Drug elimination is the pharmacokinetic term that describes all the processes that remove a drug from the body. Although the liver and the kidneys are considered the major organs of drug elimination, drug metabolism can occur at many other locations that contain active drug metabolizing enzymes (e.g., the pulmonary vasculature, red blood cells), and drugs can be excreted unchanged from other organs (e.g., the lungs).

1. Elimination clearance (drug clearance) is the theoretical volume of blood from which drug is completely and irreversibly removed in a unit of time.
2. Biotransformation Reactions. Most drugs that are excreted unchanged from the body are hydrophilic and therefore readily passed into urine or stool. Drugs that are not sufficiently hydrophilic to be able to be excreted unchanged require modification (enzymatic reactions) into more hydrophilic, excretable compounds.
   1. Phase I reactions may hydrolyze, oxidize, or reduce the parent compound.
      1. Cytochrome P450 enzymes (CYPs) are a superfamily of constitutive and inducible enzymes that catalyze most phase I biotransformations. CYP3A4 is the single most important enzyme, accounting for 40% to 45% of all CYP-mediated drug metabolism.
      2. CYPs are incorporated into the smooth endoplasmic reticulum of hepatocytes and the membranes of the upper intestinal enterocytes in high concentrations (Table 7-1: Substrates for CYP Isoenzymes Encountered in Anesthesiology).
   2. Phase II reactions are known as conjugation or synthetic reactions. Similar to the cytochrome P450 system, the enzymes that catalyze phase II reactions are inducible.
   3. Genetic Variations in Drug Metabolism. Drug metabolism varies substantially among individuals because of variability in the genes controlling the numerous enzymes responsible for biotransformation.
   4. Chronologic Variations in Drug Metabolism. The activity and capacity of the CYP enzymes increase from subnormal levels in the fetal and neonatal period to reach normal levels at about 1 year of age. Neonates have a limited ability to perform phase II conjugation reactions, but after normalizing phase II activity over the initial year of life, advanced age does not affect the capacity to perform phase II reactions.
3. Renal Drug Clearance. The primary role of the kidneys in drug elimination is to excrete into urine the unchanged hydrophilic drugs and the hepatic derived metabolites from phase I and II reactions of lipophilic drugs. In patients with acute and chronic causes of decreased renal function, including advanced age, low cardiac output states, and hepatorenal syndrome, drug dosing must be altered to avoid accumulation of parent compounds and potentially toxic metabolites (Table 7-2: Drugs with Significant Renal Excretion Encountered in Anesthesiology).
4. Hepatic Drug Clearance. Drug elimination by the liver depends on the intrinsic ability of the liver to metabolize the drug and the amount of drug available to diffuse into the liver (hepatic blood flow) (Table 7-3: Classification of Drugs Encountered in Anesthesiology According to Hepatic Extraction Ratios).

Basic Principles of Clinical Pharmacology

1. Pharmacokinetic Principles: Drug Absorption and Routes of Administration
2. Drug Distribution
3. Drug Elimination
4. Pharmacokinetic Models
5. Compartmental Pharmacokinetic Models
6. Pharmacodynamic Principles
7. Drug–Receptor Interactions
8. Drug Interactions
9. Clinical Applications of Pharmacokinetic and Pharmacodynamics to the Administration of IV Anesthetics