The absorption of a drug is largely dependent on the route of delivery. Drugs can be administered by depot type of routes: oral, inhaled, subcutaneous, intramuscular, sublingual, rectal, intraocular, intranasal, vaginal, and transdermal. Although intravenous and intra-arterial technically do have an aspect of absorption (i.e., release of drug from a syringe or i.v./i.a. bag), these routes deliver drug directly into the systemic circulation and are a special subset of PK input (i.e., instantaneous absorption processes having a bioavailability of 1.0). The physicochemical properties (i.e., solubility, pKa, ionization, polarity, molecular weight, partition coefficient) play a critical role in the absorption of drugs. The route of delivery impacts the rate of absorption as well as the extent of absorption. Bioavailability is defined as the rate and extent of drug absorption or the percentage or fraction of the parent compound that reaches systemic (plasma) circulation. The bioavailability of the same drug in the same patient may be different depending on the route of administration. Drug references frequently provide the bioavailabilities of drugs and are typically denoted as F. The extent of absorption, but not the rate, can be described by the parameter area under the curve (AUC). In an acute setting, the rate of absorption, generally k _a , tends to be more important, whereas the extent of absorption tends to be more important in chronic use medications. The salt factor (S) is the fraction of a dose that is the active base form of the drug and pragmatically can be viewed as an attenuation of F (e.g., “effective dose” = F*S*dose). Probably, the most frequently used routes of administration of drugs in anesthesiology are oral, intravenous/intra-arterial, inhaled, and local (epidural, interscalene, etc.).

The absolute bioavailability, F, is determined by comparing the availability for any given extravascular (e.v.) route of administration measured against an i.v. point of reference of availability of the drug administered intravenously (Eq. 1.1):

Since anesthetics and pain management medications can be delivered via numerous routes of administration, the value of F is important in determining the “effective dose” for these e.v. drugs. The physicochemical properties, previously mentioned, of the drug affect the drug’s ability to partition from lipid to aqueous phases, and therefore, F. Food, drug interactions, and gastrointestinal (GI) motility can all affect drug solubility and absorption. First-pass metabolism, which is pre-systemic metabolism of the drug, can occur in the GI tract and the liver prior to reaching systemic circulation. All of these factors can affect F and the route will sometimes dictate the countersalt needed, thus affecting S, as well.

For inhaled anesthetics, three major factors influencing absorption are solubility in the blood, alveolar blood flow, and the partial pressure gradient between alveolar gas and venous blood. The solubility of inhaled anesthetics in blood is described by blood/gas partition coefficients (Table 1.1). The inhaled anesthetics are absorbed almost completely and rapidly through the lungs. A lower blood/gas partition coefficient indicates a more rapid onset and dissipation of anesthetic action.

The volume of distribution V _d is a PK parameter characterizing the extent of drug distribution into the tissue from the blood. The physicochemical properties of a drug, plasma protein binding, and tissue binding influence V _d. It has also been termed apparent volume of distribution because it does not correlate with an actual physiological volume compartment in the human body, but rather, it is the inferred volume in which the drug appears to be dissolved. It is inferred because as Eq. 1.2 shows, the clinician knows the dose given and Cp (drug plasma concentration) is measured; the V _d is inferred or calculated from the two values of dose and Cp. The lower limit for nearly all drugs is 3 L or the actual average volume of human plasma. As the apparent or inferred volume of distribution increases in size, the interpretation begins to focus on the distribution of drug into extravascular tissues. The apparent or inferred V _d can be calculated using Eq. 1.2:

If the plasma concentration Cp of a drug is small immediately following a single-bolus dose, this generally indicates substantial drug permeation into the tissue(s), and the resultant V _d is >40–80 L, indicating extensive distribution into the tissue. In contrast, if V _d is small (close to 3 L), a large fraction of the drug is assumed to reside in the blood plasma, thus suggesting a little amount of drug has permeated into the extravascular tissue(s). While V _d provides insight as to whether the drug is residing in the blood or tissue, its value does not determine which specific tissue compartment the drug permeates into.

V _d is useful in determining the loading dose necessary to achieve a targeted Cp. The usual loading dose equation is Loading Dose = V _d × Cp_target. For drugs that have a large V _d, a greater loading dose is necessary to achieve the targeted Cp. Drugs with a small V _d require a reduced loading dose to obtain the targeted Cp.

As shown in Table 1.1, the inhaled anesthetics have high brain/blood, muscle/blood, and fat/blood partition coefficients. In particular, most inhaled anesthetics distribute extensively into the fat tissues.

Clearance is an independent PK parameter quantifying the rate the body is able to eliminate a drug. More specifically, clearance is the volume of blood that is completely cleared of the drug per unit time. The units are in volume/time, usually liters per hour (L/h) or milliliters per minute (mL/min). While the liver is primarily responsible for drug metabolism and the kidneys are primarily responsible for parent drug and metabolite excretion (filtration and secretion), other routes of elimination include the chemical decomposition, feces, skin, and lungs. Hepatic metabolism and elimination are components of drug clearance. Total clearance is characterized by Eq. 1.3:

Total clearance Cl_Total is used in most dose calculations without taking into account the specific route of elimination. Clearance is an important parameter because it controls the steady-state concentration Cp_ss as shown in Eq. 1.4:

S is the salt factor, F is the bioavailability, and tau (τ) is the dosing interval.

The dependent parameter K is a first-order rate constant. It is a function of V _d and Cl. K can be described as the percentage or fraction of the amount of drug that is cleared from the body per unit time. The units are typically expressed as 1/h (hr⁻¹) or 1/min (min⁻¹). As shown in Eq. 1.6, K can be viewed as a proportionality constant between V _d and Cl:

A large K value indicates rapid elimination of the drug. If two drug concentrations are drawn within the same dosing interval, K can be determined using Eq. 1.7 [4]:

Ln is natural log and Δt is the time elapsed between Cp₁ and Cp₂. The determination of K is integral to calculating half-life, t _1/2, as shown in Eq. 1.8:

Equation 1.8 also shows the relationship among t _1/2 and V _d and Cl. The t _1/2 is the amount of time it takes for the drug currently in the body to reduce by 50 %. The t _1/2 can also predict the amount of time it takes for a patient to achieve steady-state drug concentrations (assuming no loading dose and the same dose was administered at the same interval). For example, after one t _1/2, Cp is 50 % of the final steady-state Cp_ss. Under these conditions, a patient is considered to be clinically at steady state if the drug concentration is >90 % of the true steady-state level. As shown in Table 1.2, it would take approximately 3.3 half-lives for a patient to achieve 90 % of the true steady state. Conversely, it would take 3.3 half-lives for a patient to eliminate 90 % of the drug once the administration of the drug has ceased. To note, t _1/2 determines the dosing interval, but V _d and Cl determine the size of the dose.

The time-course conversion of drug concentration (Ce) into a pharmacological effect (response) is pharmacodynamics. The biosensor process is the detection of the drug’s presence, Ce. Frequently, the biosensor process is the receptor system on the cell’s surface. The white and black biosensor process rectangles indicate that the drug (Ce) either stimulates (white) or inhibits (black) the zero-order and first-order constants k _in or k _out, respectively. The biosignal is similar to the second messenger, in that it directs the end response. While the pathway in between the biosignal and the response can contain nonlinear and time-varying processes (circadian, drug-induced—such as drug tolerance), it still is the biosignal that is responsible for the end response. Alterations of k _in or k _out are frequently the sites for the nonlinearities or time-varying processes. This model is known as an “indirect” model and is relatively general; the most important aspect of this model is that a change in Cp is not instantaneously realized as a change in response (Fig. 1.2). Somewhere along the pathway of D, drug, diffusing out of Cp in to Ce or in the translation of D binding to the receptors to produce the response, there is a rate-limiting step that causes the response to lag behind changes in Cp.

A subset model of the indirect model is the direct model. In the direct model, the pharmacodynamic system very rapidly converts the Ce concentration of drug to response relative to the rate at which the Ce or Cp steady state is achieved. Or in other words, there is no time lag, as in the indirect model, between changes in Cp or Ce and response. Typical direct models have the form of , where E ₀ is the endogenous baseline (i.e., value of E in the absence of drug), E _max is the maximal effect achievable, EC₅₀ is the concentration of drug that produces ½ of the E _max response, and γ is the Hill coefficient. When γ > 1, the PD is said to have positive cooperativity; when γ < 1, the PD has negative cooperativity; and when γ = 1, the PD has no cooperativity (see Fig. 1.3 for a comparison of γ).

In the more commonly used model, notice that as “dose” or the x-axis changes, the effect or response instantaneously changes. Another way to view this relationship between “dose” and “response” is to assume that the “dose” or “log (Cp)” has reached steady state or equilibrium before the effect has been measured. The direct model can still be used to simulate drug tolerance by either attenuating E _max or increasing EC₅₀ as a function of Cp or Ce. The utility of this model cannot be overstated as it has provided many researchers and clinicians with useful pharmacodynamic insights.

Most drugs have established therapeutic ranges. Therapeutic ranges are typically expressed as a range of drug plasma concentrations that achieve an optimal effect while minimizing adverse reactions. However, drugs that require constant monitoring of drug concentrations are ones that have narrow therapeutic ranges, a low threshold for serious adverse reactions, or must reach a minimum plasma concentration to achieve an effect.

In anesthesiology, the minimum alveolar concentration (MAC; Table 1.3) of inhaled anesthetics is used as the target to achieve the necessary therapeutic effect. MAC is the amount of inhaled anesthetic required to inhibit physical movement in response to a noxious stimuli in 50 % of patients [5]. MAC values can also be used to compare the relative potencies between two inhaled anesthetic agents.

The continuous monitoring of plasma concentrations of intravenous anesthetics is not performed due to practicality. The half-lives and durations of action of most intravenous anesthetics are relatively short. It may take several hours for the laboratory to determine anesthetic concentrations. Therefore, anesthetic concentrations do not provide rapid feedback for clinicians to make necessary adjustments to doses during the course of surgery or medical intervention. Thus, monitoring of intravenous anesthetics is reliant on the signs and symptoms of anesthesia for the attainment of therapeutic efficacy and respiratory depression and blood pressure for toxicology.

Table 1.4 summarizes the pharmacokinetic (distribution, metabolism, and renal excretion) and pharmacodynamic properties (onset of action and duration of action) of various anesthetic agents.

The mechanism of action, indications, contraindications, cautions, pregnancy category, clinical pearls, dosing options, drug interactions, and side effects of commonly-used anesthetic agents are presented in Table 1.5 Lidocaine, with its numerous routes of delivery and dosing options, are presented in Table 1.6.