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KEY CONCEPTS
Drug molecules obey the law of mass action. When the plasma concentration exceeds the tissue concentration, the drug moves from the plasma into tissue. When the plasma concentration is less than the tissue concentration, the drug moves from the tissue back to plasma.
Most drugs that readily cross the blood–brain barrier (eg, lipophilic drugs like hypnotics and opioids) are avidly taken up in body fat.
Biotransformation is the chemical process by which the drug molecule is altered in the body. The liver is the primary organ of metabolism for drugs.
Small unbound molecules freely pass from plasma into the glomerular filtrate. The nonionized (uncharged) fraction of drug is reabsorbed in the renal tubules, whereas the ionized (charged) portion is excreted in urine.
Elimination half-life is the time required for the drug concentration to fall by 50%. For drugs described by multicompartment pharmacokinetics (eg, all drugs used in anesthesia), there are multiple elimination half-lives.
The offset of a drug’s effect cannot be predicted from half-lives. The context-sensitive half-time is a clinically useful concept to describe the rate of decrease in drug concentration and should be used instead of half-lives to compare the pharmacokinetic properties of intravenous drugs used in anesthesia.
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The clinical practice of anesthesiology is directly connected to the science of clinical pharmacology. One would think, therefore, that the study of pharmacokinetics and pharmacodynamics would receive attention comparable to that given to airway assessment, choice of inhalation anesthetic, neuromuscular blockade, or treatment of sepsis in anesthesiology curricula and examinations. Sadly, the frequent misidentification or misuse of pharmacokinetic principles and measurements suggests that this is not yet the case.
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Pharmacokinetics defines the relationships among drug dosing, drug concentration in body fluids and tissues, and time. It consists of four linked processes: absorption, distribution, biotransformation, and excretion.
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Absorption defines the processes by which a drug moves from the site of administration to the bloodstream. There are many possible routes of drug administration: oral, sublingual, rectal, inhalational, transdermal, transmucosal, subcutaneous, intramuscular, perineural, peridural, intrathecal, and intravenous. Absorption is influenced by the physical characteristics of the drug (solubility, pKa, diluents, binders, and formulation), dose, the site of absorption (eg, gut, lung, skin, muscle), and in some cases (eg, perineural or subcutaneous administration of local anesthetics) by additives such as epinephrine. Bioavailability defines the fraction of the administered dose that reaches the systemic circulation. For example, nitroglycerin is well absorbed by the gastrointestinal tract but has low bioavailability when administered orally. The reason is that nitroglycerin undergoes extensive first-pass hepatic metabolism before reaching the systemic circulation.
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Oral drug administration is convenient, inexpensive, and relatively tolerant of dosing errors. However, it requires cooperation of the patient, exposes the drug to first-pass hepatic metabolism, and permits gastric pH, digestive enzymes, motility, food, and other drugs to potentially reduce the predictability of ...