Pharmacokinetic Basis of Therapeutics and Pharmacodynamic Principles
Andrew M. Peterson
The art and science of clinical practice is based on understanding the relationship between the person and the disease and determining the most appropriate means for alleviating symptoms, curing disease, or preventing severe morbidity or even mortality. Very often, medications are prescribed to accomplish one or more of these goals.
Underpinning this treatment process is the intricate relationship between the body and the medication. Often, practitioners seek to understand the effect a drug has on the body (whether therapeutic or harmful) but neglect to consider the effect that the body has on the drug—even though one cannot be understood without the other. How the body acts on a drug and how the drug acts on the body are the subjects of this chapter.
Pharmacokinetics refers to the movement of the drug through the body—in essence, how the body affects the drug. This involves how the drug is administered, absorbed, distributed, and eventually eliminated from the body. Pharmacodynamics refers to how the drug affects the body— that is, how the drug initiates its therapeutic or toxic effect, both at the cellular level and systemically. Box 2.1 lists terms and definitions used throughout this chapter.
The purpose of pharmacokinetic processes is to get the drug to the site of action where it can produce its pharmacodynamic effect. There is a minimum amount of drug needed at the site of action to produce the desired effect. Although the amount of drug concentrated at the site of action is difficult to measure, the amount of drug in the blood can be measured. The relationship between the concentration of drug in the blood and the concentration at the site of action (i.e., the drug receptor) is different for each drug and each person. Therefore, measuring blood concentrations is only a surrogate marker, an indication of concentration at the receptor. Figure 2.1 shows the relationship between pharmacokinetics and pharmacodynamics.
PHARMACOKINETICS
Pharmacokinetics relates to how the drug is absorbed, distributed, and eliminated from the body. In reality, it is the study of the fate of medications administered to a person. It is sometimes described as what the body does to the drug. In theory, pharmacokinetics not only deals with medications, it deals with the disposition of all substances administered externally to any living organism. Pharmacokinetics can help the clinician determine the onset and duration of a drug’s action as well as determine blood levels that would produce therapeutic and toxic effects. As such, one can determine the blood levels necessary to produce a desired effect. This target drug concentration is key to monitoring the effects of many medications. Assuming that the magnitude of the drug concentration at the site of action influences the drug effect, whether desired or undesired, it can be inferred that a range of drug levels produces a range of effects (Figure 2.2). Below a specific level, or threshold, the drug exerts little to no therapeutic effect. Above this threshold, the concentration of drug in the blood is sufficient to produce a therapeutic effect at the site of action. However, as the drug concentration increases in the blood, so does the concentration at the site of action. Above a specific level, an increased therapeutic effect may no longer occur. Instead, an unacceptable toxicity may occur because the drug concentration is too high. Between these two levels—the minimally effective level and the toxic level—is the therapeutic window. The therapeutic window is the range of blood drug concentration that yields a sufficient therapeutic response without excessively toxic reactions.
This range should not be considered absolute because it varies from individual to individual and therefore serves only as a guide to the practitioner.
This range should not be considered absolute because it varies from individual to individual and therefore serves only as a guide to the practitioner.
BOX 2.1
Definitions of Terms Related to Pharmacokinetics and Pharmacodynamics
Definitions of Terms Related to Pharmacokinetics and Pharmacodynamics
Affinity: The attraction between a drug and a receptor.
Allosteric site: A binding site for substrates not active in initiating a response; a substrate that binds to an allosteric site may induce a conformational change in the structure of the active site, rendering it more or less susceptible to response from a substrate.
Bioavailability (F): The fraction or percentage of a drug that reaches the systemic circulation.
Biotransformation: Metabolism or degradation of a drug from an active form to an inactive form.
Chirality: Special configuration or shape of a drug; most drugs exist in two shapes.
Clearance: Removal of a drug from the plasma or organs.
Downregulation: Decreased availability of drug receptors.
Enantiomer (also called isomer): A mirror-image spatial arrangement, or shape, of a drug that suits it for binding with a drug receptor.
Enterohepatic recirculation: The process by which a drug excreted in the bile flows into the gastrointestinal tract, where it is reabsorbed and returned to the general circulation.
First-pass effect: The phenomenon by which a drug first passes through the liver where it may be degraded before distribution to the tissues.
Half-life (t½): The time required for half of a total drug amount to be eliminated from the body.
Hepatic extraction ratio: A comparison of the percentage of drug extracted and the percentage of drug remaining active after metabolism in the liver.
Ligand: Any chemical, endogenous or exogenous, that interacts with a receptor.
Pharmacodynamics: Processes through which drugs affect the body.
Pharmacokinetics: Processes through which the body affects drugs.
Prodrug: A drug that is transformed from an inactive parent drug into an active metabolite; in effect, a precursor to the active drug.
Receptor: The site of drug action.
Second messenger: A chemical produced intracellularly in response to a receptor signal; this second messenger initiates a change in the intracellular response.
Therapeutic window: The range of drug concentration in the blood between a minimally effective level and a toxic level.
Threshold: The level below which a drug exerts little to no therapeutic effect and above which a drug produces a therapeutic effect at the site of action.
Upregulation: Increased availability of receptors.
Volume of distribution (Vd): The extent of distribution of a drug in the body.
Absorption
The first aspect of pharmacokinetics to consider is how drugs are administered, how they are absorbed into the body, and how they eventually reach the bloodstream. Merely introducing the drug into the body does not ensure that the compound will reach all tissues uniformly or even that the drug will reach the target site. Commonly recognized methods of absorption include enteral absorption (after the drug is administered by the oral or rectal route) and parenteral absorption (associated with drugs administered intramuscularly [IM], subcutaneously, or topically). The various administration routes and other factors affect a drug’s ability to enter the bloodstream.
 FIGURE 2.1 Relationship between pharmacokinetics and pharmacodynamics. Note the two-way relationship between the concentration of drug in the plasma and the concentration of drug at the site of action, depicting the interrelationship between pharmacokinetics and pharmacodynamics. |
The extent to which the drug reaches the systemic circulation is referred to as bioavailability, or F, which is defined as the fraction or percentage of the drug that reaches the systemic circulation. Drugs administered intravenously are 100% bioavailable. Drugs administered by other routes (e.g., oral, IM) may be 100% bioavailable, but more often, they are less than
100% bioavailable. Therefore, bioavailability depends on the route of administration and, equally important, the drug’s ability to pass through membranes or barriers in the body. Box 2.2 discusses the specific case of oral bioavailability.
100% bioavailable. Therefore, bioavailability depends on the route of administration and, equally important, the drug’s ability to pass through membranes or barriers in the body. Box 2.2 discusses the specific case of oral bioavailability.
 FIGURE 2.2 Therapeutic window: concentration versus response. The concentration of the drug in the body produces specific effects. A low concentration is considered subtherapeutic, producing an insufficient response. As the concentration increases, the desired effect is produced at a given drug level. A drug concentration that exceeds the upper limit of the desired response may produce a toxic reaction. The concentration range within which a desired response occurs is the therapeutic window. |
Factors Affecting Absorption
A variety of factors affect absorption, such as the presence or absence of food in the stomach, blood flow to the area for absorption, and the dosage form of the drug. The following sections discuss some of the major factors affecting absorption.
BOX 2.2
Oral Bioavailability and the First-Pass Effect
Oral Bioavailability and the First-Pass Effect
Drugs given orally may be subject to the first-pass effect, by which drugs are metabolized by the liver before passing into circulation. After absorption from the alimentary canal, drugs go directly to the liver through the portal vein. In the liver, hepatic enzymes act on the drug, reducing the amount of active drug reaching the bloodstream and decreasing the amount available to the body. The fraction (or percentage) of medication reaching systemic circulation after the first pass through the liver is referred to as the drug’s bioavailability (F).
The first-pass effect is not the only factor contributing to the oral bioavailability of a drug. Poorly soluble drugs and drugs adversely affected by gastric pH or other presystemic factors can also have a low bioavailability.
Drugs not usually subject to the liver’s first-pass effect are known as drugs with a low hepatic extraction ratio because the liver does not extract a large percentage of the drug before releasing it into the circulation. Usually, drugs with a low extraction ratio have high oral bioavailability. In contrast, drugs with a high extraction ratio have low oral bioavailability. For example, lidocaine has a hepatic extraction ratio of 0.7; that is, the liver metabolizes 70% of the drug before the drug reaches the circulation and, as such, only 30% remains available systemically. This is one reason lidocaine is administered parenterally. In other words, the first-pass effect for lidocaine is of such magnitude that an alternative route of administration is required. Giving large oral doses of a drug to compensate for the high extraction ratio is often an alternative to parenteral administration. For example, because of the high extraction ratio of propranolol, a 1-mg dose administered intravenously is approximately equivalent to a 40-mg dose administered orally.
Examples of drugs with a high hepatic extraction ratio (70% or more) are imipramine (Tofranil), lidocaine (Xylocaine), and meperidine (Demerol); drugs with intermediate rankings are codeine, nortriptyline (Aventyl), and quinidine (Quinaglute); and some drugs with a low extraction ratio (30% or less) are barbiturates, diazepam (Valium), theophylline (Theo-Dur), tolbutamide (Orinase), and warfarin (Coumadin).
Movement through Membranes and Drug Solubility
Throughout the body, biologic membranes act as barriers, blocking or permitting the passage of various substances. These membranes protect certain areas of the body from harmful chemicals and allow other areas to be accessed as needed.
Biologic membranes composed of cells serve as barriers primarily because of the structure and function of the cells that make up the membrane. Cell membranes are composed of lipids and proteins, creating a phospholipid bilayer. This bilayer acts as a barrier that is almost impermeable to water, other hydrophilic (water-loving) substances, and ionized
substances. However, the bilayer does allow most lipid-soluble (hydrophobic) compounds to pass through readily. Interspersed throughout this bilayer are protein molecules and small openings, or pores. The proteins may act as carrier molecules, bringing molecules through the barrier. The pores allow hydrophilic molecules to pass through if they are small enough. Therefore, drugs and other compounds that pass through membrane barriers can do so by passive or active means.
substances. However, the bilayer does allow most lipid-soluble (hydrophobic) compounds to pass through readily. Interspersed throughout this bilayer are protein molecules and small openings, or pores. The proteins may act as carrier molecules, bringing molecules through the barrier. The pores allow hydrophilic molecules to pass through if they are small enough. Therefore, drugs and other compounds that pass through membrane barriers can do so by passive or active means.
Passive Diffusion Drugs can pass through membrane barriers by diffusion. In passive diffusion, molecules move from one side of a barrier to another without expending energy. In passing, the molecules move down a concentration gradient—that is, they move from an area of higher concentration to an area of lower concentration. The rate of diffusion depends on the differences in concentrations, the relative strength of the barrier, the distance that the molecules must travel, and the size of the molecules. This relationship is known as Fick’s law of diffusion. In essence, Fick’s law states that the greater the distance to travel and the larger the molecule, the slower the diffusion.
Another major barrier to the absorption of a drug is its solubility. To facilitate drug absorption, the solubility of the administered drug must match the cellular constituents of the absorption site. Lipid-soluble drugs can penetrate fatty cells; water-soluble drugs cannot. For example, a water-soluble drug such as penicillin cannot easily pass through the barrier between the blood and brain, whereas a highly lipid-soluble drug such as diazepam (Valium) can. The relative strength of the barrier is important because the barrier must be permeable to the diffusing substance. Drugs diffuse more readily through the lipid bilayer if they are in their neutral, nonionized form. Most drugs are weak acids or weak bases, which have the potential for becoming positively or negatively charged. This potential is created through the pH of certain body fluids. In the plasma and in most other fluids, most drugs remain nonionized. However, in the gastric acid of the stomach, weak bases become ionized and are more difficult to absorb. As this weak base progresses through the alkaline environment of the small intestines, it becomes nonionized and therefore more easily absorbed. Similarly, weak acids remain nonionized in the stomach and become ionized in the small intestines. The result is reduced absorption by the intestines.
Active Transport In active transport, membrane proteins act as carrier molecules to transport substances across cell membranes. The role of active transport in moving drugs across cell membranes is limited. To be carried through by a protein, the drug must share molecular similarities with an endogenous substance the transport system routinely carries. Cells can accomplish this through the process of endocytosis. In this process, the cell forms a vesicle surrounding the molecule, and it is subsequently invaginated in the cell. Once inside the cell, the vesicle releases the molecule into the cytoplasm of the cell.
Pharmaceutical Preparation
Drugs are formulated and administered in such a way as to produce either local or systemic effects. Local effects (e.g., antiseptic, anti-inflammatory, and local anesthetic effects) are confined to one area of the body. Systemic effects occur when the drug is absorbed and delivered to body tissues by way of the circulatory system.
Depending on how a drug is formulated (e.g., tablet or liquid), the means of drug delivery can target a site of action. Some drug formulations (dosage forms) deliver the drug into the gastrointestinal (GI) tract quickly (immediate release), whereas others release the drug slowly. This strategy for extending the activity of drugs in the body dampens the high and low swings of drug concentrations, thereby yielding a more constant blood level. Many medications are available in these controlled- or sustained-release dosage forms. The aim of sustained-release dosage forms is to administer them as infrequently as possible, improving compliance and minimize hour-to-hour or day-to-day blood level fluctuations. The various release systems available are subject to physiologic and pathophysiologic changes in patient conditions.
Blood Flow
Blood flow ensures that the concentration across a gradient is continually in favor of passive diffusion—that is, as blood flows through an area, it continually removes the drug from the area, thereby maintaining a positive concentration gradient. Many hydrophobic-lipophilic drugs can readily pass through membranes and be absorbed. However, if the blood flow to that area is limited, the extent of absorption is limited. Because of the minimal vascularization in the subcutaneous layer compared with the greater vascularity of the musculature, drugs injected subcutaneously may undergo less absorption compared with drugs delivered by IM injection.
Gastrointestinal Motility
High-fat meals and solid foods affect GI transit time by delaying gastric emptying, which in turn delays initial drug delivery to intestinal absorption surfaces. The administration of agents that delay or slow intestinal motility (e.g., anticholinergic agents) prolongs the contact time. This increased intestinal contact time secondary to prolonged intestinal transit time may increase total drug absorption. Conversely, laxatives or diarrhea can shorten an agent’s contact time with the small intestine, which may decrease drug absorption.
Enteral Absorption
Enteral absorption, with the oral route of administration being the most common and probably the most preferred, occurs anywhere throughout the GI tract by passive or active transport of the drug through the cells of the GI tract.
Following Fick’s law, low molecular weight, nonionized drugs diffuse passively down a concentration gradient from the higher concentration (in the GI tract) to the lower concentration (in the blood). Active transport across the GI tract occurs more frequently with larger, usually ionized, molecules. These active mechanisms include binding of the drug to carrier molecules in the cell membrane. The molecules carry the drug across the lipid bilayer of the cells. However, most drugs are absorbed passively.
Oral Administration
The oral route of administration refers to any medication that is taken by mouth (per os or PO). The ability to swallow is implicit in oral administration; however, many practitioners consider local action, in which absorption does not occur, also to be “oral” (e.g., troches for fungal infections of the mouth). Common dosage forms administered by mouth include tablets, capsules, caplets, solutions, suspensions, troches, lozenges, and powders.
Absorption after oral administration usually occurs in the lower GI tract (small or large intestine), is slow, and depends on the patient’s gastric-emptying time, the presence or absence of food, and the gastric or intestinal pH. Variations in one or more of these factors can affect the stability of the drug, the contact time with the intestinal walls, or the blood flow to the GI tract. Most of the absorption occurs in the small intestine, where the large surface area enhances and controls drug entry into the body.
Drugs administered orally must be relatively lipid soluble to cross the GI mucosa into the bloodstream. The diffusion rate, a function of the lipid solubility of a drug across the GI mucosa, is a major factor in determining the rate of absorption of a drug. The acid pH of the stomach and the nearly neutral pH of the intestines can degrade some medications before they are absorbed. In addition, bacteria in various parts of the intestines secrete enzymes that also can break down drugs before absorption.
Although the GI tract is generally resistant to a variety of noxious agents, considerable irritation and discomfort can arise from certain medications in some people. Nausea, vomiting, diarrhea, and less often mucosal damage are common side effects of medications, and the practitioner should monitor all patients for these effects.
Sublingual Administration
Sublingual (SL, under the tongue) drug administration relies on absorption through the oral mucosa into the veins that drain those vascular beds. These veins carry the drug to the superior vena cava and eventually the heart. Drugs administered this way are not subject to the first-pass effect (see Box 2.2). This method of administration is limited by the amount of drug that can be placed sublingually and the drug’s ability to pass through the oral mucosa into the venous system. Buccal administration, in which the drug is absorbed through the mucous membranes of the mouth, is similar to SL administration.
Rectal Administration
Drugs administered rectally (PR, per rectum) include suppositories and enemas. Primarily used in the treatment of local conditions (e.g., hemorrhoids) and inflammatory bowel disease, this method is less effective than other enteral routes because of the erratic absorption of most agents. Bowel irritation, early evacuation, and minimal surface area contribute to erratic absorption and poor tolerability of this route. Advantages, however, include the ability to administer a medication to an unconscious or nauseated patient.
Parenteral Absorption
All routes of administration not involving the GI tract are considered parenteral. Parenteral routes include inhalation, all forms of injection, and topical and transdermal administration.
Inhalation
Drugs that are gaseous or sprayable in small particles may be delivered by inhalation. The lungs provide a large surface area for absorption and quick entry into the bloodstream. Inhaled medications bypass the first-pass effect and therefore may have a high bioavailability. Examples of inhalants are anesthetic gases and beta-adrenergic agonists (e.g., albuterol) used in treating asthma. Conversely, agents such as inhaled corticosteroids are intended for local action in the lung tissue. Regardless of the intent of inhaled medications, the disadvantages include irritation to the alveolar space and the need for good coordination during self-administration, such as with metered-dose inhalers.
Intravenous Administration
The intravenous (IV) route provides rapid access to the circulatory system with a known quantity of drug. Bypassing the first-pass effect and any GI metabolism or degradation, drug absorption by this route is considered the gold standard with regard to bioavailability. IV bolus injections allow for large amounts of medication to be administered quickly for a high peak drug level and a rapid effect. However, adverse effects from these high levels of medications also occur with this form of administration. Repeated bolus doses of medications, at designated intervals, can produce large fluctuations in peak and trough (lowest concentration before next dose) levels. Although over time these peaks and troughs produce average desired concentrations, significant peak and trough fluctuations may not be desirable in some patients. Continuous administration by an infusion can minimize or eliminate these fluctuations and produce a consistent, steady-state concentration.
Like IV administration, intra-arterial administration produces a rapid effect. However, because the drug is directly instilled in an organ, this route is considered more dangerous than the IV route. Therefore, intra-arterial administration is usually reserved for a time when injection into a specific tissue is indicated (e.g., anticancer treatment for a specific tumor).
Subcutaneous Administration
Subcutaneous (SC or SQ) administration produces a slower, more prolonged release of medication into the bloodstream. Injected directly beneath the skin, a drug must diffuse through layers of fat and muscle to encounter sufficient blood vessels for entry into the systemic circulation. This route is limited by the quantity of the liquid suitable for administration (usually 2 to 3 mL). Caution must also be taken because dermal irritation, or even necrosis, may occur. More recent technological advances allow the practitioner to implant drug-releasing mechanisms under the skin, providing a reservoir of drug for long-term absorption. Levonorgestrel (Norplant), a hormonal contraceptive, is administered in this manner.
Intramuscular Administration
Injecting medications into the highly vascularized skeletal muscle is a way of administering drugs quickly and avoiding the relatively large changes in plasma levels seen with IV administration. Local pain and muscle soreness are drawbacks to this method, as is the wide variability in the rate of absorption resulting from injections given in different muscles and in different patients. Blood flow to the area is the major factor in determining the rate of absorption. This is considered a safe way to administer irritating drugs, although not all IM injections are truly IM: in grossly obese patients, presumed IM injections may actually be intralipomatous, which decreases the rate of absorption because of the lower vascularity of fatty tissue.
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