The relationship between drug concentration and response also can be altered in patients with advanced liver disease. Of greatest concern is the fact that customary doses of sedatives may precipitate the disorientation and coma that are characteristic of portal-systemic or hepatic encephalopathy. Experimental hepatic encephalopathy is associated with increased g-aminobutyric acid-mediated inhibitory neurotransmission, and there has been some success in using the benzodiazepine antagonist flumazenil to reverse this syndrome (50). This provides a theoretical basis for the finding that brain hypersensitivity, as well as impaired drug elimination, is responsible for the exaggerated sedative response to diazepam that is exhibited by some patients with chronic liver disease (51). Bakti et al. (52) conducted a particularly well-controlled demonstration of benzodiazepine hypersensitivity by showing that central nervous system (CNS) performance in cirrhotic patients was impaired when compared to subjects with normal liver function at a time when plasma concentrations of unbound triazolam were the same in both groups. Changes in the cere-brospinal fluid (CSF)/serum concentration ratio of cimetidine have been reported in patients with liver disease, suggesting an increase in blood-brain barrier permeability that also could make these patients more sensitive to the adverse CNS effects of a number of other drugs (53).
Although cirrhotic patients frequently are treated with diuretic drugs to reduce ascites, they exhibit a reduced responsiveness to loop diuretics that cannot be overcome by administering larger doses. This presumably is related to the pathophysiology of increased sodium retention that contributes to the development of ascites (54). In addition, decreases in renal function, which are often unrecognized in these patients (46), may lead to decreased delivery of loop diuretics to their renal tubular site of action. Because hyperaldo-steronism is prevalent in these patients and spirono-lactone is not dependent on glomerular filtration for efficacy, it should be the mainstay of diuretic therapy in this clinical setting (55).
When diuretic therapy does result in effective fluid removal in cirrhotic patients, it is associated with a very high incidence of adverse reactions. In one study of diuretic therapy in cirrhosis, furosemide therapy precipitated the hepatorenal syndrome in 12.8%, and hepatic coma in 11.6%, of the patients (56). Although daily doses of this drug did not differ, patients who had adverse drug reactions received total furosemide doses that averaged 1384 mg, whereas patients without adverse reactions received lower total doses that averaged 743 mg. Accordingly, when spironolactone therapy does not provide an adequate diuresis, only small frequent doses of loop diuretics should be added to the spironolactone regimen (55). Cirrhotic patients also appear to be at an increased risk of developing acute renal failure after being treated with angiotensin-converting enzyme inhibitors and nonsteroidal anti-inflammatory drugs (57).
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It seems like you hear it all the time from nearly every one you know I'm SO stressed out!? Pressures abound in this world today. Those pressures cause stress and anxiety, and often we are ill-equipped to deal with those stressors that trigger anxiety and other feelings that can make us sick. Literally, sick.