Acs0823 Clinical Pharmacology

© 2006 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice
8 CRITICAL CARE 23 Clinical Pharmacology — 1

23 CLINICAL PHARMACOLOGY
Jennifer J. Bonner, Pharm.D., Robert R. Bies, Pharm.D., Ph.D., Robert Weber, M.S., F.A.S.H.P., and Samuel A.Tisherman,
M.D., F.A.C.S., F.C.C.M.

Modern surgical care is dependent on the use of drugs, many of which ability of a given drug in a given patient depends in large part on its
can be harmful as well as beneficial. Polypharmacy is the norm, and route of administration. Inadequate bioavailability is a not uncommon
as a result, there is a high potential for adverse interactions between cause of therapeutic failure.
agents. In addition, surgical patients often exhibit abnormalities in The absorption of a drug across any membrane or barrier is
drug metabolism, for various reasons. Overall, the incidence of drug- determined by blood flow to the area of absorption, the molecular
related adverse events in hospitalized patients is difficult to determine size of the drug, and the degree to which the drug is ionized. In crit-
precisely because the causality is often unclear. In one review,1 adverse ically ill patients, regional blood flow may be abnormal, and diffu-
drug events (defined as injuries caused by the use or nonuse of drugs) sion across tissues may be limited by the presence of edema. As mol-
or adverse drug reactions (defined as nonpreventable drug reactions ecular weight increases, diffusion decreases exponentially. The ion-
resultling from the appropriate use of drugs) occurred in approxi- ization of a drug can be estimated by means of the Henderson-
mately 2% to 6% of hospital admissions. These adverse occurrences Hasselbalch equation:
increased the duration of hospitalization by 1.2 to 3.8 days and
pH = pKa + log(base form/acid form)
increased hospital costs by $2,284 to $5,640. A better understanding
of pharmacokinetics and pharmacodynamics can help surgeons min- where pH represents the hydrogen ion concentration and pKa rep-
imize the potential for harm associated with the use of pharmacolog- resents the negative logarithm of the acid ionization constant. The
ic agents. ionized form of the drug is not lipid soluble and therefore does not
cross cell membranes by diffusion; in some cases, it may be actively
transported.
Definitions of Key Terms
Routes of Drug Delivery
Pharmacokinetics may be defined in several ways. The word itself
is a combination of the element pharmaco-, meaning “related to Intravenous Many drugs can be administered directly into the
drugs” (from the Greek word pharmakon “drug or poison”), and the systemic circulation. Intravenous (I.V.) administration, by definition,
word kinetics, meaning “the change in one or more variables as a func- yields a bioavailability of 100%, thereby rendering the issue of absorp-
tion of time,” as Wagner succinctly put it.2 In the discipline of phar- tion irrelevant. Systemic availability is most rapidly achieved when the
macokinetics, the variables in question relate to the time course and drug is administered by I.V. bolus (also referred to as I.V. push).This
character of the body’s absorption, distribution, metabolism, and mode of administration involves injecting small, concentrated vol-
excretion of drugs.3 (These four processes are often collectively umes of the drug directly into the vein, generally over a period of 1 to
referred to by the abbreviation ADME.) Pharmacokinetics, then, can 5 minutes (though slower rates are sometimes called for and often
be thought of as the study of the actions of the body on a drug admin- preferred). Not surprisingly, there are many drugs that cannot be
istered to it.The body’s pharmacokinetic handling of a drug depends administered by I.V. bolus, because of the potential for vein irritation
on many factors, including the chemical characteristics of the drug, and toxicity. With a few exceptions (e.g., propofol, which is given in
the dosage, the route of administration, the pharmaceutical formula- lipid emulsions), drugs are dissolved in aqueous solutions when
tion, and the physiologic characteristics and disease status of the administered I.V.
patient. Many drugs that cannot be given in an I.V. bolus can be adminis-
Pharmacodynamics can be thought of as the study of the actions of tered via I.V. infusion. Infusion may be either intermittent or contin-
a drug on the body.The variables in question relate to the time course uous, depending on the drug’s half-life or pharmacologic duration of
and character of a drug’s effect at its site of action (i.e., at a receptor action. For example, many antibiotics are administered via intermit-
or another binding site).To ensure adequate patient response and pre- tent I.V. infusion, whereas drugs such as propofol, fentanyl, and dobu-
vent complications during the perioperative period, surgeons should tamine are typically administered via continuous infusion.Volumes as
possess a thorough understanding of both pharmacokinetics and high as 1 L may be delivered via I.V. infusion; for most drugs, flow
pharmacodynamics. rates tend to be in the range of 2 to 3 ml/min. Use of precision infu-
sion pumps is preferred to manual control of the infusion.

Basic Pharmacokinetic Principles Oral Bioavailability is a critical consideration when a drug is
being administered orally because the rate and extent of absorption
ABSORPTION
from the gastrointestinal tract will have to be taken into account.The
Absorption is defined as the extent to which a substance moves into bioavailability of a drug after oral administration depends on three
the systemic circulation from its site of administration. The pharma- major variables: the fraction of the dose absorbed across the apical cell
cokinetic parameter that is generally used to quantify drug absorption membrane (i.e., the portion of the membrane bordering the intestinal
is bioavailability—that is, the fraction of an administered dose that lumen) into the cellular space of the enterocyte (fa), the intestinal first-
becomes systemically available (often abbreviated as F).The bioavail- pass extraction of the drug (EG), and the hepatic first-pass extraction


of the drug (EH).The relations among these factors may be described low-molecular-weight heparins (LMWHs). Generally, no more than
by the following equation4: 0.5 to 1 ml of a drug may be administered subcutaneously. Peri-
pheral edema or hypoperfusion may limit systemic absorption after
F = fa × (1 – EG) × (1 – EH)
subcutaneous injection.
Most drug absorption after oral administration occurs in the small
intestine.The value of fa depends on several factors, including the dis- Transdermal Although most topically administered drugs are
solution rate of the drug formulation (for drugs given in a solid form, meant to exert only local effects, some are meant to reach the sys-
such as a tablet or capsule), gastric motility and emptying rate, and temic circulation.To be systemically distributed after topical applica-
the solubility of the drug in GI fluids. Enteral feeding can also affect tion, drug molecules must pass through the stratum corneum and the
drug absorption. For example, tube feedings can impair absorption of epidermis to reach the blood vessels of the dermis. To traverse these
phenytoin.5 Drugs and surgery can affect intestinal motility. outer layers of the skin, the molecules must be lipophilic, of a low
Once a drug molecule is absorbed through the intestinal cell mem- molecular weight, and nonionized. Drugs that are administered trans-
brane, it may be subject to intestinal first-pass metabolism by dermally bypass both hepatic and intestinal first-pass metabolism and
enzymes within the cells, as well as by efflux pumps embedded with- are absorbed continuously for as long as any available drug remains
in the apical side of the cell membrane. Both cytochrome P-450 in the skin. Most transdermal patches are designed so that the rate of
(CYP) and UDP-glucoronosyltransferase (UGT) enzymes are found drug release is significantly slower than the rate of absorption through
in the small intestine.These enzymes contribute to the metabolism of the skin, thereby permitting gradual and continuous absorption into
certain orally administered drugs before they reach the systemic cir- the systemic circulation. Sometimes, a loading dose is contained in
culation. Drugs whose oral absorption is significantly affected by the the adhesive layer (as with the scopolamine patch for motion sick-
intestinal enzyme CYP3A4 include the immunosuppressive agents ness), allowing more rapid attainment of therapeutic blood levels.
cyclosporine, tacrolimus, and sirolimus; the calcium channel block- Examples of common transdermal formulations include the fentanyl
ers; and some HIV protease inhibitors. patch, which releases the drug over a 72-hour period, and the cloni-
P-glycoprotein (P-gp) is a large protein that is the product of the dine patch, which releases the drug continuously for 7 days.
multidrug resistance–1 (MDR1) gene. It is found on the apical mem- The main advantage of the transdermal method of administration
brane of enterocytes and acts as an efflux pump to remove exogenous is that it allows blood levels of a drug to be maintained at a desired
substances.6 P-gp is found in many organs, including the kidneys, the level for a relatively long period without I.V. administration. One dis-
brain, the lungs, the liver, and the GI tract.7 Many clinically used advantage is that after removal of the patch or other formulation, a
drugs are P-gp substrates, including tacrolimus, sirolimus, residual amount of the drug may be left in the skin layer, and this
cyclosporine, verapamil, diltiazem, digoxin, dexamethasone, and residuum may continue to be absorbed into the systemic circulation
methylprednisolone; most P-gp substrates are also substrates for even after therapy has been discontinued.
CYP3A4.8,9 The presence of the P-gp efflux pump keeps these drugs
from undergoing enzymatic metabolism within the enterocytes. Some Sublingual and transmucosal Some drugs (in particular,
drugs are inhibitors or inducers of P-gp. those that are in a nonionized form and that exhibit high lipid solu-
After a drug is absorbed into the intestine, it is transported to the bility) are well enough absorbed via the oral mucosa that they may be
liver via the portal vein. At this point, the drug may be subject to given sublingually or simply dissolved in the mouth. This route of
hepatic first-pass metabolism by enzymes within the liver. After pas- administration is especially advantageous for drugs that undergo sig-
sage through the liver, the drug, its metabolites, or both pass into the nificant hepatic first-pass metabolism when administered orally (e.g.,
systemic circulation. Drugs that are substrates of CYP2D6 and nitroglycerin) because when a drug is absorbed through the oral
CYP3A4 are especially vulnerable to hepatic first-pass metabolism.5 mucosa, it passes directly into the systemic circulation. Drugs that are
sometimes administered in this manner include buprenorphine and
Intramuscular Drug absorption after I.M. injection is highly fentanyl.
variable and depends on the properties of the drug molecule, the for-
mulation, and the injection site. Because muscle is highly vascular- Rectal Rectal administration of a drug may be convenient in
ized, drugs in aqueous solutions often are absorbed quite rapidly after clinical situations where (1) nausea and vomiting is present or oral
I.M. administration (albeit more slowly than they are after I.V. admin- intake is restricted (e.g., before an operation), (2) I.V. administration
istration). Any condition that reduces blood flow to the muscle at the is not desirable, and (3) the drug of interest is available in a supposi-
site of injection will decrease the rate and extent of drug absorption tory form. Unfortunately, drug absorption from the rectum is hard to
after I.M. administration. Drugs in aqueous vehicles are absorbed predict and often incomplete.The rectum is drained by both the sys-
more rapidly than those in lipid vehicles. In some cases, the slower temic circulation and the portal circulation. From a pharmacokinetic
absorption associated with lipid emulsions constitutes a practical standpoint, this means that approximately 50% of a rectally adminis-
advantage. For example, with certain medications (e.g., penicillin G tered drug dose will bypass the liver and reach the systemic circula-
benzathine, risperidone, and haloperidol), long-acting I.M. formulation without undergoing hepatic first-pass metabolism.10 Drugs avail-
tions are made by suspending the drug in a lipid vehicle specifically able in rectal suppository form that are absorbed systemically include
for the purpose of extending the duration of the therapeutic effect to acetaminophen, aspirin, and the antiemetics promethazine and
as long as 4 weeks. prochlorperazine. In addition, various drugs may be administered
rectally with the intention of producing a local or colonic effect (e.g.,
Subcutaneous In a subcutaneous injection, the drug is inject- anesthetic suppositories in patients with hemorrhoids and sucralose
ed into the connective tissue that lies underneath the dermal layer of or neomycin retention enemas in patients with hepatic failure).
the skin. This tissue is not as well vascularized as muscle.
Consequently, a drug typically is absorbed more slowly after subcu- Vaginal Vaginal administration of drugs is usually intended to
taneous administration than after I.M. administration. Drugs com- produce local effects, except in the case of hormonal treatments (e.g.,
monly given via subcutaneous injection include insulin, heparin the vaginal contraceptive ring, the estradiol ring, and estradiol or
(which, unlike most drugs, is rapidly absorbed via this route), and progesterone creams), which are intended to have at least some


degree of systemic absorption. An important consideration prescrib- for the therapeutic effect, and it may cause toxicity.14 The vasocon-
ing topical vaginal products (e.g., antifungal agents) is the age of the strictor epinephrine is often administered along with a local anesthet-
patient. The pH of the vagina ranges from 3.5 to 4.2 in women of ic during a spinal block because it decreases blood flow around the
reproductive age, but it is either neutral or slightly basic in post- injection area, thereby reducing systemic absorption and potentiating
menopausal women and girls who have not yet reached puberty. the effects of the anesthetic. Epinephrine also acts on alpha2 adreno-
These pH changes can alter the ionization state of antifungals such as ceptors on the nerve terminals to enhance the anesthetic effect by
ketoconazole. At an acidic pH, ketoconazole is protonated, but at a inhibiting the release of substance P and reducing nerve firing.
neutral or basic pH, it is nonionized and therefore able to cross the
DISTRIBUTION
membranes of the vagina, undergoing unwanted systemic absorption
and exerting undesired side effects. While a drug is being absorbed into the systemic circulation, it may
simultaneously be distributed into other physiologic fluids and tissues,
Nasal Most drugs that are administered nasally are topical depending on the physiology of the patient and the physiochemical
agents employed to produce local effects. However, the nasal mucosa properties of the drug. Patient variables that may affect distribution
has much the same capacity for systemic absorption that the oral include body size, fluid distribution within the body, amount of adi-
mucosa does: the area is highly vascularized, allowing rapid absorp- pose tissue, cardiac output, tissue blood flow, and amount of func-
tion of lipophilic and nonionized drugs. Currently, only desmopressin tional plasma proteins. Drug variables that affect distribution include
acetate (1-deamino-8-D arginine vasopressin, or DDAVP) and calci- lipophilicity, molecular weight, and affinity for plasma proteins and
tonin are administered nasally for systemic therapy, though intranasal tissues. The distribution of a drug beyond the systemic circulation is
formulations of other drugs (e.g., insulin) are now in development. typically described in terms of volume of distribution (Vd).
The mucosal membranes of the nose contain a number of drug-
Volume of Distribution
metabolizing enzymes, including CYPs, which may result in first-pass
metabolism of certain drugs. Vd is a pharmacokinetic parameter that relates the amount of a
given drug in the body to the concentration of the drug in the area
Inhalational The large surface area of the lung, the high perme- from which it was sampled (usually the bloodstream). It is not an
ability of the alveolar surfaces, and the highly vascular nature of lung actual physical volume; rather, it is estimated by means of pharma-
tissue allow rapid systemic absorption of drugs,11 especially those in cokinetic techniques. There are several types of Vd parameters, the
gaseous form (e.g., inhaled general anesthetics). In terms of the onset calculation of which depends on the route of administration of the
of therapeutic effect, however, the partial pressure of these agents in drug and the pharmacokinetic model used to describe its disposition.
blood and tissue is more important than the actual concentration.12 Vd is usually expressed in liters and may range from a value approxi-
Inhalational general anesthetics aside, most inhaled prescription drugs mately equivalent to blood volume (5 to 7 L), in the case of a drug
(e.g., beta2 agonists and corticosteroids for treatment of asthma and such as warfarin, to values as high as 200 L, in the case of digoxin
amphotericin B and tobramycin for treatment of lung infections) are (which is extensively distributed to and readily binds to tissues out-
designed to exert local effects on lung tissue. Systemic absorption side the vasculature). In a clinical setting,Vd may be used to estimate
does occur, but it is minimal and is partly attributable to swallowing the quantity of drug (A) needed to achieve a desired plasma concen-
of the drug during inhalation. tration (C), as follows:
At present, the only inhaled drug formulation on the market that is
designed for systemic delivery via the lungs is inhaled insulin A = Vd × C
(Exubera; Pfizer, New York, New York), which was approved by the Plasma Protein Binding
United States Food and Drug Administration in January 2006. An
advantage of this inhaled insulin formulation is that its absorption into A number of commonly used drugs exhibit significant plasma pro-
the systemic circulation is independent of body mass index (BMI)— tein binding [see Table 1]. Of the more than 60 different proteins that
in contrast with subcutaneously administered regular insulin, which is are found in plasma,15 three types are responsible for most instances of
absorbed more slowly in obese patients.13 drug binding: albumin, α1-acid glycoprotein (AAG), and lipoprotein.
The pulmonary route of administration is also particularly effective Albumin is a 66.3 kd protein that comprises approximately 580
at ensuring a high spike in drug concentration in the central nervous amino acid residues. It is made by the liver and broken down by the
system. Currently, this property is taken advantage of by cigarette liver, the kidneys, the spleen, and the lymph nodes. Its half-life is
smokers and users of freebase cocaine, crack cocaine, and crystal approximately 19 days, and at any given point, 40% of the body’s sup-
methamphetamine; in the future, it may be taken advantage of by ply of albumin is circulating in plasma, with the remaining 60% locat-
developers of therapeutic drugs. ed in interstitial fluid.The albumin molecule possesses two main drug-
binding sites. The first site is called the warfarin-binding area, but it
Nervous system In some situations, it is desirable to obtain par- also binds other drugs, such as valproic acid, phenytoin, and sulfon-
ticular drug levels in the cerebrospinal fluid. However, under normal amides. The second binding site is called the indole-benzodiazepine–
circumstances (i.e., in the absence of conditions such as inflammation binding area; it binds drugs such as certain penicillins and medium-
and trauma), many drugs, especially those that are water-soluble or chain fatty acids. Some drugs, such as the nonsteroidal anti-inflam-
ionized, have difficulty penetrating the blood-brain barrier. Even when matory drugs (NSAIDs), bind to both sites. In addition to the main
a drug does cross this barrier and reach the brain, the choroid plexus binding sites, separate binding sites for bilirubin, digitoxin, and tamox-
may secrete it back into the blood, making it difficult to reach the ifen have been discovered. Albumin binds mainly with weakly acidic
desired drug levels in the CSF. To overcome this difficulty, certain (anionic) drugs, though it also binds with certain basic drugs (e.g.,
drugs (typically local anesthetics or analgesics) may be injected in or benzodiazepines) and some neutral drugs (e.g., dexamethasone).
near the spinal canal in the vicinity of the nerve fibers that are to be There are a few rare genetic polymorphisms that are known to
blocked. Examples of this type of injection include epidural blocks, affect albumin levels or function. Certain disease states may induce
paravertebral nerve blocks, and spinal nerve blocks. Systemic absorp- alterations in the concentration or binding ability of albumin, thereby
tion occurs, but it should be kept to a minimum: it is not necessary potentially resulting in a higher free fraction of the drug (and thus an


Table 1 Commonly Used Drugs That Are Highly Bound to Plasma Proteins
Bound to Albumin Bound to Albumin and Bound to Albumin, AAG,
Bound to Albumin Bound to AAG and AAG Lipoproteins and Lipoproteins

Ceftriaxone Diisopyramide Alfentanil Amiodarone Amphotericin B
Citalopram Promethazine Amprenavir Cyclosporine Bupivicaine
Clofibrate Carbamazepine Chlorpromazine
Dexamethasone Clindamycin Diltiazem
Diazepam Erythromycin Felodipine
Fluoxetine Fosphenytoin Propranolol
Fluvoxamine Lidocaine Quinidine
Ibuprofen Lopinavir
Indomethacin Meperidine
Itraconazole Methadone
Ketoconazole Nelfinavir
Ketorolac Olanzapine
Losartan Ritonavir
Mycophenolate Saquinavir
Nafcillin Verapamil
Naproxen
Paroxetine
Phenytoin
Prednisolone
Sertraline
Thiopental
Tiagabine
Valproic acid
Warfarin

AAG—α1-acid glycoprotein

increased amount of drug available to exert pharmacologic effects) ing affinity. Structurally, they comprise a lipid core made up of cho-
and, often, lower total drug concentrations. In addition, drug dis- lesterol and triglycerides, which is surrounded by an outer layer made
placement interactions may occur when a previously administered up of phospholipids, cholesterol, and apolipoproteins. They are pro-
drug that is already bound to albumin is followed by a drug that has duced by the liver and the intestinal mucosa and are metabolized by
a higher affinity to albumin. Salicylate and the sulfonamides are exam- the liver, the kidneys, and the intestine. Lipoproteins are classified into
ples of drugs with high albumin-binding affinities that are capable of four groups: very low-density lipoproteins (VLDLs), low-density
displacing other drugs from albumin binding sites, thereby causing lipoproteins (LDLs), intermediate-density lipoproteins (IDLs), and
the unbound fraction of the displaced drug to increase. Nevertheless, high-density lipoproteins (HDLs). Of these, VLDLs, LDLs, and
the majority of displacements from binding sites on the albumin mol- HDLs account for the bulk of lipoprotein drug binding. The most
ecule result in the same free concentrations of the drug, though the common mechanism by which drugs attach to lipoproteins is believed
total concentrations may decrease precipitously. In this situation, if the to be a nonsaturable partitioning into the lipid core15,16; drugs that
total concentrations are followed and the dosage increased to achieve appear to exemplify this mechanism include cyclosporine,17 propran-
a specific total concentration, the increase in the unbound fraction olol, digoxin, and tetracycline.15 Some drugs, however, such as pro-
that results from the drug interaction (or from a decreased albumin pranolol and certain tricyclic antidepressants, are believed to bind to
concentration caused by a disease state) may lead to toxicity. Because specific sites in a saturable manner.15,16 Lipoproteins may bind addi-
albumin levels are frequently low in surgical patients, measurement of tional drug when albumin binding sites become saturated.18
free drug levels is recommended if available. The amount of free (unbound) drug in the plasma has pharmaco-
AAG is an acute-phase protein that is both produced and metabo- logic implications. Tissue and plasma protein binding influence the
lized by the liver. It is somewhat smaller than albumin (38 to 48 kd) apparent volume of distribution of a drug according to the following
and has a half-life of 5 days. Approximately 60% of the body’s supply equation:
of AAG circulates in plasma, with the remaining 40% in interstitial
Vd = VB + (fB/fT)VT
fluid. AAG tends to bind basic drugs, but it also binds some that are
neutral or acidic.There are three known genetic variants of AAG, but where VB is blood volume (0.07 L/kg), VT is tissue volume, fB is the
it is unclear whether this variation is of any clinical significance. unbound fraction of drug in the blood, and fT is the unbound frac-
Elevated AAG levels may lead to a decrease in the unbound fraction tion of drug in tissue. For lipophilic drugs, tissue volume is calculat-
of a drug and thus to a reduction in the amount of drug available for ed as total body water minus plasma volume (approximately 0.6
pharmacologic activity. L/kg). For hydrophilic drugs, tissue volume is calculated as extracel-
The lipoproteins are a diverse group of proteins that vary signifi- lular fluid minus plasma volume (approximately 0.13 L/kg). The
cantly with respect to molecular weight, lipid content, and drug bind- degree of a drug’s affinity for plasma proteins as opposed to tissue


components is the main determinant of its volume of distribution. intestine, the colon, the kidneys, the brain, the lungs, the heart, the
Changes in fB, however, lead to changes in Vd only when a drug has skin, the nasal mucosa, the heart, and the eyes.
a Vd of at least 30 L (i.e., when blood volume constitutes no more To date, 18 families of CYP enzymes and 42 subfamilies have been
than a small fraction the drug’s total volume of distribution).19 identified.These enzymes exhibit many genetic polymorphisms, some
Uremia, cirrhosis, nephrotic syndrome, epilepsy, hepatitis, and var- of which do not affect function, some of which restrict function, and
ious other disease staes have been shown to decrease protein binding some of which encode nonfunctional proteins. Particular polymor-
of drugs. Plasma protein binding is also reduced in pregnant women, phisms may alter a person’s ability to metabolize drugs. In addition,
neonates, and persons who have sustained severe burns. Accordingly, some persons have gene duplications that give rise to increased
clinicians often assume that pregnant patients, newborns, or burn enzyme activity. Thus, there is a great deal of interindividual variabil-
patients who are taking a highly protein-bound drug are automatical- ity with respect to CYP-related metabolic capacity.
ly at risk for alterations in the unbound fraction of the drug; however, A number of common drugs are known to induce, inhibit, or serve
this assumption is not always valid.19 As noted (see above),Vd depends as substrates for CYP [see Table 2]. Some of these drugs have multiple
on several factors, including fB, fT,VB, and VT. effects.
Increased binding of drugs to plasma proteins decreases the
ELIMINATION
amount of drug available for diffusion into tissues, thereby limit-
ing Vd. In contrast, increased binding of drugs to tissue proteins Half-life
increases the apparent Vd. Increased protein binding also limits drug
Half-life (t1/2) is a pharmacokinetic parameter that represents the
elimination because for the most part, only unbound drug can be
amount of time necessary for the amount or concentration of drug in
eliminated.
the body to decrease by 50%. As a general rule, almost all (97%) of a
METABOLISM drug will have been eliminated after five half-lives. For a first-order
process, half-life is described by the following equation:
Hepatic Metabolism
t1/2 = 0.693/ke
With a few exceptions, drug metabolism (also known as biotransfor-
mation) consists of converting a lipophilic drug to a more hydrophilic where ke is the elimination rate constant in inverse time units. It is
metabolite, which is then more easily excreted by the kidneys. (The important to remember that half-life should not be used as a measure
only agents excreted by the pulmonary route are the volatile anesthetic of hepatic clearance or liver function, because it changes proportion-
agents.) Metabolic reactions are generally divided into two phases: ately with clearance only when Vd remains constant.
phase I reactions, which include oxidation, reduction, and hydrolysis; Clearance of the drug [see Clearance, below] in volume units per
and phase II reactions, which include glucuronidation, sulfation, unit of time (CL) and Vd are independent (albeit correlated) parame-
methylation, acetylation, and amino acid and glutathione conjugation. ters that are related via ke, as shown in the following equation:
From a clinical standpoint, the most important drug-metabolizing CL = ke × Vd
enzymes are the CYP enzymes. They are part of the microsomal
mixed-function oxidase system and work in combination with CYP Thus, ke is equivalent to CL/Vd, which means that the equation for
reductase, molecular oxygen, and nicotinamide adenine dinucleotide half-life (see above) can also be written as follows:
phosphate (NADPH) to perform many of the phase I metabolic reac- t1/2 = (0.693 × Vd)/CL
tions.The CYP enzymes also help synthesize and metabolize endoge-
nous substrates (including hormones) and break down nondrug xeno- Clearance
biotics (e.g., environmental pollutants). The liver, as the main meta-
Clearance is an independent pharmacokinetic parameter that is
bolic organ of the body, contains more CYP enzymes than any other
defined as the volume of plasma, serum, or blood that is cleared of the
organ, but CYPs are also found in significant quantities in the small
drug per unit of time. The liver is the organ primarily responsible for
drug clearance. Clearance may be considered the most important of
Table 2 Common Substrates, Inducers, and the pharmacokinetic parameters because it determines what the
Inhibitors of Cytochrome P-450 maintenance dose (MD) of a drug should be to achieve a desired
steady-state plasma concentration (Cpss):
Substrates Inducers Inhibitors
MD = Cpss × CL
Acetaminophen Carbamazepine Amiodarone Renal Clearance
Caffeine Cigarette smoke Cimetidine
Cyclosporine A Dexamethasone
Renal clearance of drugs is the result of three processes: tubular
Ciprofloxacin
secretion, tubular reabsorption, and glomerular filtration. The
Diazepam Ethanol (in chronic setting) Diltiazem
glomerular filtration rate (GFR) is generally considered the best over-
Diltiazem Isoniazid Ethanol (in acute
all indicator of kidney function. It may be determined through I.V.
Fentanyl Omeprazole setting)
administration of a substance (e.g., inulin or iothalamate) that is freely
Fluoxetine Phenobarbital Fluconazole
filtered at the glomerulus but is not subject to reabsorption or secre-
Haloperidol Phenytoin Fluoxetine tion by the tubules. In a routine clinical setting, however, estimation
Midazolam Rifampin Metronidazole of renal function by direct measurement of the GFR is impractical. A
Morphine Omeprazole common alternative is to measure creatinine clearance (CrCL), which
Phenobarbital Propofol is generally accepted as a reasonably accurate estimate of the GFR
Phenytoin and therefore of renal function.This is done by collecting the patient’s
Tacrolimus urine over a 24-hour period and determining the concentrations of
Warfarin creatinine in serum and urine. CrCL is then calculated according to
the following equation:


CrCL (ml/min) = rate of urinary creatinine excretion/serum Thus, drugs may compete with each other or with endogenous sub-
creatinine concentration strates, and toxicities may result.

CrCL (ml/min) = (UCrV × 100)/(SCr × 1,440)
Metrics Reflecting Magnitude of Drug Exposure
where UCr is the urinary creatinine concentration (mg/ml),V is the vol-
ume of urine produced over a 24-hour period (ml), and SCr is the AREA UNDER THE CURVE
serum creatinine concentration (mg/dl) measured at the 12th hour Area under the curve (AUC) is a pharmacokinetic parameter
(i.e., the midpoint) of the urine collection period. that reflects the extent of a drug’s bioavailability—that is, it reflects
For practical purposes, CrCL is usually estimated by applying any the total amount of active drug that reaches the systemic circulation
of a number of commonly accepted equations.The equation most fre- after administration. The AUC is usually calculated from the actu-
quently employed to estimate CrCL in patients with stable renal func- al area under a curve generated by plotting plasma concentrations
tion is that of Cockcroft and Gault, which derives CrCL from the of an administered drug over a period of time (whether from time
patient’s age, ideal body weight (IBW), and SCr: 0 to infinity or from one dose to the next). For drugs exhibiting lin-
CrCL = [(140 − age) × IBW]/(72 × SCr) ear (i.e., first-order) kinetics, the AUC is proportional to the dose
administered. With some drugs, however, this may not be the case
Because women have less muscle mass in relation to their body weight at higher dosages, because drug elimination pathways may become
than men do, the value for CrCL in female patients is calculated by saturated.
multiplying this equation by 0.85.The Cockcroft-Gault equation uses
IBW rather than actual body weight because adipose tissue contains PEAK PLASMA CONCENTRATION
little if any muscle and therefore is believed to contribute little to the Peak plasma concentration (Cmax) is a pharmacokinetic parame-
serum creatinine level; if actual body weight were used, CrCL might ter that quantifies the highest level reached in the plasma after
be overestimated. administration of a drug. Knowledge of Cmax may be advantageous
It should be kept in mind that the various methods of estimating in certain situations. For example, some antibiotics (e.g., amino-
CrCL are necessarily imperfect, in that SCr may be abnormally high or glycosides) depend on a high Cmax rather than on sustained drug
abnormally low for reasons that have nothing to do with kidney func- levels for their bactericidal effects. Other drugs may cause toxicity
tion. For example, SCr may be decreased in elderly, bedridden, or if Cmax reaches inappropriately high levels. Cmax is expressed in
wheelchair-bound patients (because of the loss of muscle mass), and units of concentration (e.g., μg/ml or mg/L). It may be calculated
it may be elevated in patients with increased muscle mass, those who in several ways; which equation is used depends on the route
have recently undergone strenuous exercise, trauma patients, and even of administration of the drug and the model used to describe its
persons who consume high quantities of red meat. Liver dysfunction disposition.
can affect the accuracy of CrCL estimates by decreasing the conver-
sion of creatine to creatinine. TIME OF PEAK PLASMA CONCENTRATION
Unbound drugs of low molecular weight are readily filtered by Time of peak plasma concentration (Tmax) is simply the time at
the glomeruli.The ionized fraction is then excreted.The nonionized which the maximum plasma concentration is reached after extravas-
fraction, however, is reabsorbed by the tubules and is typically cular drug administration. As such, it is also an indication of the
metabolized by the liver to the ionized form.With some drugs, reab- time of peak drug absorption, at which absorption and elimination
sorption is dependent on pH; consequently, when these drugs cause (expressed in mass units per time unit) are equal. Comparison of
toxicity, manipulation of urinary pH to increase their elimination Tmax between two extravascular dosage forms allows determination
can be a useful therapeutic measure. Secretion of drugs into the of relative absorption rates. Tmax decreases as the absorption rate
renal tubules is an active process that is not particularly specific. increases.

a ONE COMPARTMENT b TWO COMPARTMENTS

Distribution Phase
Predominant

Elimination Phase
Log Cp

Log Cp

Predominant

Time Time
Figure 1 Depicted are (a) one-compartment and (b) two-compartment pharmacokinetic models. (Cp—plasma
concentration)


Fundamental Pharmacokinetic Concepts
A
COMPARTMENTAL PHARMACOKINETIC MODELING

As the study of pharmacokinetics has progressed, various models
for the disposition of drugs in the body have been proposed. Many of B
these models portray the body as a collection of spaces with volumes
and elimination rates (clearance rates). These spaces, commonly
referred to as compartments, are not actual anatomic realities, though

Log Cp
they may have characteristics that are very similar to those of true
b
anatomic spaces. They represent conceptual adaptations of monoex-
ponential or multiexponential concentration-versus-time curves, in
which the curves are converted to virtual spaces that have specific
finite volumes and elimination rates.
The simplest compartmental model is the one-compartment a
model. This model assumes that the body is a single homogeneous
unit in terms of a particular drug’s pharmacokinetic profile. It there-
fore also assumes that the drug is instantaneously distributed through-
out the compartment after administration. Obviously, this assumption
is purely theoretical and, from a practical standpoint, impossible.
Time
Nevertheless, the one-compartment model adequately describes the
disposition of many drugs that are rapidly distributed in the body. A Figure 2 In a two-compartment model of pharmacokinetics,
plasma concentration can be estimated by using intercepts A and
concentration time profile that has a monoexponential character in
B and microconstants a and b.
the decline (see below) is often characterized as a one-compartment
model. It is important to remember that the signal characteristic of the
one-compartment model is not that the actual drug concentrations whereas a drug that follows a two-compartment model shows two dis-
are the same in all body tissues as in blood or plasma (which is not tinct phases, a distribution phase and an elimination phase [see Figure
necessarily the case) but that the rate at which drug or metabolite lev- 1b]. The drug does not switch from one phase to the other in an on-
els change is constant throughout the entire body. and-off fashion; rather, the two phases predominate at different stages
Elimination from a compartment may be assumed to be a first- of drug disposition after administration.
order or linear process. In a static first-order process, a constant pro- The first phase of the two-compartment concentration-time curve,
portion of the drug is eliminated over a given unit of time. The first- the distribution phase, primarily reflects the distribution of the drug
order elimination rate constant k (or ke) is a proportionality constant from the rapidly perfused tissues of the central compartment into the
that relates clearance to Vd. It is expressed in reciprocal time units (i.e., more poorly perfused tissues of the peripheral compartment. During
hr−1 or min−1) because it is derived by dividing a rate (the volume from this phase, the drug concentration in the peripheral compartment
which all material is removed per unit of time, expressed in L/hr) by a gradually increases until it reaches a maximum. At this maximum
volume (Vd, expressed in liters). The overall clearance of a drug is the peripheral tissue concentration, the rate of drug input into the tissue
sum of the clearances attributable to all of the routes by which the drug is equal to the rate of drug output from the tissue, and the portion of
may be eliminated (e.g., CL = CLrenal + CLhepatic + CLbiliary ….); the pre- drug in the central compartment is in equilibrium with the portion of
cise value depends on the particular elimination pathways that are drug in the peripheral compartment.This point in time is termed dis-
open to the drug. If a drug has nonlinear elimination characteristics, tribution equilibrium. After this point, the drug amounts in the cen-
clearance will constantly change in conjunction with concentration. tral and peripheral compartments decline at similar rates, and the
As noted (see above), in a one-compartment model, whereas the kinetics of the drug begin to resemble those of a one-compartment
rate of change in the drug concentration may be the same in all body model.
tissues, the actual drug concentrations in particular tissues may be dif- The second portion of the concentration-time curve, the elimina-
ferent from each other and from those in blood or plasma. The usual tion phase, reflects the passage of the drug from the body. It is usual-
assumption, however, is that the ratios between tissue concentrations ly assumed that drug elimination occurs via the central compartment.
and plasma concentrations are constant. This assumption then leads This assumption is based on the observation that most drugs are elim-
to the further assumption that the relation between plasma concen- inated mainly via the liver or the kidneys, both of which are highly per-
tration and the total amount of drug in the body is also constant.The fused organs that are usually included in the central compartment.
relation between these two factors is represented by the volume of dis- The rate constants describing the rate of transfer between com-
tribution term Vd. partments in a two-compartment model are often referred to as
For many drugs, distribution can be more accurately described by microconstants because they cannot be determined by direct mea-
employing a multicompartment model, which incorporates both a surement; however, they can be estimated from a logarithmic graph of
central compartment (as in the one-compartment model) and one or plasma concentration versus time after an I.V. bolus [see Figure 2].
two (or, in rare cases, more than two) peripheral compartments.These Plasma (or central compartment) drug concentration (Ccentral) may be
peripheral compartments may represent more poorly perfused tissues related to time by means of the following equation:
of the body that have a different affinity for the drug. Peripheral com-
Ccentral = Ae−at + Be−bt
partments are hypothetical constructs, in that the actual drug con-
centrations in tissues are not known, but their presence is often where e is the base of the natural system of logarithms, and A and B
assumed on the basis of plasma concentrations measured over time are intercepts on the y axis for each segment of the concentration-time
after an I.V. bolus. When a concentration-time curve is plotted on a curve. The hybrid constants A and B have no real physiologic signifi-
semilogarithmic graph after injection of an I.V. bolus, a drug that fol- cance, but they are useful for solving this equation as a sum of expo-
lows a one-compartment model shows a linear decline [see Figure 1a], nentials.The terms a and b represent the first-order rate constants for


time. When Vmax is reached, a constant amount of drug is eliminated
per unit of time, and elimination is truly a zero-order process. Km, the
so-called Michaelis constant, is a reflection of the metabolizing capac-
ity of the enzyme system. It is equal to the drug concentration in the
body when V is one half of Vmax.This equation is appropriate at a wide
range of drug concentrations because if Cp is much larger than Km, the
enzymatic processes become saturated, Km can be considered negligi-
ble and drops out of the equation, and V is approximately equal to
Vmax.
Log Cp

PHYSIOLOGICALLY BASED PHARMACOKINETICS

A very useful pharmacokinetic modeling approach that is some-
times employed as an alternative to compartmental modeling is phys-
iologically based pharmacokinetics (PBPK). PBPK is similar to com-
partmental modeling in that spaces are represented as instantaneous-
ly mixing compartments. However, it differs from classical compart-
mental modeling in that the compartments in a PBPK model are con-
strained to the actual space occupied by a particular tissue or organ.
In addition, tissues are connected not by first-order rate constants or
clearances but directly by blood flows originating in the arterial circu-
lation and emptying into the venous system (with the exception of the
lungs) [see Figure 4]. Drugs introduced into the vascular system circu-
Time
late and are delivered to various tissues. Within tissues, any sort of
transfer may be specified, from instantaneous transfer with a partition
Zero-Order Elimination First-Order Elimination coefficient to linear or nonlinear transfer to or from a tissue space or
within tissue subspaces. A great advantage of PBPK is that it permits
Figure 3 Plotting of plasma concentration against time
modeling of tissue-specific concentrations and time courses of con-
illustrates the difference between zero-order (saturable) drug
centration changes. This advantage is especially important if the
elimination and first-order elimination.
desired drug action depends on exposure within a particular space.

the distribution phase and the elimination phase, respectively. As may
be seen from the concentration-time curve [see Figure 2], the decline Pharmacodynamics
in drug concentration is steeper in the initial (distribution) phase than The discipline of pharmacodynamics aims to define the relation
in the second (elimination) phase. between pharmacokinetics and response to the drug. PBPK modeling
Many agents are eliminated in a nonlinear manner (so-called zero- is very useful for capturing effect-site concentrations that can be
order elimination), and their elimination half-life lengthens as the linked to a particular drug effect. Effect-site concentrations are not
dosage increases [see Figure 3]. This phenomenon is usually attribut- directly measurable in clinical situations, but estimating such concen-
able to saturation of the enzyme systems responsible for metabolizing trations can help distinguish distributional effects that cause a dissoci-
the drug. Such saturation can cause changes in the metabolite profile. ation between observed plasma concentration and physiologic
When there is saturation of elimination, the area under the concen- response from tolerance-type or sensitization-type responses that
tration-time curve ceases to be proportional to drug exposure, and the occur at the site of action. With sensitization, a plasma concentration
AUC does not increase linearly with increasing doses (as it does with observed early in the exposure profile evokes a lesser response than
first-order kinetic processes). the same concentration observed later (i.e., the patient becomes more
Saturable GI absorption may occur with drugs such as gabapentin, sensitive to the drug). This development is often seen as a counter-
baclofen, and riboflavin, and saturation of intestinal metabolism may clockwise hysteresis when the drug’s concentration is plotted against
occur with propranolol. In addition, saturable plasma protein binding its effect over time. With tolerance, a concentration observed early in
may occur with drugs such as lidocaine, ceftriaxone, warfarin, disopyr- the exposure profile evokes a greater response than the same concen-
amide, and phenytoin. Saturable tissue transport may occur with tration observed later (i.e., the patient becomes tolerant to the drug).
drugs such as methotrexate.18 The most clinically relevant zero-order This development is seen as a clockwise hysteresis when concentra-
processes, however, are those related to hepatic metabolism. Two tion is plotted against effect over time.
drugs with narrow therapeutic indices whose metabolism follows
BASIC PHARMACODYNAMIC MODELS
zero-order kinetics are the antiepileptic medications phenytoin and
valproic acid. The linear-response pharmacodynamic model, as its name sug-
A drug with saturable elimination will, at a large enough dose, gests, describes the relation between drug concentration (whether in
demonstrate a disproportionately large increase in AUC with a dose plasma, in a particular compartment, or at the biophase) and physio-
increase once the saturation point of the elimination system is reached. logic response as a linear one [see Figure 5]. The general form of this
The term Michaelis-Menten kinetics is used to describe elimination of model is as follows:
drugs by saturable enzymatic processes. The standard Michaelis-
Response = baseline + (concentration × response factor)
Menten equation for estimating the elimination rate (V) is as follows:
The maximum-response model determines the relation between
V = VmaxCp/(Km + Cp) = dCp/dt
concentration and response on the basis of the maximum response
where Vmax is the maximum metabolic rate of the enzymes, Cp is the (Emax), the concentration at which 50% of Emax is observed (EC50),
plasma concentration, and dCp/dt is the rate at which Cp changes over and, optionally, other factors (e.g., exponents applied to both Emax and


Heart

Q Lung Lungs

Q Brain Brain

Venous System
Arterial System

Q Mesentery Mesentery

Q Hepatic Artery Liver Q Liver

Clearance

Q Kidney Kidney

Q Rest Rest of Body

Figure 4 Shown is a schematic structural depiction of physiologically based
pharmacokinetics (PBPK). In PBPK, unlike standard one- or two-compartment modeling,
the compartments are restricted to the actual spaces occupied by particular tissues or
organs. In this example, elimination occurs as clearance from the liver. (Q—blood flow)

EC50 that modify the steepness of the response).This model may also patient becomes oliguric, the GFR is probably less than 10 ml/min. In
be modified to take into account the baseline response [see Figure 6]. critically ill patients, renal function may deteriorate rapidly. Because
The general form of the maximum-response model is as follows: actual measurement of the GFR is usually impractical, estimation of
the GFR, based on creatinine level and urine output, should be con-
Response = (Emax × concentration)/(EC50 + concentration)
sidered. Besides lowering the GFR, renal failure reduces tubular
Indirect-response models may be used to describe systems in which excretion.The transport systems in the renal tubules may become sat-
there is either constant production or constant elimination of the drug urated, further decreasing drug elimination.
effect. In addition, however, the drug concentrations observed will Other aspects of renal failure can affect pharmacokinetics. Renal
have an impact on the elimination or production of the drug effect.

Physiologic Factors That Alter Pharmacokinetics and
Pharmocodynamics
For the most part, the pharmocokinetic and pharmacodynamic
modeling methods used to determine dosing regimens are based on
study data from normal subjects. For this reason, they may not be
applicable to surgical patients without some modification. Such
Response

patients often have significant physiologic derangements that alter
drug metabolism. If these physiologic derangements are not taken
into account, patients may be at risk not only for drug toxicity and
adverse events but also for inadequate drug administration.
ORGAN SYSTEM DYSFUNCTION

Renal
Renal insufficiency, whether acute or chronic, can have pro-
nounced effects on drug disposition, not only because of impaired Concentration
excretion of drugs and metabolites eliminated by the kidneys but also Figure 5 Illustrated is the linear-response pharmacodynamic
because of other disease-induced physiologic alterations. The degree model, in which the relation between drug concentration and
of impairment is proportional to the decrease in the GFR. If the physiologic response is a linear one.


extraction ratios (e.g., diazepam and warfarin), decreased protein
binding and metabolism by hepatic enzymes such as CYP have a
greater effect on pharmacokinetics. Decreased protein binding is com-
mon in surgical patients, whether from decreases in total proteins
(especially albumin), production of abnormal proteins, or displace-
ment of drugs from proteins by endogenous substances or other
drugs.The end result of decreased protein binding is an increase in the
Response

level of active drug, which leads to an increased potential for toxicity
or prolonged effects.
Because there is no readily available method for measuring hepatic
function, it is difficult to predict the impact of hepatic dysfunction on
the pharmacokinetics of a given drug. Any attempt at such a prediction
must begin with a high index of suspicion that hepatic function has
deteriorated to the point where it may affect pharmacokinetics. Drug
dosing must then be carefully planned on the basis of the estimated
severity of the dysfunction. In practice, clinicians often do not consid-
Concentration
er the possibility that hepatic dysfunction is affecting pharmacokinetics
Figure 6 Illustrated is the maximum-response pharmacody- until the patient exhibits signs of decreased drug metabolism (e.g.,
namic model, in which the relation between drug concentration slow awakening from anesthesia or benzodiazepine infusion).
and physiologic response is a nonlinear one that is determined by
the maximum response (Emax), the concentration at which 50% of Cardiac
Emax is observed (EC50), and, sometimes, other factors. The major effects of cardiac dysfunction on pharmacokinetics can
be attributed to hypoperfusion, venous congestion, or both. Reduced
gut perfusion and congestion can hinder absorption of enterally
failure may reduce gastric acid secretion, thereby decreasing the administered drugs. Hypoperfusion can also affect absorption via the
absorption of some drugs, and may inhibit hepatic metabolism, there- intramuscular, subcutaneous, or transcutaneous route; accordingly, to
by decreasing the first-pass effect and increasing systemic drug ensure appropriate systemic drug levels, the I.V. route is preferred.
absorption. With many hydrophilic drugs, congestion and increased total body
Edema formation and decreased plasma protein levels may have water can lead to an increase in Vd.With lipophilic drugs, however,Vd
complex effects on Vd and t1/2. Although Vd tends to be increased, may be unaffected or even reduced.
decreased plasma protein binding may raise unbound drug levels and The effects of cardiac dysfunction on renal and hepatic blood flow
increase potential toxicity. The higher unbound drug concentrations may result in diminished elimination of drugs. Hepatic congestion
may actually increase drug excretion, thereby reducing t1/2. may worsen the situation. Congestive heart failure tends to have more
Great care should be taken in administering drugs that are mainly severe adverse effects on hepatic function than it does on renal func-
excreted by the kidneys and that have significant toxicity or a narrow tion. It is important to keep this difference in mind when administer-
therapeutic range.Typically, the initial loading dose is appropriate, but ing drugs that are mainly metabolized by the liver. Hemodynamically
subsequent dosing should be based on estimates of the GFR. If pos- active medications (e.g., inotropes, afterload reducers, and vasopres-
sible, drug levels should be monitored. The timing of monitoring sors) or diuretics can have a significant impact on renal and hepatic
depends on the expected t1/2. Trough drug levels are often used. blood flow and function.
Particular caution should be exercised with drugs whose levels or
physiologic effects cannot be reliably monitored in a clinical setting Respiratory
(e.g., LMWHs). These drugs should be avoided in patients with sig- Chronic pulmonary disease with pulmonary hypertension can
nificant renal impairment. lead to hepatic congestion. Less commonly, respiratory failure with
For patients who require renal replacement therapy, drug clearance secondary right heart failure can lead to hypoperfusion of the kidneys
varies from agent to agent. Intermittent hemodialysis and continuous and liver. Mechanical ventilation can exacerbate the effects on con-
renal replacement therapy can have substantial and varying effects on gestion and hypoperfusion, especially if very high intrathoracic pres-
clearance. Knowledge of clearance rates can greatly facilitate the plan- sures are employed. The resulting hepatic or renal dysfunction can
ning of dosing regimens. affect drug metabolism.
Hepatic Systemic inflammatory responses can alter organ blood flow and
thereby affect drug metabolism. In addition, if changes in arterial car-
The effects of hepatic dysfunction on pharmacokinetics are com- bon dioxide tension (PaCO2) lead to changes in arterial pH, protein
plex and difficult to predict. In general, hepatic impairment must be binding and drug ionization status can be affected.
severe to have a significant direct effect on drug metabolism. It must
AGE
be kept in mind, however, that hepatic dysfunction frequently leads to
some degree of renal impairment, even in the absence of overt hepa- Renal function (specifically, the GFR) varies significantly with age.
torenal syndrome. In neonates, the normal value for the GFR is only 2 to 4 ml/min, com-
How hepatic dysfunction affects the metabolism of a given drug is pared to a normal adult value of more than 100 ml/min. Over the 6
determined by how readily the drug is normally extracted by the liver months following birth, however, the GFR increases to a level approx-
(i.e., how high the extraction ratio is). For drugs with high extraction imately twice the normal adult level, then slowly decreases.
ratios (e.g., morphine and labetalol), hepatic removal becomes depen- Consequently, many drugs may have a shorter t1/2 in children than in
dent on hepatic blood flow. If blood flow is limited by end-stage liver adults. Hepatic function, particularly with regard to drug metabolism,
disease or portosystemic shunting, bioavailability increases and elimi- follows a similar pattern in the first few months of life: an increase to
nation decreases, leading to a prolonged t1/2. For drugs with lower supra-adult levels followed by a slow decline.


Gastric emptying is slower in neonates than in adults, and gastric pneumonia can lead to therapeutic failure.21 The relative risks for any
acidity is lower as well; both of these differences may affect absorption particular drug can be determined by considering the therapeutic
of oral medications. In addition, neonates have lower plasma protein index for that agent.The therapeutic index is approximated as follows:
levels, which may alter Vd. Common medications whose pharmacoki-
Therapeutic index = LD50/ED50
netics may be different in the pediatric population include antibiotics,
narcotics, benzodiazepines, and anticonvulsants. where LD50 is the dose that would cause death in 50% of cases and
Increasing age leads to substantial changes in drug pharmacokinet- ED50 is the dose that would be effective in 50% of cases. If there is any
ics. Elderly persons have 10% to 15% less total body water than overlap between the range of effective doses and the lowest lethal dose
younger persons do, as well as a higher proportion of body fat; they for a given drug (i.e., if the risk of death is substantial even in the drug’s
also have 20% to 30% less lean body mass. These changes in body therapeutic range), it is worthwhile to consider the drug’s standard
composition can affect Vd. Renal function decreases with age, resulting margin of safety. This parameter is defined as follows:
in decreased clearance of many drugs. Intrinsic hepatic function is Standard margin of safety = LD1/ED99
usually well preserved, though blood flow to the liver may diminish.
where LD1 is the dose that would cause death in 1% of cases and ED99
NUTRITIONAL STATUS
is the dose that would be effective in 99% of cases. For drugs with a
Severe malnutrition leads to a relative increase in total body water narrow margin of safety, it is critical to monitor their levels whenever
as fat stores are depleted, as well as to a decrease in plasma protein lev- possible [see Drug Level Monitoring, below]. These metrics (i.e., stan-
els. Vd increases, and the GFR decreases. Hepatic clearance of drugs dard margin of safety and therapeutic index) are confounded if the
is reduced, particularly in cases of protein malnutrition. Consequently, slopes of the concentration effect and concentration toxicity relation-
t1/2 increases, thereby increasing the risk of drug toxicity.These abnor- ships are different.
malities resolve with adequate nutritional support. A common way of achieving therapeutic drug levels is to adminis-
Obesity also can have significant effects on pharmacokinetics. To ter a loading dose. The size of the loading dose can be calculated on
assess the potential implications, it is useful to compare total body the basis of volume of distribution, desired plasma concentration, and
weight (TBW) to IBW. IBW is calculated as follows: bioavailability:
Men: 50 kg + 2.3 kg for each 1 in. of height over 5 ft Loading dose = (Vd × C)/F

Women: 45.5 kg + 2.3 kg for each 1 in. of height over 5 ft As noted (see above), F (i.e., bioavailability) equals 1 if the drug is
administered I.V. If there is concern about potential toxicity, the drug
For persons shorter than 5 ft, 2.3 kg is subtracted for each 1 in. below dose may be given over a prolonged period (e.g., a phenytoin load over
this height. 1 hour) or divided into smaller doses and given over an even longer
Because of the greatly increased amount of body fat in obese period (e.g., a digoxin load over 24 hours). The optimal dosing inter-
patients, lipophilic drugs can be distributed into and sequestered in val for the maintenance doses is often close to the drug’s expected t1/2.
adipose tissue. This effect becomes more pronounced with increasing The goal of maintenance dosing is to achieve a steady-state plasma
lipid solubility. Deposition of drugs in fat increases Vd but also increas- concentration that is within the therapeutic range. Generally, this goal
es t1/2. For highly lipophilic drugs (e.g., halothane, enflurane, sufen- is reached after five half-lives of the drug. From this point on, the
tanil, and various benzodiazepines), the doses required to achieve the amount of drug administered with each dose is equal to the amount
desired effect may be quite high. For hydrophilic medications, dosing of drug eliminated between doses.The steady-state plasma concentra-
adjustments generally are not necessary. Some agents, however, are tion may be approximately calculated from the drug’s bioavailability,
relatively hydrophilic but are still distributed into fat stores to some the maintenance dose (MD), the clearance rate, and the dosing inter-
extent. Ciprofloxacin is an example of such a drug; its partial absorp- val (τ):
tion into fat has led many to recommend that the dose be based on
45% of TBW in addition to IBW.The initial dose of gentamicin should Cpss = (F × MD)/(CL × τ)
be increased by as much as 40% because of the risk of an increased Vd. Cpss may be too low if the MD is too small, if F is too low, if CL is too
high, or if τ is too long. Should it prove necessary to adjust the dosing
FLUID RESUSCITATION
regimen, changes in one or more of these parameters will be indicat-
Aggressive fluid resuscitation, such as is performed after trauma or ed. For example, if a higher peak drug level is desired, the maintenance
a major surgical procedure, increases interstitial and intracellular vol- dose can simply be increased. However, if a lower trough level is
ume, as well as plasma volume, and reduces plasma protein levels. desired to alleviate concern about toxicity, the dosing interval can be
Consequently,Vd is significantly increased for many drugs.20 The con- extended, or (depending on the peak level) the maintenance dose can
centration of a drug can be estimated on the basis of the relative quan- be decreased.
tity of fluid sequestration and the size of the reduction in the serum In addition to monitoring drug levels when possible [see Drug Level
albumin concentration. Underdosing of medications is common in Monitoring, below], it is crucial to monitor the clinical effect of a drug
patients who have undergone aggressive fluid resuscitation. regimen. At times, this effect may be immediate, as when a vasopres-
sor is administered to a patient in septic shock. At other times, the
effect may be delayed, as when a course of antibiotics is administered
Drug Dosing
to for a patient with pneumonia. Monitoring the clinical efficacy of a
treatment regimen is essential for determining the appropriate timing
INITIAL DOSING
of discontinuance.
In deciding on the initial dosing of a drug, particularly in the acute
DRUG LEVEL MONITORING
care setting, it is essential to strike a balance between the risk of caus-
ing toxicity, on one hand, and the risk of failing to achieve therapeutic Monitoring of the plasma concentration is most commonly
efficacy because of underdosing, on the other. For example, there is employed with drugs that have a low therapeutic index—that is, drugs
ample evidence that inadequate dosing of antibiotics in patients with for which there is a narrow margin between the level that is therapeu-


tic and the level that causes toxicity. It should be kept in mind, how- needed for adequate tissue penetration (as, for example, in patients
ever, that these therapeutic and toxic levels are not absolute indicators with pneumonia).
of safety or efficacy: they only represent values at which certain per- Monitoring of the drug’s effect is also important. For example, the
centages of patients are treated effectively or certain percentages expe- prothrombin time may be measured in a patient receiving warfarin, or
rience suffer adverse events. Accordingly, such levels are not infallible the activated partial thromboplastin time may be measured in a patient
guides for drug dosing. As an example, there are circumstances in receiving heparin.
which a clinician, knowing the drug levels and weighing the various
risks and benefits, might elect to push the drug levels toward, or even
into, the toxic range; for instance, in a patient with recalcitrant seizures, Drug Interactions
the plasma phenytoin level might be pushed to 25 μg/ml, which is The more drugs a patient is given, the greater the potential for
above the standard therapeutic range. As another example, there are adverse drug interactions. This is particularly true for critically ill
circumstances in which normal therapeutic drug levels are main- patients. Not only do such patients receive multiple medications, but
tained, but the patient still experiences toxicity. they also are frequently experiencing organ system dysfunction that
The timing of drug monitoring is important if the results are to be can affect drug metabolism, and they often have multiple medical
accurately interpreted. The sample for the peak level should be issues that may mask the adverse drug effects. Interaction between
drawn 30 to 60 minutes after a dose is administered; the sample for drugs may lead directly to toxic effects, or it may be indirectly harm-
the trough level should be drawn just before the next dose is to be ful by decreasing the efficacy of one or both agents.
administered. If there is significant concern about a potentially toxic Drug interactions may affect any or all of the four primary phar-
trough level, the next dose may be held until the level can be deter- macokinetic parameters (i.e., ADME). Absorption effects are mainly
mined. The timing of these blood draws should be noted as precise- limited to simultaneous administration of enteral medications.
ly as possible. Ideally, samples should not be drawn until the drug Incompatibilities may also arise with I.V. medications, but usually, the
has been administered for five half-lives. When a patient is critically only practical consequence is that the two incompatible agents cannot
ill, however, five half-lives may be too long to wait. If so, samples may be administered through the same I.V. tubing at the same time.
be drawn before and after the third dose (for trough and peak levels, Distributional effects are usually secondary to competition for binding
respectively). In such cases, the levels obtained must be interpreted sites on proteins. Once the sites are saturated, the amount of free drug
carefully, first, because a true steady-state may not have been can increase if the metabolism and elimination pathways are intact and
achieved, and second, because these trough and peak levels are not unsaturated. Clinically, drugs that compete with warfarin for protein
from the same dose. binding sites may significantly increase the level of unbound warfarin,
It should be kept in mind that standard drug level monitoring thus increasing the risk of bleeding. Metabolic effects primarily involve
measures both the bound fraction and the unbound fraction of the induction or inhibition of CYP enzymes [see Table 2]. Elimination
drug. In certain circumstances (e.g., a patient with low plasma pro- effects primarily involve impairment of renal function or competition
tein levels), the drug level can be misleading. Phenytoin is an exam- for tubular secretion pathways.
ple of a drug that is highly protein bound. If plasma protein levels are Pharmacodynamic interactions can either enhance or decrease the
low, unbound drug levels can rise significantly even when total drug efficacy of a drug. For example, two antihypertensive medications
levels do not. In addition, a number of drugs are metabolized to an from different classes may have additive effects when used together. In
active metabolite that may contribute to toxicity. Some such metabo- contrast, two β-lactam antibiotics may be antagonistic when used
lites, (e.g., the procainamide metabolite N-acetylprocainamide) can together if one induces production of a β-lactamase that subsequently
be measured. metabolizes the other.
Desired peak and trough ranges vary from one drug to another
according to the desired effect and the risk of toxicity.With aminogly-
cosides, for example, toxicity is related to both the peak level (ototox- Adverse Effects of Drugs
icity) and the trough level (renal toxicity), whereas efficacy is mostly As noted (see above), critically ill and postoperative patients tend to
based on the peak level (concentration-dependent bacterial killing). be experiencing multiple medical issues and to be taking multiple
Once-daily administration of a large dose to achieve a high plasma pharmacologic agents, both of which make it difficult to determine
concentration seems to be advantageous in terms of maximizing the what the adverse effects of any single drug may be. Accordingly, a high
efficacy of aminoglycosides and minimizing their toxicity. (This index of suspicion is critical in these patients. Drugs can cause nephro-
approach differs from the once-daily dosing that may be necessary in toxicity via acute tubular necrosis, interstitial nephritis, or glomeru-
a patient with renal insufficiency.) In contrast, with vancomycin, effi- lonephritis. For example, aminoglycosides and amphotericin B can
cacy depends on maintaining an adequate plasma level for as long as cause acute tubular necrosis, whereas penicillins tend to cause inter-
possible.Thus, the trough level is used to determine adequacy of dos- stitial nephritis through immune responses. Hepatic dysfunction can
ing, particularly in situations where higher than normal levels may be be caused by direct hepatocellular effects or by cholestasis.


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