Practical Pharmacokinetics of Anesthetic Drugs
After an appropriate drug has been selected for the treatment of a disease, successful pharmacotherapy will depend on selecting an appropriate dosing regimen to ensure that effective concentrations of the drug are achieved and maintained at the site of action without causing toxicity. Very rarely can a drug be administered directly at the site of action. Rather, most drugs move from the site of administration to the site of action while also being distributed throughout the rest of the body, including the organs of elimination (most notably the kidney and the liver). Questions that need to be answered to determine a dosage regimen are as follows: By which route should the drug be administered? How much of the drug should be administered? How often should the drug be administered? For how long should the drug be administered?
Pharmacokinetics is the study of drug disposition and how drug concentrations change in the body over time following administration. Measurements of drug concentrations are usually taken from blood, which is a practical and convenient site for sampling and also the vehicle that receives the drug from site of administration and carries it to the site of action and organs of elimination. A successful dosage regimen may, therefore, be defined as one that achieves and maintains blood, plasma, or serum concentrations that are associated with therapeutic success without producing unacceptable toxicity (often referred to as the therapeutic window).
The observed data, typically measurements of drug concentrations in blood, plasma, or serum, with samples taken at different time points following administration, are summarized and described using mathematic equations. These equations may then be used to predict plasma concentrations for different doses and, depending on the complexity of the model, could also be used to account for changes in disposition caused by factors such as species, age, and disease. Clinical pharmacokinetics is the application of these mathematic models in the rational design of dosage regimens to achieve target plasma concentrations.
Following the administration of a drug formulation to an animal, blood and tissue concentrations change over time as a result of three processes: (1) absorption, (2) distribution, and (3) elimination (Figure 43-1). These processes occur simultaneously, with each dominating at a different time following administration. Initially, absorption dominates, adding drug to the body and resulting in rising drug concentrations in blood and other tissues. Later, distribution and elimination dominate, with both removing the drug from the systemic circulation, resulting in decreasing blood concentrations and ultimately subsiding effect(s).
Absorption, distribution, and elimination require that drug molecules be transported across a series of membranes and spaces. In addition, elimination may require that the drug be metabolized. Differences in the rates of these processes result in variations in the time–concentration profiles observed for different drugs and animals. The barriers across which drugs must move are composed of lipophilic cellular membranes, aqueous interstitial spaces, and, in some membranes (e.g., capillary endothelia and intestinal epithelia), narrow aqueous-filled channels between cells. Most drugs pass through these membranes by simple diffusion from areas of higher concentration to areas of lower concentration. The rate of drug penetration is, therefore, determined by the magnitude of the concentration difference across the membrane, the surface area of the membrane, and the ease with which the drug can penetrate through the membrane. The last is quantitatively expressed as permeability, which is affected by the molecular size, lipophilicity, and the charge of the drug. Active and passive carrier-mediated transport processes may be involved for some drugs, resulting in the rate of transport approaching a maximum value at high concentrations (Figure 43-2). Since saturation of active transport processes is uncommon at concentrations typically used for treatment, this phenomenon will not be considered further for the purposes of this chapter.
A parameter may be defined as a quantifiable characteristic of a system that is used as input for a predictive model. In pharmacokinetic modeling, parameters are quantitative estimates of the rate and extent of distribution, elimination, and absorption, which are used to predict plasma drug concentrations for specific drug dosages in individuals or groups of animals. These pharmacokinetic parameters are estimated by fitting a pharmacokinetic model to observed data and are then used to construct dosage regimens that will achieve a specified target plasma concentration. Examples of target concentrations include the minimum inhibitory concentration (MIC) (or a multiple thereof) for antimicrobial drugs or, in the case of drugs used to induce anesthesia, concentrations associated with the desired depth and duration of anesthesia.
Bolus intravenous (IV) administration ensures that the entire dose enters the general circulation and that effective concentrations are achieved quickly. Typical drugs that are administered by this route include those for the management of acute pain, anesthesia, and severe bacterial infections. It is also the route that should be used to investigate the disposition of a drug (distribution and elimination) because the time–concentration curve is not confounded by variations in the rate and extent of absorption.
A graphic representation of the time–concentration data for a hypothetical drug following IV administration is shown in Figure 43-3. Note that the relationship between the x (time) and y (concentration) variables becomes linear if the y-axis is transformed to a logarithmic scale. Also, note that the concentration declines over time at a constant rate (see Figure 43-3). The data may, therefore, be described using a simple monoexponential mathematic equation that is conventionally referred to as a one-compartment pharmacokinetic model (see Equation 1). Drugs that can be described using a one-compartment model typically equilibrate rapidly between blood and tissues. This makes it possible to describe their disposition as the drug being injected into a single compartment of uniform liquid with the dose distributing instantaneously and homogeneously throughout this compartment and the drug being eliminated from the compartment immediately after injection.