Pharmacokinetics

CHAPTER 4


Pharmacokinetics


The term pharmacokinetics is derived from two Greek words: pharmakon (drug or poison) and kinesis (motion). As this derivation implies, pharmacokinetics is the study of drug movement throughout the body. Pharmacokinetics also includes drug metabolism and drug excretion.


There are four basic pharmacokinetic processes: absorption, distribution, metabolism, and excretion (Fig. 4–1). Absorption is defined as the movement of a drug from its site of administration into the blood. Distribution is defined as drug movement from the blood to the interstitial space of tissues and from there into cells. Metabolism (biotransformation) is defined as enzymatically mediated alteration of drug structure. Excretion is the movement of drugs and their metabolites out of the body. The combination of metabolism plus excretion is called elimination. The four pharmacokinetic processes, acting in concert, determine the concentration of a drug at its sites of action.


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Figure 4–1  The four basic pharmacokinetic processes.
Dotted lines represent membranes that must be crossed as drugs move throughout the body.



Application of pharmacokinetics in therapeutics


By applying knowledge of pharmacokinetics to drug therapy, we can help maximize beneficial effects and minimize harm. Recall that the intensity of the response to a drug is directly related to the concentration of the drug at its site of action. To maximize beneficial effects, we must achieve concentrations that are high enough to elicit desired responses; to minimize harm, we must avoid concentrations that are too high. This balance is achieved by selecting the most appropriate route, dosage, and dosing schedule. The only way we can rationally choose the most effective route, dosage, and schedule is by considering pharmacokinetic factors.


As a nurse, you will have ample opportunity to apply knowledge of pharmacokinetics in clinical practice. For example, by understanding the reasons behind selection of route, dosage, and dosing schedule, you will be less likely to commit medication errors than will the nurse who, through lack of this knowledge, administers medications by blindly following prescribers’ orders. Also, as noted in Chapter 2, prescribers do make mistakes. Accordingly, you will have occasion to question or even challenge prescribers regarding their selection of dosage, route, or schedule of administration. In order to alter a prescriber’s decision, you will need a rational argument to support your position. To present that argument, you will need to understand pharmacokinetics.


Knowledge of pharmacokinetics can increase job satisfaction. Working with medications is a significant component of nursing practice. If you lack knowledge of pharmacokinetics, drugs will always be somewhat mysterious and, as a result, will be a potential source of unease. By helping to demystify drug therapy, knowledge of pharmacokinetics can decrease some of the stress of nursing practice and can increase intellectual and professional satisfaction.



A note to chemophobes


Before we proceed, some advance notice (and encouragement) are in order for chemophobes (students who fear chemistry). Because drugs are chemicals, we cannot discuss pharmacology meaningfully without occasionally talking about chemistry. This chapter has some chemistry in it. In fact, the chemistry presented here is the most difficult in the book. Accordingly, once you’ve worked your way through this chapter, the chapters that follow will be a relative breeze. Because the concepts addressed here are fundamental, and because they reappear frequently, all students, including chemophobes, are encouraged to learn this material now, regardless of the effort and anxiety involved.


I also want to comment on the chemical structures that appear in the book. Structures are presented only to illustrate and emphasize concepts. They are not intended for memorization, and they are certainly not intended for exams. So, relax, look at the pictures, and focus on the concepts I am trying to help you grasp.



Passage of drugs across membranes


All four phases of pharmacokinetics—absorption, distribution, metabolism, and excretion—involve drug movement. To move throughout the body, drugs must cross membranes. Drugs must cross membranes to enter the blood from their site of administration. Once in the blood, drugs must cross membranes to leave the vascular system and reach their sites of action. In addition, drugs must cross membranes to undergo metabolism and excretion. Accordingly, the factors that determine the passage of drugs across biologic membranes have a profound influence on all aspects of pharmacokinetics.



Membrane structure


Biologic membranes are composed of layers of individual cells. The cells composing most membranes are very close to one another—so close, in fact, that drugs must usually pass through cells, rather than between them, in order to cross the membrane. Hence, the ability of a drug to cross a biologic membrane is determined primarily by its ability to pass through single cells. The major barrier to passage through a cell is the cytoplasmic membrane (the membrane that surrounds every cell).


The basic structure of the cell membrane is depicted in Figure 4–2. As indicated, the basic membrane structure consists of a double layer of molecules known as phospholipids. Phospholipids are simply lipids (fats) that contain an atom of phosphate.


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Figure 4–2  Structure of the cell membrane.
The cell membrane consists primarily of a double layer of phospholipid molecules. The large globular structures represent protein molecules imbedded in the lipid bilayer. (Modified from Singer SJ, Nicolson GL: The fluid mosaic model of the structure of cell membranes. Science 175:720, 1972.)

In Figure 4–2, the phospholipid molecules are depicted as having a round head (the phosphate-containing component) and two tails (long-chain hydrocarbons). The large objects embedded in the membrane represent protein molecules, which serve a variety of functions.



Three ways to cross a cell membrane


The three most important ways by which drugs cross cell membranes are (1) passage through channels or pores, (2) passage with the aid of a transport system, and (3) direct penetration of the membrane itself. Of the three, direct penetration of the membrane is most common.




Transport systems

Transport systems are carriers that can move drugs from one side of the cell membrane to the other. Some transport systems require the expenditure of energy; others do not. All transport systems are selective: They will not carry just any drug. Whether a transporter will carry a particular drug depends on the drug’s structure.


Transport systems are an important means of drug transit. For example, certain orally administered drugs could not be absorbed unless there were transport systems to move them across the membranes that separate the lumen of the intestine from the blood. A number of drugs could not reach intracellular sites of action without a transport system to move them across the cell membrane. Renal excretion of many drugs would be extremely slow were it not for transport systems in the kidney that can pump drugs from the blood into the renal tubules.



P-glycoprotein.

One transporter, known as P-glycoprotein or multidrug transporter protein, deserves special mention. P-glycoprotein is a transmembrane protein that transports a wide variety of drugs out of cells. This transporter is present in cells at many sites, including the liver, kidney, placenta, intestine, and capillaries of the brain. In the liver, P-glycoprotein transports drugs into the bile for elimination. In the kidney, it pumps drugs into the urine for excretion; in the placenta, it transports drugs back into the maternal blood, thereby reducing fetal drug exposure. In the intestine, it transports drugs into the intestinal lumen, and can thereby reduce drug absorption into the blood. And in brain capillaries, it pumps drugs into the blood, thereby limiting drug access to the brain.




Polar molecules


Polar molecules are molecules with uneven distribution of electrical charge. That is, positive and negative charges within the molecule tend to congregate separately from one another. Water is the classic example. As depicted in Figure 4–3A, the electrons (negative charges) in the water molecule spend more time in the vicinity of the oxygen atom than in the vicinity of the two hydrogen atoms. As a result, the area around the oxygen atom tends to be negatively charged, whereas the area around the hydrogen atoms tends to be positively charged. Kanamycin (Fig. 4–3B), an antibiotic, is an example of a polar drug. The hydroxyl groups, which attract electrons, give kanamycin its polar nature.


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Figure 4–3  Polar molecules.
A, Stippling shows the distribution of electrons within the water molecule. As indicated, water’s electrons spend more time near the oxygen atom than near the hydrogen atoms, making the area near the oxygen atom somewhat negative and the area near the hydrogen atoms more positive. B, Kanamycin is a polar drug. The 2 –OH groups of kanamycin attract electrons, thereby causing the area around these groups to be more negative than the rest of the molecule.

Although polar molecules have an uneven distribution of charge, they have no net charge. Polar molecules have an equal number of protons (which bear a single positive charge) and electrons (which bear a single negative charge). As a result, the positive and negative charges balance each other exactly, and the molecule as a whole has neither a net positive charge nor a net negative charge. Molecules that do bear a net charge are called ions. These are discussed below.


There is a general rule in chemistry that states: “like dissolves like.” In accord with this rule, polar molecules will dissolve in polar solvents (such as water) but not in nonpolar solvents (such as oil). Table sugar provides a common example. I’m sure you’ve observed that sugar, a polar compound, readily dissolves in water but not in salad oil, butter, and other lipids, which are nonpolar compounds. Just as sugar is unable to dissolve in lipids, polar drugs are unable to dissolve in the lipid bilayer of the cell membrane.



Ions


Ions are defined as molecules that have a net electrical charge (either positive or negative). Except for very small molecules, ions are unable to cross membranes.



Quaternary ammonium compounds

Quaternary ammonium compounds are molecules that contain at least one atom of nitrogen and carry a positive charge at all times. The constant charge on these compounds results from atypical bonding to the nitrogen. In most nitrogen-containing compounds, the nitrogen atom bears only three chemical bonds. In contrast, the nitrogen atoms of quaternary ammonium compounds have four chemical bonds (Fig. 4–4A). Because of the fourth bond, quaternary ammonium compounds always carry a positive charge. And because of the charge, these compounds are unable to cross most membranes.


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Figure 4–4  Quaternary ammonium compounds.
A, The basic structure of quaternary ammonium compounds. Because the nitrogen atom has bonds to four organic radicals, quaternary ammonium compounds always carry a positive charge. Because of this charge, quaternary ammonium compounds are not lipid soluble and cannot cross most membranes. B, Tubocurarine is a representative quaternary ammonium compound. Note that tubocurarine contains two “quaternized” nitrogen atoms.

Tubocurarine (Fig. 4–4B) is a representative quaternary ammonium compound. Until recently, purified tubocurarine was employed as a muscle relaxant for surgery and other procedures. A crude preparation—curare—is used by South American Indians as an arrow poison. When employed for hunting, tubocurarine (curare) produces paralysis of the diaphragm and other skeletal muscles, causing death by asphyxiation. Interestingly, even though meat from animals killed with curare is laden with poison, it can be eaten with no ill effect. Why? Because tubocurarine, being a quaternary ammonium compound, cannot cross membranes, and therefore cannot be absorbed from the intestine; as long as it remains in the lumen of the intestine, curare can do no harm. As you might gather, when tubocurarine was used clinically, it could not be administered by mouth. Instead, it had to be injected. Once in the bloodstream, tubocurarine then had ready access to its sites of action on the surface of muscles.



PH-dependent ionization

Unlike quaternary ammonium compounds, which always carry a charge, certain drugs can exist in either a charged or uncharged form. Many drugs are either weak organic acids or weak organic bases, which can exist in charged and uncharged forms. Whether a weak acid or base carries a charge is determined by the pH of the surrounding medium.


A review of acid-base chemistry should help. An acid is defined as a compound that can give up a hydrogen ion (proton). Put another way, an acid is a proton donor. A base is defined as a compound that can take on a hydrogen ion. That is, a base is a proton acceptor. When an acid gives up its proton, which is positively charged, the acid itself becomes negatively charged. Conversely, when a base accepts a proton, the base becomes positively charged. These reactions are depicted in Figure 4–5, which shows aspirin as a representative acid and amphetamine as a representative base. Because the process of an acid giving up a proton or a base accepting a proton converts the acid or base into a charged particle (ion), the process for either an acid or a base is termed ionization.


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Figure 4–5  Ionization of weak acids and weak bases.
The extent of ionization of weak acids (A) and weak bases (B) depends on the pH of their surroundings. The ionized (charged) forms of acids and bases are not lipid soluble and hence do not readily cross membranes. Note that acids ionize by giving up a proton and that bases ionize by taking on a proton.

The extent to which a weak acid or weak base becomes ionized is determined in part by the pH of its environment. The following rules apply:



To illustrate the importance of pH-dependent ionization, let’s consider the ionization of aspirin. Being an acid, aspirin tends to give up its proton (become ionized) in basic media. Conversely, aspirin keeps its proton and remains nonionized in acidic media. Accordingly, when aspirin is in the stomach (an acidic environment), most of the aspirin molecules remain nonionized. Because aspirin molecules are nonionized in the stomach, they can be absorbed across the membranes that separate the stomach from the bloodstream. When aspirin molecules pass from the stomach into the small intestine, where the environment is relatively alkaline, they change to their ionized form. As a result, absorption of aspirin from the intestine is impeded.



Ion trapping (pH partitioning)

Because the ionization of drugs is pH dependent, when the pH of the fluid on one side of a membrane differs from the pH of the fluid on the other side, drug molecules will tend to accumulate on the side where the pH most favors their ionization. Accordingly, since acidic drugs tend to ionize in basic media, and since basic drugs tend to ionize in acidic media, when there is a pH gradient between two sides of a membrane,



The process whereby a drug accumulates on the side of a membrane where the pH most favors its ionization is referred to as ion trapping or pH partitioning. Figure 4–6 shows the steps of ion trapping using aspirin as an example.


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Figure 4–6  Ion trapping of drugs.
This figure demonstrates ion trapping using aspirin as an example. Because aspirin is an acidic drug, it will be nonionized in acid media and ionized in alkaline media. As indicated, ion trapping causes molecules of orally administered aspirin to move from the acidic (pH 1) environment of the stomach to the more alkaline (pH 7.4) environment of the plasma, thereby causing aspirin to accumulate in the blood. In the figure, aspirin (acetylsalicylic acid) is depicted as ASA with its COOH (carboxylic acid) group attached.
Step 1: Once ingested, ASA dissolves in the stomach contents, after which some ASA molecules give up a proton and become ionized. However, most of the ASA in the stomach remains nonionized. Why? Because the stomach is acidic, and acidic drugs don’t ionize in acidic media.
Step 2: Because most ASA molecules in the stomach are nonionized (and therefore lipid soluble), most ASA molecules in the stomach can readily cross the membranes that separate the stomach lumen from the plasma. Because of the concentration gradient that exists between the stomach and the plasma, nonionized ASA molecules will begin moving into the plasma. (Note that, because of their charge, ionized ASA molecules cannot leave the stomach.)
Step 3: As the nonionized ASA molecules enter the relatively alkaline environment of the plasma, most give up a proton (H+) and become negatively charged ions. ASA molecules that become ionized in the plasma cannot diffuse back into the stomach.
Step 4: As the nonionized ASA molecules in the plasma become ionized, more nonionized molecules will pass from the stomach to the plasma to replace them. This movement occurs because the laws of diffusion demand equal concentrations of diffusible substances on both sides of a membrane. Because only the nonionized form of ASA is able to diffuse across the membrane, it is this form that the laws of diffusion will attempt to equilibrate. Nonionized ASA will continue to move from the stomach to the plasma until the amount of ionized ASA in plasma has become large enough to prevent conversion of newly arrived nonionized molecules into the ionized form. Equilibrium will then be established between the plasma and the stomach. At equilibrium, there will be equal amounts of nonionized ASA in the stomach and plasma. However, on the plasma side, the amount of ionized ASA will be much larger than on the stomach side. Because there are equal concentrations of nonionized ASA on both sides of the membrane but a much higher concentration of ionized ASA in the plasma, the total concentration of ASA in plasma will be much higher than in the stomach.

Because ion trapping can influence the movement of drugs throughout the body, the process is not simply of academic interest. Rather, ion trapping has practical clinical implications. Knowledge of ion trapping helps us understand drug absorption as well as the movement of drugs to sites of action, metabolism, and excretion. Understanding of ion trapping can be put to practical use when we need to actively influence drug movement. Poisoning is the principal example: By manipulating urinary pH, we can employ ion trapping to draw toxic substances from the blood into the urine, thereby accelerating their removal.



Absorption


Absorption is defined as the movement of a drug from its site of administration into the blood. The rate of absorption determines how soon effects will begin. The amount of absorption helps determine how intense effects will be.



Factors affecting drug absorption


The rate at which a drug undergoes absorption is influenced by the physical and chemical properties of the drug itself and by physiologic and anatomic factors at the absorption site.









Characteristics of commonly used routes of administration


The routes of administration that are used most commonly fall into two major groups: enteral (via the gastrointestinal [GI] tract) and parenteral. The literal definition of parenteral is outside the GI tract. However, in common parlance, the term parenteral is used to mean by injection. The principal parenteral routes are intravenous, subcutaneous, and intramuscular.


For each of the major routes of administration—oral (PO), intravenous (IV), intramuscular (IM), and subcutaneous (subQ)—the pattern of drug absorption (ie, the rate and extent of absorption) is unique. Consequently, the route by which a drug is administered will significantly affect both the onset and the intensity of effects. Why do patterns of absorption differ between routes? Because the barriers to absorption associated with each route are different. In the discussion below, we examine these barriers and their influence on absorption pattern. In addition, as we discuss each major route, we will consider its clinical advantages and disadvantages. The distinguishing characteristics of the four major routes are summarized in Table 4–1.




Intravenous




Advantages. 






Disadvantages. 



Irreversibility.


More important than cost or convenience, IV administration can be dangerous. Once a drug has been injected, there is no turning back: The drug is in the body and cannot be retrieved. Hence, if the dose is excessive, avoiding harm may be impossible.


To minimize risk, IV drugs should be injected slowly (over 1 minute or more). Because all of the blood in the body is circulated about once every minute, by injecting a drug over a 1-minute interval, we cause it to be diluted in the largest volume of blood possible. By doing so, we can avoid drug concentrations that are unnecessarily high—or even dangerously high.


Performing IV injections slowly has the additional advantage of reducing the risk of toxicity to the central nervous system (CNS). When a drug is injected into the antecubital vein of the arm, it takes about 15 seconds to reach the brain. Consequently, if the dose is sufficient to cause CNS toxicity, signs of toxicity may become apparent 15 seconds after starting the injection. If the injection is being done slowly (eg, over a 1-minute interval), only 25% of the total dose will have been administered when signs of toxicity appear. If administration is discontinued immediately, adverse effects will be much less than they would have been had the entire dose been given.





Embolism.


Intravenous administration carries a risk of embolism (blood vessel blockage at a site distant from the point of administration). Embolism can be caused in several ways. First, insertion of an IV needle can injure the venous wall, leading to formation of a thrombus (clot); embolism can result if the clot breaks loose and becomes lodged in another vessel. Second, injection of hypotonic or hypertonic fluids can destroy red blood cells; the debris from these cells can produce embolism.


Lastly, injection of drugs that are not fully dissolved can cause embolism. Particles of undissolved drug are like small grains of sand, which can become embedded in blood vessels and cause blockage. Because of the risk of embolism, you should check IV solutions prior to administration to ensure that drugs are in solution. If the fluid is cloudy or contains particles, the drug is not dissolved and must not be administered.



The importance of reading labels.


Not all formulations of the same drug are appropriate for IV administration. Accordingly, it is essential to read the label before giving a drug IV. Two examples illustrate why this is so important. The first is insulin. Seven types of insulin are now available (eg, regular insulin, insulin aspart, NPH insulin). Some of these formulations can be given IV; others cannot. Regular insulin, for example, is formulated as a clear liquid, and is safe for IV use. In contrast, NPH insulin is formulated as a particulate suspension. This suspension is safe for subQ use, but its particles could be fatal if given IV. By checking the label, inadvertent IV injection of particulate insulin can be avoided.


Epinephrine provides our second example of why you should read the label before giving a drug IV. Epinephrine, which stimulates the cardiovascular system, can be injected by several routes (IM, IV, subQ, intracardiac, intraspinal). Be aware, however, that a solution prepared for use by one route will differ in concentration from a solution prepared for use by other routes. For example, whereas solutions intended for subcutaneous administration are concentrated, solutions intended for intravenous use are dilute. If a solution prepared for subQ use were to be inadvertently administered IV, the result could prove fatal. (Intravenous administration of concentrated epinephrine could overstimulate the heart and blood vessels, causing severe hypertension, cerebral hemorrhage, stroke, and death.) The take-home message is that simply giving the right drug is not sufficient; you must also be sure that the formulation and concentration are appropriate for the intended route.

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Jul 24, 2016 | Posted by in NURSING | Comments Off on Pharmacokinetics

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