The effects of altered enzyme function

Most drugs are metabolized from active fat-soluble compounds into inactive water-soluble compounds that can be excreted by the kidneys and bile. Usually this involves two phases of metabolism, so-called phase I and phase II metabolism.

Phase I metabolism usually involves the cytochrome P-450 superfamily of enzymes, performing reactions such as oxidation and hydroxylation. There are about 25 such enzymes, each identified by a number identifying the family, a letter identifying the subfamily, and a further number identifying the gene product. Each enzyme metabolizes multiple substrates; some examples relevant to critical care are shown in Table 1. The products of phase I metabolism may be highly active and, indeed, even toxic. For example, ^-acetyl-p-benzoquinone, the phase I metabolite of acetaminophen (paracetamol), is hepatotoxic and causes the damage seen after an overdose of acetaminophen.

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Table 1 Some of the cytochrome P-450 enzymes and the drugs that they metabolize

After phase I metabolism, further metabolism occurs involving the phase II enzymes. These commonly conjugate the phase I product with a group such as glutathione, glucuronic acid, or a sulfate.

The phase I enzymes are present in small amounts and are profoundly affected by disease. However, phase II enzymes are present in much larger amounts and are less affected by disease. Both acute and chronic liver disease reduce the amount of phase I enzymes, in turn reducing the ability of the liver to metabolize drugs dependent on this route of elimination. Those few drugs whose elimination is dependent only on phase II metabolism, such as propofol, morphine, and remifentanil, will have relatively normal metabolism in the presence of severe disease.

Benzodiazepines should be chosen with care. Those such as lorazepam and oxazepam which are metabolized mostly by glucuronidation may be preferred as their metabolism is not affected by liver disease. Diazepam and others dependent upon phase I pathways may have reduced elimination.

Enzymes responsible for the metabolism of most drugs are found in the greatest amounts in the liver, although concentrations may be higher in other tissues. The highest concentrations of the cytochrome P-450 enzymes are in the nose where they break down amines that cause smell, and in the adrenals where they make steroids.

Several studies performed during the anhepatic phase of liver transplantation have shown that many drugs are metabolized at these extrahepatic sites. The hepatic extraction ratio of propofol is greater than unity, showing that there is significant extrahepatic metabolism. However, the metabolic capacity of these sites is only about 10 per cent of that of the liver.

A third group of enzymes are becoming increasingly important for drug metabolism. These are the plasma and tissue esterases; for example, butyrl esterase is important in the metabolism of suxamethonium. Muscle relaxants such as mivacurium are being designed to avoid hepatic metabolism using this system of elimination. Because of their dependence on this one enzyme, they still risk genetic variability. Remifentanil, a new opioid, is metabolized by many esterases found both in the blood and elsewhere. Because it is metabolized by so many different esterases, its elimination is unlikely to be affected by disease or genetic variation.

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