OVERVIEW ― 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 (e.g., acute kidney injury) in patients with cirrhosis.
PHARMACOKINITIC & PHARMACODYNAMIC CHANGES IN CIRRHOSIS
Cirrhosis may result in hemodynamic changes and complications (e.g., ascites) that may impact drug pharmacokinetics; however, the effect of these factors is variable depending on patient characteristics (e.g., severity of cirrhosis) and the specific drug (see Table 1).
Risk factors for adverse drug reactions in patients with cirrhosis include (1) 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. In addition, patients with cirrhosis may develop capillarization of the hepatic sinusoids, and this impedes the transfer of substrates to the hepatocytes for metabolism. This may lead to increased bioavailability and higher serum concentrations of some drugs. (2) 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). (3) Changes in cytochrome P450 activity. (4) Hypoalbuminemia: Patients with cirrhosis may have decreased albumin as the result of a combination of impaired production and dilution from fluid retention. 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. (5) Cholestasis: Impaired bilirubin secretion and bile formation can impact drug clearance and subsequently increase serum drug levels, resulting in toxicity. (6) Portal hypertension: Portal hypertension indirectly affects drug metabolism by ascites can impact the volume of distribution for some drugs. Ascites can also contribute to intestinal edema and impaired permeability, which impacts bioavailability of oral medications and portal gastropathy can impact absorption of oral medications and impact the drug's bioavailability and 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).
When a patient with cirrhosis begins a medication, we monitor the patient for signs of decompensation (e.g., ascites) or extrahepatic ADRs (e.g., rash), in addition to advising the patient to report any side effects (e.g., anorexia, nausea). The monitoring plan is individualized based on the risk of drug toxicity, the severity of cirrhosis, and the patient's coexisting conditions.
| Table (1). Pharmacokinitics and pharmacodynamic changes | |
|---|---|
| Pathophysiological factor | Clinical consequence |
| Reduced hepatic blood flow/lower first‐pass extraction and portosystemic shunting | Higher bioavailability/serum levels |
| Hypoalbuminaemia | Less protein binding (increased serum concentrations) |
| Ascites/oedema | Increased volume of distribution for hydrophilic drugs |
| Portal gastropathy | Altered (increased or decreased) drug absorption |
| Loss of CYP metabolic activity | Reduced first‐pass metabolism/clearance |
| Reduced glutathione stores | Increased toxicity |
| Impaired biliary excretion | Increased serum concentrations |
| Impaired renal excretion | Increased serum concentrations |
CARDIOVASCULAR MEDICATIONS
ACEI AND ARBs ― 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. 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 (i.e, maintaining MAP > 82 mmHg), electrolytes, and kidney function. Both ACEIs and ARBs are effective for treating arterial hypertension, but they do not lower portal pressures.
BETA BLOCKERS ― 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 (i.e, maintaining mean arterial pressure > 82 mmHg) and based on heart rate response while observing for adverse effects (e.g, fatigue, acute kidney injury). For further information, see note on "Management of esophageal varices". Avoid the following beta blockers for patients with cirrhosis: (1) Labetalol, beta and alpha blocker, has been associated with fatal drug-induced liver injury. (2) Nebivolol, beta 1 selective blocker, has been shown to increase portal pressures.
DIURETICS ― Thiazide diuretics are rarely used in cirrhosis. They have minimal impact on ascites and are associated with electrolyte abnormalities (e.g., hyponatremia, hypokalemia) that can precipitate hepatic encephalopathy. Other diuretics ― For further information, see note on "Clinical management of ascites".
CALCIUM CHANNEL BLOCKERS (CCBs) ― Avoid CCBs that do not have modifiable doses. For CCBs with various dosing options, reduce the initial dose and maintain the lowest effective total daily dose. CCBs, including the dihydropyridines (nifedipine) and nondihydropyridines (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.
ANTICOAGULANTS ― Using anticoagulation in many cirrhosis patients doesn't seem to be riskier than in those without cirrhosis. But when patients also have esophageal varices, bleeding risk with anticoagulation seems to go up. Anticipate use of low-molecular-weight heparin (LMWH) to treat VTE, with bridging to warfarin unless the INR is elevated. Some experts allow warfarin when baseline INRs are elevated, but still below 1.7. Or a direct oral anticoagulant (DOAC) may be chosen in Child-Pugh A cirrhosis or possibly Child-Pugh B. Limited evidence suggests bleeding risk is similar to using warfarin or LMWH. For more information, see note on "Safety of using anticoagulants in patients with cirrhosis".
LIPID LOWERING AGENT ― Statins are not used for patients with decompensated cirrhosis or significant cholestasis (i.e, 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.
Avoid atorvastatin (Lipitor) for patients with cirrhosis because of higher serum drug concentrations that may increase the risk of rhabdomyolysis. Pravastatin is not extensively metabolized by the liver and may be used for patients with compensated cirrhosis because the risk of liver injury is low. For patients with compensated cirrhosis, statins are associated with beneficial effects, including decreased portal pressures (simvastatin [Zocor]) and lower risk for hepatocellular carcinoma.
HYPOGLYCEMIC MEDICATIONS
- Insulin is generally regarded as safe for patients with cirrhosis, while dose titration should be done cautiously because of possible coexisting conditions or symptoms (e.g., early satiety, poor appetite). The pharmacokinetics of insulin are largely unchanged in the setting of cirrhosis. For further information, see note on "Precautions or contraindications for the use of antidiabetic drugs - Section 'Special Situations'".
- 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 (e.g., alcohol use, impaired renal function).
- Sulfonylureas: 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. As a result, serum drug levels may be increased, and this may lead to higher risk of hypoglycemia.
- Meglitinides: Repaglinide (Novonorm) is avoided in patients with cirrhosis, because the pharmacokinetics of repaglinide are significantly altered in patients with hepatic impairment.
- Pioglitazone: Avoid in patients with decompensated cirrhosis or peripheral edema, however, it can be used for patients with compensated cirrhosis without peripheral edema.
GASTROINTESTINAL AGENTS
Proton pump inhibitors (PPIs) ― For patients with cirrhosis and an indication for PPIs, esomeprazole (Nexium) is typically used, when available, based on pharmacokinetic data. For patients with decompensated cirrhosis, omeprazole (Losec), lansoprazole (Zoton), and rabeprazole (Pariet, Bepra) are generally avoided.
Long-term safety data for PPIs in patients with cirrhosis are uncertain because some studies suggest an increased risk of infection (spontaneous bacterial peritonitis, Clostridium difficile infection) or hepatic encephalopathy. The pharmacokinetics of PPIs vary depending on the specific drug. For example, the pharmacokinetics of esomeprazole are largely unchanged, while other PPIs (omeprazole, lansoprazole, rabeprazole) have altered pharmacokinetics in the setting of hepatic impairment due to decreased rates of hepatic clearance. For further information, see note on "Pharmacotherapy of oral proton pump inhibitors (PPIs)".
Histamine type 2 receptor antagonists — Avoid cimetidine (Tegamet) because it is associated with encephalopathy. When histamine type 2 receptor antagonists are indicated, use famotidine (Antodine) 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. For further information, see note on "Pharmacology of histamine 2 (H2) antagonists".
ANTIBIOTICS
Avoid the following antimicrobial agents because of the increased risk of hepatotoxicity in patients with cirrhosis...- Macrolides: Avoid erythromycin and azithromycin because of increased risk of acute liver injury and mortality in patients with cirrhosis
- Chloramphenicol
- Erythromycin
- Ketoconazole
- Tetracycline
ANALGESICS
Analgesic choice in patients with cirrhosis should be individualized depending on etiology of cirrhosis, nutritional status, adherence, renal function, liver transplant candidacy, and drug-drug interaction. Nonsteroid anti-inflammatory agents are contraindicated as they can induce GI bleed and renal failure. Opioid analgesic should be used with caution as it can precipitate encephalopathy. Acetaminophen at a dose less than 2 gm/day is a reasonably safe option. In case of inadequate pain relief, tramadol 25 mg every 8 hours can be used. For intractable pain hydromorphone orally or fentanyl topical patch can be used.
REFERENCES
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Amarapurkar, D.N. (2011). Prescribing Medications in Patients with Decompensated Liver Cirrhosis. [online] International Journal of Hepatology. Available at: https://www.hindawi.com/journals/ijh/2011/519526
Lewis, J.H. and Stine, J.G. (2013). Review article: prescribing medications in patients with cirrhosis - a practical guide. Alimentary Pharmacology & Therapeutics, 37(12), pp.1132–1156
Jennings, J. (2020). [online] UpToDate. Available at: https://www.uptodate.com/contents/overview-of-medication-adjustments-for-adult-patients-with-cirrhosisWestphal, J.-F. and Brogard, J.-M. (1997). Drug Administration in Chronic Liver Disease. Drug Safety, 17(1), pp.47–73. Available at: https://pubmed.ncbi.nlm.nih.gov/9258630