Effects of liver diseases on pharmacokinetics

Effects of liver diseases on pharmacokinetics

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  EFFECT OF HEPATICDISEASE ON PHARMACOKINETICS Dr. Ramesh Bhandari Asst. Professor Department of Pharmacy Practice KLE College of Pharmacy, Belagavi
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  How liver handlesthe drug?  Blood supply to the liver:  Hepatic artery  Superior mesenteric artery, and the portal vein  Liver blood flow averages:  1-1.5 L/min in adults about one-third from hepatic artery and two third from portal vein  Most lipid soluble drugs undergo metabolism in liver:  Phase I  Phase II  First pass metabolism (Oral administration only)  Transporter protein (P-gp) actively secrete drugs into the bile.
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  Hepatic diseases  Hepaticdisease can alter drug pharmacokinetics (absorption and disposition) as well as pharmacodynamics (efficacy and safety).  Hepatic disease includes: A. Common hepatic diseases: i. Alcoholic liver disease (Cirrhosis) ii. Chronic infections (Hepatitis B and hepatitis C) B. Less common hepatic diseases: i. Acute hepatitis D or E ii. Primary biliary cirrhosis iii. Primary sclerosing cholangitis iv. Alpha 1 antitrypsin deficiency C. Drug induced hepatotoxicity
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  Hepatic diseases  Drugsare 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.
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  Assessing the degreeof liver failure  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.  Other laboratory tests, such as serum bilirubin, are used to measure biliary obstruction or interference with bile flow.
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  Assessing the degreeof liver failure  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.  A few tests have been used to relate the severity of hepatic impairment to predicted changes in the pharmacokinetic profile of a drug.  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
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  Assessing the degreeof liver failure The most common way to estimate the ability of the liver to metabolize drug is to determine the 1. Child Pugh (Child –turcotte-pugh) score
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  Child Pugh Classificationof severity of liver disease Parameter Points Assgined 1 2 3 Ascitis Absent Slight Moderate Bilirubin (mg/dl) ≤ 2 2-3 >3 Albumin (mg/dl) >3.5 2.8-3.5 <2.8 Prothrombin time Seconds over control 1-3 4-6 >6 INR <1.8 1.8-2.3 >2.3 Encephalopathy None Grade 1-2 Grade 3-4
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  Child Pugh Classificationof severity of liver disease  Normal liver function – score of 5  Severe Hepatic impairment – score of 15
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  Dosage consideration inHepatic Diseases Item Comments Nature and severity of liver disease Not all liver disease affect the pharmacokinetic of the drugs to the same extent. Drug Elimination Drugs eliminated by the liver >20 % are less likely to be affected by liver diseases Route of drug administration Oral drug bioavilability may be increased by liver disease due to decreased first pass effects Protein Binding Drug protein binding may be altered due to alteration in heaptic synthesis of albumin Hepatic Blood flow Instrinsic Clearance Metabolism of drugs with high intrinsic clearance may be impaired Biliary Obstruction Biliary excretion of some drugs and metabolites, particularly glucuronide metabolites, may be impaired Pharmacodynamic Changes Tissue sensitivity to drug may be altered Therapeutic Range Drugs with a wide therapeutic range will be less affected by moderate hepatic impairment.
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  Dosage consideration inHepatic Diseases 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.
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  Dosage consideration inHepatic Diseases 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.
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  Dosage consideration inHepatic Diseases When necessary, doses of these drugs may need to be reduced to as low as one-tenth of the conventional dose for an orally administered agent. Starting therapy with low doses and monitoring response or plasma levels provides the best opportunity for safe and efficacious treatment.
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  Dosage consideration inHepatic Diseases If some of the efflux proteins that normally protect the body against drug accumulation are reduced or not functioning, this could potentially cause hepatic drug injury as drug concentration begins to increase. Compounds that form glucuronide, sulfate, glutathione (GSH), and other substrates that are involved in phase II metabolism may be depleted during hepatic impairment, potentially interrupting the normal path of drug metabolism.
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  FRACTION OF DRUGMETABOLIZED  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.  Knowing the fraction of drug eliminated by the liver allows estimation of total body clearance when hepatic clearance is reduced.
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  FRACTION OF DRUGMETABOLIZED Drugs with low fe values (or, conversely, drugs with a higher fraction of metabolized drug) are more affected by a change in liver function due to hepatic disease. Clh = Cl (1 – fe) Above equation assumes that drug metabolism occurs in the liver and the unchanged drug is excreted in the urine.
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  Active Drug andthe Metabolite For many drugs, both the drug and the metabolite contribute to the overall therapeutic response of the drug to the patient. The concentration of both the drug and the metabolite in the body should be known.
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  Active Drug andthe Metabolite  When the pharmacokinetic parameters of the metabolite and the drug are similar, the overall activity of the drug can become more or less potent as a result of a change in liver function; that is, (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.
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  Hepatic Blood Flowand Intrinsic Clearance  Blood flow changes can occur in patients with chronic liver disease (often due to viral hepatitis or chronic alcohol use).  In some patients with severe liver cirrhosis, fibrosis of liver tissue may occur, resulting in intra- or extrahepatic shunt.  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
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  Hepatic Blood Flowand Intrinsic Clearance  Following equation may be applied to estimate hepatic clearance of a drug after assessing changes in blood flow and intrinsic clearance (Clint) 𝐶𝑙ℎ = 𝑄 . 𝐶𝑙𝑖𝑛𝑡 (𝑄 + 𝐶𝑙𝑖𝑛𝑡)  If Extraction ratio is known then, 𝐶𝑙ℎ = 𝑄 (𝐸𝑅)
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  Hepatic Impairment andDose Adjustment  Hepatic impairment may not sufficiently alter the pharmacokinetics of some drugs to require dosage adjustment.  Drugs that have the following properties are less likely to need dosage adjustment in patients with hepatic impairment. • The drug is excreted entirely via renal routes of elimination with no involvement of the liver. • The drug is metabolized in the liver to a small extent (<20 %) and the therapeutic range of the drug is wide. • Drug is gaseous or volatile (excreted via lungs)
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  Hepatic Impairment andDose Adjustment  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.