Hepatic disease

Apart from these two Vertex compounds, only one other caspase inhibitor, BDN-6556, has been used in clinical trials. This compound belongs to the class of oxamyl dipeptides and was originally developed by Idun Pharmaceuticals (taken over by Pfizer). It is the only pan-caspase inhibitor that has been evaluated in humans. BDN-6556 displays inhibitory activity against all tested human caspases. It is also an irreversible, caspase-specific inhibitor that does not inhibit other major classes of proteases, or other enzymes or receptors. The therapeutic potential of BDN-6556 was first evaluated in several animal models of liver disease because numerous publications suggested that apoptosis contributes substantially to the development of some hepatic diseases, such as alcoholic hepatitis, hepatitis B and C (HBV, HCV), non-alcoholic steato-hepatitis (NASH), and ischemia/reperfusion injury associated with liver transplant. Accordingly, BDN-6556 was tested in a phase I study. The drug was safe and... 

Chloroquine is contraindicated in patients with known hypersensitivity. It is a good idea to use chloroquine cautiously in patients with hepatic disease or bone marrow depression and during pregnancy. Children are very sensitive to chloroquine, and the drug should be used with extreme caution in children. 

The skeletal muscle relaxants are contraindicated in patients with known hypersensitivity. Baclofen is contraindicated in skeletal muscle spasms caused by rheumatic disorders. Carisoprodol is contraindicated in patients with a known hypersensitivity to meprobamate. Cyclobenzaprine is contraindicated in patients with a recent myocardial infarction, cardiac conduction disorders, and hyperthyroidism, hi addition, cyclobenzaprine is contraindicated within 14 days of the administration of a monoamine oxidase inhibitor. Oral dantrolene is contraindicated in patients with active hepatic disease and muscle spasm caused by rheumatic disorders and during lactation. See Chapter 30 for information on diazepam. 

Chap. 31), and during lactation. Levodopa is used cautiously in patients with cardiovascular disease, bronchial asthma, emphysema, peptic ulcer disease, renal or hepatic disease and psychosis. Levodopa and combination antiparkinsonism drugs (eg, carbidopa/levodopa) are classified as Pregnancy Category C and are used with caution during pregnancy and lactation. 

Amantadine is used cautiously in patients with seizure disorders, hepatic disease, psychosis, cardiac disease, and renal disease The antihistamines, pheno-thiazines, disopyramide, and alcohol increase the risk of adverse reactions when administered with amantadine... 

These drug are used cautiously in patients with renal or hepatic disease, bladder obstruction, seizure disorders, sick sinus syndrome, gastrointestinal bleeding, and asthma Individuals with a history of ulcer disease may have a recurrence of the bleeding. 

All antiarrhythmic dra are used cautiously in patients with renal or hepatic disease. When renal or hepatic dysfunction is present, a dosage reduction may be necessary. All patients should be observed for renal and hepatic dysfunction. Quinidine and procainamide are used cautiously in patients with CHF. Disopyramide is used cautiously in patients with CHF, myasthenia gravis, or glaucoma, and in men with prostate enlargement. Bretylium is used cautiously in patients with digitalis toxicity because the initial release of norepinephrine with digitalis toxicity may exacerbate arrhythmias and symptoms of toxicity. Verapamil is used cautiously in patients with a history of serious ventricular arrhythmias or CHF. Electrolyte disturbances such as hypokalemia, hyperkalemia, or hypomagnesemia may alter the effects of the antiarrhythmic dru . Electrolytes are monitored frequently and imbalances corrected as soon as possible... 

Warfarin is used cautiously in patients with fever, heart failure, diarrhea, malignancy, hypertension, renal or hepatic disease, psychoses, or depression. Women of childbearing age must use a reliable contraceptive to prevent pregnancy. 

The glucocorticoids are administered with caution to patients with renal or hepatic disease hypothyroidism, ulcerative colitis, diverticulitis, peptic ulcer disease, inflammatory bowel disease hypertension, osteoporosis, convulsive disorders, or diabetes. The glucocorticoids... 

Preexisting disease, such as renal or hepatic disease, can especially influence the metabolism and excretion of certain drugs. In clinical trials, and in electronic longitudinal medical records, it is important to have sufficient variability in disease states and concomitant diseases among subjects in both the... 

Numerous factors, many of them poorly understood, are involved in the development of HE. In severe hepatic disease, systemic circulation bypasses the liver, so many of the substances normally metabolized by the liver remain in the systemic circulation and accumulate to toxic levels. In excess, these metabolic by-products, especially nitrogenous waste, cause alterations in central nervous system functioning.20... 

Diuretics are often required in addition to the sodium restriction described previously. Spironolactone and jurosemide form the basis of pharmacologic therapy for ascites. Spironolactone is an aldosterone antagonist and counteracts the effects of activation of the renin-angiotensin-aldosterone system. In hepatic disease not only is aldosterone production increased, but its half-life is prolonged because it is hepatically metabolized. Spironolactone acts to conserve the potassium that would be otherwise excreted because of elevated aldosterone levels. 

Chronic hepatitis (disease lasting longer than 6 months) is usually associated with hepatitis B, C, and D. Chronic viral hepatitis may lead to the development of cirrhosis, which may induce end-stage liver disease (ESLD). Complications of ESLD include ascites, edema, jaundice, hepatic encephalopathy, infections, and bleeding esophageal varices. Therefore, prevention and treatment of viral hepatitis may prevent ESLD. 

Avoid if CrCI less than 30 mL/minute and in all patients with hepatic disease Can raise BP Do not discontinue abruptly (withdrawal syndrome)... 

Suicide risk even in patients without psychiatric disease Avoid in uncontrolled narrow-angle glaucoma (causes mydriasis) Hepatotoxic avoid in alcoholics even if signs/symptoms of hepatic disease are absent. 

Human foods that are particularly rich in copper (20 to 400 mg Cu/kg) include oysters, crustaceans, beef and lamb livers, nuts, dried legumes, dried vine and stone fruits, and cocoa (USEPA 1980). In humans, copper is present in every tissue analyzed (Schroeder et al. 1966). A 70-kg human male usually contains 70 to 120 mg of copper (USEPA 1980). The brain cortex usually contains 18% of the total copper, liver 15%, muscle 33%, and the remainder in other tissues — especially the iris and choroid of the eye. Brain gray matter (cortex) has significantly more copper than white matter (cerebellum) copper tends to increase with increasing age in both cortex and cerebellum. In newborns, liver and spleen contain about 50% of the total body burden of copper (USEPA 1980). Liver copper concentrations were usually elevated in people from areas with soft water (Schroeder et al. 1966). Elevated copper concentrations in human livers are also associated with hepatic disease, tuberculosis, hypertension, pneumonia, senile dementia, rheumatic heart disease, and certain types of cancer (Schroeder et al. 1966). 

HEP, hepatic disease REN, renal dysfunction SR, sustained-release. 

Fresh frozen plasma replaces clotting factors. Although it is often overused, the product is indicated if there is ongoing hemorrhage in patients with a PT or aPTT greater than 1.5 times normal, severe hepatic disease, or other bleeding disorders. 

Endocrine abnormalities Hypothyroidism Adrenal insufficiency Pituitary insufficiency Chronic renal disease Chronic inflammatory disease Granulomatous diseases Collagen vascular diseases Hepatic disease... 

Dose adjustment may be required for weight, renal, or hepatic disease, and drug interactions. 

Hepatic diseases do not change the serum levels of G-6-PDH (B15, K6, LI). In malignant occlusion jaundice, elevated levels of G-6-PDH have been reported (LI). 

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