Pharmacokinetics

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Chapter 2 Pharmacokinetics

For a drug to exert an effect, it must reach its intended molecular target. Conversely, removal of drug from its intended site of action is an important factor in terminating drug action. Pharmacokinetics is the study of the variables that affect drug delivery to, and removal from, its site of action. Pharmacokinetics includes the study of absorption, distribution, storage, and elimination of drugs. Elimination of drugs consists of biotransformation (metabolism), in which the drug’s chemical properties are altered by the body, and/or excretion of the drug, in which the drug (or its metabolites) are removed from the body. Pharmacokinetics is influenced by the properties of the drug itself, the properties of the body, and the actions of the body on the drug. The pharmacokinetic behavior of drugs is a dynamic balance among drug absorption, distribution, sequestration in tissues, biotransformation, and excretion. The summation of these processes will determine the plasma drug concentrations at any point in time. An understanding of these processes is helpful in the determination of drug dosage and administration protocols.

Basic Concepts

Drug Transfer

Drugs must traverse a number of barriers to be absorbed, distributed, and eliminated. Major mechanisms are described in the following paragraphs.

Active Transport

Active transport is mediated by a very large family of transporters collectively referred to as ATP binding cassette transporters (or ABC transporters). These transporters rely on adenosine triphosphate (ATP) as a source of energy to transport drug molecules across biologic membranes. There are several important features of this mechanism, including saturability, structural selectivity, and ATP dependence.

Drug Properties

The general chemical properties of a drug can greatly influence its pharmacokinetics. For a drug to be absorbed and distributed to its site of action or its site of elimination, it must be liberated from its formulation, it must dissolve in aqueous solutions, and at the same time it must be able to cross several hydrophobic barriers (e.g., plasma membrane).

Drug Formulations (Table 2-1)

TABLE 2-1 Pharmacokinetic Characteristics of Different Drug Formulations

Drug Formulations Examples General Pharmacokinetic Characteristics
Solids

Semisolids

Liquids Polymers

Effect of pH

Most drugs are weak acids or bases and, as such, in solution show varying degrees of dissociation into their ionized and nonionized forms. The distribution between ionized and nonionized forms will be determined by the pKa of the drug and the pH of the solution in which the drug is dissolved.

The practical implications are as follows: The ionized form of the drug may become stranded in certain locations. This effect, referred to as ion trapping or pH trapping, occurs when drugs accumulate in a certain body compartment because they can diffuse into this area, but then become ionized owing to the prevailing pH and are unable to diffuse out of this location. An example, shown in Figure 2-1, is the trapping of basic drugs (e.g., morphine, pKa 7.9) in the stomach. The drug is approximately 50% nonionized in the plasma (pH approximately 7.4) because it is in an environment with a pH close to its pKa. In the stomach (pH approximately 2), the drug is highly ionized (approximately 200,000×), it cannot diffuse across the cells lining the stomach, and the drug molecules are trapped in the stomach.

The concepts of acidic and basic drugs and their relative ionization at different pH values can be used clinically. For example, acidification of the urine is used to increase the elimination of amphetamine, a basic drug with pKa approximately 9.8. Rendering the urine acidic increases the amount of amphetamine in the ionized state, preventing its reabsorption from the urine into the bloodstream. Conversely, alkalinization of the urine is used to increase the excretion of acetylsalicylic acid (aspirin), an acidic drug. Increasing the pH of urine above the pKa of acetylsalicylic acid increases the proportion of the drug in the ionized state by about 10,000 times. The ionized form of the drug is not able to be reabsorbed across the renal tubule into the bloodstream. Moreover, the low concentration of the non-ionized form in the renal tubule compared with that in the blood favors diffusion of the non-ionized drug into the renal tubules (see Figure 2-2).

Absorption

In general, for a drug to reach its intended target, the drug must be present in the bloodstream (an exception is application of drug for local effects such as local anesthesia). Thus, absorption of drugs refers to the amount of drug reaching the general circulation from its site of administration. The fraction of drug reaching the systemic circulation is expressed as the bioavailability. The concept of bioavailability is important in practice because the clinician can use routes of administration that maximize bioavailability. In addition, changes in bioavailability resulting from genetic variation, disease, or drug interactions are a frequent cause of loss of drug effectiveness, because of a decrease in bioavailability, or, conversely drug toxicity, because of an increase in bioavailability.

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Bioavailability will be influenced by any factors that impede the active drug from reaching the systemic circulation (Figure 2-3). These include diffusion across physiologic barriers, the effect of transporters that prevent accumulation of drug in the blood, and metabolism of the drug before it reaches the systemic circulation. For example, after oral administration, a drug may have low bioavailability if:

Factors that alter a drug’s ability to cross biologic membranes, its interaction with pumping mechanisms, or its metabolism will affect drug bioavailability, drug effect, and drug toxicity.

Oral bioavailability of some drugs (e.g., nitroglycerin) can be reduced so severely by these mechanisms that this route of administration is not practical, requiring the use of alternate routes of administration that bypass the major barriers to bioavailability.

Routes of Administration

Routes of administration greatly affect bioavailability by changing the number of biologic barriers a drug must cross or by changing the exposure of drug to pumping and metabolic mechanisms.

Enteral Administration

Enteral administration involves absorption of the drug via the GI tract and includes oral, gastric or duodenal (e.g., feeding tube), and rectal administration

image Oral (PO) administration is the most frequently used route of administration because of its simplicity and convenience, which improve patient compliance. Bioavailability of drugs administered orally varies greatly. This route is effective for drugs with moderate to high oral bioavailability and for drugs of varying pKa because gut pH varies considerably along the length of the GI tract. Administration via this route is less desirable for drugs that are irritating to the GI tract or when the patient is vomiting or unable to swallow. Drugs given orally must be acid stable or protected from gastric acid (e.g., by enteric coatings). Additional factors influencing absorption of orally administered drugs include the following:

Parenteral Administration

Parenteral administration refers to any routes of administration that do not involve drug absorption via the GI tract (par = around, enteral = gastrointestinal), including the IV, intramuscular (IM), subcutaneous (SC or SQ), and transdermal routes. Reasons for choosing a parenteral route over the oral route include drugs with low oral bioavailability, patients who are unable to take the drug by mouth (e.g., it irritates the GI tract), the need for immediate effect (e.g., emergency situations), or the desire to control the rate of absorption and duration of effect.