Medication prescribing in liver dysfunction

Patients with mental illness often have co-occurring substance abuse which increases the risk for developing cirrhosis, particularly with common etiologies such as hepatitis and alcoholic liver disease.^1,2 Drug information resources often provide vague recommendations, as there is a paucity of data to guide medication prescribing in these patients. This article will focus on considerations for prescribing medications in patients with liver dysfunction, including changes in pharmacokinetic and pharmacodynamics properties, etiology of liver disease, use of hepatotoxic medications, and considerations for coagulopathy.

Unlike creatinine, which guides dosage adjustments for medications that are renally-eliminated there is not a single reliable laboratory parameter to use to guide dosage regimens for patients with hepatic dysfunction. The most common assessment in patients with cirrhosis is the Child-Turcotte-Pugh (CTP) scoring classification system. The CTP is a composite assessment of ascites, encephalopathy, total bilirubin, albumin, and prothrombin time. The CTP score is used to characterize liver severity as class A (mild, score 5–6 points), B (moderate, score 7–9 points), or C (severe or 10–15 points; Table 1).^3,4 CTP class A is considered compensated cirrhosis whereas class B and C are considered to reflect decompensated cirrhosis. Drug information resources may include possible dose recommendations relative to the CTP score; however, this serves only as an estimate since the score does not provide information on the ability of the liver to metabolize specific drugs. Other methods of predicting liver function such as clearance of indocyanine green, antipyrine, monoethylene-zylidide, and galactose are not reliable, and thus, are not routinely employed in clinical practice.^5–7 

While not legally mandated, the Food and Drug Administration (FDA) has published formal guidelines for industry regarding pharmacokinetic assessment in patients with impaired hepatic function. This document highlights when studies should and should not be conducted, recommended study designs, inclusion criteria, as well as analysis, interpretation, and reporting of the study results and product labeling descriptions. Of importance, the FDA recommends the following criteria warrant hepatic impairment pharmacokinetic studies: (1) hepatic metabolism and/or drug excretion account for a substantial portion (20%) of elimination of a parent drug or metabolite, (2) the drug has a narrow therapeutic index regardless of route of elimination, or (3) if there is a paucity of information indicating route of elimination. The FDA recommends dose adjustments if there is a >2-fold increase in area under the curve (AUC) or for prodrugs where a higher dose or shorter interval may be needed. Conversely, the following drug properties may support a decision not to study pharmacokinetics per the guidance document: (1) drugs entirely renally excreted, (2) hepatically metabolized by a small extent (<20%) and with a wide therapeutic index, and (3) gaseous or volatile substances with elimination via the pulmonary system.⁵ Further, Table 2, while not all inclusive, may be utilized to determine which psychotropic agents require adjustment in patients with hepatic dysfunction.

In the absence of literature supporting dose adjustments, theoretical considerations guide medication prescribing and dose regimen adjustments in patients with liver dysfunction. Of utmost importance is the understanding that the extent of pharmacokinetic changes that may occur is complex, unpredictable, and drug specific. Knowledge of the pharmacokinetic and adverse effect profile of a medication is essential to guide clinical decision-making in a patient with liver disease.

Typically, patients with cirrhosis have unchanged drug absorption although the rate may be decreased.⁷ These patients also have impaired gastric emptying which may further delay onset of delayed release preparations (e.g. Prozac Weekly^®, Effexor XR^®, Pristiq^®).⁷ In patients with cholestatic disease, bile flow from the liver to the duodenum is impaired. The efficacy of lipophilic drugs dependent on the action of bile salts for absorption (e.g. cyclosporine) may be reduced secondary to lower plasma concentrations of the medication.⁸ 

In the presence of ascites, the volume of distribution (V_d) for hydrophilic drugs will be increased.⁷ If a loading dose is needed in these patients, larger doses may be required. Increases in V_d are also associated with prolonged elimination half-life.⁷ Secondary to decreased synthetic function, patients can have low serum albumin as liver disease progresses. Hypoalbuminaemia can cause higher serum concentrations of highly protein bound (>90%) drugs, such as valproic acid. Hyperbilirubinemia may also cause displacement of drug from protein sites. In both cases, an increase in adverse effects, including toxicity, may occur.⁹ 

In general, the degree of drug metabolism impairment is least affected in chronic liver disease without cirrhosis (e.g. viral hepatitis), moderately affected in compensated cirrhosis, and most affected in decompensated cirrhosis and acute liver failure, particularly fulminant hepatitis.^10,11 The bioavailability of medications can be substantially altered in liver disease depending on (1) the route of metabolism, (2) whether a medication is a prodrug, or (3) the hepatic extraction ratio of the medication.

A clinical decision point for medication prescribing in patients with liver disease is whether medications metabolized through certain routes are preferred or safer compared to other metabolic pathways. The liver has a role in biotransformation of medications to enhance elimination. These biotransformations are referred to as phase I or phase II reactions. Phase I reactions include oxidation, reduction, or hydrolysis reactions, where phase II reactions involve glucuronidation, sulfation, and acetylation reactions.¹¹ Glucuronidation, a type of conjugation reaction, is typically selectively spared versus oxidative metabolic function in the later stages of liver dysfunction.^12,13 As such, medications metabolized through glucuronidation, such as lorazepam, oxazepam, and temazepam, are often preferred for this reason.⁸ Regarding, phase II reactions, research has led to development of the “sequential progressive model of hepatic dysfunction” to account for observations in which cytochrome P450 (CYP) activity is reduced in a selective and sequential fashion depending on the severity and etiology of liver disease.^9,14,15 For example, research demonstrates non-cholestatic liver disease may reduce the activity of CYP1A2, CYP2C19, and CYP3A4 relative to the activity of CYP2D6, CYP2C9, and CYP2E1.¹⁴ In contrast, primary biliary cirrhosis is associated with less effect on CYP3A4 activity compared to non-cholestatic liver disease. Interestingly, patients with non-alcoholic steatohepatitis and other inflammatory diseases may exhibit an upregulation of CYP2E1; however,the impact of this on medication prescribing is not likely clinically significant since the fraction of drug (e.g. acetaminophen) metabolized is often unchanged as long as phase I metabolic pathways are preserved and unsaturated.^14,16 Therefore, the etiology of liver disease may initially guide clinical decisions of which medication to prescribe with continued monitoring for adverse reactions to tailor management.

The efficacy of a prodrug depends on successful conversion to the active moiety, traditionally by hepatic enzymes. Depending on the metabolic requirement for a successful conversion (e.g. de-acetylation, hydrolysis, etc), liver disease may lead to impaired ability or failure to form an active metabolite. Thus, prodrugs, such as tamoxifen, may have diminished therapeutic efficacy in liver disease patients.¹³ 

The bioavailability of a medication is also dependent on the extraction ratio (E), a measure of an organ's ability to remove the drug from systemic circulation. A number closer to one indicates significant elimination by the liver whereas a number closer to zero indicates minimal removal by the organ. The hepatic clearance (Cl_H) of a medication is a product of extraction ratio and hepatic blood flow (Q) such that Cl_H = E x Q. Medications with high extraction ratios (>0.6), like oxcarbazepine, perphenazine, and bupropion, are rate-limited by hepatic blood flow.¹⁷ Patients with cirrhosis often develop portosystemic collaterals secondary to portal hypertension or undergo transjugular intrahepatic porto-systemic shunt (TIPS) surgery.¹¹ This would allow medications to bypass hepatocytes, leading to drug accumulation with higher maximal plasma concentration, increased bioavailability, and slowed elimination.^11,12 These medications, when administered orally, will yield unpredictable serum levels and may not be ideal to incorporate into treatment regimens for patients with cirrhosis. Medications with low extraction ratios (<0.3), like lamotrigine, fluoxetine, or aripiprazole, may be better suited for use in this patient population as only elimination is slowed.¹⁷ Delco et al. offer some guidance on dose reduction using the equation, reduced dose = (normal dose x bioavailability)/100. Extraction ratios can be found for many psychotropic agents and have been published elsewhere.^7,17 Table 3 offers some insight to compare extraction ratios across various psychotropic medication classes. In the event a value cannot be identified, it may be possible to extrapolate the extraction ratio based on the bioavailability of the medication, as bioavailability (F) = 1 – E. This is particularly the case when an agent has a high bioavailability; the medication has a low hepatic extraction ratio. However, the converse may not be true due to multiple factors which can lead to decreased bioavailability.

Providers should consider alternative routes of elimination including biliary excretion, enterohepatic circulation, and renal elimination. If patients present with cholestatic disease, agents eliminated through biliary excretion (e.g. hydroxyzine) or recycled through enterohepatic circulation should be avoided.^13,17 Additionally, serum creatinine significantly overestimates glomerular filtration in these patients secondary to reduced muscle mass and conversion of creatine to creatinine (e.g. paliperidone, lithium).⁷ 

Patients with liver dysfunction have been reported to be more sensitive to both the therapeutic and adverse effects of medications. Specifically, the central nervous system effects of depressants, such as benzodiazepines and opioids, regardless of route of metabolism (phase I or II).⁷ Use of any benzodiazepine may induce encephalopathy, which can be reversed with a benzodiazepine antagonist.²⁹ As such, use of any benzodiazepine is cautioned, in particular those with long-half lives and which are metabolized by phase I reactions (e.g. diazepam), especially as liver disease worsens. Patients with TIPS have an increased risk of developing encephalopathy as blood flow is shunted away from the liver.

The use of non-steroidal anti-inflammatory drugs (NSAIDs) should also be avoided, particularly in moderate-severe liver disease. In cirrhosis, patients have a hyperdynamic circulation. Increased vasodilating substances, such as nitric oxide, activate the renin angiotensin aldosterone system leading to vasoconstriction. Therefore, to maintain renal perfusion and adequate glomerular filtration pressure, these patients are dependent on prostaglandin mediated vasodilation of the renal arteries.⁷ 

The choice to use or avoid a medication with known hepatotoxic potential in a patient with liver disease represents a major clinical controversy. A frequent assumption is chronic liver disease is a risk factor for drug-induced liver injury (DILI); however, whether hepatic dysfunction is a risk factor for hepatotoxicity depends on the etiology of liver disease. For example, patients co-infected with human immunodeficiency virus (HIV) and hepatitis B or C receiving treatment with antiretrovirals are at a higher risk for DILI.^18–20 

Mechanisms of hepatotoxicity are typically classified as (1) intrinsic, dose dependent reactions which are predictable (e.g. acetaminophen-induced liver injury) or (2) idiosyncratic, unpredictable drug reactions. The majority of drug-induced hepatoxicity reactions are idiosyncratic and may either be classified as hypersensitivity/immunoallergic or metabolic-idiosyncratic reactions. As such, researchers have argued baseline liver disease should not place the patient at higher risk for DILI since it is likely genetically or immunologically determined. In this case, liver injury may be protective by reducing the unpredictable generation of a toxic metabolite.^20,21 

Risk factors for DILI may include race, age (elderly patients are typically at higher risk given their age-related decline in liver function with valproic acid being a notable exception), sex (women are at higher risk), alcohol ingestion (secondary to alcohol induced liver injury and depleted glutathione stores), genetic differences in CYP enzyme activity, and certain comorbidities (patients diagnosed with acquired immune deficiency syndrome or those who are malnourished/fasting secondary to reduced glutathione).^18,22 

When monitoring for DILI, one should consider the mechanism of hepatotoxicity to determine appropriate monitoring parameters. Alanine aminotransferase and aspartate aminotransferase, are traditionally used for monitoring DILI, particularly in intrinsic hepatotoxicity reactions. Increases in these enzymes > 3–5 times the upper normal limit (UNL) may indicate acute liver injury resulting from enzyme release from hepatocytes and cholangiocytes, although the positive predictive value of this method is poor and cost effectiveness has been challenged.^21,23 For idiosyncratic reactions, clinicians should monitor for fever, eosinophilia, and rash/dermatologic manifestations.²⁴ Increases in bilirubin (>2x UNL) and alkaline phosphatase would indicate cholestatic injury and would likely be accompanied by symptoms such as jaundice and/or pruritus.²³ General, nonspecific symptoms of hepatoxicity include malaise, nausea, vomiting, anorexia, and abdominal pain should be discussed with patients and monitored throughout the course of therapy.

Although chronic liver disease may not represent a risk factor for hepatotoxicity, patients with baseline hepatic dysfunction would likely poorly tolerate DILI. Patients with cirrhosis are at risk for decompensation when toxic drugs are administered.¹⁸ However, baseline liver disease is not an absolute contraindication to use of a potential hepatotoxin. Use of medications known to cause DILI should be avoided if possible, particularly when other risk factors for hepatoxicity or alternative medications exist, and more vigilant monitoring employed.

An inclusive description of all psychotropics which may cause DILI is beyond the scope of this article. Please see Table 2 for some guidance on medications to avoid in active liver disease. As mentioned, DILI is often an idiosyncratic event. DILI is often captured in post-marketing studies rather than clinical trials as a result of the low incidence.³⁰ Prior to prescribing a medication, a review of the literature should be performed to search for case reports or case series which may have identified risk factors for specific agents.

Patients with liver disease may suffer from coagulopathy, particularly in the end stages of liver disease. A misconception is patients with coagulopathy are “auto-anticoagulated”, likely secondary to higher INR values in these patients. In fact, there is a parallel decrease in both procoagulant and anticoagulant factors in these patients. Therefore, current laboratory tests, such as PT and INR, do not truly represent the risk of bleeding in these patients where there is a restored balance of coagulation status with the concomitant decrease in pro- and anticoagulant drives. An excellent review of this phenomenon has previously been published.²⁵ 

Concerns regarding use of psychotropics in this patient population may include increased bleeding risk from selective serotonin reuptake inhibitor (SSRI)/serotonin-norepinephrine reuptake inhibitor (SNRI) induced gastric ulcers, SSRI/SNRI related decreased platelet aggregation, and use of agents which may cause bone marrow suppression, such as thrombocytopenia. It is advisable to strongly evaluate use in patients by considering concomitant medications (e.g. NSAIDs, anticoagulants, antiplatelets, etc.), current disease states (e.g. cirrhosis with gastroesophageal varices), and past medical history (e.g. frequent surgeries, past ulcers) which may contribute to elevated risk of bleeding. Use of non-SSRIs/SNRIs or agents with minimal effects at the serotonin receptor (e.g. buproprion, mirtazapine, nortriptyline, and desipramine) in the absence of other contraindications would be a preferred alternative for use in patients with coagulopathy.²⁶ Medications which may cause thrombocytopenia should be avoided if platelets are < 60,000 as research has supported this minimum threshold to support thrombin generation in patients with cirrhosis at a comparable level to those in healthy subjects.²⁵ 

Overall, more research is necessary to quantify risk in these patients and support clinical decision-making with outcomes-based research.

Table 2 highlights select commonly utilized psychotropic medications from a few medication classes (antidepressants, mood stabilizers, antipsychotics, and benzodiazepines) and recommendations on use in this population according to product labeling information.²⁷ As this article discusses, this information should be used as one piece of information in the clinical decision-making process in addition to the etiology of disease, adverse effect profile, as well as the following pharmacokinetic parameters:

• Absorption: Solubility and product formulation

• Distribution: Protein binding and hydrophilicity

• Metabolism: Metabolic pathway, bioavailability and/or extraction ratio

• Excretion: Route and half-life

The type and severity of liver dysfunction provides some predictive value in determining pharmacokinetic and pharmacodynamics changes in drug response. Sufficient evidence guiding medication management in this population is lacking, particularly in severe liver disease. Extensive research opportunities exist to improve our current understanding of drug metabolism, disposition, and effects in patients with impaired hepatic function. Careful consideration of the principles and information outlined in this article will assist in identifying appropriate medications as well as starting doses and frequency. The cautious clinician can utilize the following key points when managing patients with liver dysfunction:

• Ensure every medication has an appropriate indication and evaluate the need for each medication. For example, consider variables which may be distorting the clinical picture and creating a false need for medication such as hepatoencephalopathy or medication side effects.

• A risk versus benefit assessment by the medical team should occur to prevent unnecessary use in patients with cirrhotic complications associated with poor life expectancy such as hepatrorenal syndrome.²⁸ 

• Following the adage “start low, go slow” will help minimize adverse effects.

• Knowledge of the etiology and relative severity of liver disease will help assess the likelihood of higher serum levels of medication and guide initial choice and dosage of medication.

• Medications with high extraction ratios and those which are prodrugs should be used cautiously since higher, yet unpredictable, steady state levels are more likely relative to those with lower extraction ratios or non-prodrugs; however, this will depend on the nature of the prodrug and site of metabolism/activation.¹⁰ 

• Medications metabolized via glucuronidation are typically preferred, particularly in patients with more severe liver disease, as this functionality is traditionally spared relative to metabolism by CYP-P450 enzymes.¹⁰ 

• Monitor drug levels for those with an established therapeutic range.

• Consider the need for renal dose adjustment as well in patients with liver dysfunction as serum creatinine significantly overestimates glomerular filtration in these patients, secondary to reduced muscle mass and conversion of creatine to creatinine.¹² 

• The use of hepatotoxic medications is not contraindicated by expert opinion in patients with chronic liver disease; however, patients with baseline liver disease have lower reserves for responding to an insult should DILI occur. Alternatives and risk factors for DILI should be considered prior to use and vigilant monitoring is necessary.^19,21 

• Thoughtful evaluatation of the risks versus benefits of agents which may cause bone marrow suppression and increase bleeding risk in patients with coagulopathy and synthetic dysfunction is recommended.