Scientific Principles |
|Part A:||Inhaled Anesthetics|
|Chapter 6:||Metabolism and Toxicity of Inhaled Anesthetics|
Function of the Liver in Drug Metabolism
Inhaled anesthetics are primarily metabolized by the liver and, to a lesser extent, by other tissues (e.g., gastrointestinal tract, kidneys, lungs, skin). The following discussion of drug metabolism is limited to the liver because most anesthetic biotransformation occurs in this organ, and the principles of drug metabolism are similar from tissue to tissue.
Hepatic physiology is fully discussed in Chapter 17 ; however, a brief description is included in this discussion to aid in understanding the relationship between drug metabolism and toxicity. The liver is the largest organ in the body and weighs about 1,500 g in adult humans. It is unique from the standpoint that it has a double blood supply: 70 percent of the flow from the portal vein and 30 percent from the hepatic artery. Blood in the portal vein comes from the alimentary canal, pancreas, and spleen. Thus, any toxic material absorbed from the alimentary canal is processed by the liver before it enters the systemic circulation. Blood flows through the hepatic sinusoids from the periphery of the hepatic lobule, fed by portal veins and hepatic arteries, to the centrally located hepatic venule (central vein).
The hepatocyte contains several structures that are involved in intermediary and drug metabolism, most notably the endoplasmic reticulum. This membranous matrix of lipoprotein is the major site of protein synthesis, electron transfer, lipid metabolism, and hormone and drug metabolism. It is also the main site for the synthesis of the lipoid and protein structural components for the cell and its organelles. The rough endoplasmic reticulum (RER) is the site of protein synthesis and is identified by the presence of adjacent ribosomes. The RER is extensively developed in protein-secreting cells. The smooth endoplasmic reticulum (SER) is identified by its lack of ribosomes. It is the site of drug metabolism, bilirubin conjugation, steroid synthesis, and some enzyme synthesis. The SER is extensively developed in steroid-secreting cells. In hepatocytes, both RER and SER participate in drug metabolism. Many in vitro studies of the liver and its drug-metabolizing capability are performed with hepatocytes and microsomes. The latter organelles are not naturally occurring, but they are formed from the breakage and reformation of the RER and SER during cell fractionation.
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