Altered Pharmacokinetics in Liver Diseases

Altered pharmacokinetics in liver diseases

By B.Samyuktha

http://pharmacy2011foru.blogspot.com/

The liver is both a synthesizing and an excreting organ. Drugs are often metabolized by one or more enzymes located in cellular membranes in different parts of the liver. A pharmacokinetic model simulating hepatic metabolism should involve several elements, including the heterogenicity of the liver, the hydrodynamics of hepatic blood flow, the nonlinear kinetics of drug metabolism, and any unusual or pathologic condition of the subject in order to study metabolism of drugs by liver.

Hepatic Enzymes Involved in the Biotransformation of Drugs: Mixed-Function Oxidases: The hepatic parenchymal cells contain MFOs in association with the endoplasmic reticulum. The mixed-function oxidase enzymes are structural enzymes that constitute an electron-transport system that requires reduced NADPH (NADPH2), molecular oxygen, cytochrome P-450, NADPHcytochrome P-450 reductase, and phospholipid. Cytochrome P-450 consists of closely related isoenzymes (isozymes) that differ somewhat in amino acid sequence and drug specificity.


Fig 1:Electron flow pathway in the microsomal drug-oxidizing system.


Table 1: Cytochrome P450 Isoforms and Examples


Table 2: Examples of Drug Interactions Affecting Mixed Function Oxidase Enzymes


Biliary Excretion of Drugs: Drugs that are excreted mainly in the bile have molecular weights in excess of 500. Drugs with molecular weights between 300 and 500 are excreted both in urine and in bile. Table 3:Examples of Drugs Undergoing Enterohepatic Circulation and Biliary Excretion


Estimation of Biliary Clearance

Drug secretion into bile is an active process, this process can be saturated with high drug concentrations. Moreover, other drugs may compete for the same carrier system. Enterohepatic Circulation: The cycle in which the drug is absorbed, excreted into the bile, and reabsorbed into hepatic portal vein is known as enterohepatic circulation. Some drugs excreted as a glucuronide conjugate become hydrolyzed in the gut back to the parent drug by the action of a F-glucuronidase enzyme present in the intestinal bacteria.http://pharmacy2011foru.blogspot.com/

With a large dose or multiple doses, a larger amount of drug is secreted in the bile, from which drug is then reabsorbed. This reabsorption process may affect the absorption and elimination rate constants. Furthermore, the biliary secretion process may become saturated, thus altering the plasma leveltime curve. Drugs that undergo enterohepatic circulation sometimes show a small secondary peak in the plasma drugconcentration curve. Liver Extraction Ratio The liver extraction ratio (ER) provides a direct measurement of drug removal from the liver after oral administration of a drug

where C a is the drug concentration in blood entering the liver and C v is the drug concentration leaving the liver.


Effect of Hepatic Disease on Pharmacokinetics 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, and kidney function. A few tests have been used to relate the severity of hepatic impairment to predicted changes in the pharmacokinetic profile of the 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, have been used for the evaluation of liver impairment. 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.http://pharmacy2011foru.blogspot.com/

Dosage Considerations in Hepatic Disease:Table 3:Considerations in Dosing Patients with Hepatic Impairment


The Child-Turcotte score was designed to estimate the operative risk of an alcoholic patient with cirrhosis. The parameters used include serum concentrations of bilirubin and albumin, prothrombin time, nutritional status and ascites.



Changes in the pharmacokineticsDrug absorption Drug absorption is decreased in patients with liver cirrhosis due to ulcers of GIT, or may be increased because of portal hypertension.

Drug distributionIn the patients with liver cirrhosis oedema and ascites persists,volume of distribution of hydrophillic drugs is increased, so loading dose of the drug should be increased. example- F-lactam antibiotics. Increased volume of distribution is associated with increased half life of the drugs.


Hepatic Blood Flow and Intrinsic Clearance Blood flow changes can occur in patients with chronic liver disease, liver cirrhosis, resistance to blood flow may be increased as a result of tissue damage and fibrosis, causing a reduction in intrinsic hepatic clearance. The following equation may be applied to estimate hepatic clearance of a drug after assessing changes in blood flow and intrinsic clearance (Cl int):

Alternatively, when both Q and the extraction ratio, ER, are known in the patient, Cl may also be estimated:


Relationship between Absolute Bioavailability and Liver Extraction

where F is the fraction of bioavailable drug, ER is the drug fraction extracted by the liver, and F is the fraction of drug removed by nonhepatic process. If F is assumed to be negligiblethat is, there is no loss of drug due to chemical degradation, gut metabolism, and incomplete absorptionER may be estimated from


Liver ER provides valuable information in determining the oral dose of a drug when the intravenous dose is known.


High extraction drugs undergo a high extraction during the first passage across the liver (60%) and bio-availability of (40%). Elimination of drugs in retarded to cirrhotic patients. So, the initial and maintainence doses have to be reduced in these patients in oral drug administration. For drugs with high ER, that are administered I.V, normal initial dose can be administered and maintainence dose have to be reduced according to the hepatic clearance.

For low extracted drugs with low binding to albumin undergo first pass metabolism about 30%. Maintainence dose should be reduced in them. For low extracted drugs with high binding to albumin (90%) may represent an exception from the rule that hepatic clearance is determined by the activity of metabolising enzymes. Intermediate extraction drugs with hepatic clearance is reduced which necessitates the adjustment of maintainence dose.http://pharmacy2011foru.blogspot.com/


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. Starting therapy with low doses and monitoring response or plasma levels provides the best opportunity for safe, efficacious treatment. 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.

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.


Many variables can complicate dose correction when binding profoundly affects distribution, elimination, and penetration of the drug to the active site. For drugs with restrictive binding, the fraction of free drug must be used to correct the change in free drug concentration and the change in free drug clearance. In some cases, the increase in free drug is partly offset by a larger volume of distribution resulting from the decrease in protein binding. Since there are many variables that complicate dose correction for patients with hepatic disease, dose correction is limited to drugs whose hepatic metabolism is approximated by linear pharmacokinetics. Examples include opiates, benzodiazepines, NSAIDs, anti -psychotics and diuretics. Such drugs may exhibit unusual adverse effects that clinicians should be aware of for their safe use.


Active Drug and the 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 disease patient will decrease because less of the active metabolite is formed.



Chronic hepatic disease is more likely to change the metabolism of a drug. The clinician may make an assessment based on acceptable risk criteria on a case-by-case basis. list useful endpoints for assessing the extent of hepatic dysfunction. Drug clearance based on individual eliminating organs is more informative and provides more insight into the pharmacokinetic changes in the disease process.

The hepatic blood flow model is useful for predicting changes in hepatic clearance resulting from alterations in hepatic blood flow, Q a, and Q v, extra hepatic changes can also influence pharmacokinetics in hepaticimpaired patients.


Evaluating the drug in question If a drug is dependent on hepatic elimination, there are several factors to consider when prescribing for patients with liver disease. Determining the hepatic contribution to elimination is paramount and the following general rules should be considered. Drugs with a narrow therapeutic range that are extensively metabolised by the liver (that is, greater than 20% of their total elimination) should either be avoided altogether (e.g. pethidine) or used with extreme caution (e.g. morphine, theophylline) in patients with significant liver disease. Drugs with a wide therapeutic range which also undergo extensive hepatic metabolism should be used with caution. In particular, the dosing interval should be increased or the total dose reduced (e.g. carvedilol). If greater than 90% of the compound is excreted unchanged in the urine, then hepatic impairment is unlikely to play a significant role in the accumulation of the drug and therefore toxicity.


If hepatic elimination is limited (that is, accounting for less than 20% of total elimination), then the therapeutic range of the compound should be reviewed. If the drug has a wide therapeutic index, then the likelihood of an adverse effect related to hepatic impairment is low. However, if the drug has a narrow therapeutic index, then caution should be exercised as significant hepatic impairment may have a clinically relevant effect on the pharmacokinetics (e.g. lamotrigine).


Factors to consider when prescribing drugs dependent on hepatic elimination Ascertain how much drug depends on hepatic metabolism for its elimination from the body. Determine the degree of hepatic impairment using the Child-Pugh classification, hepatic enzyme levels and possibly an ultrasound of the liver with portal vein Doppler study. If there is doubt about the degree of hepatic impairment or the drug has a narrow therapeutic index (that is, the upper dose range for efficacy is close to the lower concentration range of toxicity), then lower the recommended starting dose by approximately 50%, and titrate to effect under careful supervision 'start low and go slow'. Determine possible interactions between the new drug and any drugs the patient is already taking.


Conclusion Prescribing in hepatic impairment is less well defined when compared to guidelines for prescribing in renal failure. Hepatic dysfunction is less overt and may not be apparent until much of the functioning liver is lost. Knowledge of the metabolism of drugs eliminated by the liver is useful along with close monitoring of the patient for unwanted adverse effects related to possible toxicity. When introducing long-term treatment with a drug with high hepatic clearance or a narrow therapeutic index, assess liver function (clinically and with baseline liver function tests). However, once the drug is commenced routine monitoring is costly and its role is unclear in most cases of prescribing in patients with hepatic dysfunction.


REFERENCES Prescribing in liver disease-Available from: URL http://www.australianprescriber.com/magazine/32/2/32/5 The fifth edition of Applied Biopharmaceutics and PharmacokineticsLeon Shargel, Susanna Wu-Pong,Andrew, B.C. Yu August 2004 Chapter 11. Hepatic Elimination of Drugs and Chapter 21. Dose Adjustment in Renal and Hepatic Disease.



Altered Pharmacokinetics in Liver Diseases

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