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CLINICAL PHARMACOLOGY 2003 (PART 34)

The liver is the most important organ in which drugs are structurally altered. Some of the resulting metabolites may be biologically inactive, some active and some toxic (see Chapter 7).The liver is exposed to drugs in higher concentrations than are most organs because most are administered orally and are absorbed from the gastrointestinal tract.Thus the whole dose must pass through the liver to reach the systemic circulation. Because of this the liver is a vulnerable target for injury from chemicals and drugs, and disordered hepatic function is an important cause of abnormal drug handling and response. . | SECTION 7 Liver biliary tract pancreas SYNOPSIS The liver is the most important organ in which drugs are structurally altered. Some of the resulting metabolites may be biologically inactive some active and some toxic see Chapter 7 .The liver is exposed to drugs in higher concentrations than are most organs because most are administered orally and are absorbed from the gastrointestinal tract.Thus the whole dose must pass through the liver to reach the systemic circulation. Because of this the liver is a vulnerable target for injury from chemicals and drugs and disordered hepatic function is an important cause of abnormal drug handling and response. Drugs and the liver Pharmacodynamic and pharmacokinetic changes Prescribing in liver disease Drug-induced liver injury Aspects of therapy Bile salts and gallstones Pancreas and drugs PHARMACODYNAMIC CHANGES IN LIVER DISEASE Patients with severe liver disease characteristically show abnormal end-organ response to drugs. For example CNS sensitivity to opioids sedatives and antiepilepsy drugs is increased. The effect of oral anticoagulants is increased because synthesis of coagulation factors is impaired. Fluid and electrolyte balance are altered. Sodium retention may be more readily induced by NSAIDs or corticosteroids ascites and oedema become more resistant to diuretics. PHARMACOKINETIC CHANGES IN LIVER DISEASE The liver has a large metabolic reserve and it is only when disease becomes decompensated that 651 SECTION 7 23 LIVER biliary tract pancreas important changes in drug handling occur. Parenchymal liver disease e.g. chronic viral or alcoholic liver disease has more impact on hepatic drugmetabolising enzyme activity than primarily cholestatic conditions e.g. primary biliary cirrhosis although clearance of drugs eliminated mainly by biliary excretion will be impaired in the latter. Hepatocellular injury toxic infectious leads to decreased activity of drug-metabolising enzymes which is reflected in diminished plasma .