Liver disease altered drug metabolism

A number of conditions are indicative of liver disease including (1) jaundice, (2) portal hypertension, (3) abnormal hepatorenal function, (4) altered drug metabolism, (5) nutritional and metabolic abnormalities, (6) disordered hemostasis, and (7) the release of enzymes into various body fluids. 

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. 

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. 

Most sulfonylureas are at least partly metabolized in the liver (SEDA-9, 709) (57), and hence liver insufficiency, liver disease, and liver enzyme inhibition (alcohol) or induction (drugs) can alter the half-life of the drug and its duration of action. 

The liver is the principal metabolic organ, and hepatic disease or dysfunction may impair drug elimination. Any alteration in the serum albumin or bilirubin levels and in the prothrombin time indicates impaired liver function. Similarly, skin bruising and bleeding tendency indicate decreased production of clotting factors by the liver. 

Macrolides are metabolized primarily in the liver with their metabolites excreted into bile metabolism occurs to a lesser degree in the kidneys and lungs [259, 260]. Since macrolides vary widely in their serum and tissue concentrations, half-lives, and active metabolites, knowledge of their metabolism is important for optimizing dosage schedules. Some macrolides also influence the metabolism of certain other drugs, and modified metabolic conditions such as liver disease may alter antibiotic concentrations [260-264]. Because such events can lead to toxicity from either excess antibiotic or adverse drug interactions, metabolism is examined in patients... 

There are no good predictors of the occurrence of dysrhythmias, but there are several susceptibility factors (26 7), including a history of sustained tachydysrhythmias, poor left ventricular function, and myocardial ischemia. Potassium depletion and prolongation of the QT interval are particularly important, and these particularly predispose to polymorphous ventricular dysrhythmias (for example torsade de pointes). Altered metabolism of antidysrhjdhmic drugs (for example liver disease, polymorphic acetylation or hydroxylation, and drug interactions) can also contribute. 

Susceptibility factors genetic (long QT syndrome) altered physiology (hypokalemia) drug interactions (metabolism inhibitors drugs that prolong the QT interval) diseases (liver disease cardiac disease with prolongation of QT interval)... 

Metyrapone (m). 2-methyl-l,2-bis-(3-pyridyl)-l-propanone, continues to be used clinically for determining the pituitary s ability to secrete ACTH. The adrenal response to the drug as measured by the secretion of F and S is found to depend on the pituitary reserve of ACTH and the degree of dose-dependent inhibition of lip-hydroxylase39. The failure to include the increased secretion of DOC leads to a low value for the inhibition of the enzyme. The varied M response seen in liver disease may result from altered metabolism of the drug. NADPH does not reverse the M inhibited conversion of P to B, 18-OH B and Aldo by mouse adrenal quarters. ... 

Clomipramine, fluoxetine, sertraline, paroxetine, fluvoxamine, and citalopram are extensively metabolized in the Liver, and patients with significant liver disease should be prescribed these drugs cautiously and in lower doses than those used in healthy subjects. The pharmacokinetics of fluoxetine and fluvoxamine were similar in patients with renal faUme and in healthy subjects however, the manufacturer recommends starting with a lower dose in patients with renal impairment. The pharmacokinetics of sertraline are not altered in patients with significant renal dysfunction, and dosage adjustment is not necessary in these patients. Increased plasma concentrations of paroxetine occur in subjects with renal impairment. The initial dose of paroxetine should be reduced in patients with severe renal impairment, and upward titration should occm more slowly. No dosage adjustment is necessary for patients with mild to moderate renal impairment receiving citalopram. 

Taken together, FXR not only regulates bile acid homeostasis but also greatly impacts on transporters and enzymes involved in drug metabolism. Effects on phase I—III genes by bile acid-activated FXR may therefore at least in part explain alterations of drug metabolism in cholestatic liver disease [62, 85, 86]. 

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