Pathways of Metabolism. The four basic pathways of metabolism are (a) oxidation, (b) reduction, (c) hydrolysis, and (d) conjugation.

1. Phase I reactions include oxidation, reduction, and hydrolysis, which increase the drug’s polarity and prepare it for phase II reactions.

2. Phase II reactions are conjugation reactions that covalently link the drug or metabolites with a highly polar molecule (carbohydrate or an amino acid) that renders the conjugate more water soluble for subsequent excretion.

3. Hepatic microsomal enzymes (hepatic smooth endoplasmic reticulum but also present in kidneys and gastrointestinal tract) are responsible for the metabolism of most drugs.

Phase I enzymes responsible for phase I reactions include cytochrome P-450 enzymes (predominantly hepatic microsomal enzymes), noncytochrome P-450 enzymes, and flavin-containing monooxygenase enzymes.

1. The cytochrome P-450 enzyme system is a large family of membrane-bound proteins.

2. Drugs can alter the activity of these enzymes through induction and inhibition (phenobarbital induces microsomal enzymes and thus can render drugs less effective through increased metabolism).

3. Oxidation. Cytochrome P-450 enzymes are crucial for oxidation reactions. Examples of oxidative metabolism of drugs catalyzed by cytochrome P-450 enzymes include hydroxylation, deamination, desulfuration, dealkylation, and dehalogenation.

4. Reduction. Cytochrome P-450 enzymes are also essential for reduction reactions. Under conditions of low oxygen partial pressures, cytochrome P-450 enzymes transfer electrons directly to a substrate such as halothane rather than to oxygen.

5. Conjugation with glucuronic acid involves cytochrome P-450 enzymes. The resulting water-soluble glucuronide conjugates are then excreted in bile and urine.

6. Hydrolysis. Enzymes responsible for hydrolysis of drugs, usually at an ester bond, do not involve the cytochrome P-450 enzyme system. Hydrolysis often occurs outside of the liver (remifentanil, succinylcholine, esmolol, and the ester local anesthetics are cleared in the plasma and tissues via ester hydrolysis).

Phase II enzymes include glucuronosyltransferases, glutathione-S-transferases, N-acetyl-transferases, and sulfotransferases.

1. Glucuronidation is an important metabolic pathway for several drugs used during anesthesia, including propofol, morphine (yielding morphine-3-glucuronide and the pharmacologically active morphine-6-glucuronide), and midazolam (yielding the pharmacologically active 1-hydroxymidazolam).

2. Glutathione-S-transferase (GST) enzymes are primarily a defensive system for detoxification and protection against oxidative stress.