Effects of Liver disease on Pharmacokinetics
56 likes13,355 views
Hepatic disease can significantly impact drug pharmacokinetics by altering metabolism and excretion of drugs. The liver metabolizes many drugs through enzyme systems that may be impaired in diseases like cirrhosis and hepatitis. This can cause drug accumulation, changes in active metabolites, and altered protein binding. While laboratory tests can detect liver damage, no single test assesses total liver function. The Child-Pugh score is used to classify the severity of hepatic impairment. For drugs that are highly metabolized by the liver, dosage may need to be reduced based on the Child-Pugh score to avoid toxicity. The degree of dosage adjustment depends on the individual drug's pharmacokinetics and the patient's liver function status.
Effects of Liver disease on Pharmacokinetics
- 1. EFFECT OF HEPATIC DISEASE ON PHARMACOKINETICS
- 2. • Hepatic disease can alter drug pharmacokinetics and pharmacodynamics. • Hepatic disease may include common hepatic diseases, such as • alcoholic liver disease (cirrhosis) and • chronic infections with hepatitis viruses B and C, • and less common diseases, such as • acute hepatitis D or E, • primary biliary cirrhosis, • primary sclerosing cholangitis, and • a1-antitrypsin deficiency • In addition, drug-induced hepatotoxicity is the leading cause of acute liver failure in the United States (Chang and Schiano, 2007).
- 3. • Drugs are often metabolized by one or more enzymes located in cellular membranes in different parts of the liver. • Drugs and metabolites may also be excreted by biliary secretion. • • Hepatic disease may lead to • drug accumulation, • failure to form an active or inactive metabolite, • increased bioavailability after oral administration, • and other effects including possible alteration in drug–protein binding. • Liver disease may also alter kidney function, which can lead to accumulation of a drug and its metabolites even when the liver is not primarily responsible for elimination.
- 4. • The major difficulty in estimating hepatic clearance in patients with hepatic disease is the complexity and stratification of the liver enzyme systems. • In contrast, creatinine clearance has been used successfully to measure kidney function and renal clearance of drugs. • Clinical laboratory tests measure only a limited number of liver functions. • Some clinical laboratory tests, such as the aspartate aminotransferase (AST) and alanine aminotransferases (ALT), are common serum enzyme tests that detect liver cell damage rather than liver function.
- 5. • Other laboratory tests, such as serum bilirubin, are used to measure biliary obstruction or interference with bile flow. • Presently, no single test accurately assesses the total liver function. • Usually, a series of clinical laboratory tests are used in clinical practice to detect the presence of liver disease, distinguish among different types of liver disorders, gauge the extent of known liver damage, and follow the response to treatment.
- 6. • A few tests have been used to relate the severity of hepatic impairment to predicted changes in the pharmacokinetic profile of a drug (FDA Guidance for Industry, 2003). • Examples of these tests include the ability of the liver to eliminate marker drugs such as antipyrine, indocyanine green, monoethylglycine-xylidide, and galactose. • Furthermore, endogenous substrates, such as albumin or bilirubin, or a functional measure, such as prothrombin time, has been used for the evaluation of liver impairment.
- 7. Dosage Considerations in Hepatic Disease • Several physiologic and pharmacokinetic factors are relevant in considering dosage of a drug in patients with hepatic disease (Table 24-10). • Chronic disease or tissue injury may change the accessibility of some enzymes as a result of redirection or detour of hepatic blood circulation. • Liver disease affects the quantitative and qualitative synthesis of albumin, globulins, and other circulating plasma proteins that subsequently affect plasma drug protein binding and distribution. • As mentioned, most liver function tests indicate only that the liver has been damaged; they do not assess the function of the cytochrome P-450 enzymes or intrinsic clearance by the liver.
- 9. • Because there is no readily available measure of hepatic function that can be applied to calculate appropriate doses, enzyme-dependent drugs are usually given to patients with hepatic failure in half-doses, or less. • Response or plasma levels then must be monitored. • Drugs with flow-dependent clearance are avoided if possible in patients with liver failure.
- 10. Fraction of Drug Metabolized • Drug elimination in the body may be divided into • (1) fraction of drug excretion unchanged, fe, and • (2) fraction of drug metabolized. • The latter is usually estimated from 1 – fe; • alternatively, the fraction of drug metabolized may be estimated from the ratio of Clh/Cl, where Clh is hepatic clearance and Cl is total body clearance.
- 11. PRACTICE PROBLEM • The hepatic clearance of a drug in a patient is reduced by 50% due to chronic viral hepatitis. • How is the total body clearance of the drug affected? • What should be the new dose of the drug for the patient? • Assume that renal drug clearance (fe = 0.4) and plasma drug protein binding are not altered.
- 12. Active Drug and the Metabolite • (1) when the drug is more potent than the metabolite, the overall pharmacologic activity will increase in the hepatic-impaired patient because the parent drug concentration will be higher; • (2) when the drug is less potent than the metabolite, the overall pharmacologic activity in the hepatic patient will decrease because less of the active metabolite is formed.
- 13. Hepatic Blood Flow and Intrinsic Clearance • Blood flow changes can occur in patients with chronic liver disease. • Hepatic arterial-venous shunts may lead to reduced fraction of drug extracted and an increase in the bioavailability of drug. • In other patients, resistance to blood flow may be increased as a result of tissue damage and fibrosis, causing a reduction in intrinsic hepatic clearance.
- 14. • The following equation may be applied to estimate hepatic clearance of a drug after assessing changes in blood flow and intrinsic clearance (Clint):
- 15. Pathophysiologic Assessment • In practice, patient information about changes in hepatic blood flow may not be available, because special electromagnetic or ultrasound techniques are required to measure blood flow and are not routinely available. • The clinician/ pharmacist may have to make an empirical estimate of the blood flow change after examining the patient and reviewing the available liver function tests.
- 16. approaches to assess hepatic impairment • The Child–Pugh (or Child–Turcotte–Pugh) score assesses the overall hepatic impairment as mild, moderate, or severe (Figg et al, 1995; Lucey et al, 1997). • The score employs five clinical measures of liver disease, including • total bilirubin, • serum albumin, • International Normalized Ratio (INR), • ascites, and • hepatic encephalopathy
- 18. • chronic hepatic disease is more likely to change the metabolism of a drug than acute hepatitis • Chronic liver disease has been shown to decrease the metabolism of many drugs as shown in Table 24-13. • However, the amount of decrease in metabolism is difficult to assess.
- 20. Hepatic Impairment and Dose Adjustment • Drugs that have the following properties are less likely to need dosage adjustment in patients with hepatic impairment (FDA Guidance for Industry, 2003) 1. The drug is excreted entirely via renal routes of elimination with no involvement of the liver. 2. The drug is metabolized in the liver to a small extent (<20%), and the therapeutic range of the drug is wide, so that modest impairment of hepatic clearance will not lead to toxicity of the drug directly or by increasing its interaction with other drugs. 3. The drug is gaseous or volatile, and the drug and its active metabolites are primarily eliminated via the lungs.
- 21. • For each drug case, the physician needs to assess the degree of hepatic impairment and consider the known pharmacokinetics and pharmacodynamics of the drug. • For example, Mallikaarjun et al (2008) studied the effects of hepatic or renal impairment on the pharmacokinetics of aripiprazole (Abilify), an atypical antipsychotic used to treat schizophrenia. These investigators concluded that there were no meaningful differences in aripiprazole pharmacokinetics between groups of subjects with normal hepatic or renal function and those with either hepatic or renal impairment. Thus, the adjustment of the aripiprazole does not appear to be required in populations with hepatic or renal impairment.
- 22. • In contrast, Muirhead et al (2002) studied the effects of age and renal and hepatic impairments on the pharmacokinetics, tolerability, and safety of sildenafil (Viagra), a drug used to treat erectile dysfunction. Muirhead et al (2002) observed significant differences in Cmax and AUC between the young and the elderly subjects for both the parent drug and the metabolite. In addition, the hepatic impairment study demonstrated that pharmacokinetics of sildenafil was altered in subjects with chronic stable cirrhosis, as shown by a 46% reduction in CL/F and a 47% increase in Cmax compared with subjects with normal hepatic function. Sildenafil pharmacokinetics was affected by age and by renal and hepatic impairments, suggesting that a lower starting dose of 25 mg should be considered for patients with severely compromised renal or hepatic function.
- 23. Adjustment based on Child-Pugh score • The Child-Pugh score for a patient with normal liver function is 5 • while the score for a patient with grossly abnormal serum albumin, total bilirubin, and prothrombin time values in addition to severe ascites and hepatic encephalopathy is 15.
- 24. • A Child-Pugh score equal to 8-9 is grounds for a moderate decrease (∼ 25%) in initial daily drug dose for agents that are primarily (≥60%) hepatically metabolized, • and a score of 10 or greater indicates that a significant decrease in initial daily dose (∼ 50%) is required for drugs that are mostly liver metabolized. • As in any patient with or without liver dysfunction, initial doses are meant as starting points for dosage titration based on patient response and avoidance of adverse effects.
- 25. • For example, the usual dose of a medication that is 95% liver metabolized is 500 mg every 6 hours, and the total daily dose is 2000 mg/d. • For a hepatic cirrhosis patient with a Child-Pugh score of 12, an appropriate initial dose would be 50% of the usual dose or 1000 mg/d. The drug could be prescribed to the patient as 250 mg every 6 hours or 500 mg every 12 hours. The patient would be closely monitored for pharmacologic and toxic effects due to the medication, and the dose would be modified as needed.