Chapter 056

response to low molecular weight compounds administered with
therapeutic intent; the goal is to nd the right drug for the right
disease.
DEFINITION OF PHARMACOGENETIC TERMS
All copies of a specic gene present within a population may not
have identical nucleotide sequences (genetic polymorphisms);
these contribute to the variability observed in that population.
The presence of different nucleotides at a given position within
a gene is a single-nucleotide polymorphism (SNP) [see Chapter
82]. Haplotypes are collections of SNPs and other allelic varia-
tions that are located close to each other and when inherited
together create a catalog of haplotypes, or HapMap. In genes in
which polymorphisms are detected, alternative forms of the gene
are called alleles. When the alleles at a particular gene locus on
both chromosomes are identical, a homozygous state exists,
whereas the term heterozygous refers to the situation in which
different alleles are present at the same gene locus. Genotype
refers to an individuals genetic constitution, whereas the observ-
able characteristics or physical manifestations constitute the
phenotype, which is the net consequence of genetic and
environmental effects (see Chapters 7883). Pharmacogenetics
focuses on the phenotypic consequences of allelic variation in
single genes. Pharmacogenetic polymorphism is a monogenic trait
caused by the presence (in the same population) of >1 allele (at
the same locus) and >1 phenotype with regard to drug interac-
tion with the organism. The key elements of pharmacogenetic
polymorphisms are heritability, the involvement of a single gene
locus, and the fact that distinct phenotypes are observed within
the population only after drug challenge. Furthermore, ethnicity
is another potential genetic determinant of drug variability.
Chinese patients who are HLA-B*1502-positive have an
increased risk of carbamazepine-induced Stevens-Johnson syn-
drome; white patients who are HLA-B*5701-positive have an
increased risk of hypersensitivity to abacavir (Table 56-3).
DEVELOPMENTAL OR PEDIATRIC
PHARMACOGENETICS AND PHARMACOGENOMICS
Our current understanding of pharmacogenetic principles
involves enzymes responsible for drug biotransformation. Indi-
viduals are classied as being fast, rapid, or extensive
metabolizers at 1 end of the spectrum, and slow or poor
metabolizers at the other end of a continuum that may, depend-
ing on the particular enzyme, also include an intermediate
metabolizer group. Pediatric patients have more complexity
because fetuses and newborns may be phenotypically slow or
poor metabolizers for certain drug-metabolizing pathways,
acquiring a phenotype consistent with their genotype at some
point later in the developmental process as those pathways
mature (glucuronidation, some cytochrome P450 [CYP] activi-
ties) [see Chapters 57, 96, and 97]. It is apparent that not all
infants acquire drug metabolism activity at the same rate due to
the interaction between genetics and environmental factors.
Interindividual variability in the trajectory (rate and extent) of
acquired drug biotransformation capacity may be considered a
developmental phenotype (Fig. 56-2), and it helps to explain the
considerable variability in some CYP activities observed immedi-
ately after birth.
321
Chapter 56
Pharmacogenetics,
Pharmacogenomics, and
Pharmacoproteomics J. Steven Leeder,
Gideon Koren, and Jacob V. Aranda
Interindividual variability in the response, intended or unantici-
pated, to similar doses of a given drug is an inherent character-
istic of drug therapy. The role of genetic factors in drug
disposition and response is termed pharmacogenetics and is due
to variations in human genes that can lead to variability in drug
responses in individual patients (Table 56-1). Pharmacogenetic
variability contributes to the broad range of drug responses
observed in children at any given age or developmental stage;
pharmacogenetics will help to identify the right drug for the right
patient (Fig. 56-1).
PHARMACOGENETICS, PHARMACOGENOMICS, AND
THE CONCEPT OF PERSONALIZED MEDICINE
Certain adverse drug reactions, such as unusually prolonged
respiratory muscle paralysis due to succinylcholine, hemolysis
associated with antimalarial therapy, and isoniazid-induced
neurotoxicity, are a consequence of inherited variations in
enzyme activity. Pharmacogenetics is the study of genetically
determined variations in drug response; the importance of genetic
variation in drug disposition is illustrated by observations that
the half-lives of several drugs are more similar in monozygotic
twins than in dizygotic twins. In addition, environmental factors
(diet, smoking status, concomitant drug or toxicant exposure),
physiologic variables (age, sex, disease, pregnancy), and patient
compliance contribute to variations in drug metabolism and
response. Therapeutic drug monitoring programs have been the
earliest application of personalized medicine; these programs rec-
ognize that all patients are unique and that the serum concen-
tration-time data for an individual patient theoretically could be
used to optimize pharmacotherapy. Routine therapeutic drug
monitoring, however, does not necessarily translate to improved
patient outcome in all situations.
The pharmacokinetic properties of a drug are determined by
the genes that control its disposition in the body (absorption,
distribution, metabolism, excretion), with drug-metabolizing
enzymes and drug transporters assuming particularly important
roles (Table 56-2). The functional consequences of genetic varia-
tions in several drug-metabolizing enzymes have been described
in subjects representative of different ethnic groups. The most
common clinical manifestation of pharmacogenetic variability in
drug biotransformation is an increased risk of concentration-
dependent toxicity due to reduced clearance and drug
accumulation. In addition, the concentration-effect relationship
(pharmacodynamics) is more relevant for optimizing drug ef-
cacy. The pharmacogenetics of drug receptors and other target
proteins involved in signal transduction or disease pathogenesis
can also be expected to contribute signicantly to interindividual
variability in drug response.
Pharmacogenomics represents the marriage of pharmacology
and genomics and can be dened as the study of the genome-wide
Part VII
Pediatric Drug Therapy

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322 PART VII Pediatric Drug Therapy
TABLE 56-1. Examples of Effects of Gene Polymorphisms on Drug Response
GENE ENZYME/TARGET DRUG CLINICAL RESPONSE
CYP2D6 Cytochrome P450 2D6 Codeine Individuals homozygous for an inactivating mutation do not metabolize codeine to morphine and thus experience no
analgesic effect; rapid metabolizers may experience opiate toxicity
CYP2C9 Cytochrome P450 2C9 Warfarin Individuals heterozygous for a polymorphism need a lower dose of warfarin to maintain anticoagulation
NAT2 N-Acetyltransferase 2 Isoniazid, hydralazine Individuals homozygous for slow acetylation polymorphisms are more susceptible to isoniazid toxicity, or
hydralazine-induced systemic lupus erythematosus
TPMT Thiopurine S-methyltransferase Azathioprine Individuals homozygous for an inactivating mutation have severe toxicity if treated with standard doses of
azathioprine; rapid metabolism causes undertreatment
ADRB2 b-Adrenergic receptor Albuterol Individuals homozygous for a polymorphism get worse with regular use of albuterol
KCNE2 Potassium channel, voltage gated Erythromycin Individuals heterozygous for a polymorphism are more susceptible to life-threatening arrhythmias
SUR1 Sulfonylurea receptor 1 Sulfonylureas Individuals heterozygous for a polymorphism exhibit diminished sensitivity in sulfonylurea-stimulated insulin secretion
F5 Coagulation factor V (Leiden) Oral contraceptives Individuals heterozygous for a polymorphism are at increased risk for venous thrombosis
RYR1 Calcium ion release channel Halothane, succinylcholine Malignant hyperthermia
BCHE Butyrylcholinesterase Succinylcholine Prolonged paralysis
G6PD Glucose-6-phosphate dehydrogenase Primaquine (others) Hemolysis
CYP3A Cytochrome P450 Grapefruit juice Moderate inhibitor of intestinal (presystemic) rst pass metabolism of many drugs*
DRD3 Dopamine D
3
receptor Antipsychotic agents Tardive dyskinesia
DHFR Dihydrofolate reductase Methotrexate Drug resistance
TOP1 Topoisomerase 1 Anthracycline agents Drug resistance
EGFR Epidermal growth factor receptor Getinib Drug resistance
*Albendazole, benzodiazepines, buspirone, carbamazepine, cyclosporine, fexofenadine, uoxetine, indinavir, itraconazole, sertraline, sirolimus, tacrolimus, verapamil, warfarin.
Modied from Jorde LB, Carey JC, Bamshad MJ, et al: Medical Genetics, 3rd ed. St. Louis, Mosby, 2006, p 157.
TABLE 56-2. Some Important Relationships Between Drugs and Cytochrome P450 (CYP) Enzymes* and P-Glycoprotein (P-gp) Transporter
ENZYME DRUG SUBSTRATES INHIBITORS INDUCERS
CYP1A2 Caffeine, clomipramine (Anafranil
), clozapine (Clozaril
), theophylline Cimetidine (Tagamet
) Omeprazole (Prilosec
)
Flucoxamine (Luvox
) Tobacco
Ciprooxacin (Cipro)
CYP2C9 Diclofenac (Voltaren
), ibuprofen (Motrin
), piroxicam (Feldene
), Iosartan (Cozaar), irbesartan (Avapro), celecoxib (Celebrex), Fluconazole (Diucan) Rifampin (Rifadin
)
tolbutamide (Orinase
), warfarin (Coumadin
), phenytoin (Dilantin) Fluvastatin (Lescol)

Amiodarone (Cordarone)
Zarlukast (Accolate)
CYP2C19 Omeprazole, Iansoprazole (Prevacid), pantoprazole (Protonix), (S)-mephenytoin, nelnavir (Viracept), diazepam (Valium
), Cimetidine Rifampin
voriconazole (Vfend) Fluvoxamine
CYP2D6 CNS-active agents: Atomoxetine (Strattera), amitriptyline (Elavil
), desipramine (Norpramin
), imipramine (Tofranil
), Amidoarone (Cordarone
)
paroxetine (Paxil), haloperidol (Haldol
), risperidone (Risperdal), thioridazine (Mellaril
) Cimetidine
Antiarrhythmic agents: Mexiletine (Mexitil), propafenone (Rythmol) Fluoxetine (Prozac
)
b Blockers: Propranolol (Inderal
), metoprolol (Lopressor
), timolol (Blocadren
) Terbinane
Narcotics: Codeine, dextromethorphan, hydrocodone (Vicodin
) Paroxetine (Paxil )
Tamoxifen (Nolvadex) Quinidine (Quinidex
)
Ritonavir
CYP3A4 Calcium channel blockers: Diltiazem (Cardizem
), felodipine (Plendil), nimodipine (Nimotop), nifedipine (Adalat
), Amiodarone Barbiturates
nisoldipine (Sular), nitrendipine, verapamil (Calan
) Clarithromycin Carbamazepine (Tegretol
)
Immunosupressive agents: Cyclosporine A (Sandimmune, Neoral
), tacrolimus (Prograf) Erythromycin Efavirenz (Sustiva)

Steroids: Budesonide (Pulmicort), cortisol, 17-estradiol, progesterone, testosterone Fluconazole Nevirapine (Viramune)
Macrolide antibiotics: Clarithromycin (Biaxin), erythromycin (Ertythrocin
), troleandomycin (TAO) Grapefruit juice Phenytoin (Dilantin
)
Anticancer agents: Cyclophosphamide (Cytoxan
), getinib (Iressa), ifosfamide (Ifex), tamoxifen, vincristine (Oncovin
), Imatinib Rifampin
vinblastine (Velban
), Itraconazole (Sporanox) Ritonavir
Benzodiazepines: Alprazolam (Xanax
), midazolam Versed
), triazolam (Halcion
) Ketoconazole (Nizoral
) St. Johns wort

Opioids: Alfentanyl (Alfenta
), fentanyl (Sublimaze
), sufentanil (Sufenta
) Nefazodone (Serzone)
HMG-CoA reductase inhibitors: Lovastatin (Mevacor
, simvastitin (Zocor), atorvastatin (Lipitor) Ritonavir
HIV protease inhibitors: Indinavir (Crixivan), nelnavir, ritonavir (Norvir), saquinavir (Invirase, Fortovase), Indinavir
amprenavir (Agenerase)
Others: Quinidine (Quinidex
), sildenal (Viagra), eletriptan (Relpax), ziprasidone (Geodon) Troleandomycin

P-gp Aldosterone, amprenavir, atorvastatin, cyclosporine,dexamethasone (Decadron
), digoxin (Lanoxin
), diltiazem, domperidone Amiodarone Amprenavir

(Motilium), doxorubicin (Adriamycin
), erythromycin, etoposide (Vepesid), fexofenadine (Allegra), hydrocortisone, Carvedilol (Coreg) Clotrimazole (Mycelex
)
indinavir, ivermectin (Stromectol), lovastatin loperamide (lmodium
), nelnavir, ondansetron (Zofran), Clarithromycin Phenothiazine

paclitaxel (Taxol), quinidine, saquinavir, simvastatin, verapamil, vinblastine, vincristine Cyclosporine Rifampin
Erythromycin Ritonavir
Itraconazole St. Johns wort

Ketoconazole
Quinidine
Ritonavir
Tamoxifen
Verapamil
*www.drug-interactions.com.
Also available generically.
Can be both an inhibitor and an inducer.

From Med Lett 2003;45:47.
CNS, central nervous system.
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Chapter 56 Pharmacogenetics, Pharmacogenomics, and Pharmacoproteomics 323
Treatment Outcome
M
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Failure Success
Treat with alternative
drug
Drug C
drug
drug or dose
Treat with conventional
drug and dose Drug B
Figure 56-1. The promise of genomic medicine to human health and disease. The goal of personalized medicine will be achieved by identifying subgroups of
patients who will respond favorably to a given drug with a minimum of side effects, as well as those who will not respond or who will show excessive toxicity
with standard doses. A further benet of pharmacogenomics will be the ability to select the most appropriate alternative drug for patients who cannot be treated
successfully with conventional drugs and doses.
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PHARMACOGENETIC, PHARMACOGENOMIC, AND PHARMACOPRO-
TEOMIC TOOLS. In contrast to pharmacogenetic studies that
typically target single genes, pharmacogenomic analyses are
considerably broader in scope because they focus on complex and
highly variable drug-related phenotypes (valproic acid hepato-
toxicity or weight gain; tumor response to cancer chemotherapy;
drug response in asthma, epilepsy, and attention-decit/hyperac-
tivity disorder). Systematic surveys of gene expression in differ-
ent cell types (tumor cells vs normal cells) are often conducted
with the hope of identifying new targets for pharmacothera-
peutic intervention. Cataloging differential gene expression
before and after drug exposure has the potential to correlate gene
expression with variable drug responses and possibly uncover the
mechanisms of tissue-specic drug toxicities. These types of
studies use microarray, or gene-chip, technology to monitor
global changes in expression of thousands of genes simultane-
ouslyglobal gene prolingin marked contrast to the labo-
ratory technique of Northern blot analysis that studies gene
expression 1 gene at a time. A microarray consists of a matrix of
DNA fragments (probes) precisely positioned at high density on
a solid support, such as a glass slide or a lter (see Chapter 79).
The probes serve as molecular detectors for messenger RNA
(mRNA) in the sample. Common experimental designs involve
TABLE 56-3. Internet Resources for Pharmacogenetics and
Pharmacogenomics*
INTRODUCTION TO PHARMACOGENOMICS
http://www.ornl.gov/TechResources/Human_Genome/medicine/pharma.html
http://www.ama-assn.org/ama/pub/category/2306.html
http://www.ncbi.nlm.nih.gov/About/primer/pharm.html
http://pubs.acs.org/cen/coverstory/7933/7933pharmacogenomics.html
PHARMACOGENETICS: ALLELIC VARIANTS OF DRUG METABOLIZING ENZYMES
CYP2C9 http://www.imm.ki.se/CYPalleles/cyp2c9.htm
CYP2C19 http://www.imm.ki.se/CYPalleles/cyp2c19.htm
CYP2D6 http://www.imm.ki.se/CYPalleles/cyp2d6.htm
CYP3A4 http://www.imm.ki.se/CYPalleles/cyp3a4.htm
CYP3A5 http://www.imm.ki.se/CYPalleles/cyp3a5.htm
UGTs http://som.inders.edu.au/FUSA/ClinPharm/UGT/allele_table.html
NAT1 and NAT2 http://www.louisville.edu/medschool/pharmacology/NAT.html
PHARMACOGENETICS: SUBSTRATES OF DRUG METABOLIZING ENZYMES
http://www.drug-interactions.com
INTRODUCTION TO PROTEOMICS
http://www.ama-assn.org/ama/pub/category/3668.html
http://www.e-proteomics.net
*All sites were accessible on March 31, 2006.
80
100
60
5 Birth 15 10 20 25
5 Birth 15 10 20 25
20
40
80
100
60
0
20
40
A
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Adult Child
Age (yr)
Infant
Figure 56-2. Developmental phenotypes. Variability in devel-
opmental changes in gene expression and functional enzyme
activity are superimposed on pharmacogenetic determinants.
The top panel shows the developmental prole of a theoretical
drug-metabolizing enzyme over a 25 yr span in 20 subjects. At
maturity (adults), allelic variation within the coding region of the
gene gives rise to 2 distinct phenotypes, high activity in 92% of
the population (extensive metabolizers; red circles) and low
activity in 8% of the population (poor metabolizers; yellow
circles). However, there is also interindividual variability in the
rate at which functional activity is acquired after birth. For
example, the 2 phenotypes may not be readily distinguishable in
newborn infants immediately after birth. Furthermore, there may
be discrete periods during childhood in which the genotype-phe-
notype relationship may differ from that observed in adults (e.g.,
developmental stages at which enzyme activity appears to be
greater in children than in adults).
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labeling mRNA (or complementary DNA [cDNA]) from a
control sample with 1 uorescent dye and mRNA or cDNA from
the disease or treatment sample with a 2nd uorescent dye, using
an experimental strategy that allows expression to be compared
with the sample pair. The expression pattern of thousands of
genes can be analyzed in a single sample with the underlying
hypothesis that the measured intensity for each arrayed gene rep-
resents its relative expression level. DNA chips can also be made
that focus on specic polymorphisms in a particular enzyme
system. The FDA has approved a chip for the P450 system
enzymes CYP2D6 and CYP2C19, which may be responsible for
25% of all drug metabolism in humans. A 2nd expression pro-
ling technique, serial analysis of gene expression (SAGE), over-
comes technical limitations of microarrays related to their ability
to conduct comparative data analyses and effectively detect low-
abundance transcripts.
Proteomic studies use many different techniques to detect,
quantify, and identify proteins in a sample (expression pro-
teomics), and to characterize protein function in terms of
activity and protein-protein or proteinnucleic acid interactions
(functional proteomics). Two-dimensional electrophoresis (2DE)
coupled with mass spectral detection (2DE-MS) is the mainstay
of expression proteomics. Protein spots of interest are
picked; digested with a proteolytic enzyme, such as trypsin;
and identied by mass spectrometry. The data generated are
compared with theoretically derived peptide mass databases for
protein identication.
DEVELOPMENTAL PHARMACOGENETICS OF DRUG
BIOTRANSFORMATION: APPLICATIONS TO
PEDIATRIC DRUG THERAPY PRACTICE
The major consequence of pharmacogenetic polymorphism in
drug-metabolizing enzymes is concentration-dependent toxicity
due to impaired drug clearance. In certain cases, reduced con-
version of prodrug to therapeutically active compounds is also of
clinical importance (see Table 56-1). Chemical modication of
drugs via biotransformation reactions generally results in termi-
nation of biologic activity through decreased afnity for recep-
tors or other cellular targets as well as more rapid elimination
from the body. The process of drug biotransformation can be very
complex, but is characterized by 3 important features. First is the
concept of broad substrate specicitya single isozyme may
metabolize a large variety of chemically diverse compounds.
Second, many different enzymes may be involved in the bio-
transformation of a single drug (enzyme multiplicity). Finally, a
given drug may undergo several different reaction types. One
example of this product multiplicity is racemic warfarin, where
at least 7 hydroxylated metabolites have been identied and are
produced by different CYP isoforms.
Drug biotransformation reactions are conveniently classied
into 2 main types, phase I and phase II reactions, which occur
sequentially (see Chapter 57). Phase I reactions introduce or
reveal (by oxidation, reduction, or hydrolysis) a functional group
within the substrate drug molecule that serves as a site for a phase
II conjugation reaction. Conjugation with endogenous substrates,
such as acetate, glucuronic acid, glutathione, glycine, and sulfate,
further increases the polarity of an intermediate metabolite and
thereby enhances its renal excretion. Interindividual variability in
drug biotransformation activity is a consequence of the complex
interplay among genetic (genotype, sex, race or ethnic back-
ground) and environmental (diet, disease, concurrent medication,
other xenobiotic exposure) factors. The pathway and rate of a
given compounds biotransformation is a function of each indi-
viduals unique phenotype with respect to the forms and amounts
of drug-metabolizing enzymes expressed.
The CYPs, quantitatively the most important of the phase I
enzymes, are heme-containing proteins that catalyze the metabo-
lism of many lipophilic endogenous substances (steroids, fatty
acids, fat-soluble vitamins, prostaglandins, leukotrienes, throm-
boxanes) and exogenous compounds, such as drugs. CYP nomen-
clature is based on evolutionary considerations and uses the root
symbol CYP for cytochrome P450. CYPs that share at least 40%
homology are grouped into families denoted by an Arabic
number after the CYP root. Subfamilies, designated by a letter,
appear to represent clusters of highly related genes. Members of
the human CYP2 family, for example, have >67% amino acid
sequence homology. Individual P450s in a subfamily are num-
bered sequentially (CYP3A4, CYP3A5). CYPs that have been
identied as being important in human drug metabolism are pre-
dominantly found in the CYP1, CYP2, and CYP3 gene families.
Enzyme activity may be induced or inhibited by various agents
(see Table 56-2).
Phase II enzymes include arylamine N-acetyltransferases
(NAT1, NAT2), glucuronosyl transferases (UGTs), epoxide
hydrolase, glutathione S-transferases (GSTs), sulfotransferases
(SULTs), and methyltransferases (catechol O-methyltransferase,
thiopurine S-methyltransferase, several N-methyltransferases).
Like the CYPs, UGTs, SULTs, and GSTs are gene families with
multiple individual isoforms, each having its own preferred
substrates, mode of regulation, and tissue-specic pattern of
expression.
For most CYPs, genotype-phenotype relationships are inu-
enced by development in that fetal expression is limited (with
the exception of CYP3A7) and functional activity is acquired
postnatally in isoform-specic patterns. Clearance of some
compounds appears to be greater in children relative to adults,
obscuring the correlation between genotype and phenotype in
neonatal life through adolescence.
CYP2D6. The CYP2D6 gene locus is highly polymorphic, with >75
allelic variants identied to date (http://www.imm.ki.se/CYPalle-
les/cyp2d6.htm; see Table 56-2). Individual alleles are designated
by the gene name (CYP2D6) followed by an asterisk, and an
Arabic number; CYP2D6*1 designates, by convention, the fully
functional wild-type allele. Allelic variants are the consequence
of point mutations, single base pair deletions or additions, gene
rearrangements, or deletion of the entire gene, resulting in a
reduction or complete loss of activity. Inheritance of 2 recessive
loss-of-function alleles results in the poor-metabolizer phenotype,
which is found in approximately 510% of white subjects and
approximately 12% of Asian subjects. In white subjects, the *3,
*4, *5, and *6 alleles are the most common loss-of-function
alleles and account for approximately 98% of poor-metabolizer
phenotypes. In contrast, CYP2D6 activity on a population basis
tends to be lower in Asian and African-American populations due
to a lower frequency of nonfunctional alleles (*3, *4, *5, and *6)
and a relatively high frequency of population-selective alleles that
are associated with decreased activity relative to the wild-type
CYP2D6*1 allele. The CYP2D6*10 allele occurs at a frequency
of approximately 50% in Asians, whereas CYP2D6*17 and
CYP2D6*29 occur at relatively high frequencies in subjects of
black African origin. Homozygosity for the *10 allele is associ-
ated with decreased clearance of CYP2D6 substrates, such as
metoprolol and nortriptyline.
CYP2D6 is involved in the biotransformation of >40
therapeutic entities, including several -receptor antagonists,
antiarrhythmics, antidepressants, antipsychotics, and morphine
derivatives (for an updated list, see http://medicine.iupui.edu/
ockhart; see Table 56-2). Selective serotonin reuptake inhibitors
(SSRIs; uoxetine, paroxetine, sertraline), atomoxetine, codeine,
and dextromethorphan are commonly encountered in pediatrics.
Very limited CYP2D6 activity is present in fetal liver in vitro
(1% of adult values), but CYP2D6 protein is detectable in all
samples from newborns. Thereafter, both CYP2D6 protein and
catalytic activity progressively increase over the 1st 28 days of
life to 20% of activity observed in adult samples. In contrast, in
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vivo data derived from a longitudinal phenotyping study con-
ducted over the 1st year of life using dextromethorphan as a
probe compound suggest that the CYP2D6 phenotype is concor-
dant with genotype by 2 wk of age. Dextromethorphan pheno-
typing data from older children suggest that CYP2D6 catalytic
activity in children is comparable to that in adults by at least
10 yr of age, and probably much earlier. There are insufcient
data from pharmacokinetic studies to determine the age at
which the clearance of CYP2D6 substrates is comparable to
that observed in adults.
One consequence of CYP2D6 developmental pharmacogenet-
ics may be the syndrome of irritability, tachypnea, tremors,
jitteriness, increased muscle tone, and temperature instability in
neonates born to mothers receiving SSRIs during pregnancy. Con-
troversy currently exists as to whether these symptoms reect a
neonatal withdrawal (hyposerotonergic) state or represent man-
ifestations of serotonin toxicity analogous to the hyperseroton-
ergic state associated with the SSRI-induced serotonin syndrome
in adults (see Chapter 106). Delayed expression of CYP2D6 (and
CYP3A4) in the 1st few wk of life is consistent with a hyper-
serotonergic state due to delayed clearance of paroxetine and u-
oxetine (CYP2D6) or sertraline (CYP3A4) in neonates exposed
to these compounds during pregnancy. Furthermore, decreases in
plasma SSRI concentrations and resolution of symptoms would
be expected with increasing postnatal age and maturation of these
pathways. Given that treatment of a withdrawal reaction may
include administration of an SSRI, there is considerable potential
for increased toxicity in affected neonates. Resolution of the
hyperserotonergic vs hyposerotonergic pathogenesis is essential
for appropriate management of SSRI-induced neonatal adapta-
tion syndromes. Until further data are available, it would be
prudent to consider newborns and infants younger than 28 days
of age as CYP2D6 poor metabolizers.
In older children, drug accumulation and resultant concentra-
tion-dependent toxicities in CYP2D6 genotypic poor metaboliz-
ers should be anticipated as they are in adults due to the risk of
signicant morbidity and mortality. Experience with paroxetine
shows that the risk of drug accumulation is not necessarily limited
to the poor-metabolizer phenotype. Although the pharmacoki-
netics of the CYP2D6 substrates paroxetine and nefazodone cor-
relate with the CYP2D6 phenotype in children and adolescents
717 yr of age, chronic dosing of paroxetine may lead to greater
than anticipated drug accumulation in children classied as
CYP2D6 extensive metabolizers. In depressed children and ado-
lescents as well as in adults, there is a disproportionate increase
in peak concentration and area under the serum concentration-
time curve at higher dose levels. However, nonlinearity is more
prominent in patients who are CYP2D6 extensive metabolizers,
especially those with gene duplication events and 3 or more
functional alleles. The largest decreases in paroxetine clearance
observed with ascending dose are seen in patients who have the
greatest clearance at the initial dose level (10 mg/day) and are pre-
dicted to have the greatest CYP2D6 activity, based on CYP2D6
genotype. This rather paradoxical effect is best explained in the
context of recent data from in vitro studies. One proposed mech-
anism involves oxidation of paroxetine within the CYP2D6 active
site to form a reactive intermediate that is associated with irre-
versible modication of the CYP2D6 protein in or near the active
site. The greater the initial CYP2D6 activity, the greater the
burden of reactive metabolite formation and thereby the greater
the loss of CYP2D6 catalytic activity. As a consequence, as the
paroxetine dose is increased in patients with higher initial drug
clearance, the risk of excessive drug accumulation escalates
disproportionately.
Theoretically, younger children may experience decreased ef-
cacy or therapeutic failure with drugs such as codeine and tra-
madol that are dependent on functional CYP2D6 activity for
conversion to the pharmacologically active species. Infants and
children appear capable of converting codeine to morphine,
achieving morphine : codeine ratios comparable to those of
adults. However, in one study, morphine and its metabolites were
not detected in 36% of children receiving codeine and codeine
analgesia was found to be unreliable in the studied pediatric pop-
ulation and not related to the CYP2D6 phenotype. Ultrarapid
CYP2D6 metabolism of codeine may result in opiate intoxica-
tion. CYP2D6 catalyzes the O-demethylation of codeine to mor-
phine. Ultrarapid metabolism of codeine results in high serum
and breast milk concentrations of morphine and may have
adverse effects in the breastfed neonate.
CYP2C9. Although several clinically useful compounds are sub-
strates for CYP2C9 (http://medicine.iupui.edu/ockhart) [see
Table 56-2], the effects of allelic variation are most profound
for drugs with a narrow therapeutic index, such as phenytoin,
warfarin, and tolbutamide. In vitro studies show a progressive
increase in CYP2C9 expression from 12% of mature levels in
the 1st trimester to approximately 30% at term. Considerable
variability (35-fold) in expression is apparent over the 1st 5 mo
of life, with approximately
1
/
2
of the samples exhibiting values
equivalent to those observed in adults. One interpretation of these
data is broad interindividual variability in the rate at which
CYP2C9 expression is acquired after birth, and in general, the
ontogeny of CYP2C9 activity in vivo, as inferred from pharma-
cokinetic studies of phenytoin in newborns, is consistent with the
in vitro results. The apparent half-life of phenytoin is prolonged
(approximately 75 hr) in preterm infants, but decreases to
approximately 20 hr in term newborns during the 1st yr of life.
By 2 wk of age, the half-life has further declined to 8 hr. The
appearance of concentration-dependent (saturable) metabolism
of phenytoin, reecting the functional acquisition of CYP2C9
activity, does not appear until approximately 10 days of age. The
maximal velocity of phenytoin metabolism has been reported
to decrease from an average of 14 mg/kg/day in infants to
8 mg/kg/day in adolescents, which may reect changes in the ratio
of liver mass to total body mass observed over this period of
development, as has been observed for warfarin.
At least 24 allelic variants of CYP2C9 have been reported, but
not all have been evaluated for their functional consequences. The
CYP2C9*2 allele is associated with approximately 5.5-fold
decreased intrinsic clearance for S-warfarin relative to the wild-
type enzyme. Allelic variations resulting in amino acid changes
within the enzyme active site, such as the CYP2C9*3,
CYP2C9*4, and CYP2C9*5 alleles, are associated with activities
that are approximately 5% of the wild-type protein. Approxi-
mately
1
/
3
of the white population carries a variant CYP2C9 allele
(*2 and *3 alleles, most commonly), whereas the *2 and *3
alleles are virtually nonexistent in African-American, Chinese,
Japanese, or Korean populations. In contrast, the *5 allele has
been detected in African-Americans, but not in white subjects.
The risk of bleeding complications in patients treated with war-
farin and with concentration-dependent phenytoin toxicity is
most pronounced for individuals with a CYP2C9*3/*3 genotype.
Although the relationship between the CYP2C9 genotype and
warfarin dosing and pharmacokinetics has not been as exten-
sively studied in children, consequences of allelic variation can be
expected to be similar to those observed in adults.
CYP2C19. In vitro, CYP2C19 protein and catalytic activity can be
detected at levels representing 1215% of mature values by 8 wk
gestation and remain essentially unchanged throughout gestation
and at birth. Over the 1st 5 mo of postnatal age, CYP2C19 activ-
ity increases linearly. Adult levels are achieved by 10 yr of age,
although variability in expression is estimated to be approxi-
mately 21-fold between 5 mo and 10 yr of age. The major source
of this variability likely is pharmacogenetic in nature. The
CYP2C19 poor-metabolizer phenotype (also known as mepheny-
toin hydroxylase deciency) is present in 35% of the white pop-
ulation and 2025% of Asians. Although 19 variant alleles have
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been reported to date, the 2 most common variant alleles,
CYP2C19*2 and CYP2C19*3, result from single base substitu-
tions that introduce premature stop codons and, consequently,
truncated polypeptide chains that possess no functional activity.
Despite the increases in CYP2C19 activity observed in vitro over
the 1st 5 mo of life, the results of an in vivo phenotyping study
with omeprazole in Mexican children implied that 17% of infants
younger than 4 mo of age could be classied as poor metaboliz-
ers, whereas none were detected beyond that point. In contrast,
20% of children 39 mo old were classied as ultrarapid metab-
olizers compared with 6% of infants 13 mo of age. For omepra-
zole, pharmacokinetic parameters comparable to those observed
in adults are achieved by 2 yr of age.
In Japanese adults treated with lansoprazole, amoxicillin, and
clarithromycin for Helicobacter pylori infection, the eradication
rate for CYP2C19 poor metabolizers (97.8%) and heterozygous
extensive metabolizers (1 functional CYP2C19 allele; 92.1%)
was signicantly greater than that observed in homozygous
extensive metabolizers (72.7%). Of the 35 patients in whom
initial treatment did not eradicate H. pylori, 34 had at least 1
functional CYP2C19 allele and eradication could be achieved
with higher lansoprazole doses in almost all cases. Given that the
frequency of the functional CYP2C19*1 allele is considerably
greater in white subjects (0.84 [84%]) compared with Japanese
subjects (0.55 [55%]), eradication failure can be expected to
occur more frequently in whites. Because proton pump inhibitors
are also widely used clinically in pediatrics, pharmacogenetic as
well as developmental considerations should guide dosing strate-
gies in children.
CYP3A4, CYP3A5, AND CYP3A7. The CYP3A subfamily consists of
4 members in humans (CYPs 3A4, 3A5, 3A7, and 3A43) and is
quantitatively the most important group of CYPs in terms of
human hepatic drug biotransformation. These isoforms catalyze
the oxidation of many different therapeutic entities, several of
which are of potential importance to pediatric practice (for an
updated list, see http://medicine.iupui.edu/ockhart; see Table 56-
2). CYP3A7 is the predominant CYP isoform in fetal liver and
can be detected in embryonic liver as early as 5060 days gesta-
tion. CYP3A4, the major CYP3A isoform in adults, is essentially
absent in fetal liver, but increases gradually throughout child-
hood. Over the 1st 6 mo of life, CYP3A7 expression exceeds that
of CYP3A4, although its catalytic activity toward most CYP3A
substrates is rather limited compared with that of CYP3A4.
CYP3A4 is also abundantly expressed in intestine, where it
contributes signicantly to the 1st-pass metabolism of orally
administered substrates, such as midazolam. CYP3A5 is
polymorphically expressed and is present in approximately 25%
of adult liver samples studied in vitro.
Several methods have been proposed to measure CYP3A activ-
ity. Using these various phenotyping probes, CYP3A4 activity has
been reported to vary widely (up to 50-fold) among individuals,
but the population distributions of activity are essentially
unimodal and evidence for polymorphic activity has been
elusive. Although 20 allelic variants have been identied
(http://www.imm.ki se/CYPalleles/cyp3a4.htm), most occur rela-
tively infrequently and do not appear to be of clinical importance.
Of interest to pediatrics is the CYP3A4*1B allele present in the
CYP3A4 promoter region. The clinical signicance of this allelic
variant appears limited with respect to drug biotransformation
activity, despite being associated with 2-fold increased activity
over the wild-type CYP3A4*1 allele in in vitro assays. Although
there does not appear to be an association between the
CYP3A4*1B allele and age of menarche, a signicant relation-
ship does exist between the number of CYP3A4*1B alleles
and the age at onset of puberty, as dened by Tanner breast score.
In one study, 90% of 9 yr old girls with a CYP3A4*1B/*1B geno-
type had a Tanner breast score of 2 compared with 56% of
CYP3A4*1A/*1B heterozygotes and 40% of girls homozygous
for the CYP3A4*1A allele. Because CYP3A4 plays an important
role in testosterone catabolism, the authors of the latter study
proposed that the estradiol : testosterone ratio may be shifted
toward higher values in the presence of the CYP3A4*1B allele
and trigger the hormonal cascade that accompanies puberty.
Intestinal CYP3A4 activity is inhibited by grapefruit juice and
may result in higher levels of the many drugs metabolized by this
enzyme; very large quantities of grapefruit juice may also inhibit
the hepatic CYP3A4 enzyme (see Table 56-1).
Polymorphic CYP3A5 expression is largely due to a SNP in
intron 3 that creates a cryptic splice site and gives rise to mRNA
splice variants that retain part of intron 3 with a premature stop
codon. The truncated mRNA transcripts associated with this
allele, CYP3A5*3, cannot be translated into a functional protein.
Individuals with at least 1 wild-type CYP3A5*1 allele express
functional CYP3A5 protein, whereas those homozygous for
CYP3A5*3 (CYP3A5*3/*3) do not. Approximately 60% of
African-Americans show functional hepatic CYP3A5 activity
compared with only 33% of European Americans. Clinically
important consequences of CYP3A5 allelic variation have been
reported in children. In pediatric heart transplant patients with a
CYP3A5*1/*3 genotype, tacrolimus concentrations were approx-
imately 50% of those observed in patients with CYP3A5*3/*3
genotypes, when corrected for dose, 3 mo, 6 mo, and 12 mo after
transplant. Thus, larger doses of tacrolimus are required to
achieve comparable blood levels to minimize the risk of rejection.
GLUCURONOSYL TRANSFERASES. The UGT gene superfamily
catalyzes the conjugation of several drugs used clinically in
pediatrics, including morphine, acetaminophen, nonsteroidal
anti-inammatory drugs, and benzodiazepines, with glucuronic
acid. The effect of development on glucuronidation capacity is
well known to pediatricians in the form of hyperbilirubinemia,
gray baby syndrome (the cardiovascular collapse associated with
high doses of chloramphenicol in newborns), and the 3.5-fold
increase in morphine clearance observed in premature neonates
at 2439 wk post-conceptional age. As with the CYPs, there are
multiple UGT isoforms, and the acquisition of functional UGT
activity appears to be isoform- and substrate-specic.
UGT1A1 is the major UGT gene product responsible for biliru-
bin glucuronidation, and >60 genetic alterations have been
reported, most of which are rare and are more properly consid-
ered mutations rather than gene polymorphisms (see Chapters
102 and 354.1). Inheritance of 2 defective alleles is associated
with reduced bilirubin-conjugating activity and gives rise to
clinical conditions, such as Crigler-Najjar syndrome and Gilbert
syndrome. More frequently occurring polymorphisms involve
a dinucleotide (TA) repeat in the atypical TATA box of the
UGT1A1 promoter. The wild-type UGT1A1*1 allele has 6
repeats (TA
6
), and the TA
5
(UGT1A1*33), TA
7
(UGT1A1*28),
and TA
8
(UGT1A1*34) variants are all associated with reduced
activity. UGT1A1*28, the most frequent variant, is a contribu-
tory factor to prolonged neonatal jaundice and is associated with
impaired glucuronidation and thus toxicity of the irinotecan
active metabolite, SN-38. Allelic variation in UGT1A7 and
UGT1A9 also has been associated with irinotecan toxicity in
adults with colorectal cancer.
The consequences of allelic variation in the UGT2B family are
less certain. The predominant routes of morphine elimination
include biotransformation to the pharmacologically active 6-glu-
curonide (M6G) and the inactive 3-glucuronide (M3G). M6G
formation is almost exclusively catalyzed by UGT2B7, whereas
several UGTs in the UGT1A subfamily, as well as UGT2B7, con-
tribute to M3G formation. Increased M6G : morphine ratios
have been reported in individuals homozygous for the SNPs
constituting the UGT2B7*2 allele. Although individuals geno-
typed as UGT2B7*2/*2 may produce higher than anticipated
concentrations of pharmacologically active morphine and its
metabolites, prospective pharmacogenetic studies addressing
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phenotype-genotype correlations and the consequences of mor-
phine analgesia have not been conducted.
Arylamine N-Acetyltransferases. One of the earliest discovered
and most widely recognized genetic polymorphisms is the NAT2
polymorphism. Approximately 50% of whites and African-
Americans in North America are phenotypically slow metaboliz-
ers, placing a substantial number of individuals at increased risk
for the development of adverse drug effects, such as sulfasalazine-
induced hemolysis, hydrazine or arylamine-induced peripheral
neuropathy, procainamide- or isoniazid-induced systemic lupus
erythematosus, and Stevens-Johnson syndrome or toxic epider-
mal necrolysis associated with sulfonamide administration.
NAT2 function is inherited in an autosomal dominant fashion,
with the inheritance of 2 slow alleles required for expression
of the slow-metabolizer phenotype. The relative proportion of
rapid and slow metabolizers varies considerably with ethnic or
geographic origin. The percentage of slow acetylators among
Canadian Eskimos is 5%, but it approaches 90% in some
Mediterranean populations. According to the standardized NAT2
nomenclature, the wild-type and 3 additional fast alleles give
rise to the rapid acetylator phenotype, whereas 9 slow alleles
have been described.
In vivo, with the use of caffeine as a phenotyping probe, all
infants 055 days of age appear to be phenotypically slow acety-
lators, whereas 50% and 62% of infants 122224 and 225342
days of age, respectively, can be characterized as fast acetylators.
Several independent studies indicate that maturation of the NAT2
phenotype occurs during the rst 4 yr of life. Phenotype-genotype
discordance is likely to be most apparent in the rst 24 mo of
life, and drugs that are highly dependent on NAT2 function for
their elimination should be used with caution.
Thiopurine S-Methyltransferase. Thiopurine S-methyltransferase
(TPMT) is a cytosolic enzyme that catalyses the S-methylation of
aromatic and heterocyclic sulfur-containing compounds, such as
6-mercaptopurine (6MP), azathioprine, and 6-thioguanine, used
in the treatment of acute lymphoblastic anemia (ALL), inam-
matory bowel disease, and juvenile arthritis, and to prevent renal
allograft rejection. To exert its cytotoxic effects, 6MP requires
metabolism to thioguanine nucleotides by a multistep process
that is initiated by hypoxanthine guanine phosphoribosyl trans-
ferase. TPMT prevents thioguanine nucleotide production by
methylating 6MP (Fig. 56-3A). TPMT activity is usually mea-
sured in blood, with activity in erythrocytes reecting that found
in other tissues, including liver and leukemic blasts. Although
approximately 89% of whites and African-Americans have high
TPMT activity and 11% have intermediate activity, 1 in 300 indi-
viduals inherits TPMT deciency as an autosomal recessive trait
(Fig. 56-3B). In newborn infants, peripheral blood TPMT activ-
ity is reported to be 50% greater than in race-matched adults and
shows a distribution of activity that is consistent with the poly-
morphism characterized in adults. There are no data currently to
indicate how long this higher activity is maintained, although
TPMT activities were comparable to previously reported adult
values in a population of Korean schoolchildren aged 79 yr. In
patients with intermediate or low activity, more drug is shunted
toward production of cytotoxic thioguanine nucleotides. TPMT
can also methylate 6-thioinosine 5-monophosphate to generate
a methylated metabolite that is capable of inhibiting de novo
purine synthesis (Fig. 56-3C). In the small population (i.e., 0.3%)
of treated patients with relative TPMT deciency, severe and
potentially life-threatening myelosuppression can develop in
those receiving standard doses of thiopurine; starting doses must
be reduced to 610% of the normal dose.
TPMT*3A is the most common mutant allele and is charac-
terized by 2 nucleotide transition mutations, G460A and A719G,
that lead to 2 amino acid substitutions Ala154Thr and
Tyr240Cys (Fig. 56-3D). Although the *3A allele only has a fre-
quency of 0.03% in the general population, it represents 55% of
all mutant alleles. Either mutation alone results in loss of func-
tional activity through the production of unstable proteins that
are subject to accelerated proteolytic degradation. Less frequent
allelic variants involve SNPs that produce amino acid substitu-
tions in the coding region and defective intron-exon splicing. A
polymorphic locus has been identied in the promoter region of
the TPMT gene involving 48 repeats of a specic nucleotide
sequence in tandem. Although these repeats appear to modulate
TPMT activity when expressed in vitro, their role in regulating
activity in vivo has not been clearly established.
The relatively few patients with low to absent TPMT activity
are at increased risk for severe myelosuppression if treated with
routine doses of thiopurines; thus, they require a 1015-fold
reduction in dose to minimize this risk. Furthermore, these
patients may be at increased risk for relapse as a result of
inadequate or absent treatment with thiopurines. Given the
expanding use of 6MP and azathioprine in pediatrics to treat
inammatory bowel disease and juvenile arthritis and to prevent
renal allograft rejection, TPMT deciency is not a trivial matter.
Introduction of the TPMT phenotype or genotype determina-
tion into pediatric practice will lead to safer, more efcacious
treatment in pediatric patient groups. Although most research has
been conducted in ALL, the observation that patients classied
as having intermediate TPMT activity are more likely to be intol-
erant of 6MP or azathioprine and to require more frequent
dosage reductions in response to drug-induced myelosuppression
is equally applicable to other pediatric patient groups treated with
this family of drugs.
DEVELOPMENTAL PHARMACOGENETICS OF DRUG
TRANSPORTERS
ORGANIC ANION TRANSPORTERS. The organic anion transporter
(OAT) family transports a wide variety of xenobiotics, including
penicillins, cephalosporins, sulfonamides, loop and thiazide
diuretics, barbiturates, salicylates, and ochratoxin A, 2,4-
dichlorophenoxyacetic acid, as well as nonsteroidal anti-inam-
matory drugs. Located at the basolateral membrane of the
tubular cells, the OAT family is capable of removing scores of
xenobiotics through active tubular secretion. This transport is ter-
tiary, involving Na
+
, K
+
-ATPase, which maintains the Na
+
gradi-
ent between the blood and tubular cells. The Na
+
gradient drives
a Na
+
dicarboxylate cotransporter, sustaining a dicarboxylate
gradient that is used by a dicarboxylate/organic anion exchanger
to move the substrate into the cell. This cascade allows an organic
anion to enter the tubular cell against its concentration gradient
and against the electric potential of the cell.
The identication of the gene encoding for the OAT1 trans-
porter led to the discovery of several isoforms, including cOAT2,
hOAT3, and hOAT4. The different OATs have substantial
overlap in substrate specicity, while maintaining important dif-
ferences. Para-aminohippurate has high afnity for OAT1 and
OAT3, but much lower afnity for OAT2 and OAT4.
The newborn excretes penicillins (renal) at very low rates com-
pared with children and adults, whereas toddlers need a much
higher dose per kilogram of body weight compared with adults.
Before the maturation of tubular expression and function of the
OAT family, neonates exhibit very limited capacity to eliminate
renally anionic drugs. This is followed by an overshoot during
which toddlers have higher expression and function than adults,
subsequently decreasing to levels that are maintained during
adulthood. The fact that all members of the OAT family appear
to develop in a coordinated fashion suggests that these proteins
are controlled by a common signal for expression and/or tran-
scription. Another important phenomenon encountered with the
tubular secretion of organic anions is substrate induction, leading
to enhanced elimination of organic anions with repeated expo-
sure. This phenomenon is unique, although its biologic pattern
has not yet been elucidated.
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number of medicinal and other organic cations from the plasma,
against the concentration gradient. Most of the transporters that
secrete organic cations belong to a single family of transport pro-
teins, the OCT family.
Neonates possess very limited ability to eliminate organic
cations. This ability increases rapidly during the 1st few months
of life, and when standardized for body weight or surface area,
it tends to exceed adult levels during the toddler stage. Subse-
SCH
3
6TU
(inactive)
MeTIMP
Inhibition of de novo
purine synthesis
Anti-leukemic effect
Myelosuppression
TGNs TIMP
DNA
incorporation
TPMT
TPMT
XO
6MP
HPRT
MeMP
(inactive)
N
N
ribose P
N
N
SH
N
N
ribose P P P
N
N
SH
N
N
ribose P
N
N
SH
HO
H
2
N
OH
N
N
H
N
N
SH
N
N
H
N
N
SCH
3
N
N
H
N
N
wt/wt
wt/mut
mut/
mut
10
0
2
4
P
e
r
c
e
n
t

o
f

p
o
p
u
l
a
t
i
o
n8
6
0 10 5 15 20 25 30
TPMT activity
TPMT*1
(wild-type)
TPMT*3A
460 GA
AlaThr
719 AG
TyrCys
wt/wt wt/mut mut/mut TPMT genotype:
3000
0
1000
I
n
t
r
a
c
e
l
l
u
l
a
r

T
G
N
c
o
n
c
e
n
t
r
a
t
i
o
n
2000
Myelosuppression
Risk secondary cancer
Toxicity
Risk of relapse
A
B
D
C
Figure 56-3. Thiopurine S-methyl-
transferase (TPMT) polymorphism.
A, 6-Mercaptopurine (6MP) under-
goes metabolism to thioguanine
nucleotides (TGNs) to exert its cyto-
toxic effects. TPMT and xanthine
oxidase reduce the amount of 6MP
available for the bioactivation
pathway to TGNs. TPMT can
also methylate 6-thioinosine 5-
monophosphate (TIMP) to generate
a methylated compound capable of
inhibiting de novo purine synthesis.
B, Distribution of TPMT activity in
humans. Of the population, 89% has
high activity, whereas 11% has inter-
mediate activity. Approximately 1 in
300 individuals homozygous for 2
loss-of-function alleles has very low
activity. C, Correlation between the
TPMT genotype and intracellular
TGN concentrations. In TPMT poor
metabolizers, more 6MP is available
to go down the bioactivation
pathway to form TGNs; this situa-
tion is associated with an increased
risk of myelosuppression. D, The
most common variant TPMT allele is
the result of 2 mutations that give
rise to an unstable protein product
that undergoes proteolytic degrada-
tion. 6TU, 6-thiouric acid; MeMP,
6-methylmercaptopurine; HPRT,
6-thiomethylinosine 5-monophos-
phate; MeTIMP, hypoxanthine-
guanine phosphoribosyl transferase;
wt, wild type; mut, mutant. (Modi-
ed with permission from Relling
MV, Dervieux T: Pharmacogenetics
and cancer therapy. Nat Rev Cancer
2001;11:99108; copyright 2001,
Macmillan Magazines Ltd [130.])
ORGANIC CATION TRANSPORTERS. An organic cation transport
system in the renal tubular cell is responsible for active renal
secretion of several cationic drugs.
This secretory process occurs mostly at the proximal tubule.
More specically, the organic cation is located at the brush border
membrane, and its function is mediated by an organic cation-
proton antiporter. Similar to the OAT family, the organic cation
transporter (OCT) plays a critical role in removing a large
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quently, secretory function decreases to adult levels. This pattern
of development has major implications for the dosing of cationic
drugs: newborns require reductions in dose, whereas toddlers
commonly need much larger doses than older children and adults
when corrected for body weight or surface area.
THE ABC SUPERFAMILY. A variety of epithelial barriers, including
the kidney, liver, and blood-brain barrier have abundant expres-
sion of ABC transporters, such as P-glycoprotein (P-gp; also
known as MDR1), and multidrug resistance proteins (MRPs) 1,
2, and 3 (MRP1, MRP2, and MRP3, respectively). Powered by
ATP, these transporters actively extrude substrates from the
respective cell and organ.
Multidrug resistance transporters lead to lower cellular con-
centrations of drugs via an efux mechanism, creating pharma-
cologic sanctuaries. In the placenta, MRP1 and MRP3
preferentially transport organic anions, promote the excretion of
glutathione/glucuronide metabolites, and thus prevent their entry
into fetal blood.
The rst identied active drug transporter of the ATP-binding
cassette transporter family was P-gp, which has a wide range
of substrates. Abundant in apical membranes, P-gp transports
substrates in an outward (extracellular) direction. P-gp can be
detected in placental trophoblasts during the 1st trimester of
pregnancy, suggesting that it may play an important role in pro-
tecting the fetus from amphipathic xenotoxins.
In an attempt to reverse multidrug resistance in solid tumors,
the use of cyclosporine, an inhibitor of P-gp, has been shown to
increase tumor concentrations of daunorubicin, vinblastine, and
some other antitumor agents. Correlation has been repeatedly
shown between high expression of P-gp and tumor resistance to
anticancer therapy in both children and adults. The complexity
of these systems can be shown by cases of children with
retinoblastoma in whom high expression of P-gp was reversed by
the administration of cyclosporine, but who were still resistant
to chemotherapy in the presence of high expression of MRPs. The
ubiquitous expression of the MDR1 gene has led researchers to
try to link its levels and the function of P-gp to failure to achieve
adequate intracellular levels of chemotherapeutic agents in cancer
cells.
High expression of different ABC transporters, including BCRP
(breast cancer-resistant protein), MRP2, MRP3, MRP4, and
MRP5, has been correlated with response to therapy in childhood
acute myeloid leukemia. It appears that MRP3 and possibly
MRP2 are involved in drug resistance in this disease. These 2
transport proteins may well predict chemotherapy failure and
lead to the possible development of specic drugs to overcome
multidrug resistance.
ONTOGENY OF ABC TRANSPORTERS. The potential importance of
age-related development of ABC transporters has been docu-
mented with P-gp. Digoxin is eliminated by the renal tubular cell
by P-gp. Neonates need only a fraction of the weight-adjusted
dose of digoxin given to older children or adults. P-gp also trans-
ports a variety of other compounds, including vinblastine, vera-
pamil, cyclosporine A, and daunomycin. High expression of P-gp
at a young age may lead to a protective mechanism in which both
endogenous and exogenous toxins are efciently excreted from
the body. P-gp, MRP1, and MRP2 act synergistically with CYPs
to protect the organism against potentially toxic compounds.
With each having its own specic age-dependent expression
throughout kidney development, they may prevent the body from
obtaining the desired therapeutic concentration.
Digoxin serves as an excellent example of the ontogeny of renal
elimination by P-gp. The drug is excreted by glomerular ltra-
tion, but is also extensively secreted by the tubular cell by P-gp.
Young children need 3-fold higher doses of digoxin per kilogram
of body weight than adults. This difference could not be
explained by changes in the glomerular ltration rate alone,
because the glomerular ltration rate per kilogram of body
weight in young children is <2-fold higher than in adults. A sig-
nicant correlation has been demonstrated between renal P-gp
expression and the clearance rate of digoxin in developing rats,
implying that the ontogeny of P-gp renders young children more
likely to have higher renal clearance of P-gp substrates.
PHARMACOGENETICS OF DRUG RESPONSE:
POLYMORPHISMS IN DRUG RECEPTORS,
EFFECTORS, AND ION CHANNELS DURING GROWTH
AND DEVELOPMENT
Receptors are the targets for drugs and endogenous transmitters
due to their inherent molecular recognition sites. Drugs and
transmitters bind to the receptor to produce a pharmacologic
effect. Variability in the receptor protein or the ion channel
may determine the magnitude of the pharmacologic response.
Polymorphisms of the
2
-adrenergic receptor gene (ADRB2)
have been associated with variable responses to bronchodilator
drugs.
Drug responses are seldom monogenic events because multiple
genes are involved in drug binding to the pharmacologic target
and the subsequent downstream signal transduction events that
ultimately manifest as a therapeutic effect. Although genotypes
at a particular locus may show a statistically signicant effect on
the outcome of interest, they may account for a relatively small
amount of the overall population variability in that measure. A
particular group of SNPs in the corticotropin-releasing hormone
receptor 1 (CRHR1) gene is associated with a statistically signif-
icant improvement in forced expiratory volume in 1 sec, but
accounts for only 6% of the overall variability in the response to
inhaled corticosteroids (see Chapter 143). A series of subsequent
studies determined that allelic variation in several genes in the
steroid pathway contributes to overall response to this form of
therapy.
The listing and classication of receptors is a major initiative
of the International Union of Pharmacology (IUPHAR). The list
of receptors and voltage-gated ion channels is available on the
IUPHAR website (http://www.iuphar-db.org). The effect of
growth and development on the activities and binding afnities
of these receptors, effectors, and ion channels remain to be
elucidated.
CURRENT AND FUTURE APPLICATIONS FOR
PHARMACOGENOMICS IN PEDIATRICS
The best example of the application of pharmacogenomic prin-
ciples to pediatric drug therapy is the progress being made in the
treatment of ALL (see Chapter 495). Despite improved under-
standing of the genetic determinants of drug response, many com-
plexities remain to be resolved. Patients with ALL who have 1
wild-type allele and intermediate TPMT activity tend to have a
better response to 6MP therapy than patients with 2 wild-type
alleles and full activity. Reduced TPMT activity also places
patients at risk for irradiation-induced secondary brain tumors
and etoposide-induced acute myeloid leukemias. Pharmacoge-
netic polymorphisms of several additional genes also have the
potential to inuence successful treatment of ALL. Multiple
genetic and treatment-related factors interact to create patient
subgroups with varying degrees of risk, and these represent an
opportunity for pharmacogenomic approaches to identify sub-
groups of patients who will tolerate specic treatment regimens
and those who will be at risk for short- and long-term toxicities.
The 20% of patient with ALL who do not respond to
chemotherapy represent an additional challenge for pharma-
cogenomic research. Gene expression (microarray) studies in ALL
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Chapter 57 Principles of Drug Therapy 331
blasts are able to discriminate among phenotypic subtypes and
identify some individuals who are at risk for treatment failure.
An analysis of acute treatment-induced changes in the gene
response of ALL blasts obtained 1 day after the initiation of
6MP and methotrexate as single agents or in combinations of
high-dose or low-dose methotrexate and 6MP showed several
important insights into the cellular response to these treatment.
Changes in gene expression were treatment-specic and could
accurately discriminate among the 4 treatments. ALL cells of dif-
ferent molecular subtypes shared common cellular responses to
treatment, suggesting that it may be possible to personalize treat-
ment strategies in ALL.
AmpliChip CYP450 test. Med Lett Drugs Ther 2005;47:7172.
Blake MJ, Castro L, Leeder JS, et al: Ontogeny of drug metabolizing enzymes
in the neonate. Semin Fetal Neonatal Med 2005;10:123138.
Chen N, Aleksa K, Woodland C, et al: Ontogeny of drug elimination by the
human kidney. Pediatr Nephrol 2006;21:160168.
CYP3A and drug interactions. Med Lett Drugs Ther 2005;47:5455.
Drug interactions with grapefruit juice. Med Lett Drugs Ther 2004;46:24.
Eliasson E: Ethnicity and adverse drug reactions. BMJ 2006;332:1163
1164.
Evans WE, McLeod HL: Pharmacogenomics: Drug disposition, drug targets,
and side effects. N Engl J Med 2003;348:538549.
Freund CL, Gregory DF, Clayton EW: Evaluating pharmacogenetic tests. Arch
Pediatr Adolesc Med 2004;158:276279.
Gasche Y, Daali Y, Fathi M, et al: Codeine intoxication associated with ultra-
rapid CYP2D6 metabolism. N Engl J Med 2004;351:28272830.
Goldstein JA: Clinical relevance of genetic polymorphisms in the human
CYP2C subfamily. Br J Clin Pharmacol 2001;52:349355.
Haga SB, Burke W: Using pharmacogenetics to improve drug safety and ef-
cacy. JAMA 2004;291:28692871.
Hines RN, McCarver DG: The ontogeny of human drug-metabolizing
enzymes: Phase I oxidative enzymes. J Pharmacol Exp Ther 2002;300:
355360.
Hines RN, McCarver DG: Pharmacogenomics and the future of drug therapy.
Pediatr Clin North Am 2006;53(4):591619.
Johnson JA, Lima JJ: Drug receptor/effector polymorphisms and pharmaco-
genetics: Current status and challenges. Pharmacogenetics 2003;13:
525534.
Kim H, Neubert JK, San Miguel A, et al: Genetic inuence on variability in
human acute experimental pain sensitivity associated with gender, ethnicity
and psychological temperament. Pain 2004;109:488496.
Koren G, Cairns J, Chitayat D, et al: Pharmacogenetics of morphine poison-
ing in a breastfed neonate of a codeine-prescribed mother. Lancet 2006;368:
704705.
Leeder JS: Pharmacogenetics and pharmacogenomics. Pediatr Clin North Am
2001;48:756781.
McCarver DG, Hines RN: The ontogeny of human drug metabolizing
enzymes: Phase II conjugation enzymes and regulatory mechanisms. J Phar-
macol Exp Ther 2002;300:361366.
McLeod HL, Marsh S: Pharmacogenetics goes 3D. Nat Genet 2005;37:
794795.
Need AC, Motulsky AG, Goldstein DB: Priorities and standards in pharma-
cogenetic research. Nat Genet 2005;37:671681.
Shah J: Criteria inuencing the clinical uptake of pharmacogenomic strategies.
BMJ 2004;328:14821486.
Tucker G: Pharmacogenetics: Expectations and reality. BMJ 2004;329:46.
Wall AM, Rubnitz JE: Pharmacogenomic effects on therapy for acute lym-
phoblastic leukemia in children. Pharmacogenomics J 2003;3:128135.
Weinshilboum R: Inheritance and drug response. N Engl J Med
2003;348:529537.
Weiss ST, Litonjua AA, Lange C, et al: Overview of the pharmacogenetics
of asthma treatment. Pharmacogenomics J 2006;6:311326.
Wilkerson GR: Drug metabolism and variability among patients in drug
response. N Engl J Med 2005;352:22112221.
Williams DG, Patel A, Howard RF: Pharmacogenetics of codeine metabolism
in an urban population of children and its implications for analgesic relia-
bility. Br J Anaesth 2002;89:839845.
Witzman FA, Grant RA: Pharmacoproteomics in drug development. Pharma-
cogenomics J 2003;3:6976.
The use of drugs requires a clear understanding of the predeter-
mined targeted end-points, the likelihood of achieving the effects
sought, and the relative risks of exposing patients to the drug(s)
selected. The pediatric population is not well studied for most
drug therapies. The need for safe and effective drugs for use in
sick neonates, infants, children, and adolescents requires the
establishment of thoughtful drug therapy strategies.
Clinical pharmacology incorporates numerous concepts com-
bined to deliver drugs in the correct amount to the desired site
to achieve the correct action while avoiding unwanted toxicity.
Principles applied include pharmacokinetics, pharmacodynamics,
pharmacogenomics, proteomics, chronopharmacology, and phar-
macophysiology. Pharmacokinetics describes a drugs disposition
within the body and is most often characterized by the following
pharmacokinetic parameter estimates: systemic bioavailability,
distribution, metabolism, and elimination, as well as the factors
that inuence these processes. Classically, these processes are
described by the acronym ADME: absorption, distribution,
metabolism, and excretion. However, pharmacokinetics is a far
more complex process. Absorption is one process by which drugs
are made bioavailable to the body, and thus is more aptly
described as drug delivery to the body through any of multiple
processes and routes, including oral, buccal, rectal, percutaneous,
intrauterine, inhalation, intranasal, intramuscular, subcutaneous,
intraocular, and otic. In the absence of administration of prodrugs
(pharmacologically inactive parent compounds), the systemic
bioavailability of a drug administered in a manner that results in
the release of the parent compound after intravenous drug admin-
istration equals 100%. Drug distribution throughout the body is
inuenced by a variety of drug-specic physiochemical factors,
including the role of drug transporters, blood/tissue protein
binding, and blood and tissue pH and perfusion. Metabolism
involves conversion of drugs in the body to active or inactive
compounds that can be more readily excreted either by the
kidneys or by other routes (hepatic/bile, exhalation). Most drug
metabolism takes place in the liver via hepatic enzymes, although
other organ systems are sometimes involved. Excretion or secre-
tion of drugs involves not only the kidneys or liver, but also
removal of drugs by extracorporeal systems, such as dialysis,
hemoltration, or heart-lung bypass machines.
Pharmacodynamics describes the relationship between drug
dose or drug concentration and response. The response may be
desirable (effectiveness) or untoward (toxicity). Although in clin-
ical practice the response to drugs in different patient populations
is often described by a standard dosing or concentration range,
response is best described on a continuum. At a lower concen-
tration range, response rates may be quite low, and with gradual
increases in drug concentration, a higher proportion of patients
achieve the desired response. If this concentration-response curve
is plotted in parallel with a concentration-toxicity curve, a sense
of the therapeutic index of the drug (i.e., relative efcacy and
safety prole) can be obtained (Fig. 57-1). Pharmacodynamic
proles may involve the parent drug, active metabolites, or some
combination.
The nding that drug responses can be inuenced by the
patients genetic prole has offered great hope for realizing
patient-specic targeted pharmacotherapy (see Chapter 56).
Studies of single-gene variants and multiple-gene interactions
have documented their inuence on the manner and extent of
drug metabolism, the susceptibility of certain patient groups to
drug response or toxicity, and the genetic proles of patients who
benet most from selected therapies (see Chapter 56). Genetic
polymorphisms occur in at least 1% of the population. Impor-
Chapter 57
Principles of Drug Therapy

Peter Gal and Michael D. Reed
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tant cytochrome P450 (CYP) drug-metabolizing enzyme genes
associated with drug response include the phase I enzymes
CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and
CYP3A4, and the phase II enzymes N-acetyltransferase, uridine
diphosphate glucoronyltransferase, and glucose-6-phosphate
dehydrogenase (see Chapter 56). Polymorphisms responsible for
clinically important interpatient variability in patient response to
drugs metabolized by polymorphically expressed CYP isoen-
zymes have been described for CYP2C9 and CYP2D6. In addi-
tion, some drug transporter proteins control drug efux from
cells (P-glycoprotein, multidrug resistant proteins [MRPs] 1 and
2), impart drug resistance to cancer cells and infectious agents,
and inuence drug distribution to various parts of the body (pla-
centa, central nervous system [cerebrospinal uid]).
Chronobiology, chronopharmacology, and chronotherapeutics
involve the study of circadian rhythms and timing of drug doses
on pharmacologic effects. Optimal timing of certain drug doses
can affect the efcacy or toxicity of drug therapy. This has been
particularly important in asthma, hypertension, H
2
receptor
antagonist therapy for peptic ulcer disease, and cancer
chemotherapy. Time-sensitive changes are noted in both the phar-
macokinetics and the pharmacodynamics of certain drugs. Phys-
iologic changes affect drug disposition; pharmacophysiology is
the use of a drugs pharmacokinetic prole to help identify a
physiologic response. Examples of this application are the use
of a large gentamicin volume of distribution to detect clinically
silent patent ductus arteriosus and an abrupt reduction in
the indomethacin volume of distribution when the patent ductus
arteriosus is closed. A common practical approach is to use
aminoglycoside clearance as a marker of the patients glomerular
ltration rate.
INFLUENCE OF AGE ON DRUG THERAPY. Pediatrics encompasses a
broad range of ages at which certain stages of life profoundly
inuence drug response and disposition. Dramatic pharmacoki-
netic, pharmacodynamic, and psychosocial changes occur as
preterm infants mature toward term, as infants mature during the
1st few yr of life, and as children reach puberty and adolescence.
To meet the needs of these different pediatric groups, different
formulations are needed for drug delivery that can inuence drug
absorption and disposition, and different psychosocial issues
inuence compliance, timing of drug administration, and reac-
tions to drug use. These additional factors must be considered in
conjunction with known pharmacokinetic and pharmacodynamic
inuences of age when developing an optimal, patient-specic
drug therapy strategy.
DRUG ADMINISTRATION ISSUES AND BIOAVAILABILITY. The
administration of drugs can occur via multiple routes, and during
acute and chronic illness, the amount of drug that is delivered to
the bloodstream (bioavailability) or that reaches the intended site
of action may vary. Common routes of drug delivery include oral,
sublingual, rectal, intravenous, intramuscular, subcutaneous,
inhaled, topical, transdermal, intraocular, intranasal, and otic.
The success of each of these routes depends on proper adherence
to the administration technique and awareness of the limitations
and problems that may arise with each route. Because children
may resist the administration of drugs that have an unpleasant
taste or that cause pain, burning, or other discomfort, strategies
for reducing these problems must be addressed. Not all drugs
administered by a particular route are administered in the same
way. Some oral medications are best taken with food, whereas
others require an empty stomach. Some inhaled medications
require rapid inspiration for delivery, whereas others require slow
and steady inhalation. Because the proper administration tech-
nique may affect therapeutic success, it is desirable to advise the
patient to review the proper administration technique for all
drugs with the dispensing pharmacist. Although certain xenobi-
otics and nutrients are absorbed by active transport or facilitated
diffusion, most drugs are absorbed from the gastrointestinal tract
by passive diffusion. A number of important patient variables can
affect the rate and extent of gastrointestinal drug absorption,
including pH-dependent diffusion; the presence, absence, and
type of gastric contents; gastric emptying time; and gastrointesti-
nal motility. These physiologic processes reect a clear, but highly
variable dependence on a patients age (Tables 57-1 and 57-2).
Despite the clear maturational changes observed in the functional
capacity of these processes and their importance to intestinal drug
absorption, the overall bioavailability of most orally administered
medications in neonates, infants, children, and adolescents is ade-
quate. For acid-labile drugs, such as penicillin or ampicillin, oral
absorption may actually be increased in premature and newborn
infants vs older infants and children with age-appropriate gastric
acid concentrations. Other drugs may have slower absorption,
with delayed and blunted peak concentrations (phenobarbital).
The dosage form may also be important, particularly for infants
and younger children, because spitting of foul-tasting medication
and accurate measurement of small volumes of liquid medications
may inuence the accuracy of the drug dosage actually delivered.
Solid dosage forms (tablets, capsules) must dissolve into solution
Drug concentration
Increasing
%

p
a
t
i
e
n
t
s
Drug B effect
Drug A effect
Drug A toxicity
Drug B toxicity
Figure 57-1. Drugs with a narrow therapeutic index (drug A, solid lines) vs a
wide therapeutic index (drug B, dashed lines). Note that a drug with a narrow
therapeutic index is more likely to cause toxicity at serum concentrations
needed to obtain an adequate therapeutic response, whereas a drug with a
wide therapeutic index is unlikely to cause toxicity at concentrations needed
for an adequate therapeutic response.
TABLE 57-1. Physiologic Factors that Inuence the Oral Absorption of
Medications
PARAMETER NEONATE INFANT CHILD
Gastric acid secretion Reduced Normal Normal
Gastric emptying time Decreased Increased Increased
Intestinal motility Reduced Normal Normal
Biliary function Reduced Normal Normal
Microbial ora Acquiring Adult pattern Adult pattern
TABLE 57-2. Developmental Aspects of Body Fluid Compartment Sizes
AGE TOTAL BODY WATER* EXTRACELLULAR FLUID* INTRACELLULAR FLUID*
<3 mo fetus 92 65 25
Term gestation 75 3544 33
46 mo 60 23 37
12 mo 2630
Puberty 60 20 40
Adult 5060 20 40
*Expressed as percentage of total body weight.
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before the drug can cross cell membranes. Most drugs adminis-
tered to infants and young children are available in a liquid for-
mulation, including some as a suspension. In general, the rate of
absorption is faster after administration of a liquid dosing for-
mulation (liquid > suspension) compared with solid formulations
(capsule tablet > sustained/delayed-release tablet). Drug inter-
actions with concurrent medications or dietary intake may
markedly alter the bioavailability (especially oral) of selected
drugs and should be considered when dosing drugs.
Intravenous drug administration is assumed to be the most
dependable and accurate route for drug delivery. However, intra-
venous drug administration systems have many potential sources
of error, resulting in incomplete drug delivery or unintended bolus
doses that may lead to serious adverse drug reactions. Many
pediatric hospitals use syringe pumps as a means to increase
accuracy, but regardless of the system used, drug loss in the
intravenous tubing through binding to the tubing or inactivation,
delayed drug delivery, unintended bolus infusions, and occlusion
of the intravenous catheter confound reliable prediction of the
dosage delivered. The frequency and magnitude of errors are
increased when pump ow rates are low, especially <1/hr, as is
often the case in small infants or uid-restricted patients. Even
with the smart pumps designed to reduce drug administration
problems, the rates of drug errors may not signicantly change
due to poor nursing compliance with pump specications. Drug
administration errors must be considered when unexpected
adverse drug reactions occur, patient response to drug therapy
is unexpectedly poor, or drug concentrations are unexpectedly
low.
DRUG DISTRIBUTION. Understanding the distribution characteris-
tics of a drug in the body is important when selecting the dose.
Although the distribution volume (V
d
), or apparent volume of
distribution, for a drug does not denote any real physiologic
volume, an estimate of this pharmacokinetic parameter provides
insight into the total amount of drug present in the body relative
to its concentration in blood and thus the tissue distribution.
Knowledge of the V
d
of a drug is important when selecting an
initial loading dose or designing an optimal dosage regimen to
attain a preselected target concentration. The V
d
for a number of
drugs is inuenced by patient age and can differ markedly among
newborns (premature vs full-term), infants, and children com-
pared with adults. These differences are the result of many impor-
tant age-dependent variables, including the composition and size
of body water compartments, protein-binding characteristics, and
hemodynamic factors, including cardiac output, regional blood
ow, and membrane permeability. The absolute amounts and
distribution of body water and fat depend on a childs age and
nutritional habits. Obesity is common in children and affects the
volume of distribution of various drugs. Changes in body water
compartment sizes, blood volume, and water distribution account
for the differences observed in the V
d
in infants and children.
The extent to which a drug is bound to circulating plasma pro-
teins directly inuences the drugs distribution characteristics.
Only free, unbound drug can be distributed from the vascular
space into other body uids and tissues, where it binds to its
receptor and stimulates a response. Drug binding to plasma pro-
teins depends on a number of age-related variables, including the
absolute amount of proteins available, their respective number of
available binding sites, the afnity constant of the drug for the
protein, the inuence of pathophysiologic conditions, and the
presence of endogenous substances, which may compete for
protein binding (protein displacement interactions). These and
other clinically important variables can affect drug protein
binding relative to age. The extent to which a drug is bound to
protein markedly inuences its V
d
and body clearance (Cl) as well
as the intensity of pharmacologic effects.
Albumin,
1
-acid glycoprotein, and lipoproteins are the most
important circulating proteins responsible for drug binding in
plasma. The absolute concentration of these proteins is inuenced
by age, nutrition, and disease. Basic drugs bind mainly to
albumin,
1
-acid glycoprotein, and lipoprotein, whereas acidic
and neutral compounds bind primarily to albumin. Serum
albumin and total protein concentrations are decreased during
infancy, approaching adult values by the age of 1012 mo. A
similar pattern of maturation is observed with
1
-acid glycopro-
tein; concentrations appear to be approximately 3 times lower in
neonatal plasma compared with maternal plasma, achieving
values comparable to those of adults by 12 mo of age.
Several endogenous substances present in human plasma may
bind to plasma proteins and compete for available drug-binding
sites. During the neonatal period, free fatty acids, bilirubin, and
2-hydroxybenzoylglycine compete for albumin-binding sites and
inuence the resultant balance between free and bound drug con-
centrations. Clinically signicant protein-binding displacement
reactions occur only when a drug of high potency is >8090%
protein-bound and has a small V
d
. The requirement for all 3 of
these variableshigh potency, extensive degree of protein
binding, and a small V
d
for a clinically relevant drug-protein
displacement reaction explains why such reactions are unusual in
pediatric practice. It is prudent to assess a drugs potential for dis-
placement of bilirubin from protein-binding sites before its
administration to premature and newborn infants.
For some drugs in which the unbound portion of the drug may
be measured to guide clinical decisions, it is important to con-
sider sample handling, because changes in sample temperature or
pH can markedly alter results, affording false values and exag-
gerating unbound drug concentrations. In addition to protein
binding, drug transporters, such as P-glycoprotein, MDR1, and
MDR2, (multidrug resistance 1 or 2) play an important role in
drug distribution. These drug transporters can markedly inuence
the extent to which drugs cross membranes in the body and
whether drugs can penetrate or are secreted from the target sites
(inside cancer cells or microorganisms, or crossing the blood-
brain barrier). Thus, drug resistance to cancer chemotherapy,
antibiotics, or epilepsy may be conferred by these drug transport
proteins and their effect on drug distribution.
DRUG METABOLISM. The moment a drug molecule is present
within the body, the process of its removal begins. The overall
rate of drug removal is described by the pharmacokinetic para-
meter clearance (Cl), or body Cl. A drugs body Cl is the sum-
mation of all clearance mechanisms involved in removing that
compound from the body. The primary organ for drug metabo-
lism is the liver, although the kidney, intestine, lung, adrenals,
blood (phosphatases, esterases), and skin can also biotransform
certain compounds. For most drugs (lipophilic weak acids or
weak bases), biotransformation to more polar, water-soluble
compounds facilitates their elimination from the body through
the bile, kidney, or lung. Although the biotransformation of most
drugs results in pharmacologically weaker or inactive com-
pounds, parent compounds may be transformed into active
metabolites or intermediates (theophylline to caffeine, carba-
mazepine to 10,11-carbamazepine epoxide). Conversely, phar-
macologically inactive parent compounds, or prodrugs, may
be converted to an active moiety (chloramphenicol succinate
to active chloramphenicol base, cefuroxime axetil to active
cefuroxime) before subsequent biotransformation and body
elimination.
Drug metabolism within the hepatocyte involves 2 primary
enzymatic processes: phase I, or nonsynthetic, and phase II, or
synthetic, reactions. Phase I reactions include oxidation, reduc-
tion, hydrolysis, and hydroxylation reactions, whereas phase II
reactions primarily involve conjugation with glycine, glu-
curonide, or sulfate. Most drug-metabolizing enzymes are located
in the smooth endoplasmic reticulum of cells. Of these mixed-
function oxidase systems, the CYP450 system has been studied
in greatest detail. The CYP450 enzyme system is a supergene
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family, with at least 16 primary enzymes and a number of
isozymes of specic gene families. The specic subfamilies, or
isozymes, most responsible for human drug metabolism involve
CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4
(see Chapter 56). At birth, the concentration of drug-oxidizing
enzymes in fetal liver (corrected for liver weight) appears similar
to that in adult liver. The activity of these oxidizing enzyme
systems is reduced, which is reected by prolonged body elimi-
nation of drugs that depend on oxidation pathways in newborns
(phenytoin, caffeine, diazepam, and many others). Postnatally,
the hepatic CYP mono-oxygenase enzymes appear to mature at
different rates; for example, CYP1A2 and CYP3A4 mature a few
mo before CYP2C9 and CYP2C19 (see Chapter 56). Metabolic
activity similar to or in excess of the adult value is achieved by
approximately 612 mo of age. An understanding of the sub-
strates for specic isozymes and the effects certain drugs may
have on isoenzyme activity (induction, inhibition) allows the clin-
ician to predict the possibility of clinically important metabolic-
based drug-drug interactions (see Table 56-2). These are so
numerous that the potential for signicant interactions with
current therapies should always be checked in a database before
new drugs or diets are recommended for the patient. Most phar-
macies use electronic databases that can screen for such interac-
tions, and many electronic drug resources available to prescribers
offer a basic list. Commonly prescribed medications in pediatrics
linked to the specic CYP isoenzymes responsible for their metab-
olism with clinically important CYP inducers and inhibitors are
shown in Table 56-2.
The activity of certain hydrolytic enzymes, including blood
esterases, is also reduced during the neonatal period. Blood
esterases are important for the metabolic clearance of cocaine,
and the reduced activity of these plasma esterases in the newborn
may account for the delayed metabolism of cocaine in neonates.
Because elimination of metabolites is reduced in preterm and
full-term infants, accumulation of active metabolites that are not
considered clinically relevant in older infants, children, and adults
may occur in infants. Such is the case with the N-methylation of
theophylline to caffeine. This pathway becomes more important
in neonates because theophylline is less readily metabolized,
making it more available for N-methylation. Caffeine itself is nor-
mally metabolized before elimination, but in preterm infants with
immature liver enzymes, caffeine elimination is primarily by the
kidneys. This renal elimination is slow because of the immaturity
of renal function in young infants, resulting in the potential for
caffeine accumulation, contributing to the possibility that
methylxanthine effect or toxicity will be undetected if only theo-
phylline concentrations are monitored.
Understanding the sequence of maturation of processes of drug
metabolism is important when developing dosage recommenda-
tions for drugs that undergo extensive hepatic metabolism. An
example of the consequences of failing to appreciate these
processes is the tragedy that occurred after the administration of
usual doses of chloramphenicol (75100 mg/kg/24 hr) to prema-
ture and newborn infants (fatal gray baby syndrome) and the
resultant benecial use of this compound in the same patient
population when the dose was appropriately adjusted (15
50 mg/kg/24 hr) to compensate for the decreased hepatic ability
for glucuronidation. Chloramphenicol glucuronide is the primary
metabolite of chloramphenicol, which is then excreted through
the kidneys.
The ultimate ability of children to metabolize drugs is geneti-
cally modulated. Pharmacogenetic predisposition to slow drug
metabolism along certain enzymatic pathways can provide
important clues to patients who are at risk for drug toxicity. The
polymorphic characteristics of the important human drug-metab-
olizing CYP isoenzymes are shown in Tables 56-1 and 56-2.
DRUG EXCRETION. The amount of drug that is ltered by the
glomerulus per unit of time depends on the functional ability of
the glomerulus, the integrity of renal blood ow, and the extent
of drug-protein binding. The amount of drug ltered is inversely
related to the degree of protein binding. Only free drug is ltered
by the glomerulus and excreted. Although highly variable, renal
blood ow averages 12 mL/min at birth, approaching adult
values by 512 mo of age (see Chapter 508). The glomerular
ltration rate is 24 mL/min in full-term infants, increases to
820 mL/min by 23 days of life, and approaches adult values by
35 mo of age. Before 34 wk of gestation, glomerular ltration
is markedly reduced and increases more slowly than in term
infants.
PHARMACOKINETICS AND DRUG DOSING
CONSIDERATIONS
Pharmacokinetic-based methods can be used to predict drug con-
centration at any time after a dose is administered and can facil-
itate calculation of a drug dose to achieve a desired concentration.
Recognizing that the pharmacologic and toxicologic effects cor-
relate best with a drugs concentration in a biologic uid (blood,
cerebrospinal uid), rather than the absolute dose administered,
is the foundation of applied clinical pharmacokinetics. The
biodisposition of most drugs used clinically is best described
using the principles of linear, or 1st-order, pharmacokinetics: The
serum concentration (or the amount of drug in the body) is
directly proportional to the dose administered. If the dose of a
drug that follows linear pharmacokinetics is doubled, its resul-
tant concentration in blood (at steady state) also doubles. This
characteristic of proportionality, combined with appropriate
patient monitoring, is often used clinically to make adjustments
in drug dosing. In contrast, some drugs, such as phenytoin, sali-
cylate, and alcohol, exhibit saturation kinetics; their elimination
pathways become saturated, and the resultant drug concentration
in the blood changes disproportionately to the dose administered.
Under usual clinical conditions, these drugs often exhibit linear
(1st-order) elimination characteristics at low doses (low serum
concentrations), but as the amount of drug in the body increases
with increasing dose, their elimination pathways become satu-
rated. Such drugs are often referred to as following the principles
of zero-order (or Michaelis-Menten) kinetics. The classic princi-
ples of elimination half-life (t
1/2
) and Cl do not apply to drugs
that exhibit zero-order kinetics.
PHARMACOKINETIC CALCULATIONS AND BOLUS DOSING CONSID-
ERATIONS. In the event that therapeutic drug monitoring is avail-
able, calculation of individualized pharmacokinetic parameters is
feasible. When this is not practical, age-appropriate, population-
based pharmacokinetic values can be used to design an optimum
dosing strategy.
Typically, in the acute setting, a loading dose or bolus dose of
drug is provided to achieve effective drug serum (tissue/receptor)
concentrations rapidly. To do this effectively, a dose can be cal-
culated using the known relationship between the dose, the drugs
volume of distribution (V
d
), and the serum concentration
achieved. This relationship is described by:
Where population values are known, this is a practical way to
determine an appropriate loading dose. If the volume of distri-
bution of caffeine is 1 L/kg and the target concentration is
10 mg/L, then the loading dose of caffeine base is 10 mg/kg:
It is important to recognize that this calculated dose represents
that of caffeine base. Because caffeine is available as a salt (citrate,
benzoate) and only 50% of a caffeine citrate dose is caffeine base,
Dosemg kg L kg mg L mg kg = ( ) ( ) = 1 0 10 10 .
Dose mg kg V L kg changeinserumconcentrationdesired mg L
d
( ) = ( ) ( )
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the actual caffeine citrate dose needed to achieve a target serum
caffeine concentration of 10 mg/L would be 20 mg/kg.
This same principle can be used to adjust a specic dose
regimen to achieve an alternate serum drug concentration. For
example, a patients serum caffeine concentration is 10 mg/L, but
the desired target serum concentration is 15 mg/L. Using the same
calculation:
The V
d
can also be applied as a physiologic marker for certain
diseases. For example, a gentamicin V
d
of >0.7 L/kg has 92%
specicity for physiologically signicant patent ductus arteriosus,
even when it is clinically silent.
It is apparent from the relationship described by the formula
relating V
d
to dose and drug concentration that drug elimination
from the body, or drug clearance (Cl), does not inuence the
initial or loading dose of a drug. Although a drug may be
eliminated from the body only through the kidneys, the initial
dose is the same for patients with normal renal function as for
those with compromised or no renal function. The 1st dose of
drug achieves an equilibrium concentration between body uids
and tissues. If a drug dose is administered by a route other than
intravenously (oral, rectal, intramuscular, subcutaneous), the
bioavailability of the drug must also be taken into account. In
that case, the loading dose is calculated as: intravenous loading
dose/bioavailability.
MAINTENANCE DOSING CONSIDERATIONS. The elimination half-
life (t
1/2
) of a drug is the time required for any given concentra-
tion in blood (or other biologic uid) to decrease to
1
/
2
of the
initial value, or the time required for
1
/
2
of the amount of drug
present in the uid to be cleared. The t
1/2
can be determined as:
where Kd is equal to the slope of the terminal portion of the
natural log of the linear serum concentration-time curve. The t
1/2
depends on both the Cl and the V
d
of the drug. A more useful
formula for t
1/2
, which reects these important relationships, is:
A change in t
1/2
does not necessarily reect a change in the body
Cl of a drug. This dependence of t
1/2
on V
d
is exemplied by the
inuence of extracorporeal membrane oxygenation (ECMO) on
drug disposition. For most drugs, ECMO-induced changes are
due to an increase in drug V
d
(volume present within the appa-
ratus) rather than a change in drug Cl. Despite this important
distinction, the t
1/2
is often used clinically to adjust dosing inter-
vals, primarily because it can easily be calculated in the clinic or
at the patients bedside. The t
1/2
of a drug can also be used to
determine the time necessary to achieve the steady-state concen-
tration, or the point at which the amount of drug administered
(dose) is equivalent to the amount of drug cleared from the body.
For drugs whose pharmacokinetic characteristics are best
described by a linear, or 1st-order, process, 87.5% of the steady-
state concentration is achieved after 3 half-lives; after 4 half-lives,
it is 93.8%; and after 5 half-lives, it is 100%. When integrated
with a target concentration strategy, the t
1/2
of a drug is often used
to determine a drugs dosage interval.
Clearance (Cl) is the pharmacokinetic parameter that estimates
the theoretical volume from which a drug is removed per unit of
time. The body Cl of a drug reects the amount of drug removed
or eliminated from the body per unit of time, whereas renal Cl
reects the amount of drug cleared by the kidneys per unit of
time. Total body Cl is the summation of all Cl mechanisms for a
t
V
Cl
d
1 2
0 693
=
( )( ) .
t Kd
1 2
0 693 = .
Dose mg kg L kg mg L mg kgcaffeinebase ( ) = ( ) = ( ) = 1 0 15 10 5 5 .
given drug (Cl
renal
, Cl
hepatic
, Cl
lung
). The body Cl can be calculated
as:
with the preferred mathematical method of: drug dose/plasma
drug area under the concentration-time curve where the dose is
corrected for bioavailability.
Knowledge of a drugs Cl is fundamental and a necessity when
determining the dose for a drug and how often its dose must be
repeated to maintain a given serum concentration. It is the most
important pharmacokinetic parameter for determining the
steady-state drug concentration for a given dose rate. Changes in
organ function that affect the removal of a drug from the body
are reected as a change in the drugs Cl. A drugs body Cl is
inuenced by the integrity of blood ow and the functional ability
of the organs involved in removing the drug from the body.
Diminished drug Cl can be used as an important marker of com-
promised organ function in situations such as perinatal asphyxia
or progressive renal or liver dysfunction, and may be used to
prompt other diagnostic tests. When Cl is known and a target
steady-state serum concentration (C
ss
) is determined, the mainte-
nance dose (MD) can be calculated by the formula:
Again, it is important to correct for bioavailability by dividing
the calculated MD by bioavailability.
INDIVIDUALIZATION OF DRUG DOSE. The clinical response to an
average or usual recommended dose of drug can vary consider-
ably, even when the dose is administered relative to a patients
body weight, surface area, and stage of maturation (see Chapter
56). This variation is a result of interindividual differences in drug
pharmacokinetics and pharmacodynamics and a number of bio-
logic variables, including genetic differences in drug metabolism
or drug receptors, and concurrent pathophysiology or the pres-
ence of enzyme-inhibiting or enzyme-inducing drugs. Individual
variability with respect to drug efcacy and possibly toxicity fre-
quently necessitates the adjustment of dosage regimens for spe-
cic patients, especially for drugs with a low therapeutic index.
For some drugs, the dose may be adjusted according to the
patients immediate and readily quantiable clinical response. For
other drugs, dosage adjustment may be guided more appropri-
ately by combining clinical response with measurement of the
concentration of drug in plasma or serum. Such an approach to
therapy is often called a target concentration strategy, where a
drugs pharmacologic or toxicologic response can be directly
related to a specic serum concentration range. It is important to
recognize that the therapeutic ranges described for drugs reect
a continuum of concentrations along which increasing percent-
ages of patients can be expected to have a clinical response and
toxicity (pharmacodynamic curves), and it is the tradeoff between
benet and risk that each clinician must use to decide whether
targeting the lower or upper region of the therapeutic range, or
even exceeding the therapeutic range, is optimal. Close attention
to pharmacologic actions and physiologic responses is necessary
for this optimal target concentration strategy.
Reported therapeutic concentration ranges for drugs are
usually determined from studies of only a limited number of
patients, mostly adults, and these therapeutic ranges represent an
average (mean) value; therefore, not all in the population will be
encompassed within the 2 standard deviations that surround this
mean value. Thus, clinical monitoring of serum drug concentra-
tions serves only as a guide to pharmacologic intervention and
dose adjustment. Serum drug concentration values must be inter-
preted individually. One patient may have a complete clinical
response when the serum concentration of drug X is within the
MD mg C mg L L hr do g erval hr
ss
( ) = ( ) ( ) ( ) 1 sin int
Cl
V
t
d
=
( )( ) 0 693
1 2
.
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low portion of the therapeutic range or window. The next
patient, with the same disease of similar severity and requiring
the same drug X, may require a serum drug concentration above
or below the reported therapeutic concentration range to achieve
the same degree of positive therapeutic response. Toxicity may
limit how much above the therapeutic range the serum drug con-
centration may safely be raised. Therapeutic ranges for serum
drug concentrations serve only as guidelines for therapy. Drug
efcacy must be assessed by the clinical response.
Serum drug concentration-time values or proles may also be
compared with previously determined patient-specic values or
literature reports to assess patient compliance with a prescribed
drug regimen. If drug concentrations are very low at fairly high
doses, poor compliance or drug delivery problems may be sus-
pected. More commonly, determination of a drug concentration
in biologic uid helps to achieve an optimal therapeutic regimen
while reducing the likelihood of drug toxicity. Finally, determi-
nation of a drug concentration in a biologic uid provides a
means to assess the inuences, if any, of a disease process or drug
interaction on a drugs disposition prole.
Therapeutic drug monitoring is not appropriate, necessary, or
practical for all drugs. Drugs with well-dened and easily recog-
nizable and monitored pharmacodynamic effects do not warrant
routine monitoring (diuresis with diuretics, lowering of blood
pressure by an antihypertensive). For therapeutic drug monitor-
ing to be of clinical value, a clear concentration-response or
concentration-toxicity relationship should be identiable. Patient
age and the extent or severity of disease can inuence the
relationships among drug concentration, efcacy, and toxicity.
A clear relationship between a specic serum drug concentra-
tion and effect is available for only a limited number of drugs
in contrast to the large number of drugs with recommended
therapeutic ranges.
A number of variables should be considered when designing
strategies to monitor therapy using a serum drug concentration.
When measuring a drugs concentration in blood, the pharmaco-
kinetic characteristics of that drug must be recalled so that blood
samples can be obtained at appropriate times in relation to
administration of the drug. This permits proper interpretation of
drug concentrations and therapeutic effects and helps to avoid
serious therapeutic errors. Peak drug concentrations in blood
usually do not refer to the highest concentration achieved in
blood with that drug, but instead to the postdistribution peak
drug concentration. Thus, a lag time often exists between the time
of drug administration and the time that is recommended to
obtain the peak blood sample. Most clinical determinations of
drug concentrations in biologic uids routinely measure (report)
the total drug concentration in that uid:
Free drug concentration + concentration of drug bound to protein =
total drug concentration
This approach assumes a constant ratio of free to bound drug
at various concentrations and under differing pathophysiologic
conditions, which may not always be true; thus, caution must be
exercised in its extrapolation. Clinically important imbalances
between free and total drug concentrations have been observed
with the drug phenytoin in critically ill trauma patients and in
patients with severe renal dysfunction. As a result, many labora-
tories report both free and total serum concentrations of drugs
or have these results available on request. Despite these differ-
ences, it is unusual for an imbalance in this ratio to be clinically
signicant, except for drugs whose protein binding, under normal
circumstances, is >90%.
ADDITIONAL CONSIDERATIONS
METHOD OF DRUG ADMINISTRATION. Intravenous administration
of a drug is not always rapid or complete. The length of time nec-
essary to infuse the total dose of an intravenously administered
drug depends on a number of factors, including the ow rate of
the primary intravenous uid, the dead space of the system into
which the drug is injected, and the total volume in which the drug
is diluted. Because most standard intravenous uid delivery
systems, including their tubing, are designed for adult use, they
contain a large volume per unit of length. This introduces a rel-
atively large dead space factor, which causes substantial infusion
delays when operated at the slow ow rates necessary for infants
and children. Even intravenous infusion systems designed for
pediatric patients can have problems and limitations that may
confound drug therapy management and require clinician
awareness.
Several steps can be taken to minimize problems with intra-
venous drug administration to small infants and children,
including standardization and documentation of the total
administration time; documentation of the volume and content
of the solution used to ush an intravenous dose; standard-
ization of specic infusion techniques (infusion duration,
volumes) for drugs with a narrow therapeutic index; standard-
ization of dilution and infusion volumes for drugs given by inter-
mittent intravenous injection; avoidance of the practice of
attaching lines for drug infusion to a central hub with other solu-
tions infused concurrently at widely disparate rates; preferential
use of large-gauge cannulas; maintenance of the recommended
solution at a specied height above the infusion site for use with
a gravity-based controller; and the use of low-volume tubing and
the most distal sites for access of the drug into an existing intra-
venous line.
DRUG-DRUG INTERACTIONS. When 2 or more drugs are adminis-
tered to the same patient, the pharmacokinetic and pharmaco-
dynamic properties of each agent may be modied by their
interaction. Drugs may interact by a number of mechanisms clas-
sied on the basis of pharmaceutics, pharmacokinetics, pharma-
codynamics, or a combination thereof. These interactions may
result in unpredictable clinical effects or toxicologic responses.
Pharmaceutic interactions include those resulting in drug inacti-
vation when compounds are mixed together physically before
patient administration, as with the use of syringes, infusion
tubing, dialysate solutions, or parenteral uid preparations.
Pharmacokinetic interactions can occur when the disposition
characteristics of 1 compound (absorption, distribution, metab-
olism, excretion, or a combination thereof) are inuenced by
those of another. This type of interaction may involve 1 or more
aspects of the pharmacokinetic prole of the drug. One drug
may reduce the rate, but not the overall extent of absorption,
or a compound may displace a drug from its protein-binding
sites while concomitantly retarding its elimination from the
body. Metabolic-based drug-drug interactions can occur when-
ever 2 compounds compete for the same metabolic site (see
Table 56-2).
Drugs may interact pharmacodynamically and compete for the
same receptor or physiologic system, thus altering a patients
response to drug therapy. The number of known, clinically
important drug interactions, combined with the ever-increasing
number of available pharmacologic agents, emphasizes the need
to critically assess the possibility of drug-drug and drug-food
interactions in any patient receiving multiple drugs (Table 56-3).
DRUGS IN HUMAN MILK. Almost all drugs administered to lactat-
ing women are secreted to some extent into their milk and may
be ingested by the nursing infant (see Chapter 94). Although drug
use should be as minimal as possible during (pregnancy and) lac-
tation, it is not possible or desirable for lactating women to stop
taking needed medications. There are very few drug contraindi-
cations for maternal use during lactation. Although a drug may
distribute or concentrate in breast milk, the actual infant dose
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TABLE 57-3. Partial Listing of Drug Interactions of Potential Importance in Pediatric Practice
INTERACTING AGENT ADVERSE EFFECT
ACETAMINOPHEN
Alcohol Hepatotoxicity
Oral anticoagulants Anticoagulation
Probenecid Acetaminophen toxicity
Zidovudine Granulocytopenia
ACYCLOVIR
Narcotics Narcotic toxicity?
Zidovudine Lethargy
ALCOHOL
Antidepressants (tricyclic) Toxicity
Barbiturates CNS depression (acute)
Benzodiazepines CNS depression
Cephalosporins (not all) Disulram effect
Chloral hydrate CNS depression
Doxycycline Antibiotic effect
Isoniazid Hepatotoxicity
Metronidazole Disulram effect
Phenothiazines Impaired coordination
Phenytoin Phenytoin toxicity
ALLOPURINOL
Aluminum hydroxide Allopurinol absorption
Ampicillin Rash
Anticoagulants (oral) Anticoagulant effect
Azathioprine Azathioprine toxicity
Captopril Cutaneous hypersensitivity
Cyclophosphamide Cyclophosphamide toxicity
Theophylline Theophylline toxicity
Thiazide diuretics Allopurinol toxicity
AMINOGLYCOSIDE ANTIBIOTICS
Amphotericin B Nephrotoxicity
Bumetanide Ototoxicity
Cisplatin Nephrotoxicity
Cyclosporine Nephrotoxicity
Furosemide Nephrotoxicity and ototoxicity
Magnesium Neuromuscular blockade
Neuromuscular blocking agents Blockade
Vancomycin Nephrotoxicity?
ANTACIDS
-Adrenergic blockers Absorption
Captopril Absorption
Cimetidine Absorption
Corticosteroids Absorption
Digoxin Absorption
Iron Absorption
Isoniazid Absorption
Ketoconazole Absorption
Nonsteroidal anti-inammatory agents Absorption
Phenytoin Absorption
Salicylates Absorption
Tetracycline Absorption
Theophylline Toxicity
ASPIRIN
Anticoagulants (oral) Bleeding
Captopril Antihypertensive effect
BARBITURATES
Anticoagulants (oral) Anticoagulation
-Adrenergic blockers Blockade
Carbamazepine Production of carbamazepine epoxide
Chloramphenicol Barbiturate toxicity
Contraceptives (oral) Contraception
Corticosteroids Steroid effect
Inuenza vaccine (viral) Barbiturate toxicity
Rifampin Barbiturate effect
Theophylline Theophylline effect
Valproate Barbiturate toxicity
BLEOMYCIN
Oxygen Pulmonary toxicity
CAPTOPRIL
Allopurinol Cutaneous hypersensitivity
Aspirin Antihypertensive effect
Cimetidine Neuropathy
Nonsteroidal anti-inammatory agents Antihypertensive effect
Potassium Hyperkalemia
Spironolactone Hyperkalemia
CARBAMAZEPINE
Antidepressants (tricyclic) Toxicity (both drugs)
Cimetidine Carbamazepine toxicity
Corticosteroids Steroid effect
Cyclosporine Cyclosporine effect
Erythromycins Carbamazepine toxicity
Inuenza vaccine (viral) Carbamazepine toxicity
Isoniazid Toxicity (both drugs)
Phenytoin Carbamazepine effect
Valproate Valproate effect
CIMETIDINE
Alcohol Alcohol effect
Antacids Cimetidine effect
Antidepressants (tricyclic) Antidepressant toxicity
Benzodiazepines Benzodiazepine toxicity
-Adrenergic blocking agents -Blockade toxicity
Captopril Neuropathy
Carbamazepine Carbamazepine toxicity
Digoxin Digoxin toxicity
Ketoconazole Ketoconazole absorption
Metoclopramide Cimetidine effect
CONTRACEPTIVES (ORAL)
Antidepressants (tricyclic) Antidepressant toxicity
Barbiturates Contraception
Carbamazepine Contraception
Griseofulvin Contraception
Penicillins (ampicillin, oxacillin) Contraception?
Phenytoin Contraception
Rifampin Contraception
CYCLOSPORINE
Alkylating agents Nephrotoxicity
Aminoglycosides Nephrotoxicity
Amphotericin B Nephrotoxicity
Carbamazepine Cyclosporine effect
Erythromycins Cyclosporine toxicity
Furosemide Gout
Ketoconazole Nephrotoxicity
Metoclopramide Cyclosporine toxicity
Nafcillin Cyclosporine effect
Phenytoin Cyclosporine effect
Rifampin Cyclosporine effect
DIGOXIN
Antacids Absorption
Anticholinergics Digoxin toxicity
Cholestyramine Absorption
Cimetidine Digoxin toxicity
Diuretics (hypokalemia) Digoxin toxicity
Phenytoin Digoxin effect
Quinidine Digoxin toxicity
Verapamil Digoxin toxicity
ERYTHROMYCINS
Astemizole (Hismanal) Astemizole toxicity: arrhythmias
Carbamazepine Carbamazepine toxicity
Cyclosporine Cyclosporine toxicity
Phenytoin Phenytoin effect
Terfenadine (Seldane) Terfenadine toxicity: arrhythmias
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received (volume of milk consumed), combined with the drugs
bioavailability (in the infant) and the amount of drug (over the
feeding periods), usually negates any clinically relevant effects in
the breast-fed infant. If a question exists about the amount of
drug a breast-feeding infant may be receiving or about possible
drug effects in the infant, a sample of the mothers milk can be
analyzed. Up-to-date and specic information about breast milk
distribution of medications and the amount a nursing infant
would actually receive (absorb) can be obtained by consulting a
clinical pharmacy/pharmacology service.
PRESCRIBING MEDICATIONS. Factors such as taste, smell, color,
consistency, dosing frequency, and cost affect the degree to which
patients comply with their therapeutic drug regimen. Prescribing
TABLE 57-3. Partial Listing of Drug Interactions of Potential Importance in Pediatric Practicecontd
FLUOROQUINOLONES
Antacids Antibiotic effect
GRISEOFULVIN
Anticoagulants (oral) Anticoagulants
Contraceptive (oral) Contraceptive
ISONIAZID
Alcohol Hepatitis
Antacids Isoniazid absorption
Carbamazepine Toxicity (both)
Ketoconazole Ketoconazole effect
Rifampin Hepatotoxicity
Valproate Hepatic and CNS toxicity
KETOCONAZOLE
Antacids Absorption
Cimetidine Ketoconazole effect
Cyclosporine Nephrotoxicity
Isoniazid Ketoconazole effect
Phenytoin Altered metabolism of both drugs
Rifampin Effects of both drugs
METHOTREXATE
Blood transfusion Toxicity
Cisplatin Methotrexate toxicity
Etretinate Hepatotoxicity
Nonsteroidal anti-inammatory drugs Methotrexate toxicity
Trimethoprim/sulfamethoxazole Megaloblastic anemia
METOCLOPRAMIDE
Carbamazepine Neurotoxicity
Cimetidine Cimetidine effect
Cyclosporine Cyclosporine toxicity
Digoxin Absorption
Narcotics Sedation
NIFEDIPINE
-Adrenergic blockers Heart failure, atrioventricular block
Cyclosporine Gingival hyperplasia
Prazosin Hypotension
Quinidine Quinidine effect
PHENYTOIN
Alcohol Toxicity (acute)
Antacids Phenytoin effect
Anticoagulants (oral) Phenytoin toxicity, anticoagulation
Antidepressants (tricyclic) Phenytoin toxicity
Carbamazepine Carbamazepine effect
Chloramphenicol Toxicity (both drugs)
Cimetidine Phenytoin toxicity
Contraceptives (oral and implant) Contraception
Corticosteroids Corticosteroid effect
Digoxin Digoxin effect
Dopamine Hypotension
Folic acid Phenytoin effect
Isoniazid Phenytoin toxicity
Miconazole Phenytoin effect
Neuromuscular blocking agents Blockade
Nifedipine Phenytoin toxicity
Rifampin Phenytoin effect
Theophylline Effects (both drugs)
Valproate Phenytoin toxicity
QUINIDINE
Amiodarone Quinidine toxicity
Barbiturates Quinidine effect
Cimetidine Quinidine toxicity
Digoxin Digoxin toxicity
Metoclopramide Quinidine effect
Phenytoin Quinidine effect
Procainamide Procainamide toxicity
Rifampin Quinidine effect
Verapamil Hypotension
RIFAMPIN
Barbiturates Barbiturate effect
-Adrenergic blockers Blockade
Chloramphenicol Chloramphenicol effect
Corticosteroids Corticosteroid effect
Isoniazid Hepatotoxicity
Ketoconazole Effects (both drugs)
Phenytoin Phenytoin effect
Verapamil Verapamil effect
THEOPHYLLINE
Barbiturates Theophylline effect
-Adrenergic blockers Theophylline toxicity
Carbamazepine Theophylline effect
Cimetidine Theophylline toxicity
Erythromycins Theophylline toxicity
Fluoroquinolones Theophylline toxicity
Inuenza vaccine (viral) Theophylline toxicity
Interferon Toxicity?
Marijuana smoking Theophylline effect
Phenytoin Effect (both drugs)
Rifampin Theophylline effect
Tobacco smoking Theophylline effect
Troleandomycin Theophylline toxicity
TRIMETHOPRIM/SULFAMETHOXAZOLE
Antidepressants (tricyclic) Depression
Mercaptopurine Antileukemia effect
Methotrexate Megaloblastic anemia
VALPROATE
Barbiturates Phenobarbital toxicity
Benzodiazepines Diazepam toxicity
Carbamazepines Valproate effect
Cimetidine Valproate toxicity?
Ethosuximide Ethosuximide toxicity?
*When possible, an alternate drug combination should be given. If not possible, drug levels and signs of toxicity must be monitored.
Modied from Rizack M, Hillman C: The Medical Letter Handbook of Adverse Drug Interactions. New Rochelle, NY, The Medical Letter, 1989.
CNS, central nervous system; ?, possible effect.
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Chapter 58 Poisonings 339
generically equivalent medications can sometimes reduce the
cost of a drug. Such prescribing should be done only when it
is clearly known that the generic brand affords equivalent
bioavailability, bioeffectiveness, and patient acceptability. Com-
plete bioequivalence data are not available for all drugs; when
in doubt, the prescribing physician should consult with the
pharmacist.
A prescription issued by the prescribing physician should
always direct the dispensing of just enough drug to treat the
patient, leaving only a small amount of drug left over after the
prescribed course of therapy has been completed. This small
residual allows for the loss of some drug in case of doses acci-
dentally spilled, spit out, or lost. Parents should be instructed to
discard all remaining doses of a prescribed medication after the
completed course of therapy to protect against accidental poi-
soning or improper self-medication at a later date. Patient med-
ication instructions on the prescription should state the specic
number of doses the patient should receive each day and the total
duration of therapy (number of days of therapy). The number of
times the prescribing physician allows the prescription to be
relled should be noted on the prescription label; if no rells are
to be permitted, this should also be specied on the written
prescription.
COMPLIANCE WITH THE PRESCRIBED REGIMEN. Little is known
about the many factors that determine the degree of compliance
with a physicians instructions, but many patients frequently do
not take medication consistently or in the manner intended or
prescribed. Patients frequently take home remedies or medica-
tions that are not recommended or prescribed by their physician.
A childs compliance with a prescribed therapeutic regimen is
usually only as good as that of the parents. Compliance can be
maximized by carefully educating the family about the nature of
the childs illness, the action of the medications prescribed, and
the importance of following the instructions precisely. Compli-
ance with the therapeutic regimen is improved when the instruc-
tions are written down clearly and in detail for the family and
when the regimen results in minimal interference with the daily
living schedule (particularly parental sleeping habits). Collabora-
tion between the prescribing physician and the dispensing phar-
macist can often identify compliance problems and improve
compliance through patient education.
Benedetti MS, Baltes E: Drug metabolism and disposition in children. Fund
Clin Pharmacol 2003;17:281299.
Bjrkman S: Prediction of drug disposition in infants and children by
means of physiologically based pharmacokinetic (PBPK) modeling:
Theophylline and midazolam as model drugs. Br J Clin Pharmacol
2004;59:691704.
Carr RR, Ensom MHH: Drug disposition and therapy in adolescence: The
effects of puberty. J Pediatr Pharmacol Ther 2003;8:8696.
Eichelbaum M, Ingelman-Sundberg M, Evans WE: Pharmacogenomics and
individualized drug therapy. Ann Rev Med 2006;57:11.111.19.
Johnson TN: The development of drug metabolising enzymes and their inu-
ence on the susceptibility to adverse drug reactions in children. Toxicology
2003;192:3748.
Kearns GL, Abdel-Rahman SM, Alander SW, et al: Developmental pharma-
cology: Drug disposition, action, and therapy in infants and children.
N Engl J Med 2003;349:11571167.
Paul IM: Advances in pediatric pharmacology, therapeutics, and toxicology.
Adv Pediatr 2005;52:321365.
Stephenson T: How childrens responses to drugs differ from adults. Br J Clin
Pharmacol 2005;59:670673.
Waters MD, Fostel JM: Toxicogenomics and systems toxicology: Aims and
prospects. Nat Rev Genet 2004;5:936948.
EPIDEMIOLOGY
Of the >2 million human poisoning exposures reported annually
to the Toxic Exposure Surveillance System (TESS) of the
American Association of Poison Control Centers (AAPCC),
>50% occur in children 5 yr of age or younger. Almost all of
these exposures are unintentional and reect the propensity for
children in this age group to put virtually anything in their
mouths.
More than 90% of toxic exposures in children occur in the
home, and most involve only a single substance. Ingestion is the
most common route of poisoning exposure (77% of cases), with
the dermal, inhalation, and ophthalmic routes accounting for
approximately 7.5%, 6%, and 5% of cases, respectively. Approx-
imately 50% of cases involve nondrug substances, such as
common household products (cosmetics, personal care items,
cleaning solutions, plants, foreign bodies, hydrocarbons). Phar-
maceutical preparations comprise the remainder, with analgesics,
cough and cold products, antimicrobial agents, and vitamins the
most common categories. These are products that are familiar to
young children; in addition, they are usually manufactured in
visually appealing and great-tasting formulations. More than
85% of pediatric poisoning exposures can be managed without
direct medical intervention, because either the product involved
is not inherently very toxic or the quantity of the material
involved is not sufcient to produce clinically relevant toxic
effects (Table 58-1). Death due to unintentional poisoning
in young children is uncommon owing to increased product
safety measures (child-resistant packaging), increased poison pre-
vention education, early recognition of exposure, improvements
in medical management, and the availability of 24 hr/day, 7
day/wk 800 number access to regionally based poison control
centers.
Poison prevention education should be an integral part of all
well child visits, even before a child is mobile. Counseling parents
and other caregivers about potential poisoning risks, how to
poison-proof a childs environment, and what to do if a poi-
soning occurs diminishes the likelihood of serious morbidity
or mortality from an exposure. Poison prevention educational
materials are available from both the American Academy of
Pediatrics and regional poison control centers. A network of
poison control centers exists in the U.S., and anyone at any
time can contact a regional poison center by calling a toll-free
number: 1-800-222-1222. The ready access to this number
should be discussed often during the 1st 2 yr of ofce visits and
annually thereafter. The sharing of this toll-free number with
grandparents, relatives, and caregiver programs is also highly
desirable.
Poisoning exposures in children 612 yr of age are much
less common, involving approximately 6% of all pediatric
exposures. Toxic exposures in adolescents are primarily inten-
tional (suicide, abuse) or occupational. Pediatricians should be
aware of the signs of drug abuse or suicidal ideation in this
population and should aggressively intervene. Pediatric fatalities
after a poisoning exposure are most common in adolescents,
with 6.1% of the 1,261 fatalities reported to the TESS program
in 2005 occurring in 1319 yr old patients compared with 1.9%
in children 6 yr old or younger and 1.0% in children 612 yr of
age.
Chapter 58
Poisonings
George C. Rodgers, Jr.,
Tania Condurache, Michael D. Reed,
Michelle Bestic, and Peter Gal
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APPROACH TO THE POISONED PATIENT
The initial approach to the patient with a documented or sus-
pected poisoning should be no different than that in any other sick
child. A detailed history and physical examination serves as the
foundation for a thoughtful differential diagnosis and the forma-
tion of an initial prognosis (Table 58-2). The history and physical
examination should not await the collection of body uid and the
results of a tox screen. Toxicology laboratory analyses, or
screens, in fact evaluate for only a small fraction of common
pediatric exposures and rarely make (vs conrm) the diagnosis.
INITIAL PATIENT EVALUATION
PATIENT HISTORY. Obtaining an accurate problem-oriented
history is of paramount importance if a poisoning has occurred
or is suspected. The following information should be obtained
during the initial assessment.
Description of Toxins. Product names (brand, generic, chemical)
and ingredients, along with their concentrations, may be obtained
from labels. Because many brand names that sound alike have
very different ingredients, it is important to be precise. If the
ingredient information is not readily available on the product,
consultation with a poison control center can usually provide this
information rapidly. Most products used in the home or work-
place contain multiple ingredients in varying concentrations, and
the poison control center can provide specic information regard-
ing all ingredients in the particular product as well as prioritize
possible clinical effects from individual ingredients or a combi-
nation of ingredients. Furthermore, most pills and capsules have
markings, including letters, numerals, or both, and based on these
markings, the poison center may be able to identify the ingredi-
ents. Several characteristic toxic syndromes, or toxidromes,
exist for some of the more common exposures and may assist in
identifying the offending agent. The more common toxidromes
and other poisoning manifestations categories are shown in
Tables 58-3 to 58-5.
Magnitude of Exposure. It is important to attempt to determine
as accurately as possible how much of the substance has been
ingested. This may be difcult, but is of paramount importance
in rening the initial prognosis guiding the initial management
plans. Numerous methods can be used to estimate the amounts
TABLE 58-1. Common Nontoxic and Minimally Toxic* Products
Abrasives Ink (black, bluenonpermanent)
Antacids, non-salicylate-containing Iodophil disinfectants (unless the individual is allergic)
Antibiotics, topical Laxatives
Antifungals, topical Lipstick
Ballpoint pen ink Lozenges (without anesthetics)
Bathtub oating toys Lubricating oils (unless aspirated)
Bath oil (unless aspirated) Magazines
Body conditioners Markers, porous tip
Bubble bath soap Makeup
Calamine lotion Matches
Candles (beeswax or parafn) Mineral oil (unless aspirated)
Caps (toy pistols, potassium chlorate) Modeling compound (Play-Doh)
Chalk (calcium carbonate) Newspaper (chronic ingestion may result in lead poisoning)
Childrens toy cosmetics Paint, indoor latex, water-based
Clay (modeling) Paints, watercolor
Oral contraceptives without iron Pencil lead (graphite, coloring)
Corticosteroids, topical Petroleum jelly (Vaseline)
Cosmetics Plant food (no insecticides or herbicides)
Crayons (marked A.P. or C.P., gel) Polaroid picture coating uid
Dehumidifying packets (e.g., silica) Putty
Deodorants, underarm Rubber cement
Fabric softeners Shampoo
Fertilizers (no insecticides or herbicides) Shaving creams and lotions
Detergents, hand, dishwashing Silica gel
Diaper rash creams/ointments Soap and soap products (noncaustic)
Fishbowl additives Spackles
Glow products Starch
Glues and paste Sunscreen
Golf ball (core may cause mechanical injury) Sweetening agents (saccharin, aspartame)
Grease Toothpaste(with and without uoride)
Hand lotions and creams Warfarin rodenticides (<0.5%)
Hydrogen peroxide (medicinal 3%) Watercolor paints
Incense Zinc oxide
Indelible markers
*The potential for toxicity is dependent on the magnitude and amount of exposure. These agents are considered nontoxic or
minimally toxic for mild to moderate exposure.The potential for toxicity increases with increased amount of exposure.
TABLE 58-2. Historical and Physical Findings in Poisoning
ODOR
Bitter almonds Cyanide
Acetone Isopropyl alcohol, methanol, paraldehyde, salicylates
Alcohol Ethanol
Wintergreen Methyl salicylate
Garlic Arsenic, thallium, organophosphates
OCULAR SIGNS
Miosis Narcotics (except meperidine), organophosphates, muscarinic mushrooms,
clonidine, phenothiazines, chloral hydrate, barbiturates (late), PCP
Mydriasis Atropine, alcohol, cocaine, amphetamines, antihistamines, cyclic antidepressants,
cyanide, carbon monoxide
Nystagmus Phenytoin, barbiturates, ethanol, carbon monoxide
Lacrimation Organophosphates, irritant gas or vapors
Retinal hyperemia Methanol
Poor vision Methanol, botulism, carbon monoxide
CUTANEOUS SIGNS
Needle tracks Heroin, PCP, amphetamines
Bullae Carbon monoxide, barbiturates
Dry, hot skin Anticholinergic agents, botulism
Diaphoresis Organophosphates, nitrates, muscarinic mushrooms, aspirin, cocaine
Alopecia Thallium, arsenic, lead, mercury
Erythema Boric acid, mercury, cyanide, anticholinergics
ORAL SIGNS
Salivation Organophosphates, salicylates, corrosives, strychnine
Dry mouth Amphetamines, anticholinergics, antihistamine
Burns Corrosives, oxalate-containing plants
Gum lines Lead, mercury, arsenic
Dysphagia Corrosives, botulism
INTESTINAL SIGNS
Cramps Arsenic, lead, thallium, organophosphates
Diarrhea Antimicrobials, arsenic, iron, boric acid
Constipation Lead, narcotics, botulism
Hematemesis Aminophylline, corrosives, iron, salicylates
CARDIAC SIGNS
Tachycardia Atropine, aspirin, amphetamines, cocaine, cyclic antidepressants, theophylline
Bradycardia Digitalis, narcotics, mushrooms, clonidine, organophosphates, blockers, calcium
channel blockers
Hypertension Amphetamines, LSD, cocaine, PCP
Hypotension Phenothiazines, barbiturates, cyclic antidepressants, iron, blockers, calcium
channel blockers
RESPIRATORY SIGNS
Depressed respiration Alcohol, narcotics, barbiturates
Increased respiration Amphetamines, aspirin, ethylene glycol, carbon monoxide, cyanide
Pulmonary edema Hydrocarbons, heroin, organophosphates, aspirin
CNS SIGNS
Ataxia Alcohol, antidepressants, barbiturates, anticholinergics, phenytoin, narcotics
Coma Sedatives, narcotics, barbiturates, PCP, organophosphates, salicylates, cyanide,
carbon monoxide, cyclic antidepressants, lead
Hyperpyrexia Anticholinergics, quinine, salicylates, LSD, phenothiazines, amphetamines, cocaine
Muscle fasciculation Organophosphates, theophylline
Muscle rigidity Cyclic antidepressants, PCP, phenothiazines, haloperidol
Paresthesia Cocaine, camphor, PCP, MSG
Peripheral neuropathy Lead, arsenic, mercury, organophosphates
Altered behavior LSD, PCP, amphetamines, cocaine, alcohol, anticholinergics, camphor
From Kliegman RM, Marcdante KJ, Jenson HB (editors): Nelson Essentials of Pediatrics, 5th ed. Philadelphia, Elsevier, 2006, p 205.
CNS, central nervous system; LSD, lysergic acid diethylamide; MSG, monosodium glutamate; PCP, phencyclidine.
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involved; it is better to overestimate than to underestimate. Esti-
mates can often be accomplished by counting the remaining
tablets or measuring the remaining volume of liquid. Whatever
amount is missing and cannot be denitively accounted for
should be assumed to be the amount (dose) to which the
patient was exposed. When >1 child is involved, initial clinical
assessments should assume that each child was exposed to the
entire amount estimated, even if the child or children state oth-
erwise. These probable overestimates of exposure provide a safety
margin early during the clinical assessment. Estimates can be
rened as the patient is assessed over time and initial laboratory
data become available. Because the toxicity of most agents is
dose-related, knowing the age or weight of the child aids in
assessment. For inhalation, ocular, or dermal exposures, the con-
centration of the offending agent and the length of contact time
with the material should be determined, in addition to the time
course for associated symptoms to occur, their progression, and
possible resolution.
Time of Exposure. For some products, toxic manifestations may
be delayed for hr or days. Knowing the time lapse between expo-
TABLE 58-3. Recognizable Poison Syndromes
POISON SYNDROME ASSOCIATED SIGNS POSSIBLE TOXINS
Increased sympathetic Pyrexia Cough and decongestant
nervous system Flushing preparations
activity Tachycardia Amphetamines
Hypertension Cocaine
Pupillary constriction Ecstasy
Sweating Theophylline
Anticholinergic Similar clinical picture to Tricyclic antidepressants
activity sympathomimetics Antiparkinsonian drugs
Clinical differences include: Antihistamines
pupillary dilation, Atropine and nightshade
dry mouth, Antispasmodics
hot, dry skin Phenothiazines
Mushroom poisoning (Amanita
species)
Cyclopentolate eyedrops
Increased Pupillary constriction Organophosphate insecticides
parasympathetic Diarrhea Drugs for myasthenia gravis (e.g.,
nervous system Urinary incontinence pyridostigmine)
activity: Sweating Nicotine
cholinergic Excessive salivation Carbamate insecticides
crisis Muscle weakness
Fasciculation
Paralysis
Lacrimation
Metabolic acidosis Tachyopnea Ethanol
Kussmaul breathing (sighing Carbon monoxide
respiration) Antifreeze
Iron
Diabetic medication
Tricyclic antidepressants
Salicylates
Chemical Cough Stoddard solvent (white spirit)
pneumonitis Respiratory distress Turpentine
Central nervous system depression Essential oils
A history of vomiting after ingestion
need not be a feature
Acute ataxia or Antihistamines
nystagmus Alcohol
Anticonvulsants (especially
phenytoin and
carbamazepine)
Piperazine
Diphenylhydantoin
Barbiturates
Carbon monoxide
Organic solvents
Bromides
Methemoglobinemia Cyanosis resistant to oxygen therapy Alanine dyes
Nitrates
Benzocaine
Phenacetin
Nitrobenzene
Chlorates
Sulphonamides and
metoclopramide (in neonates)
POISON SYNDROME ASSOCIATED SIGNS POSSIBLE TOXINS
Renal failure Oliguria or anuria Carbon tetrachloride
Hematuria Ethylene glycol
Myoglobinuria Methanol
Mushrooms
Oxalates
Violent emesis Aspirin
Theophylline
Corrosives
Fluoride
Boric acid
Iron
Generalized muscle Seizure-like, generalized muscle contractions Strychnine
rigidity or painful spasms (neck and limbs) and
usually tachycardia and hypertension
Intact sensorium
Oropharyngeal pain Lip, mouth, and pharyngeal ulcerations and Paraquat*
and ulcerations burning pain Diquat
Dyspnea and hemoptysis secondary to Caustics (i.e., acids and alkalis)
pulmonary edema or hemorrhage; can Inorganic mercuric salts
progress to pulmonary brosis over days Mustards (e.g., sulfur)
to weeks
Cellular hypoxia Mild: Nausea, vomiting, and headache Cyanide* (e.g., hydrogen cyanide
Severe: Altered mental status, dyspnea, gas or sodium cyanide)
hypotension, seizures, and metabolic Sodium monouoroacetate
acidosis (SMFA)*
Bitter almond odor
Carbon monoxide
Hypocalcemia or hypokalemia Hydrogen sulde
Sodium azide
Methemoglobin-causing agents
Peripheral neuropathy Peripheral neuropathy signs and symptoms: Mercury (organic)*
and/or Muscle weakness and atrophy,glove and Arsenic (inorganic)*
neurocognitive stocking sensory loss, and depressed or Thallium
effects absent deep tendon reexes Lead
Neurocognitive effects: Memory loss, delirium, Acrylamide
ataxia, and/or encephalopathy
Visual disturbances, paresthesias, and/or ataxia
Delirium and/or peripheral neuropathy
Encephalopathy and/or peripheral neuropathy
Severe gastrointestinal Abdominal pain, vomiting, profuse diarrhea Arsenic*
illness, dehydration (possibly bloody), and hypotension, Ricin*
possibly followed by multisystem organ Colchicine
failure Barium
Inhalation an additional route of exposure;
severe respiratory illness possible
Hypokalemia common
Serotonin Altered mental status (agitation, confusion, SSRIs, antidepressants, some
coma), autonomi instability (tachycardia, opioids (meperidine),
hyper- or hypotension), hyperkinetic tramadol, St. Johns wort,
neuromuscular (tremor, clonus, MAOIs
hyperreexia), mydriasis, diaphoresis,
increased bowel motility
Withdrawal Abdominal cramps, diarrhea, lacrimation, Cessation of alcohol, barbiturates,
sweating,goose esh, yawning, benzodiazepines, narcotics
tachycardia, restlessness, hallucinations
*Potential agents for a covert chemical release based on historic use (i.e., intentional or inadvertent use), high toxicity, and/or ease of availability.
Unreliable sign.
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sure and the onset of symptoms and/or medical evaluation will
markedly inuence decisions about obtaining certain diagnostic
testing as well as therapeutic intervention.
Progression of Symptoms. Knowing the nature and progression
of symptoms is very helpful for assessing the need for immediate
life support, the prognosis, and the type of intervention that may
be needed.
MEDICAL HISTORY. Underlying diseases may make a child more
susceptible to the effects of a toxin. Concurrent drug therapy may
also increase susceptibility because certain drugs may interact
with the toxin. Pregnancy is a common precipitating factor in
adolescent suicide attempts and can inuence the patient evalua-
tion and treatment plan. At 6 mo of age or younger, it is very
unlikely that an infant could become accidentally exposed to a
sufcient quantity of a potentially harmful product in the absence
of other extraneous factors that require further investigation
(social environment).
DEMOGRAPHIC INFORMATION. It is particularly important to
obtain demographic information regarding the patient and the
caller. Obtaining the callers telephone number and street address
is important for follow-up and also to allow for dispatch of
emergency personnel if telephone contact is disrupted.
INITIAL MEDICAL CARE
If the patient is managed at home, follow-up assessment calls
should be made at varying times after exposure because any
change in the patients condition may alter the decision to remain
at home. The timing of follow-up calls depends on the type and
extent of the exposure, combined with a number of clinical vari-
ables, including the expectation for when symptoms would begin
to occur and progress. Usually, it is advisable to initiate the 1st
follow-up call 0.51.0 hr after the exposure to detect any symp-
toms that may manifest if the timing, nature, and/or amount of
exposure were different than initially thought; a 2nd follow-up
call should be made 13 hr after the rst. Consultation with a
poison control center for assistance in monitoring such patients
should be considered. Poison control centers are staffed by
nurses, pharmacists, and physicians specially trained to respond
TABLE 58-4. Screening Laboratory Clues in Toxicologic Diagnosis
METABOLIC ACIDOSIS (MNEMONIC = MUDPIES)
Methanol,* carbon monoxide
Uremia*
Diabetes mellitus*
Paraldehyde,* phenformin
Isoniazid, iron
Ethanol,* ethylene glycol*
Salicylates, starvation, seizures
HYPOGLYCEMIA
Ethanol
Isoniazid
Insulin
Propranolol
Oral hypoglycemic agents
Salicylates
HYPERGLYCEMIA
Salicylates
Isoniazid
Iron
Phenothiazines
Sympathomimetics
HYPOCALCEMIA
Oxalate
Ethylene glycol
Fluoride
RADIOPAQUE SUBSTANCE ON KUB (MNEMONIC = CHIPPED)
Chloral hydrate, calcium carbonate
Heavy metals (lead, zinc, barium, arsenic, lithium, bismuth, as in Pepto-Bismol)
Iron
Phenothiazines
Play-Doh, potassium chloride
Enteric-coated pills
Dental amalgam
*Hyperosmolar condition.
From Kliegman RM, Mascdante KJ, Jenson HB (editors): Nelson Essentials of Pediatrics, 5th ed. Philadelphia, Elsevier, p 207.
KUB, kidney-ureter-bladder radiograph.
TABLE 58-5. Drugs Associated with Major Modes of Presentation
COMMON TOXIC CAUSES OF CARDIAC ARRHYTHMIA
Amphetamine
Antiarrhythmics
Anticholinergics
Antihistamines
Arsenic
Carbon monoxide
Chloral hydrate
Cocaine
Cyanide
Cyclic antidepressants
Digitalis
Freon
Phenothiazines
Physostigmine
Propranolol
Quinine, quinidine
Theophylline
CAUSES OF COMA
Alcohol
Anticholinergics
Antihistamines
Barbiturates
Carbon monoxide
Clonidine
Cyanide
Cyclic antidepressants
Hypoglycemic agents
Lead
Lithium
Methemoglobinemia*
Methyldopa
Narcotics
Phencyclidine
Phenothiazines
Salicylates
COMMON AGENTS CAUSING SEIZURES (MNEMONIC = CAPS)
Camphor
Carbamazepine
Carbon monoxide
Cocaine
Cyanide
Aminophylline
Amphetamine
Anticholinergics
Antidepressants (cyclic)
Pb (lead) [also lithium]
Pesticide (organophosphate)
Phencyclidine
Phenol
Phenothiazines
Propoxyphene
Salicylates
Strychnine
*Causes of methemoglobinemia: amyl nitrite, aniline dyes, benzocaine, bismuth subnitrate, dapsone, primaquone, quinones,
spinach, sulfonamides.
From Kliegman RM, Mascdante KJ, Jenson HB (editors): Nelson Essentials of Pediatrics, 5th ed. Philadelphia, Elsevier, 2006, p 208.
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to and monitor poisoning exposures. If the patient requires hos-
pital treatment, the probability of life-threatening symptoms dic-
tates the mode of transportation used (see Chapter 63). After a
decision to transport a patient is made, emergency department
personnel should be notied so that they can properly prepare.
All product containers related to the exposure should be collected
and transported with the patient. If the patient has vomited, the
emesis should also be brought to the emergency department for
possible toxicologic analysis.
Once the patient has arrived in the appropriate medical care
setting, initial attention should focus on life support, with
primary emphasis on cardiorespiratory care. Initial treatment of
shock, dysrhythmias, and seizures is generally the same as for any
other critically ill patient (see Chapter 66). Only a small number
of antidotes exist for only a few poisons (Tables 58-6 and 58-7),
underscoring the importance of thoughtful, timely institution and
maintenance of supportive measures, combined with close, con-
tinuous clinical monitoring.
PREVENTING ABSORPTION. Most toxins are rapidly absorbed
from the gastrointestinal tract or through inhalation. Many
toxins may also be well absorbed on dermal contact (insecticides).
TABLE 58-6. Common Antidotes for Poisoning
ANTIDOTE POISONING DOSE ROUTE ADVERSE EFFECTS/WARNINGS/COMMENTS
N-Acetylcysteine (Mucomyst) Acetaminophen; carbon tetrachloride and 140 mg/kg loading, followed by 70 mg/kg q4h for PO Nausea, vomiting
chloroform (experimental) 17 doses
N-Acetylcysteine (Acetodote) Acetaminophen 150 mg/kg over 3060 min, followed by 50 mg/kg over IV Nausea, vomiting, allergic reactions
4 hrs, followed by 100 mg/kg over 16 hrs.
Atropine Organophosphate and carbamate pesticides; 0.05 mg/kg repeated q510min as needed; dilute in IV/ET Tachycardia, dry mouth, blurred vision, urinary retention
bradycardia due to atrioventricular 12 mL of NS for ET instillation
conduction defects, -blocking agents
BAL in oil (dimercaprol) Arsenic, mercury, other metals 35 mg/kg/dose q4hr, for the 1st day; subsequent dosing Deep IM Local injection site pain and sterile abscess, nausea,
depends on the toxin vomiting, fever, salivation, nephrotoxicity
Benztropine (Cogentin) Acute dystonic reactions 0.020.05 mg/kg/dose qd or bid (max, 4 mg) IV/PO Sedation, blurred vision, dry mouth, tachycardia
Cyanide antidote kit Cyanide Amyl nitrite: 1 crushable ampule; inhale 30 sec of each min Inhalation Methemoglobinemia
Hydrogen sulde (nitrites only) Sodium nitrite: 0.33 mL/kg of 3% solution if hemoglobin IV Methemoglobinemia
level is not known; otherwise, based on tables with
product
Sodium thiosulfate: 1.6 mL (400 mg)/kg of 25% solution; IV
may be repeated every 3060 min to max of 50 mL
Deferoxamine (Desferal) Iron Infusion of 15 mg/kg/hr (max, 6 g/24 hr) IV(preferred) Hypotension (minimized by avoiding rapid infusion rates)
IM: 90 mg/kg/dose q8h (max, 6 g/24 hr) IM
Digoxin-specic Digitalis glycosides (synthetic or natural) 1 vial binds 0.6 mg of digitalis glycoside; ingested dose IV Allergic reactions (rare), return of condition being treated
Fab antibodies (Digibind) may be estimated from the serum level (see with digitalis glycoside
table with product)
Dimercaptosuccinic acid (succimer, Lead and probably mercury, arsenic, and 10 mg/kg/dose q8h for 5 days, then 10 mg/kg q12h for PO Nausea and vomiting; repeated courses may be needed
DMSA, Chemet) perhaps other metals 14 days
Diphenhydramine (Benadryl) Extrapyramidal symptoms, acute dystonic 5 mg/kg divided q8h; max, 300 mg/24 hr IV/PO Sedation or paradoxical agitation, ataxia
reactions, allergic reactions
EDTA, calcium (calcium disodium, Lead, manganese, nickel, zinc, and perhaps 11.5 g/m
2
/24 hr in divided doses q12h for 5 days IV Nausea, vomiting, fever, hypertension, arthralgias, allergic
Versenate) chromium reactions, local inammation, nephrotoxicity (maintain
adequate hydration)
Ethanol (ethyl alcohol) Methanol, ethylene glycol 750 mg/kg loading dose followed by 80150 mg/kg/hr IV/PO Nausea, vomiting, sedation, add folate for methanol
infusion of 5% or 10% ethanol
Flumazenil (Romazicon) Benzodiazepines 0.2 mg over 30 sec; if response is inadequate, repeat q1min IV Nausea, vomiting, facial ushing, agitation, headache,
to 1 mg max dizziness, seizures; do not use for unknown or
antidepressant ingestions
Note: May not reverse respiratory depression
Fomepizole (4-methylpyrazole, Ethylene glycol, methanol 15 mg/kg load; 10 mg/kg q12h for 4 doses; 15 mg/kg IV Infuse slowly over 30 min; increase doses to q4h if dialysis
Antizole) q12h until level is <20 mg/dL is concurrent
No specic dose for children Thiamine and pyridoxine may be helpful
Glucagon Blockers, calcium channel blockers, 0.05 mg/kg bolus followed by infusion of 0.05 mg/kg/hr IV Hyperglycemia, nausea, vomiting
hypoglycemic agents
Methylene blue Methemoglobinemia 0.10.2 mL/kg of 1% solution by slow infusion; may be IV Nausea, vomiting, headache, dizziness
repeated q3060min
Naloxone (Narcan) Narcotics 0.01 mg/kg; if no effect, give 0.1 mg/kg; may be repeated IV Acute withdrawal symptoms if given to addicted patients
Clonidine (inconsistent response) as needed; may give continuous infusion
Octreotide Sulfonylureas 12 g/kg q8hr IV/SC Used in addition to high-dose glucose; may add glucagon
Physostigmine (Antilirium) Anticholinergic agents 0.02 mg/kg by slow push; may repeat q510min to 2 mg IV/IM Bradycardia, asystole, seizures, bronchospasm, vomiting,
max headache
Note: Do not use with cyclic antidepressants
Pralidoxime (2-PAM, Protopam) Organophosphate insecticides 2550 mg/kg over 510 min (max, 200 mg/min); can be IV/IM Nausea, dizziness, headache, tachycardia, muscle rigidity,
repeated after 12 hr, then q1012hr as needed bronchospasm (rapid administration)
Pyridoxine (Vitamin B
6
) Isoniazid, Gyromitra mushrooms Isoniazid; dose = dose of isoniazid IV Uncommon
Ethylene glycol (investigational) Mushrooms: 25 mg/kg
Oxygen Carbon monoxide 100%, hyperbaric Inhalation Half-life of carboxyhemoglobin is 5 hr in room air, but
1.5 hr in 100% O
2
and 1530 min in 3 atmospheres
hyperbaric
Vitamin K Coumarin 510 mg IV/SC Monitor prothrombin time; give fresh frozen plasma for
acute bleeding; repeat vitamin K for superwarfarin
BAL, British antilewisite; DMSA, dimercaptosuccinic acid; EDTA, ethylene diamine tetraacetic acid; ET, endotracheal; IM, intramuscular; IV, intravenous; max, maximum; NS, normal saline; PO, Oral.
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Prompt action to remove the toxin and minimize contact with
the absorptive surface is crucial and may prevent the develop-
ment of major toxicity. Dermal and ocular decontamination can
be accomplished by ushing the affected area with tepid water.
Flushing for a minimum of 10 min is recommended for ocular
exposures, although some chemicals, particularly alkaline corro-
sives, may require much longer periods of ushing. Effective
ocular irrigation can be instituted by positioning the patients face
under a faucet to allow a mild (not forceful) stream of tepid water
to hit the side of the nose and stream across the eye and down
the cheek. It is probably advisable to prevent the irrigation uid
from owing from 1 eye across to the other eye. It is better to
irrigate 1 eye for 2030 sec and then to switch to irrigating the
other affected eye, and so forth, for approximately 10 min. For
dermal exposures, copious irrigation, followed by a mild soap
wash, can be used. For inhaled toxins, decontamination is gen-
erally accomplished simply by immediately moving the patient to
fresh air and, if necessary, administering oxygen. In addition to
supportive care, a few specic antidotes are used for some spe-
cic inhaled toxins.
Several procedures are used to prevent absorption of an
ingested toxin from the stomach and gastrointestinal tract, and
each has limitations and risks. The decision to use one particu-
lar method over another should be based on whether the tech-
nique chosen is likely to be of sufcient value to merit the risk of
the procedure. Timing is a limitation because many toxins are
rapidly absorbed from the stomach. With the exception of orally
administered activated charcoal (see Activated Charcoal), a
decontamination procedure instituted after the drug is absorbed
poses a risk to the patient with no potential for benet. Most
liquid drug products are almost completely absorbed within
3045 min of ingestion, and most solid dosage forms are
absorbed within 12 hr. When a large overdose involves solid
dose forms (tablets, powder-lled capsules), complete intestinal
absorption can be delayed by as much as 36 hr, and for drugs
or toxins with anticholinergic (intestinal slowing) properties,
absorption can be delayed by up to 812 hr. Certain drugs are
predisposed to bezoar formation, which must also be considered
in the formulation of the patients initial decontamination and
treatment plans (Table 58-8). While bezoars are rare, a bezoar
should be suspected in any patient who has symptoms days after
apparent complete resolution of the associated symptoms.
Activated Charcoal. An effective means to decrease or prevent
the intestinal absorption of a few drugs and toxins as well as
enhance the elimination of drugs already absorbed and present
within the systemic circulation is oral administration of activated
charcoal. Activated charcoal is specially prepared to have a very
large adsorptive surface area. Many, but not all, toxins are
adsorbed onto its surface, preventing absorption from the gas-
trointestinal tract. Some toxins, including heavy metals, iron,
lithium, hydrocarbons, cyanide, and low molecular weight alco-
hols, are not signicantly bound to charcoal.
Usually, a dose of 1050 g (1 g/kg) for a child and 50100 g
for an adolescent or an adult is administered. In practice, the
usual dose administered to a child represents the maximum
tolerated dose. Airway reexes must be preserved or the airway
protected by endotracheal intubation.
Activated charcoal is commercially available in many forms
and is commonly mixed as a slurry in water or a solution of sor-
bitol, a cathartic. Flavoring may be added to improve palatabil-
ity, but it rarely improves the acceptance to drinking in younger
children. A cathartic should be used only with the 1st charcoal
dose to prevent major uid loss and dehydration. Approximately
25% of patients receiving activated charcoal experience 1 episode
of vomiting. Aspiration of activated charcoal into the lungs
occurs occasionally. There is no evidence that aspiration of acti-
vated charcoal is more serious than aspiration of gastric contents
alone. If charcoal is given through a gastric tube, placement of
the tube should be carefully conrmed before activated charcoal
is given because instillation of charcoal directly into the lungs has
disastrous effects.
The use of repeat-dose activated charcoal (a dose every 24 hr)
is recommended by some toxicologists for the hospitalized poi-
soned patient at a dose of approximately 0.250.50 g/kg every
24 hr or hourly at a rate of approximately 0.25 g/kg for 24 hr
as long as bowel sounds are present due to the risk of constipa-
tion or intestinal impaction. The primary benet of oral activated
charcoal in the treatment of severe poisonings is its effect of
increasing the body (systemic) clearance of toxins already present
within the body.
A nasogastric tube should be inserted for charcoal instillation
if the child will not voluntarily swallow the charcoal slurry or is
otherwise unable to protect the airway due to the risk of aspira-
tion. If the patient cannot tolerate a bolus dose of activated
charcoal via the nasogastric tube, the charcoal dose can be
administered as a slow continuous drip (0.25 g/kg/hr).
Cathartics. Cathartics have been used in conjunction with acti-
vated charcoal to hasten clearance of the charcoal-toxin complex.
There is no evidence demonstrating their value. Cathartics do not
need to be administered with each dose of activated charcoal and
should only be administered as needed. Commonly used cathar-
tics are sorbitol (maximum dose, 1 g/kg), magnesium sulfate
(maximum dose, 250 mg/kg), and magnesium citrate (maximum
dose, 250 mL/kg). Cathartics should be used with care in young
children because of the risk of dehydration and electrolyte
imbalance.
TABLE 58-7. Additional Antidotes
ANTIDOTES TOXIN/POISON
Latrodectus antivenin Black widow spider
Botulin antitoxin Botulism
Glucagon and/or insulin and glucose Calcium channel antagonists
Diphenhydramine and/or benztropine Dystonic reactions
Calcium salts Fluoride, calcium channel blockers
Protamine Heparin
Folinic acid Methotrexate, trimethoprim, pyrimethamine
Crotab-specic fab antibodies Rattlesnake envenomation
Sodium bicarbonate Sodium channel blockade (tricyclic antidepressants, type 1
antiarrhythmics)
TABLE 58-8. Common Medications Implicated in Bezoar Formation
ANTACIDS
Aluminum hydroxide
BULK-FORMING LAXATIVES
Combination laxatives (e.g., Perdiem)
Psyllium
EXTENDED-RELEASE PRODUCTS
Nifedipine
Procainamide
Verapamil
ION-EXCHANGE RESINS
Sodium polystyrene sulfonate
Calcium polystyrene sulfonate
VITAMIN AND NATURAL PRODUCTS
Ascorbic acid
Ferrous sulfate
Lecithin
OTHER MEDICATIONS
Carbamazepine
Cholestyramine
Enteric-coated aspirin
Lithium
Salicylic acid
Sucralfate
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Whole Bowel Irrigation. Whole bowel irrigation involves instill-
ing large volumes (30 mL/kg/hr) of a nonabsorbed polyethylene
glycol electrolyte solution (e.g., Colyte, GoLYTELY) into the
stomach to ow through the entire length of the bowel to
cleanse the entire gastrointestinal tract. This technique has
been successfully used to remove slowly absorbed products, such
as iron or sustained-release preparations, as well as foreign
bodies, including drug packets (cocaine packets via body
packers). Whole bowel irrigation can be combined with the use
of activated charcoal, if appropriate (cocaine body packers). It
should be used with caution in young children because of the
possibility of uid and electrolyte imbalance.
Enhancing Elimination. Enhancing excretion is useful for only a
few toxins. Dialytic techniques are not useful for drugs that are
either highly protein-bound or have a large volume of distribu-
tion. These techniques are also invasive and associated with risk.
Certain procedures can be used for very specic agents.
Emesis. The emetic used in the past was syrup of ipecac; it con-
tains 2 emetic alkaloids that work both in the central nervous
system (CNS) and locally in the gastrointestinal tract to produce
vomiting. The onset of emesis is usually 2030 min after dosing,
with vomiting occurring in 9095% of patients. Several episodes
of vomiting usually occur over a 12 hr period. The dose is 10
mL for infants 612 mo of age, 1530 mL for children 112 yr
of age, and 30 mL for older children and adults. Ipecac should
not be used in infants younger than 6 mo of age because these
infants have a far greater risk of aspiration. Ipecac should be
followed by at least 68 oz of water or other clear uid, with
the actual nal volume age- and child-dependent.
The use of ipecac syrup is not recommended for routine inges-
tions. Emesis with syrup of ipecac removes approximately
1
/
3
of
the stomach contents. Because of the delay in onset of emesis and
the poor yield, it should not be used as a general treatment for
ingestions. Ipecac-induced emesis is contraindicated after the
ingestion of caustics (acids/bases), hydrocarbons, and agents
likely to cause rapid onset of CNS or cardiovascular symptoms.
Ipecac abuse and cardiac toxicity is noted in some adolescents
with bulimia (see Chapter 27).
Gastric Lavage. This technique involves placing a tube into the
stomach to aspirate contents, followed by ushing with aliquots
of uid, usually normal saline. Although gastric lavage was used
for many years, objective data do not document or support clin-
ically relevant efcacy, particularly in children, in whom only
small-bore tubes often can be used. Lavage is time-consuming,
and under the best circumstances, it removes only a fraction of
gastric contents. Lavage should only be used in older children and
possibly only in select situations (iron, calcium channel blockers,
tricyclic antidepressants, lithium). If gastric lavage is to be per-
formed, repeated instillation and removal of small volumes of
lavage solution is generally better tolerated, with less risk of aspi-
ration. The airway also needs to be secure.
Diuresis. For most toxins, renal clearance is not proportional
to urine volume; thus, diuresis or forced diuresis alone does
not increase elimination. Increasing the pH of the urine with IV
bicarbonate can augment the elimination of weak acids, such as
salicylates and phenobarbital. Alternately, acidifying the urine to
increase the elimination of weak bases, such as amphetamine and
phencyclidine, is rarely clinically useful. Despite the theoretical
advantages of such a therapeutic approach, the need to closely
monitor uid balance, combined with the need to alter systemic
pH to change the urine pH, restricts the use of this therapeutic
maneuver to very rare circumstances.
Dialysis. Hemodialysis and peritoneal dialysis have been used
successfully to treat poisonings by select agents. Although
hemodialysis is generally more efcient at removing toxins, peri-
toneal dialysis is often easier to perform in young children, and
may be sufcient. Few drugs or toxins are removed by dialysis in
amounts sufcient to justify the risks and difculty of dialysis.
Examples of toxins for which dialysis may be useful include the
toxic alcohols, methanol, and ethylene glycol as well as large
symptomatic ingestions of salicylates, theophylline or lithium.
Hemoperfusion. Hemoperfusion is a dialytic technique in which
blood is passed through a column of activated charcoal or resin.
It can successfully treat large ingestions of salicylate, theo-
phylline, and a few other selected agents. It is rarely used because
of the associated risks.
LABORATORY EVALUATION. For some intoxications (salicylates,
anticonvulsants, acetaminophen, iron, digoxin, methanol,
lithium, theophylline, ethylene glycol, carbon monoxide), blood
concentrations can be integral to conrming the diagnosis and
formulating the treatment plan. For most intoxicants, qualitative
measurement is not possible or likely to change treatment. Exam-
ples include opioid toxicity, in which denitive treatment is based
on symptoms, not serum drug concentrations, and cyanide, in
which treatment must be started rapidly and would be signi-
cantly delayed if the clinician were to wait for laboratory conr-
mation. Comprehensive, qualitative drug screens vary widely
in their ability to detect toxins and generally add little informa-
tion, particularly if the agent is known and the patients symp-
toms are consistent with that agent (see Tables 58-3 to 58-5). If
a drug screen is ordered, it is important to know the specic drugs
that can be identied by the test because the components screened
for in the tox screen vary from hospital to hospital. Although
drug screens can be performed on any body uid, urine is gen-
erally the best uid to sample because the toxin or metabolite is
concentrated in the urine. The best way to use the laboratory is
to discuss the case with the poison control center, a medical tox-
icologist, or a laboratory technologist and to provide appropri-
ate samples and clinical data so that the most appropriate tests
can be performed and properly interpreted.
SELECTED COMPOUNDS COMMONLY INVOLVED IN
PEDIATRIC POISONINGS
ACETAMINOPHEN. Acetaminophen is the most widely used anal-
gesic and antipyretic in pediatrics, primarily due to the nding of
a relationship between Reye syndrome and salicylates. Conse-
quently, acetaminophen, which is available in multiple formula-
tions and different strengths, is commonly available in the home,
where it can be unintentionally ingested by young children (good-
tasting chewable tablets) or taken in an intentional overdose by
adolescents and adults. Acetaminophen intoxication is a common
cause of acute liver failure in adolescents and adults.
Pathophysiology. Acetaminophen toxicity results from the
formation of a highly reactive intermediate metabolite, N-acetyl-
p-benzoquinoneimine (NAPQI). When therapeutic doses are
administered, only a small amount (4%) of a dose is metabo-
lized by the hepatic cytochrome P450 enzyme CYP2E1 to
NAPQI, which is immediately conjugated with glutathione to
form a harmless mercapturic acid conjugate. When hepatic stores
of glutathione are depleted to <70% of normal, the NAPQI
metabolite can combine with hepatic macromolecules to produce
hepatocellular damage. The acute toxic dose of acetaminophen
is generally considered to be >200 mg/kg in children younger than
12 yr of age; a single ingestion of >7.5 g is considered a minimum
toxic dose in adolescents and adults. Repeated administration
of acetaminophen at doses exceeding those recommended
(>60 mg/kg/day for consecutive days) may lead to hepatic injury
or failure in some children. Parents should be advised to follow
closely the manufacturers dosing guidelines and should be aware
of the availability of sustained-release formulations and the drugs
presence in many combination products.
Children younger than 6 yr of age are unlikely to have signif-
icant toxicity after a single ingestion of even relatively large doses
of acetaminophen. Any child with a history of a signicant inges-
tion should have the plasma acetaminophen concentration mea-
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sured and receive treatment with N-acetylcysteine (NAC) if the
plasma concentration falls within the toxic range on the nomo-
gram (Fig. 58-1). In infants whose nutritional intake has been
compromised by the concurrent intestinal illness and whose
hepatic glutathione stores are suboptimal, the risk may possibly
be higher for acetaminophen hepatotoxicity. Adolescents have a
higher incidence of toxic plasma concentrations after ingestion
than do children, and their exposures are often associated with
intentional overdose. Chronic alcohol ingestion increases the risk
of acetaminophen hepatotoxicity. Even if a serious case of hepa-
totoxicity develops, the mortality rate is <0.5%, reecting the
safety and efcacy of NAC antidote therapy. Severely affected
patients may require liver transplantation (see Chapter 365).
Clinical and Laboratory Manifestations. If untreated, patients
with an acute overdose may pass through the 4 stages of aceta-
minophen toxicity (Table 58-9). Because early symptoms are non-
specic, physicians may not diagnose the ingestion without a
good history or a high index of suspicion. If a toxic ingestion is
suspected, the plasma acetaminophen concentration should be
measured 4 hr or more after ingestion. Measurement earlier than
4 hr after ingestion may be useful to determine if ingestion has
occurred, but it cannot be used to determine the severity of an
overdose. The plasma acetaminophen concentration should be
plotted on the Rumack-Matthew nomogram (see Fig. 58-1) to
determine whether antidotal treatment is indicated. The nomo-
gram should only be used to evaluate the risk after acute expo-
sure to regular-release products. The nomograms predictive
strength does not apply to plasma acetaminophen concentrations
obtained after the use of sustained-release formulations,
ingestions involving repeated exposures over multiple days. The
nomograms predictive strength may not always extend to
patients who are believed to have depleted glutathione stores
(malnourishment, prolonged illness). A minimum of 2 plasma
acetaminophen concentrations should be obtained from patients
who have ingested a sustained-release preparation; the 1st at least
4 hr after the exposure and a 2nd sample 46 hr after the 1st. If
at any time the plasma acetaminophen concentration exceeds the
treatment value of the Rumack-Matthew nomogram, the patient
should receive NAC antidote therapy. This approach is conserv-
ative, and more data are needed to better dene an optimal
approach to treating patients ingesting sustained-release formu-
lations as well as those with consecutive days of high-dose inges-
tion. Weighing the real toxicity associated with acetaminophen
intoxication against the denite benet of treatment with a very
safe antidote, a conservative approach dictates treating if toxic-
ity is suspected, despite the plasma concentration plot on the
treatment nomogram (see Fig. 58-1). These plasma aceta-
minophen concentrations are most useful for the asymptomatic
patient; symptomatic patients require therapy individualized to
their specic requirements. Liver function studies, including
hepatic enzymes, bilirubin, and prothrombin time, should be fol-
lowed daily to every other day in all patients with plasma aceta-
minophen concentrations falling within the toxic range on the
nomogram.
Treatment. After a large acute oral overdose, and when the need
for antidotal treatment is determined, treatment should be started
as soon as possible, including within 12 hr of the ingestion. The
antidote for acetaminophen poisoning is NAC, which serves as a
precursor for hepatic glutathione synthesis, replenishing glu-
tathione stores and preventing the reaction of NAPQI with hepa-
tocytes. NAC therapy is most effective when initiated early in the
course of intoxication (within 8 hr), but may have value even if
started 2436 hr after the ingestion in severe cases. It is impor-
tant to note that NAC administration has no effect on the plasma
acetaminophen concentration or the drugs elimination from the
body. In acute large overdoses, particularly patients ingesting
sustained-release preparations or co-ingestions with drugs that
decrease gastrointestinal transit, oral administration of activated
charcoal should be considered. The extent to which activated
charcoal may bind to orally administered NAC (30%) remains
a point of debate, although most authorities administer the same
oral NAC dose (140 mg NAC/kg oral loading dose +70 mg oral
NAC/kg every 4 hr, for a total of 17 doses), regardless of whether
oral activated charcoal has been administered. Oral NAC is
unpalatable and can be irritating to the gastrointestinal tract, so
it should be diluted to a 5% solution with soda or fruit juice to
minimize vomiting. Antiemetics (ondansetron) may be used to
control vomiting and/or NAC may be administered directly into
Hours After Ingestion
0 4 8 12
1,000
(S.I. Units)
M per L g per mL
Probable Hepatic Toxicity
P
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i
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e

H
e
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a
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i
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T
o
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i
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25%
500
200
150
100
50
A
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300
400
500
600
700
800
900
1,000
1,300
2,000
3,000
4,000
5,000
6,000
16 20 24
Figure 58-1. Rumack-Matthew nomogram for acetaminophen poisoning, a
semilogarithmic plot of plasma acetaminophen concentrations vs time. Cau-
tions for the use of this chart: (1) The time coordinates refer to time after
ingestion. (2) Serum concentrations obtained before 4 hr may not represent
peak concentrations. (3) The graph should be used only in relation to a single
acute ingestion. This nomogram is not useful for chronic exposures, nor has
it been validated for use after ingestions involving sustained-release aceta-
minophen products. (4) The lower solid line 25% below the standard nomo-
gram is included to allow for possible errors in acetaminophen plasma assays
and estimated time from ingestion of an overdose. (From Rumack BH, Hess
AJ [editors]: Poisindex. Denver, Micromedix, 1995. Adapted from Rumack
BH, Matthew H: Acetaminophen poisoning and toxicity. Pediatrics 1975;55:
871876.)
TABLE 58-9. Classic Stages in the Clinical Course of Acetaminophen
Toxicity
STAGE TIME AFTER INGESTION CHARACTERISTICS
I 0.524 hr Anorexia, nausea, vomiting, malaise, pallor, diaphoresis
II 2448 hr Resolution of earlier symptoms; right upper quadrant abdominal
pain and tenderness; elevated bilirubin, prothrombin time,
hepatic enzymes; oliguria
III 7296 hr Peak liver function abnormalities; anorexia, nausea, vomiting, and
malaise may reappear
IV 4 days2 wk Resolution of hepatic dysfunction or complete liver failure
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the stomach or upper intestine by tube. An IV preparation of
NAC is also available (Acetadote) and was approved by the U.S.
Food and Drug Administration for IV administration within
810 hr after ingestion of a potentially hepatotoxic quantity of
acetaminophen. For the IV formulation, an initial IV loading dose
of 150 mg/kg is infused over 1560 min, followed by an initial
maintenance dose of 50 mg/kg infused over 4 hr, followed by
100 mg/kg infused over 16 hr. Anaphylactoid reactions may be
minimized by a 60 min infusion. Clinicians are encouraged to
consult with a medical toxicologist or a regional poison control
center for cases involving subacute or chronic exposure,
extended-release products, or co-ingestions, as stated earlier; the
Rumack-Matthew nomogram is not always useful in making
treatment decisions under these circumstances.
SALICYLATES. The incidence of salicylate poisoning is low,
particularly in young children, because the use of alternative
antipyretics has increased in an effort to avoid Reye syndrome.
Salicylate toxicity must still be considered in therapeutic situa-
tions as well as in cases of acute overdose; the common use of
baby aspirin preparations by parents and grandparents for car-
diovascular prophylaxis places the drug in many home environ-
ments and thus makes it available for accidental poisoning.
Methyl salicylate is the active ingredient in oil of wintergreen, a
common component in rubefacients. Every 1 g of methyl salicy-
late contains the equivalent of 1.5 g of salicylate, underscoring
the risk of moderate to serious symptoms associated with what
might seem a small amount of commonly used over-the-counter
rubs or topical sports medicines.
Pathophysiology. Salicylates directly or indirectly affect most
organ systems by uncoupling oxidative phosphorylation, inhibit-
ing Krebs cycle enzymes, and inhibiting amino acid synthesis.
Various complex metabolic abnormalities result. Salicylates also
decrease platelet adhesiveness and increase pulmonary capillary
permeability. The acute toxic dose of salicylates is generally con-
sidered >150 mg/kg for mild symptoms and >300500 mg/kg for
moderate to severe intoxication.
Clinical and Laboratory Manifestations. The clinical presentation
after acute poisoning differs signicantly from that of chronic
toxicity. Chronic toxicity results in signs and symptoms that are
easily attributed to other causes, such as u or other febrile
illness. Young children are more susceptible to toxic effects
because they are less able to buffer the acid load produced by
salicylates.
After acute salicylate ingestion, nausea and vomiting occur due
to gastric irritation. Salicylates directly stimulate the respiratory
center, leading to hyperventilation and hyperpnea. An increased
respiratory rate results in respiratory alkalosis with compensatory
alkaluria. Both potassium and sodium bicarbonate are excreted
in the urine; however, soon after exposure, the serum potassium
concentration may be in the normal range. When sufcient potas-
sium has been lost through the kidneys, an exchange of potas-
sium for hydrogen ion occurs and the urine becomes relatively
acidic. This paradoxical aciduria occurs in the presence of con-
tinued respiratory alkalosis. Dehydration and progressive meta-
bolic acidosis, caused by the accumulation of lactic acid and other
metabolic acids, eventually develop. Seriously poisoned patients
are >510% dehydrated. Patients with chronic salicylate poison-
ing usually present with metabolic acidosis.
Important signs of serious toxicity are CNS changes. Agitation,
restlessness, and confusion are common in children. Coma may
develop as a result of cerebral edema. Pulmonary edema or hem-
orrhage may develop in more severe cases. Hyperglycemia (acute)
or hypoglycemia (chronic), particularly in infants, has also been
observed. Hepatotoxicity occurs after chronic exposure or with
very large acute ingestions. Death results from pulmonary edema
and respiratory failure, cerebral edema, hemorrhage, severe elec-
trolyte imbalance, or cardiovascular collapse. Hyperpyrexia may
also occur.
Serial serum salicylate concentrations (initially at 4 hr
postingestion and then every 34 hr) should be monitored to eval-
uate for either continued absorption or impairment of excretion.
After acute ingestion, patients with serum salicylate concentra-
tions of >20 mg/dL should undergo continued observation and
monitoring. Acute serum concentrations of >70100 mg/dL may
produce life-threatening effects. Plasma levels do not always
correlate with clinical toxicity. The Done nomogram is of poor
value and is no longer used. Patients with chronic salicylate tox-
icity may have a serum concentration within the usual therapeu-
tic range (1020 mg/dL). Salicylate disposition is characterized by
nonlinear Michaelis-Menten characteristics, where the drugs
body elimination is saturable. The disproportionate increase in
the serum salicylate concentration, but more importantly, the dis-
proportionality of the drugs slow body clearance, particularly in
overdose, should be anticipated and the treatment plan adjusted
accordingly.
Urine pH and volume should be measured hourly in all
seriously poisoned children. Plasma pH, glucose, potassium,
and other electrolytes should be monitored at regular intervals.
Clotting studies and liver function tests should also be closely
monitored in all severely poisoned patients.
Treatment. Initial treatment should include gastric decontami-
nation, preferably with activated charcoal, if the patient presents
soon after an acute ingestion. Salicylate tablets occasionally form
into bezoars, which may be suspected if serum salicylate concen-
trations continue to rise many hr after ingestion or are persis-
tently elevated. Gastric decontamination is typically not useful
after chronic exposure.
Initial therapy focuses on aggressive rehydration and correc-
tion of electrolyte abnormalities (see Chapter 52). Large quanti-
ties of potassium and bicarbonate may be needed if symptoms
have been present for some time after an acute ingestion or in the
case of chronic salicylate poisoning, because body stores of these
electrolytes may be severely depleted.
Urinary excretion of unmetabolized salicylate becomes an
important route of elimination in overdose. Urinary clearance of
salicylate is affected by urine pH. Because metabolic acidosis pro-
duces more acidic urine, a higher percentage of ltered salicylate
remains in the un-ionized form, which is effectively reabsorbed.
Urinary salicylate elimination can be increased using ion trap-
ping by increasing urine pH to convert a greater percentage of
salicylate to the ionized form, which is then excreted in the urine.
Each 1-unit increase in urine pH increases urinary salicylate clear-
ance 4-fold. Urine pH should be increased to at least 7.07.5,
using IV bicarbonate. The shift of salicylate to the ionized form
also serves to decrease CNS penetration because un-ionized drugs
generally cross the blood-brain barrier more efciently. It may be
difcult to alkalize the urine without adequately replenishing
tissue stores of potassium. Acetazolamide (Diamox) should not
be used in an attempt to achieve urine alkalization.
In severe cases of salicylate intoxication, dialysis may be
required both to remove salicylate and to correct electrolyte
abnormalities. Indications for extracorporeal removal include
serum salicylate concentrations of >90 mg/dL, changes in neuro-
logic status (depressed level of consciousness or difcult to
control seizures), respiratory or cardiovascular instability, refrac-
tory metabolic acidosis, severe hypokalemia, and renal failure.
Hemodialysis is preferred over either peritoneal dialysis or char-
coal hemoperfusion. Repeat-dose activated charcoal may aid in
enhancing the body clearance of salicylate. Dialysis can be effec-
tive in correcting and/or maintaining the patients uid and elec-
trolyte balance.
IBUPROFEN AND OTHER NONSTEROIDAL ANTI-INFLAMMATORY
DRUGS. Ibuprofen and other nonsteroidal anti-inammatory
drugs (NSAIDs) are often involved in unintentional and inten-
tional overdoses because of their wide distribution and their
common use as analgesics; in particular, ibuprofen is used as an
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antipyretic in pediatric practice. Fortunately, serious effects after
NSAID overdose are rare.
Pathophysiology. These drugs inhibit prostaglandin synthesis by
inhibiting the activity of cyclo-oxygenase, the primary enzyme
responsible for the biosynthesis of prostaglandins and certain
other autocoids. This disruption produces the side effects
reported with therapeutic use, such as gastrointestinal irritation,
reduced renal blood ow, and platelet dysfunction. NSAID
analogs have been developed that are more specic for the
inducible form of COX (the COX-2 isoform) vs the constitutive
form, the COX-1 isoform. These drugs attempt to minimize or
reduce the occurrence of therapy-associated adverse effects.
Overdose of the more selective COX-2 inhibitors (celecoxib
[Celebrex]) is treated no differently than for nonspecic COX
inhibitors (ibuprofen) because at higher doses, COX-2 selective
agents lose their COX inhibitory selectivity. Ibuprofen, the
primary NSAID used in pediatrics, is well tolerated, even after
overdose. In children, acute doses of <100 mg/kg rarely cause
toxicity, whereas doses of >400 mg/kg are capable of producing
more serious effects, including bradycardia, hepatic dysfunction,
seizures, and coma.
Clinical and Laboratory Manifestations. Symptoms usually
develop within 46 hr of NSAID ingestion and resolve within
24 hr. Common initial effects include nausea, vomiting, and epi-
gastric pain, followed by drowsiness, lethargy, and ataxia. Anion
gap metabolic acidosis, coma, transient apnea, renal failure,
hypotension, and seizures can occur with large overdoses, but are
rare. Other reported effects include nystagmus, diplopia,
headache, tinnitus, and transient deafness. Renal function studies
and acid-base balance should be monitored after ingestion of
large doses.
Treatment. Good supportive care is essential in the treatment of
acute NSAID overdose or poisoning. There is no specic antido-
tal therapy for this class of drugs. Emesis is of little benet, but
activated charcoal can be administered. Extracorporeal removal
methods have not been adequately evaluated and are not recom-
mended, particularly when considering the extensive degree to
which each of these analogs is bound to plasma protein.
ANTIDEPRESSANTS: TRICYCLICS AND SEROTININ-MODULATING
DRUGS. Tricyclic antidepressants (TCAs) and selective serotonin-
reuptake inhibitors (SSRIs) are the 2 most common classes of
antidepressants of toxicologic signicance (see Chapter 25). Anti-
depressants include amitriptyline, nortriptyline, and imipramine,
among others. SSRIs include uoxetine, sertraline, paroxetine,
and citalopram. Antidepressants not selective for serotonin, often
referred to as nonselective serotonin-reuptake inhibitors
(NSSRIs), include venlafaxine, bupropion, duloxetine, mirtazap-
ine, and nefazodone.
Tricyclic Antidepressants
PATHOPHYSIOLOGY. Tricyclic antidepressants block the
neuronal reuptake of norepinephrine, serotonin, and dopamine
in both the central and peripheral nervous systems. They also
produce varying degrees of sedation, -receptor blocking, and
anticholinergic effects. Inhibition of fast sodium channels in the
myocardium leads to the development of cardiac dysrhythmias
and myocardial depression.
CLINICAL AND LABORATORY MANIFESTATIONS. The
primary organ systems affected by TCAs are the CNS and car-
diovascular system. Symptoms can develop as early as 30 min
after ingestion, with serious symptoms usually developing within
6 hr of ingestion. In large ingestions, patient symptoms may be
delayed (>68+ hr), reecting the anticholinergic properties of
TCAs in slowing gastric emptying and bowel motility. The
pattern of toxicity in children is different from that described in
adolescents and adults in that CNS effects occur more frequently
in children than do cardiovascular effects. Drowsiness, lethargy,
or coma is reported in as many as 30% of pediatric cases. Coma,
when it occurs, usually resolves in a few hr, but may last >24 hr.
Seizures develop in approximately 15% of cases and can occur
without warning, but are usually brief and resolve without treat-
ment. Adolescents with comparable blood TCA levels have more
signicant toxicity than younger children.
Tachycardia, likely attributed to the anticholinergic actions of
TCAs, is the most common cardiovascular effect, but does not
usually compromise blood pressure. Hypertension may occur
soon after ingestion, but rarely requires treatment. Hypotension
is uncommon, but is a poor prognostic sign. Other cardiac nd-
ings include slowing of myocardial conduction, multifocal pre-
mature ventricular contractions, and ventricular tachycardia or
brillation. In addition to widening of the QRS complex, QT pro-
longation occurs with T-wave attening or inversion, ST segment
depression, right bundle branch block, and complete heart block.
Hypoventilation with respiratory arrest may occur without
warning. Other reported effects include hyperthermia, chor-
eiform movements, agitation, and twitching. Anticholinergic
syndrome, including mydriasis, disorientation, hallucinations,
urinary retention, and diminished bowel sounds, may be present.
The electrocardiogram (ECG) should be closely monitored for
QRS widening and QT and QTc prolongation. QRS duration
and axis deviation and the level of consciousness have been sug-
gested as predictors of potential toxicity. ECG changes may not
be useful predictors of toxicity in younger children. Plasma TCA
concentrations are not helpful in assessing or predicting the sever-
ity of exposure, but may aid in establishing a diagnosis or assess-
ing the rate of TCA body clearance with therapy.
TREATMENT. After general life support measures are insti-
tuted, including if indicated, endotracheal intubation, efforts
should be undertaken to prevent absorption. Emesis is con-
traindicated because of the danger of aspiration from vomiting
after the onset of CNS depression (loss of gag reex) or seizures.
Activated charcoal should be administered. Because of the effects
of TCAs on slowing intestinal motility, additional doses of acti-
vated charcoal can be administered 4 hr apart, concurrent with
a cathartic (sorbitol), if required, based on the patients bowel
motility status. IV sodium bicarbonate in doses sufcient to
achieve and maintain a serum pH of 7.457.50 should be admin-
istered to treat and prevent dysrhythmias. IV sodium bicarbon-
ate is one of the most effective therapies in treating and/or
preventing a TCA-induced decrease in cardiac conduction, and it
should be considered for all TCA-exposed patients with such
abnormalities on ECG. Lidocaine is used to treat dysrhythmias
that are unresponsive to serum alkalization. Quinidine and pro-
cainamide or similar agents should not be used because they
further depress cardiac conduction. Hypotension may respond to
standard uid therapy, although vasopressors, such as norepi-
nephrine, may be required. Severe, unresponsive hypotension is
a poor prognostic sign. Hypertension usually is transient and
does not require treatment. Seizures, if they require treatment,
usually respond to benzodiazepine therapy. Physostigmine, once
promoted as an antidote for TCA toxicity, is a dangerous agent
that can cause seizures and dysrhythmias and should not be used.
Because of the large volumes of distribution and the high degree
of plasma protein binding of TCAs, extracorporeal removal is of
no clinical value. Oral activated charcoal and possibly repeat-
dose activated charcoal may be effective in enhancing the body
clearance after very large overdoses, although limited data
suggest such a strategy.
Asymptomatic children should be observed and the ECG mon-
itored for at least 6 hr after exposure. If any manifestations of
toxicity, including a QRS interval of >100 msec, conduction
defects, altered mental status, hypotension, or hypoventilation,
develop, the patient should be admitted for continued monitor-
ing in an intensive care unit for 24 hr. Only completely asymp-
tomatic children should be discharged after 6 hr of observation.
Selective Serotonin-Reuptake Inhibitors. Selective serotonin-
reuptake inhibitors differ from TCAs in that they specically
inhibit reuptake of serotonin in the CNS. They have little or no
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effect on norepinephrine or dopamine reuptake and minimal, if
any, anticholinergic or -blocking effects.
CLINICAL MANIFESTATIONS. These drugs have a wide
therapeutic index, and toxic effects are usually mild. The usual
onset of symptoms is within 3 hr, with resolution of symptoms
within 24 hr in treated patients. Most children remain asympto-
matic. Drowsiness or hyperactivity, agitation, and tachycardia are
the most commonly reported effects. Nausea, vomiting, tremor,
dizziness, and abdominal pain are less common. Life-threatening
effects, such as seizures, coma, and hyperthermia, are rare, but
have been reported after very large ingestions. Cardiac conduc-
tion defects are not common. Adolescents have an increased
incidence of symptoms, although when they manifest, they are
still relatively minor. The toxic dose of these agents is not well
dened.
A serotonin syndrome has been well described after overdose
of SSRIs as well as after therapeutic use in some patients (see
Table 58-3 and Figs. 58-2 and 58-3). Certain drug-drug interac-
tions (meperidine, monoamine oxidase inhibitor) also manifest as
serotonin syndrome, which is a predictable reaction that results
from excess serotonin agonism of CNS and peripheral serotonin
receptors and includes confusion and disorientation, agitation,
coma, hyperthermia, myoclonus, hyperreexia, tremor, and
muscle rigidity (Table 58-10).
TREATMENT. Gastrointestinal decontamination with acti-
vated charcoal is the preferred treatment of the serotonin syn-
drome; emesis should not be attempted because of the real
potential for CNS depression. Treatment depends on the severity
of symptoms, but requires removal of the inciting drugs and
prompt provision of supportive care, allowing the severity of the
Muscular
hypertonicity
Akathisia
Tremor Clonus
(inducible)
Altered
mental status
Clonus
(sustained)
Hyperthermia
Life
threatening
toxicity
Mild
symptoms
Muscular
hypertonicity
Figure 58-2. Manifestations of the serotonin syn-
drome range from mild to life-threatening. The
arrows suggest the approximate point at which each
clinical nding initially appears in the spectrum of
the disease, but all ndings may not be consistently
present in a single patient. Severe signs may mask
other clinical ndings. For example, muscular
hypertonicity can overwhelm tremor and hyper-
reexia. (From Boyer EW, Shannon M: The sero-
tonin syndrome. N Engl J Med 2005;352:
11121120.)
Diaphoresis
Agitation
Increased bowel
sounds; may
have diarrhea
Autonomic instability:
often hypertensive
Hyperreflexia
(greater in lower
extremities)
Tremor
(greater in lower
extremities)
Clonus
(greater in lower
extremities)
Tachycardia
Mydriasis
Figure 58-3. Findings in a patient with moderately severe serotonin syndrome. Hyperkinetic neuromuscular ndings of tremor or clonus and hyperreexia should
lead the clinician to consider the diagnosis of the serotonin syndrome. (From Boyer EW, Shannon M: The serotonin syndrome. N Engl J Med
2005;352:11121120.)
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patients symptoms to direct specic therapies, including benzo-
diazepine for control of agitation and hyperreexia or tremors.
All patients with moderate to severe symptoms require continu-
ous cardiac and body temperature monitoring. Patients whose
muscle effects and resultant hyperthermia are poorly responsive
to benzodiazepines should be intubated, ventilated, and pharma-
cologically paralyzed with a neuromuscular blocking drug.
Because the hyperthermia is a direct result of increased muscle
activity, antipyretic drugs have no role in the treatment of sero-
tonin syndrome. The predominant receptor responsible for sero-
tonin syndrome may be the 5-HT
2A
receptor because case reports
have suggested therapeutic benet in moderate to severe SSRI
intoxications with the 5-HT
2A
antagonist cyproheptadine or
newer atypical antipsychotic drugs with 5-HT
2A
antagonistic
activity (olanzapine).
CLONIDINE. Clonidine was rst introduced for use as an antihy-
pertensive, but has found use in attention-decit/hyperactivity
disorder and tic syndromes in children (see Chapters 23 and 31).
Increased use for pediatric indications as well as greater popu-
larity of the use of the patch formulation for adults with hyper-
tension has resulted in an escalation of acute poisoning and
therapeutic misadventures.
Pathophysiology. The toxic effects of clonidine are the direct
result of
2
-adrenergic receptor inhibition in the CNS. Children
are very sensitive to the toxic effects of clonidine, with as little
as 0.1 mg reported to produce signicant toxicity in young
infants. Serious toxicity has developed after sucking or chewing
on a new or discarded topical patch preparation. It is of para-
mount importance to inform families in which a member uses the
clonidine patch that a substantial amount of clonidine remains in
the patch on removal and that the used patch should be folded
by sealing the adhesive surface and then discarded in the trash.
Clinical and Laboratory Manifestations. In clonidine-nave chil-
dren, symptoms frequently develop within 1 hr of ingestion; thus,
rapid recognition and intervention is essential. Lethargy, miosis,
bradycardia, and hypotension occur in all age groups. Apnea, res-
piratory depression, and coma are common ndings in younger
children. Serious symptoms usually resolve within 24 hr of
ingestion. Serum clonidine concentrations are not readily avail-
able and are of no clinical value.
Treatment. Immediate recognition of an exposure, with trans-
fer to a health care facility, is of paramount importance. Gastric
decontamination is usually of little value owing to the small quan-
tities usually ingested and the rapid onset of serious symptoms.
Aggressive supportive care is imperative. The ECG, vital signs,
and blood gases are monitored as symptoms dictate. Naloxone
has been used with mixed success to reverse CNS and respiratory
depression; its use should not replace aggressive supportive care.
Because the duration of effect of naloxone is shorter than that of
clonidine, repeat doses or administration by continuous infusion
may be necessary. Extracorporeal removal techniques are not of
value.
IRON. Iron is one of the most common causes of childhood poi-
soning death. Iron-containing products are common in many
homes, and iron-containing vitamins, which often resemble
candy, are frequently freely given to children by their parents. The
potential severity of exposure is based on the amount of elemen-
tal iron ingested. The amount of elemental iron ingested is cal-
culated on the basis of the number of tablets ingested and the
percentage of elemental iron present in the salt form ingested. The
amount of elemental iron is 20% in ferrous sulfate, 12% in
ferrous gluconate, and 33% in ferrous fumarate. Most multivit-
amin products containing iron list on the product label the
amount of iron per tablet as the elemental iron content.
Pathophysiology. Iron is corrosive to the gastrointestinal
mucosa and may lead to intestinal ulceration, edema, and occa-
sionally melena, hematemesis, and possibly perforation. It also
accumulates in the mitochondria and tissues to produce cellular
damage and systemic toxicity. Iron causes venodilation and
increased capillary permeability, leading to hypotension. Early
hypovolemia from intestinal losses, leading to reduced peripheral
perfusion and mitochondrial damage, results in lactic and citric
acid accumulation, causing metabolic acidosis. Hepatic necrosis
develops after serious poisoning, resulting in abnormal liver func-
tion test results and coagulopathies. Drowsiness and coma may
develop as a result of hemodynamic instability or possibly as a
direct toxic effect of iron in the CNS. Greater than 60 mg/kg of
elemental iron is generally considered a toxic dose.
Clinical and Laboratory Manifestations. Nausea, vomiting, diar-
rhea, and abdominal pain reective of irons corrosive effects are
the hallmark of iron poisoning, and usually develop within 30
min to 6 hr after ingestion. Hematemesis and bloody diarrhea
may develop in more serious poisonings. Gastrointestinal signs
may subside over 612 hr; however, careful observation is war-
ranted because systemic toxicity due to cellular damage may
ensue, particularly in patients with severe gastrointestinal signs,
early hypotension, or drowsiness. All infants and children with a
history of clinically signicant iron ingestion who experience
unprompted emesis should be immediately referred to a health
care facility. Because iron is radiopaque, an abdominal radi-
ograph may conrm the ingestion. Repeat radiographs may help
with assessment of the efciency of gastric decontamination
methods. A negative result does not rule out iron ingestion
because only undissolved tablets can be seen. Iron present in chil-
drens chewable multiple vitamins is usually not visualized on the
radiograph because of the low concentration of iron and the
rapid dissolution of the chewed tablet. Gastric scarring, pyloric
stenosis, and intestinal strictures can develop 24 wk after a large
ingestion or in instances when iron tablets remain in prolonged
TABLE 58-10. Drugs and Drug Interactions Associated with Serotonin
Syndrome
DRUGS ASSOCIATED WITH SEROTONIN SYNDROME
Selective serotonin-reuptake inhibitors: Sertraline, uoxetine, uvoxamine, paroxetine, citalopram
Antidepressant drugs:Trazodone, nefazodone, buspirone, clomipramine, venlafaxine
Monoamine oxidase inhibitors: Phenelzine, moclobemide, clorgiline, isocarboxazid
Anticonvulsants:Valproate
Analgesics: Meperidine, fentanyl, tramadol, pentazocine
Antiemetic agents: Ondansetron, granisetron, metoclopramide
Antimigraine drugs: Sumatriptan
Bariatric medications: Sibutramine
Antibiotics: Linezolide (a monoamine oxidase inhibitor), ritonavir (through inhibition of cytochrome P450
enzyme isoform 3A4)
Over-the-counter cough and cold remedies: Dextromethorphan
Drugs of abuse: Methylenedioxymethamphetamine (MDMA, or ecstasy), lysergic acid diethylamide
(LSD), 5-methoxydiisopropyltryptamine (foxy methoxy), Syrian rue (contains harmine and harmaline, both
monoamine oxidase inhibitors)
Dietary supplements and herbal products:Tryptophan, Hypericum perforatum (St. Johns wort), Panax
ginseng (ginseng)
Other: Lithium
DRUG INTERACTIONS ASSOCIATED WITH SEVERE SEROTONIN SYNDROME
Sertraline (Zoloft), uoxetine (Prozac, Savatem), uvoxamine (Luvox), paroxetine (Paxil), citalopram (Celexa),
trazodone (Desyrel), nefadozone (Serzone), buspirone (Buspar), clomipramine (Anafranil), venlafaxim
(Effexor), phenelzine (Navdil), moclobemide (Manerex), isocarboxazid (Marplan), divalproex (Depakote),
meperidine (Demerol), utanyl (Duragesic, Sublimaze), tramadol (Ultram), pentazoicine (Talwin),
ondansetron (Zofran), granisetron (Kytril), metoclopramide (Reglan), sumatriptun succinate (Imitrex),
sibutramine (Meridia), dexfenuramine (Redux), fenuramine (Pondimin), linezolid (Zyvox), ritonavir
(Norvir), tranylcypromine (Parnate), imipramine (Tofranil), mirtazapine (Remeron)
Phenelzine and meperidine
Tranylcypromine and imipramine
Phenelzine and selective serotonin-reuptake inhibitors
Paroxetine and buspirone
Linezolide and citalopram
Moclobemide and selective serotonin-reuptake inhibitors
Tramadol, venlafaxine, and mirtazapine
From Bayer EW, Shannon M:The serotonin syndrome. N Engl J Med 2005; 352:11121120.
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contact with the gastrointestinal mucosa. Strictures may be symp-
tomatic and occasionally require surgical intervention.
Serum iron concentrations should be measured and evaluated
in the context of symptoms and should be obtained approxi-
mately 4 hr after ingestion. Serum iron concentrations of
<500 g/dL, measured 48 hr after ingestion, indicate a low risk
of signicant toxicity. Serum concentrations of >500 g/dL
indicate that signicant toxicity is likely. Serum iron concentra-
tions are of greatest prognostic value in the asymptomatic iron-
exposed patient. Because of the severe morbidity and mortality
associated with iron intoxication and the time-sensitive variabil-
ity of serum iron values (best obtained 46 hr postingestion),
symptomatic patients with a history of even mild to moderate
exposure should be referred to a health care facility for evalua-
tion and possible chelation therapy. Blood gas levels, the serum
glucose concentration, liver function tests, and coagulation
studies should be obtained in symptomatic patients and those
with serum iron concentrations of >500 g/dL. Further, the
patients cardiovascular status should be continuously monitored
because early and evolving hypovolemia resulting from gastroin-
testinal losses may culminate in hypovolemic shock. Direct
iron toxicity to mitochondria may also produce cardiovascular
collapse.
Treatment. Close clinical monitoring, combined with good
supportive and symptomatic care, is essential in cases of iron
poisoning. Ipecac-induced emesis may be used to remove tablets
from the stomach, but appears to be of limited utility once the
patient presents to the health care facility. Gastric lavage is not
recommended in young children because of its inefciency, par-
ticularly because of the large size of many iron tablets. Activated
charcoal does not adsorb iron and should not be used, whereas
whole bowel irrigation may be of benet. In cases in which tablets
adhere to the gastric mucosa, removal by endoscopic or surgical
intervention (gastrotomy) or aggressive whole bowel irrigation
has been attempted with mixed success. Oral bicarbonate, dilute
oral saline laxative, and magnesium hydroxide (milk of magne-
sia) react with iron to form less soluble, poorly absorbed iron
salts; this technique is of very questionable clinical benet and
should not be attempted. Complexation of iron in the gastroin-
testinal tract using oral deferoxamine is expensive, may actually
increase iron absorption, and is generally not recommended.
Whole bowel irrigation should be used for patients with numer-
ous iron tablets present in the gastrointestinal tract.
Deferoxamine is a specic chelator of iron and is the antidote
for moderate to severe iron intoxication (see Table 58-6). Acute,
transient hypotension, with or without ushing, may be observed
on instituting deferoxamine administration, particularly if a
loading dose is given. These effects associated with deferoxam-
ine administration appear to be due to the drugs ability to induce
histamine release, which often resolves on slowing of the IV infu-
sion rate. Indications for deferoxamine include a serum iron con-
centration of >500 g/dL, regardless of symptoms, or moderate
to severe symptoms, regardless of the serum iron concentration.
It should be administered as a continuous IV infusion and con-
tinued until the patient is symptom-free. Prolonged deferoxam-
ine infusion (>24 hr) has been associated with pulmonary toxicity
(adult respiratory distress syndrome) and Yersinia sepsis. The
deferoxamine-iron complex may color the urine reddish (vin
ros), although this is an unreliable indicator of iron excretion
and is rarely observed. Intramuscular deferoxamine administra-
tion should be avoided whenever possible because absorption
may be erratic, particularly in more severely intoxicated patients
with impaired cardiovascular function.
CALCIUM CHANNEL BLOCKERS. Calcium channel blockers (CCBs)
encompass a variety of chemical structures that produce various
effects on the myocardium and the systemic vasculature. Specic
agents include nifedipine, diltiazem, verapamil, amlodipine, and
felodipine. They are available as regular-release and sustained-
release preparations, as well as in combination with diuretics and
other antihypertensives. Their expanding therapeutic use, while
making CCBs the most commonly prescribed cardiovascular
drugs, has also increased the incidence of poisoning exposure.
Pathophysiology. The toxic effects of these drugs are an exten-
sion of their therapeutic effect in that they antagonize L-type
calcium channels, inhibiting calcium inux into myocardial and
vascular smooth muscle cells; this results in depressed myocar-
dial contractility and conduction as well as peripheral vasodila-
tion, with subsequent hypotension and bradydysrhythmias.
Calcium inux is also impaired in the -islet cells of the pancreas,
leading to impaired insulin release and subsequent hyper-
glycemia. CCBs have a narrow therapeutic index; thus, any dose
greater than the usual maximum daily therapeutic dose should
be considered potentially toxic.
Clinical and Laboratory Manifestations. The onset of symptoms
may occur within minutes of the ingestion of a regular-release
product or may be delayed several hr after the ingestion of a sus-
tained-release product. All CCBs invariably cause hypotension,
accompanied by bradycardia, normal heart rate, or even tachy-
cardia, depending on the agent. Myocardial depression may lead
to shock in severe cases. One clinical characteristic of CCB over-
dose is profound hypotension with preserved consciousness.
Nausea and vomiting are common.
Careful blood pressure and electrocardiographic monitoring is
essential. The electrocardiogram may show variable prolongation
of the P-R interval with normal QRS width. Hyperglycemia is
another characteristic of CCB overdose, so serial serum glucose
measurements should be followed. Although these agents block
calcium channels, the serum calcium level is not affected. Blood
levels of CCBs are not readily available and are not useful in
guiding therapy.
Treatment. After appropriate supportive care has been insti-
tuted, absorption should be prevented by early administration of
activated charcoal. Whole bowel irrigation should be considered
if a sustained-release product has been ingested. Pharmacother-
apy should be directed at maintaining cardiac output and periph-
eral vascular tone, both of which are impaired in CCB poisonings.
Useful agents include atropine, calcium, insulin, glucagon, uids,
and vasopressors. Atropine is the drug of choice for symptomatic
bradycardia; a pacemaker should be considered for refractory
cases.
Administration of IV calcium may reverse myocardial depres-
sion, impaired conduction, and hypotension, but it is not consis-
tently effective. Calcium chloride is preferred over calcium
gluconate because it contains a greater amount of calcium per
gram. Because calcium salts have a much shorter duration of
action than CCBs, administration by continuous infusion may be
necessary (see Table 58-7). Hypercalcemia does not produce
clinical effects and is not a concern.
High-dose insulin combined with euglycemic therapy has been
successfully used to treat hypotension, especially in verapamil
overdoses. Insulin has intrinsic inotropic effects and also
improves the use of glucose by the myocardium. Glucagon
improves cardiac conduction and contractility by promoting
calcium ion inux through calcium channels indirectly (see Table
58-7). Its efcacy in the treatment of CCB overdose is not con-
sistent. Other inotropic agents have also been used with mixed
success. Extracorporeal membrane oxygenation and cardiac
assist devices have been successfully used to support cardiac func-
tion until the drug is cleared from the body. Extracorporeal elim-
ination methods are not useful for removing CCBs.
b-ADRENERGIC RECEPTOR BLOCKERS. Also known as type II anti-
dysrhythmic agents, these drugs competitively block the action of
catecholamines at the receptor. They are used for the treatment
of a wide variety of cardiac and noncardiac problems. Cardio-
selective agents, such as metoprolol, atenolol, and esmolol, act
selectively at the
1
receptors, whereas others, such as propra-
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nolol, sotalol, timolol, and labetalol, block both
1
and
2
recep-
tors.
Pathophysiology. In overdose, blockers lead to decreased
chronotropy, impaired AV conduction, and decreased inotropy,
manifested as bradycardia, heart block, and hypotension. Patients
with reactive airway disease may have severe bronchospasm as a
result of -blocker toxicity (the
2
-mediated bronchodilation
being blocked).
2
-receptor blockers also interfere with
glycogenolysis and gluconeogenesis, impairing the ability to
recover from hypoglycemia.
Clinical and Laboratory Manifestations. The onset of symptoms
usually occurs within 13 hr of the ingestion of a regular-release
product or may be delayed up to 10 hr with a sustained-release
product. The most common features of severe poisoning are
bradycardia, hypotension, low-output cardiac failure, and car-
diogenic shock due to delayed conduction and poor myocardial
contractility. Blood pressure and ECG monitoring are essential.
The ECG may show decreased sinoatrial node function with sinus
bradycardia, sinus pauses, or sinus arrest, or decreased AV con-
duction with various degrees of AV block. Respiratory depression
is also common, along with bronchospasm, in susceptible
patients. Delirium, altered level of consciousness, coma, and
seizures occur with more lipophilic agents and with membrane-
stabilizing agents. Hypoglycemia is also characteristic of -
blocker overdose, especially in children, and blood glucose
should be monitored. Serum levels of blockers are not readily
available for routine clinical use, and are not useful.
Treatment. Supportive care is essential. Gastrointestinal decon-
tamination is very important. Orogastric lavage can be consid-
ered in older patients who present within 1 hr of ingestion, but
only after atropine administration. Activated charcoal is also rec-
ommended, and whole bowel irrigation should be considered
after the ingestion of sustained-release preparations. Pharmaco-
logic therapy should be directed at maintaining cardiac output,
heart rate, contractility, and blood pressure. Useful agents include
atropine, uid boluses, glucagon, high-dose insulin, and vaso-
pressors. Glucagon is the drug of choice for -blocker poisonings,
given its
1
agonist effects and the lack of undesirable peripheral
vasodilatory effects. If symptomatic bradycardia is refractory to
all of the measures described earlier, ventricular pacing should be
considered, although it may not improve cardiac output; extra-
corporeal membrane oxygenation or cardiac assist devices may
be necessary for refractory hypotension.
DIGOXIN. Digoxin is a cardiac glycoside extracted from the leaves
of Digitalis lanata; Digitalis glycosides are also present in Digi-
talis purpura (foxglove), Nerium oleander (oleander), convallaria
majalis (lily of the valley), Siberian ginseng, and some toads
venom (Bufo bufo). As a therapeutic agent, digoxin is used in
children for the treatment of heart failure and some supraven-
tricular tachydysrhythmias. Although digoxin was once consid-
ered 1 of the most dangerous poisons, the incidence of digoxin
toxicity has decreased, due in part to progress in the under-
standing of its pharmacodynamics and drug interactions and in
part to the availability of an effective antidote. Acute overdose
may occur from dosing errors (especially in younger children),
from accidental or intentional medication ingestion, or from
ingestion of plant material containing digitalis glycosides.
Chronic overdose occurs most frequently in 1 of the following 3
circumstances: alteration of the digoxin dose, alteration in
digoxin clearance due to renal impairment, or drug interactions.
Pathophysiology. Digoxin blocks the Na
+
, K
+
-ATPase pump,
leading to intracellular loss of K
+
and gain of Na
+
and Ca
2+
, thus
increasing the Ca
2+
available to the contractile myocardium after
excitation (positive inotropic effect). The increased intracellular
calcium leads to increased myocardial automaticity, with subse-
quent atrial, nodal, and ventricular ectopy. The impaired Na-K
exchange also leads to dangerously high levels of serum potas-
sium in these patients. Digoxin also affects the cardiac autonomic
system (vagally mediated mechanism), leading to an increased
refractory period, decreased sinus node ring, and slowed con-
duction through the AV node, with sinus bradycardia, AV block,
or even sinus arrest. The overall effect of digoxin overdose is a
combination of slowed or blocked conduction and increased
ectopy. Digoxin has a very narrow therapeutic index; toxicity can
develop even from therapeutic doses. The therapeutic plasma
concentration is 0.52.0 ng/mL, whereas levels >2 ng/mL are con-
sidered toxic; a digoxin level of >6 ng/mL is considered poten-
tially lethal. Digoxin interacts with a wide variety of other drugs,
by a variety of mechanisms, increasing the potential for toxicity
at therapeutic doses.
Clinical and Laboratory Manifestations. Acute toxic effects
usually occur within 6 hr of ingestion and include gastrointesti-
nal, cardiovascular, and CNS manifestations. Nausea and vomit-
ing are invariably associated with acute digoxin toxicity and
usually represent the presenting symptoms. Cardiovascular man-
ifestations include bradycardia, heart block, and ventricular dys-
rhythmias. Bradydysrhythmias are more common in previously
healthy hearts, whereas previously diseased hearts usually
respond with tachydysrhythmias. Continuous ECG monitoring is
crucial for assessing digoxins effects and guiding therapy. Blood
pressure is usually preserved despite signicant bradycardia. CNS
manifestations include visual changes, headache, fatigue,
lethargy, confusion, and hallucinations. Chronic cardiac glyco-
side toxicity leads to a combination of ventricular dysrhythmias
and impaired AV conduction. The serum digoxin level should be
assessed at least 6 hr after ingestion and carefully interpreted in
the clinical context because the digoxin level alone is not reec-
tive of the severity of intoxication. The serum potassium level
should be monitored as a useful marker of severe toxicity: It may
be dangerously increased (a poor prognostic sign), although
decreased potassium levels may occur with concomitant use of
loop diuretics, and hypokalemia enhances digoxin toxicity. Renal
function should also be monitored.
Treatment. Initial treatment includes good general supportive
care in an intensive care unit and gastric decontamination with
activated charcoal if the ingestion was recent. Immediate therapy
should aim for early recognition and aggressive treatment of
life-threatening effects of digoxin toxicity, including mounting
hyperkalemia and ventricular dysrhythmias. Hemodialysis may
temporarily attenuate hyperkalemia, but digoxin cannot be elim-
inated in this way, due to its high tissue binding. An antidote for
digoxin, digoxin-specic Fab antibody fragments (Digibind) is
available (see Table 58-6). Digibind binds free digoxin in both
the intravascular and the interstitial spaces and facilitates its renal
clearance. Effects of Digibind usually begin within 1 hr of admin-
istration. Indications for the use of Digibind include digoxin-
related life-threatening dysrhythmias, K
+
value of >5 mEq/L in the
setting of acute digoxin overdose, signicantly altered mental
status, renal failure, serum digoxin level of >10 ng/mL, and inges-
tion of >4 mg in children or >10 mg in adults. In the absence of
Digibind, ventricular ectopy should be treated with phenytoin,
which may reverse the digoxin-induced slowed AV conduction
and suppress the tachydysrhythmia without diminishing contrac-
tility. Atropine is the standard therapy for symptomatic brady-
cardia associated with digoxin overdose while Digibind is being
prepared for administration.
CAUSTICS. Caustics include acids and alkalis as well as a few
common oxidizing agents, such as bleach (see Chapter 324.2).
Pathophysiology. Acids coagulate proteins, causing local tissue
necrosis, which limits its tissue penetration. Alkalis digest and dis-
solve proteins, producing transmural liquefaction necrosis, with
the risk of perforation if the injury is located in the intestinal
tract. The severity of the chemical burn produced depends on the
pH, the concentration of the agent, and the length of contact
time. Agents with a pH of <2 or >12 are most likely to produce
signicant injury.
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Clinical Manifestations. Ingestion of caustic materials may
produce oral burns, visualized as reddened areas or whitish
plaques. Symptoms include pain, drooling, vomiting, and dif-
culty swallowing or refusal to swallow. Circumferential burns of
the esophagus are likely to cause strictures on healing, which may
require repeated dilation or surgical correction (see Chapter
324.2). Strong acids may sometimes produce scarring around the
pylorus, leading to delayed onset of gastric obstruction. Caustics
on the skin or in the eye can cause signicant tissue damage.
Treatment. Initial treatment of caustic exposure includes thor-
ough removal of the product from the skin or eye by ushing
with water. Contaminated clothing should also be removed.
Ingested agents should be rinsed from the oral cavity. Emesis and
lavage are contraindicated. Activated charcoal should not be used
because it does not bind these agents and may predispose the
patient to violent vomiting and possible aspiration. Patients
should be evaluated for evidence of esophageal burns, and if
symptoms are present, oral uids or solids should be withheld.
The absence of visible oral injury does not preclude signicant
esophageal lesions. Endoscopy should be performed in sympto-
matic patients or those in whom injury is suspected on the basis
of history. The use of corticosteroids and esophageal stents is con-
troversial. Prophylactic antibiotics do not improve outcomes.
METHANOL AND ETHYLENE GLYCOL. Methanol is commonly found
in windshield washer uids, fuel additives, liquid fuel canisters,
and industrial solvents. Ethylene glycol is commonly found in
car radiator antifreeze. Both solvents are well absorbed via the
intestine, through inhalation, or after skin contact; accidental
ingestion is the most common route of exposure in children. The
pathophysiology, clinical effects, and treatment of both chemicals
are similar. Although each parent compound is capable of pro-
ducing mild toxicity, it is the metabolites of each product that are
responsible for the serious clinical effects that can follow expo-
sure. Isopropyl alcohol (rubbing alcohol) also causes intoxication
similar to that associated with ethanol; its metabolite is acetone.
Its management is similar to that for ethanol (see Chapter 113.1).
Methanol
PATHOPHYSIOLOGY. Methanol is metabolized in the liver
by alcohol dehydrogenase to formaldehyde, which is further
metabolized to formic acid by aldehyde dehydrogenase. Formic
acid is metabolized through folate-dependent pathways to carbon
dioxide and water. Toxicity is caused primarily by formic acid,
which inhibits mitochondrial respiration. The development of
serious toxic effects is delayed while formic acid is generated and
accumulates in blood and tissues.
CLINICAL AND LABORATORY MANIFESTATIONS.
Drowsiness, mild inebriation, and gastric irritation, including
nausea and vomiting, develop early after ingestion. The onset of
serious effects, including profound metabolic acidosis and visual
disturbances, is often delayed for up to 1012 hr, and possibly up
to 24 hr, as the parent methanol is undergoing metabolic activa-
tion to its toxic metabolites. Visual disturbances include blurred
or cloudy vision, constricted visual elds, decreased acuity, and
the feeling of being in a snowstorm. Small children may not
be able to describe these visual changes. Pupils may be dilated
and nonreactive to light; retinal edema and optic disc hyperemia
may be noted. Visual disturbances are usually reversible, but in
signicant poisonings, blindness has occasionally been perma-
nent. An anion gap metabolic acidosis and an osmolar gap
develop; thus, serum electrolytes, pH, osmolarity, and acid-base
balance should be monitored.
Children are usually discovered with an open container of
product soon after an exposure, and determining if a signicant
exposure has occurred is usually a problem. Methanol blood con-
centrations are usually available and can rule out an exposure;
however, blood concentrations do not correlate well with toxic-
ity. Formic acid concentrations may correlate more closely with
toxicity; however, these blood concentration determinations are
not routinely available. If methanol blood concentrations are not
available, estimation of an osmolar gap has been recommended
as a surrogate. Serum osmolarity is measured by the freezing
point depression method and compared with a calculated serum
osmolarity. The osmolar gap can be used to estimate the serum
methanol concentration using the following formula:
TREATMENT. Treatment is discussed later.
Ethylene Glycol
PATHOPHYSIOLOGY. Ethylene glycol is metabolized by
alcohol dehydrogenase in the liver to glycoaldehyde, which is
further converted to glycolic acid by aldehyde dehydrogenase.
Glycolic acid is metabolized to glyoxylic acid and oxalic acid,
which are responsible for most of the observed toxicity. The
development of serious toxic effects is delayed while these acids
are generated and accumulate in blood and tissues. Oxalic acid
combines with serum and tissue calcium, causing hypocalcemia
and the formation of calcium oxalate crystals.
CLINICAL AND LABORATORY MANIFESTATIONS. As
with acute methanol consumption, early symptoms associated
with ethylene glycol exposure occur 112 hr after ingestion and
include gastric irritation, including nausea and vomiting, and
CNS effects, including drowsiness and inebriation. Metabolic
acidosis begins to develop. Approximately 1224 hr after ethyl-
ene glycol ingestion, cardiac dysrhythmias, muscle pain, and
tetany due to hypocalcemia may occur. Later in the clinical
course, cardiac failure, seizures, cerebral edema, and renal failure
can occur. Renal failure is caused by the deposition of calcium
oxalate crystals in renal tubules.
Ethylene glycol blood concentrations are often readily avail-
able, but as with methanol, the values do not correlate well with
toxicity. Glycolic acid and glyoxylic acid concentrations may cor-
relate more closely with ethylene glycol toxicity, but these deter-
minations are not routinely available. Sodium uorescein is an
additive in many commercial antifreeze products. It is renally
excreted and may be visualized in urine up to 6 hr after ingestion
when illuminated with a Wood lamp. This simple test may be
used to conrm ethylene glycol ingestion in children; a negative
test result does not preclude a possible ingestion. Ethylene glycol
serum concentrations can be estimated from an osmolar gap.
Serum osmolarity is measured by the freezing point depression
method and compared with a calculated serum osmolarity. The
osmolar gap can be used to estimate the serum ethylene glycol
concentration using the following formula:
Calcium oxalate crystals are commonly observed in urine on
microscopy, but may not be evident early after exposure. Elec-
trolytes, including calcium, should be monitored, as well as ECG
and renal function studies.
TREATMENT. Because methanol and ethylene glycol are
rapidly absorbed, gastric decontamination is usually not of value.
Activated charcoal does not bind either agent and thus should
not be used. Metabolic acidosis is treated with IV sodium bicar-
bonate at doses of 12 mEq/kg or, if needed, via extracorporeal
hemoltration. With the prompt institution of effective treatment
(discussed later), the need for sodium bicarbonate is often limited.
In patients with moderate to severe systemic metabolic imbal-
ance, hemoltration or dialysis may be far more effective in cor-
recting these abnormalities while concurrently enhancing body
elimination of the toxic alcohol and metabolites (discussed later).
Ethanol is considered the classic antidote for both methanol
and ethylene glycol poisoning because it is preferentially metab-
olized over methanol and ethylene glycol by alcohol dehydro-
genase, thus minimizing the formation of toxic metabolites (see
Table 58-6). The parent compounds are then excreted via the
Osmolar gap estimatedethylene glycol concentration mg dL = ( ) 6 2 .
Osmolar gap estimatedmethanol bloodconcentration mg dL = ( ) 3 2 .
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lungs and kidneys. Fomepizole, a potent competitive inhibitor of
alcohol dehydrogenase, if available, has replaced the use of
ethanol because of its ease of administration, lack of CNS and
metabolic effects, and overall excellent patient tolerability prole.
Indications for fomepizole or ethanol therapy are a serum ethyl-
ene glycol concentration of >25 mg/dL or a serum methanol con-
centration of >20 mg/dL, a signicantly symptomatic patient,
ingestion of >0.4 mL/kg of 100% ethylene glycol or methanol,
and systemic acid-base abnormalities.
Hemodialysis effectively removes ethylene glycol, methanol,
the acid metabolites, and any antidote administered (fomepra-
zole, ethanol). Thus, specic supplemental doses of either anti-
dote are required in patients undergoing hemodialysis. Dialysis is
also useful for correcting severe metabolic acidosis. Indications
for hemodialysis include methanol or ethylene glycol levels
>50 mg/dL refractory metabolic acidosis and renal failure. When
treating these patients, it is advisable to consult with a regional
poison control center regarding therapy, in particular, supple-
mental antidote administration in dialyzed patients.
HYDROCARBONS. Hydrocarbons include a wide array of chemi-
cal substances found in thousands of commercial products. Many
factors determine whether a particular product and exposure will
produce systemic toxicity, local toxicity, or both. Nevertheless,
aspiration of hydrocarbons into the lung can lead to serious, even
life-threatening toxicity, underscoring the need for prompt atten-
tion in exposed patients.
Pathophysiology. The most important adverse effect of hydro-
carbons is aspiration pneumonitis (see Chapter 394). Aspiration
usually occurs at the time of ingestion, when coughing and
gagging are common, but can also be secondary to vomiting,
which commonly occurs after ingestion. The propensity of a
hydrocarbon to cause aspiration pneumonitis is inversely pro-
portional to its viscosity. Compounds with low viscosity, such as
mineral spirits, naphtha, kerosene, gasoline, and lamp oil, spread
rapidly across surfaces and cover large areas of the lungs when
aspirated. Only small quantities (<1 mL) of low-viscosity hydro-
carbons need be aspirated to produce signicant injury. Pneu-
monitis does not result from dermal absorption of hydrocarbons
or from ingestion in the absence of aspiration. Gasoline and
kerosene are poorly absorbed, but often cause considerable
gastrointestinal mucosal irritation as they pass through the
intestines.
Certain hydrocarbons, most notably, halogen-substituted com-
pounds, can be absorbed after ingestion, inhalation, or dermal
contact. Most of these hydrocarbons have anesthetic properties
and can cause transient CNS depression. Several chlorinated sol-
vents, most notably, carbon tetrachloride, can produce hepatic
toxicity. A few hydrocarbons have also been associated with renal
and bone marrow toxicity. Benzene is known to cause cancer in
humans after long-term exposure. The malignancy most com-
monly associated with benzene is acute myelogenous leukemia.
Methylene chloride, found in some paint removers, is metabo-
lized to carbon monoxide. Nitrobenzene, aniline, and related
compounds can produce methemoglobinemia. Methemoglobin
can be identied in the laboratory; its presence is also suggested
if a drop of blood applied to lter paper remains brown as it
dries. Methemoglobinemia is treated with the antidote methylene
blue (see Table 58-6).
A number of volatile hydrocarbons, including toluene, propel-
lants, refrigerants, and volatile nitrites, are commonly abused
by inhalation. Some of these substances can sensitize the
myocardium to the effects of endogenous catecholamines, with
the risk of dysrhythmias and sudden death. Chronic abuse of
these agents can lead to cerebral atrophy, neuropsychological
changes, peripheral neuropathy, and renal disease (see Chapter
113.4). All volatile hydrocarbons are lipid solvents and can cause
defatting of the skin, producing local irritation or, with prolonged
exposure, chemical burns.
Clinical and Laboratory Manifestations. Transient, mild CNS
depression is common after hydrocarbon ingestion. Aspiration is
characterized by coughing, which usually is the rst clinical
nding. Cough usually begins immediately or within 25 min of
the aspiration, and persists. Chest radiographs may be normal for
as long as 812 hr after aspiration, but more often will be posi-
tive after 6 hr or longer from the time of exposure. Whenever
possible, chest radiograph should be delayed until 6 hr or longer
after the hydrocarbon exposure. Respiratory symptoms may
remain mild or may progress rapidly to respiratory failure.
Patient symptoms often correlate very poorly with abnormalities
observed on chest radiograph, underscoring the importance of
close clinical monitoring of the patients respiratory status. Fever
occurs and may persist for as long as 10 days after aspiration.
Accompanying leukocytosis may be misleading because, in most
cases of aspiration pneumonitis, no bacteria are present in the
lungs. Chest radiographs may remain abnormal long after the
patient is clinically normal, and they should not be used to guide
acute treatment. Pneumatoceles may appear on the chest
radiograph 23 wk after exposure.
Treatment. Emesis is contraindicated because of the risk of aspi-
ration. Likewise, gastric lavage is contraindicated, except under
special circumstances of ingestion of highly toxic hydrocarbons
(carbon tetrachloride), because of the risk of vomiting and aspi-
ration. If gastric lavage is to be performed, the patient should be
intubated with a cuffed tube to protect the airway from further
aspiration. Activated charcoal also is not useful because it does
not bind the common hydrocarbons. If hydrocarbon-induced
pneumonitis develops, respiratory treatment is supportive (see
Chapter 394). Corticosteroids should be avoided because they are
not effective and may increase the risk of infection. Prophylactic
antibiotics should not be given because bacterial pneumonia
occurs in only a very small percentage of cases. Respiratory
failure has been successfully treated both with standard ventila-
tion and with extracorporeal membrane oxygenation.
CHOLINESTERASE-INHIBITING INSECTICIDES. The most commonly
used insecticides are organophosphates and carbamates; both are
inhibitors of cholinesterase enzymes. Nerve agents used in
warfare are usually organophosphates. Most pediatric poisonings
occur as the result of accidental exposure to insecticides in and
around the home or farm.
Pathophysiology. Both organophosphates and carbamates bind
to cholinesterase enzymes, preventing the degradation of acetyl-
choline, resulting in its accumulation at nerve synapses. Enzymes
affected include acetylcholinesterase or red blood cell
cholinesterase, pseudocholinesterase (found in plasma), and neu-
rotoxic esterase (nervous system). If left untreated, organophos-
phates form a permanent bond to these enzymes, inactivating
them. This process, called aging, occurs over a variable period,
but may occur as soon as 18 hr to 23 days after exposure. A
period of weeks to months is required to regenerate inactivated
enzymes. In contrast, carbamates form a temporary bond to the
enzymes, allowing regeneration of the enzymes over several
hours.
Clinical and Laboratory Manifestations. Clinical manifestations
of organophosphate and carbamate toxicity relate to the accu-
mulation of acetylcholine at peripheral nicotinic and muscarinic
synapses and in the CNS (see Table 58-3). Muscarinic signs and
symptoms include diaphoresis, emesis, urinary and fecal inconti-
nence, tearing, drooling, bronchorrhea and bronchospasm,
miosis, hypotension, and bradycardia. Nicotinic signs and symp-
toms include muscle weakness, fasciculations, tremors, hypoven-
tilation (diaphragm paralysis), hypertension, tachycardia, and
dysrhythmias. CNS effects include malaise, confusion, delirium,
seizures, and coma. Symptoms caused by carbamate toxicity are
usually less severe than those seen with organophosphates. A
commonly used mnemonic for the most common symptoms
of cholinergic excess is DUMB BELS, which stands for
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diarrhea/defecation, urination, miosis, bronchorrhea, bradycar-
dia, excitation (muscle)/emesis, lacrimation and salivation, and
gastrointestinal cramps. Severe manifestations include coma,
seizures, shock, arrhythmias, and respiratory failure.
Red blood cell cholinesterase and pseudocholinesterase con-
centrations can be readily measured in the laboratory. They may
be useful in documenting an exposure, but do not correlate well
with the magnitude of exposure or symptoms. Signicant
symptoms do not generally occur until measured enzyme con-
centrations fall to <25% of normal. Red blood cell cholinesterase,
although more difcult to measure, is a better reection of
enzyme activity in the nervous system. Nevertheless, the magni-
tude and rate of progression of the patients clinical ndings are
of greatest importance in determining the patients disposition.
These laboratory acetylcholinesterase determinations are of
limited utility in acute exposures, although they may be of value
in conrming an exposure or determining the extent of prolonged
exposure.
Treatment. Basic decontamination should be performed on
exposed persons, including washing all exposed skin with soap
and water and immediate removal of all exposed clothing. Acti-
vated charcoal can be used for gastric decontamination, but for
insecticides, it is of limited value because these highly lipid-
soluble agents are rapidly absorbed. Basic supportive care should
be provided, including uid and electrolyte replacement and intu-
bation, with articial ventilation, if necessary. Two antidotes
are useful to treat poisoning with cholinesterase inhibitors:
atropine and pralidoxime (see Table 58-6). Atropine, which
antagonizes the muscarinic acetylcholine receptor, is useful for
both organophosphate and carbamate intoxication. Often, large
doses of atropine must be administered by intermittent bolus or
via continuous infusion. The absolute amount (dose) combined
with the frequency of need for atropine can be used to estimate
the magnitude of the patients exposure and the probable time
course to resolution. Pralidoxime chemically breaks the bond
between the organophosphate and the enzyme, liberating
the enzyme and thus enhancing the insecticides body clearance.
Pralidoxime is only effective if used before the bond ages
and becomes permanent. For most commercially available
organophosphate insecticides, this aging process evolves, usually
becoming clinically relevant within approximately 18 hr after
exposure. In the case of military nerve gases, shorter aging
times are desired to limit the effectiveness of current antidote
therapy. Pralidoxime is not necessary for carbamate poisonings
because the bond between the insecticide and the enzyme
degrades spontaneously. For signicant organophosphate poi-
sonings, both antidotes are used and large doses of atropine may
be necessary to achieve adequate reversal of symptoms. Without
treatment, symptoms of organophosphate poisoning may persist
for weeks, requiring continuous supportive care. Even with treat-
ment, neurologic symptoms may occur and persist.
TOXIC GASES
CARBON MONOXIDE. Although many industrial and naturally
occurring gases pose a health risk by inhalation, the most
common gas involved in pediatric exposures is carbon monoxide
(CO). CO is a colorless, odorless gas produced during the com-
bustion of any carbon-containing fuel. The less efcient the com-
bustion, the greater the amount of CO produced. Wood-burning
stoves, old furnaces, and automobiles are potential sources.
Pathophysiology. Toxicity develops through at least 3 mecha-
nisms. First, it binds to hemoglobin, displacing oxygen-forming
carboxyhemoglobin (COHb), with an afnity for hemoglobin
that is approximately 250 times that of oxygen. Second, CO
impairs the ability of hemoglobin to release oxygen to tissues.
Finally, CO binds to cytochrome oxidase in tissues, impeding
oxygen use. Although the relative contribution of each of these
mechanisms to CO toxicity is unclear, the net result is tissue
hypoxia.
Clinical and Laboratory Manifestations. Symptoms of CO poi-
soning are usually proportional to the concentration of COHb in
the blood. COHb concentrations can be measured in almost all
hospital laboratories. Early symptoms are nonspecic and include
headache, malaise, and nausea, which are often confused with
the u. At higher exposure levels, headaches become severe,
and dizziness, visual changes, and weakness may be present.
Cherry-red mucosal coloring and retinal hemorrhage may also be
present. Children may experience syncopal episodes as a rst
symptom. At high concentrations, coma, seizures, respiratory
instability, and death may occur (see Chapter 74). Symptoms
usually appear at COHb levels of >15%, toxicity is present at
levels of >20%, and severe neurologic effects are universal at
levels of >40%.
Treatment. In addition to general supportive care, treatment of
CO poisoning requires the administration of 100% oxygen. High
concentrations of oxygen shorten the COHb half-life in the blood
and tissues. In healthy volunteers, the COHb half-life averages
56 hr (range, 27 hr), which is dramatically reduced to approx-
imately 4060 min by the administration of 100% oxygen at
normal atmospheric pressures by a non-rebreathing face mask.
In more severe and/or chronic exposures, hyperbaric oxygen
therapy may be required, which at 2.53.0 atm reduces the
COHb half-life to approximately 1530 min. Severely poisoned
patients benet from hyperbaric oxygen therapy. Indications for
hyperbaric oxygen include neurologic symptoms compatible with
CO poisoning and a COHb level of >25% in children and preg-
nant women. After a signicant exposure, some patients may
experience delayed-onset neurotoxicity, which may be perma-
nent. Aggressive early treatment of patients with signicant symp-
toms may diminish the risk of neurologic sequelae.
HYDROGEN CYANIDE
Pathophysiology. Cyanide produces toxicity by interfering with
oxygen use in the cytochrome oxidase system, resulting in cellu-
lar hypoxia.
Clinical and Laboratory Manifestations. Clinical symptoms occur
rapidly after signicant exposure and include headache, agitation
and confusion, loss of consciousness, convulsions, and cardiac
dysrhythmias. Severe metabolic acidosis occurs rapidly, and death
may occur. Cyanide levels can be measured in the blood, but tests
are not readily available and levels do not correlate well with
symptoms. Severe metabolic acidosis in a patient with suspected
cyanide exposure (re victims) should be assumed to be cyanide
poisoning.
Treatment. The cornerstone of treatment is rapid administration
of high concentrations of oxygen, together with the use of the
Lilly cyanide antidote kit. The kit includes nitrites (amyl nitrite
and sodium nitrite) used to produce methemoglobin, which reacts
with cyanide, forming cyanmethemoglobin. The kit also contains
sodium thiosulfate, which is given to hasten the metabolism of
cyanmethemoglobin to hemoglobin and the less toxic thio-
cyanate. Hydroxocobalamin (vitamin B
12a
), which reacts with
cyanide to produce cyanocobalamin (vitamin B
12
), is an alterna-
tive antidote, but is not currently available in the U.S.
PLANTS. Exposure to plants, both inside the home and outside in
backyards and elds, is one of the most common causes of unin-
tentional poisoning in children. Ingestion of most plant parts
(leaves, seeds, owers) results in mild, self-limiting effects (Table
58-11). The treatment is symptomatic and supportive. The inher-
ent toxicity of the product is so low that the ingestion of small
to moderate quantities of plant material is unlikely to produce
toxic symptoms.
The potential toxicity of a particular plant is highly variable,
depending on the part of the plant involved (owers are gener-
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ally less toxic than the root or seed), the time of year, growing
conditions, and the route of exposure. Assessment of the poten-
tial severity after a plant exposure is also complicated by the dif-
culty in properly identifying the plant. Many plants are known
by several common names, which may vary between communi-
ties. Poison control centers have access to individuals able to
assist in the proper identication of plants. They also keep current
on the common poisonous plants in their service area and the
seasons in which they are more abundant; thus, consultation with
a poison control center is recommended if a potentially toxic
plant is involved in the exposure (Table 58-12). Gastrointestinal
decontamination for potentially toxic ingestions includes the use
of activated charcoal; otherwise, treatment is supportive and
symptomatic. Parents and grandparents of young children should
be reminded to obtain the botanical and common names for
plants that they purchase. In addition, for indoor plants, it is
important to label the container (on the underside, for aesthetic
acceptance), so that the poison control center can be given the
correct name in case of an exposure. Similarly, landscapers or
TABLE 58-12. Commonly Ingested Plants with Signicant Toxic Potential
PLANT POISONOUS PARTS SYMPTOMS MANAGEMNT
Laburnum All parts Vomiting Activated charcoal if >5 seeds ingested
Seed ingestion is the must common Pallor Observation
presentation Dilated pupils
Tachycardia
Dizziness
Deadly nightshade (Atropa All parts are poisonous, but berry ingestion Dry mouth Activated charcoal if any plant material has been ingested; additional methods of gastric
belladonna) is the most common presentation Dilated pupils decontamination if >5 berries ingested; intestinal motility may be impaired and
Hallucinations absorption prolonged
Urinary retention Treatment is supportive, physostigmine should be reserved for cases where life-threatening
Agitation symptoms do not respond to adequate supportive measures
Ataxia Symptoms can be delayed for up to 12 hr after ingestion
Muscle incoordination Hospital admission is mandatory
Convulsions
Coma
Laurel (Prunus laurocerasus) Leaves and broken seeds of the fruit are the Gastrointestinal upset If only the pulp of the berry was eaten, or if stones were swallowed whole, no treatment is
most poisonous parts Salivation required
Flushing Activated charcoal is given if leaves or broken seeds were eaten
Convulsions Symptoms can be delayed for up to 4 hr
Coma
Arrhythmias
Lupin Only toxic in large quantities
Activated charcoal is given
Yew trees All parts of the tree are toxic, except the Nausea Asymptomatic children should be observed for 4 hr
pulp of the berry Vomiting Gastric decontamination does not seem to inuence outcome
Anticholinergic effects Treatment is supportive
Drowsiness Serious cases are very rare
Bradycardia
Arrhythmia
Convulsions
Woody nightshade (Solanum All parts of the plant are toxic, particularly Drowsiness Activated charcoal is given if >5 ripe berries or any unripe berries have been consumed
dulcamara) Bittersweet unripe fruits Ataxia Asymptomatic patients should be observed for 8 hr
Nausea Treatment is supportive
Vomiting
Oropharyngeal irritation
Cuckoo pint (Arum maculatum) Mucosal irritation, edema, and occasionally Treatment is symptomatic
ulceration Analgesia and antihistamines
Local skin irritation and blistering Effects appear rapidly; observation of asymptomatic children is unnecessary
Elder (Sambucus nigra) All parts of the plant are mildly toxic, Nausea Consider gastric decontamination if >10 berries were consumed
particularly unripe berries Vomiting Treatment is symptomatic
Dizziness
Tachycardia
Convulsions
Mistletoe All parts of the plant are toxic except the Nausea Symptoms are unlikely if <3 berries were consumed
esh of the berry Vomiting Treatment is symptomatic; atropine is given for bradycardia
Diarrhea Effects can last for several days
Muscle weakness
Pupil dilation
Diuresis
Bradycardia can occur
Rhubarb The leaves contain oxalates and are toxic Symptoms of gastric irritation predominate Milk may help to neutralize oxalic acid
Oxalates chelate calcium and hypocalcemia Treatment is otherwise supportive
can complicate ingestion
From Riordan M, Rylance G, Berry K: Poisoning in Children 4: Household products, plants, and mushrooms. Arch Dis Child 2002; 87:403406.
TABLE 58-11. Nontoxic and Minimally Toxic Plants
*
African violet Dracaena Palm
Aluminum plant Fern species (not asparagus fern) Peperomia
Aralia, false Fig Petunia
Aster Gardenia Poinsettia
Barberry Geranium Pokeberries
Begonia species Hen and chicks Pyracantha
Boston fern Honeysuckle Rose
Carnation Impatiens Rubber plant
Chinese evergreen Jade plant Schefera
Christmas cactus Kalanchoe Snake plant
Coleus Magnolia Spider plant
Corn plant Marigold Violet
Dandelion Mother-in-laws tongue Wandering Jew
Daylily Nasturtium Yucca
Dogwood Norfolk Island pine
*The potential for toxicity is dependent on the magnitude and amount of exposure. These agents are considered nontoxic or
minimally toxic for mild to moderate exposure. The potential for toxicity increases with increased amount of exposure.
Further, many plants contain substances that can be irritating to the mucosa (dermal/oroesophageal) and/or may
precipitate allergic responses.
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Chapter 59 Herbal Medicines 357
nurseries can identify outdoor plants surrounding the childs
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Chapter 59
Herbal Medicines
Kathi J. Kemper and Paula Gardiner
Herbs and other dietary supplements are the most commonly
used complementary therapies for children and adolescents. More
than $4 billion is spent on these products each year in the U.S.
Use rates are higher among children with chronic, incurable, or
recurrent conditions, such as asthma, allergies, arthritis, cancer,
chronic or recurrent pain, cystic brosis, and inammatory bowel
disease, but even previously healthy children seen in primary care
and emergency departments frequently use herbs, home remedies,
or supplements. Use is also common among teenagers; 41% of
adolescents reported having used herbs and supplements, such as
echinacea, ginseng, ginger, Ginkgo biloba, green tea, omega-3
fatty acids, soy supplements, St. Johns wort, valerian, or zinc.
Fewer than
1
/
2
of patients who use herbs and supplements have
talked with their physician about their use, in part because physi-
cians have not routinely asked patients and families about their
use of these products.
Herbal products are widely perceived as being safe because
they are natural. They are also frequently considered as having
low therapeutic efcacy, owing to a paucity of publications about
them in scientic journals. Conventional wisdom may be mis-
taken, resulting in risks to patients and providers.
Although they are generally safe, herbal products can cause
serious toxicity. Acute hepatic toxicity and death may result from
ingestion of even small amounts of Amanita mushrooms; over-
doses of other herbs, such as digitalis, ephedra, and pennyroyal
can cause life-threatening complications. Ephedra has signicant
cardiac toxicity. A widely used anxiolytic herb, kava kava
(banned in several countries), has been linked to hepatotoxicity.
Chronic use of other herbs, such as Aristolochia, coltsfoot, and
licorice can cause severe hepatic or renal damage, cancer, or life-
threatening electrolyte disturbances. Earl Grey tea causes muscle
cramps, paresthesias, and blurred vision, whereas Japanese star
anise (often a contaminant of Chinese star anise) is a neurotoxin.
Even when an herb is safe when used correctly, it can cause mild
or severe toxicity when used incorrectly. Tea tree oil is safe when
applied to mild fungal infections of the skin, but can cause sting-
ing and irritation when applied to eczema; if taken orally, it can
cause coma in small children. Although peppermint is a com-
monly used and usually benign gastrointestinal spasmolytic
(included in after-dinner mints and teas and increasingly used to
ease discomfort during colonoscopy), it can exacerbate gastroe-
sophageal reux in other patients.
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Because of natural variability, herbal products may contain
widely varying concentrations of active ingredients; variations
of 10- to 1,000-fold have been reported for several popular
herbs, even across lots produced by the same manufacturer.
Labels may not accurately reect the contents or the concentra-
tions of ingredients. Herbal products may be unintentionally
contaminated with pesticides, animal wastes, or the wrong
herb that was misidentied during harvesting. Products from
developing countries (e.g., Ayurvedic products from South Asia)
TABLE 59-1. Herbs for Asthma
HERB OR COMBINATION RCTs DEMONSTRATED BENEFIT ADVERSE EFFECTS/DRUG INTERACTIONS PURPORTED MECHANISM
Coffee/tea None recently in children Epidemiologic data suggest fewer Tachycardia, insomnia, jitteriness, decreased Methylxanthines
symptoms in coffee drinkers appetite; potential interaction with agonists Increased intracellular cAMP
Bronchodilator
Shinpi-to None in children Yes, in historical data Unknown; potential interaction with leukotriene blockers Blocks 5-lipo-oxygenase and phospholipase A
2
Saiboku-to Yes, in adults Yes, corticosteroid-sparing effects Unknown; potential increase in corticosteroid adverse effects Inhibits 11 -hydroxylase (blocks steroid breakdown)
in adults Blocks 5-lipo-oxygenase
Inhibits platelet-activating factor
Ma huang (Ephedra sinica) Yes Yes Cardiovascular and central nervous system toxicity, deaths Agonist
reported, potential interaction with agonists Bronchodilator
Licorice (Glycyrrhize glabra) No Case series suggest corticosteroid- Pseudohyperaldosteronism, hypertension, peripheral edema, Inhibits 11 -hydroxylase and cortisol breakdown
sparing effects potential increase in corticosteroid adverse effects
Coleus forskolii No Case series in adults Unknown Decreased cAMP metabolism
Bronchodilator
Tylophora indica Yes, in adults Yes Unknown Unknown
Ginkgo biloba No Yes, in a pilot study Unknown Platelet-activating factor antagonist
Antioxidant
Onions (Allium cepa) No In vitro and animal Hypersensitivity is rare Blocks leukotriene synthesis
data support use
Bee pollen No No Anaphylaxis Unknown
From Kemper KJ, Lester MR: Alternative asthma therapies: An evidence-based review. Contemp Pediatr 1999;16:162195.
cAMP, cyclic adenosine monophosphate; RCT, randomized controlled trials.
TABLE 59-2. Commonly Used Sedative Herbs
SEDATIVE HERBS SCIENTIFIC STUDIES POTENTIAL ADVERSE EFFECTS OR INTERACTIONS ADULT DOSE
German chamomile In controlled trials, chamomile and its constituents have Adverse effects: Allergic reactions Tea: 150 mL of boiling water over 3 g fresh ower heads,
positive effects as a mild sedative Pregnancy and lactation: No known adverse effects in pregnancy, steep for 510 min; 3 day
lactation, and childhood
Drug interactions: None known
Hops (Humulus Iupulus) Historical and anecdotal use Adverse effects: Allergic reactions, skin irritation Tea: 0.51.0 g dried hops before bed, typically in combination
Controlled trials have used hops/valerian combinations; Pregnancy and lactation: No data available with valerian
these show improvements in sleep with the Drug interactions: Sedative activity increases the sleeping time
combination induced by pentobarbital
Kava kava (Piper Randomized controlled trials in adults show anxiolytic Adverse effects: Drowsiness, lethargy; slowed reaction time; Capsules: 60120 mg kava lactones, up to 300 mg of kava
methysticum) effects withdrawal syndrome; chronic use may lead to yellow, dry skin and lactones daily to dried root/rhizome; 1.53.0 g/day in
red eyes divided doses
Pregnancy and lactation: Insufcient information available
Drug interactions: May potentiate sedative and anxiolytic effects
of other herbs and medications
Lavender (Lavandula) Animal data, adult case series, and controlled trials Adverse effects: Allergies with topical use; toxic if large doses taken Massage aromatherapy: 110 mL of the essential oil can
suggest anticonvulsant and sedative effects internally be added to 25 mL of a carrier oil
Pregnancy and lactation: Historically contraindicated during Bath soak: add
1
/
4
1
/
2
cup of dried lavender owers to hot
pregnancy owing to possible emmenagogue effects; no documented bath water
adverse effects
Drug interactions: May potentiate sedative and anticonvulsant
effects of other drugs
Lemon balm (Melissa Animal data suggest sedative hypnotic effects Adverse effects: Allergic reactions are possible Tea: 23 g of dried herb, steeped in water; usually combined
ofcinalis) All RCTs have examined lemon balm/valerian Pregnancy and lactation: Insufcient data; generally recognized with valerian or lavender
combinations; most show enhanced sleep quality as safe
Drug interactions: None known
Passionower (Passiora Case reports and historical use; most often combined Adverse effects: Allergic reactions are possible Tea: 0.251 g (about 1 tsp of crushed dried owers/cup
alata) with other herbs, such as valerian Pregnancy and lactation: Insufcient data of water)
Drug interactions: None known Solid extract: 150300 mg (sold in capsules) daily
Valerian (Valeriana Randomized double-blind placebo controlled studies Adverse effects: Headaches, insomnia Tea: 23 g of fresh or dried root/cup; 13 day
ofcinalis) in adults show decreased sleep latency and Pregnancy and lactation: Insufcient data Capsules: 400 mg before bed
improved sleep quality Drug interactions: Sedative activity increases the sleeping time
induced by pentobarbital
From Gardiner P, Kemper KJ: Herbs for sleep problems. Contemp Pediatr 2002;19(2):6987 and Gardiner P, Kemper KJ: Herbs in pediatric and adolescent medicine. Pediatr Rev 2000;21:4457.
TABLE 59-3. Herbs for Skin Conditions
ACTION HERB/SUPPLEMENT FOR TOPICAL USE
Soothing/emollient Aloe, calendula
Anti-inammatory Aloe, chamomile, evening primrose oil, lemon balm
Antiviral Aloe vera, calendula, chamomile, lemon balm
Antibacterial Aloe vera, calendula, chamomile, lavender, lemon balm, tea tree oil
Antifungal Lavender, tea tree oil
From Gardiner P, Coles D, Kemper KJ: The skinny on herbal remedies for dermatologic disorders. Contemp Pediatr
2001;18:103104, 107110, 112114.
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TABLE 59-4. Potentially Toxic Herbs
HERB TOXIC CONSTITUENTS TYPICAL USES POTENTIAL ACUTE ADVERSE EFFECTS HOW TO TREAT OVERDOSE
Aconitum (monkshood, Diester alkaloids: Hypaconitine and Facial neuralgia and sciatica Nausea, vomiting, hypersalivation Supportive care
wolfsbane) aconitine (aconitine increases Headache and migraines Central nervous system: Paresthesias, muscular weakness, Dioxin-specic antibodies, unless history
permeability for sodium ions and dizziness, ataxia, seizures, coma excludes cardiac glycosides
slows down repolarization, leading Rheumatic pain, arthritis, gout Cardiac: Bradycardia, hypotension, rhythm disorders Do not give ipecac
to paralysis of the nerve) Pericarditis sicca Activated charcoal and gastric emptying
may help
Avoid type 1 antiarrhythmics
Artemisia absinthium Thujone and isothujone: Anorexia Mental status changes: Restlessness, vertigo, tremors, Supportive care
(wormwood) Neurotoxins Dyspeptic conditions agitation, seizures, headache Benzodiazepines
Liver and gallbladder disorders Vomiting, stomach and intestinal cramps
Rhabdomyolysis and renal failure
Atropa belladonna Alkaloids: Hyoscyamine (the L-isomer Gastrointestinal symptoms Anticholinergic reaction: Tachycardia, hyperthermia, Gastric lavage
(deadly nightshade) of atropline) Cardiac insufciency and mydriasis, urinary and bowel retention, restlessness Physostigmine given in consultation with a
arrhythmia Nervous system and respiratory depression poison specialist
Asthma External cooling if temperature is >102F
Benzodiazepines
Hydration
Ayurvedic herbal Contaminated with lead, mercury, or Traditional medicine from India; Acute or chronic heavy metal toxicity Depends on heavy metal
remedies arsenic many purposes
Digitalis purpurea Cardioactive glycosides: Purpurea Ulcers, boils, headaches, abscesses, Nausea and vomiting, headache, loss of appetite Supportive care
(foxglove) glycoside, digitoxin gitoxin paralysis, cardiac insufciency Cardiac rhythm disorders Gastric lavage
Central nervous system: Stupor, confusion, visual Activated charcoal
disorders, depression, psychosis, hallucinations Treatment of symptoms
Ephedra sinica (ma huang) Alkaloids: Ephedrine, pseudoephedrine Decongestant for upper respiratory Cardiac: Hypertension, cardiomyopathy, myocardial infarction, Activated charcoal
Common names: (stimulates sympathomimetic infection arrhythmias Benzodiazepine for seizures and sedation
Miners tea receptors and the central nervous Asthma Central nervous system: Dizziness, restlessness, headaches, Vasodilators for hypertension
Mexican tea system) Weight loss anxiety, hallucinations, tremors, seizures, psychosis, strokes Lidocaine and blockers for arrhythmias
Desert herb Stimulant Nausea and vomiting External cooling if temperature is >102F
Contraindicated in diabetes or hypertension, angle-closure Hydration therapy
glaucoma, anxiety, prostate adenoma, thyroid disease,
pheochromocytoma
Illicium anisatum (Japanese Anisatins; block -aminobutyric acid Colic in Latino and Caribbean Seizures, tonic postures, myoclonus, hyperexcitability, irritability Recovery with supportive care within 48 hr
star anise tea) populations
Lobelia inata (lobelia) Piperidine alkaloid: L-Lobeline Expectorant Gastrointestinal: Nausea and vomiting, abdominal pain, Supportive care
(stimulates nicotinic receptors) Asthma diarrhea Gastric emptying
Spasmolytic Central nervous system: Anxiety, headache, dizziness, Activated charcoal
Emetic tremors, seizures, paresthesias, euphoria Benzodiazepines
To induce mental clarity and a Cardiac: Arrhythmias, bradycardia, transient increase in blood
feeling of well-being pressure, decreased respiratory rate
In overdose, lobeline may cause hypotension
Diaphoresis, muscle fasciculations and weakness, tremors,
respiratory depression
Dermatitis
Longdan xieganwan Aristolochic acid Enhance health Renal interstitial brosis Supportive care
End stage renal failure
Renal cell carcinoma
Mentha pulegium Pennyroyal oil has a hepatotoxic effect Insect repellent Uterine contractions Supportive care
(pennyroyal) Acute poisoning is not found with Respiratory illness Gastrointestinal: Nausea, vomiting, abdominal pain, hepatitis N-Acetylcysteine
proper administration of the Digestive disorders Neurotoxin: Delirium, dizziness, convulsions, seizures, paralysis,
designated therapeutic use of Emmenagogue encephalopathy, coma
pennyroyal leaf; however, the drug is Abortifacient Renal failure and hypertension
not recommended owing to Wound treatment Shock and disseminated Intravascular coagulation
hepatotoxicity Gout Contraindicated in pregnancy
Pausinystalia yohimbe Indole alkaloids Sexual disorders Adverse reactions: Dizziness, headache, anxiety, hypertension, Gastric emptying
(yohimbe) Yohimbe:
2
-Adrenoreceptor Exhaustion indigestion, rash, insomnia, tachycardia, tremor, vomiting, Activated charcoal
antagonist Improve muscle function hallucinations, nervousness, paresthesias, hypothermia, Antiarrhythmics
salivation, mydriasis, diarrhea, palpations, tachycardia Hydration
Contraindicated in kidney and liver disease
Phytolacca americana Triterpene saponins (irritate mucous Anti-inammatory Dizziness, somnolence, nausea, vomiting, diarrhea, tachycardia, Hydration therapy, electrolyte correction,
(pokeweed, American membranes) Arthritis hemorrhagic gastritis, hypotension, lymphocytosis, headache, gastric emptying
nightshade) Lectins (toxic) Cancer respiratory depression, seizures Activated charcoal
Emetic and cathartic Electrolyte replacement
Rheumatism
Emesis should not be induced if patient is
experiencing symptoms of overdose
Stramonium folium Alkaloids: Hyoscyamine (the Asthma and cough In high doses, leads to restlessness, mania, hallucinations, delirium Supportive care
(jimsonweed) L-isomer of atropine) Diseases of the autonomic Overdose: Tachycardia, mydriasis, ushing, dry mouth, Gastric lavage
nervous system decreased sweating, miction, constipation Decreasing temperature
Physostigmine
Benzodiazepines
Viscum album Alkaloids Antineoplastic adjuvant Fever, headaches, nausea, vomiting, diarrhea, bradycardia, angina, Supportive therapy
(mistletoe) Viscotoxins (Viscum album) cause Antihypertensive change in blood pressure, seizures, confusion, hallucination, Data inconclusive for inducing emesis
hypotension, bradycardia, and Nervous disorders: calmative agent allergic reactions, miosis, mydriasis, chills, coma Activated charcoal
arterial vasoconstriction Rheumatism 2 reported deaths in the last 35 yr; most ingestions lead to
Lectins Antispasmodic mild reactions
From Gardiner P, Kemper KJ: Herbs for sleep problems. Contemp Pediatr 2002;2:6987: and Gardiner P, Kemper KJ: Herbs in pediatric and adolescent medicine. Pediatr Rev 2000;21:4457.
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may contain toxic levels of mercury, cadmium, arsenic, or lead,
either from unintentional contamination during manufacturing
or from intentional additions by producers who believe that
these metals have therapeutic value. Approximately 3040%
of Asian patent medicines include potent pharmaceuticals, such
as analgesics, antibiotics, hypoglycemic agents, or corticoster-
oids; typically, the labels for these products are not written
in English and do not note the inclusion of pharmaceutical
agents.
Many families use dietary supplements concurrently with
medications, thus posing hazards of interactions. St. Johns wort
induces CYP3A4 activity of the P450 enzyme system (see Chapter
56) and thus can enhance elimination of digoxin, cyclosporine,
protease inhibitors, and numerous antibiotics, leading to sub-
therapeutic serum levels of these important medications. It may
also increase the risk of serotonin syndrome in patients taking
antidepressant medications. Ginkgo may increase the risk of
bleeding in patients taking anticoagulants. Licorice may enhance
the anti-inammatory effects and adverse effects of glucocorti-
coid medications.
In the U.S., herbal products are not regulated in the same way
as medications. The 1994 U.S. Dietary Supplement and Health
Education Act (DSHEA) allows herbal products to be marketed
without previous testing for efcacy or safety. Products may
contain little or none of the herb listed on the label, and they may
contain other herbs. Although they may not claim to prevent or
treat specic medical conditions, product labels may make struc-
ture-function claims. A label may claim that a product pro-
motes a healthy immune system, but it may not claim to cure
the common cold. The U.S. Food and Drug Administration (FDA)
can only restrict sales of certain products after receiving reports
of adverse effects. Adverse reactions should be reported to the
FDAs MedWatch program; failure to do so limits the FDAs
ability to monitor and manage the clinical and public health risks
of these products.
Some widely used products are relatively safe, but do not
appear to be effective in the treatment of conditions for which
they are promoted. One trial did not show that echinacea reduced
the severity or duration of cold symptoms in children. In addi-
tion, St. Johns wort was equivalent to placebo in the treatment
of mild to moderate depression.
Some herbal products may be helpful adjunctive treatments for
common childhood problems. Two studies, 1 with fennel and
another with an herbal combination (chamomile, fennel, vervain,
licorice, balm mint), found that these remedies were helpful for
infant colic. Ginger has been shown to be an effective antiemetic;
herbal eardrops have been shown to provide signicant analge-
sia for children with mild to moderate otitis media. Enteric-
coated peppermint oil may be helpful for children with irritable
bowel syndrome. Probiotics may help prevent and treat diarrhea
in children (see Chapter 337).
Most herbs have undergone far more testing in adult than in
pediatric populations. Herbalists recommend that teenagers use
adult doses, children 712 yr of age use
1
/
2
of the adult dose, chil-
dren 36 yr of age use
1
/
4
of the adult dose, and that herbs be used
only cautiously, if at all, in children 2 yr of age or younger. Herbs
used for common conditions and the toxicity of selected herbs
are described in Tables 59-1 through 59-5, and resources for
information on herbal medicine are listed in Table 59-6.
Alexandrovich I, Rakovitskaya O, Kolmo E, et al: The effect of fennel
(Foeniculum vulgare) seed oil emulsion in infantile colic: A randomized,
placebo-controlled study. Altern Ther Health Med 2003;9:5861.
Ball SD, Kertesz D, Moyer-Mileur LJ: Dietary supplement use is prevalent
among children with a chronic illness. J Am Diet Assoc 2005;105:7884.
Centers for Disease Control and Prevention: Suspected moonower intoxica-
tionOhio, 2002. MMWR 2003;52:788791.
De Smet PAGM: Herbal remedies. N Engl J Med 2002;347:20462056.
TABLE 59-5. Spanish-English Botanical Name Translation Chart*
SPANISH NAME ENGLISH NAME BOTANICAL NAME
Ajo Garlic Allium sativum
Azarcon Lead tetraoxide Not a plant
Azogue Mercury Not a plant
Cebolla Onion Allium cepa
Cenela Cinnamon Cinnamomum aromaticum
Clavo Cloves Eugenia aromatica
Comino Cumin Cuminum cyminum
Epasote or Herba Sancti Mariae Wormseed Chenopodium anthelminticum
Estaate Wormwood Artemisia absinthium
Eucalipto Eucalyptus Eucalyptus globulus
Granada Pomegranate Punica granatum
Jengibre Ginger Zingiber ofcinale
Limon Lemon Citrus limon
Manzanilla Chamomile Anthemis nobilis or
Chamomilla recutita or
Matricaria chamomilla
Oregano Oregano Origanum vulgare
Pelos de elote Corn silk Zea mays
Savila Aloe vera Aloe vera
Siete jarabes Mixture of syrup of sweet almond,
castor oil, balsam resin, wild cherry,
licorice, cocillana bark, honey
Tomillo Thyme Thymus vulgaris
Una de gato Cats claw Uncaria tomentosa
Valeriana Valerian Valeriana ofcinalis
Yerba buena Spearmint Mentha spicata
*Prepared with assistance from Laura Howell, MD.
TABLE 59-6. Resources
PERIODICALS Prescribers Letter. Therapeutic Research Center (209-472-2240)
Review of Natural Products. Facts and Comparison (1-800-223-0554)
WEB SITES Academic
Longwood Herbal Task Force: http://www.mcphs.edu/MCPHSWeb/herbal
Memorial Sloan-Kettering Cancer Center: http://www.mskcc.org/mskcc/html/11570.cfm
University of Texas M. D. Anderson Cancer Center:
http://www.mdanderson.org/departments/CIMER/dIndex.cfm?pn=6EB86A59-
EBD9-11D4-810100508B603A14
Wake Forest University School of Medicine, BestHealth:
http://www.besthealth.com/cam/The_Herbs_Supplements.htm
Government
FDA MEDWATCH, monitoring program for reporting adverse effects:
http://www.fda.gov/medwatch (1-800-FDA-1088)
International Bibliographic Information on Dietary Supplements (IBIDS):
http://ods.od.nih.gov/databases/ibids.html
National Cancer Institute: http://www.cancer.gov/cam
National Center for Complementary and Alternative Medicine:
http://www.nccam.nih.gov/health/bottle
NIG Ofce of Dietary Supplements: http://odp.od.nih.gov
U.S. Department of Agriculture Food and Nutrition Center:
http://www.nal.usda.gov/fnic/etext/000015.html
U.S. Food and Drug Administration Ofce of Dietary Supplements:
http://vm.cfsan.fda.gov/~dms/supplmnt.html
Nonprot
American Botanical Council: http://www.herbalgram.org
Childrens Hospital and Boston Medical Center: www.holistickids.org
The Natural Pharmacist: www.tnp.com
Subscription Products
Micromedex Internet Health Care Series: www.micromedex.com
Natural Medicine Comprehensive Database: http://www.naturaldatabase.com
Natural Standards: www.naturalstandards.com
ConsumerLabs: www.consumerlabs.com
Toxicology Information
Toxicology Information Resource Center:
http://www.ornl.gov/TechResources/tirc/hmepg.html
TOXLINE and TOXNET, from the National Library of Medicine:
http://sis.nlm.nih.gov/ToxSearch.htm
Ch056-059-X2450.qxd 2/5/07 1:36 PM Page 360
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Chapter 59 Herbal Medicines 361
Finkel RS: Blue cohosh and perinatal stroke. N Engl J Med 2004;351:
302303.
Finsterer J: Earl Grey tea intoxication. Lancet 2002;359:14841485.
Garrard J, Harms S, Eberly LE, et al: Variations in product choices of fre-
quently purchased herbs. Arch Intern Med 2003;163:22902295.
Ize-Ludlow D, Ragone S, Bruck IS, et al: Neurotoxicities in infants seen with
the consumption of star anise tea. Pediatrics 2004;114:e653e656.
Kline RM, Kline JJ, Di Palma J, et al: Enteric-coated, pH-dependent pepper-
mint oil capsules for the treatment of irritable bowel syndrome in children.
J Pediatr 2001;138:125128.
Koretz RL, Rotblatt M: Complementary and alternative medicine in gas-
troenterology: The good, the bad, and the ugly. Clin Gastroenterol Hepatol
2004;2:957967.
Laing C, Hamour S, Sheaff M, et al: Chinese herbal uropathy and nephropa-
thy. Lancet 2006;368:338339.
Lanski SL, Greenwald M, Perkins A, et al: Herbal therapy use in a pediatric
emergency department population: Expect the unexpected. Pediatrics
2003;111:981985.
Markowitz JS, Donovan JL, DeVane CL, et al: Effect of St. Johns wort on
drug metabolism by induction of cytochrome P450 3A4 enzyme. JAMA
2003;290:15001504.
McBride BF, Karapanos AK, Krudysz A, et al: Electrocardiographic and hemo-
dynamic effects of a multicomponent dietary supplement containing
ephedra and caffeine. JAMA 2004;291:216221.
Mills E, Montori VM, Wu P, et al: Interaction of St. Johns wort with con-
ventional drugs: Systematic review of clinical trials. BMJ 2004;329:2730.
Saper RB, Kales SN, Paquin J, et al: Heavy metal content of Ayurvedic herbal
medicine products. JAMA 2004;292:28682873.
Shekelle PG, Hardy ML, Morton SC, et al: Efcacy and safety of ephedra and
ephedrine for weight loss and athletic performance. JAMA 2003;289:
15371544.
Sibinga EM, Ottolini MC, Duggan AK, et al: Parent-pediatrician communi-
cation about complementary and alternative medicine use for children. Clin
Pediatr (Phila) 2004;43:367373.
Szajewska H, Mrukowicz JZ: Probiotics in the treatment and prevention
of acute infectious diarrhea in infants and children: A systematic review of
published randomized, double-blind, placebo-controlled trials. J Pediatr
Gastroenterol Nutr 2001;33:S17S25.
Taylor JA, Weber W, Standish L, et al: Efcacy and safety of echinacea in treat-
ing upper respiratory tract infections in children: A randomized controlled
trial. JAMA 2003;290:28242830.
Turner RB, Bauer R, Woelkart K, et al: An evaluation of Echinacea angusti-
folia in experimental rhinovirus infections. N Engl J Med 2005;353:
341348.
Wilson KM, Klein JD: Adolescents use of complementary and alternative
medicine. Ambul Pediatr 2002;2:104110.
Yussman SM, Ryan SA, Auinger P, et al: Visits to complementary and alter-
native medicine providers by children and adolescents in the United States.
Ambul Pediatr 2004;4:429435.
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response to low molecular weight compounds administered with

Pediatric Drug Therapy

), theophylline Cimetidine (Tagamet

), phenytoin (Dilantin) Fluvastatin (Lescol)

), risperidone (Risperdal), thioridazine (Mellaril

), felodipine (Plendil), nimodipine (Nimotop), nifedipine (Adalat

) Clarithromycin Carbamazepine (Tegretol

), tacrolimus (Prograf) Erythromycin Efavirenz (Sustiva)

), troleandomycin (TAO) Grapefruit juice Phenytoin (Dilantin

), getinib (Iressa), ifosfamide (Ifex), tamoxifen, vincristine (Oncovin

), Itraconazole (Sporanox) Ritonavir

Benzodiazepines: Alprazolam (Xanax

) St. Johns wort

, simvastitin (Zocor), atorvastatin (Lipitor) Ritonavir

), sildenal (Viagra), eletriptan (Relpax), ziprasidone (Geodon) Troleandomycin

), diltiazem, domperidone Amiodarone Amprenavir

), nelnavir, ondansetron (Zofran), Clarithromycin Phenothiazine

Itraconazole St. Johns wort

Also available generically.

Can be both an inhibitor and an inducer.

Principles of Drug Therapy

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