Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems PDF

Made with Xodo PDF Reader and Editor UNIT I Principles of Drug Therapy Pharmacokinetics Venkata Yellepeddi...

Made with Xodo PDF Reader and Editor UNIT I Principles of Drug Therapy Pharmacokinetics Venkata Yellepeddi 1 I. OVERVIEW Drug at site of administration Pharmacokinetics refers to what the body does to a drug, whereas phar- macodynamics (see Chapter 2) describes what the drug does to the body. Four pharmacokinetic properties determine the onset, intensity, and the duration of drug action (Figure 1.1): 1 Absorption (input) Absorption: First, absorption from the site of administration permits entry of the drug (either directly or indirectly) into plasma. Drug in Distribution: Second, the drug may then reversibly leave the blood- plasma stream and distribute into the interstitial and intracellular fluids. 2 Distribution Metabolism: Third, the drug may be biotransformed by metabolism by the liver or other tissues. Elimination: Finally, the drug and its metabolites are eliminated from Drug in the body in urine, bile, or feces. tissues Using knowledge of pharmacokinetic parameters, clinicians can design optimal drug regimens, including the route of administration, the dose, 3 Metabolism the frequency, and the duration of treatment. Metabolite(s) II. ROUTES OF DRUG ADMINISTRATION in tissues The route of administration is determined by the properties of the drug (for example, water or lipid solubility, ionization) and by the therapeutic 4 Elimination objectives (for example, the desirability of a rapid onset, the need for (output) long-term treatment, or restriction of delivery to a local site). Major routes of drug administration include enteral, parenteral, and topical, among others (Figure 1.2). Drug and/or metabolite(s) in Figure 1.1 urine, bile, tears, breast milk, saliva, sweat, or feces Schematic representation of drug absorption, distribution, metabolism, and elimination. 1  Made with Xodo PDF Reader and Editor 2 1. Pharmacokinetics A. Enteral Otic Enteral administration (administering a drug by mouth) is the saf- Ocular Parenteral: est and most common, convenient, and economical method of drug IV, IM, SC administration. The drug may be swallowed, allowing oral delivery, or Inhalation it may be placed under the tongue (sublingual), or between the gums and cheek (buccal), facilitating direct absorption into the bloodstream. Oral 1. Oral: Oral administration provides many advantages. Oral drugs Sublingual Buccal are easily self-administered, and toxicities and/or overdose of oral drugs may be overcome with antidotes, such as activated char- Transdermal coal. However, the pathways involved in oral drug absorption are patch Topical the most complicated, and the low gastric pH inactivates some Epidural drugs. A wide range of oral preparations is available including enteric-coated and extended-release preparations. a. Enteric-coated preparations: An enteric coating is a chemi- cal envelope that protects the drug from stomach acid, deliv- ering it instead to the less acidic intestine, where the coating dissolves and releases the drug. Enteric coating is useful for certain drugs (for example, omeprazole) that are acid unstable. Drugs that are irritating to the stomach, such as aspirin, can be formulated with an enteric coating that only dissolves in the small intestine, thereby protecting the stomach. Figure 1.2 b. Extended-release preparations: Extended-release (abbrevi- Commonly used routes of drug ated ER or XR) medications have special coatings or ingredi- administration. IV = intravenous; IM = ents that control the drug release, thereby allowing for slower intramuscular; SC = subcutaneous. absorption and a prolonged duration of action. ER formulations can be dosed less frequently and may improve patient com- pliance. Additionally, ER formulations may maintain concentra- tions within the therapeutic range over a longer period of time, as opposed to immediate-release dosage forms, which may result in larger peaks and troughs in plasma concentration. ER formulations are advantageous for drugs with short half-lives. For example, the half-life of oral morphine is 2 to 4 hours, and it must be administered six times daily to provide continuous pain relief. However, only two doses are needed when extended- release tablets are used. Unfortunately, many ER formulations have been developed solely for a marketing advantage over immediate-release products, rather than a documented clinical advantage. 2. Sublingual/buccal: Placement under the tongue allows a drug to diffuse into the capillary network and enter the systemic circu- lation directly. Sublingual administration has several advantages, including ease of administration, rapid absorption, bypass of the harsh gastrointestinal (GI) environment, and avoidance of first- pass metabolism (see discussion of first-pass metabolism below). The buccal route (between the cheek and gum) is similar to the sublingual route. B. Parenteral The parenteral route introduces drugs directly into the systemic cir- culation. Parenteral administration is used for drugs that are poorly  Made with Xodo PDF Reader and Editor II. Routes of Drug Administration3 absorbed from the GI tract (for example, heparin) or unstable in the GI tract (for example, insulin). Parenteral administration is also A Intramuscular used if a patient is unable to take oral medications (unconscious injection patients) and in circumstances that require a rapid onset of action. Subcutaneous injection In addition, parenteral routes have the highest bioavailability and Epidermis are not subject to first-pass metabolism or the harsh GI environ- ment. Parenteral administration provides the most control over the Dermis actual dose of drug delivered to the body. However, these routes of administration are irreversible and may cause pain, fear, local tissue damage, and infections. The three major parenteral routes are intravascular (intravenous or intra-arterial), intramuscular, and subcutaneous (Figure 1.3). 1. Intravenous (IV): IV injection is the most common parenteral route. It is useful for drugs that are not absorbed orally, such as the neuromuscular blocker rocuronium. IV delivery permits a rapid effect and a maximum degree of control over the amount of drug delivered. When injected as a bolus, the full amount of Muscle Subcutaneous tissue drug is delivered to the systemic circulation almost immediately. If administered as an IV infusion, the drug is infused over a longer period of time, resulting in lower peak plasma concentrations and an increased duration of circulating drug levels. IV administration B is advantageous for drugs that cause irritation when administered via other routes, because the substance is rapidly diluted by the 200 Plasma concentration blood. Unlike drugs given orally, those that are injected cannot be 5 mg intravenous midazolam recalled by strategies such as binding to activated charcoal. IV (ng/mL) injection may inadvertently introduce infections through contami- 100 nation at the site of injection. It may also precipitate blood con- stituents, induce hemolysis, or cause other adverse reactions if the medication is delivered too rapidly and high concentrations are reached too quickly. Therefore, patients must be carefully moni- 5 mg intramuscular midazolam 0 tored for drug reactions, and the rate of infusion must be carefully 0 30 60 90 controlled. Time (minutes) 2. Intramuscular (IM): Drugs administered IM can be in aque- ous solutions, which are absorbed rapidly, or in specialized Figure 1.3 depot preparations, which are absorbed slowly. Depot prepara- A. Schematic representation of tions often consist of a suspension of the drug in a nonaqueous subcutaneous and intramuscular injection. B. Plasma concentrations vehicle such as polyethylene glycol. As the vehicle diffuses out of midazolam after intravenous and of the muscle, the drug precipitates at the site of injection. The intramuscular injection. drug then dissolves slowly, providing a sustained dose over an extended period of time. Examples of sustained-release drugs are haloperidol (see Chapter 11) and depot medroxyprogester- one (see Chapter 26). 3. Subcutaneous (SC): Like IM injection, SC injection provides absorption via simple diffusion and is slower than the IV route. SC injection minimizes the risks of hemolysis or thrombosis associ- ated with IV injection and may provide constant, slow, and sus- tained effects. This route should not be used with drugs that cause tissue irritation, because severe pain and necrosis may occur. Drugs commonly administered via the subcutaneous route include insulin and heparin.  Made with Xodo PDF Reader and Editor 4 1. Pharmacokinetics C. Other A Clear backing 1. Oral inhalation: Inhalation routes, both oral and nasal (see Drug reservoir discussion of nasal inhalation), provide rapid delivery of a drug Skin Drug-release across the large surface area of the mucous membranes of the membrane respiratory tract and pulmonary epithelium. Drug effects are Contact almost as rapid as those with IV bolus. Drugs that are gases (for adhesive example, some anesthetics) and those that can be dispersed in an aerosol are administered via inhalation. This route is effective and convenient for patients with respiratory disorders (such as asthma or chronic obstructive pulmonary disease), because the drug is delivered directly to the site of action, thereby minimizing systemic side effects. Examples of drugs administered via inha- lation include bronchodilators, such as albuterol, and corticoste- roids, such as fluticasone. BLOOD VESSEL 2. Nasal inhalation: This route involves administration of drugs directly into the nose. Examples of agents include nasal decon- Drug diffusing from reservoir gestants, such as oxymetazoline, and corticosteroids, such as into subcutaneous tissue mometasone furoate. Desmopressin is administered intranasally in the treatment of diabetes insipidus. B 3. Intrathecal/intraventricular: The blood–brain barrier typically delays or prevents the absorption of drugs into the central nervous system (CNS). When local, rapid effects are needed, it is neces- sary to introduce drugs directly into the cerebrospinal fluid. For example, intrathecal amphotericin B is used in treating cryptococ- cal meningitis (see Chapter 42). 4. Topical: Topical application is used when a local effect of the drug is desired. For example, clotrimazole is a cream applied directly to the skin for the treatment of fungal infections. 5. Transdermal: This route of administration achieves systemic effects by application of drugs to the skin, usually via a transder- mal patch (Figure 1.4). The rate of absorption can vary markedly, Figure 1.4 depending on the physical characteristics of the skin at the site A. Schematic representation of a of application, as well as the lipid solubility of the drug. This route transdermal patch. B. Transdermal is most often used for the sustained delivery of drugs, such as nicotine patch applied to the arm. the antianginal drug nitroglycerin, the antiemetic scopolamine, and nicotine transdermal patches, which are used to facilitate smoking cessation. 6. Rectal: Because 50% of the drainage of the rectal region bypasses the portal circulation, the biotransformation of drugs by the liver is minimized with rectal administration. The rectal route has the additional advantage of preventing destruction of the drug in the GI environment. This 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.] Rectal absorption is often erratic and incomplete, and many drugs irritate the rectal mucosa. Figure 1.5 summarizes the characteristics of the common routes of administration.  Made with Xodo PDF Reader and Editor II. Routes of Drug Administration 5 ROUTE OF ABSORPTION ADVANTAGES DISADVANTAGES ADMINISTRATION PATTERN Oral Variable; affected by many Safest and most common, Limited absorption of some drugs factors convenient, and economical Food may affect absorption route of administration Patient compliance is necessary Drugs may be metabolized before systemic absorption Intravenous Absorption not required Can have immediate effects Unsuitable for oily substances Ideal if dosed in large volumes Bolus injection may result in adverse Suitable for irritating substances effects and complex mixtures Most substances must be slowly Valuable in emergency situations injected Dosage titration permissible Strict aseptic techniques needed Ideal for high molecular weight proteins and peptide drugs Subcutaneous Depends on drug diluents: Suitable for slow-release drugs Pain or necrosis if drug is irritating Aqueous solution: prompt Ideal for some poorly soluble Unsuitable for drugs administered in Depot preparations: suspensions large volumes slow and sustained Intramuscular Depends on drug diluents: Suitable if drug volume is moderate Affects certain lab tests (creatine Suitable for oily vehicles and certain kinase) Aqueous solution: prompt irritating substances Can be painful Depot preparations: Preferable to intravenous if patient Can cause intramuscular slow and sustained must self-administer hemorrhage (precluded during anticoagulation therapy) Transdermal Slow and sustained (patch) Bypasses the first-pass effect Some patients are allergic to Convenient and painless patches, which can cause irritation Ideal for drugs that are lipophilic and Drug must be highly lipophilic have poor oral bioavailability May cause delayed delivery of drug Ideal for drugs that are quickly to pharmacological site of action eliminated from the body Limited to drugs that can be taken in small daily doses Rectal Erratic and variable Partially bypasses first-pass effect Drugs may irritate the rectal Bypasses destruction by stomach acid mucosa Ideal if drug causes vomiting Not a well-accepted route Ideal in patients who are vomiting, or comatose Absorption is rapid; can have Most addictive route (drug can Inhalation Systemic absorption may immediate effects occur; this is not always enter the brain quickly) desirable Ideal for gases Patient may have difficulty Effective for patients with respiratory regulating dose problems Some patients may have Dose can be titrated difficulty using inhalers Localized effect to target lungs: lower doses used compared to that with oral or parenteral administration Fewer systemic side effects Bypasses first-pass effect Limited to certain types of drugs Sublingual Depends on the drug: Bypasses destruction by stomach Few drugs (for example, Limited to drugs that can be acid taken in small doses nitroglycerin) have rapid, direct systemic absorption Drug stability maintained because May lose part of the drug dose if the pH of saliva relatively neutral swallowed Most drugs erratically or incompletely absorbed May cause immediate pharmacologi- cal effects Figure 1.5 The absorption pattern, advantages, and disadvantages of the most common routes of administration.  Made with Xodo PDF Reader and Editor 6 1. Pharmacokinetics III. ABSORPTION OF DRUGS 1 Passive diffusion Passive diffusion Passive diffusion Absorption is the transfer of a drug from the site of administration to the of a water-soluble of a lipid-soluble bloodstream. The rate and extent of absorption depend on the environ- drug through an drug dissolved aqueous channel in a membrane ment where the drug is absorbed, chemical characteristics of the drug, or pore and the route of administration (which influences bioavailability). Routes of administration other than intravenous may result in partial absorption Drug Drug and lower bioavailability. D A. Mechanisms of absorption of drugs from the GI tract D D D Extracellular D D Depending on their chemical properties, drugs may be absorbed from D D space the GI tract by passive diffusion, facilitated diffusion, active transport, Cell membrane or endocytosis (Figure 1.6). 1. Passive diffusion: The driving force for passive absorption of Cytosol a drug is the concentration gradient across a membrane sepa- D D rating two body compartments. In other words, the drug moves from a region of high concentration to one of lower concentra- 2 Facilitated diffusion tion. Passive diffusion does not involve a carrier, is not saturable, and shows a low structural specificity. The vast majority of drugs Drug D D are absorbed by this mechanism. Water-soluble drugs pene- D D Drug trate the cell membrane through aqueous channels or pores, transporter whereas lipid-soluble drugs readily move across most biologic D D membranes due to their solubility in the membrane lipid bilayers. 2. Facilitated diffusion: Other agents can enter the cell through spe- D cialized transmembrane carrier proteins that facilitate the passage of large molecules. These carrier proteins undergo conformational changes, allowing the passage of drugs or endogenous molecules 3 Active transport into the interior of cells and moving them from an area of high con- centration to an area of low concentration. This process is known D ATP ADP as facilitated diffusion. It does not require energy, can be saturated, D and may be inhibited by compounds that compete for the carrier. D 3. Active transport: This mode of drug entry also involves spe- Drug transporter D D cific carrier proteins that span the membrane. A few drugs that D D D closely resemble the structure of naturally occurring metabolites are actively transported across cell membranes using specific carrier proteins. Energy-dependent active transport is driven by 4 Endocytosis Large drug the hydrolysis of adenosine triphosphate. It is capable of moving drugs against a concentration gradient, from a region of low drug molecule concentration to one of higher drug concentration. The process is saturable. Active transport systems are selective and may be com- petitively inhibited by other cotransported substances. 4. Endocytosis and exocytosis: This type of absorption is used to transport drugs of exceptionally large size across the cell membrane. Endocytosis involves engulfment of a drug by the cell membrane and transport into the cell by pinching off the drug- filled vesicle. Exocytosis is the reverse of endocytosis. Many cells use exocytosis to secrete substances out of the cell through a similar process of vesicle formation. Vitamin B12 is transported Figure 1.6 across the gut wall by endocytosis, whereas certain neurotrans- Schematic representation of mitters (for example, norepinephrine) are stored in intracellular drugs crossing a cell membrane. vesicles in the nerve terminal and released by exocytosis. ATP = adenosine triphosphate; ADP = adenosine diphosphate.  Made with Xodo PDF Reader and Editor III. Absorption of Drugs7 B. Factors influencing absorption 1. Effect of pH on drug absorption: Most drugs are either weak A Weak acid acids or weak bases. Acidic drugs (HA) release a proton (H+), Lipid causing a charged anion (A−) to form: membrane HA  H+ + A − H + A– Weak bases (BH+) can also release an H+. However, the proton- ated form of basic drugs is usually charged, and loss of a proton HA produces the uncharged base (B): H + A– BH+  B + H+ HA A drug passes through membranes more readily if it is uncharged (Figure 1.7). Thus, for a weak acid, the uncharged, proton- ated HA can permeate through membranes, and A− cannot. For Body Body compartment compartment a weak base, the uncharged form B penetrates through the cell membrane, but the protonated form 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 B Weak base is, in turn, determined by the pH at the site of absorption and by Lipid membrane the strength of the weak acid or base, which is represented by the ionization constant, pKa (Figure 1.8). [Note: The pKa is a mea- + BH sure of the strength of the interaction of a compound with a proton. + H 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 B BH + is achieved when the permeable form of a drug achieves an equal + H concentration in all body water spaces. B 2. Blood flow to the absorption site: The intestines receive much more blood flow than the stomach, so absorption from the intestine is favored over the stomach. [Note: Shock severely reduces blood Body Body compartment compartment flow to cutaneous tissues, thereby minimizing absorption from SC administration.] 3. Total surface area available for absorption: With a surface rich Figure 1.7 in brush borders containing microvilli, the intestine has a surface A. Diffusion of the nonionized area about 1000-fold that of the stomach, making absorption of the form of a weak acid through a lipid drug across the intestine more efficient. membrane. B. Diffusion of the nonionized form of a weak base through a lipid membrane. When pH is less than pKa, When pH is greater than pKa, the protonated forms the deprotonated forms HA and BH+ predominate. A– and B predominate. When pH = pKa, [HA] = [A–] and [BH+] = [B] pH < pKa pH > pKa 2 pH 3 4 5 6 7 8 9 10 11 pKa Figure 1.8 The distribution of a drug between its ionized and nonionized forms depends on the ambient pH and pKa of the drug. For illustrative purposes, the drug has been assigned a pKa of 6.5.  Made with Xodo PDF Reader and Editor 8 1. Pharmacokinetics 4. Contact time at the absorption surface: If a drug moves through the GI tract very quickly, as can happen with severe diar- rhea, it is not well absorbed. Conversely, anything that delays the Drug (extracellular) transport of the drug from the stomach to the intestine delays the rate of absorption of the drug. [Note: 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.] 5. Expression of P-glycoprotein: P-glycoprotein is a transmem- brane transporter protein responsible for transporting various molecules, including drugs, across cell membranes (Figure 1.9). It is expressed in tissues throughout the body, including the liver, kidneys, placenta, intestines, and brain capillaries, and is involved in transportation of drugs from tissues to blood. That is, it ADP + Pi “pumps” drugs out of the cells. Thus, in areas of high expression, Drug (intracellular) P-glycoprotein reduces drug absorption. In addition to transport- ATP ing many drugs out of cells, it is also associated with multidrug resistance. C. Bioavailability Figure 1.9 Bioavailability is the rate and extent to which an administered drug The six membrane-spanning loops reaches the systemic circulation. For example, if 100 mg of a drug of the P-glycoprotein form a central is administered orally and 70 mg is absorbed unchanged, the bio- channel for the ATP-dependent availability is 0.7 or 70%. Determining bioavailability is important for pumping of drugs from the cell. calculating drug dosages for nonintravenous routes of administration. 1. Determination of bioavailability: Bioavailability is determined by comparing plasma levels of a drug after a particular route of administration (for example, oral administration) with levels AUC oral achieved by IV administration. After IV administration, 100% of the Bioavailability = x 100 AUC IV drug 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, the area Plasma concentration of drug under the curve (AUC) can be measured. The total AUC reflects Drug the extent of absorption of the drug. Bioavailability of a drug given IV given orally is the ratio of the AUC following oral administration to the AUC following IV administration (assuming IV and oral doses are AUC equivalent; Figure 1.10). (IV) Drug given orally 2. Factors that influence bioavailability: In contrast to IV admin- istration, which confers 100% bioavailability, orally administered AUC (oral) drugs often undergo first-pass metabolism. This biotransformation, Time in addition to the chemical and physical characteristics of the drug, determines the rate and extent to which the agent reaches the systemic circulation. Drug administered a. First-pass hepatic metabolism: When a drug is absorbed from the GI tract, it enters the portal circulation before enter- Figure 1.10 ing the systemic circulation (Figure 1.11). If the drug is rap- Determination of the bioavailability idly metabolized in the liver or gut wall during this initial of a drug. AUC = area under curve; passage, the amount of unchanged drug entering the sys- IV = intravenous temic circulation is decreased. This is referred to as first-pass  Made with Xodo PDF Reader and Editor IV. Drug Distribution9 metabolism. [Note: First-pass metabolism by the intestine or liver limits the efficacy of many oral medications. For Drugs administered orally are first exposed to the example, more than 90% of nitroglycerin is cleared during liver and may be extensively first-pass metabolism. Hence, it is primarily administered metabolized before via the sublingual or transdermal route.] Drugs with high reaching the rest of body. first-pass metabolism should be given in doses sufficient to ensure that enough active drug reaches the desired site of Drugs administered IV enter directly into the action. systemic circulation and have direct access to the b. Solubility of the drug: Very hydrophilic drugs are poorly rest of the body. absorbed because of their inability to cross lipid-rich cell mem- branes. Paradoxically, drugs that are extremely lipophilic 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 lipophilic, yet have some solubility in aqueous solutions. This is one reason why many drugs are either weak acids or IV weak bases. c. 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. d. 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 Portal coatings, and the presence of excipients (such as binders and circulation dispersing agents) can influence the ease of dissolution and, therefore, alter the rate of absorption. D. Bioequivalence Two drug formulations are bioequivalent if they show comparable bio- availability and similar times to achieve peak blood concentrations. Systemic circulation E. Therapeutic equivalence Two drug formulations are therapeutically equivalent if they are Figure 1.11 First-pass metabolism can occur pharmaceutically equivalent (that is, they have the same dosage with orally administered drugs. form, contain the same active ingredient, and use the same route of IV = intravenous. administration) with similar clinical and safety profiles. [Note: Clinical effectiveness often depends on both the maximum serum drug con- centration and the time required (after administration) to reach peak concentration. Therefore, two drugs that are bioequivalent may not be therapeutically equivalent.] IV. DRUG DISTRIBUTION Drug distribution is the process by which a drug reversibly leaves the bloodstream and enters the interstitium (extracellular fluid) and the tis- sues. For drugs administered IV, absorption is not a factor, and the ini- tial phase (from immediately after administration through the rapid fall in concentration) represents the distribution phase, during which the drug  Made with Xodo PDF Reader and Editor 10 1. Pharmacokinetics rapidly leaves the circulation and enters the tissues (Figure 1.12). The distribution of a drug from the plasma to the interstitium depends on car- diac output and local blood flow, capillary permeability, the tissue volume, 1.5 the degree of binding of the drug to plasma and tissue proteins, and the 1.25 relative lipophilicity of the drug. Plasma concentration 1 A. Blood flow Elimination 0.75 phase The rate of blood flow to the tissue capillaries varies widely. For 0.5 instance, blood flow to the “vessel-rich organs” (brain, liver, and kid- Distribution ney) is greater than that to the skeletal muscles. Adipose tissue, skin, 0.25 phase and viscera have still lower rates of blood flow. Variation in blood flow partly explains the short duration of hypnosis produced by an 0 1 2 3 4 Time IV bolus of propofol (see Chapter 13). High blood flow, together with IV Bolus high lipophilicity of propofol, permits rapid distribution into the CNS and produces anesthesia. A subsequent slower distribution to skel- Figure 1.12 etal muscle and adipose tissue lowers the plasma concentration so Drug concentrations in serum after that the drug diffuses out of the CNS, down the concentration gradi- a single injection of drug. Assume ent, and consciousness is regained. that the drug distributes and is subsequently eliminated. B. Capillary permeability Capillary permeability is determined by capillary structure and by the chemical nature of the drug. Capillary structure varies in terms of the fraction of the basement membrane exposed by slit junc- tions between endothelial cells. In the liver and spleen, a signifi- cant portion of the basement membrane is exposed due to large, discontinuous capillaries through which large plasma proteins can pass (Figure 1.13A). In the brain, the capillary structure is con- tinuous, and there are no slit junctions (Figure 1.13B). To enter the brain, drugs must pass through the endothelial cells of the CNS capillaries or be actively transported. For example, a specific transporter carries levodopa into the brain. By contrast, lipid-solu- ble drugs readily penetrate the CNS because they dissolve in the endothelial cell membrane. Ionized or polar drugs generally fail to enter the CNS because they cannot pass through the endothelial cells that have no slit junctions (Figure 1.13C). These closely jux- taposed cells form tight junctions that constitute the blood–brain barrier. C. Binding of drugs to plasma proteins and tissues 1. Binding to plasma proteins: Reversible binding to plasma proteins sequesters drugs in a nondiffusible form and slows their transfer out of the vascular compartment. Albumin is the major drug-binding protein and may act as a drug reservoir (as the concentration of free drug decreases due to elimination, the bound drug dissociates from the protein). This maintains the free- drug concentration as a constant fraction of the total drug in the plasma. 2. Binding to tissue proteins: Many drugs accumulate in tissues, leading to higher concentrations in tissues than in the extracel- lular fluid and blood. Drugs may accumulate as a result of binding  Made with Xodo PDF Reader and Editor IV. Drug Distribution11 to lipids, proteins, or nucleic acids. Drugs may also be actively transported into tissues. Tissue reservoirs may serve as a major A Structure of liver source of the drug and prolong its actions or cause local drug capillary toxicity. (For example, acrolein, the metabolite of cyclophospha- Large fenestrations allow drugs to mide, can cause hemorrhagic cystitis because it accumulates in move between blood and interstitium in the liver. the bladder.) D. Lipophilicity The chemical nature of a drug strongly influences its ability to cross cell membranes. Lipophilic drugs readily move across most biologic Drug Endothelial membranes. These drugs dissolve in the lipid membranes and pen- cell etrate the entire cell surface. The major factor influencing the distribu- Slit junctions tion of lipophilic drugs is blood flow to the area. In contrast, hydrophilic drugs do not readily penetrate cell membranes and must pass through slit junctions. Basement membrane E. Volume of distribution B Structure capillary of a brain The apparent volume of distribution, Vd, is defined as the fluid volume that is required to contain the entire drug in the body at the same Astrocyte foot processes concentration measured in the plasma. It is calculated by dividing the dose that ultimately gets into the systemic circulation by the plasma Basement membrane concentration at time zero (C0). Amount of drug in the body Vd = Brain C0 endothelial cell Although Vd has no physiologic or physical basis, it can be useful to compare the distribution of a drug with the volumes of the water com- At tight junctions, two partments in the body. adjoining cells merge so that the cells are physically joined and 1. Distribution into the water compartments in the body: Once a form a continuous wall drug enters the body, it has the potential to distribute into any one that prevents many of the three functionally distinct compartments of body water or to substances from Tight jjunction entering the brain. become sequestered in a cellular site. a. Plasma compartment: If a drug has a high molecular weight or is extensively protein bound, it is too large to pass through the C Permeability of a brain capillary slit junctions of the capillaries and, thus, is effectively trapped within the plasma (vascular) compartment. As a result, it has a low Vd that approximates the plasma volume or about 4 L in a Charged 70-kg individual. Heparin (see Chapter 22) shows this type of drug distribution. Lipid-soluble drugs b. Extracellular fluid: If a drug has a low molecular weight but Carrier-mediated is hydrophilic, it can pass through the endothelial slit junctions transport of the capillaries into the interstitial fluid. However, hydrophilic drugs cannot move across the lipid membranes of cells to enter the intracellular fluid. Therefore, these drugs distribute into a volume that is the sum of the plasma volume and the interstitial fluid, which together constitute the extracellular Figure 1.13 fluid (about 20% of body weight or 14 L in a 70-kg individual). Cross section of liver and brain Aminoglycoside antibiotics (see Chapter 39) show this type of capillaries. distribution.  Made with Xodo PDF Reader and Editor 12 1. Pharmacokinetics c. Total body water: If a drug has a low molecular weight and A is lipophilic, it can move into the interstitium through the slit junctions and also pass through the cell membranes into the Distribution Elimination intracellular fluid. These drugs distribute into a volume of about phase phase 60% of body weight or about 42 L in a 70-kg individual. Ethanol 4 exhibits this apparent Vd. 2. Apparent volume of distribution: A drug rarely associates Plasma concentration (Cp) 1 exclusively with only one of the water compartments of the body. Most drugs show an exponential decrease Instead, the vast majority of drugs distribute into several compart- in concentration with ments, often avidly binding cellular components, such as lipids 2 time during the (abundant in adipocytes and cell membranes), proteins (abundant elimination phase. in plasma and cells), and nucleic acids (abundant in cell nuclei). Therefore, the volume into which drugs distribute is called the 1 apparent volume of distribution (Vd). Vd is a useful pharmacokinetic parameter for calculating the loading dose of a drug. 0 3. Determination of Vd: The fact that drug clearance is usually a 0 1 2 3 4 Time first-order process allows calculation of Vd. First order means that IV bolus a constant fraction of the drug is eliminated per unit of time. This process can be most easily analyzed by plotting the log of the plasma drug concentration (Cp) versus time (Figure 1.14). The concentration of drug in the plasma can be extrapolated back to time zero (the time of IV bolus) on the Y axis to determine C0, Extrapolation to time which is the concentration of drug that would have been achieved if the distribution phase had occurred instantly. This allows calcu- B zero gives C0, the hypothetical drug lation of Vd as concentration 4 predicted if the 3 distribution had been Dose Vd = 2 achieved instantly. C0 Plasma concentration C0 = 1 For example, if 10 mg of drug is injected into a patient and the plasma concentration is extrapolated back to time zero, and C0 = 1 mg/L 0.5 (from the graph in Figure 1.14B), then Vd = 10 mg/1 mg/L = 10 L. 0.4 0.3 4. Effect of Vd on drug half-life: Vd has an important influence on 0.2 the half-life of a drug, because drug elimination depends on the t1/2 amount of drug delivered to the liver or kidney (or other organs 0.1 where metabolism occurs) per unit of time. Delivery of drug to the organs of elimination depends not only on blood flow but also on 0 1 2 3 4 the fraction of the drug in the plasma. If a drug has a large Vd, Time most of the drug is in the extraplasmic space and is unavailable to the excretory organs. Therefore, any factor that increases Vd can IV bolus increase the half-life and extend the duration of action of the drug. [Note: An exceptionally large Vd indicates considerable sequestra- tion of the drug in some tissues or compartments.] The half-life (the time it takes to reduce the plasma drug concentration by half) is equal to 0.693 Vd/CL. V. DRUG CLEARANCE THROUGH METABOLISM Once a drug enters the body, the process of elimination begins. The three major routes of elimination are hepatic metabolism, biliary elimination, Figure 1.14 and urinary elimination. Together, these elimination processes decrease Drug concentrations in plasma after the plasma concentration exponentially. That is, a constant fraction of the a single injection of drug at time = 0. drug present is eliminated in a given unit of time (Figure 1.14A). Most A. Concentration data are plotted on a linear scale. B. Concentration data are plotted on a log scale.  Made with Xodo PDF Reader and Editor V. Drug Clearance Through Metabolism13 drugs are eliminated according to first-order kinetics, although some, With a few drugs, such as aspirin, such as aspirin in high doses, are eliminated according to zero-order ethanol, and phenytoin, the doses are very large. Therefore, the plasma drug or nonlinear kinetics. Metabolism leads to production of products with concentration is much greater than Km, increased polarity, which allows the drug to be eliminated. Clearance and drug metabolism is zero order, that is, constant and independent of the (CL) estimates the amount of drug cleared from the body per unit of time. drug dose. Total CL is a composite estimate reflecting all mechanisms of drug elimi- nation and is calculated as follows: 100 CL = 0.693 × Vd / t1/ 2 Rate of drug metabolism m where t1/2 is the elimination half-life, Vd is the apparent volume of distribu- tion, and 0.693 is the natural log constant. Drug half-life is often used as a measure of drug CL, because, for many drugs, Vd is a constant. 50 A. Kinetics of metabolism 1. First-order kinetics: The metabolic transformation of drugs is catalyzed by enzymes, and most of the reactions obey Michaelis- 0 Menten kinetics. 0 Dose of drug Vmax [C] With most drugs the plasma drug concentration is less than Km, and v = Rate of drug metabolism = K m + [C] drug elimination is first order, that is, proportional to the drug dose. In most clinical situations, the concentration of the drug, [C], is much less than the Michaelis constant, Km, and the Michaelis- Menten equation reduces to Figure 1.15 Effect of drug dose on the rate of Vmax [C] metabolism. v = Rate of drug metabolism = Km That is, the rate of drug metabolism and elimination is directly pro- portional to the concentration of free drug, and first-order kinetics is observed (Figure 1.15). This means that a constant fraction of drug is metabolized per unit of time (that is, with each half-life, the concentration decreases by 50%). First-order kinetics is also referred to as linear kinetics. 2. Zero-order kinetics: With a few drugs, such as aspirin, ethanol, and phenytoin, the doses are very large. Therefore, [C] is much greater than Km, and the velocity equation becomes Vmax [C] v = Rate of drug metabolism = = Vmax [C] The enzyme is saturated by a high free drug concentration, and the rate of metabolism remains constant over time. This is called zero-order kinetics (also called nonlinear kinetics). A con- stant amount of drug is metabolized per unit of time. The rate of elimination is constant and does not depend on the drug concentration. B. Reactions of drug metabolism The kidney cannot efficiently eliminate lipophilic drugs that readily cross cell membranes and are reabsorbed in the distal convoluted tubules. Therefore, lipid-soluble agents are first metabolized into more  Made with Xodo PDF Reader and Editor 14 1. Pharmacokinetics Some drugs directly enter phase II metabolism. Oxidation, reduction, Conjugation Drug phase I and/or phase II products lic) (lipophilic) hydrolysis hydr (water solub soluble) (polar) (po Following phase I, the drug may be activated, Conjugated drug unchanged, or, most often, inactivated. is usually inactive. Figure 1.16 The biotransformation of drugs. polar (hydrophilic) substances in the liver via two general sets of reac- tions, called phase I and phase II (Figure 1.16). 1. Phase I: Phase I reactions convert lipophilic drugs into more polar molecules by introducing or unmasking a polar functional group, such as –OH or –NH2. Phase I reactions usually involve reduc- tion, oxidation, or hydrolysis. Phase I metabolism may increase, decrease, or have no effect on pharmacologic activity. a. Phase I reactions utilizing the P450 system: The phase I reactions most frequently involved in drug metabolism are cata- lyzed by the cytochrome P450 system (also called microsomal mixed-function oxidases). The P450 system is important for the metabolism of many endogenous compounds (such as ste- roids, lipids) and for the biotransformation of exogenous sub- stances (xenobiotics). Cytochrome P450, designated as CYP, is a superfamily of heme-containing isozymes that are located in most cells, but primarily in the liver and GI tract. CYP2E1 4% Nomenclature: The family name is indicated by the Arabic CYP2C19 number that follows CYP, and the capital letter designates 8% the subfamily, for example, CYP3A (Figure 1.17). A second number indicates the specific isozyme, as in CYP3A4. Specificity: Because there are many different genes that CYP2D6 CYP2C8/9 CYP1A2 encode multiple enzymes, there are many different P450 19% 16% 11% isoforms. These enzymes have the capacity to modify a large number of structurally diverse substrates. In addi- tion, an individual drug may be a substrate for more than one isozyme. Four isozymes are responsible for the vast majority of P450-catalyzed reactions. They are CYP3A4/5, CYP2D6, CYP2C8/9, and CYP1A2 (Figure 1.17). Considerable amounts of CYP3A4 are found in intestinal CYP2A6 mucosa, accounting for first-pass metabolism of drugs such CYP3A4/5 3% as chlorpromazine and clonazepam. 36% CYP2B6 Genetic variability: P450 enzymes exhibit considerable 3% genetic variability among individuals and racial groups. Variations in P450 activity may alter drug efficacy and the Figure 1.17 risk of adverse events. CYP2D6, in particular, has been Relative contribution of cytochrome shown to exhibit genetic polymorphism. CYP2D6 mutations P450 (CYP) isoforms to drug result in very low capacities to metabolize substrates. Some biotransformation. individuals, for example, obtain no benefit from the opioid  Made with Xodo PDF Reader and Editor V. Drug Clearance Through Metabolism15 analgesic codeine, because they lack the CYP2D6 enzyme Isozyme: CYP2C9/10 that activates the drug. Similar polymorphisms have been characterized for the CYP2C subfamily of isozymes. For COMMON SUBSTRATES INDUCERS instance, clopidogrel carries a warning that patients who are poor CYP2C19 metabolizers have a higher incidence Warfarin of cardiovascular events (for example, stroke or myocar- Phenytoin Phenobarbital Ibuprofen Rifampin dial infarction) when taking this drug. Clopidogrel is a pro- Tolbutamide drug, and CYP2C19 activity is required to convert it to the active metabolite. Although CYP3A4 exhibits a greater than 10-fold variability between individuals, no polymorphisms have been identified so far for this P450 isozyme. Isozyme: CYP2D6 COMMON SUBSTRATES INDUCERS Inducers: The CYP450-dependent enzymes are an important target for pharmacokinetic drug interactions. One None* Desipramine such interaction is the induction of selected CYP isozymes. Imipramine Xenobiotics (chemicals not normally produced or expected Haloperidol Propranolol to be present in the body, for example, drugs or environ- mental pollutants) may induce the activity of these enzymes. Certain drugs (for example, phenobarbital, rifampin, and Isozyme: CYP3A4/5 carbamazepine) are capable of increasing the synthesis of one or more CYP isozymes. This results in increased COMMON SUBSTRATES INDUCERS biotransformation of drugs and can lead to significant Carbamazepine Carbamazepine decreases in plasma concentrations of drugs metabolized Cyclosporine Dexamethasone by these CYP isozymes, with concurrent loss of pharma- Erythromycin Phenobarbital cologic effect. For example, rifampin, an antituberculosis Nifedipine Phenytoin Verapamil Rifampin drug (see Chapter 41), significantly decreases the plasma concentrations of human immunodeficiency virus (HIV) pro- tease inhibitors, thereby diminishing their ability to suppress Figure 1.18 HIV replication. St. John’s wort is a widely used herbal prod- Some representative cytochrome uct and is a potent CYP3A4 inducer. Many drug interactions P450 isozymes. CYP = cytochrome P. have been reported with concomitant use of St. John’s wort. *Unlike most other CYP450 enzymes, Figure 1.18 lists some of the more important inducers for CYP2D6 is not very susceptible to representative CYP isozymes. Consequences of increased enzyme induction. drug metabolism include 1) decreased plasma drug con- centrations, 2) decreased drug activity if the metabolite is inactive, 3) increased drug activity if the metabolite is active, and 4) decreased therapeutic drug effect. Inhibitors: Inhibition of CYP isozyme activity is an impor- tant source of drug interactions that lead to serious adverse events. The most common form of inhibition is through com- petition for the same isozyme. Some drugs, however, are capable of inhibiting reactions for which they are not sub- strates (for example, ketoconazole), leading to drug inter- actions. Numerous drugs have been shown to inhibit one or more of the CYP-dependent biotransformation pathways of warfarin. For example, omeprazole is a potent inhibi- tor of three of the CYP isozymes responsible for warfarin metabolism. If the two drugs are taken together, plasma concentrations of warfarin increase, which leads to greater anticoagulant effect and increased risk of bleeding. [Note: The more important CYP inhibitors are erythromycin, ketoconazole, and ritonavir, because they each inhibit several CYP isozymes.] Natural substances may also inhibit drug metabolism. For instance, grapefruit juice inhibits CYP3A4  Made with Xodo PDF Reader and Editor 16 1. Pharmacokinetics and leads to higher levels and/or greater potential for toxic effects with drugs, such as nifedipine, clarithromycin, and simvastatin, that are metabolized by this system. b. Phase I reactions not involving the P450 system: These include amine oxidation (for example, oxidation of catechol- amines or histamine), alcohol dehydrogenation (for example, ethanol oxidation), esterases (for example, metabolism of aspirin in the liver), and hydrolysis (for example, of procaine). 2. Phase II: This phase consists of conjugation reactions. If the metabolite from phase I metabolism is sufficiently polar, it can be excreted by the kidneys. However, many phase I metabolites are still too lipophilic to be excreted. A subsequent conjugation reac- tion with an endogenous substrate, such as glucuronic acid, sulfu- ric acid, acetic acid, or an amino acid, results in polar, usually more water-soluble compounds that are often therapeutically inactive. A notable exception is morphine-6-glucuronide, which is more potent than morphine. Glucuronidation is the most common and the most important conjugation reaction. [Note: Drugs already possessing an –OH, –NH2, or –COOH group may enter phase II directly and become conjugated without prior phase I metabolism.] The highly Free drug enters polar drug conjugates are then excreted by the kidney or in bile. 1 glomerular filtrate VI. DRUG CLEARANCE BY THE KIDNEY Bowman Drugs must be sufficiently polar to be eliminated from the body. Removal capsule of drugs from the body occurs via a number of routes, the most important being elimination through the kidney into the urine. Patients with renal Active dysfunction may be unable to excrete drugs and are at risk for drug accu- 2 secretion Proximal mulation and adverse effects. of drugs tubule A. Renal elimination of a drug Elimination of drugs via the kidneys into urine involves the processes Loop of Henle of glomerular filtration, active tubular secretion, and passive tubular reabsorption. 1. Glomerular filtration: Drugs enter the kidney through renal arter- Passive Distal 3 reabsorption tubule ies, which divide to form a glomerular capillary plexus. Free drug of lipid-soluble, (not bound to albumin) flows through the capillary slits into the unionized Bowman space as part of the glomerular filtrate (Figure 1.19). The drug, which has been Collecting glomerular filtration rate (GFR) is normally about 125 mL/min but concentrated so duct may diminish significantly in renal disease. Lipid solubility and pH that the intra- luminal concen- do not influence the passage of drugs into the glomerular filtrate. tration is greater However, variations in GFR and protein binding of drugs do affect than that in the perivascular space this process. 2. Proximal tubular secretion: Drugs that were not transferred into Ionized, lipid- the glomerular filtrate leave the glomeruli through efferent arterioles, insoluble drug into urine which divide to form a capillary plexus surrounding the nephric lumen in the proximal tubule. Secretion primarily occurs in the proximal tubules by two energy-requiring active transport systems: one for Figure 1.19 anions (for example, deprotonated forms of weak acids) and one for Drug elimination by the kidney. cations (for example, protonated forms of weak bases). Each of these  Made with Xodo PDF Reader and Editor VII. Clearance by Other Routes17 transport systems shows low specificity and can transport many compounds. Thus, competition between drugs for these carriers can Drug occur within each transport system. [Note: Premature infants and neonates have an incompletely developed tubular secretory mecha- nism and, thus, may retain certain drugs in the glomerular filtrate.] 3. Distal tubular reabsorption: As a drug moves toward the dis- tal convoluted tubule, its concentration increases and exceeds that of the perivascular space. The drug, if uncharged, may dif- fuse out of the nephric lumen, back into the systemic circulation. Drug Proximal Manipulating the urine pH to increase the fraction of ionized drug tubule in the lumen may be done to minimize the amount of back diffusion and increase the clearance of an undesirable drug. As a general rule, weak acids can be eliminated by alkalinization of the urine, Loop of whereas elimination of weak bases may be increased by acidifica- Henle tion of the urine. This process is called “ion trapping.” For example, a patient presenting with phenobarbital (weak acid) overdose can be given bicarbonate, which alkalinizes the urine and keeps the Distal tubule drug ionized, thereby decreasing its reabsorption. 4. Role of drug metabolism: Most drugs are lipid soluble and, without Passive reabsorption chemical modification, would diffuse out of the tubular lumen when of lipid-soluble, un the drug concentration in the filtrate becomes greater than that in the ionized drug Drug perivascular space. To minimize this reabsorption, drugs are modi- fied primarily in the liver into more polar substances via phase I and Phase I and II phase II reactions (described above). The polar or ionized conjugates metabolism are unable to back diffuse out of the kidney lumen (Figure 1.20). Ionized or polar metabolite VII. CLEARANCE BY OTHER ROUTES Drug clearance may also occur via the intestines, bile, lungs, and breast milk, among others. Drugs that are not absorbed after oral administration or drugs that are secreted directly into the intestines or into bile are elimi- nated in the feces. The lungs are primarily involved in the elimination of Figure 1.20 anesthetic gases (for example, isoflurane). Elimination of drugs in breast Effect of drug metabolism on milk may expose the breast-feeding infant to medications and/or metabo- reabsorption in the distal tubule. lites being taken by the mother and is a potential source of undesirable side effects to the infant. Excretion of most drugs into sweat, saliva, tears, hair, and skin occurs only to a small extent. Total body clearance and drug half-life are important measures of drug clearance that are used to optimize drug therapy and minimize toxicity. A. Total body clearance The total body (systemic) clearance, CLtotal, is the sum of all clear- ances from the drug-metabolizing and drug-eliminating organs. The kidney is often the major organ of elimination. The liver also contrib- utes to drug clearance through metabolism and/or excret