Thromboembolism: Most studies indicate that OCs, including the newer low-dose (less than 50 µg of estrogen) preparations, are associated with a threefold to sixfold increased risk of venous thrombosis and pulmonary thromboembolism resulting from increased hepatic synthesis of coagulation factors. This risk may be even higher with newer “third-generation” OCs that contain synthetic progestins, particularly in women who are carriers of the factor V Leiden mutation. To put this complication into context, however, the risk of thromboembolism associated with OC use is two to six times lower than the risk of thromboembolism associated with pregnancy.
Cardiovascular disease: There is considerable uncertainty about the risk of atherosclerosis and myocardial infarction in users of OCs. It seems that OCs do not increase the risk of coronary artery disease in women younger than 30 years or in older women who are nonsmokers, but the risk approximately doubles in women older than 35 years who smoke.
Hepatic adenoma: There is a well-defined association between the use of OCs and this rare benign hepatic tumor, especially in older women who have used OCs for prolonged periods (Chapter 14).
Obviously, the pros and cons of OCs must be viewed in the context of their wide applicability and acceptance as a form of contraception that protects against unwanted pregnancies.
At therapeutic doses, acetaminophen, a widely used nonprescription analgesic and anti-pyretic, is mostly conjugated in the liver with glucuronide or sulfate. About 5% or less is metabolized to NAPQI (N-acetyl-p-benzoquinoneimine) through the hepatic P-450 system. With very large doses, however, NAPQI accumulates, leading to centriloblar hepatic necrosis. The mechanisms of injury produced by NAPQI include (1) covalent binding to hepatic proteins and (2) depletion of reduced GSH. The depletion of GSH makes the hepatocytes more susceptible to cell death caused by ROS. The window between the usual therapeutic dose (0.5 g) and the toxic dose (15 to 25 g) is large, and the drug ordinarily is very safe. Nevertheless, accidental overdoses occur in children, and suicide attempts using acetaminophen are not uncommon, particularly in the United Kingdom. In the United States, acetaminophen toxicity is causes about 50% of acute liver failure. Toxicity begins with nausea, vomiting, diarrhea, and sometimes shock, followed in a few days by the appearance of jaundice. Overdoses of acetaminophen can be treated in early stages by the administration of N-acetylcysteine, which restores GSH. With serious overdoses, liver failure ensues, and centrilobular necrosis may extend to involve entire lobules; such patients often require liver transplantation. Some patients also show evidence of concurrent renal damage.
Aspirin overdose may result from accidental ingestion in young children or suicide attempts in adults. The major untoward consequences are metabolic, with few morphologic changes. At first, respiratory alkalosis develops, followed by a metabolic acidosis that often proves fatal. Fatal doses may be as little as 2 to 4 g in children and 10 to 30 g in adults, but survival has been reported after doses five times larger.