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Lucy Hennessy, MPharm (hons)
Specialist Medicines Information Pharmacist, Leeds Teaching Hospitals NHS Trust
Janet Tweed, BPharm (hons)
Medicines Information Services Development Manager, Leeds Teaching Hospitals NHS Trust Leeds, UK
Liver dysfunction is not a single disease, but rather a variety of conditions, each affecting the function of the liver and consequently the handling of drugs in different ways. Most pharmacists would include drug metabolism as an important consideration in medicines use in liver disease, but liver dysfunction has a wider impact on drug handling than purely metabolism. The type and extent of the effects on drug handling may be predicted from the diagnosis, accurate interpretation of liver function tests (LFTs), results of other laboratory tests, results of scans and biopsies, and the presence of signs and symptoms of liver disease. Unlike renal impairment, there is no endogenous marker in the body that can be used to predict the effect of liver dysfunction on drug handling. The decisions regarding the use of medicines must be made following careful evaluation of the nature and severity of the liver disease and the adverse effects profile, pharmacokinetics and pharmacodynamics of the chosen pharmacological agent.
Hepatotoxicity is an obvious concern when prescribing for a patient with liver dysfunction, but other side effects of the chosen agent should also be considered because the complications of the liver disease can increase their significance.
The risks of starting a drug known to be hepatotoxic should be considered in all patients with liver dysfunction.1,2 The majority of adverse effects upon the liver are idiosyncratic, but there are some exceptions, such as those caused by paracetamol and methotrexate, where the reaction is predictable and dose-dependent.3 The decision to use a medicine known to be hepatotoxic will depend on the individual situation, including the urgency for treatment, the availability of safer alternatives, the required length of treatment and the type, incidence, severity and reversibility of the hepatotoxicity known to occur.
In patients with unstable liver disease, the risks and benefits of starting a potentially heptatotoxic drug need to be considered closely.4 It may be safest to delay commencement until after the liver disease has stabilised, otherwise it may be difficult to establish the cause of any further deterioration – new medicine or disease. Many medicines may cause a transient increase in LFTs that is often clinically insignificant, but any changes in LFTs may distort the monitoring of the pre-existing disease, especially if the LFTs have been previously unstable. Medicines that rarely cause liver damage can often be used with caution.2
In general, patients with pre-existing liver disease are thought to be at no greater risk of drug-induced liver damage than the general population, although there are a few exceptions to this rule, including that caused by methotrexate and valproate.1,3,4,5 However, patients with pre-existing liver dysfunction may be less likely to cope following the development of hepatotoxicity, as they may have less hepatic reserve. It may be wise to avoid medicines with a high incidence of liver damage in these patients.2,4
An awareness of the pharmacokinetics of drugs (absorption, distribution, metabolism and excretion) helps to inform the choice of the safest medicine that is least affected by a patient’s liver disease. However, using the pharmacokinetic information to predict changes in drug handling and to estimate dose amendments can be speculative, and the clinical significance of changes in more than one pharmacokinetic parameter can be impossible to predict.
The preferred approach is to perform a literature search to identify clinical studies or published guidance for use of the drug in the specific type of liver disease in question.
This information may report actual pharmacokinetic changes and necessary dose adjustments, and avoid the need to make decisions based on predictions from first principles.4,6
Liver diseases often fits into one or more of the following four categories: cirrhosis, cholestasis, hepatitis or acute liver failure. Allocating a patient to one or more of these categories allows the consideration of the most important factors for drug handling in each case. It is important to note that overlap between these categories and progression from one to another is common and care must be taken not to inappropriately compartmentalise patients.4
Several of these factors may be affected, making the choice of agent more difficult and the patient’s response more unpredictable:
Absorption of some medicines is delayed in patients with cirrhosis and ascites. This is not generally predictable from looking at pharmacokinetic data in healthy individuals.4
Water-soluble medicines may distribute into the ascitic fluid, which may reduce concentrations of the drug achieved in other areas of the body, including its site of action. Larger doses may therefore be required.4
Highly protein-bound drugs are affected by hypoalbuminaemia, which is often seen in chronic liver disease such as cirrhosis. This may result in increased therapeutic or toxic effects as a result of an increased proportion of free unbound drug.3,4,6 In jaundiced patients bilirubin may also displace some highly protein-bound drugs from their binding sites, again leading to an increased proportion of free drug.4
Reduced hepatic cell mass in cirrhotic patients may lead to a subsequent reduction in drug metabolising enzymes, accumulation of active drug, and the potential for enhanced response and increased adverse effects. If the metabolites are also active, the outcome is even less predictable. This is most significant in decompensated cirrhotic patients (signs of decompensation include elevated international normalised ratio [INR], hypoalbuminaemia and/or hepatic encephalopathy). Reducing the maintenance dose of hepatically metabolised drugs may be required in these cases.3,4,7
Pro-drugs requiring activation in the liver may have reduced activation and a lower therapeutic effect in patients with reduced hepatic metabolic capacity. However, the activated drug itself may be metabolised in the liver or excreted via the biliary route (see cholestasis) and therefore the rate or the extent of excretion may also be affected. The overall impact on the drug’s activity and the necessity for dose adjustment may be difficult to predict.6
Portal hypertension, which may occur in advanced cirrhosis, leads to the development of varices. If a medicine undergoes high first-pass metabolism, a greater proportion of absorbed drug will enter the systemic circulation because first-pass metabolism is bypassed or reduced. A reduction of initial and maintenance doses may be required, but the extent of the dosage reduction is generally not predictable.3,4,7
In cirrhotic patients the creatinine clearance may overestimate the renal drug clearance rate, and dosage reductions may need to be considered if active drugs or active/toxic metabolites are renally excreted or if the patient has hepatorenal syndrome.3,4,6,7 For some drugs, increased renal excretion may compensate for reduced hepatic metabolism.3
Patients with cirrhosis may be more sensitive to some of the therapeutic and toxic effects of drugs. Common examples of this include increased sensitivity to drugs acting on the central nervous system and increased sensitivity to the renal side effects of non-steroidal anti-inflammatory drugs (NSAIDs). Conversely, patients with cirrhosis may also have a reduced response to some drugs (for example, diuretics).3,6,7
Adverse effect considerations
Patients with cirrhosis may have or may be at risk of developing hepatic encephalopathy. Drugs with the potential to cause electrolyte disturbances, constipation and/or sedation may exacerbate or mask the signs of encephalopathy.4,8,9
Patients with decompensated cirrhosis may have pre-existing clotting abnormalities, primarily due to reduced synthesis of clotting factors by the liver. Anticoagulants or other medicines that affect clotting should be avoided or used with caution.4
Gastric and oesophageal varices can develop in patients with portal hypertension and are prone to bleeding.8,9 Medicines, such as NSAIDs or bisphosphonates, that irritate the gastrointestinal tract, or those that increase the risk of bleeding, should be avoided.4,8
Patients with cirrhosis and portal hypertension are at an increased risk of developing renal impairment. Potentially nephrotoxic medicines should be used with caution and avoided altogether in patients with hepatorenal syndrome.4,5,8
Fatigue is a common symptom of chronic liver disease. Medicines that cause fatigue will only exacerbate the problem.10
Cirrhotic patients with ascites may be required to adhere to low sodium diets. Medicines with a high sodium content, or those that inhibit salt and water excretion (for example, NSAIDs), are best avoided in these patients.3,4
Lipid-soluble drugs may be reliant on the action of bile salts to aid their absorption, leading to reduced plasma concentrations and reduced efficacy in cholestatic patients.4
If hyperbilirubinaemia accompanies the cholestasis, highly protein-bound drugs may be displaced from their binding sites by bilirubin, resulting in higher proportions of free drug.7
Elimination via the biliary route may be reduced, resulting in drug accumulation. This may be clinically relevant if a drug or active metabolite normally undergoes significant biliary excretion.3,4,6,7
Enterohepatic recirculation may be reduced in these patients,3 the drug may be excreted more slowly than usual, and predictions of outcomes are likely to be difficult.4
Adverse effect considerations
Pruritus and intense itching are complications of cholestasis4,8,10 and medication with a high incidence of these effects should generally be avoided.
Fatigue is a common symptom of cholestasis and medicines that cause fatigue will only exacerbate the problem.10
Cholestatic patients have a reduced ability to absorb fat-soluble vitamins, including vitamin K.4,10 This may impair clotting and increase the risk of bleeding. Anticoagulants and other agents that increase the risk of bleeding should be avoided in patients at risk.
Acute liver failure
Patients with acute liver failure can suffer from encephalopathy, clotting abnormalities, ascites and hepatorenal syndrome, and the guidance described in the section for cirrhotic patients in this article may be used.8 However, because these patients are often treated in intensive care units, it is frequently not possible to avoid high risk drugs (for example, sedatives in encephalopathic patients).11
Conditions causing hepatocellular damage cover a range of disorders of differing severity, some acute and some chronic. Mild hepatitis may have no effect on drug handling. Clotting abnormalities may be present in severe hepatitis, and medicines that increase the risk of bleeding should then be avoided. Some patients progress to cirrhosis or acute liver failure; the advice described in previous sections of this article should then be applied.4
In general, medicines with shorter half-lives are preferred when prescribing for patients with liver disease because of the reduced potential for drug accumulation. In addition, agents that are easily reversed, or that have antidotes, may be preferred in case accumulation occurs.3,7 For instance, oral administration of an antipsychotic would be preferable to a depot injection because of the inability to remove and reverse the effects of the depot. Drugs with a narrow therapeutic index should be used with caution.3,7
Hepatic impairment is a complex area that can impact significantly on drug handling. However, application of the principles covered in this article will facilitate informed decision making regarding drug use in patients with liver disease.
1. Zimmerman HJ. Hepatotoxicity – the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott Williams & Wilkins, 1999.
2. Bleibel W, Kim S, D’Silva K et al. Drug-induced liver injury: review article. Dig Dis Sci 2007; 52: 2463–71.
3. Delco C, Tchambaz L, Schlienger R et al. Dose adjustment in patients with liver disease. Drug Safety 2005; 28: 529–45.
4. North-Lewis P. Drugs and the Liver. London: Pharmaceutical Press, 2008: 49–54, 103–33, 148–50, 154.
5. Lee A. Adverse Drug Reactions. 2nd ed. London: Pharmaceutical Press, 2006: 193–216.
6. Morgan DJ, McLean AJ. Clinical pharmacokinetic and pharmacodynamic considerations in patients with liver disease: an update. Clin Pharmacokinet 1995; 29: 370–91.
7. Verbeeck RK. Pharmacokinetics and dosage adjustments in patients with hepatic dysfunction. Eur J Clin Pharmacol 2008; 64: 1147–61.
8. Walker R, Whittlesea C. Clinical Pharmacy and Therapeutics. 4th ed. Edinburgh: Churchill Livingstone, 2007: 219–23, 225, 227.
9. Kumar P, Clark M. Clinical Medicine. 6th ed. Edinburgh: Elsevier Saunders, 2005: 378–84.
10. Jones DJ. Complications of cholestasis. Medicine 2006; 35: 96–98.
11. Bernal W, Auzinger G, Sizer E et al. Intensive care management of acute liver failure. Semin Liver Dis 2008; 28: 188–200.