CHAPTER 148 · CHAPTER 148 Pharmacologic Principles AngelA A. SlAmpAk-CindriC IntroductIon Pharmacotherapy is an essential component of the successful treatment of the critically

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CHAPTER

148Pharmacologic PrinciplesAngelA A. SlAmpAk-CindriC

IntroductIon

Pharmacotherapy is an essential component of the successful treatment of the critically ill patient. Clinicians have access to an armamentarium of more than 10,000 prescription medica-tions, and critical care practitioners must be adept at under-standing the pharmacokinetic and pharmacodynamic principles of these medications to optimally care for their patients. Many agents employed in critical care therapeutics are affected by acute or chronic impairment of metabolic organs such as the liver, kidney, and lungs; changes in fluid balance; drug–drug and drug–nutrient interactions; and other factors.

The goal of pharmacotherapy is the attainment of a desired therapeutic response without untoward toxicity. To that end, herein we present principles that will be clinically useful in developing a practical approach to pharmacotherapy in the crit-ically ill patient. Pharmacokinetic principles, special population considerations, drug–drug interactions, adverse drug reactions (ADRs), and the role of the clinical pharmacist are reviewed.

PharmacokInetIcs and PharmacodynamIcs

Pharmacokinetics can be defined as the quantitative study of the processes of absorption, distribution, metabolism, and elimina-tion of a drug in the body (1). The use of mathematical models describing these processes allows predictions to be made about drug concentrations in various parts of the body as a function of dosage, route of administration, clearance, and time.

Pharmacodynamics is the study of the relationship between the concentration of a drug and the biochemical or physiologic response obtained by that drug in a given patient (2). Some drugs exhibit a linear dose–response relationship through the entire range of clinically used doses; that is, doubling the dose doubles the response. Others may exhibit a linear dose–response relationship to a response ceiling, where increases in drug dose do not elicit any additional response. Some agents do not behave in a linear fashion at all. A decrease in heart rate during β-antagonist or calcium channel antagonist therapy and decrease in ectopy during antiarrhythmic therapy are examples of quantifiable pharmacodynamic measurements. Some phar-macodynamic responses are more difficult to measure, such as the response to corticosteroid or anticonvulsant therapies.

A pharmacokinetic–pharmacodynamic relationship exists in most cases, as demonstrated in Figure 148.1. Free or unbound drug in the plasma is considered to be the pharmaco-logically active component in achieving efficacy or producing toxicity, because it crosses tissues and elicits a pharmacody-namic response. The free drug fraction is also the portion available to be metabolized and eliminated.

Pharmacokinetics

As stated, pharmacokinetics is the study of the absorption, dis-tribution, metabolism, and elimination of drugs. Much of our knowledge of this subject has resulted from the development of sensitive and specific assays for determining drug concen-trations in biologic fluids. Conceptual models and mathemati-cal equations have been devised to describe these behaviors (3); however, the pharmacokinetic parameters described in the literature often are based on data from small numbers of patients or normal volunteers, which may not accurately reflect the behavior of a drug in a critically ill patient. In indi-vidualizing a patient’s drug therapy, appropriate interpretation of accurately obtained plasma level measurements of a given drug in a specific patient provides significantly more informa-tion than any empiric calculation could provide.

The simplest pharmacokinetic model describes the body as a singular “compartment” or one-compartment model. Drugs enter the compartment at rates determined by routes of administration (e.g., intravenous [IV] bolus, IV infusion, intramuscular, oral, or transdermal) and leave the compartment at rates determined by routes of elimination (e.g., renal, hepatic, or pulmonary).

A two-compartment model reasonably describes the behav-ior of most drugs in humans (4). In this model, a small central compartment consists of the rapidly perfused organs (heart, lungs, kidney, and endocrine glands), and a larger peripheral compartment consists of the less rapidly perfused organs (skin, muscle, bone, and fat). After administration, drugs initially dis-tribute into the central compartment and then redistribute into the peripheral compartment, reaching equilibrium between compartments at a rate dependent on the perfusion of periph-eral compartment tissues and the tissue affinity for the drug.

The two-compartment model assumes that the drug obeys first-order, or linear, kinetics in which a constant proportion of the drug is removed per unit of time. Rate of elimination of the drug is proportional to the serum concentration and dimin-ishes logarithmically over time. However, the fraction of drug removed per unit of time remains constant and independent of dose. In first-order elimination, both clearance and volume of distribution also remain constant. Thus, serum concentration can be affected by changing the dose in relation to the desired change in concentration; in the simplest terms, doubling the dose doubles the concentration.

Some drugs follow zero-order kinetics, in which a constant amount of drug is eliminated per unit of time, irrespective of serum concentration. Other medications obey nonlinear or saturable kinetics; drugs having saturable kinetics exhibit capacity-limited metabolism; and elimination may not be pro-portional to serum concentration. For example, phenytoin exhibits Michaelis–Menten kinetics and demonstrates linear elimination to a point where the patient’s hepatic enzyme sys-tem is functioning at the maximum rate. Subsequently, phenyt-oin serum levels increase out of proportion to dose, meaning

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CHAPTER 148 pharmacologic principles e423

an increase in dose from 300 to 400 mg/d may result in an exponentially greater increase in serum level.

In first-order kinetics, a plot of the logarithm of serum con-centration after initial distribution versus time is a straight line. As seen in Figure 148.2, the IV injection of a drug results in an initially high serum drug concentration, followed by a rapid decrease because of drug distribution. After the distribution (or alpha) phase, the serum concentration further decreases because of the drug elimination (or beta) phase. At any point in time, the serum drug concentration (Cs) can be calculated from the biexponential disappearance function:

Cs = Ae−αt + Be−βt

where α and β are the first-order rate constants for the alpha and beta phases, respectively (5).

Pharmacokinetic parameters of particular value in the application of pharmacokinetic principles to clinical practice include the volume of distribution, clearance, half-life, and bioavailability.

Volume of distribution (Vd) is the apparent volume of fluid in which a given dose would have to be distributed to achieve the observed serum concentration as mathematically described by the following equations:

Cs = dose/Vd or Vd = dose/Cs

Clinically, the volume of distribution is useful for esti-mating the initial loading dose required to achieve a desired serum concentration or for calculating an incremental bolus dose required to raise a serum level by a desired amount. For instance, theophylline has a volume of distribution of approxi-mately 0.5 L/kg in most patients; thus a 60-kg person would have an apparent volume of distribution of 30 L. If the desired serum concentration is 15 mg/L, the loading dose required to achieve this goal may be calculated as follows:

Dose = (Vd)(Cs) = (30 L)(15 mg/L) = 450 mg

Clearance (Cl) is defined as the volume of blood or serum from which all drug is removed per unit of time. Clearance can be affected by alterations in distribution, metabolism, or excretion. Specific issues relating to changes in clearance from impairment of renal or hepatic function are discussed later in this chapter. At steady state, the drug administration rate equals the drug elimi-nation rate (6). Based on this principle, drug clearance can be useful in determining the amount of drug required to maintain a therapeutic drug level. With an intravenously administered or completely absorbed oral agent, the steady-state serum concen-tration (Css) can be determined by the following equations:

Css = dose(dosage interval)(Cl)

Half-life (t1/2) is a function of both drug volume of distribu-tion and clearance:

t1/2 = (0.693)(Vd)

Cl

In most cases, this variable refers to elimination half-life, meaning the time required to reduce the initial serum con-centration by 50% after the initial distribution phase. The drug half-life can be useful in determining the amount of time

ABSORPTION

LOCUS OFACTION

“RECEPTORS”

SYSTEMICCIRCULATION

BIOTRANSFORMATION

TISSUERESERVOIRS

EXCRETION

Bound Free

Free Drug

Bound Drug

Bound

Metabolites

Free

FIGure 148.1 Schematic representation of the interrelationship of the absorp-tion, distribution, binding, metabolism, and excretion of a drug and its con-centration at its locus of action. possible distribution and binding of metabolites are not depicted. (Adapted from Benet lZ, kroetz dl, Sheiner lB. pharmacokinet-ics: the dynamics of drug absorption, distribution and elimination. in: Hardin Jg, limbird le, gilman Ag, et al., eds. Goodman and Gilman’s The Pharma-cologic Basis of Therapeutics. 9th ed. new York: mcgraw-Hill; 1996:3.)

Time after dose (t)

Distribution

A + B

IV Bolus

Elimination

Ser

um

co

nce

ntr

atio

n (

CS)

B

CS = Ae–αt + Be–β

slope = β

slope = α

t ½ = 0.693β

β

t ½ = 0.693α

α

FIGure 148.2 Schematic graph of serum drug concentrations (Cs) plot-ted on a logarithmic scale versus time after a single intravenous bolus injection. (Adapted from greenblatt dJ, koch-Weser J. Clinical pharma-cokinetics. N Engl J Med. 1975;293:703.)

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e424 SECTion 18 pHArmACologY, nutrition, toxiCologY, And tHe environment

required to reach steady-state serum concentration. Four elim-ination half-lives are required to achieve approximately 94% of steady state. The time required to reach steady-state serum concentration is independent of dose and dosage interval. As seen in Figure 148.3, drug accumulation occurs with repeated dosing until equilibrium or steady state is reached at approxi-mately four to five half-lives. If, in this example, the desired pharmacologic response is observed at a serum concentration of 1 to 2 units, a period of time after the initiation of therapy exists during which the serum concentration is subtherapeu-tic. To attain therapeutic levels at the initiation of therapy, a loading dose may be given, followed by maintenance doses.

For example, digoxin has an elimination half-life of 36 hours in a patient with normal renal function. Therefore, a period of 6 days is required to achieve a steady-state drug level with daily dosing. If a loading dose of 1 mg is incrementally administered over 24 hours, therapeutic digoxin concentra-tions may be achieved more rapidly.

The bioavailability of a drug is defined as the fraction of a drug dose that reaches the systemic circulation. Bioavailability is a consideration primarily with orally administered agents. Absorption can be affected by many factors relating to the pharmaceutical dosage form (e.g., tablet, capsule, oral liq-uid, suspension, or sustained-release product), gastric pH and emptying time, intestinal motility, and drug complex forma-tion with other drugs or nutrients (7). Many orally absorbed drugs demonstrate a first-pass effect with significant metabo-lism in the liver before the drug enters the systemic circula-tion. Examples are propranolol, hydralazine, verapamil, and lidocaine. Lidocaine’s first-pass effect is so great that it must be administered by the parenteral route. For other drugs, such as propranolol and verapamil, oral doses need to be substan-tially higher than parenteral doses to account for this effect. For these drugs, the fraction of drug available to the systemic circulation or bioavailability (F) must be included in the calcu-lation of steady-state serum concentration as follows:

Css = (F)(dose)(dosage interval)(Cl)

Pharmacodynamics

Whereas pharmacokinetics is a detailed, often mathematical, approach to the way that the body handles a drug, pharma-codynamics is the discipline that defines the mechanisms of

action of medications and their biochemical and physiologic effects on the patient (8). Although frequently discussed sep-arately, in reality, pharmacokinetics and pharmacodynam-ics are closely interconnected. For example, along with the dosing regimen, the pharmacokinetic properties of a drug determine the concentration of that drug in the body, and in many situations, the drug concentration is directly related to the effects experienced by the patient. In addition, the degree of protein binding that a particular drug exhibits is typically considered a pharmacokinetic property. However, in many cases, it is only the unbound drug that is pharmaco-logically active and therefore responsible for the pharmaco-dynamic effects.

Drugs produce desired effects through various types of mechanisms of action. Some drugs demonstrate a relatively direct mechanism of action, such as mannitol administered for osmotic diuresis. When mannitol is administered intra-venously, the osmolarity of the blood and other body flu-ids is increased, causing shifts in the distribution of water. Other medications, such as epinephrine and β-blockers, act by agonizing or antagonizing physiologic receptors. The effect of the drug is, therefore, directly related to the physi-ologic action of the associated receptor. Continued stimu-lation of some receptors with agonists frequently results in a state of downregulation. In the intensive care unit (ICU), where exogenous catecholamines are commonly used, recep-tor downregulation is important given that the continued or subsequent exposure to the same concentration of a particu-lar agonist may have a lesser clinical effect over time. Other drugs, such as steroids, have very complex mechanisms of action involving crossing the cell membrane, regulating the transcription of specific genes, and ultimately altering pro-tein synthesis. A practitioner’s knowledge of the mechanisms of action and physiologic effects of medications will help in determining appropriate therapy, anticipating pharmaco-dynamic drug interactions, and monitoring for therapeutic success.

sPecIal PoPulatIons

Renal Impairment

Whether a pre-existing disease state or a new condition devel-oped in the ICU, renal dysfunction is often present in critically

0

1

2

2 4 6

CS

Time (multiples of elimination half-time)

Steady state• attained after approximately four half-times• time to steady state independent of dosage

Steady-state concentrations• proportional to dose/dosage interval• proportional to CL/F

Fluctuations• proportional to dosage interval/half-time• blunted by slow absorption

FIGure 148.3 Fundamental pharmacokinetic relationships for repeated administration of drugs. (Adapted from Benet lZ, kroetz dl, Sheiner lB. pharmacokinetics: the dynamics of drug absorption, distribution and elimination. in: Hardin Jg, limbird le, gilman Ag, et al., eds. Goodman and Gilman’s The Pharmacologic Basis of Therapeutics. 9th ed. new York: mcgraw-Hill; 1996:23.)

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ill patients. Reduced renal function may be related to a disease state, either iatrogenic or age related. Acute and chronic renal impairment can have profound effects on the pharmacokinet-ics and pharmacodynamics of many commonly used agents. In addition, the degree of renal dysfunction and resulting degree of fluid retention and uremia determine the degree of phar-macokinetic and pharmacodynamic changes. For example, a drug may exhibit no clinically significant changes in a patient with mild renal dysfunction, or the medication may be contra-indicated in a patient with renal failure. The practitioner must evaluate each drug individually in relation to the degree of renal dysfunction present.

Renal dysfunction has been shown to alter bioavailability, protein binding, volume of distribution, and excretion of cer-tain compounds (9). There are relatively few data providing details regarding the alteration of bioavailability of most drugs in patients with renal dysfunction. However, certain condi-tions that are more common among uremic patients, including a higher gastric pH, altered gastric emptying time, vomiting, and intestinal edema, are known to alter the absorption and bioavailability of enterally administered drugs.

The distribution of some drugs may also be significantly altered in renal dysfunction. Because patients with significant renal dysfunction have a higher percentage of their body mass as water, the apparent volume of distribution for water-soluble drugs is often increased. In addition, the protein binding of drugs is often altered in the presence of uremia, which changes the apparent volume of distribution. In general, the plasma protein binding of acidic drugs, like phenytoin, is decreased (10). Because there is a larger percentage of unbound (free) drug available for pharmacologic activity, uremic patients may experience toxicity with total drug concentrations in the therapeutic range. For this reason, some practitioners prefer to measure free phenytoin, instead of total phenytoin, concentra-tions in patients with renal failure. Altered tissue binding also may affect the apparent volume of distribution of a drug. For example, digoxin’s volume of distribution has been reported to be significantly reduced in patients with renal disease (11). As a result, in patients with renal dysfunction, digoxin load-ing doses should be used cautiously and serum concentrations should be monitored carefully.

The major pharmacokinetic effect seen in renal dysfunction is the impaired elimination of drugs and their metabolites by the kidney. Renal clearance of pharmacologic agents is com-plex, involving one or more of the processes of filtration, tubu-lar secretion, and reabsorption. Few drugs are excreted solely by glomerular filtration. Additionally, tubular secretion and reabsorption for many compounds may vary with the type of renal dysfunction and the administration of other agents (e.g., probenecid).

Clinicians must also consider that renal elimination in criti-cally ill patients is a very dynamic process. Renal function can deteriorate very quickly when patients are hemodynamically compromised. Additionally, many agents frequently used in critically ill patients may cause renal dysfunction; radiographic contrast media, aminoglycoside antibiotics, amphotericin B, nonsteroidal anti-inflammatory drugs (NSAIDs), and calci-neurin inhibitors are common examples (12). Changes in renal function may be acute or progressive and may or may not be reversible. Drug clearance requires constant reassessment in the ICU setting. It is essential to modify medication dosages in instances of renal compromise, and it is equally critical to

adjust dosages as patients experience renal recovery to avoid therapeutic failure from suboptimal doses.

In evaluating medication use in renal impairment, the first step is to estimate the degree of dysfunction. Most medica-tions that require dosage adjustment in patients with renal dys-function are adjusted based on creatinine clearance. Although many hospital laboratories now report estimated glomerular filtration rate (eGFR) along with serum creatinine values, the National Kidney Disease Education Program recommends the use of equations such as the Modification of Diet in Renal Disease (MDRD) Study Equation, the Chronic Kidney Dis-ease Epidemiology Collaboration (CKD-EPI) Equation, and the Cockrtoft-Gault Equation to estimate glomerular filtration rate and creatinine clearance to guide drug dosing (13).

When evaluating a medication profile, the intensivist must evaluate each drug individually and determine if a dosage adjustment or additional monitoring is necessary. Although, for many medications, the initial or loading dose does not need to be altered in renal dysfunction, maintenance dosing regi-mens may need to be adjusted by prolonging dosing intervals, reducing the standard maintenance dose, or both, depending on the individual medication and degree of renal dysfunction. In cases of drugs with a narrow therapeutic index, serum con-centrations should be monitored carefully to avoid potential toxicity. In general, steady state should be achieved before a serum concentration is obtained. If a therapeutic effect has not been achieved—as with uncontrolled seizures—or toxicity is suspected, an earlier sample may be warranted to assess the appropriateness of redosing or holding therapy. For example, in patients with normal renal function, a vancomycin trough level is typically obtained before the third or fourth dose; how-ever, in the setting of renal dysfunction, a trough level prior to the second dose may be beneficial to help determine the patient’s ability to clear the drug before further dosing.

In addition to the parent drug, practitioners must also con-sider the elimination route of any metabolites. For example, the active metabolite of morphine, morphine-6-glucuronide, is renally excreted and may exert important clinical effects when it accumulates in patients with renal failure (14). Although this does not prohibit the use of morphine in patients with renal dysfunction, practitioners may want to consider another agent, such as fentanyl, that does not have an active metabo-lite (15). If morphine is the preferred drug, a longer duration of action should be expected in a patient with renal impair-ment when compared to the same dose in a patient with nor-mal renal function. Frequent assessment of morphine use by pain score and sedation level should be planned.

Critical care practitioners must also be mindful of the effect of renal replacement therapy on drug clearance. The degree of drug clearance is determined by both drug-specific factors and the type of renal replacement therapy used. Drug-specific factors include molecular weight, solubility, degree of ion-ization, protein binding, and volume of distribution (9). For example, standard modes of dialysis are relatively ineffective in significantly clearing phenytoin, a highly protein-bound drug, from the body. However, more complicated techniques such as high-flux dialysis with charcoal hemoperfusion have been reported to remove considerable amounts of drug in a patient with phenytoin toxicity (16). Dialysis-specific factors that can affect the degree of drug clearance include the mode of dialysis, type of filter used, filter pore size, ultrafiltration rate, and blood and dialysate flow rates (17). As a general rule,

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peritoneal dialysis is less efficient in drug removal compared to intermittent hemodialysis and continuous renal replacement therapies (such as continuous venovenous hemodiafiltration) (9). Because of the potential complexity of drug dosing in the presence of renal replacement therapy, consulting a clinician or clinical pharmacist who is readily familiar with the phar-macokinetic implications of intermittent or continuous renal replacement is advisable.

Hepatic Disease

Like renal insufficiency, hepatic disease can also significantly alter the pharmacokinetic profile of a drug and the ultimate effect on the patient. Unfortunately, data relating the degree of hepatic dysfunction in relation to drug metabolism and elimination is limited, and dosage adjustment guidelines for hepatic dysfunction are available for a limited number of medications.

As patients with severe liver failure often suffer from sec-ondary gastrointestinal problems, the bioavailability of some orally administered drugs may be altered (18). Severe liver failure and cirrhosis have been associated with delayed gastric emptying and delayed absorption (18). For example, enteral furosemide has been shown to have delayed absorption in patients with mild and severe cirrhosis irrespective of the pres-ence of ascites (19). In addition, patients with cirrhosis are at increased risk for severe upper gastrointestinal tract bleeding, which can limit enteral medication tolerance (20).

Hepatic failure also affects the volume of distribution of some drugs. Patients with significant ascites comprise a larger portion of their body weight as water. Therefore, the volume of distribu-tion of hydrophilic drugs is increased (18). Most patients with significant liver dysfunction are also hypoalbuminemic, leading to a higher free fraction of highly protein-bound drugs.

Many factors influence hepatic drug clearance; however, the most significant characteristics are hepatic blood flow and enzyme activity. High-extraction drugs are significantly removed (>60%) during the first passage across the liver, and the clearance of these drugs is significantly dependent on hepatic blood flow (18). In significant liver disease, such as cir-rhosis, hepatic blood flow is decreased or totally shunted if por-tosystemic shunt is present (21). When a drug is administered enterally in these patients, drug enters the systemic circulation with minimal or no first-pass effect (22). Thus, the bioavailabil-ity of some orally administered drugs with extensive first-pass effect is greatly increased, and dosages should be appropriately reduced to prevent adverse side effects (23). Table 148.1 lists some of the high-extraction drugs that may be used in the ICU.

Low-extraction drugs are those that experience a relatively minimal first-pass effect (<30%), and initial bioavailability is not largely affected by liver disease (18). The clearance of hepatically metabolized, low-extraction drugs may be influ-enced by the effects of liver disease on the enzyme system responsible for the metabolic process. A reduction in the activity of drug-metabolizing enzymes in livers from cirrhotic patients is associated with increasing disease severity (24,25). However, a large variation in the degree of enzyme activity impairment exists, probably due to the heterogeneity of the enzymes involved in drug metabolism processes. Numerous enzymes are affected differently by liver disease. For example, oxidation reactions tend to be more sensitive than glucuroni-dation (26).

Low-extraction ratio drugs are less dependent on hepatic blood flow but are highly dependent on protein binding and the level of enzymatic capacity of the liver. These drugs are susceptible to changing clearance because of the induction or inhibition of liver enzymes and are sometimes referred to as enzyme limited or capacity limited (27). The hepatic clear-ance of some enzyme-limited drugs is termed binding sensi-tive or binding restrictive when only the circulating free drug is removed. Therefore, a decrease in drug binding causes an increase in the hepatic clearance of the drug. Drugs that are highly protein bound, such as phenytoin and warfarin, are most sensitive to this change in clearance.

Multiple factors determine the degree of impairment for the hepatic clearance of medications, and no comprehensive standard guidelines are available to aid practitioners in the dosage adjustments of these medications. In addition, most available data that addresses the effect of liver disease on drug clearance are from studies evaluating patients with a single-organ dysfunction (e.g., alcoholic cirrhosis); this is frequently not the case in critically ill patients. Therefore, any degree of other organ dysfunction, such as renal impairment or low cardiac output state, could further alter the pharmacokinet-ics and pharmacodynamics of the drug. The critical care team must initially evaluate the extent of organ dysfunction and determine if a dosage adjustment is likely to be needed, and then monitor the patient carefully for early signs of toxicity. When possible, blood concentrations of the affected medica-tions should be monitored and monitoring of the free drug concentrations may be preferred. Dosing recommendations may be available for some medications based on the Child–Turcotte–Pugh (CTP) score. The labeling guidelines of selected medications offer dosing guidelines based on the CTP score and an FDA guidance statement included its use for pharma-cokinetic studies in hepatic impairment (28). Clinicians should note that these recommendations are often based on chronic, rather than acute, liver failure. For medications without CTP-score-based recommendations, doses may be modified based

TABLE 148.1 High-Extraction Drugs Commonly Used in the Intensive Care Unit

Buspirone

Chlorpromazine

Cyclosporine

Fluvastatin

isosorbide dinitrate

labetalol

lovastatin

metoprolol

midazolam

morphine

nicardipine

propranolol

Quetiapine

Sertraline

Sildenafil

Sirolimus

tacrolimus

venlafaxine

verapamil

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on the basis of the drug’s protein binding and hepatic extrac-tion ratio.

Pregnancy

Pregnant women represent a subset of critically ill patients with unique needs and characteristics. Clinicians must con-sider maternal physiologic changes and assess the risks and benefits for both mother and fetus as they formulate treatment plans. Each subspecialty discipline must share their expertise with the intensivist team, and when possible, decisions should be made collaboratively with both the mother and fetus in mind. Even in the otherwise healthy pregnant female, deter-mining the optimal dosing regimen presents a considerable challenge due to the significant pharmacokinetic changes that occur during pregnancy.

Few gastrointestinal tract changes may affect drug absorp-tion during pregnancy (29). With the exception of the active labor period, gastric emptying time appears to be unchanged. However, due to a decrease in gastrin secretion, pregnant women have a higher gastric pH and slower intestinal motility (30); the clinical significance of these changes in relation to drug absorption is not known. Some women experience signif-icant nausea and vomiting, especially during the first trimester, which may affect their ability to tolerate some enteral medica-tions. Noxious stimuli of any kind should be minimized.

Unlike absorption, the volume of distribution of certain drugs can be significantly changed by pregnancy. Most impres-sively, blood volume increases by approximately 40% to 50% during pregnancy (31). The exception is patients with severe pre-eclampsia or eclampsia; blood volume may expand very little in this population (29). Changes in plasma protein con-centrations, such as a decrease in albumin concentration, can affect the free fraction of some drugs. Some examples of drugs that have a higher free fraction during pregnancy include diaz-epam, valproic acid, and phenytoin (32).

Pregnancy can also affect the metabolism and elimination of drugs as well. Interestingly, hepatic metabolism via the cyto-chrome P450 (CYP) system may be increased or decreased, depending on the specific enzyme. Pregnancy decreases the activity of CYP1A2 and CYP2C19. However, the activities of CYP3A4, CYP2D6, CYP2C9, and CYP2A6 are increased (30). The renal clearance of some medications is also signifi-cantly increased during pregnancy due to an increase in GFR of approximately 50% (30). For example, several β-lactam antibiotics, such as ampicillin, cefazolin, and piperacillin, have been shown to have increased clearance in pregnant women (33–35). Alterations in tubular secretion/reabsorption may also occur; however, few data are available in this area. Based on the available pharmacokinetic studies of renally excreted drugs, the effect of pregnancy on drug clearance varied widely from 20% to 65% above the clearance in nonpregnant women (30). For this reason, drugs that are primarily renally excreted unchanged may require a dosage increase of 20% to 65% to maintain prepregnancy blood concentrations (30).

In addition to pharmacokinetic changes that occur during pregnancy, the critical care practitioner must also consider other physiologic changes that may affect the patient’s need for drug therapy. For example, pregnant women are normally hypercoagulable and are at risk for venous thrombosis. The addition of other factors commonly seen in the ICU, such as immobility and endothelial injury, may put them at even

higher risk. Unfractionated heparin and low–molecular-weight heparins (LMWHs) are the drugs of choice for the prevention or treatment of thrombosis during pregnancy. Practitioners should be aware that many pregnant women require higher doses of heparin compared to nonpregnant counterparts due to increased concentrations of heparin-binding proteins, increased volume of distribution, and increased clearance (36). In fact, the dose required for therapeutic anticoagulation may be as much as twice the typical weight-based dose (37). LMWHs are considered to be a safe alternative to unfractionated hepa-rin during pregnancy, but their use in the acute setting for the treatment of venous thrombosis is controversial. Similar to unfractionated heparin, the clearance of LMWHs is increased during pregnancy, making dosing less straightforward than in the nonpregnant patient. Pregnant women have been shown to require higher than standard doses of LMWH to maintain goal antifactor Xa concentrations (37,38). Therefore, frequent monitoring of antifactor Xa concentrations is recommended, and multiple dosage adjustments may be required. With this increase in monitoring and related potential dosage adjust-ments, some argue that many of the advantages, both clinical and financial, of LMWHs are lost in this setting.

In summary, when the critical care practitioner is faced with determining the drug regimen for a pregnant woman, several steps should be taken. Most importantly, a multidisciplinary approach, including experts in the area of obstetrics and drug therapy, is invaluable. Next, the need to prescribe any drug must be carefully considered prior to the ordering process, and standard protocols should be modified as appropriate. Once the need for a drug is determined, the practitioner must con-sider the implications on fetal development and choose the safest drug available that will appropriately treat the mother. Historically, in considering the safety of a drug during preg-nancy, many practitioners referenced the drug package labeling or an information database to view the pregnancy risk factor category (A, B, C, D, or X) used by the U.S. Food and Drug Administration to classify risk. In December of 2014, the FDA published the Content and Format of Labeling for Human Prescription Drug and Biological Products; Requirements for Pregnancy and Lactation Labeling, otherwise known as the “Pregnancy and Lactation Labeling Rule” or PLLR. This rule, effective June 30, 2015, mandated modifications to both the content and format for prescription drug labeling to assist clini-cians in characterizing the relative safety of a medication during pregnancy and in counseling of pregnant and nursing mothers to empower them to make informed decisions. The pregnancy letter categories were removed, and the subsections of preg-nancy, labor and delivery, and nursing mothers were replaced by pregnancy, lactation, and females and males of reproductive potential. The pregnancy section was expanded and includes a risk summary, clinical considerations, data and information for a pregnancy exposure registry. The lactation subsection offers information about drug transfer into breast milk and potential implications for the infant. The women and men of reproduc-tive potential subsection include information about require-ments for pregnancy testing, contraceptive recommendations and information about infertility. The PLLR mandates that the labeling for prescription medications be updated when infor-mation is outdated. Labeling for over-the-counter medications has not changed and is unaffected by the new rule.

In addition to utilizing the information provided in a medi-cation’s package labeling, a thorough search for information

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should be conducted, and the current trimester of the preg-nancy should be considered. Some medications are safer for use during certain periods of the pregnancy. For example, NSAIDs are thought to carry the most risk during the first and third trimesters (39). In addition to primary literature, a medi-cal reference that specifically addresses medication use in preg-nancy should be consulted (39). Once a treatment has been chosen, the practitioner must also consider the physiologic changes during pregnancy that may necessitate dosage adjust-ment and utilize therapeutic drug monitoring when available.

adverse druG reactIons

The term ADRs encompasses a broad range of drug effects, ranging from exaggerated but predictable pharmacologic actions of the drug to toxic effects unrelated to intended pharmacologic effects (40). As such, the true incidence rate of ADRs is difficult to determine, with estimates ranging from 5% to 47% (41–43). There are patient specific as well as drug specific risk factors. Polypharmacy, the use of multiple medications or more medications than are clinically necessary, is likely the strongest risk factor. Clinicians must vigilantly monitor drug therapy regimens to minimize the number of medications, identify adverse outcomes early and discontinue offending agents as appropriate to optimize patient outcomes.

A small group of widely used drugs account for a dispropor-tionate number of ADRs. Aspirin, anticoagulants, diuretics, digoxin, antimicrobials, steroids, and hypoglycemic agents account for 90% of reactions (40).

The most frequent ADRs result from the exaggerated, but predicted, pharmacologic actions of the drug and, as such, are readily identifiable and often preventable. Examples include hemorrhagic complications caused by anticoagulants, or hypo-glycemia caused by oral hypoglycemic agents or insulin. The most important determinant for such adverse effects is an abnor-mally high drug concentration at the receptor site. This can occur for a variety of reasons, ranging from errors in adminis-tration, dose calculation, alterations in pharmacokinetics—such as reduction in the volume of distribution, rate of metabolism, or rate of excretion—or drug interactions resulting in increased concentration of free drug at the receptor site. Regardless of etiology, all have the potential to negatively impact the patient.

Other ADRs result from toxic effects unrelated to intended pharmacologic actions. Such events are, therefore, often unpredictable and frequently severe. Various mechanisms are involved: genetic, immunologic and nonimmunologic, or idiosyncratic. A list of genetic susceptibilities leading to ADRs with certain drugs is presented in Table 148.2. The most rel-evant examples are succinylcholine-induced prolonged apnea

(suxamethonium sensitivity) and drug-induced malignant hyperthermia (MH).

Succinylcholine is a depolarizing neuromuscular blocking agent that is rapidly metabolized by plasma pseudocholines-terase, with a normal duration of blockade (paralysis) of 2 to 4 minutes. Approximately 1 in 3,200 patients is homozygous for a defective pseudocholinesterase, which has an autosomal recessive transmission and demonstrates markedly prolonged block with succinylcholine in the range of 3 to 8 hours (44).

MH is a clinical syndrome of muscle rigidity, tachycardia, tachypnea, rapidly increasing temperature, hypoxia, hyper-capnia, hyperglycemia, hyperkalemia, hypercalcemia, lactic acidosis, and eventual cardiovascular collapse that occurs dur-ing, or after, general anesthesia (45). Several drugs have been implicated in triggering MH, particularly the halogenated inhalational agents (halothane, enflurane, and isoflurane), succinylcholine, and possibly an amino amide local anesthetic (lidocaine or bupivacaine) (46,47).

The cause of MH seems to be an inability of the sarco-plasmic reticulum of skeletal muscle to take up released myoplasmic calcium. When an MH episode is triggered, the myoplasmic levels of calcium rise tremendously, accelerating muscle metabolism and contraction, and leading to the clini-cal manifestations of the syndrome (45). The manifestation of MH may appear in the operating room or in the ICU shortly after the end of the surgical procedure.

Dantrolene is the cornerstone of therapy for MH (48). It reduces rigidity and restores muscle function by preventing calcium release from the sarcoplasmic reticulum and antago-nizes its effects on muscle contraction (49). Treatment of MH is initiated by discontinuing the anesthetic and other possible triggering agents, ventilating the patient with 100% oxygen, providing hemodynamic support as needed, and administering dantrolene. The mortality rate from the fulminant syndrome was approximately 70% before the use of dantrolene (50). With early recognition and optimal therapy, reported mortality rates decreased from 10% to 7% (50).

An immunologically mediated ADR is epitomized by the clas-sic anaphylactic reaction, which is IgE mediated, and a serum sickness–like condition. A similar reaction, but not immunolog-ically mediated, known as anaphylactoid reaction, is sometimes seen as an indirect histamine release from the mast cells by mor-phine, or a complement activation leading to mediator release from the mast cell and basophil by aspirin and radiographic contrast media. There are a host of drug reactions for which the exact underlying mechanism of toxicity is not well under-stood, which are termed idiosyncratic reactions. Every organ system can potentially be adversely affected by drug exposures. Of the multisystem manifestations of ADRs, drug fever, drug withdrawal reactions, and anaphylaxis are worth elaborating.

TABLE 148.2 Examples of Inherited Disorders Involving an Abnormal Response to Drugs

Disorder

Characteristic Suxamethonium Sensitivity Malignant Hyperthermia Warfarin Insensitivity

molecular abnormality pseudocholinesterase in plasma unknown Altered receptors

mode of inheritance Autosomal recessive Autosomal dominant Autosomal dominant

Clinical effects Apnea Hyperpyrexia, muscle rigidity inability to achieve anticoagulation

drugs producing abnormal response

Succinylcholine Halothane, succinylcholine, cyclopropane

Warfarin

From goldstein Jl, Brown mS. genetics and disease. Harrison’s Principles of Internal Medicine. 13th ed. new York: mcgraw-Hill; 1994:349, with permission.

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Drug-induced fever should always be considered in the workup of pyrexia in the ICU, and more so when no other obvious source is apparent. Fever is thought to be relatively rare as a primary or sole manifestation of a drug reaction and is usually associated with other hypersensitivity type reactions like anaphylaxis, serum sickness, rash, or eosinophilia. Yet, fever may be the only manifestation of an ADR. Antibiotics, cardiovascular drugs, and central-acting agents are the largest categories of drugs causing fever (51). Patients with hypersen-sitivity-induced drug fever have been observed to have fevers as high as 40°C and yet generally appear well, which can be an important clue to the presence of a drug-related fever (52).

Medication withdrawal can trigger fever. Opiate and benzodiazepine tolerance and dependence can develop over a short period. Subsequent attempts at withdrawing these medications may be associated with hypermetabolism and “sympathetic overdrive” characterized by fever, hypertension, mental confusion, seizures, and cardiac arrhythmias, a clinical picture that may be confused with an underlying disease pro-cess (53). Management consists of the gradual withdrawal of the drug and substitution of longer-acting agents; clonidine, a centrally acting drug, has been used with some success in these circumstances (54). The pathophysiology of anaphylac-tic shock from drug reactions has been described elsewhere in this text.

Mental confusion is a common problem in the ICU, and the etiology is often multifactorial (55). Drugs that have been reported to alter mood and increase mental confusion, especially in the elderly, include corticosteroids, histamine-2 receptor antagonists, fluoroquinolones, theophylline, barbi-turates, benzodiazepines, digoxin, antidepressants, penicillin, lidocaine, antihistamines, quinidine, opiates, and phenothi-azines. Occasionally, confusion is associated with discontinu-ation of one of the aforementioned medications if used for a long period of time. Drugs like imipenem–cilastatin have been implicated as an inducer or promoter of seizure-like activity (56).

Some of the antidysrhythmic drugs, particularly procain-amide, have a strong prodysrhythmic effect, and drug levels should be closely monitored during use. Torsade de pointes, a form of polymorphic ventricular tachyarrhythmia caused by drugs that can prolong the QTc interval (such as phenothiazines and tricyclic antidepressants), can be fatal. Treatment with IV magnesium and overdrive pacing has been used with some suc-cess to reverse cardiac arrest associated with this dysrhythmia.

Drug-induced renal injury remains a major cause of increased morbidity, and contributes to the overall mortality of the critically ill. The aminoglycoside antibiotics and radio-graphic contrast agents are the leading causes of acute nephro-toxicity in the ICU. Other risk factors that make patients prone to develop nephrotoxicity include advanced age, prior renal disease, intravascular volume depletion, simultaneous use of other nephrotoxic agents, and certain disease states such as con-gestive heart failure, liver cirrhosis, and diabetes mellitus (57).

Drugs can cause abnormalities in any of the formed elements of blood, which can lead to diagnostic confusion in separating these from primary disease processes. Drug-induced pancytope-nia, hemolytic anemia, thrombocytopenia, and granulocytope-nia all have been well described (57). Some of these conditions are more pertinent to ICU patients than others; heparin-induced thrombocytopenia (HIT) is an example. The mechanism is believed to be the induction of platelet-specific IgG antibody

by heparin, with subsequent aggregation of platelets caus-ing vascular thrombosis and fall in circulating platelets (58). Once the syndrome occurs, even trivial amounts of heparin can perpetuate the pathology. Heparin-containing flush solu-tions, indwelling catheters, and even heparin-coated pulmonary artery catheters have been reported to sustain the syndrome.

Generalized skin reactions of various forms occur as a part of a hypersensitivity reaction to various drugs. The drugs fre-quently involved are sulfonamides, the penicillins, and phe-nytoin. Of concern to intensivists are the three major types of drug-induced skin diseases with the potential for life-threatening complications, including erythema multiforme (Stevens–Johnson syndrome), toxic epidermal necrolysis, and exfoliative eryth-roderma (40). The lesions range from typical target-shaped eruptions to extensive bullous eruptions and large areas of skin sloughing. These conditions are usually associated with hypo-volemic shock, a hypercatabolic state, and multisystem organ dysfunction; the management is mainly supportive.

druG InteractIons

Conventionally, a drug interaction is regarded as the modifica-tion of the effect of one drug by prior or concomitant adminis-tration of another (59). Several textbooks (60–64) and reviews (65) have compiled extensive listings of potential interactions. Most drug interaction studies report on small numbers of non-critically ill patients or volunteers, and thus, extrapolation of these studies to the ICU setting is undesirable, possibly lead-ing to an unnecessary restriction of useful medications. This section reviews clinically significant drug interactions encoun-tered in the ICU.

Drug interactions can result from pharmacokinetic or phar-macodynamic causes. Pharmacokinetic interactions affect the process of drug absorption, distribution, metabolism, and excretion. Pharmacodynamic interactions alter the biochemical or physiologic effect of a drug.

Pharmacokinetic Interactions

Absorption

Many drug interactions affect the bioavailability of drugs through their effects on absorption. These include adsorption and formation of drug complexes, changes in gastric empty-ing time and pH, alteration in intestinal motility and mucosal function, and reduction in splanchnic perfusion. Phenytoin absorption has been found to vary with the type of enteral feeding (66). Anion exchange resins (cholestyramine), alumi-num-containing drugs such as sucralfate and antacids, kaolin pectin, activated charcoal, and iron-containing preparations impair the absorption of various drugs such as digoxin, war-farin, and levothyroxine by forming insoluble complexes. In response, the safest action is to not administer any oral medi-cation within 2 hours of administering these chelating agents. Many critically ill patients receive proton pump inhibitors (PPIs) or histamine-2 receptor antagonists (H2RAs) for stress ulcer prophylaxis; these agents may decrease the absorption of medications that require an acidic environment for absorption such as ketoconazole and dipyridamole.

Drug incompatibilities in IV preparations also can pres-ent as drug interaction or absorption problems. Precipitation

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or chemical alteration may occur before parenteral dosing. Knowledge of in vitro drug incompatibilities is, therefore, essential, and in-depth resources are available (66,67). The precipitation of phenytoin in glucose-containing solution is a relevant example (68).

Distribution

Many drugs circulate in the plasma partly bound to plasma proteins. Because the free or unbound serum concentration of a drug determines its biologic activity, changes in protein bind-ing induced by another agent can have an important effect on the drug’s pharmacologic response (69–72). Displacement from a protein of one drug by another depends on the con-centration and relative binding affinities of the drugs. A drug with a higher serum concentration and higher protein-binding affinity displaces a second drug more readily. For example, warfarin’s displacement by another drug can result in clini-cal bleeding complications. The acute elevation of free drug concentration in serum often is accompanied by an increased distribution to other tissues or increased elimination by metabolism and excretion until a new steady state is reached. Thus, when a new steady state is reached, the total drug level in the blood will be lower because of less protein-bound drug, whereas the free drug level will be in the therapeutic range. Individualization of drug therapy should be based on the clini-cal response or the plasma concentration of unbound drug, if available. Highly protein-bound drugs are particularly suscep-tible to these interactions (Table 148.3).

Metabolism

The metabolism of most drugs occurs largely in the liver. Quantitatively, the cytochrome P450 microsomal enzyme sys-tem containing mixed-function oxidases present in smooth endoplasmic reticulum is most important for initial metabolic conversion. The activity of these enzymes can be profoundly influenced by genetic factors and the coadministration of many drugs. These enzymes can be induced or inhibited by various agents (73,74).

Some common enzyme-inducing agents include the anti-convulsants, phenytoin, phenobarbital, and carbamazepine; ethanol and rifampin (Table 148.4). Cigarette smoking has been shown to be an excellent inducer of isoenzymes respon-sible for theophylline metabolism. Enzyme induction increases the rate of elimination of various drugs, leading to lower plasma levels (Table 148.5).

Several compounds (see Table 148.4) inhibit microsomal enzyme function, inhibiting the metabolism of many of the same drugs affected by enzyme induction (see Table 148.5). For

example, cimetidine is a potent inhibitor of oxidative metabo-lism of warfarin, quinidine, nifedipine, lidocaine, theophyl-line, and phenytoin. Erythromycin inhibits the metabolism of cyclosporine, warfarin, carbamazepine, and theophylline.

TABLE 148.3 Drugs with High Plasma Protein-Binding Affinity

digoxin

Hydralazine

nonsteroidal anti-inflammatory drugs

phenytoin

Quinidine

Salicylates

Sulfonamides

tolbutamide

valproic acid

Warfarin

TABLE 148.4 Drugs Commonly Affecting Metabolizing Enzymes in Liver

Inducing agentsAcetaminophen

Barbiturates

Carbamazepine

Cimetidine

Clonazepam

Cyclosporine

digoxin

glucocorticoids

methadone

metoprolol

phenytoin

Quinidine

rifampin

theophylline

Inhibiting agentsAllopurinol

Amiodarone

Chlorpromazine

Cimetidine

Ciprofloxacin

diltiazem

erythromycin

ethyl alcohol (acute)

inH

ketoconazole

oral contraceptives

propranolol

Quinidine

Sulfonamide

tolbutamide

trimethoprim

verapamil

From Chernow B, ed. The Pharmacologic Approach to the Critically Ill Patient. Baltimore, md: Williams & Wilkins, 1983, with permission.

TABLE 148.5 Drugs Commonly Affected by Enzyme-Inducing or Enzyme-Inhibiting Agents

Carbamazepine

Chlorpropamide

Cyclosporine

digoxin

glucocorticoids

lidocaine

metoprolol

phenobarbital

phenytoin

propranolol

Quinidine

rifampin

tolbutamide

theophylline

Warfarin

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Excretion

The most important route of drug excretion is renal and involves the processes of filtration, secretion, and reabsorption (75,76). All of these aspects of renal handling of compounds can potentially lead to drug interactions.

Several drugs, such as the aminoglycoside antibiotics, are eliminated almost completely by glomerular filtration. Furosemide, a potent loop diuretic, by causing intravascular volume depletion, can decrease renal perfusion pressure and filtration rate, thereby reducing elimination of gentamicin.

Many drugs are actively secreted in the proximal tubule. The most important of these agents include the organic acids, captopril, cephalosporins, sulfonamides, sulfonylureas, penicil-lins, diuretics, probenecid, and nonsteroidal anti-inflammatory agents. These compounds can block each other’s secretions, thus decreasing their urinary excretion. Further, quinidine decreases the tubular secretion of digoxin; the coadministra-tion of quinidine and digoxin approximately doubles the serum digoxin concentration. Inhibition of the tubular cation trans-port system by cimetidine impedes the renal clearance of pro-cainamide and its active metabolite, N-acetyl procainamide.

The reabsorption of filtered or secreted compounds occurs in the distal tubule or collecting duct as a function of drug con-centration, urinary flow, and pH of the urine. Alteration in distal urine pH can cause ion trapping of certain weak acids or bases and reduce passive reabsorption. Thus, alkalinization of urine by sodium bicarbonate facilitates the excretion of acidic drugs such as phenobarbital, salicylates, and amphetamines (40).

Lithium is reabsorbed with sodium in the kidney by the same renal mechanism. In cases of volume depletion from chronic diuretic use, renal increases in sodium and lithium reabsorption occur, leading to a potentially toxic lithium level (40).

Pharmacodynamic Interactions

Unlike pharmacokinetic interactions, pharmacodynamic inter-actions occur when a pharmacodynamic effect of one medi-cation affects the actions or effects of a second medication. As critically ill patients are frequently receiving many medica-tions for multiple indications, they are at high risk for these types of interactions. In some cases, pharmacodynamic inter-actions may be purposely used to achieve a desired therapeu-tic end point. For example, opioids and benzodiazepines are frequently used in combination to take advantage of their synergistic effects, possibly allowing for lower doses of each to be used (77,78). More frequently in the ICU, however, the pharmacodynamic interactions experienced are not desired and may lead to suboptimal therapy and adverse events.

Because of the numerous drug combinations and disease states that are seen in ICUs, the number of potential pharmacodynamic drug interactions is infinite and continues to grow as more medications are developed. For example, the chronic use of some antiepileptic medications may cause resistance to nonde-polarizing neuromuscular blocking agents due both to enzyme induction, a pharmacokinetic interaction, and an upregulation of acetylcholine receptors—namely, a pharmacodynamic inter-action (79). In addition, the fluoroquinolone gatifloxacin, ulti-mately withdrawn from the market, was reported to cause severe hypoglycemia when used in combination with oral hypoglyce-mic medications (80). Perhaps one of the most well-recognized pharmacodynamic interactions is the increased risk of torsade de

pointes and death when two drugs that are known to cause QT prolongation are used in combination (81).

The principles of pharmacokinetics and pharmacodynam-ics are key to optimizing drug therapy of all types. If practitio-ners are unfamiliar with a medication, they should investigate the pharmacokinetic and pharmacodynamic characteristics of that drug to avoid subtherapeutic or supratherapeutic dosing, maximize efficacy, and minimize adverse events. Practitioners must be particularly cautious in the ICU as critically ill patients frequently have some degree of organ dysfunction and require numerous medications.

the clInIcal PharmacIst’s role In crItIcal care

In the multidisciplinary approach to care of the critically ill patient, the pharmacist is an essential member of the ICU team (77–79). The impact of a pharmacist on the delivery of cost-effective care has been established in multiple settings, including the spectrum of ICUs (80–91). In addition to impacting econom-ics, the critical care pharmacist directly influences clinical out-comes. Pharmacist involvement in critically ill patient care has been associated with optimal fluid and neuromuscular blockade management as well as significant reductions in adverse drug events, medication errors, unnecessary serum drug measure-ments, and ventilator-associated pneumonia rates (92–104).

As outlined by the Society of Critical Care Medicine and American College of Clinical Pharmacy Task Force on Criti-cal Care Pharmacy Services position paper, fundamental criti-cal care pharmacist activities include prospective medication therapy evaluation; prevention, management, and reporting of adverse drug events; pharmacokinetic monitoring; drug infor-mation and education services; medication policy and procedure implementation and maintenance; cost-effectiveness analyses; and quality assurance measures and reviews (79). With depart-mental and service support, many critical care pharmacists par-ticipate in didactic and clinical teaching programs as well as clinical critical care pharmacotherapy research endeavors.

summary

Pharmacotherapy in the critically ill patient is extremely complex. A deep understanding of pharmacologic principles, special population considerations, impact of single or mul-tiple organ dysfunction, drug–drug interactions, and ADRs is paramount to optimize outcomes and minimize iatrogenic complications. Although the exact role and activities may vary in any given institution and patient population, the inclusion of a critical care pharmacist in daily patient care is recom-mended given the demonstrated cost savings and morbidity and mortality reductions.

• Knowledge of pharmacokinetic principles, drug–drug interactions, changes related to systemic diseases, and possible drug toxicities enables the critical care clinician to design an appropriate medication regimen.

key Points

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CHAPTER 148 · CHAPTER 148 Pharmacologic Principles AngelA A. SlAmpAk-CindriC IntroductIon Pharmacotherapy is an essential component of the successful treatment of the critically