Pharmacokinetics

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Chapter 2 Pharmacokinetics

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

Basic Concepts

Drug Transfer

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

Drug Properties

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

Drug Formulations (Table 2-1)

Solid formulations (e.g., tablets, capsules, suppositories) must disintegrate to release the drug. Disintegration of the dosage form may be compromised under certain conditions (e.g., dry mouth caused by aging, disease, or concurrent drug treatment slows dissolution of nitroglycerin tablets). On the other hand, drugs may be specifically formulated to allow disintegration only in certain sections of the gastrointestinal (GI) tract (e.g., enteric-coated tablets disintegrate in the small intestine), for the purpose of protecting the drug from destruction by gastric acid of the stomach (e.g., erythromycin) or protecting the stomach from an irritant drug (e.g., enteric-coated aspirin). Tablets and capsules may also be formulated to slowly release drugs (controlled-release, extended-release, or sustained-release formulations) and prolong their duration of action. Sustained-release formulations are particularly useful for drugs that have very short durations of action (see Table 2-1).

Semisolid formulations include creams, ointments, and pastes. These formulations are generally for topical application to the skin and require liberation and diffusion of the drug across the skin.

Liquid formulations may be suspensions or solutions, which do not require disintegration of the formulation and thus are generally absorbed more readily than solid formulations. Suspensions or solutions are also advantageous for patients who cannot swallow tablets or capsules. Drugs in suspension are not dissolved in the liquid vehicle. Therefore, the drug must first dissolve before it can be absorbed. Drugs in solution are already dissolved. Consequently, solutions are generally absorbed more rapidly than suspensions. Drug solutions may also be administered directly into the bloodstream.

Polymer formulations are a special category of solid formulations that incorporate the drug into a matrix that then gradually releases the drug over a prolonged period of time or at specific locations. Examples include transdermal patches and drug-eluting stents. Novel polymer-based formulations for intravenous (IV) delivery are also being designed.

TABLE 2-1 Pharmacokinetic Characteristics of Different Drug Formulations

Drug Formulations	Examples	General Pharmacokinetic Characteristics
Solids	Tablets Capsules Powders Suppositories

For absorption:

Solid must disintegrate to release drug

Drug must dissolve into solution

For a drug intended for the sublingual or buccal route of administration, disintegration of solid may be an issue in patients with drymouth (e.g., elderly).

Slow disintegration may be designed into the drug formulation to produce extended-release formulations.

Solid formulations may be designed to disintegrate only at certain pH levels to protect the stomach from the drug (e.g., enteric-coated aspirin).

Semisolids

Drug must be liberated from the formulation

Drug must dissolve into solution

Drugs can be applied for local or systemic action.

For systemic action, drug must diffuse across skin or mucous membranes.

Liquids

Suspensions

Solutions

Drug in suspension must dissolve into solution.

Drug in solution is already dissolved.

Solutions are generally absorbed more quickly than suspensions.

Suspensions and solutions are useful for patients who cannot swallow tablets or capsules.

Solutions can be administered directly into the bloodstream.

Polymers

Transdermal patches

Drug-eluting stents

Drug is impregnated into a polymer matrix.

Drug diffuses out of the matrix, across a membrane to the site of action.

Duration of action is controlled by rate of release of the drug from the polymer.

With transdermal patches, the drug must diffuse through the skin to enter the circulation.

With drug-eluting stents, the polymer is coated onto the mesh of the stent. Drug diffuses out of polymer directly into surrounding tissue.

Drug Chemistry

The physical and chemical properties of a drug will influence its ability to traverse biologic membranes and to be dissolved and transported in biologic fluids.

Molecular size and shape. Smaller molecules are absorbed more readily. Drug shape affects affinity of the drug for carrier molecules or other binding sites such as plasma proteins or tissue. Drugs of similar structure may exhibit competition for such binding sites, which can affect their pharmacokinetics.

State of ionization. The nonionized form of drugs is more lipid permeable and therefore better able to diffuse across biologic barriers. The pK_a is a characteristic of the drug and reflects the pH at which the drug will be equally partitioned between the ionized and nonionized forms.

The lipid-water partition coefficient is an index of lipid solubility. Drugs with higher lipid-water partition coefficients will cross biologic membranes more quickly.

Effect of pH

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

For drugs that are weak acids, the following equation applies, where HA = drug with proton, which is therefore nonionized. H⁺ = proton, and A⁻ is the ionized drug.

Under basic conditions, weak acids are ionized to a greater extent (because the basic environment will shift the reaction to the right).

Under acidic conditions, weak acids are nonionized to a greater extent (because the acidic environment will shift the reaction to the left).

The greater the difference between the pH and the pK_a, the greater the degree of ionization or nonionization.

The relationship between the pH of the drug’s environment and the degree of its ionization is determined by the Henderson-Hasselbalch equation:

Henderson-Hasselbalch Equation Applied to Acidic Drugs

For drugs that are weak bases, the reverse is true compared with weak acids: HB⁺ = drug with proton, which is therefore ionized. H⁺ = proton, and B is the nonionized drug.

Under basic conditions, weak bases are nonionized to a greater extent (because the basic environment will shift the reaction to the right).

Under acidic conditions, weak bases are ionized to a greater extent (because the acidic environment will shift the reaction to the left).

Again, the greater the difference between the pH and the pK_a, the greater the degree of ionization or nonionization.

The relationship between the pH of the drug’s environment and the degree of its ionization is determined by the Henderson-Hasselbalch equation:

Henderson-Hasselbalch Equation Applied to Basic Drugs

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

Figure 2-1 Effect of pH on drug ionization: ion trapping or pH trapping.

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

Figure 2-2 Application of pH trapping to renal drug elimination.

Absorption

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

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

The drug is highly ionized at gut pH (does not readily cross lipid barrier).

The drug is actively transported from the epithelial cell cytoplasm back into the gut lumen by drug transporters such as P-glycoprotein (e.g., cyclosporine).

The drug is extensively metabolized during its passage through the liver.

Figure 2-3 Factors affecting bioavailability of drugs.

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

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

Routes of Administration

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

Enteral Administration

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

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

Gastric emptying time. For most drugs the greatest absorption occurs in the small intestine owing to its large surface. More rapid gastric emptying facilitates their absorption because the drug is delivered to the small intestine more quickly. Conversely, factors that slow gastric emptying (e.g., food, anticholinergic drugs) generally slow absorption.

Intestinal motility. Increases in intestinal motility (e.g., diarrhea) may move drugs through the intestine too rapidly to permit effective absorption.

Food. In addition to affecting gastric emptying time, food may reduce the absorption of some drugs (e.g., tetracycline) owing to physical interactions with the drug (e.g., chelation). Alternatively, absorption of some drugs (e.g., clarithromycin) is improved by administration with food.

Intestinal metabolism and transport. The intestinal wall has extensive metabolic processes and transport mechanisms (e.g., P-glycoprotein) that affect absorption of drugs given via the oral route.

Hepatic metabolism. Orally administered drugs are absorbed into the portal circulation and carried directly to the liver. The liver has extensive metabolic processes that can affect drug bioavailability.

Rectal administration via suppositories to produce a systemic effect is useful in situations in which the patient is unable to take medication orally (e.g., is unconscious, vomiting, convulsing). Drugs are absorbed through the rectal mucosa. Because of the anatomy of the venous drainage of the rectum, approximately 50% of the dose bypasses the portal circulation, which is an advantage if the drug has low oral bioavailability. On the other hand, drug absorption via this route is incomplete and erratic, in part because of variability in drug dissociation from the suppository. Rectal administration is also used for local topical effects (e.g., antiinflammatory drugs in the treatment of colitis).

Sublingual (under the tongue) or buccal (between gum and cheek) administration is advantageous for drugs that have low oral availability because venous drainage from the mouth bypasses the liver. Drugs must be lipophilic and are absorbed rapidly. Buccal formulations can provide extended-release options to provide long-lasting effects.

Parenteral Administration

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

IV administration is the most reliable method for delivering drug to the systemic circulation because it bypasses many of the absorption barriers, efflux pumps, and metabolic mechanisms. In fact, by definition, bioavailability of drugs is 100% by IV injection because the drug is administered directly into the vascular space. It is also one of the preferred routes of administration to rapidly achieve therapeutically effective drug concentrations. IV infusions may be used to achieve a constant level of drug in the bloodstream. Drugs must be in aqueous solution or very fine suspensions to avoid the possibility of embolism. Caution must be used with drugs or drug combinations with the propensity to form precipitates.

IM administration of drugs in aqueous solution results in rapid absorption of drug in most cases. Drug absorption is dependent on muscle blood flow and thus is influenced by factors that alter blood flow to the muscle (e.g., exercise). It is also possible to achieve a slower, more constant absorption and effect of drug by altering the drug vehicle. Depot IM injections use drug formulation to slowly release drug at the site of injection.

SC administration is used for drugs that have low oral bioavailability (e.g., insulin). In addition, the rate of absorption can be manipulated by using different formulations of the drug (e.g., fast-acting versus slow-acting insulin preparations). This route is not appropriate for solutions that are irritating to tissue because these may produce necrosis and sloughing of the skin.

Transdermal administration is administration through the skin. The drug must be highly lipophilic. Drugs may be applied as ointments or in special matrices (e.g., transdermal patches). Absorption via this route is slow but conducive to producing long-lasting effects. Special slow-release matrices in some transdermal patches can maintain steady drug concentrations that approach those of constant IV infusion.

Inhalational administration can be used. The lungs serve as an effective route of administration of drugs. The pulmonary alveoli represent a large surface and a minimal barrier to diffusion. The lungs also receive the total cardiac output as blood flow. Thus, absorption from the lungs can be very rapid and complete. Drugs must be nonirritating and gaseous or very fine aerosols. The intended effects may be systemic (e.g., inhaled general anesthetics) or local (e.g., bronchodilators in the treatment of asthma).

Topical administration involves application of the drug primarily to elicit local effects at the site of application and to avoid systemic effects. Examples include drugs administered to the eye, the nasal mucosa, or the skin. Generally drugs are formulated to be less lipophilic to reduce systemic absorption.

Intrathecal administration penetrates the subarachnoid space to allow access of the drug to the cerebrospinal fluid of the spinal cord. This approach is used to circumvent the blood-brain barrier. Intrathecal administration is used to produce spinal anesthesia and in pain management and, in select cases, to administer cancer therapy.

Drug Distribution

After absorption into the bloodstream, drugs are distributed to the tissues via blood flow and diffusion and/or filtration across the capillary membranes of various tissues. Because the circulatory system is the main distribution mechanism and it is a readily accessible body compartment, plasma concentrations are used as an index of tissue concentrations in determining pharmacokinetics of drugs and in clinical management of drug therapy.

Initial Drug Distribution

Initial distribution is determined by cardiac output and regional blood flow.

Drugs are initially distributed to tissues with the highest blood flow (e.g., brain, lungs, kidney, and liver).

Tissues with lower blood flow (e.g., fat) receive drugs later.

Distribution to some tissue compartments is restricted by barriers.

The blood-brain barrier restricts distribution of hydrophilic drugs into the brain.

Drug Redistribution

After the initial distribution to high–blood flow tissues, drugs redistribute to those tissues for which they have affinity.

Drugs may sequester in tissues for which they have affinity. These tissues may then act as a sink for the drug and increase its apparent volume of distribution (see later). In addition, as plasma concentrations of drug fall, the tissue releases drug back into the circulation, thus prolonging the duration of action of the drug.

Effect of Drug Binding on Distribution

In addition to specific molecular targets, drugs show varying degrees of binding to different components in body compartments. These binding sites are not specific sites linked to coupling mechanisms. However, this type of binding can play an important role in a drug’s pharmacokinetic profile and in drug interactions.

Plasma Protein Binding

Plasma proteins, such as albumin, α-glycoprotein, and steroid hormone binding globulins, exhibit affinity for a number of drugs.

Binding to plasma protein is generally reversible and determined by the concentration of drug, the affinity of the protein for the drug, and the number of binding sites available.

Plasma protein binding greatly reduces the amount of drug free in the plasma.

Only free drug in the plasma is able to diffuse to its molecular site of action. Thus plasma protein binding can greatly reduce the concentration of drug at the sites of action and necessitate larger doses.

For highly protein-bound drugs, a small change in plasma protein binding can lead to a large change in the proportion of free drug in the plasma and may lead to toxicity.

For a drug that is 99% bound to plasma protein, only 1% is free in the plasma. Reduction of plasma protein binding to 98% results in a doubling of free drug and drug effect.

Changes in plasma protein binding can occur as a result of:

Disease

Competition between drugs for the same binding site

Saturation of binding sites

Volume of Distribution

The volume of distribution represents the theoretical volume in liters (therefore also called apparent volume of distribution) into which a drug is dissolved to produce the plasma concentration observed at steady state. Volume of distribution is calculated as the quotient of the amount of drug administered and the steady state plasma concentration (Figure 2-4).

Figure 2-4 Volume of distribution.

V_d will be affected by drug binding to different physiologic compartments.

V_d can be used to infer some characteristics of drug distribution.

V_d is largely determined by the chemical characteristic of the drug and its ability to interact with various tissue compartments.

V_d in excess of total body water (approximately 42 L) indicates that drug is being sequestered in a tissue compartment.

• Lipophilic drugs (e.g., thiopental) tend to sequester in fat.

• Some drugs bind with high affinity to certain tissues. Digoxin tends to bind to protein in skeletal muscle.

Water-soluble drugs have a V_d that approximates the total extracellular water (approximately 14 L).

Drugs that bind extensively to plasma proteins generally have a relatively small volume of distribution (e.g., 7 to 8 L) because these drugs will be highly restricted to the plasma.

Changes in V_d influence drug plasma concentrations and may necessitate changes in dosage or result in toxicity. For example, loss of skeletal muscle mass with aging or disease (heart failure) requires a reduction in the dose of digoxin, a drug that is highly bound to skeletal muscle protein. The dose of digoxin is often adjusted to lean body mass.

Drug Elimination

Drugs are eliminated from the body via two basic mechanisms: biotransformation (metabolism) and excretion. These processes are initiated as soon as the drug reaches the systemic circulation. Accordingly, elimination mechanisms also contribute to the plasma concentration profile of drugs.

Biotransformation (Metabolism)

Many drugs are lipophilic molecules that resist excretion via the kidney or gut because they can readily diffuse back into the circulation. Biotransformation is an essential step in eliminating these drugs by converting them to more polar water-soluble compounds. There are several different biotransformation pathways that drug molecules may follow (Figure 2-5). Biotransformation:

May convert drugs to inactive metabolites, thus terminating their actions

May convert drugs to active metabolites that may have the same or different beneficial actions as the parent drug

May convert inactive drug molecules (prodrugs) to active drugs

May convert drugs to reactive intermediates that exert toxic effects

Occurs in many tissues including the kidney, gut, and lungs, but for most drugs the liver is the major site of biotransformation

Factors affecting drug biotransformation include the following:

Interactions with other drugs or dietary substances

Aging, generally associated with a decrease in drug biotransformation

Disease, especially liver disease, which may reduce drug biotransformation

Genetic polymorphisms affecting biotransformation, which can result in loss of effectiveness or toxicity of a number of drugs

Figure 2-5 Drug biotransformation pathways.

Two major processes contribute to biotransformation of drugs.

Phase I Reactions

Phase I reactions are also called oxidation-reduction reactions or handle reactions.

These reactions uncover or add a reactive group to the drug molecule through oxidation, reduction, or hydrolysis.

They make the drug molecule more polar and more reactive, which facilitates excretion or further biotransformation of the drug through phase II reactions.

Oxidation

Oxidation accounts for a large proportion of drug metabolism.

It is mediated primarily by mixed function oxygenases (monooxygenases; microsomal mixed function oxidases) located in endoplasmic reticulum, which include the following:

Cytochrome P-450 (CYP) family of enzymes

Flavin monooxygenase family of enzymes

Hydrolytic enzymes (e.g., epoxide hydrolase)

The cytochrome P-450 family accounts for over 80% of drug oxidation. In this group of enzymes:

CYPs account for over 80% of drug oxidation.

Isoform family is indicated by a numeral (e.g., CYP3).

Isoform subfamily is indicated by capital letter (e.g., CYP3A).

Specific isoform is denoted by a numeral (e.g., CYP3A4).

CYP1, CYP2, and CYP3 families account for most drug metabolism.

CYPs are not substrate selective, meaning that many different drugs may be metabolized by one or more CYP isoforms, although there is generally one isoform that accounts for the majority of a given drug’s biotransformation.

Interaction at CYPs is an important pharmacokinetic mechanism that can affect clinical use of drugs. Knowledge of CYP isoforms involved in metabolism of drugs and the type of interaction can guide clinical selection of drugs and explain adverse drug interactions. Interactions may take the form of competition, inhibition, or induction.

• Competition between drugs that are substrates for the same CYP isoform, which may inhibit the biotransformation of each

• Inhibition of CYP isoforms by dietary substances or other drugs, which is a major mechanism of drug toxicity

• Inhibition of CYP activity will:

Generally increase plasma concentrations of substrate drugs, drug effect, and potentially drug toxicity

Decrease plasma concentrations of active drug and drug effect of prodrugs that rely on biotransformation to an active form (e.g., codeine must be metabolized to morphine for analgesic effect)

Often result from interaction between grapefruit juice and many drugs because compounds in grapefruit juice inhibit CYP3A4 and greatly increase bioavailability of drugs metabolized by CYP3A4

• Induction, a process by which expression and activity of the CYP enzyme are increased, such that other drugs are more extensively metabolized

• Induction of CYP activity will:

Generally decrease plasma concentrations of drugs and reduce their effectiveness

Generally increase the active form of prodrugs and increase their effect, possibly leading to toxicity

Increase reactive intermediates of drug metabolism that may contribute to drug toxicity (e.g., metabolism of acetaminophen biotransformation leads to formation of reactive intermediate associated with liver damage)

Examples of clinically important CYP isoforms include the following:

CYP1A2

• CYP1A2 is induced by smoking.

• Smokers require higher doses of drugs that are CYP1A2 substrates.

CYP2D6

• CYP2D6 exhibits genetic polymorphism.

• Approximately 10% of patients show reduced CYP2D6 expression and increased plasma concentrations of drugs that are CYP2D6 substrates.

• Important for metabolism of:

Antidepressants

Antipsychotics

Some narcotics (e.g., codeine)

CYP2C9

• CYP2C9 is important for metabolism of anticoagulants such as warfarin.

• Antifungal drugs are potent inhibitors.

CYP3A4

• CYP3A4 is the most abundant hepatic CYP (approximately 30% total).

• It has significant expression in the intestine.

• It is involved in metabolism of a wide spectrum of drugs.

• CYP34A is involved in many drug interactions; it is inhibited by:

Antidepressants

Antifungals

Macrolide antibiotics

For example, azole antifungals (e.g., ketoconazole) and macrolide antibiotics (e.g., erythromycin) inhibit CYP3A4, which may lead to accumulation of drugs that are CYP3A4 substrates (e.g., verapamil).

Non-CYP forms of oxidation also contribute to drug oxidation. Notable examples are the conversion of ethanol to acetaldehyde via alcohol dehydrogenase, and monoamine oxidase, which is responsible for biotransformation of catecholamines.

Reduction

Reduction quantitatively accounts for a much smaller proportion of drug metabolism; however, it is involved in biotransformation of some common drugs with low therapeutic indices. One example is nitroglycerin, a drug used in the treatment of angina.

Hydrolysis

Hydrolysis is mediated by enzymes such as hydrolases and esterases. Examples include the following:

Epoxide hydrolase is responsible for the degradation of highly reactive epoxide intermediates formed by CYP biotransformation. Thus epoxide hydrolases play an important protective role.

Cholinesterases degrade acetylcholine.

Phase II Reactions

Phase II reactions are also called conjugation reactions.

These reactions add a polar group, such as glucuronide, glutathione, acetate, or sulfate, to the drug molecule.

They increase the water solubility of compounds to facilitate excretion.

Generally they inactivate the drug but in some cases can produce active metabolites (e.g., conversion of procainamide to N-acetylprocainamide).

Conjugation reactions can occur:

Directly with the parent drug molecule or

With a reactive intermediate generated by phase I reactions. In this case, conjugation reactions may play an important role in neutralizing reactive intermediates. For example, phase I metabolism of acetaminophen generates a reactive intermediate capable of producing liver damage. Generally, liver damage does not occur because the reactive intermediate is rapidly conjugated to glutathione. However, under conditions in which cellular glutathione levels are depleted or excessive doses of acetaminophen lead to such high levels of reactive intermediate that glutathione conjugation is overwhelmed, acetaminophen will cause liver damage.

Phase II reactions are also subject to genetic polymorphisms. Acetylation capacity is an important polymorphism. Approximately 40% to 50% of the population exhibits slow acetylation capacity (slow acetylators). In these patients, drugs that are biotransformed through acetylation (e.g., hydralazine, isoniazid, procainamide) exhibit slowed metabolism. Dosages of such drugs must be adjusted downward to account for slowed biotransformation in affected patients.

Drug Excretion

Drug excretion refers to the removal of drug from the body. Generally, only hydrophilic molecules are excreted effectively. Accordingly, drugs may be excreted as unchanged parent molecules if they are sufficiently hydrophilic. Lipophilic drugs must be biotransformed to hydrophilic drug metabolites to be excreted. Drug may be excreted via a number of routes, such as the kidney or in bile, sweat, and breast milk. The lungs are an excretion route by which volatile lipophilic substances (e.g., inhaled general anesthetics) can be excreted. Changes in excretion rates will affect the plasma concentration of drugs and their metabolites and thus play an important role in the design of drug regimens.

Renal Excretion

Renal excretion is quantitatively the most important route of excretion for most drugs and drug metabolites. Renal excretion involves three processes: glomerular filtration, tubular secretion, and/or tubular reabsorption (Figure 2-6). The sum of these processes determines the extent of net renal drug excretion.

Glomerular filtration

The kidney filters approximately 180 L of fluid per day; thus there is a large capacity for drug excretion via this route.

The glomerular barrier restricts passage of plasma proteins, red blood cells, and other large blood constituents. Accordingly, drugs that are bound to these blood elements will not be effectively filtered.

Free drug in the plasma will be carried by bulk flow through the glomerulus into the renal tubules.

Factors influencing the amount of drug excreted by filtration include the following:

• Renal blood flow influences the rate of delivery of drug to the kidney.

• Glomerular filtration rate can be affected by disease or age. Glomerular filtration rate decreases by approximately 1% per year and may be significantly compromised in elderly patients. The decline in glomerular filtration rate is accelerated by disease states such as diabetes. For drugs that are eliminated by glomerular filtration, dosages are often adjusted based on the patient’s glomerular filtration rate.

Tubular secretion

Secretory mechanisms in the renal tubules actively transport endogenous substances and drug molecules from the plasma in peritubular capillaries to the tubular lumen.

Although quite diverse in some characteristics, the tubular transporters can be classified into two major groups: the organic anion transporter (OAT) and the organic cation transporter (OCT) families.

Members of the OAT and OCT families belong to the larger superfamilies of ATP binding cassette (ABC) transporters and the solute carrier proteins (SLCs).

Tubular transporters exhibit:

• Saturability. Transporters reach a maximum rate of excretion, after which further increases in drug concentration do not cause further increases in secretion.

• Overlapping substrate specificities. Multiple compounds may be transported via the same mechanism.

Compounds may compete for the same transporter.

Compounds may inhibit transporters.

Competition at, or inhibition of, the transporter results in decreased excretion and increases in plasma concentrations of substrate drugs.

Tubular secretion is:

• Especially important for drugs that are highly plasma protein bound, because these drugs are not excreted effectively by glomerular filtration.

• Important in delivering some drugs, such as diuretics, to their site of action in the renal tubule.

• Not affected by the degree to which a drug binds to plasma proteins.

• Manipulated clinically via the use of inhibitors to extend the duration of action and increase the plasma concentration of drugs that are rapidly excreted by tubular secretion. For example, the drug probenecid blocks the OAT transporter responsible for secretion of some penicillin and cephalosporin antibiotics into the renal tubule. Probenecid can be prescribed along with antibiotics in the penicillin and cephalosporin families to prolong their duration of action.

• Reduced in neonates, infants, and the elderly.

• Affected by genetic polymorphisms in the OAT and OCT family of transporters.

Tubular reabsorption

Once in the renal tubule, the nonionized form of the drug is able to diffuse across the tubular membrane and reenter the plasma.

As water is reabsorbed along the renal tubule the tubular drug concentration increases, providing a concentration gradient favoring drug reabsorption.

Manipulation of the pH of the tubular fluid can be used to enhance or inhibit tubular reabsorption according to the Henderson-Hasselbalch relationship. Acidification of urine can be used to decrease reabsorption of weak bases by increasing the proportion of drug in the ionized form. Conversely, alkalinization of urine can be used to increase the renal excretion of acidic drugs because a greater proportion of the drug is in the ionized form.

Figure 2-6 Renal mechanisms in drug excretion.

Biliary Excretion

Biliary excretion involves active secretion of drug molecules or their metabolites from hepatocytes into the bile. The bile then transports the drugs to the gut, where the drugs are excreted. The transport process is similar to those described for renal tubular secretion. The efficiency of biliary excretion is quite variable. Although many drugs may reach the gut through this route, deconjugating enzymes in the gut and the gut pH cause many drugs to assume nonpolar lipophilic forms that then are promptly reabsorbed by diffusion into the plasma. This process is referred to as enterohepatic cycling. Drugs that undergo extensive enterohepatic cycling generally have long durations of action.

Pulmonary Excretion

Pulmonary excretion is important for gaseous lipophilic substances. The gaseous general anesthetics are the most common example. Drug diffuses from the plasma into the alveolar space and is excreted during expiration.

Excretion via Breast Milk

Breast milk is a quantitatively relatively minor route of drug excretion. Nevertheless, it is clinically important for breastfeeding mothers and their infants. The baby will ingest drugs excreted in the breast milk. Moreover, breast milk has a lower pH than plasma. Accordingly, basic drugs will be concentrated in the breast milk through the phenomenon of ion (pH) trapping. A number of drugs can reach clinically significant concentrations in the breast milk and thereby affect nursing babies.

Clinical Pharmacokinetics

The ultimate goal of pharmacotherapy is to produce drug concentrations at the site of action that exert beneficial effects with minimal adverse effects. In most cases, drug concentrations at the site of action are not known directly but are inferred from plasma concentrations. Clinical pharmacokinetics uses mathematical modeling to predict the plasma drug concentration to better manage pharmacotherapy. This is particularly important for drugs with low therapeutic indices, where even minor changes in pharmacokinetics could lead to toxicity. Knowledge of pharmacokinetic variables is not quite as critical for (safer) drugs with large therapeutic windows, because toxic concentrations far exceed effective concentrations. Nevertheless, a general grasp of pharmacokinetic principles is invaluable in understanding dosages, dosing intervals, and duration of drug action.

Plasma Concentration Curves

Plasma concentration curves depict the plasma concentration of drugs over time (Figure 2-7). These curves are useful in illustrating several important principles. Although the different phases of the plasma drug profile will be discussed sequentially, it is important to note that the processes of absorption, distribution, and elimination occur simultaneously. As soon as a drug reaches the systemic circulation (absorption), it is also being distributed and eliminated.

Plasma concentrations that exceed the minimally therapeutic concentration will exert a pharmacologic effect. The point at which plasma concentrations exceed this level represents the onset of action of the drug. The duration of action of the drug is the time over which the plasma concentrations exceed the minimally therapeutic concentration. Plasma concentrations that exceed the minimally toxic concentration will produce toxic effects. An important goal of pharmacotherapy is to maintain plasma concentrations between the minimally therapeutic and minimally toxic concentrations.

IV administration delivers drug directly to the systemic circulation. If given as a single bolus injection, drugs will reach their peak concentration immediately. Subsequently, plasma concentrations will decrease rapidly as drug is distributed to various tissues. This is the so-called alpha (α) or redistribution phase. The plasma concentration profile then enters a phase of slower monoexponential decay that reflects predominantly elimination of the drug and is called the beta (β) or elimination phase. Plasma sampling for drug-monitoring purposes is generally performed in the β phase, because plasma concentrations in this stage are deemed to be representative of the drug concentrations at the site of action.

Oral or other nonvascular routes of administration result in a delayed peak plasma concentration.

The rate of absorption and bioavailability of the drug determine the magnitude and time of peak drug concentration. Slower absorption will result in reduced peak concentration and increased time to peak concentration.

The area under the plasma concentration curve (AUC) reflects the total amount of drug absorbed.

Distribution also affects this plasma profile, but the effects are not as evident because absorption and distribution occur at the same time.

Figure 2-7 Plasma concentration curves.

The Drug Elimination or β Phase

Although drug elimination via biotransformation and excretion begin as soon as the drug reaches the circulation, as absorption and distribution end, elimination dominates the latter stages of the plasma concentration profile.

Elimination Kinetics

Drug elimination is the summation of the processes described earlier. Drug elimination proceeds in two types of time dependent patterns: first-order kinetics and zero-order kinetics.

First-Order Kinetics

When drug elimination proceeds by first-order kinetics, a constant proportion or fraction of drug is eliminated per unit time (e.g., 25%/hr). As a result, plasma drug concentrations decline exponentially. This occurs because the elimination mechanisms adjust their activity to the prevailing drug concentration. When drug concentrations increase, elimination mechanisms can accept more drug. Conversely, when plasma concentrations decline, the elimination mechanisms process less drug. Important: as long as elimination proceeds by first-order kinetics the fraction of drug eliminated per unit time remains constant regardless of the starting concentration. An example is shown in Figure 2-8. In this example 50% of the drug is eliminated in 1 hour. One hour after the peak concentration of 16 mg/mL, the drug concentration is 8 mg/mL. After 1 additional hour, the plasma concentration has been reduced to 50% of 8 mg/mL, and so on for each additional hour. An important feature of first-order kinetics is that the proportion of drug eliminated is independent of the starting concentration. If the dose of drug was doubled and peak concentration reached 32 mg/mL, 50% of the drug would still be eliminated each hour. The constant proportionality of first-order elimination allows relatively accurate prediction of plasma concentrations over time. Doubling of the dose results in a doubling of plasma concentrations at any time point. As a result, for drugs that are eliminated by first-order kinetics:

The time to eliminate the drug is independent of dose.

Increasing dose or frequency of administration produces predictable rises in plasma concentrations.

Figure 2-8 Drug elimination: first-order kinetics.

Zero-Order Kinetics

Zero-order kinetics is also called saturation kinetics. In this case, elimination mechanisms become saturated and unable to process more drug when drug concentrations rise. Consequently, for drugs that are eliminated by zero-order kinetics, a constant amount of drug is eliminated per unit time (e.g., 5 mg/hr) regardless of drug plasma concentration. Plasma concentrations decline in linear fashion (Figure 2-9). As a result, a progressively smaller proportion of drug is eliminated as plasma concentrations increase. In other words, the proportion of drug eliminated depends on the starting concentration. Zero-order kinetics makes prediction of drug concentrations over time problematic. In the example shown in Figure 2-9, 4 mg/mL of drug is eliminated per hour. In the case of a dose that produced a starting concentration of 16 mg/mL, plasma concentrations will have declined to 4 mg/mL in 3 hours. However if the dose is doubled to achieve initial plasma concentrations of 32 mg/mL, after 3 hours plasma concentrations would be 20 mg/mL or 5 times higher than the lower dose at a comparable time, a much greater level than we would have predicted by doubling the dose. Thus, the effects of changing dosage can be quite unpredictable for drugs that are eliminated by zero-order kinetics. For drugs that are eliminated by zero-order kinetics:

The time to completely eliminate the drug is dependent on dose. This make repetitive administration complicated.

Increasing dose or frequency of administration can produce unpredictable increases in plasma concentrations.

Figure 2-9 Drug elimination: zero-order kinetics.

The majority of drugs are eliminated by first-order kinetics. For drugs that exhibit first-order kinetics, the β phase is used to obtain several important parameters (Figure 2-10).

Figure 2-10 Elimination rate constant for first-order kinetics.

Elimination Rate Constant (k_el, k_e)

First-order kinetics dictate that plasma concentrations fall exponentially during the elimination phase. It is typical to plot these data on a semilogarithmic scale to linearize the plasma concentration time curve. The slope of this curve is the elimination rate constant (k_el). The elimination rate constant describes the fraction of drug eliminated per unit of time or the rate at which plasma concentrations will decline during the elimination phase. For example (see Figure 2-10), if 25% of a drug were eliminated per hour, then k_el would be 0.25/hr. The value for k_el is estimated as the slope of the elimination phase of the plasma concentration curve. Note that k_el is independent of the dose or starting concentration for drugs that follow first-order kinetics. As long as elimination mechanisms are not saturated, in our example, 25% of the starting concentration will be eliminated per hour whether the starting concentration (dose) is 10 units or 100 units. The elimination rate constant (proportion per unit time) can be used to calculate the time necessary to eliminate a certain proportion of drug (inverse of rate constant). Clinically, a very useful time interval is the time necessary to reduce drug concentration by one half—in other words, the half-life.

Half-life (t_1/2) is the time for plasma concentrations to decline to one half their starting value. Half-life is calculated as:

where 0.693 is a constant derived from the natural log (ln) (because the decay is exponential for first-order kinetics) of the ratio of drug concentration at the beginning and end of one half-life, which by definition is 2 (100%/50%) (ln 2 = 0.693).

Thus the half-life is inversely related to the elimination rate constant because t_1/2 estimates the time needed to eliminate a specific proportion (50%) of drug. This makes the t_1/2 a very useful parameter that can be used to estimate the:

Time for the drug to be completely eliminated from the body. Four to five half-lives are necessary to reduce drug concentration by 95% to 97%.

Duration of action of the drug. The longer the half-life of the drug, the longer the plasma concentration of the drug will remain above the minimally effective concentration.

Time to achieve steady state. On continuous or repeated administration, approximately 4 to 5 half-lives are required to reach steady state.

Appropriate dosage interval to achieve steady state concentrations.

Because the half-life is derived from the k_el, half-life is also independent of dosage, as long as the drug is eliminated by first-order kinetics. In contrast, for drugs that exhibit zero-order kinetics (saturable elimination), half-life generally increases with dosage because a constant amount (not proportion) of drug is eliminated.

Clearance

Clearance is another index of the ability of the body to eliminate drug. Rather than describing the amount of drug eliminated, clearance describes the volume of plasma from which drug would be totally removed per unit time. Clearance can be visualized as the circulation consisting of units or packets of blood containing a given concentration of drug. Clearance removes all of the drug from a certain unit of plasma in a given period of time (Figure 2-11). Although somewhat difficult conceptually, clearance is very valuable practically. Having an idea of how much plasma is cleared of drug over time allows estimation of how much drug must be given to maintain a constant plasma concentration.

Clearance is expressed in units of volume and time (e.g., milliliters per minute). Because clearance is removal of drug from the circulation, clearance is related to the elimination rate constant and the apparent volume into which the drug is dissolved:

Figure 2-11 Clearance and drug administration.

Clearance is inversely related to half-life. Intuitively, the higher the clearance, the shorter the half-life and vice versa. Mathematically, clearance can be determined as follows:

Clearance can be used to calculate the rate at which drug must be added to the circulation to maintain the steady state plasma concentration or, in other words, the dosage rate. If you know what is going out, you can administer the same amount going in, and theoretically the plasma concentration should remain constant.

Administration Protocols

If a single administration of drug is given, plasma concentrations will rise to a peak and then fall to zero if another dose is not given. The challenge then is to design a protocol to maintain therapeutic drug concentrations, to avoid toxic drug concentrations, and to minimize fluctuations away from the desired drug concentration between administrations.

Continuous Administration

The most effective way to achieve a desired steady state drug concentration with minimal fluctuations is to administer the drug as a continuous infusion. Figure 2-12 illustrates that plasma drug concentrations begin to rise with the onset of an IV infusion because drug is continually delivered directly into the circulation. As plasma concentrations begin to increase with onset of the infusion, drug elimination will also begin to occur. Thus, simultaneously, drug is being added to the circulation and drug is being taken away. Plasma drug concentrations will continue to rise as long as the rate of drug delivery exceeds the rate of drug elimination until a point is reached at which the clearance of the drug from plasma is equal to the delivery of new drug into the plasma. At this point the rate of drug delivery equals the rate of elimination, and steady state has been achieved. This balance between drug in and drug out, or steady state, will be achieved in four to five half-lives. A change in the infusion rate will result in a change in the steady state plasma concentrations; however, the time to reach steady state will still be four to five half-lives. Plasma drug concentrations will remain stable unless the rate of infusion or the clearance is altered in some way (e.g., by induction of metabolic enzymes).

For direct administration into the circulation (e.g., IV route), the dosing rate is calculated as follows:

Figure 2-12 Continuous drug administration.

Rearranging this, the steady state plasma concentration can be estimated as a ratio of delivery over removal rate, or:

For other routes of administration, it is important to take into account the bioavailability of the drug. Accordingly, dosage rate is then calculated as follows:

Intermittent Administration

Although there are many examples in which continuous administration of drug is practiced, drugs are usually administered on an intermittent basis. Intermittent administration will result in much greater fluctuations in plasma drug concentrations. Plasma concentrations will rise in the absorptive phase to reach a peak and then decrease in the redistribution and elimination phases to reach a trough concentration until the next dose is given (Figure 2-13). In keeping with the general principle discussed earlier, stable average plasma drug concentrations will be reached when the amount of drug added in the next dose equals the amount eliminated during the interval between doses. For drugs that obey first-order kinetics, stable average drug concentrations will be achieved in 4 to 5 half-lives. Thus, the clinician must estimate a dose and administration interval to attain the desired steady state concentration of drug while once again minimizing the fluctuations in drug concentrations to avoid potential toxicity or lack of efficacy. An additional factor to consider is patient compliance. It would be possible to closely approximate a continuous infusion and very steady plasma concentrations using very small doses administered very frequently. However, most patients would not readily accept such a regimen. Thus dosage schedules should also be designed to provide convenient intervals to promote patient compliance. For intermittent dosage regimens:

The plasma concentration of drug is constantly changing, rising to a peak value sometime after absorption and falling to a trough value immediately before the next dose.

Accordingly, steady state concentrations are never truly achieved. Instead an average drug concentration between the peak and trough concentration is achieved.

Average drug concentrations will be determined by the size of the dose, the time between each dose (dosage interval), the bioavailability, and the clearance of the drug.

Figure 2-13 Intermittent drug administration.

Intuitively, as bioavailability and dose increase, so should the average concentration of drug in the plasma. Conversely as the interval between doses increases, the average concentration should decrease. Similarly, as clearance of drug increases, for any given dose and dosage interval, the average concentration should decrease.

In many cases, only a limited number of dosage strengths are available based on what is manufactured (only certain strengths of tablets are available). Thus, the clinician can adjust the dosage interval. Rearranging the previous equation, the dosage interval can be calculated as follows:

It is important to note that dose and dosage interval, the two variables most readily controlled by the physician, will affect the average drug concentration in the plasma and therefore the time to reach a therapeutic concentration. However, dose and dosage interval do not affect the time to reach a stable average concentration.

The time to reach a stable average concentration will be determined by clearance and half-life. As described earlier, 4 to 5 half-lives will be required to reach a stable average drug concentration regardless of the dose or dosage interval. In practice:

For a drug with a t_1/2 of 5 hours, stable average plasma concentrations will be obtained in about a day (20 to 25 hours).

Administering a drug at a dosage interval equal to the drug’s t_1/2 will result in peak drug concentration of approximately twice that of trough concentrations, or a twofold variation of concentrations between doses. Unless the drug has a low therapeutic index, this is generally an acceptable fluctuation in drug concentrations.

Figure 2-14 illustrates the effect of altering dosage intervals on a drug that is eliminated by first-order kinetics. Note that in all cases the initial dose produces approximately equivalent plasma concentrations. However, plasma concentrations at subsequent doses differ greatly based on how much time is available for drug elimination during the dosage interval. Halving the dosage interval (purple curve) approximately doubles the average plasma concentration. Peak concentrations of drug exceed the minimal toxic concentrations and may be associated with adverse effects. Conversely, when the dosage interval is doubled (yellow curve), the peak concentrations initially exceed the minimal therapeutic concentrations but fall below that level during the dosage interval. The average plasma concentration also falls below therapeutic levels, and the drug is not effective. In both cases, the time to achieve stable average concentrations is approximately 4 to 5 half-lives.