Liver disease drug metabolism

Lactic acidosis occurs in two clinical settings (1) type A (hypoxic), associated with decreased tissue oxygenation, such as shock, hypovolemia, and left ventricular failure and (2) type B (metabolic), associated with disease (e.g., diabetes melUtus, neoplasia, liver disease), drugs and/or toxins (e.g., ethanol, methanol, and salicylates), or inborn errors of metabolism (e.g., methylmalonic aciduria, propionic acidemia, and fatty acid oxidation defects). Lactic acidosis is not uncommon and occurs in approximately 1% of hospital admissions. It has a mortality rate greater than 60%, which approaches 100% if hypotension is also present. Type A is much more common. 

In liver disease, for example, the ability to metabolize or detoxify a specific type of drug may be impaired. If the average or normal dose of the drug is given, the liver may be unable to metabolize the drug at a normal rate Consequently, the drug may be excreted from the body at a much slower rate than normal. The primary health care provider may then decide to prescribe a lower dose and lengthen the time between doses because liver function is abnormal. 

Medication use must be monitored carefully for potential hepatotoxicity. Hepatically metabolized medications have the potential to accumulate in patients with liver disease. Little guidance is available on drug dosing in hepatic impairment because these patients are often excluded from drug trials. Daily acetaminophen use should not exceed 2 g. Dietary supplements have not been well studied in hepatic impairment and cannot be recommended. 

Hepatic function impairment In patients with preexisting severe liver disease, hepatic encephalopathy (manifested by tremors, confusion, and coma, and increased jaundice) may occur. Because amiloride is not metabolized by the liver, drug accumulation is not anticipated in patients with hepatic dysfunction, but accumulation can occur if hepatorenal syndrome develops. 

Renal/Hepatic function impairment The drug is metabolized in liver and excreted by the kidney administer with caution to patients with such impairment. Extensive liver disease predisposes to greater side effects and may be the result of decreased drug metabolism. 

Hepatic function impairment Administer with caution to patients with diseases that may alter the absorption, metabolism, or excretion of drugs. The bioavailability may be markedly increased in patients with liver disease. No dosage adjustment is necessary when frovatriptan or eletriptan is given to patients with mild to moderate hepatic impairment. Do not use eletriptan in severe hepatic impairment. 

Hepatic function impairment Ritonavir is principally metabolized by the liver. Exercise caution when administering this drug to patients with pre-existing liver diseases, liver enzyme abnormalities, or hepatitis. 

Liver disease or injury may impair bile secretion and thereby lead to accumulation of certain drugs, for example probenecid, digoxin, and diethylstilbestrol. Impairment of liver function can lead to decreased rates of both drug metabolism and secretion of drugs into bile. These two processes, of course, are frequently interrelated, since many drugs are candidates for biliary secretion only after appropriate metabolism has occurred. 

Colchicine is rapidly absorbed after oral administration and tends to concentrate in the spleen, kidney, liver, and gastrointestinal tract. Leukocytes also avidly accumulate and store colchicine even after a single intravenous injection. Since colchicine can accumulate in cells against a concentration gradient, it is postulated that an active transport process may be involved in its cellular uptake. The drug is metabolized, primarily in the liver, by deacetylation. Fecal excretion plays a major role in colchicine elimination, since it and its metabolites are readily secreted into the bile. Only about 15 to 30% of the drug is eliminated in the urine except in patients with liver disease urinary excretion is more important in these individuals. 

Theophylline should be used with caution in patients with myocardial disease, liver disease, and acute myocardial infarction. The half-life of theophylline is prolonged in patients with congestive heart failure. Because of its narrow margin of safety, extreme caution is warranted when coadministering drugs, such as cime-tidine or zUeuton, that may interfere with the metabolism of theophylline. Indeed, coadministration of zileu-ton with theophylline is contraindicated. It is also prudent to be careful when using theophylline in patients with a history of seizures. 

Abacavir undergoes extensive hepatic metabolism therefore, patients with liver disease should be monitored closely if this drug is given. Ethanol inhibits the metabolism of abacavir because it competes for metab-... 

Certain drugs are excreted in urine only in small amounts but appear in high concentrations in the bile for example, erythromycin, novobiocin, tetracycline, phenolphthalein etc. The abnormality or any disease related to liver may impair bile secretion which can lead to the accumulation of certain drugs like probenecid, digoxin etc. This can also lead to decreased drug metabolism and decreased rates of secretion of drugs into bile. 

Some drugs are metabolized so readily that even marked reduction in liver function does not significantly prolong their action. However, cardiac disease, by limiting blood flow to the liver, may impair disposition of those drugs whose metabolism is flow-limited (Table 4-7). These drugs are so readily metabolized by the liver that hepatic clearance is essentially equal to liver blood flow. Pulmonary disease may also affect drug metabolism, as indicated by the impaired... 

The plasma clearance of theophylline varies widely. Theophylline is metabolized by the liver, so typical doses may lead to toxic concentrations of the drug in patients with liver disease. Conversely, clearance may be increased through the induction of hepatic enzymes by cigarette smoking or by changes in diet. In normal adults, the mean plasma clearance is 0.69 mL/kg/min. Children clear theophylline faster than adults (1-1.5 mL/kg/min). Neonates and young infants have the slowest clearance (see Chapter 59). Even when maintenance doses are altered to correct for the above factors, plasma concentrations vary widely. 

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