Editors: Finkel, Richard; Clark, Michelle A.; Cubeddu, Luigi X. Title: Lippincott's Illustrated Reviews: Pharmacology, 4th Edition Copyright ©2009 Lippincott Williams & Wilkins > Front of Book > Acknowledgments Acknowledgments We are grateful to the many friends and colleagues who generously contributed their time and effort to help us make this book as accurate and as useful as possible. The editors and production staff of Lippincott William & Wilkins were a constant source of encouragement and discipline. We particularly want to acknowledge the tremendously helpful, supportive, creative contributions of our editors, Betty Sun, Donna Balado, and Kelly Horvath, whose imagination and positive attitude helped us out of the valleys. Final editing and assembly of the book has been greatly enhanced through the efforts of Kathleen Scogna and Jennifer Glazer. Ovid: Lippincott's Illustrated Reviews: Pharmacology file:///F:/DOWNLOADS%20FIREFOX/LIRP4/Lippincott%27s%20Illustr... 1 of 1 11/8/2008 11:40 AM Editors: Finkel, Richard; Clark, Michelle A.; Cubeddu, Luigi X. Title: Lippincott's Illustrated Reviews: Pharmacology, 4th Edition Copyright ©2009 Lippincott Williams & Wilkins > Front of Book > Editors Editors Richard Finkel Pharm.D. Department of Pharmaceutical and Administrative Sciences, Nova Southeastern University, College of Pharmacy, Fort Lauderdale, Florida Michelle A. Clark Ph.D. Department of Pharmaceutical and Administrative Sciences, Nova Southeastern University, College of Pharmacy, Fort Lauderdale, Florida Luigi X. Cubeddu M.D., Ph.D. Department of Pharmaceutical and Administrative Sciences, Nova Southeastern University, College of Pharmacy, Fort Lauderdale, Florida Series Editors Richard A. Harvey Ph.D. Department of Biochemistry, University of Medicine and Dentistry of New Jersey–Robert Wood Johnson Medical School, Piscataway, New Jersey Pamela C. Champe Ph.D. Department of Biochemistry, University of Medicine and Dentistry of New Jersey–Robert Wood Johnson Medical School, Piscataway, New Jersey Contributing Authors Kathy Fuller Pharm.D., BCNSP Department of Pharmaceutical and Administrative Sciences, Nova Southeastern University, College of Pharmacy, Fort Lauderdale, Florida David Gazze Ph.D. Department of Pharmaceutical and Administrative Sciences, Nova Southeastern University, College of Pharmacy, Fort Lauderdale, Florida Kathleen K. Graham Pharm.D. Children's Diagnostic & Treatment Center and Nova Southeastern University, College of Pharmacy, Ft. Lauderdale, Florida Katherine Heller Pharm.D. Palm Beach Atlantic University, Lloyd L. Gregory School of Pharmacy, West Palm Beach, Florida Ovid: Lippincott's Illustrated Reviews: Pharmacology file:///F:/DOWNLOADS%20FIREFOX/LIRP4/Lippincott%27s%20Illustr... 1 of 2 11/8/2008 11:39 AM Sharon S. Kelley B.S., PMD Associates in Emergency Medical Education, Inc., Tampa, Florida Deborah J. Larison Pharm.D. Lakeland Regional Medical Center, Lakeland, Florida Ruth E. Nemire Pharm.D. Touro College of Pharmacy, New York, New York Appu Rathinavelu Ph.D. Department of Pharmaceutical and Administrative Sciences, Nova Southeastern University, College of Pharmacy, Fort Lauderdale, Florida Jose Rey Pharm.D. Department of Pharmaceutical and Administrative Sciences, Nova Southeastern University, College of Pharmacy, Fort Lauderdale, Florida Devada Singh-Franco Pharm.D. Department of Pharmacy Practice, Nova Southeastern University, College of Pharmacy, Fort Lauderdale, Florida Lester G. Sultatos Ph.D. Department of Pharmacology, New Jersey Medical School, Newark, New Jersey Sony Tuteja Pharm.D., BCPS Division of Clinical and Administrative Pharmacy, University of Iowa, College of Pharmacy, Iowa City, Iowa Karen Whalen Pharm.D., BCPS Department of Pharmacy Practice, Nova Southeastern University, College of Pharmacy, Fort Lauderdale, Florida Illustration and Graphic Design Michael Cooper Cooper Graphic, www.cooper247.com Christopher T. Flatt Department of Visual Communications, Ivy Tech Community College, Sellersburg, Indiana Ovid: Lippincott's Illustrated Reviews: Pharmacology file:///F:/DOWNLOADS%20FIREFOX/LIRP4/Lippincott%27s%20Illustr... 2 of 2 11/8/2008 11:39 AM Editors: Finkel, Richard; Clark, Michelle A.; Cubeddu, Luigi X. Title: Lippincott's Illustrated Reviews: Pharmacology, 4th Edition Copyright ©2009 Lippincott Williams & Wilkins > Table of Contents > Unit I - Introduction to Pharmacology > Chapter 1 - Pharmacokinetics Chapter 1 Pharmacokinetics I. Overview The goal of drug therapy is to prevent, cure, or control various disease states. To achieve this goal, adequate drug doses must be delivered to the target tissues so that therapeutic yet nontoxic levels are obtained. Pharmacokinetics examines the movement of a drug over time through the body. Pharmacological as well as toxicological actions of drugs are primarily related to the plasma concentrations of drugs. Thus, the clinician must recognize that the speed of onset of drug action, the intensity of the drug's effect, and the duration of drug action are controlled by four fundamental pathways of drug movement and modification in the body (Figure 1.1). First, drug absorption from the site of administration (Absorption) permits entry of the therapeutic agent (either directly or indirectly) into plasma. Second, the drug may then reversibly leave the bloodstream and distribute into the interstitial and intracellular fluids (Distribution). Third, the drug may be metabolized by the liver, kidney, or other tissues (Metabolism). Finally, the drug and its metabolites are removed from the body in urine, bile, or feces (Elimination). This chapter describes how knowledge of these four processes (Absorption, Distribution, Metabolism, and Elimination) influences the clinician's decision of the route of administration for a specific drug, the amount and frequency of each dose, and the dosing intervals. Ovid: Lippincott's Illustrated Reviews: Pharmacology file:///F:/DOWNLOADS%20FIREFOX/LIRP4/Lippincott%27s%20Illustr... 1 of 35 11/8/2008 11:38 AM P.2 Figure 1.1 Schematic representation of drug absorption, distribution, metabolism, and elimination. II. Routes of Drug Administration The route of administration is determined primarily by the properties of the drug (for example, water or lipid solubility, ionization, etc.) and by the therapeutic objectives (for example, the desirability of a rapid onset of action or the need for long-term administration or restriction to a local site). There are two major routes of drug administration, enteral and parenteral. (Figure 1.2 illustrates the subcategories of these routes as well as other methods of drug administration.) A. Enteral Enteral administration, or administering a drug by mouth, is the simplest and most common means of administering drugs. When the drug is given in the mouth, it may be swallowed, allowing oral delivery, or it may be placed under the tongue, facilitating direct absorption into the bloodstream. Oral: Giving a drug by mouth provides many advantages to the patient; oral drugs are easily self-administered and limit the number of systemic infections that could complicate treatment. Moreover, toxicities or overdose by the oral route may be overcome with antidotes such as activated charcoal. On the other hand, the pathways involved in drug absorption are the most complicated, and the drug is exposed to harsh gastrointestinal (GI) environments that may limit its absorption. Some drugs are absorbed from the stomach; however, the duodenum is a major site of entry to the systemic circulation because of its larger absorptive surface. Most drugs absorbed 1. Ovid: Lippincott's Illustrated Reviews: Pharmacology file:///F:/DOWNLOADS%20FIREFOX/LIRP4/Lippincott%27s%20Illustr... 2 of 35 11/8/2008 11:38 AM from the GI tract enter the portal circulation and encounter the liver before they are distributed into the general circulation. These drugs undergo first-pass metabolism in the liver, where they may be extensively metabolized before entering the systemic circulation (Figure 1.3). [Note: First-pass metabolism by the intestine or liver limits the efficacy of many drugs when taken orally. For example, more than ninety percent of nitroglycerin is cleared during a single passage through the liver, which is the primary reason why this agent is not administered orally.] Drugs that exhibit high first-pass metabolism should be given in sufficient quantities to ensure that enough of the active drug reaches the target organ. Ingestion of drugs with food, or in combination with other drugs, can influence absorption. The presence of food in the stomach delays gastric emptying, so drugs that are destroyed by acid (for example, penicillin) become unavailable for absorption (see p. 364). [Note: Enteric coating of a drug protects it from the acidic environment; the coating may prevent gastric irritation, and depending on the formulation, the release of the drug may be prolonged, producing a sustained- release effect.] Figure 1.2 Commonly used routes of drug administration. IV = intravenous; IM = intramuscular; SC = subcutaneous. Sublingual: Placement under the tongue allows a drug to diffuse into the capillary network and, therefore, to enter the systemic circulation directly. Administration of an agent, sublingually, has several advantages including rapid absorption, convenience of administration, low incidence of infection, avoidance of the harsh GI environment, and avoidance of first-pass metabolism. 2. B. Parenteral The parenteral route introduces drugs directly across the body's barrier defenses into the systemic circulation or other vascular tissue. Parenteral administration is used for drugs that are poorly absorbed from the GI tract (for example heparin) and for agents that are unstable in the GI tract (for example, insulin). Parenteral administration is also used for treatment of unconscious patients and under circumstances that require a rapid onset of action. In addition, these routes have the highest bioavailability and are not subject to first-pass metabolism or harsh GI environments. Parenteral administration provides the most control over the actual dose of drug delivered to the Ovid: Lippincott's Illustrated Reviews: Pharmacology file:///F:/DOWNLOADS%20FIREFOX/LIRP4/Lippincott%27s%20Illustr... 3 of 35 11/8/2008 11:38 AM P.3 body. However, these routes are irreversible and may cause pain, fear, and infections. The three major parenteral routes are intravascular (intravenous or intra-arterial), intramuscular, and subcutaneous (see Figure 1.2). Each route has advantages and drawbacks. Figure 1.3 First-pass metabolism can occur with orally administered drugs. IV = intravenous. Intravenous (IV): Injection is the most common parenteral route. For drugs that are not absorbed orally, such as the neuromuscular blocker atracurium, there is often no other choice. With IV administration, the drug avoids the GI tract and therefore, first-pass metabolism by the liver. Intravenous delivery permits a rapid effect and a maximal degree of control over the circulating levels of the drug. However, unlike drugs in the GI tract, those that are injected cannot be recalled by strategies such as emesis or by binding to activated charcoal. Intravenous injection may inadvertently introduce bacteria through contamination at the site of injection. IV injection may also induce hemolysis or cause other adverse reactions by the too-rapid delivery of high concentrations of drug to the plasma and tissues. Therefore, the rate of infusion must be carefully controlled. Similar concerns apply to intra-arterially injected drugs. 1. Intramuscular (IM): Drugs administered IM can be aqueous solutions or specialized depot preparations—often a suspension of drug in a nonaqueous vehicle such as polyethylene glycol. Absorption of drugs in an aqueous solution is fast, whereas that from depot preparations is slow. As the vehicle diffuses out of the muscle, the drug precipitates at the site of injection. The drug then dissolves slowly, providing a sustained dose over an extended period of time. An example is sustained-release haloperidol decanoate (see p. 155), which slowly diffuses from the muscle and produces an extended neuroleptic effect. 2. Subcutaneous (SC): This route of administration, like that of IM injection, requires absorption and is somewhat slower than the IV route. Subcutaneous injection minimizes the risks associated with intravascular injection. [Note: Minute amounts of epinephrine are sometimes combined with a drug to restrict its area of action. Epinephrine acts as a local vasoconstrictor and decreases removal of a drug, such as lidocaine, from the site of administration.] Other examples of drugs utilizing SC administration include solids, such as a single rod 3. Ovid: Lippincott's Illustrated Reviews: Pharmacology file:///F:/DOWNLOADS%20FIREFOX/LIRP4/Lippincott%27s%20Illustr... 4 of 35 11/8/2008 11:38 AM P.4 containing the contraceptive etonogestrel that is implanted for long-term activity (see p. 306), and also programmable mechanical pumps that can be implanted to deliver insulin in diabetic patients. C. Other Inhalation: Inhalation provides the rapid delivery of a drug across the large surface area of the mucous membranes of the respiratory tract and pulmonary epithelium, producing an effect almost as rapidly as with IV injection. This route of administration is used for drugs that are gases (for example, some anesthetics) or those that can be dispersed in an aerosol. This route is particularly effective and convenient for patients with respiratory complaints (such as asthma, or chronic obstructive pulmonary disease) because the drug is delivered directly to the site of action and systemic side effects are minimized. Examples of drugs administered via this route include albuterol, and corticosteroids, such as fluticasone. 1. Intranasal: This route involves administration of drugs directly into the nose. Agents include nasal decongestants such as the anti-inflammatory corticosteroid mometasone furoate. Desmopressin is administered intranasally in the treatment of diabetes insipidus; salmon calcitonin, a peptide hormone used in the treatment of osteoporosis, is also available as a nasal spray. The abused drug, cocaine, is generally taken by intranasal sniffing. 2. Intrathecal/intraventricular: It is sometimes necessary to introduce drugs directly into the cerebrospinal fluid. For example, amphotericin B is used in treating cryptococcal meningitis (see p. 408). 3. Topical: Topical application is used when a local effect of the drug is desired. For example, clotrimazole is applied as a cream directly to the skin in the treatment of dermatophytosis, and tropicamide or cyclopentolate are instilled (administered drop by drop) directly into the eye to dilate the pupil and permit measurement of refractive errors. 4. Transdermal: This route of administration achieves systemic effects by application of drugs to the skin, usually via a transdermal patch. The rate of absorption can vary markedly, depending on the physical characteristics of the skin at the site of application. This route is most often used for the sustained delivery of drugs, such as the antianginal drug nitroglycerin, the antiemetic scopolamine, and the once-a-week contraceptive patch (Ortho Evra) that has an efficacy similar to oral birth control pills. 5. Rectal: Fifty percent of the drainage of the rectal region bypasses the portal circulation; thus, the biotransformation of drugs by the liver is minimized. Like the sublingual route of administration, the rectal route of administration has the additional advantage of preventing the destruction of the drug by intestinal enzymes or by low pH in the stomach. The rectal route is also useful if the drug induces vomiting when given orally, if the patient is already vomiting, or if the patient is unconscious. [Note: The rectal route is commonly used to administer antiemetic agents.] On the other hand, rectal absorption is often erratic and incomplete, and many drugs irritate the rectal mucosa. 6. III. Absorption of Drugs Absorption is the transfer of a drug from its site of administration to the bloodstream. The rate and efficiency of absorption depend on the route of administration. For IV delivery, absorption is complete; that is, the total dose of drug reaches the systemic circulation. Drug delivery by other routes may result in only partial absorption and, thus, lower bioavailability. For example, the oral route requires that a drug dissolve in the GI fluid and then penetrate the epithelial cells of the intestinal mucosa, yet disease states or the presence of food may affect this process. Ovid: Lippincott's Illustrated Reviews: Pharmacology file:///F:/DOWNLOADS%20FIREFOX/LIRP4/Lippincott%27s%20Illustr... 5 of 35 11/8/2008 11:38 AM P.5 Figure 1.4 Schematic representation of drugs crossing a cell membrane of an epithelial cell of the gastrointestinal tract. ATP = adenosine triphosphate; ADP = adenosine diphosphate. A. Transport of a drug from the GI tract Depending on their chemical properties, drugs may be absorbed from the GI tract by either passive diffusion or active transport. Passive diffusion: The driving force for passive absorption of a drug is the concentration gradient across a membrane separating two body compartments; that is, the drug moves from a region of high concentration to one of lower concentration. Passive diffusion does not involve a carrier, is not saturable, and shows a low structural specificity. The vast majority of drugs gain access to the body by this mechanism. Lipid-soluble drugs readily move across most biologic membranes due to their solubility in the membrane bilayers. Water-soluble drugs penetrate the cell membrane through aqueous channels or pores (Figure 1.4). Other agents can enter the cell through specialized transmembrane carrier proteins that facilitate the passage of large molecules. These carrier proteins undergo conformational changes allowing the passage of drugs or endogenous molecules into the interior of cells, moving them from an area of high concentration to an area of low concentration. This process is known as facilitated diffusion. This type of diffusion does not require energy, can be saturated, and may be inhibited. 1. Ovid: Lippincott's Illustrated Reviews: Pharmacology file:///F:/DOWNLOADS%20FIREFOX/LIRP4/Lippincott%27s%20Illustr... 6 of 35 11/8/2008 11:38 AM Figure 1.5 A. Diffusion of the non-ionized form of a weak acid through a lipid membrane. B. Diffusion of the nonionized form of a weak base through a lipid membrane. Active transport: This mode of drug entry also involves specific carrier proteins that span the membrane. A few drugs that closely resemble the structure of naturally occurring metabolites are actively transported across cell membranes using these specific carrier proteins. Active transport is energy-dependent and is driven by the hydrolysis of adenosine triphosphate (see Figure 1.4). It is capable of moving drugs against a concentration gradient—that is, from a region of low drug concentration to one of higher drug concentration. The process shows saturation kinetics for the carrier, much in the same way that an enzyme-catalyzed reaction shows a maximal velocity at high substrate levels where all the active sites are filled with substrate.1 2. Endocytosis and exocytosis: This type of drug delivery transports drugs of exceptionally large size across the 3. Ovid: Lippincott's Illustrated Reviews: Pharmacology file:///F:/DOWNLOADS%20FIREFOX/LIRP4/Lippincott%27s%20Illustr... 7 of 35 11/8/2008 11:38 AM P.6 cell membrane. Endocytosis involves engulfment of a drug molecule by the cell membrane and transport into the cell by pinching off the drug-filled vesicle. Exocytosis is the reverse of endocytosis and is used by cells to secrete many substances by a similar vesicle formation process. For example, vitamin B12 is transported across the gut wall by endocytosis. Certain neurotransmitters (for example, norepinephrine) are stored in membrane-bound vesicles in the nerve terminal and are released by exocytosis. B. Effect of pH on drug absorption Most drugs are either weak acids or weak bases. Acidic drugs (HA) release an H+ causing a charged anion (A-) to form:2 Weak bases (BH+) can also release an H+. However, the protonated form of basic drugs is usually charged, and loss of a proton produces the uncharged base (B): Passage of an uncharged drug through a membrane: A drug passes through membranes more readily if it is uncharged (Figure 1.5). Thus, for a weak acid, the uncharged HA can permeate through membranes, and A- cannot. For a weak base, the uncharged form, B, penetrates through the cell membrane, but BH+ does not. Therefore, the effective concentration of the permeable form of each drug at its absorption site is determined by the relative concentrations of the charged and uncharged forms. The ratio between the two forms is, in turn, determined by the pH at the site of absorption and by the strength of the weak acid or base, which is represented by the pKa (Figure 1.6). [Note: The pKa is a measure of the strength of the interaction of a compound with a proton. The lower the pKa of a drug, the more acidic it is. Conversely, the higher the pKa, the more basic is the drug.] Distribution equilibrium is achieved when the permeable form of a drug achieves an equal concentration in all body water spaces. [Note: Highly lipid-soluble drugs rapidly cross membranes and often enter tissues at a rate determined by blood flow.] Figure 1.6 The distribution of a drug between its ionized and non-ionized forms depends on the ambient pH and pKa of the drug. For illustrative purposes, the drug has been assigned a pKa of 6.5. 1. Determination of how much drug will be found on either side of a membrane: The relationship of pKa and the ratio of acid-base concentrations to pH is expressed by the Henderson-Hasselbalch equation:3 2. Ovid: Lippincott's Illustrated Reviews: Pharmacology file:///F:/DOWNLOADS%20FIREFOX/LIRP4/Lippincott%27s%20Illustr... 8 of 35 11/8/2008 11:38 AM P.7 This equation is useful in determining how much drug will be found on either side of a membrane that separates two compartments that differ in pH—for example, stomach (pH 1.0–1.5) and blood plasma (pH 7.4). [Note: The lipid solubility of the non-ionized drug directly determines its rate of equilibration.] C. Physical factors influencing absorption Blood flow to the absorption site: Blood flow to the intestine is much greater than the flow to the stomach; thus, absorption from the intestine is favored over that from the stomach. [Note: Shock severely reduces blood flow to cutaneous tissues, thus minimizing the absorption from SC administration.] 1. Total surface area available for absorption: Because the intestine has a surface rich in microvilli, it has a surface area about 1000-fold that of the stomach; thus, absorption of the drug across the intestine is more efficient. 2. Contact time at the absorption surface: If a drug moves through the GI tract very quickly, as in severe diarrhea, it is not well absorbed. Conversely, anything that delays the transport of the drug from the stomach to the intestine delays the rate of absorption of the drug. [Note: Parasympathetic input increases the rate of gastric emptying, whereas sympathetic input (prompted, for example, by exercise or stressful emotions), as well as anticholinergics (for example, dicyclomine), prolongs gastric emptying. Also, the presence of food in the stomach both dilutes the drug and slows gastric emptying. Therefore, a drug taken with a meal is generally absorbed more slowly.] 3. Ovid: Lippincott's Illustrated Reviews: Pharmacology file:///F:/DOWNLOADS%20FIREFOX/LIRP4/Lippincott%27s%20Illustr... 9 of 35 11/8/2008 11:38 AM P.8 Figure 1.7 Determination of the bioavailability of a drug. (AUC = area under curve.) IV. Bioavailability Bioavailability is the fraction of administered drug that reaches the systemic circulation. Bioavailability is expressed as the fraction of administered drug that gains access to the systemic circulation in a chemically unchanged form. For example, if 100 mg of a drug are administered orally and 70 mg of this drug are absorbed unchanged, the bioavailability is 0.7 or seventy percent. A. Determination of bioavailability Bioavailability is determined by comparing plasma levels of a drug after a particular route of administration (for example, oral administration) with plasma drug levels achieved by IV injection—in which all of the agent rapidly enters the circulation. When the drug is given orally, only part of the administered dose appears in the plasma. By plotting plasma concentrations of the drug versus time, one can measure the area under the curve (AUC). This curve reflects the extent of absorption of the drug. [Note: By definition, this is 100 percent for drugs delivered IV.] Bioavailability of a drug administered orally is the ratio of the area calculated for oral administration compared with the area calculated for IV injection (Figure 1.7). B. Factors that influence bioavailability First-pass hepatic metabolism: When a drug is absorbed across the GI tract, it enters the portal circulation before entering the systemic circulation (see Figure 1.3). If the drug is rapidly metabolized by the liver, the amount of unchanged drug that gains access to the systemic circulation is decreased. Many drugs, such as propranolol or lidocaine, undergo significant biotransformation during a single passage through the liver. 1. Solubility of the drug: Very hydrophilic drugs are poorly absorbed because of their inability to cross the lipid-rich cell membranes. Paradoxically, drugs that are extremely hydrophobic are also poorly absorbed, because they are totally insoluble in aqueous body fluids and, therefore, cannot gain access to the surface of cells. For a drug to be readily absorbed, it must be largely hydrophobic, yet have some solubility in aqueous solutions. This is one reason why many drugs are weak acids or weak bases. There are some drugs that are highly lipid-soluble, and they are transported in the aqueous solutions of the body on carrier proteins such as albumin. 2. Chemical instability: Some drugs, such as penicillin G, are unstable in the pH of the gastric contents. Others, such as insulin, are destroyed in the GI tract by degradative enzymes. 3. Nature of the drug formulation: Drug absorption may be altered by factors unrelated to the chemistry of the drug. For example, particle size, salt form, crystal polymorphism, enteric coatings and the presence of excipients (such as binders and dispersing agents) can influence the ease of dissolution and, therefore, alter the rate of absorption. 4. C. Bioequivalence Two related drugs are bioequivalent if they show comparable bioavailability and similar times to achieve peak blood concentrations. Two related drugs with a significant difference in bioavailability are said to be bioinequivalent. D. Therapeutic equivalence Two similar drugs are therapeutically equivalent if they have comparable efficacy and safety. [Note: Clinical effectiveness often depends on both the maximum serum drug concentrations and on the time required (after administration) to reach peak concentration. Therefore, two drugs that are bioequivalent may not be Ovid: Lippincott's Illustrated Reviews: Pharmacology file:///F:/DOWNLOADS%20FIREFOX/LIRP4/Lippincott%27s%20Illustr... 10 of 35 11/8/2008 11:38 AM therapeutically equivalent.] V. Drug Distribution Drug distribution is the process by which a drug reversibly leaves the bloodstream and enters the interstitium (extracellular fluid) and/or the cells of the tissues. The delivery of a drug from the plasma to the interstitium primarily depends on blood flow, capillary permeability, the degree of binding of the drug to plasma and tissue proteins, and the relative hydrophobicity of the drug. Ovid: Lippincott's Illustrated Reviews: Pharmacology file:///F:/DOWNLOADS%20FIREFOX/LIRP4/Lippincott%27s%20Illustr... 11 of 35 11/8/2008 11:38 AM