Transfer of Drugs across Membranes. Even the simplest drug that is directly administered into the blood to exert its action must move across at least one cell membrane to its site of action.
Because biologic membranes are lipid bilayers composed of a lipophilic core sandwiched between two hydrophilic layers, only small lipophilic drugs can passively diffuse across the membrane down its concentration gradient.
For water-soluble drugs to passively diffuse across the membrane down its concentration gradient, transmembrane proteins that form a hydrophilic channel are required.
Intravenous (IV) administration results in rapid increases in drug concentration. Although this can lead to a very rapid onset of drug effect, for drugs that have a low therapeutic index (the ratio of the IV dose that produces a toxic effect in 50% of the population to the IV dose that produces a therapeutic effect in 50% of the population), rapid overshoot of the desired plasma concentration can potentially result in immediate and severe side effects.
Bioavailability is the relative amount of a drug dose that reaches the systemic circulation unchanged and the rate at which this occurs. For most intravenously administered drugs, the absolute bioavailability of drug available is close to unity, and the rate is nearly instantaneous.
The pulmonary endothelium can slow the rate at which intravenously administered drugs reach the systemic circulation if distribution into the alveolar endothelium is extensive such as occurs with the pulmonary uptake of fentanyl. The pulmonary endothelium also contains enzymes that may metabolize intravenously administered drugs (propofol) on first pass and reduce their absolute bioavailability.
Oral administration is not used significantly in anesthetic practice because of the limited and variable rate of bioavailability.
Because of this extensive first-pass metabolism, the oral dose of most drugs must be significantly higher to generate a therapeutic plasma concentration.
Highly lipophilic drugs that can maintain a high contact time with nasal or oral (sublingual) mucosa can be absorbed without needing to traverse the gastrointestinal (GI) tract. Sublingual administration of drug has the additional advantage over GI absorption in that absorbed drug directly enters the systemic venous circulation, so it is able to bypass the metabolically active intestinal mucosa and the hepatic first-pass metabolism.
Transcutaneous Administration. A few lipophilic drugs (e.g., scopolamine, nitroglycerin, fentanyl) have been manufactured in formulations that are sufficient to allow penetration of intact skin.
Intramuscular and Subcutaneous Administration. Absorption of drugs from the depots in the subcutaneous tissue or in muscle tissue directly depends on the drug formulation and the blood flow to the depot.
Intrathecal, Epidural, and Perineural Injection. The major downside to these three techniques is the relative expertise required to perform regional anesthetics relative to oral, IV, and inhalational drug administration.
Inhalational Administration. The large surface area of the pulmonary alveoli available for exchange with the large volumetric flow of blood found in the pulmonary capillaries makes inhalational administration an extremely attractive method (approximates IV administration) by which to administer drugs.