk of infection (eg, spontaneous bacterial peritonitis, Clostridioides [formerly Clostridium] difficile infection) or hepatic encephalopathy, while other studies do not [24,46].
The pharmacokinetics of PPIs vary depending on the specific drug. For example, the pharmacokinetics of esomeprazole are largely unchanged, while other PPIs (eg, omeprazole, lansoprazole, rabeprazole) have altered pharmacokinetics in the setting of hepatic impairment due to decreased rates of hepatic clearance [22,47].
Histamine type 2 receptor antagonists — We avoid cimetidine because it is associated with encephalopathy [48]. When histamine type 2 receptor antagonists are indicated, we use famotidine for patients with cirrhosis, and dose adjustments are not needed due to cirrhosis. However, dose modification is typically needed for patients with coexisting renal impairment. (See "Medical management of gastroesophageal reflux disease in adults".)
ANTIMICROBIALS TO AVOID — We avoid the following antimicrobial agents because of the increased risk of hepatotoxicity in patients with cirrhosis [3]:
●Azithromycin: We avoid azithromycin because of increased risk of acute liver injury and mortality in patients with cirrhosis [49,50].
OTHER DRUGS TO AVOID — In addition to the high-risk drugs listed above, we avoid the following medications in patients with cirrhosis because of the increased risk of hepatotoxicity [3,18]:
●Disulfiram (see "Alcohol use disorder: Treatment overview")
●Methotrexate (see "Major side effects of low-dose methotrexate", section on 'Hepatotoxicity')
●Methimazole (see "Thionamides: Side effects and toxicities", section on 'Hepatotoxicity')
●Nefazodone (see "Serotonin modulators: Pharmacology, administration, and side effects", section on 'Nefazodone')
●Ranolazine (see "New therapies for angina pectoris", section on 'Ranolazine')
●Vitamin A (see "Overview of vitamin A", section on 'Excess')
SPECIAL POPULATIONS
Patients with renal impairment — Patients with cirrhosis and coexisting kidney disease may need drug dose adjustments based on the severity of renal impairment in addition to the severity of hepatic impairment (refer to Lexicomp and the drug label for dosing information for patients with renal impairment). For some patients, a multidisciplinary approach (hepatology, nephrology, pharmacy) is used to reduce the risk of adverse drug reactions.
The management of patients with hepatorenal syndrome is discussed separately. (See "Hepatorenal syndrome".)
Patients undergoing chemotherapy — Patients with cirrhosis who are undergoing chemotherapy require monitoring with liver tests both prior to and during therapy, and chemotherapy may worsen existing liver disease. Patients with cirrhosis are screened for hepatitis B virus prior to undergoing chemotherapy, and this is discussed separately [51]. (See "Hepatitis B virus reactivation associated with immunosuppressive therapy".)
The relationship between liver function and chemotherapy is discussed separately. (See "Chemotherapy hepatotoxicity and dose modification in patients with liver disease: Conventional cytotoxic agents" and "Chemotherapy hepatotoxicity and dose modification in patients with liver disease: Molecularly targeted agents".)
Patients undergoing anesthesia — Patients with cirrhosis may require procedural intervention and anesthesia, and they are at increased risk for intraoperative complications and postoperative morbidity and mortality. Anesthetic management of patients with liver disease is discussed separately. (See "Anesthesia for the patient with liver disease".)
Patients with hepatitis C virus infection — Direct-acting antivirals are medications for treating patients with chronic hepatitis C virus (HCV) infection, and the pharmacology and use of these agents are discussed separately. (See "Direct-acting antivirals for the treatment of hepatitis C virus infection".)
Certain direct-acting antiviral regimens are avoided in patients with decompensated cirrhosis and chronic HCV infection, and this is discussed separately. (See "Management of chronic hepatitis C virus infection: Initial antiviral therapy in adults" and "Management of chronic hepatitis C virus infection: Antiviral retreatment following relapse in adults".)
Patients with tuberculosis — Hepatotoxicity syndromes associated with isoniazid and other antituberculous drugs are discussed separately. (See "Isoniazid hepatotoxicity" and "Antituberculous drugs: An overview", section on 'Hepatotoxicity'.)
Patients with acute or chronic pain — The safety of medications used for pain management in patients with cirrhosis is discussed separately. (See "Management of pain in patients with advanced chronic liver disease or cirrhosis".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Cirrhosis".)
SUMMARY AND RECOMMENDATIONS
●For patients with cirrhosis, risk factors for adverse drug reactions may include (see 'Impact of cirrhosis on pharmacokinetics' above):
•Alterations in hepatic blood flow and portosystemic shunting
•Changes in cytochrome P450 metabolic activity
•Hypoalbuminemia
•Cholestasis
•Complications of portal hypertension (ascites, portal gastropathy)
●For patients with cirrhosis, drug selection and dose adjustments are guided by the following (see 'Factors that guide decision-making' above):
•Indication for therapy (ie, underlying diagnosis, need for long-term therapy)
•Drug pharmacokinetics (eg, hepatic metabolism, excretion)
•Safety of alternative medications
•Coexisting medical conditions (eg, renal impairment)
•Concurrent medications (ie, potential for drug-drug interactions)
•Severity of liver disease
●While data on drug dose modification for patients with cirrhosis are limited, empiric dose reduction combined with clinical monitoring (eg, liver tests) is a commonly used strategy to reduce the risk of adverse drug reactions. (See 'Rationale for dose modification' above.)
●Medication selection, dose adjustments, and monitoring for patients with cirrhosis typically involve a multidisciplinary approach (hepatology, primary care, pharmacy, and other medical subspecialities). (See 'Multidisciplinary team' above.)
●Patients with cirrhosis may have complications that require drug therapy:
•For primary or secondary prevention of esophageal variceal bleeding, the dosing and safety of beta blockers are discussed separately. (See "Primary prevention of bleeding from esophageal varices in patients with cirrhosis" and "Prevention of recurrent bleeding from esophageal varices in patients with cirrhosis".)
•For patients with ascites, dosing for diuretic therapy is discussed separately. (See "Ascites in adults with cirrhosis: Initial therapy".)
•For patients with hepatic encephalopathy, adverse effects of lactulose are mainly gastrointestinal and no dose adjustment is needed to reduce the risk of worsening liver function. (See "Hepatic encephalopathy in adults: Treatment".)
●Patients with cirrhosis may have coexisting conditions (eg, diabetes mellitus) that require drug therapy. For specific drug-prescribing information, please refer to the Lexicomp database and drug label information. (See 'Drugs for coexisting conditions' above.)
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