Pharmacokinetics of Drugs in Liver Diseases PDF

PCA 501 Pharmacokinetics of Drugs in Liver Diseases The liver is the major organ of metabolism, and an impairment to the liver can alter drug pharmacokinetics, as well as the pharmacodynamics. Hepatic diseases include alcoholic liver disease, chronic infections with hepatitis viruses...

PCA 501 Pharmacokinetics of Drugs in Liver Diseases The liver is the major organ of metabolism, and an impairment to the liver can alter drug pharmacokinetics, as well as the pharmacodynamics. Hepatic diseases include alcoholic liver disease, chronic infections with hepatitis viruses B and C, primary biliary cirrhosis. Hepatotoxicity from drugs can also cause liver failure. Drugs are often metabolised by one or more enzymes located in cellular membranes in different parts of the liver. Hepatic disease may lead to impairment of the metabolism process and other pharmacokinetic processes thereby leading to accumulation of drugs, failure to form an active or inactive metabolite, increased bioavailability after oral administration, and possible alteration in drug-protein binding. Rationale for TDM in Hepatic Impairment 1) Drugs of similar structures or pharmacological action show variation in the elimination route, e.g. beta blockers; propranolol is eliminated via the hepatic route, atenolol is eliminated via the renal route and metoprolol has both hepatic and renal elimination. The extent of liver metabolism may also vary for those that are eliminated via the hepatic route, e.g. in benzodiazepines; diazepam and chlordiazepoxide undergo oxidative metabolism, whereas lorazepam and oxazepam undergo direct glucuronidation. 2) Geriatrics do not show a linear deterioration in metabolic function, however, in premature and full term neonates, enzymes may be poorly developed generally and specific metabolic pathways may be absent. Enzyme maturation is complete in 6-8 months, and hepatic metabolic capacity continues to increase to a peak till 16 years, and then starts reducing. 3) The concentration of albumin in the blood normally reflects its liver synthetic rate, however, it undergoes rapid falls as the individual becomes unwell, owing to changes in vascular permeability. 4) Highly bound drugs will have their free fraction altered, and thus (for low-extraction drugs), their clinical effect and rate of clearance will change. Normally, as the free fraction increases, the liver clearance increases, but in liver dysfunction, blood levels may rise (i.e. accumulation) significantly because the liver lacks the capacity to metabolise more drugs. 5) Absorption: Liver disease decrease first pass metabolism and so increases bioavailability. The oral bioavailability of a number of drugs with intermediate to high extraction ratios has shown to be significantly increased in patients with liver cirrhosis e.g. Clomethiazole, a sedative agent. 6) Elimination: Enzyme capacity within the hepatocytes may change as well as the number of hepatocytes, producing significant changes in enzymes functional capacity. In liver failure, both the volume of distribution and total clearance may change, e.g. the volume of distribution of Tolbutamide changes in liver failure. 1 7) Clearance: For drugs with high extraction ratio, both bound and free drugs are metabolised, but for drugs with low extraction ratio, only unbound drug is available for clearance. With low extraction, it is assumed that more free drugs (due to decrease in protein binding) will increase the rate of removal, but this is not true in liver dysfunction, because the liver does not have the capacity to metabolise all the free drugs, thereby leading to drug accumulation. 8) Extraction Ratio: This describes the amount of drug that is eliminated from the blood compared to the total quantity of the drug in the body. An extraction ratio of 1 means the drug is completely extracted by the liver, and an extraction ratio of 0 means the liver does not extract the drug. Drugs with an E.R of 0.3 or less are classified as drugs with low E.R, 0.3 – 0.7 are intermediate, while greater than 0.7 are drugs with high E.R. a) Drugs with High Extraction Ratio: For these drugs, the liver is able to eliminate all the drug in the blood passing through it, meaning that the liver clearance is dependent on the blood flow through the liver. Therefore, drugs with high extraction ratio are sensitive to altered liver blood flow. Examples of such drugs are Verapamil, Morphine, and propranolol. Being bound to plasma protein does not protect these drugs, because liver elimination is a more powerful force than that causing association between the drug and the plasma protein, so the liver can pull the drugs off the plasma protein to metabolise them. b) Drugs with Low Extraction Ratio: For these drugs, the liver finds it difficult to eliminate the drug in the blood as it passes through. Blood flow therefore becomes less important unless the blood flow is severely restricted, leading to hepatic damage. Examples of such drugs are Warfarin, Carbamazepine, Diazepam. The hepatic clearance of these drugs is mainly influenced by changes in plasma proteins binding and the intrinsic clearance of the unbound drug. The forces drawing the drug to bind to the liver enzymes are less powerful than the forces holding the drug to the plasma proteins; therefore, elimination of the drugs by the liver is determined by the functionality of the enzymes within it. 9) Protein Binding: Chronic liver disease is usually accompanied by reduced synthesis of albumin, leading to hypoalbuminaemia and reduced drug binding to plasma proteins. The protein binding affinity may be altered in liver disease as a result of the accumulation of bilirubin and endogenous products of metabolism, these compounds including urea may displace drugs from their binding sites, either by direct competition or by altering the nature of the binding site. Decreased protein may increase the free fraction of some highly bound drugs by as much as 50-100%, and in turn increases the volume of distribution and the half-life. In liver failure, the free fraction may rise at the same time as the liver has decreased capacity to remove the drug, leading to accumulation. A protein like Gamma-globulin synthesized in the lymphocytes has increased concentration in hepatic dysfunction. This increase is due to a compensatory mechanism (The lymphocytes produce more gamma-globulin – an antibody – to compensate for the reduced activity of the liver which also produces antibodies. 2  Serum glutamic oxaloacetic transaminase (SGOT) is released into the blood when the liver or the heart is damaged. 10) Metabolism: The degree of impaired metabolism of drugs in patients with chronic liver disease varies from patient to patient and depends on the type of metabolic reaction involved. Oxidative metabolic reactions (catalysed by a large number of cytochrome P- 450 isoenzymes) appear to be more affected by chronic liver disease compared to glucuronidation. 11) Biliary Excretion: Drugs normally excreted to a significant extent via the bile may accumulate in patients with obstruction of the common bile duct. In addition, biliary obstruction may lead to hepatocellular damage with impairment of metabolic drug clearance. 12) Renal Excretion: Liver impairment can lead to reduced muscle mass and impaired metabolism of creatine to creatinine in a number of patients, leading to wrong estimation of creatinine clearance. Poor liver clearance of vasodilator substances results in diversion of blood flow from liver and kidneys to the periphery, thereby leading to reduced renal blood flow. Reduced renal blood flow activates the renin-angiotensin- aldosterone pathway and produces an inappropriate tubular reabsorption of sodium and water. Aldosterone concentration is increased in the body i.e. hyperaldosteronism, because aldosterone is also metabolised by the liver. Liver Function Tests and Hepatic Metabolic Markers It is difficult to estimate hepatic clearance in patients with hepatic disease because of the complexity and stratification of the liver enzyme system. Some clinical laboratory tests are used to detect liver damage, but they don’t measure liver function. a) Aminotransferase i.e. Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT). ALT is liver specific but AST is found in the liver and other tissues, including cardiac and skeletal muscles, so is not very specific for liver damage. Leakage of the AST and ALT into the plasma is used as an indicator for many types of hepatic disease and hepatitis. When AST/ALT ≤ 1 --------------------------Acute liver injury AST/ALT >2---------------------------Alcoholic hepatitis. b) Alkaline phosphatase: It is normally present in many tissues, and it is also present in the canalicular domain of the hepatocyte plasma membrane. Plasma alkaline phosphatase may be elevated in hepatic disease because of the increased production of AP and its release into the serum. Marked AP elevation may indicate hepatic tumour or biliary obstruction in the liver. c) Bilirubin: Bilirubin can be water-soluble, conjugated, direct fraction and a lipid- soluble, unconjugated, indirect fraction. The unconjugated form is bound to albumin and is therefore, not filtered by the kidney. Impaired biliary excretion results in increases in conjugated (filtered) bilirubin (from reduced albumin concentration to bind to). Hepatobiliary impairment can also lead to increase in urinary bilirubin. 3  d) Prothrombin Time: All conjugation factors, except factor VIII, are synthesized by the liver. Therefore, hepatic disease can alter coagulation. Increases in prothrombin time (the rate of conversion of prothrombin to thrombin) are suggestive of acute or chronic liver failure or biliary obstruction. Vitamin K deficiency can also increase prothrombin time, since Vitamin K is important in coagulation. Drug markers used to measure residual hepatic function may correlate well with hepatic clearance of one drug but poorly with another substrate metabolised by a different enzyme within the same cytochrome P-450 family. Ideal properties of drug markers used to estimate liver function are 1) Its elimination should be entirely by hepatic metabolism. 2) It should have linear kinetics. 3) Its metabolism should be independent of liver blood flow and protein binding. 4) The enzymes involved should be known. 5) It should be a substrate for several isoenzymes and reflect several different pathways with measurable, inactive metabolites. 6) It should have no pharmacology at doses used. 7) It should be non-toxic in patients with liver dysfunction and healthy controls. 8) It should produce no interactions with drugs or environment (genetics, diet, and nutrition). 9) It should be administered orally with rapid and complete absorption. 10) It should be measurable in blood, saliva, urine or breath. 11) There should exist a simple analysis kit. Markers used include a) AntiPyrine (phenazone) b) Aminopyrine (aminophenazone) c) Indocyanine green d) Monoethylglycine-xylidide e) Galactose Considerations in Drug Dosing in Hepatic Impaired patients S/N Considerations Comments 1 Nature and severity of liver Not all liver diseases affect the pharmacokinetics of disease drugs to the same extent. 2 Drug elimination Drugs eliminated mainly by renal routes will be least affected by liver disease. 3 Routes of drug Oral drug bioavailability may be increased by liver administration disease due to decreased first pass effect 4 Protein binding Drug protein may be altered due to alteration of hepatic synthesis of albumin. 4  5 Hepatic blood flow Drugs with flow dependent hepatic clearance will be more affected by changes in hepatic blood flow. 6 Intrinsic clearance Metabolism of drugs with high intrinsic clearance may be impaired. 7 Biliary obstruction Biliary excretion of some drugs and metabolites, particularly glucuronide metabolites may be impaired. 8 Pharmacodynamics changes Tissue sensitivity to drugs may be impaired. 9 Therapeutic range Drugs with wide therapeutic range will be less affected by moderate hepatic impairment. Chronic disease may change accessibility of some enzymes as a result of redirection or detour of hepatic blood circulation (shunting). Enzyme-dependent drugs are usually given to patients with hepatic failure in half-doses or less, and monitored, while drugs with flow-dependent clearance are avoided if possible in liver failure. Active Drug and Metabolite When the drug is more potent than the metabolite, the overall pharmacological activity in the hepatic impaired patient will increase because the parent drug concentration is higher. When the drug is less potent than the metabolite, the overall pharmacological activity in the hepatic impaired patient will decrease because less of the active metabolite is formed. Changes in pharmacological activity due to hepatic disease may be much more complex when both the pharmacokinetic parameters and the pharmacodynamics of the drug changes as a result of the disease process. Fraction of Drug Metabolized Fraction of drug excreted unchanged = fe ----------------------------------------------------------(1) Fraction of drug metabolized = 1-fe -----------------------------------------------------------------(2) (fraction of drug eliminated through the non-renal route) Fraction of drug metabolized = Clh/Cl = 1-fe -------------------------------------------------------(3) Fraction of drug excreted unchanged = Clr/Cl = fe ------------------------------------------------(4) Where Clh =hepatic clearance Clr = renal clearance Cl = total body clearance Rearranging equation (3) and (4) Clh = Cl(1-fe) -------------------------------------------------------------------------------------------(5) 5 Clr = Cl(fe) ----------------------------------------------------------------------------------------------(6) Equation (5) assumes that drug metabolism occurs in the liver and the unchanged drug is excreted in the urine. Assuming that there is no enzyme saturation and drug exhibits linear kinetics. Dosing adjustments may then be based on residual hepatic function. Residual Liver function (RL) = Clh (hepatitis)/ Clh (normal) ------------------------------------(7) Clh (hepatitis) = RL x Clh (normal) ------------------------------------------------------------------(8) Substitute equation (5) into equation (8) Clh (hepatitis) = RL x Clnormal (1-fe) --------------------------------------------------------------(9) Assuming no renal clearance deterioration due to hepatitis, Total clearance in an hepatitis patient becomes Clhepatitis = (Clh)hepatitis + (Clr)normal -----------------------------------------------------------------(10) Substitute equation (9) and (6) into equation (10) Clhepatitis = RL x Clnormal (1-fe) + Clnormal (fe) Clhepatitis = Clnormal {RL(1-fe) + fe} Clhepatitis/ Clnormal = RL(1-fe) + fe -----------------------------------------------------------------(11) Where RL = Residual liver function (Clh)normal = Hepatic clearance of drug in normal subjects (Clh)hepatitis = Hepatic clearance of drug in patients with hepatitis. (Clr)normal = Renal clearance of drug in normal subjects Clnormal = Total clearance of drug in normal subjects Clhepatitis = Total clearance of drug in patient with hepatitis. Clhepatitis/ Clnormal = Dhepatitis/Dnormal --------------------------------------------------------------(12) Hepatic Blood Flow and Intrinsic Clearance Blood flow changes can occur in patients with chronic liver disease (often due to viral hepatitis or chronic alcohol use), while resistance to blood flow may be increased in some patients with hepatic impairment due to tissue damage and fibrosis, causing a reduction in intrinsic hepatic clearance. Intrinsic hepatic clearance is the intrinsic ability of the liver to remove (metabolise) drug in the absence of restrictions imposed on drug delivery to the liver cell by blood flow and protein 6 binding. It is what hepatic clearance would be if hepatic blood flow were unlimited and all drug were unbound, and its values can sometimes even be higher than hepatic blood flow. Hepatic clearance can also be calculated with these formula Clh = (Q x Clint)/ (Q + Clint) ------------------------------------------------------------------------(13) Clh = Q x E.R ----------------------------------------------------------------------------------------(14) Where Q = Hepatic blood flow Clint = Intrinsic clearance E.R = Extraction ratio Clh = Hepatic Clearance E.R. = (Unbound fraction x Intrinsic clearance)/ (Blood flow + Unbound fraction x Intrinsic clearance) E.R = (fu x Clint)/{QH + (fu x Clint)}-----------------------------------------------------------(15) Clint = Vmax/Km ---------------------------------------------------------------------------------(16) Where Vmax = Maximal velocity of the reaction at saturating substrate concentration i.e. the maximal rate at which the enzyme can convert the drug to a metabolite. Km = Michaelis Constant and this expresses how tightly the enzyme binds the drug substrate. Since ClH = QH x E.R (from equation 14) Then, ClH = QH x {(fu x Clint)/ (QH + fu x Clint) --------------------------------------------(17) When the intrinsic clearance of the drug is much less than the liver blood flow ClH >> fu x Clint; this is because QH is approximately same as (QH + fu xClint) When the intrinsic clearance is much higher than the liver blood flow; ClH >> QH; this is because QH +fu x Clint is approximately the same as fu x Clint. In practice, hepatic blood flow may not be available because of the required techniques involved in determining it; the pharmacist may have to make empirical estimate of the blood flow change after examining the patient and reviewing the available liver function. 7  Practice Question The hepatic clearance of a drug in a patient is reduced by 70% due to chronic viral hepatitis a) How is the total body clearance of the drug affected? b) What should be the new dose of the drug for the patient? Assume that the renal drug clearance (fe = 0.4) and plasma drug protein binding are not altered. Pharm Ochuko Orherhe Department of Clinical Pharmacy and Pharmacy Administration Faculty of Pharmacy, Obafemi Awolowo University, Ile-Ife. [email protected] 8