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Part VII Pediatric Drug Therapy

Chapter 51

. harmacogenetics,

Pharmacogenomics, and
Pharmacoproteomics . Stmen leedm

Interindividual variability in the response, intended or unanticipated, to similar doses of a given drug is an inherent characteristic 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 recognize that all patients are unique and that the serum concentration-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 variations 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 concentrationdependent toxicity due to reduced clearance and drug
accumulation. In addition, the concentration-effect relationship
(pharmacodynamics) is more relevant for optimizing drug efficacy. The pharmacogenetics of drug receptors and other target
proteins involved in signal transduction or disease pathogenesis
can also be expected to contribute significantly to interindividual
variability in drug response.
Pharmacogenomics represents the marriage of pharmacology
and genomics and can be defined as the study of the genome-wide

response to low molecular weight compounds administered with

therapeutic intent; the goal is to find the right drug for the right
disease.

DEFINITION OF PHARMACOGENETIC TERMS

All copies of a specific 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
821. Haplotypes are collections of SNPs and other allelic variations 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 individual's genetic constitution, whereas the observable characteristics or physical manifestations constitute the
phenotype, which is the net consequence of genetic and
environmental effects (see Chapters 78-83). 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 interaction 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-BS1502-positive have an
increased risk of carbamazepine-induced Stevens-Johnson syndrome; white patients who are HLA-BS5701-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. Individuals are classified 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, depending 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] activities) [see Chapters 57, 96, and 973. 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 immediately after birth.

PART VII w Pediatric Drug Therapy

GNE

ENtYMEITARGET

DRUG

Cytochrome P450 2D6

Codeine

CLINICAL RESPONSE

Individuals homozygous for an inactivating mutation do not metabolize code~neto morphine and thus experience n
analges~ceffect;rapid metabolizers may experience opiate toxic~ty
Cytochrome P450 2C9
Warfarin
Indivduals heterozygous for a polymorphism need a lower dose of warfarin to maintain anticoagulation
N-Acetyltransferase 2
Isoniazid, hydralazine
Individuals homozygous for"slow atetylation"polymorphisms are more susceptible to isoniazid toxicity,or
hydralazine-induced systemlc lupus erythematosus
TPM 1
Individuals homozygous for an inactivat~ngmutation have severe toxicity if treated with standard doses of
azath~oprine;rapid metabolism causes undertreatment
pAdrenergic receptor
1DRB2
Individuals homozygous for a polymorphism get worse with regular use of albuterol
Albuterol
Potass~umchanne1,voltage gated
CCNt2
Individuals heteiozygous for a polymorphlsrn are more susceptible to life-threaten~ngarrhythmias
Erythromyc~n
;UR 1
Sulfonylurea receptor 1
lndlviduals heterozygous for a polymorphism exhibit diminished sensitivity in sulfonylurea-stimulated insulin secret1
Sulfonylureas
Coagulation factor V (Leiden)
lndividuals heterozygous for a polymorphism are at increased risk for venous thrombosis
Oral contraceptives
1YR 1
Calc~umion release channel
Mal~gnanthyperthermia
Halothane, succinylchol~ne
KHE
Butyrylthol~nesterase
Succ~nylcholine
Prolonged paralysis
;6PD
Glucose-6-phosphate dehydrogenase
Hemolysis
Pr~maquine(others)
YP3A
Cytochrome P450
Moderate Inhibitor of intestinal (presystemic) first pas5 metabolism of many drugs*
Grapefru~tjuice
IRD3
Dopamine Dl receptor
Antipsychotic agents
Tardive dysk~nesia
lHFR
Dhydrofolate reductase
Methotrexate
Drug resistance
'OPI
Topoisomerase 1
Anthracycline agents
Drug resistance
I;FR
Epidermal growth factor receptor
Gefitinib
Drug resistance
Albendazoe, benzodiazeplnes,buspirone,tarbamazeplne, tytlosporine, fexofenadlne,fluoxetine, lndinavc araconazole, ienrallne,rliolimus,tatrolimus,verapam~l,warfarin
ilodihec

bWW&
h e bnportd Rclatiollships Between Drugs ar#l CyltodmnncP458 (QYP] Enzytm* and P-Glycepcctein (P-gp) Irmqortm

....

- - - - - - . .....- -

..

afieine, clomipramine (Anofrani/'),clozapine

YP2C9

CYP2C19
CYP2D6

CYP3A4

(llozarif), theophylline

D~tlofenac(Voitaren'), ibuprofen (Motrint), piroxicam (Feidene'), losartan (Cozaor), irbesartan (Avapro), celecox~b(Celebrex),
tolbutamide (Onnose'), warfarin (Coumodin'), phenytoin (Dilantin)

Omeprazole, lansoprazole (Prevaad), pantoprazole (Protonix), (8)-mephenytoin, nelfinavir (I/iracept),diazepam (Vahumt),

vor~conazole(Vfend)
CNS-active agents: Atornoxet~ne(Strattera),amitriptyline (ElaviT),desipramine (Norpiamint),im~pramine (bfronif),
paroxetine (Paxii), haloperidol (Haldo/'], r~speridone(RisperdaO,thior~daz~ne(Mellanf)
Antiarrhythmic agents: Mex~let~ne
(Mexitin, propafenone (RyrhmoO
$ Blockers: Propranolol (indera/'), metoprolol (Lopressor'),timolol (Blocadrent)
Narcotics: Codeine,dextromethorphan, hydrocodone (Vicodin')
Tamoxifen (Nolvodex]

Calcium channel blockers: D~ltiazem(Cardizem'), felodlp~ne(Piendin, nimodipine (Nirnotop), nifedipine (Adaiat'),

n~sold~pine
(i;ular),n~trendip~ne,verapam~l(Caian')
lmmunosupressive agents: Cytlosporine A (Sandimmune, Neoraf), tacrolimus (frogran
Steroids: Budesonide (Pulmicoit), cortisol, 17p-estradiol, progesterone,testosterone
Macrolide antibiotics: Clar~thromycin(&axin),erythromyc~n (Erryfhrocint),troleandomycin(TAO)
Anticancer agents: Cyclophospham~de(Cytoxant),gefitinib (iresso),ifosfam~de (Ifex), tamox~fen,vincristine(Oncovin'),
v~nblastine(Veiban'),
Benzodiazepines:Alprazolam (Xanaxt), midazolam Versed+), triazolam (Haiciont)
Opioids: Alfentanyl (Alfenta'), fentanyl (Sublimazet],sufenranil (Sufenta')
HMG-CoA reductase inhibitors: Lovastatin (Mevacor', s~mvastitin(Zocor), atorvastatin (Lip~ior)
HIV protease inhibitors: lndinavir (trixivan), nelfinav~r,rltonavir (Norviri, saquinavlr (lnvirase, Fortovase),
amprenav~r(Ayenerase)
Others: Quinrd~ne(Quinidex'),sildenafil (Viaqra),eletriptan (Re/pax),z~pras~done(Geodon)
Aldosterone,amprenavir,atorvastatin,cyclosporine,dexamethasone (Decodront),d~goxin(Lanox~n'),diIt~azem,domper~done
(Motihum),doxorubicin (Adnamycint),erythromycin,etoposide (Vepesid),fexofenadine (Ailegra), hydrocortisone,
~ndinavir,lvermectin(StromettoO,lovastat~n loperamide (/mod~um'),nelfinavir,ondansetron (Zofran),
pacl~taxel(Taxo~,qu~nidine,saquinavir,simvastatin,verapam~l,vinblastine,vincrist~ne

"www drug-interattlons tom

'4180 available generically
:an be both an inhibitor and an Inducer
rom Med Lett 2003;45.47
NS, tentral nervous svitei

Cimetid~ne(Togamet')
Flucoxamine (Luvoxt)
Ciprofloxacin (Cipro)
Fluconazole (D~flucan)
Fluvastatin (Lescoi)
Amiodarone (Cordarone)
Zafirlukast (Accoiate)
Cimetidine
Fluvoxamine
Amidoarone (Cordaronet)
Cimetidine
Fluoxetine (Prozact)
Terbinafine
Paroxetine (Paxil)
Quin~dine(Quin1dext)
Ritonavir
Amiodarone
Clar~thromycin
Erythromycin
Fluconazole
Grapefruit juice
lmatln~b
ltraconazole (Sporanox)
Ketoconazole (Nmraf)
Nefazodone (Serzone)
Ritonavi?
Indlnavir
Troleandomycin
Amiodarone
Carvedilol (Coreq)
Clar~thromycin
Cyclosporine
Erythromycin
ltraconazole
Ketoconazole
Quinidine
Ritonavi?
Tamoxifen
Verapamil

.,

Omeprazole (Priiosect)
Tobacco
Rifampin (R1fadint)

Rifampin

Barbiturates
Carbamazep~ne(iegreto
Efavirenz (Sustiva)
Nevirapine (Vmmune)
Phenytoin (Dilantint)
Rifampin
Ritonav~r'
St John's wort

Amprenavir
Clotrimazole (Myeelex')
Phenothiazine
Rifampin
Ritonavir'
St John's wort

Chapter 56

Pharmacogenetics, Pharmacogenomics, and Pharmacoproteomics

323

Treatment Outcome

fi

Success

Failure

Treat with conventional

drug and dose

Treat w~thalternat~ve

drug

'Dlug

Treat with alternative

drug or dose

Treat with alternative

drug

*-c

medicine will be achieved by identifying subgroups of

Figure 56-1. The promise of genomic medicine to human health and disease. The goal 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 benefit 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. (Adapted from Yaffe SJ, Aranda JV: Neonatal and Pediatric Pharmacology, 3le. Philadelphia: Lippincott Williams
& Wilkins, 2004.)

324

. .
PART V I I

Pediatric Drug Therapy

ittp:l/www.ornl gov/TechResources/Human~Genome/medicine/pharma html

html
ittp:llwww.ama-asm or~/ama/~ub/~ateaorv/2306
i ~ p : l l w w w n c bnlm
~ ni~ovl~boutl~rim~r~~harm.html
1ttp:llpubs acs orglcenlcoverstory/7933/7933pharmacogenomicshtml

PHARMACOGENETICS:ALLELIC VARIANTS OF DRUG METABOLIZING ENZYMES

:YP2C9
http:llwww.imm ki selCYPalleleslcyp2~9.htm
:YP2C19
http://www.imm kl selCYPallelesIcyp2~19.htm
:YP2D6
http:llwwwimm ki selCYPalleleslcyp2d6htm
:YP3A4
http:llwww.imm.ki seICYPalleleslcyp3a4.htm
:YP3A5
http:llwww imm k1,se/CYPalleles/cyp3a5htm
JGTs
http:llsom flinders edu aulFUSAIClinPharmlUGT1allele-table html
4ATl and NAT2
http:I1wwwlou1sv1lleedu/medsthoollpharmacology/NAThtml
PHARMACOGENETICS:SUBSTRATESOF DRUG METABOLIZING ENZYMES
ittp:llw.drug-interactions com
INTRODUCTIONTO PROTEOMICS
ittp:llwwwama-assn orglamalpublcategory13668 html
ittp:llwwwe-proteomics net
'All 8116were accessible on March 31,2006

.-

PHARMACOGENETIC, PHARMACOGENOMIC. A N D PHARMACOPROTEOMIC 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 hepatotoxicity or weight gain; tumor response to cancer chemotherapy;
drug response in asthma, epilepsy, and attention-deficitlhyperactivity disorder). Systematic surveys of gene expression in different cell types (tumor cells vs "normal" cells) are often conducted
with the hope of identifying new targets for pharmacotherapeutic 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-specific drug toxicities. These types of
studies use microarray, or gene-chip, technology to monitor
global changes in expression of thousands of genes simultaneously-"global gene profilingn-in marked contrast to the laboratory 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 filter (see Chapter 79).
The probes serve as molecular detectors for messenger RNA
(mRNA) in the sample. Common experimental designs involve

Figure 56-2. "Developmental" phenotypes. Variability in developmental changes in gene expression and functional enzyme
activity are superimposed o n pharmacogenetic determinants.
The top panel shows the developmental profile of a theoretical
drug-metabolizing enzyme over a 25 yr span in 2 0 subjects. At
maturity (adults), allelic variation within the coding reglon of the
gene gives rise to 2 distinct phenotypes, high activity in 9 2 % of
the population ("extensive metabolizers"; red ctucles) and low
activity in 8% of the population ("poor metabollzers"; yellow
crrcles). 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-phenotype 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). (Adapted from Leeder JS:
Translating pharmacogenetics and pharmacogenomics into drug
development for clinical pediatric and beyond. Drug Dtscov
Today 2004;9:567-573.)

Chapter 56

labeling mRNA (or complementary DNA [cDNA]) from a

control sample with 1 fluorescent dye and mRNA or cDNA from
the disease or treatment sample with a 2nd fluorescent 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 represents its relative expression level. DNA chips can also be made
that focus on specific 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 profiling technique, serial analysis of gene expression (SAGE), overcomes technical limitations of microarrays related to their ability
to conduct comparative data analyses and effectively detect lowabundance transcriots.
Proteomic studies use many different techniques to detect,
quantify, and identify proteins in a sample (expression proteomics), and to characterize protein function in terms of
activity and protein-protein or protein-nucleic 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 identified by mass spectrometry. The data generated are
compared with theoretically derived peptide mass databases for
protein identification.

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 conversion of prodrug to therapeutically active compounds is also of
clinical importance (see Table 56-1). Chemical modification of
drugs via biotransformation reactions generally results in termination of biologic activity through decreased affinity for receptors 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 specificity-a single isozyme may
metabolize a large variety of chemically diverse compounds.
Second, many different enzymes may be involved in the biotransformation 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 identified and are
produced by different CYP isoforms.
Drug biotransformation reactions are conveniently classified
into 2 main types, phase I and phase I1 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
I1 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 biotransforrnation activity is a consequence of the complex
interplay among genetic (genotype, sex, race or ethnic background) and environmental (diet, disease, concurrent medication,
other xenobiotic exposure) factors. The pathway and rate of a
given compound's biotransformation is a function of each individual's 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-

Pharmacogenetics, Pharmacogenomics, and Pharmacoproteomics

325

lism of many lipophilic endogenous substances (steroids, fatty

acids, fat-soluble vitamins, prostaglandins, leukotrienes, thromboxanes) and exogenous compounds, such as drugs. CYP nomenclature 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 P45Os in a subfamily are numbered sequentially (CYP3A4, CYP3A5). CYPs that have been
identified as being important in human drug metabolism are predominantly found in the CYP1, CYP2, and CYP3 gene families.
Enzyme activity may be induced or inhibited by various agents
(see Table 56-2).
Phase I1 enzymes include arylamine N-acetyltransferases
(NAT1, NAT2), glucuronosyl transferases (UGTs), epoxide
hydrolase, glutathione S-transferases (GSTs), sulfotransferases
(SULTs), and methyltransferases (catechol 0-meth~ltransferase,
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-specific pattern of
expression.

For most CYPs, genotype-phenotype relationships are influenced by development in that fetal expression is limited (with
the exception of CYP3A7) and functional activity is acquired
postnatally in isoform-specific 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.
C
m The CYP2D6 gene locus is highly polymorphic, with >75
allelic variants identified to date (http://www.imm.ki.se/CYPalleles/cyp2d6.htm; see Table 56-2). Individual alleles are designated
by the gene name (CYP2D6) followed by an asterisk, and an
Arabic number; CYP2D6"l 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 5-10% of white subjects and
approximately 1-2% 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"l allele. The CYP2D6"lO 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 associated with decreased clearance of CYP2D6 substrates, such as
metoprolol and nortriptyline.
CYP2D6 is involved in the biotransformation of >40
therapeutic entities, including several P-receptor antagonists,
antiarrhythmics, antidepressants, antipsychotics, and morphine
derivatives (for an updated list, see http://medicine.iupui.edu/
flockhart; see Table 56-2). Selective serotonin reuptake inhibitors
(SSRIs; fluoxetine, paroxetine, sertraline), atomoxetine, codeine,
and dextromethorphan are commonly encountered in pediatrics.
Very limited CYP2D6 activity is present in fetal liver in vitro
( = I % 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

326

. .
PART VII

Pediatric Drug Therapy

vivo data derived from a longitudinal phenotyping study conducted over the 1st year of life using dextromethorphan as a
probe compound suggest that the CYP2D6 phenotype is concordant with genotype by 2 wk of age. Dextromethorphan phenotyping 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 insufficient
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 pharmacogenetics may be the syndrome of irritability, tachypnea, tremors,
jitteriness, increased muscle tone, and temperature instability in
neonates born to mothers receiving SSRIs during pregnancy. Controversv currentlv exists as to whether these svmvtoms
reflect a
,
neonatal withdrawal (hyposerotonergic) state or represent manifestations of serotonin toxicity analogous to the hyperserotonergic 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 hyperserotonergic state due to delayed clearance of paroxetine and fluoxetine (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 adaptation 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 concentration-dependent toxicities in CYP2D6 genotypic poor metabolizers should be anticipated as they are in adults due to the risk of
significant morbidity and mortality. Experience with paroxetine
shows that the risk of drug accumulation is not necessarily limited
to the poor-metabolizer phenotype. Although the pharmacokinetics of the CYP2D6 substrates paroxetine and nefazodone correlate with the CYP2D6 phenotype in children and adolescents
7-17 yr of age, chronic dosing of paroxetine may lead to greater
than anticipated drug accumulation in children classified as
CYP2D6 extensive metabolizers. In depressed children and adolescents as well as in adults, there is a disproportionate increase
in peak concentration and area under the serum concentrationtime 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 predicted 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 mechanism involves oxidation of paroxetine within the CYP2D6 active
site to form a reactive intermediate that is associated with irreversible modification 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 efficacy or therapeutic failure with drugs such as codeine and tramad01 that are dependent on functional CYP2D6 activity for
conversion to the pharmacologically active species. Infants and
children appear capable of converting codeine to morphine,
L

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 population and not related to the CYP2D6 phenotype. Ultrarapid
CYP2D6 metabolism of codeine may result in opiate intoxication. CYP2D6 catalvzes the 0-demethvlation of codeine to morphine. 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 substrates for CYP2C9 (http://medicine.iupui.edu/flockhart) [see
Table 56-21, 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 1-2% 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 'I2of 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 pharmacokinetic 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, reflecting the functional acquisition of CYP2C9
activity, does not appear until approximately 1 0 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 reflect 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 wildtype enzyme. Allelic variations resulting in amino acid changes
within the enzyme active site, such as the CYP2C9"3,
CYP2C9 *4, and CYP2C9 '$5alleles, are associated with activities
that are approximately 5% of the wild-type protein. Approximately 'I3of the white population carries a variant CYP2C9 allele
("2 and '"3 alleles. most commonlv).
, 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 warfarin 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 extensively studied in children, consequences of allelic variation can be
expected to be similar to those observed in adults.
8 ,

CYP2C19. In vitro, CYP2C19 protein and catalytic activity can be

detected at levels representing 12-15% 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 activity increases linearly. Adult levels are achieved by 10 yr of age,
although variability in expression is estimated to be approximately 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 mephenytoin hydroxylase deficiency) is present in 3-5% of the white population and 20-25% of Asians. Although 19 variant alleles have

Chapter 56 rn Pharmacogenetics, Pharmacogenomics, and Pharmacoproteomics rn 327

been reported to date, the 2 most common variant alleles,

CYP2C19 "2 and CYP2C19 "3, result from single base substitutions 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 classified as poor metabolizers, whereas none were detected beyond that point. In contrast,
20% of children 3-9 mo old were classified as ultrarapid metabolizers compared with 6% of infants 1-3 mo of age. For omeprazole, pharmacokinetic parameters comparable to those observed
in adults are achieved bv, 2 vr
, of ape.
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 significantly 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"l allele is considerably
greater in white subjects ( ~ 0 . 8 4[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 strategies in children.
G.

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:l/medicine.iupui.edu/flockhart; see Table 562). CYP3A7 is the predominant CYP isoform in fetal liver and
can be detected in embryonic liver as early as 50-60 days' gestation. CYP3A4, the major CYP3A isoform in adults, is essentially
absent in fetal liver, but increases gradually throughout childhood. 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 significantly 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 activity. 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 identified
(http:llwww.imm.ki.selCYPalleles/cyp3a4.htm), most occur relatively infrequently and do not appear to be of clinical importance.
Of interest to pediatrics is the CYP3A4"l B allele present in the
CYP3A4 promoter region. The clinical significance 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"lB allele and age of menarche, a significant relationship does exist between the number of CYP3A4"lB alleles
and the age at onset of puberty, as defined by Tanner breast score.
In one study, 90% of 9 yr old girls with a CYP3A4"I B/"1 B genotype had a Tanner breast score of 22 compared with 56% of
CYP3A4"lAI"lB heterozygotes and 40% of girls homozygous

for the CYP3A4"lA 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"lB 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 CYP3A.5 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 CYP3AS activity
compared with only 33% of European Americans. Clinically
important consequences of CYP3AS allelic variation have been
reported in children. In pediatric heart transplant patients with a
CYP3A5 "lI"3 genotype, tacrolimus concentrations were approximately 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-inflammatory 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 24-39 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-specific.
UGTlAl is the major UGT gene product responsible for bilirubin glucuronidation, and >60 genetic alterations have been
reported, most of which are rare and are more properly considered 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
U G T l A l promoter. The wild-type U G T l A l " 1 allele has 6
repeats (TAG),and the TA, (UGTlA1"33), TA, (UGTlA1"28),
and TA, (UGTlA1 "34) variants are all associated with reduced
activity. U G T l A l L 2 8 ,the most frequent variant, is a contributory factor to prolonged neonatal jaundice and is associated with
impaired glucuronidation and thus toxicity of the irinotecan
active metabolite, SN-38. Allelic variation in UGTlA7 and
U G T l A 9 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-glucuronide (M6G) and the inactive 3-glucuronide (M3G). M6G
formation is almost exclusively catalyzed by UGT2B7, whereas
several UGTs in the UGTlA subfamily, as well as UGT2B7, contribute to M3G formation. Increased M6G : morphine ratios
have been reported in individuals homozygous for the SNPs
constituting the UGT2B7"2 allele. Although individuals genotyped as UGT2B7"2/"2 may produce higher than anticipated
concentrations of pharmacologically active morphine and its
metabolites, prospective pharmacogenetic studies addressing

328

PART VII w Pediatric Drug Therapy

phenotype-genotype correlations and the consequences of morphine 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 AfricanAmericans in North America are phenotypically slow metabolizers, placing a substantial number of individuals at increased risk
for the development of adverse drug effects, such as sulfasalazineinduced hemolysis, hydrazine or arylamine-induced peripheral
neuropathy, procainamide- or isoniazid-induced systemic lupus
erythematosus, and Stevens-Johnson syndrome or toxic epidermal 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
~nfants0-55 days of age appear to be phenotypically slow acetylators. whereas 50% and 62% of infants 122-224 and 225-342
days of age, respectively, can be characterized as fast acetylators.
Several independent studies indicate that maturation of the NAT2
phenotype occurs during the first 4 yr of life. Phenotype-genotype
discordance is likely to be most apparent in the first 2-4 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 cvtosolic enzvme that catalvses the S-methvlation 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), inflammatory 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 transferase. TPMT prevents thioguanine nucleotide production by
methylating 6MP (Fig. 56-3A). TPMT activity is usually measured in blood, with activity in erythrocytes reflecting 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 individuals inherits TPMT deficiency as an autosomal recessive trait
(Fig. 56-3B). In newborn infants, peripheral blood TPMT activity is reported to be 50% greater than in race-matched adults and
shows a distribution of activity that is consistent with the polymorphism 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 7-9 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 deficiency, severe and
potentially life-threatening myelosuppression can develop in
those receiving standard doses of thiopurine; starting doses must
be reduced to 6-10% of the normal dose.
TPMT"3A is the most common mutant allele and is characterized by 2 nucleotide transition mutations, G460A and A719G,
that lead to 2 amino acid substitutions Ala154Thr and
Tyr240Cys (Fig. 56-30). Although the "3A allele only has a frequency 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 substitutions in the coding region and defective intron-exon splicing. A
polymorphic locus has been identified in the promoter region of
the TPMT gene involving 4-8 repeats of a specific 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 10-15-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
inflammatory bowel disease and juvenile arthritis and to prevent
renal allograft rejection, TPMT deficiency is not a trivial matter.
Introduction of the TPMT phenotype or genotype determination into pediatric practice will lead to safer, more efficacious
treatment in pediatric patient groups. Although most research has
been conducted in ALL, the observation that patients classified
as having intermediate TPMT activity are more likely to be intolerant 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, 2,4dichlorophenoxyacetic acid, as well as nonsteroidal anti-inflammatory 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 tertiary, involving Na+, K+-ATPase,which maintains the Na' gradient 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 identification of the gene encoding for the OAT1 transporter led to the discovery of several isoforms, including cOAT2,
hOAT3, and hOAT4. The different OATS have substantial
overlap in substrate specificity, while maintaining important differences. Para-aminohippurate has high affinity for OAT1 and
OAT3. but much lower affinitv for OAT2 and OAT4.
The newborn excretes penicillins (renal) at very low rates compared 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 andlor transcription. Another important phenomenon encountered with the
tubular secretion of organic anions is substrate induction, leading
to enhanced elimination of organic anions with repeated exposure. This phenomenon is unique, although its biologic pattern
has not yet been elucidated.

Chapter 56

Figure 56-3. Thiopurine S-methyltransferase (TPMT) polymorphism.

A, 6-Mercaptopurine (6MP) undergoes metabolism to thioguanine
nucleotides (TGNs) to exert its cytotoxic effects. TPMT and xanthine
oxidase reduce the amount of 6MP
available for the bioacrivation
pathway to TGNs. TPMT can
also methylate 6-thioinosine 5'monophosphate (TIMP) to generate
a merhylated 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 intermediate 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 Door
metabolizers, more 6MP is available
to go down the bioactivation
pathway to form TGNs; this situation 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 degradation. 6721, 6-thiouric acid; MeMP,
6-methylmercaptopurine;
HPRT,
6-rhiomethylinosine 5-monophosphate; MeTIMP, hypoxanthineguanine phosphorihosyl transferase;
wt, wild type; mut, mutant. (Modified with permission from Relling
MV, Dervieux T: Pharmacogenetics
and cancer therapy. Nat ~ e v - c a n c e r
2001;11:99-108; copyright 2001,
Macmillan Magazines Ltd [130.])

Pharmacogenetics. Pharmacogenomics, and Pharmacoproteomics

329

DNA

purine synthesis

~nti-leukemiceffect
Myelosuppression

incorporatlofl

wtlwt

J
TPMT genotype: mut/mut
0

TPMT'1
(wild-type)

10 15 20
TPMT activity

25

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 specifically, the organic cation is located at the brush border
membrane, and its function is mediated by an organic cationproton antiporter. Similar to the OAT family, the organic cation
transporter (OCT) plays a critical role in removing a large

I
t

Myelosuppression

wt/mut

t Risk secondary cancer

I I I

wvwt

L Toxicity
1'Risk of relapse

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 proteins, 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-

330

PART VII rn Pediatric Drug Therapy

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.

explained by changes in the glomerular filtration rate alone,

because the glomerular filtration rate per kilogram of body
weight in young children is <2-fold higher than in adults. A significant 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.
THE ABC SUPERFAMILY , \ \-.qrtr,[\. OI r1711hcl1.tl l1.1rrlt.r~. ~ n i l ~ ~ ~ l ~ n e
ill< ~ I L ~ III ~ IC I -~. ~ 1. 1 Id~ I o o ~ ~ ~ I ~ I ~ . I I I ~ I \ I I I , ~ I C I~ I ~ I \ ' ,CI ~ ~ I I I c~\ p~r cI \I- I ~
sion of ABC transporters, such as P-glycoprotein (P-gp; also
PHARMACOGENETICS OF DRUG RESPONSE:
known as MDRI), and multidrug resistance proteins (MRPs) 1,
POLYMORPHISMS IN DRUG RECEPTORS,
2, and 3 (MRPl, MRP2, and MRP3, respectively). Powered by
EFFECTORS, AND ION CHANNELS DURING GROWTH
ATP, these transporters actively extrude substrates from the
AND DEVELOPMENT
respective cell and organ.
Multidrug resistance transporters lead to lower cellular conReceptors are the targets for drugs and endogenous transmitters
centrations of drugs via an efflux mechanism, creating pharmadue to their inherent molecular recognition sites. Drugs and
cologic sanctuaries. In the placenta, MRPl and MRP3
transmitters bind to the receptor to produce a pharmacologic
preferentially transport organic anions, promote the excretion of
effect.
Variability in the receptor protein or the ion channel
glutathione/glucuronide metabolites, and thus prevent their entry
may determine the magnitude of the pharmacologic response.
into fetal blood.
Polymorphisms of the Pz-adrenergic receptor gene (ADRB2)
The first identified active drug transporter of the ATP-binding
have been associated with variable responses to bronchodilator
cassette transporter family was P-gp, which has a wide range
drugs.
of substrates. Abundant in apical membranes, P-gp transports
Drug responses are seldom monogenic events because multiple
substrates in an outward (extracellular) direction. P-gp can be
genes
are involved in drug binding to the pharmacologic target
detected in placental trophoblasts during the 1st trimester of
and the subsequent downstream signal transduction events that
pregnancy, suggesting that it may play an important role in proultimately manifest as a therapeutic effect. Although genotypes
tecting the fetus from amphipathic xenotoxins.
at a particular locus may show a statistically significant effect on
In an attempt to reverse multidrug resistance in solid tumors,
the
outcome of interest, they may account for a relatively small
the use of cyclosporine, an inhibitor of P-gp, has been shown to
amount of the overall population variability in that measure. A
increase tumor concentrations of daunorubicin, vinblastine, and
particular group of SNPs in the corticotropin-releasing hormone
some other antitumor agents. Correlation has been repeatedly
receptor 1 (CRHR1) gene is associated with a statistically signifshown between high expression of P-gp and tumor resistance to
icant
improvement in forced expiratory volume in 1 sec, but
anticancer therapy in both children and adults. The complexity
accounts for only 6% of the overall variability in the response to
of these systems can be shown by cases of children with
inhaled corticosteroids (see Chapter 143). A series of subsequent
retinoblastoma in whom high expression of P-gp was reversed by
studies determined that allelic variation in several genes in the
the administration of cyclosporine, but who were still resistant
steroid pathway contributes to overall response to this form of
to chemotherapy in the presence of high expression of MRPs. The
therapy.
ubiquitous expression of the MDRl gene has led researchers to
The listing and classification of receptors is a major initiative
try to link its levels and the function of P-gp to failure to achieve
of the International Union of Pharmacology (IUPHAR). The list
adequate intracellular levels of chemotherapeutic agents in cancer
of receptors and voltage-gated ion channels is available on the
cells.
IUPHAR
website (http://www.iuphar-db.org). The effect of
High expression of different ABC transporters, including BCRP
growth and development on the activities and binding affinities
(breast cancer-resistant protein), MRP2, MRP3, MRP4, and
of these receptors, effectors, and ion channels remain to be
MRP5, has been correlated with response to therapy in childhood
elucidated.
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
CURRENT AND FUTURE APPLICATIONS FOR
lead to the possible development of specific drugs to overcome
PHARMACOGENOMICS IN PEDIATRICS
multidrug resistance.

W MC

The potential importance of

age-related development of ABC transporters has been documented w ~ t hP-gp. D ~ g o x ~1snel~m~nated
by the renal tubular cell
by P-gp. Neonates need only a fract~onof the we~ght-adjusted
dose of d ~ g o x ~glven
n to older ch~ldrenor adults. P-gp also transports a varlety of other compounds, lnclud~ngv~nblast~ne,
verapam~l,cyclospor~neA, and daunomycln. H ~ g hexpresslon of P-gp
at a young age may lead to a protective mechan~smIn whlch both
endogenous and exogenous toxlns are efficiently excreted from
the body. P-gp, MRP1, and MRP2 act synerg~st~cally
w ~ t hCYPs
to protect the organlsm agalnst potent~ally t o x ~ ccompounds.
W ~ t heach havlng ~ t sown spec~fic age-dependent expresslon
throughout k~dneydevelopment, they may prevent the body from
obtalnlng the des~redtherapeutic concentratlon.
Digoxin serves as an e x ~ ~ l l e example
nt
of the ontogeny of renal
elimination by P-gp.The drug is excreted by glomerular filrradon, bllr 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

- 1

The best example of the application of pharmacogenomic principles to pediatric drug therapy is the progress being made in the
treatment of ALL (see Chapter 495). Despite improved understanding of the genetic determinants of drug response, many complexities 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. Pharmacogenetic polymorphisms of several additional genes also have the
potential to influence 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 subgroups of patients who will tolerate specific 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 pharmacogenomic research. Gene expression (microarray) studies in ALL

Chapter 57 rn Principles of Drug Therapy rn 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-specific and could
accurately discriminate among the 4 treatments. ALL cells of different molecular subtypes shared common cellular responses to
treatment, suggesting that it may be possible to personalize treatment strategies in ALL.

AmpliChip CYP45O test. Med Lett Drugs Ther 2005;47:71-72.

Blake MJ, Casrro L, Leeder JS, et al: Ontogeny of drug metabolizing enzymes
in the neonate. Semin Fetal Neonatal Med 2005;10:123-138.
Chen N , Aleksa K, Woodland C, et al: Ontogeny of drug elimination by the
human kidney. Pediatr Nephrol 2006;21:160-168.
CYP3A and drug interactions. Med Lett Drugs Ther 2005;47:54-55.
Drug interactions with grapefruit juice. Med Lett Drugs Ther 2004;46:2-4.
Eliasson E: Ethnicity and adverse drug reactions. BMJ 2006;332:11631164.
Evans WE, McLeod HL: Pharmacogenomics: Drug disposition, drug targets,
and side effects. N Engl J Med 2003;348:538-549.
Freund CL, Gregory DF, Clayton EW: Evaluating pharmacogenetic tests. Arch
Pediatr Adolesc Med 2004;158:276-279.
Gasche Y, Daali Y, Fathi M, et al: Codeine intoxication associated with ultrarapid CYP2D6 metabolism. N Engl J Med 2004;351:2827-2830.
Goldstein JA: Clinical relevance of genetic polymorphisms in the human
CYP2C subfamily. Br J Clin Pharmacol2001;52:349-355.
Haga SB, Burke W: Using pharmacogenetics to improve drug safety and efficacy. J A M A 2004;291:2869-2871.
Hines RN, McCarver DG: The ontogeny of human drug-metabolizing
enzymes: Phase I oxidative enzymes. J Pharmacol Exp Ther 2002;300:
355-360.
Hines RN, McCarver DG: Pharmacogenomics and the future of drug therapy.
Pedtatr Clin North A m 2006;53(4):591-619.
Johnson JA, Lima JJ: Drug receptorleffector polymorphisms and pharmacogenetics: Current status and challenges. Pharmacogenetics 2003;13:
525-534.
Kim H, Neubert JK, San Miguel A, et al: Genetic influence on variability in
human acute experimental pain sensitivity associated with gender, ethnicity
and psychological temperament. Pain 2004;109:488-496.
Koren G, Cairns J, Chitayat D, et al: Pharmacogenetics of morphine poisoning in a breastfed neonate of a codeine-prescribed mother. Lancet 2006;368:
704-705.
Leeder JS: Pharmacogenetics and pharmacogenomics. Pediatr Clin North Am
2001;48:756-781.
McCarver DG, Hines RN: The ontogeny of human drug metabolizing
enzymes: Phase I1 conjugation enzymes and regulatory mechanisms. J Pharmacol Exp Ther 2002;300:361-366.
McLeod HL, Marsh S: Pharmacogenetics goes 3D. Nut Genet 2005;37:
794-795.
Need AC, Motulsky AG, Goldstein DB: Priorities and standards in pharmacogenetic research. Nut Genet 2005;37:671-681.
Shah J: Criteria influencing the clinical uptake of pharmacogenomic strategies.
BMJ 2004;328:1482-1486.
Tucker G: Pharmacogenetics: Expectations and reality. BMJ 2004;329:4-6.
Wall AM, Rubnitz JE: Pharmacogenomic effects on therapy for acute lymphoblastic leukemia in children. Pharmacogenomics J 2003;3:128-135.
Weinshilboum R: Inheritance and drug response. N Engl J Med
2003;348:529-537.
Weiss ST, Litonjua AA, Lange C, et al: Overview of the pharmacogenetics
of asthma treatment. Pharmacogenomics J 2006;6:311-326.
Wilkerson GR: Drug metabolism and variability among patients in drug
response. N Engl] Med 2005;352:2211-2221.
Williams DG, Patel A, Howard RF: Pharmacogenetics of codeine metabolism
in an urban population of children and its implications for analgesic reliability. Br J Anaesth 2002;89:839-845.
Witzman FA, Grant RA: Pharmacoproteomics in drug development. Pharmacogenomics J 2003;3:69-76.

rrlnclples or

urug I nerapy

.Galt
a d lkhad.10,

The use of drugs requires a clear understanding of the predetermined 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 combined to deliver drugs in the correct amount to the desired site
to achieve the correct action while avoiding unwanted toxicity.
I'rrniiplrc a p p l ~ t ' dinclude p h ; ~ r ~ r ~ a c c r k ~ ~ p
~c
l lrai crhr .l ~ a c ~ > d y ~ ~ : t ~ ~ ~ ~ c

~ I ~ ~ ~ r ~ ln~~~c~t r~r ~~ l>~rrid

t i ~, ~ lI I~I I sI I~~ J~~ I~O I. I ~ ~ : c l -35
l ttic t , i c r o r ~
that influence 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
L

rlic rrlc,iw

t,t rhc. p.lrcllr

~c\mpo[~~
.~frc.r
i c l Illtr'lvc.nollc

d r ~ .~I L ~yI T I I I I -

L ~ U ~ I I, [IO",,. Drug di5rrihutinn r l ~ r c , ~ r g l i o urhc

r Ixrcly 13
I I I ~ ~ L I liv
VIIC
L ~1rlct!
~ J ot' d r i ~ g - \ p ~ ~p -l ~~ yt ih~~ o ~ . l ~ ~t ;. ~~c~[ ~o ri \c, : ~ l
I I I C I L I L I I I I ~[liik role o t Jrug r r L ~ l i s p o r t t - r \~, ~ I ( I ~ ~ ~ ~ p/ r o~ tIc m
~ ~ I I c

I\tr.trlc>li

I ~ I I I L I I I I ~ ..111ci I>looJ J I I Jtlssui. pH nnd prrtu\rtln.

blctaholi\m
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 (hepaticlbile, exhalation). Most drug
metabolism takes place in the liver via hepatic enzymes, although
other organ systems are sometimes involved. Excretion or secretion of drugs involves not only the kidneys or liver, but also
removal of drugs by extracorporeal systems, such as dialysis,
hemofiltration, 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 clinical 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 concentration 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 efficacy and
safety profile) can be obtained (Fig. 57-1). Pharmacodynamic
profiles may involve the parent drug, active metabolites, or some
combination.
T l ~ rI i r i t l ~ i ~ grh.ar drug rcs';ponses iajl llc iriHurncrcl I>! the
1l.it1t.11[', g ~ ' l l C t 1profile
~
has otfri-ed pl.cat l i o p r tur r r i l l i z ~ n g
iwr < : I I J ~ I CiIh. ) .
p . ~ t ~ ~ , r l [ - < p ~ri ,l ~
t iri ~ c t r l>h.lrrn.~corl~cr;~p!
d

\ILILII~'LI o t \ I T I ~ ~ ~ - V~~ T~ I I. IIR CI I ~;lnJ

\
~ n u l r i ~ > l r - g c n1I~rcrrliIluns
r
II.I\.-c Llcrcunlcnrcli thsir rntlucnce o n rhe rnannrr a n ~ rxrrrlt
l
trl
drug metabolism, the susceptibility of certain patient groups to
drug response or toxicity, and the genetic profiles of patients who
benefit most from selected therapies (see Chapter 56). Genetic
polymorphisms occur in at least 1% of the population. Impor-

332

. .
PART VII

Pediatric Drug Therapy

Gastrrc a t ~ dsetretion
Gastric emptylng tlme
lntest~nalmot~lity
M a r y function
Microbial flora
-

Reduced
Decreased
Reduced
Reduced
Acquiring

Normal
Increased
Normal
Normal
Adult pattern

Normal
Increased
Normal
Normal
Adult patt

influences of age when developing an optimal, patient-specific

drug therapy strategy.

Increasing

Drug concentration

Figure i 7 - I . Drugs w ~ r ha narrow therapeutlc index (drug A, solid lines) vs a

wide therapeutlc index (drug B, dashed lznes). Note rhat a drug w ~ t ha narrow
therapeut~cIndex is Inore l~kelyto cause toxlcity at serum concentrations
needed to obtain an adequate rherapeuric response, whereas a drug with a
wide therapeutic index 1s unlikely to cause toxicity at concentrations needed
for an adequate therapeutic response.

tant cytochrome P450 (CYP) drug-metabol~zlngenzyme genes

associated wlth drug response Include the phase I enzymes
CYPlA2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and
CYP3A4, and the phase I1 enzymes N-acetyltransferase, urldlne
dlphosphate glucoronylrransferase, and glucose-6-phosphate
dehydrogenase (see Chapter 56). Polymorph~smsresponsible for
cl~n~cally
Important ~nterpatlentvarlabll~tyIn patlent response to
drugs metabol~zed by polymorph~cally expressed CYP lsoenzymes have been described for CYP2C9 and CYP2D6. In addltlon, some drug transporter protelns control drug efflux from
cells (P-glycoproteln, multldrug resistant protelns [MRPs] 1 and
2), lmpart drug resistance to cancer cells and lnfectlous agents,
and Influence drug dlstrlbut~onto varlous parts of the body (placenta, central nervous system [cerebrospinal flu~d]).
Chronobiology, chronopharmacology, and chronotherapeutics
Involve the study of clrcadlan rhythms and tlmlng of drug doses
on pharmacolog~ceffects. Optlmal tlmlng of certaln drug doses
can affect the efficacy or toxlclty of drug therapy. Thls has been
particularly Important In asthma, hypertension, Hz receptor
antagonlst therapy for peptlc ulcer dlsease, and cancer

am~noglycosldeclearance as a marker of the patlent's glomerular

filtration rate.

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, sirategies
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 technique 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 xenobiotics 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 gastrointestinal motility. These physiologic processes reflect a clear, but highly
variable dependence on a patient's 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 adequate. 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 influence the accuracy of the drug dosage actually delivered.
Solid dosage forms (tablets, capsules) must dissolve into solution

08 A@EM
m
Peiliamia cpcoqpamb a
b r a d range d ages ar which certain stages of lifk robundly
h l f k p &g
~ W O W #d
0-d~ P L d aetie, p h c o d y n a m i q and gsychoswh4 c k g e s t wcw as
p~~~ret~wasdterm,asi~sma~oduriagthe
1st few yr of li@;and as &ldm r~achpub* a ~ adokcme.
d
<3 rno fetus
To meet the needs of these d~fferentp e d ~ a t r ~groups,
c
d~fferent
formulat~onsare needed for drug dellvery that can Influence drug
absorption and dlsposltlon, and d~fferentpsychosoc~al Issues
Influence compl~ance,tlmlng of drug admln~stratlon,and reactlons to drug use. These addlt~onalfactors must be cons~deredIn
conlunct~onwlth known pharmacok~net~c
and pharmacodynam~c

Term gestation
4-6 rno
12 mo
Puberty
Adult

92
75

itage of total body we~ght

65

35-44

Chapter 57 w Principles of Drug Therapy w 333

before the drug can cross cell membranes. Most drugs administered to infants and young children are available in a liquid formulation, including some as a suspension. In general, the rate of
absorption is faster after administration of a liquid dosing formulation (liquid > suspension) compared with solid formulations
(capsule 2 tablet > sustainedtdelayed-release tablet). Drug interactions 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, intravenous 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 flow rates are low, especially <l/hr, as is
often the case in small infants or fluid-restricted patients. Even
with the "smart pumps" designed to reduce drug administration
problems, the rates of drug errors may not significantly change
due to poor nursing compliance with pump specifications. 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 characteristics of a drug in the body is important when selecting the dose.
Although the distribution volume (Vd),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 Vd of a drug is important when selecting an
initial loading dose or designing an optimal dosage regimen to
attain a preselected target concentration. The Vd for a number of
drugs is influenced by patient age and can differ markedly among
newborns (premature vs full-term), infants, and children compared with adults. These differences are the result of many important age-dependent variables, including the composition and size
of body water compartments, protein-binding characteristics, and
hemodynamic factors, including cardiac output, regional blood
flow, and membrane permeability. The absolute amounts and
distribution of body water and fat depend on a child's 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 Vd in infants and children.
The extent to which a drug is bound to circulating plasma proteins directly influences the drug's distribution characteristics.
Only free, unbound drug can be distributed from the vascular
space into other body fluids and tissues, where it binds to its
receptor and stimulates a response. Drug binding to plasma proteins depends on a number of age-related variables, including the
absolute amount of proteins available, their respective number of
available binding sites, the affinity constant of the drug for the
protein, the influence 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 influences its Vd and body clearance (Cl) as well
as the intensity of pharmacologic effects.
Albumin, al-acid glycoprotein, and lipoproteins are the most
important circulating proteins responsible for drug binding in

plasma. The absoiute con~em~ation

of these proreins is inRuenoed
by age, nu~tion,and disease. Basic drugs bind df
to
albumin, q-acid glycoprotein, and lipoprotein, w b s acidic
and neunal compounds bind primarily to albumin. Senrm
dbumin and total protein concentrations arc d
d duriag
infancy, approaching adult values by the age of 10-12 mo. A
similar parnrn of maturation is observed with al-acid glycopmtein; co-tions
appear to be approximately 3 times lo- in
neonatal plasma compared with maternal plasm, achieving
values comparable to those of adults by 12 mo of age.
Several endogenous substances present in human lama may
bind to p l a proteins
~
and compete for available rug-biidhg
sites. During the neonatal period, free fatty acids, b i i b m , and
2-hydroxybmu,ylglycinecompete for albumin-binding sites and
influence the multant balance between free and bound drug w n -

centrations. Clinically significant protein-binding displacement

reactions occur only when a drug of high potency is >80-90%

protein-bound and has a small Vd.The requirement for all 3 of
these variables-high potency, extensive degree of protein
binding, and a small V c f a r a clinically relevant drug-protein
displacement reaction explains why such reactions are unusual in
pediatric praaice. It is prudent to assess a drug's potmiat for displacement of b h b i n from protein-biding sites before its
administration to premature and newborn idants.
For some drugs in which the unbound ponion of the drug may
be measured to guide clinical d d o n s , it is important to consider sample handling, because changes in sample temperamre or
pH can markedly alter results, affording false values and exaggerating unbound drug concentrations. In addition to protein
binding, drug transporters, such as P-glycopmtein, MDR1, and
MDR.2, (multidrug mis~ance1 or 2) play an important role in
drug distribution. These drug transporterscan markedfy influence
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 bloodbrain 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 parameter clearance (Cl), or body C1. A drug's body C1 is the summation of all clearance mechanisms involved in removing that
compound from the body. The prhary organ for d ~ mtabog
lisrn is rbe liver, although the kidney, inresthe, lung, adrenais,

blood (phosphatascs, esterases), and skin can also biommform

certain compounds. For most drugs (Iipophilic weak acids or
weak bases), biotransfonnation to more poiaq water-soluble
compounds facilitates their elimination from the body &rough
the bile, kidneyyor lung. $lchough the biotrdomation of most
drugs results in pharmacoiogically weaker or inactive cornpounds, parent compounds may be transformed into active
metabolites or intermediates (theophyiline to caffeine, carbamazepine ta 10,llcarbamazepine epoxidef, Conversely, pharmacobgically inactive parent compounds, or prodtugs, may
be converted to a~ acdve moiery (chloramphenicoi succinate
to active chloramphenicol base, cefuroxime axetil to active
cefuroxime) before subsequent biotransformation and body
elimination.

Drug metabolism within the hepatocyre involves 2 primary

enzymatic processes: phase I, M fl~nsynthetic,and phase it, or
synthetic, reactions. Phase T reactions include oxidation, reduction, hydrolysis, and hydroxylation d o n s , whe~easphase rT
rations primarily involve conjugation with glycine, glucuronide, or sutfate. Most drug-metabolizing enzymes are toEa&d
in the smooth endoplasmic reticulum of cells. Of WE mixedfunction oxidase system, the CYP450 system has been smdied
in greatest detail. The CYP450 enzyme system is a supergene

334 rn PART VII rn Pediatric Drug Therapy

famiiy, with at least 16 primary enzymes and a number of

isozyrnes of specific gene families. The sp~ificsubfamilies, or
isozymes, most responsible for human drug metabolism involve
CYPlA2,CYP2C9, CYPZC19,CYP2D6, CYP2E1, and CYMA4
(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 activiry of these oxidizing enzyme
systems is reduced. which is refleckd by prolonged body elimination af drugs that depend on oxidation pathways in newborns
(phwytain, caffeine, diazepam, and many others). Postnatally,
the heparic CYP mono-oxygenase enzymes appear to mature at
different rates; for example, CYPlA2 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 6-12 mo of age. An understanding of the substrates for specific isozymes and the effects certain drugs may
have on isoenzyme activity (induction, inhibition) allows the clinician to predict the possibility of clinically important metabolicbased drug-drug interactions (see Table 56-2). These are so
numerous that the potential for significant interactions with
current therapies should always be checked in a database before
new drugs or diets are recommended for the patient. Most pharmacies use electronic databases that can screen for such interactions, and many electronic drug resources available to prescribers
offer a basic list. Commonly prescribed medications in pediatrics
linked to the specific CYP isoenzymes responsible for their metabolism with clinically important CYP inducers and inhibitors are
shown in Table 56-2.
The activity of certain hydrolytic enzymes, including blood
esterases, 1s also reduced dur~ngthe neonatal period: Blood
esterases are Important for the metabolic clearance of cocalne,
and the reduced actlvity of these plasma esterases In the newborn
may account for the delayed metabol~smof cocalne in neonates.
Because el~mlnat~on
of metabol~tesIS reduced in preterm and
full-term Infants, accumulat~onof actlve metabolites that are not
considered clin~callyrelevant In older Infants, children, and adults
may occu 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 normally metabolized before elimination, but in preterm infants with
irnmarure 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 underected if only theophyllme concentrations are monitored.
Understanding che sequence of macuration of processes of drug
metabolism is important when developing dosage recommendations for drugs that undergo extensive hepatic metabolism. An
example of he consequences of failing to appreciate these
processes is the tra~edvthat occurred after the administration of
kual doses of chlok&henicol (75-100 mglkgl24 hr) to premarure and newborn infants (fatal gray baby syndrome) and the
resultant beneficial use of this compound in the same patient
population when the dose was appropriately adjusted (1550 m w 2 4 hr) to compensate for the decreased hepatic ability
for glucuronidatjon. Chloramphenicol glucuronide is the primary
metabolite of chloramphenicol, which is then excreted through
the kidneys.
The ultimate ability of children to metabolize drugs is genetically modulated. Pharrnacogenetic predisposition to slow drug
metabolism along certain enzymatic pathways can provide
imporrant clues to patients who are at risk for drug roxicity. The
polymorphc characteristics of the important human drug-metabolizing GYP isoenzymes are shown in Tables 56-1 and 56-2.

DBUB EXglomerulus per

The amount of drug that is filtered by the

unit of time depends on the functional ability of

the glomerulus, the integrity of renal blood flow, and the extent
of drug-protein binding. The amount of drug filtered is inversely
related to the degree of protein binding. Only free drug is filtered
by the glomerulus and excreted. Although highly variable, renal
blood flow averages 12 mLlmin at birth, approaching adult
values by 5-12 mo of age (see Chapter 508). The glomerular
filtration rate is 2-4 mL1min in full-term infants, increases to
8-20 mLImin by 2-3 days of life, and approaches adult values by
3-5 mo of age. Before 34 wk of gestation, glomerular filtration
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 concentration at any time after a dose is administered and can facilitate calculation of a drug dose to achieve a desired concentration.
Recognizing that the pharmacologic and toxicologic effects correlate best with a drug's concentration in a biologic fluid (blood,
cerebrospinal fluid), 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 resultant 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, salicylate, 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 saturated. Such drugs are often referred to as following the principles
of zero-order (or Michaelis-Menten) kinetics. The classic principles of elimination half-life (tIl2)and C1 do not apply to drugs
that exhibit zero-order kinetics.
PHARMACOKINETIC CALCULATIONS AND BOLUS DOSING CONSID-

ERAnONS. In the event that therapeutic drug monitoring is available, calculation of individuaIized pharmacokinetic parameters is
feasible. When this is not practical, age-appropriate, populationbased 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 (tissudreceptor)
concentrations rapidly. To do this effectively, a dose can be calculated using the h o r n relationship between the dose, the drug's
volume of distribution (V*),and the serum concentration
ach~eved.T h ~ srelationsh~pis described by:
Dose (mg/kg) = (~,,~/kg) x change in serum concentrationdesired( m g / ~ )

Where population values are known, this is a practical way to

determine an appropriate loading dose. If the volume of distribution of caffeine is 1 Llkg and the target concentration is
10 mg/L, then the loading dose of caffeine base is 10 mg/kg:
Dose mg/kg = (1.0 L/kg) x (10 mg/U = 10 w / k g

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,

Chapter 57 w Principles of Drug Therapy

the actual caffeine citrate dose needed to achieve a target serum

caffeine concentration of 10 mg/L would be 20 rng/kg.
This same principle can be used to adjust a specific dose
regimen to achieve an alternate serum drug concentration. For
example, a patient's serum caffeine concentration is 10 mg/L, but
the desired target serum concentration is 1 5 mg/L. Using the same
calculation:
Dose (mg/kg) = (1.0 L/kg) x (15- 10 = 5 m g / ~=) 5 mg/kg caffeine base

The Vd can also be applied as a physiologic marker for certain

diseases. For example, a gentamicin Vd of >0.7 Llkg has 92%
specificity for physiologically significant patent ductus arteriosus,
even when it is clinically silent.
It is apparent from the relationship described by the formula
relating Vd to dose and drug concentration that drug elimination
from the body, or drug clearance (CI), does not influence 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 fluids
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
doselbioavailability.
MAINTENANCE DOSING CONSIDERATIONS. The elimination halflife (tlI2)of a drug is the time required for any given concentration in blood (or other biologic fluid) to decrease to 'I2 of the
initial value, or the time required for 'I2 of the amount of drug
present in the fluid to be cleared. The tlt2 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 tl12
depends on both the C1 and the Vd of the drug. A more useful
formula for tlI2,which reflects these important relationships, is:

A change in tlI2does not necessarily reflect a change in the body

C1 of a drug. This dependence of t1t2on Vd is exemplified by the
influence of extracorporeal membrane oxygenation (ECMO) on
drug disposition. For most drugs, ECMO-induced changes are
due to an increase in drug Vd (volume present within the apparatus) rather than a change in drug C1. Despite this important
distinction, the tl12is often used clinically to adjust dosing intervals, primarily because it can easily be calculated in the clinic or
at the patient's bedside. The tltz of a drug can also be used to
determine the time necessary to achieve the steady-state concentration, 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 steadystate 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 tlt2of a drug is often used
to determine a drug's 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 reflects the amount of drug removed
or eliminated from the body per unit of time, whereas renal Cl
reflects the amount of drug cleared by the kidneys per unit of
time. Total body Cl is the summation of all C1 mechanisms for a

-.

given drug (C1,,,,1, ClhepatLo

Cllung).The body C1 can be calculated
as:
CI =

(0.693)(Vd)

t1/2

with the preferred mathematical method of: drug doselplasma

drug area under the concentration-time curve where the dose is
cnrccired fur h~nnvailabiliry.
tinowlrdg~.of a cirug's C:l is tunltamenral 2nd n necessity when
dercrmin~rigthe J o s r tor J drug a n d how often its dosc must hr
rcpc.~rcclt o rtldiritain a givet~icrum concentri~rion.I t i s rhc most
1rnp)rtiant pllar'm;ic(>kinztic parameter for cirtrrin~ning the
,re;~ily.\t;itrdrug c o n s e n t r ~ r j o nfor a #]\;endose raw. Cliallgrr in
org.111tl~nctronrllar affect the rcrnoval of a drily tronr tlie I,ndy
,ire* rctlcitril a\ 1
' sli3ngr in rhr drug's C1. A drug's t ~ d C:l
y is
t y Irlood flow arid the frrnctic~iralal,~lir\;
rntlucnircl h!. rhc ~ n r e ~ r ioi
(,i rlic oryalih involved ~ r rrzmovirig the drug f r o n ~rl~chod?.
l)~ni~ntshecl
drug C.l can he uscd as an imporrant marker of comI ~ r o ~ ~ i rjryaI1
~ w ' d f~rncrionin situarir)ns sucll as per~natalasphy-iia
or progreshlvr rcn,~lor liver d v s t u n c t ~ o r ~a .n d 1 ~ 1 31jc~ uicd t o
prolilpt other d ~ i ~ g n o s t trstb.
ic
When (11 IS known anrl 3' target
steady-state srruni concentration [C:,.,j is rlercrminetl, tlie malntcn.lrice do.;e 114D)can be cslcul;~redhy the formula:
MD (mg) = C,, (mg/L) x (1 L/hr) x dosing interval (hr)

Again, it is important to correct for bioavailability by dividing

the calculated MD by bioavailability.
lNDlVlDUALlUTlON OF DRUG DOSE. The clinical response to an
ac*eer3~ror usnd recommmdrd dose of drug cat1 van. ionsidrr,iIil>, even ucllrn rhr J o s r i s atlrn~nisteredrelative tu a p3rirntX
IIOLIY \ ~ r ~ l g sh l~~, r t i area,
~ ~ r anil srage ( ~maturation
i
(scr C:h.rpter
5 .I
v r ~ r ~ tI Si ~r i
of i n t r i i i ~ dittrre~iics
l
in drug
pharn~,tcol;rr~t~trcs
anil ph,irmasoJynani~ssnrld a rluniber n t hioIo51i \'.~rr.lhlrs,~ncludrnggeneric ditfrrenccs in drug rilctaholisrn
or d i - I I reieprnrs,
~
2 n J ioncllrrcnt patllophysi~jlogyo r thc presvnir ot enzyrrlr-1nhrbrt111clr mryn~r-induein):drugs. Ind~vidual
\,lr~.rllilrr!- ~ r i t hrt.Fpect to d r ~ r gefficacy and possihly toxicity irecli~rr~tly
nrirsslratcs thr adi~lsrmrntd dosagc rcgi~ucnsfor speittii p,ir~rnt\,rspei~allytor drugs with J low rhernpruric index.
For >omc clrugs. thc dose rnay he ndiustcd ~ c c o r d ~ nIOp the
j~;rncrrr" rn1n1rdi~3re.lnJ readrl! quantihable clini~.alrrsponsr. Fur
other tlrugs. clos;lpc acljust~uentmay t)c. guided mure ;ipproprl.3tcl\ Iiy s o r n b ~ n ~clinic:il
n~
rccponsr with measuronlcnt of rhr
~oliienrr.ltlorlol' drug In plasln;~or srrum. Such a11 approach to
rherdjly I S often cnllrtl a target concentration strategy, where a
c1r11~'iph.lrn~aiologii or tosrcologic rsspon'ir car) bc riirectl!!
rrl.~tedt o .I specitic scrurn c o ~ i c ~ ~ i t rr31igc.
~ r i o I~t ~is irrrporrsnr to
r r i o ~ r l l z cthnt the rhcr:~pruricrnrlgrs Jr3cril~ctlfor Jrugr rctlect
.I corlriri~rrin~
of concrntr~ltlorls,~l~)n.q
which ir~cre;lsingprrcrntages of patients can be expected to have a clinical response and
toxicity (pharmacodynamic curves), and it is the tradeoff between
benefit 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
tor r h ~ soptlrn~tltareer L-onccnrratiorl~tr,~teg!,.
K r l w ~ - t e ~thcrapcutii
l
cnncentra~ilw r.3riges for h u g s arc
d
tjt
usu,illy d r t r r n l ~ n c dfrom stuciics of only a l ~ r n ~ r rnumhrr
,
tlirse thrrapeuirc rangcs represrnr 311
plrlcnrs, rnocrl\ ~ i i u l r s:lnJ
ayrragt. (nlr,rr~/value; therefore, not all in the poplhatiol~will bc
enio~npassedw i r h ~ nrhr 1 srandard deviations th;it surro~rrlclthis
mrnn \ , a l \ ~ rT'htrs,
.
cliniial monitoring of scrulrl drug concentratior~s5erves o11Iy ac ,I p u d c to ph~rrmrcnlogizirlrrrventiun arid
d(.)scadiustrncnt. lirrum drug cor~ientratior~
values must tw Intrrpri.rrJ inciividu.lllv. One patlerir may h3vr a complerc clin~cal
response when thr wrum conzentrnrion of drug S 1% within the

336 rn PART VII w Pediatric Drug Therapy

"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 requite a serum drug concentration above
or below the reported therapeutic concennation range to achieve
the same degree of positive therapeutic response. Toxicity may
limit how much above the therapeutic range the senun drug concentration may safely be raised. Therapeutic ranges for serum
drug concentrations serve only as guidelines for therapy. Drug
efficacy must be assessed by rhe clinical response,
Serum drug concentration-time values or profiles may also be
compared with previously determined patient-specific values or
literature repom 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 suspected. More commonly, determination of a drug concentration
in biologic fluid helps n, achieve an optimal therapeutic regimen
while reducing the likelihood of drug toxicity. Finally, determination of a drug concencration in a biologic fluid provides a
mans to assess the influences, if any, of a disease process or drug
interaction on a drug's disposition profile.
Therapeutic drug monitoring is not appropriate, necessary, or
practical for all drugs. Drugs with well-de6ned and easily recognizable and monitored pharmacodynamic effects do not warrant
routine monitoring (diuresis with diuretics, lowering of blood
pressure by an antihypertensive). For therapeutic drug monitoring" to be of clinical value. a clear concentration-res~onseor
concentrat~on-toxicityrelationship should be identifiable. Patient
age and the extent or severity of disease can influence the
relationships among drug concennation, efficacy, and toxicity.
A clear relationship between a specific serum drug concentration and effect is available for only a limited number of drugs
in contrast to the large number of drugs with 'recommendedn
therapeutic ranges.
A number of variables should be considered when designing
strategies to monitor therapy using a serum drug concenuation.
When measuring a drug's concentration in blood, the phamcokinetic 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 postdisuibution peak
drug concentration. ~ h u sa, lag time often grists between the-time
of drup. administration and the time that is recommended to
obtain:he peak blood sample. Most clinical determinations of
drug concentrations in biologic fluids routinely measure (report)
the total drug concentration in that fluid:
Free drug concentration +concentration of drug bound to protein =
total drug concentration

This approacb assumes a constant ratio of free to bound drug

a t various concentrations and under differing pathophysiologic
conditions, which may not always be true; thus, caution must be
exercised in its extrapolation. Cliiically important imbalances
between free and total drug concenaations have been observed
with the drug phenyroin in critically ill trauma patients and in
patients with severe renal dysfuncrion. As a result, many laboratories report both free and total serum concentrations of drugs
or have these results available on request. Despite these differaces, it is unusual for an imbalance in this ratio to be clinically
significant,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, hdudmg the flow rate of
the primary intravenous fluid, the dead space of the system into
which the drug is injected, and tbe total volume in which the drug
is diluted. Because most standard intravenous fluid delivery
systems, including their tubing, are designed for adult use, they
contain a large volume per unit of length, This introduces a relatively large dead space factor, which causes substantial infusion
delays when operated at the slow flow 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 intravenous 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 "flush" an intravenous dose; standardization of specific infusion techniques (infusion duration,
volumes) for drugs with a narrow therapeutic index; standardization of dilution and infusion volumes for drugs given by intermittent intravenous injection; avoidance of the practice of
attaching lines for drug infusion to a central hub with other solutions infused concurrently at widely disparate rates; preferential
use of large-gauge cannulas; maintenance of the recommended
solution at a specified 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 intravenous line.

MJWRW INTERACVOWS. When 2 or more drugs are administered to the same patiem, the pharmacokinetic and pharmacodynamic properties of each agent may be modified by their
interaction. Drugs may interact by a number of mechanisms classified on the basis of pharmaceutics, pharmacokinetics, pharrnacodynamics, or a combination thereof. These interactions may
result in unpredictable clinical effects or toxicologic responses.
Pharmaceutic interactions include those resulting in drug inacrivation when compounds are mixed together physicalIy before
patient administration, as with the use of syringes, infusion
tubing, dialysate solutions, or parentera1 fluid preparations.
Pharmacokinetic interactions can occur when the disposition
characteristics of 1 compound (absorpaon, distribution, metabolism, excretion, or a combinarion thereof) are influenced by
those of another. This type of interaction may involve 1 or more
aspects of the pharmacokinetic profile of the drug. Dm 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 whenever 2 compounds compete for the same metabolic site (see
Table 56-2).

Drugs &iy interact pharmacadynamically and compere for the

same receptor or physiologic symern, thus altering a patient's
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 cticically 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 extenr into their milk and may
be ingested by the nursing infant (see Chapter 94). Although drug
use should be as minimal as possible during (pregnancyand) lactation, it is not possible or desirable for lactating women to stop
taking needed medications. There are very few drug contraindications for maternal use during lactation. Although a drug m y
distribute or concentrate in breast milk, the a m a l infant dase

337

Chapter 57 m Principles of Drug Therapy

INTERACTIN' ""NT

.;
. ,. ADVERSE EFFECl
I

..
I

INTERACnNG AGE#
Cimetidlne
Nonsteroidal anti-~nflammatory
Potassium
Spironolactone

''

Hepatotoxicity
1'Anticoagulation
1'Acetaminophen toxicity
Granulocytopenia

CARBAMAZEPINE
Anticoagulants (oral)
Antidepressants (tricyclic)
Cimetidine
Contraceptives (oral)
Corticosteroids
Cyclosporine
Erythromytins
Influenza vaccine (viral)
lsoniazid
Phenytoin
Theophylline
Valproate

? Narcotic toxicity?
Lethargy

? Toxicity
1'CNS depression (acute)

I'
;
,-.

1'CNS deoression

1=* I

~isulfiram'effect
1'CNS depression
J Antibiotic effect
1'Hepatotoxicity
Disulfiram effect
Impaired coordination
1'Phenytoin toxicity

J Allopurinol absorption
Rash

1'Anticoagulant effect

1'Azathioprine toxicity
1'Cutaneous hypersensitivity

'

? Cyclophosphamide toxicity
? Theophyll~netox~city
7' Allopurinol toxicity

I!

1'Nephrotoxicity
1'Ototoxicity
?

I -7Nephrotoxicity

L
I

1'Nephrotoxicity
1'Nephrotoxicity and ototoxicity
1'Neurornuscular blockade

I
I
I

? Blockade
1'Nephrotoxicity?

J Absorption
J Absorption
.1Absorption
.1Absorption
h Absorption
.1Absorotion

Diaoxin

J ~bsorbtion

-1Absorption
J Absorption
J Absorption

Absorption
J Absorption
1'Toxicity

..

'

;1

--

111.:

-3
-1

1'Bleeding

.1Antihypertensive effect

DIGOXIN
Antacids
Anticholinergics
Cholestyramine
Cimetidine
Diuretics (hypokalemia)
Phenytoin
Quinidine
Verapamil

I
-I

..

J Anticoagulation
J p Blockade

1'Production of carbamazepine epoxidi

1' Barbiturate toxicity

.: -I1

.1Contraceotion
.1Steroid effect
q: 1'Barbiturare toxicity

.-

-.I
I

Barbiturate effect
J~heophyllineeffect

, ,,

1'Barbiturate toxicity

1'Pulmonary toxicity

r-

1'Cutaneous hypersensitivity

', .,,y

'.'IYA
I

_.

I$

..,
=

?i

CONTRACEPTIVES (ORAL)
Anticoagulants (oral)
Antidepressants (tricyclic)
Barbiturates
Carbamazepine
Griseofulvin
Penicillins (ampicillin,oxacillin)
Phenyto~n
Rifarnpin
Theophylline
CYCLOSPORINE
Alkylating agents
Aminoglycosides
Amphotericin B
Carbamazepine
Erythromytins
Furosemide
Ketoconazole
Metoclopramide
Nafcillin
Phenytoin
Rifarnpin

-.,.

-*

ClMFllDlNE
Alcohol
Antacids
Anticoagulants (oral)
Antidepressants (tricyclic)
Benzodiazepines
pddrenergic blocking agents
Captopril
Carbamazepine
Digoxin
Ketoconazole
Metoclopramide
Phenytoin
Theophylline

- I l l
L.

ERYTHROMYCINS
Anticoagulants (oral)
Astemizole (Hismanal)
Carbamazep~ne
Cyclosporine
Phenytoin
Terfenadine (Seldanel
Theophylltn~

ADVERSE LFFECT
Neuropathy

.1Antihypertens~veeffect
Hyperkalemia
Hyperkalemia

.1Anticoagulation
~ ' T O X I C I (both
~~

drugs)

7' Carbamazepine toxitity

4 Contraception
Steroid effect

-1 Cyclosporine effe
1'Carbamazepine toxicity

1'Carbamazepine toxicity
1'Toxicity (both drugs)
$ (arbamazepine effect
J ~ h e o ~ h ~ l leffect
ine
Valproate effect
'?Alcohol effect
J Cimetidine effect
7' Anticoagulation
1'Anridepressant toxicity
? Benzodazepine toxicity
1'p-Blockade toxicity
Neuropathy
1'(arbamazepine toxicity
1'Digoxin toxicity
J Ketoconazole absorption
h i m e t i d i n e effect

d, Anticoagulation

CF

? Antidepressant tok11'1~~

Contraception

J Contraception
Contraception

.1Contraception?
J Contraception
J Contraception
1'~heo~hylline
toxicity

zy

1'Nephrotoxi

7' Nephrotoxicity
? Nephrotoxicity
Cyclosporine effect
toxicity
Gout
7' Nephrotoxicity
1'(yclosporine toxicity
J Cyclosporine effect
$ Cycloiporine effect
k Cyclosporine effect

1'(yclosporine

.1Absorption

7' Digoxin tox

-1 Absorption'

I'r'

::

.1Digoxin effect
'T' Digoxin toxicity

I I

1' Digoxn tox I

1'Digoxin toxicity

'

Digoxin

7' Anticoagulation

1' Astemizole toxicity,arrhythmias

1'Cdrbamazepine toxic~ty
? (yclosporine t o x i
J Phenytoin effect

c p

1'Terfenadine toxicity arrhythmia'

1'Th~nphyllinetoxlilrv

338 r PART VII m Pediatric Drug Therapy

ADVERSE EFFECT

UOROQUINOLONES
[acids
?ophylline

11,*

'

IITERA(T1NG AGENT

.
.

Neuromuscular blocking agents

Nifedipine
Quinidine
Rifampin
Theophylline

Antibiotic effect
1'Theophylline toxicity

'

I
,

f -l

ticoagulants (oral)
ntraceptive (oral)
INIAZID
ohol

I .
I

-- - - -

IlFFnFlllVlN
.. . .... '

Anticoagulants
k Contraceptive

Valproare
QUlNlDlNE
Amiodarone
Anticoagulants (oral)

Hepatitis
4 lsoniazid absorption
1'Toxicity (both)
-1 Ketoconazole effect
f Phenytoin toxicity
? Hepatotoxicity
1'Hepatic and CNS toxicity

.III

t~".,"<
~ridc

bamazepine
toconazole
enytoir

I
I

tacas
ticoagulants (oral)
netidine
-1osporine
niazid
-1
enytoin
Hilampln

Barbiturates
Cimetidine
Digoxin
Metoclopramide
Phenytoin
Procainamide
Rifampin
Verapamil

Absorption

1'Anticoagulation

RlFAMPlN
Anticoagulants (oral)
Barbiturates
P-Adrenergic blockers
Chloramphenicol
Contracept~ves(oral)
Corticosteroids
Cyclosporine
lsoniazid
Ketoconazole
Phenytoin
Quinidine
Theophylline
Verapamil

.1Ketoconazole effect

1'Nephrotoxicity
1Ketoconazole effect

I I

Altered metabolism of both drugs

1'Effects of both drugs

1'Toxicity
?' Methotrexate tox~c~ty
? Hepatoroxiclty
? Methotrexate toxicity

platin
etinate
nsteroidal anti-inflammatory drugs
..nethoprim/sulfamethoxazole
METOCLOPRAMIDE
,bamazepine
netidine
,
:losporine
I

'Oxin
rcotics

= ,'-

FEDlPlNE
:
r-Adrenergic blockers
I ,-I
(yclosporine
Phenytoir
a
Prazorin
11.l
Quinidine
- .I J

''

-, .

PHENYTOIN
II Alcohol
_ .I. I
tacids
1
ticoagulants (oral) !
ttdepressants (tricyclic)
.bamazepine
I
onmphaicol
(imet~d~ne
(ontraceptives (oral and implant1
.ticosterods
if':
~~closporine
II Digoxin
Dopamine
1
Folicacid
I I n i l
/
- I
lsoniarid
Miconazole
-

:' ,,

'

-'Ir
I

1'1oxicity (acute)

i
I

!' I
I \
I
I ; '
,

1'Phenyto~ntoxicity

1 1

,,

Interferon
Marijuana smoking
Phenytoin
Rifampin
Tobacco smoking
boleandomycin
TRIMETHOPRIM/SULFAMETHOXAZOLE
Anticoagulants (oral)
Antidepressants (tricyclic)
Mercaptopurine
Methotrexate

.1Phenytoin effect
5 Phenytoin toxicity, 1'L anticoagulation

I
1

Carbamazepine
Cimetidine
Erythromycins
Fluoroquinolones
Influenza vaccine (viral)

Hypotens~on
.1Quinidine effect

'

.1Quinidine effect
.1Phenytoin effect
.1Effects (both drugs)
1'Phenytoin toxicity

'r

1'Quinidine toxicity
f Anticoagulation
.1Quinidine effect

1'Quinidine toxicity

1'Digoxin toxicity
.1Quinidine effect
.1Quinidine effect
1'Procainamide toxicity
.1Quinidine effect
Hypotension

.1Anticoagulation
.1Barbiturate effect
d p Blockade
J Chloramphenicol effect
.1Contraception
.1Corticosteroid effect
.1Cyclosporine effect

.1Carbamazepine effect
f Toxicity (both drugs)
'? Phenytoin toxicity
.1Contraception
.1Corticosteroid effect
.1Cyclosporine effect
.1Digoxin effect
Hypotension
J Phenytoin effect
1'Phenytoin toxicity
Phenytoin effect

1'Hepatotoxicity

.1Effects (both drugs)

.1Phenytoin effect
.1Quinidine effect
JTheophylline effect

JVeraoamil effect

I Th~@phyllist!liixirity

? Tl11:~1~nyliineri,xititv
? Tri?npfl:ill~iieioririlv
1'Dirophy!liv :nxLi.ity

1'T o ~ ~ ~ I I Y '

1Theophylline effect
.1Effect (both drugs)

Theophylline effect

.t Theoohvlline effect
?~heobh;lline toxicity

? Anticoagulation
Depression
Antileukemia effect
Megaloblastic anemia

VALPROATE
Barbiturates
Benzodiazeplnes
Carbamazepines

1'Phenobarbital toxicity
1'D~azepamtoxicity

Cimetidine
Ethosuximide
Phenyto~n

1'Valproate toxicity?
? Ethosuximide toxicity?
? Phenytoin toxicity

J Valproate effect

"When possble,an alternate drug iombinatlon rhould be qlven If nor poss~ble,druqlevels and slqns of toxicity must be monitored
Modified from Rizatk M, Hillman ( The Medical Letter Handbook ofAdverre Drug lnlerocrionr New Rochelle,N~TheMed~calLetter, 1989

received (volume of milk consumed), combined with &e drug's

bioavailabiiiy (in the infant) and the amount of drug (over the
feeding periods), usually negates any clinically rrlevanr effects in
the breasr-fed infant. If a question exists about the amount of
drug a brast-feeding infant may be receiving or about ~ossible
drug effects in the infant, a sample of the mother's milk can be
analyzed. Up-to-dare and spec& information abour breast milk

THEOPHYLLINE
Barbiturates
0-Adrenergic blockers

Heart failure,atrioventricular block

1'Gingival hyperplasia
1'Phenytoin toxicity

I l ! , I1 I

..

' '

Neurotoxicny
Cimetdine effect
1'Cyclosporine toxicity
-1 Absorption
1'Sedation

.;'

-If.

, -

Megaloblastic anemia

.1Blockade

1'Phenytoin toxicity

dlstrlbution of medications and the amount a nursing Infant

would actually recelve (absorb) can be obtalned by consulting a
cllnlcal pharmacylpharmacology service.

PRESCRIBING MEDICATIONS. Factors such as taste, smell, color,

consimcy, dosing frequency, and cost affect the degree to whlch
patients comply wlth their therapeutic drug reglmen. Prescribing

I
I

Chapter 58

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. Complete 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 accidentally 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 poisoning or improper self-medication at a later date. Patient medication instructions on the prescription should state the specific
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
refilled should be noted on the prescription label; if no refills are
to be permitted, this should also be specified on the written
prescription.

COMPLIANCE WITH THE PRESCRIBED REGIMEN. Little is known

about the many factors that determine the degree of compliance
with a physician's instructions, but many patients frequently do
not take medication consistently or in the manner intended or
prescribed. Patients frequently take home remedies or medications that are not recommended or prescribed by their physician.
A child's 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 child's illness, the action of the medications prescribed, and
the importance of following the instructions precisely. Compliance with the therapeutic regimen is improved when the instructions 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). Collaboration between the prescribing physician and the dispensing pharmacist 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;17:281-299.
Bjorkman S: Prediction of drug disposition in infants and children by
means of physiologically based pharmacokinetic (PBPK) modeling:
Theophylline and midazolam as model drugs. BT J Clin Pharmacol
2004;59:691-704.
Carr RR, Ensom MHH: Drug disposition and therapy in adolescence: The
effects of puberty. J Pediatr Fhamacol Ther 2003;8:86-96.
Eichelbaum M, Ingelman-Sundberg M, Evans WE: Pharmacogenomics and
individualized drug therapy. Ann Rev Med 2006;57:11.1-11,19.
Johnson TN: The development of drug metabolising enzymes and their influence on the susceptibility to adverse drug reactions in children. Toxicology
2003;192:37-48.
Kearns GL, Abdel-Rahman SM, Alander SW, et al: Developmental pharmacology: Drug disposition, action, and therapy in infants and children.
N Engl J Med 2003;349:1157-1167.
Paul IM: Advances in pediatric pharmacology, therapeutics, and toxicology.
Adv Pediatr 2005;52:321-365.
Stephenson T: How children's responses to drugs differ from adults. Br J Clin
Pharmacol2005;59:670-673.
Waters MD, Fostel JM: Toxicogenomics and systems toxicology: Aims and
prospects. Nut Rev Genet 2004;5:936-948.

Poisonings H 339

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 reflect the propensity for
children in this age group to put virtually anything in their
mouths.
hlorc. t h ~ n90?, ui [oulc expusurcs In i h ~ l i l r r noccur 111 thc
homr. rid most involvr only ;I sirlgle substance. Ingesric>n IS r l ~ r
11104r cotiirii~111
route oi poisoning rxposurt- i7"'L uU casril, with
and ophthslniic rclutrs acioilnring for
the J ~ * r m ; ~inhalatltrr~,
l,
. ~ ~ ~ r c , x ~ m a7.5'?;1,
t r l y 6'4,. dnd j?:,of cases, reapritivcjy. !Ippror~ll~,lrclyio"i, nt cases rnvolvs nurldrug suhsranccs, *uch as
iulnmon ho~lscliold produits (cosmetics. persorial care iterns,
ilc,tri~ngsoluurrni, planrh. tnre~gnborlirs, liydrr>iarhonh). P11;lrnlaicuttial prcpnr;ltiuns comprlw the r c ~ ? i ~ i n d ewith
r , analgesisr.
couch .IIIC~ cold p r o d u c r ~ ,.~nriniicrobralagents, a n d virarn~nbthe
niocr irvnt-rlorl c a t r g o r ~ r sI. h e s e nrr pruducts thilt are iam~liilrro
>,r)lingchildren: In acidrrion, rhcy are rlsually n ~ a n ~ ~ t a c t u irl rl d
\tiu,lllv appcalilig and grcar-tasting forrnulatiuas. More rhari
S S o , , ot pedrarriL po15011ing ruposurrs can hr ma~iapellu~ithout
~iirccrt i ~ ~ d i c ai nl r r r v r ~ ~ r i o nbecause
,
rirher thr prr~ductillv~)lvrd
I, not ~nhrrcntly very tovlc or the quanrlly of the m ~ ~ t e r i a l
~nvolvccl I \ not s u t h i ~ e ~ ltor produce clinically relevant roxic
~l
r l t c i ~ <iThllle 58-11. Dc:~rli J u r ru u n i n ~ c n ~ i o n ryolsoi~illp,
i r ~\,,i111g cliil~lrcn 1s urlirlmmon uw111g t o lricreascd prtducr
\,itrr\ rnr.,l\urt-s iclltld-rt-srsranr p a i k a g i n g ~ incrrased
,
p u i ~ prrr ~
\ ~ I I I I ( O IC~C ~ L I ~ ~ I I I ~ earl!
ITI.
recognition of csposurc, i~~rprt>vrnlt.nra
111 ~ i i c A ~ c .nicjn:ljirmerl[.
~l
anrl the ~ v a ~ l a h i l ~oft y 14 hrtclay. 7
J.ty!\rk 800 numhcr ai<rss ro rrgirmally hasrd pcrixon cor~trol

centers.
I'olscrn prevention rJuc,irion bhould be a n irlregral part r l i all
\tell ;li~ldvibitb, even brfort. a child ib luobilr. C(lunscl~ngparrIlts
.~nii I-~rlisrz'Iregl\-zr\ about potrntisl potsonlng r~qks,huw rrl
"poison-prtwt" .I ihild's cnvironnlcnr, and what to c f t ~i t a pniwnlng OL'iUri C f i r n i r ~ ~ ~rllr
h c ~likelilir>oJ r l i scrious ~r~urhidit!or ~ i i ~ ~ r t iron1
a l ~ r ,111
~ esptrsurr. I'oison prevcntlon ed~lcatlonal
r~l.lrc*r~.llr
.Ire a v . ~ ~ l a h lI'rurn
e
br~rh rhc American :4iade111y 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 office visits and
annually thereafter. The sharing of this toll-free number with
grandparents, relatives, and caregiver programs is also highly
desirable.
I'otstrntr~g csposurrs in c-hil~lren b-12. yr o t agr are mush
1 t . i common, in\,olving approximatelv 6'!1~ nt all ped~atric
I ' Y ~ O ~ L I K ' ; . 'lbxic exposures tn adolcssrnrs arc primarily intcnI ~ L I I ~ I C I C .ilj~iw)
.
o r o c i ~ t p a r i o n ~l'rdiatrici;a11~
l.
should he
t~c~n.il
. i ~ . . ~ r0t1 - rlii' sipis ot drug :~buse o r suisiddl idearion in thts
pup11l;irtoil
,lnJ should .~ggrrssivi-lyIntervene. Ped~atrlcfaral~tirs
.
.
.~trer,I j>ui\on~ngerposurr ;Ire must common In adolcsccnrs.
I\.IIII b. l o o I I the
~
1.26 1 tdt:~lit~rs
reported to the TESS program
l r t 21)i).io c ~ u r r i n
irr~ 1 1-1 9 y r old parirj~tssornp:lrrci wirh 1.9%
In ih~lclrenh vr old ur youngrr a n d 1.0% in childret~6-1 J yr IIC
age.

340

PART V I I rn Pediatric Drug Therapy

Abrasives
Antacids, non-salicylate-conta~ning
Antibiotics,topical
Antifungals, top~cal
Ballpoint pen ink
Bathtub floating toys
Bath oil (unless aspirated)
Body condit~oners
Bubble bath soap
Calamine lotion
Candles (beeswax or paraffin)
Caps (toy pistols,porassium chiorate)
Chalk (calcium carbonate)
Children's toy tosmet~cs
Clay (modeling)
Orai contrateptlves without iron
Cortitosteroids,topical
Cosmetics
Crayons (marked A P o r t P,gel)
Dehumidifyng packets (e g ,siltca)
Deodorants, underarm
Fabric softeners
Fertilizers(no ~nsetticidesor herbicides)
Detergents,hand, dlshwashing
Diaper rash creamslointments
Fishbowl additives
Glow products
Glues and paste
Golf ball (tore may cause mechanical injury)
Grease

ink (black,blue-nonpermanent)
lodophii disinfectants (unless the individual is allergic)
Laxatives
Lipstick
Lozenges (wlthout anesthetics)
Lubricating oils (unless asp~ratedi
Magazines
Markers, porous tip
Makeup
Matches
Mineral oii (unless aspirated)
Modeling compound (Play-Doh)
Newspaper (thron~cingestton may result in lead poison
Paint, indoor latex, water-based
Paints, watercolor
Pencil lead (graphite,coloring)
Petroleumjelly (Vaseline)
Plant food (no insectlcidesor herbicides)
Poiaroid picture coating fluid
Putty
Rubber cement
Shampoo
Shaving creams and lotions
Silica gel
Soap and soap products (nontaustic)
Spackles
Starch
Sunscreen
Sweeteningagents (sactharin,aspartame)
Toothpaste(with and without fluoride)
Warfarin rodentitides (<0 5%)

APPROACH TO THE POISONED PATIENT

The lnit~alapproach to the patlent with a documented or susg&ted pQbb&odd- be no differirrrrhan that inany otfrer sick
child. A &ed history and pbydcel examination sswsas tbe
fouacktim for a r h ~ f ud al p d~and rht
~ fanat i oo
~f arl W prognosis (Table 38-21. The histoxp and physical

ex4\mination&id
nor:await the ca&c$ion .ofbody auld and the
tesulrs of a 30%
sambaToJricoIagylahtory analpeg, or
"qcmwnin fatt 4 t w e lor ,only 4 a s l l a I l of~ ~mara an
H a w k ~~and d y make (va confi4raJ the dkgnoeia
INITIAL PATIENT EVALUATION

P
m W&TQIW. Ob-g
an accurate problem-oriented
W r t a n c e ~f a polsonlng has occurred
hisrory i8 of p-tint
o r Ts wpacrcd. The haowing information should be obtained
dwiq&W*
d
Btoduct names (brand, generlc, chem~cal)
an8 aigdoog*their
concentrations, may be obtained
ffom
h ~ yw a: y brand names that sound a l ~ k ehave

bb&.

volp &&rent iofpedien~,it is impomt M be precise. If dw

qpditnc idbrt6ation is not m d 3 y awikhlc od Be piduct,
ccmsdtatioa wid^ a-on
qmtroY cmtez can M y pro~id~tbis
t&iifwmriQnrapidlb M w P f i a a bu a d in rhe home or m&p b a m k mddPle~c~
Jg mi!yh m n m r i c w g , and

tDie~o6opntroPcenttl.can@de
hfomadon-di
i a g d hgrdients ip the pamcdar mdm &ti well as priodh
possible clinica1 &cts.fxmisdioi&ul i q p x b t s ot n -bC
narim of sqpdmis* F d o x r , most pib and wps* have
madcbqs, inc~u& h m Iamemis, or E
h
D
hand W on these

markings, the poison center may be able to identify the ingredients. 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 difficult, but is of paramount importance
in refining the initial prognosis guiding the initial management
plans. Numerous methods can be used to estimate the amounts

ODOR
Bitter almonds
Acetone
Aicohol
Wintergreen
Garlic
OCULAR SIGNS
Mlosis

Cyanide
lsopropyl alcohol, methanol, paraldehyde, salicylates
Ethanol
Methyl salicylate
Arsenic, thallium, organophosphates

Nystagmus
Lacrimation
Retinal hyperemla
Poor vlston

Narcotics (except mependine), organophosphates, mustarlnic mushrooms,

tionidlne, phenothiazines, chloral hydrate, barbiturates (late), PCP
Atropine, alcohol, cocaine, amphetamines,antihistamines, cycltc antidepressants,
cyanide, carbon monoKide
Phenytoin, barbiturates, ethanol, carbon monoxide
Organophosphates,irritant gas or vapors
Methanol
Methanol, botulism,carbon monoxide

CUTANEOUS SIGNS
Needle tracks
Bullae
Dry, hot skin
Diaphoresis
Alopecia
Erythema

Heroin, PCEamphetamines
Carbon monoxide,barbiturates
Antichol~nergicagents, botulism
Organophosphates,nitrates,muscarinic mushmoms,aspirin,tocaine
Thallium,arsenic,iead,mercury
Boric acid, mercury, cyanide, anticholinergits

ORAL SIGNS
Salivatton
Dry mouth
Burns
Gum lines
Dysphagia

Organophosphates,salicylates, torrosives,rtrythnine
Amphetamines, anticholinergics,antihistamine
Corrosives, oxalate-containing plants
Lead, mercury,arsenic
Corrosives, botul~sm

INTESTINAL SIGNS
Cramps
Diarrhea
Constipation
Hematemesls

Arsenic, lead, thallium, organophosphates

Antimitrobiais,arsenic, iron, boric acid
Lead, narcotics, botulism
Aminophylline, corrosives, iron, saltcylates

Mydriasis

CARDIAC SIGNS
Tachycardia
Bradycardia
Hypertension
Hypotension

RESPIRATORY SIGNS
Depressed respiration
Increased respiration
Pulmonary edema
CNS SIGNS
Ataxla
Coma

Atropine, aspirin,amphetamines,cocaine, cyclic antidepressants,theophylline

Digitalis, narcotics, mushrooms, clonidine, organophosphates, p blockers,calcium
channel blockers
Amphetamines,LSD,cocaine, PCP
Phenothiaztnes,barbiturates,cyclic antidepressants,iron,p blockers,calcium
channel blockers
Alcohol, narcotics, barbiturates
Amphetamines, aspirin,ethylene glycol, carbon monoxide,cyanide
Hydrocarbons,heroin, organophosphates,aspirin

Alcohol, antidepressants, barbiturates,antitholtnergics, phenytoin, narcotics

Sedatives, narcotics, barbiturates,PCForqanophosphates,sal~cylates,
cyanide,
.
.
carbon monoxide,cyclic antideprersants,lead.
Antitholtnerglcs, quinine, salicylates, LSD, phenothiazines, amphetamines, cotaint
Hyperpyrexia
Organophosphates,theophylline
Muscle fasticulation
Muscle rig~dity
Cyclic antidepressants,PCP,phenothiazines,haloperidol
Cotaine,camphor. PCCMSG
Paresthesia
Lead,arsenic, mercury, organophosphates
Peripheral neuropathy
LSD,PC! amphetamines,cocaine,alcohol, anttcholinergcs, camphor
Altered beh$,",
From Kl~egmar
nte KJ,Jenron HB(ed~torr).NeironEssentfohofPediarr~cs,3hedPhtladelph1a,Elsev1er,2006,p205

Chapter 58

Increased sympathet~c
nervous system
activity

Anticholinergic
act~vity

I
I

Pyrexia
Flushing
Tathytard~a
Hypertension
Pupillary constriction
Sweating
Similar tl~nitalpicture to
sympathomimetits
Clinical differences include
pupillary dilation,
dry mouth,
hot,dry skin

.. I,I

increased
'
parasympathetic
nervous system
activ~ty.
cholinergic
crisis

I
Metabolic acidosis

Pup~llarytonstrlction
Diarrhea
Urinary lncontinente
Sweat~ng
Excessive salivat~on
Muscle weakness
Fasciculation
Paralys~s
Lacrimation
Tathyopnea
Kussmaul breathing (sighing
respiration)

'

..,

..

cnemltal
pneumonltl!

tough
.
Respiratory distress
Central nervous system depression
A history ofvom~tingafter ingestion
need not be a feature

Acute ataxla o
nystagmu!

f
-

tyanosis resistant to oxygen therapy

Oliguria or anuria
Hematuria
Myoglobinuria

Renal failure

Violent emesis

Generalized muscle
rigidity
Oropharyngeal paln
and ulcerarionr

i-

I ,

--

Cellular hypox;ap

Ethanol
A a
Carbon monoxide
I
Antifreeze
Iron
I
"
Diabetic medication
Tricyclic antidepressants
Salicyiates
Stoddard solvent (white spirit)
Turpentine
Essential 011s

Seizure-like,generalized muscle contractions

or painful spasms (neck and limbs) and
usually tathycard~aand hypertension
Intact sensorium
Lip, mouth,and pharyngeal ulterat~onsand
burning pain
Dyspnea and hemoptysis secondary to
pulmonary edema or hemorrhage;can
progress to pulmonary fibrosis over days
to weeks
M~ld:Nausea,vomiting,andheadache
5evere:Altered mental status,dyspnea,
hypotension,seizures,dnd metabolic
acidosis
B ~ malmond
r
odor'
Hypocaltemia or hypokalemia

I,

rclpheral neuropathy
andlor
neurocognltive

D~phenylhydanto~n
Barbiturates
Carbon monoxide
Organic solvents
Bromides
Alanine dyes I,

Phenacetin
Nitrobenzene
Chlorates
Sulphonam~desand
metoclopramide ( ~ neonates)
n

Peripheral neuropathy signs and symptoms:

Muscle weakness and atrophy,"glove and
stotkingsensory loss,and depressed or

It/

absent deep tendon reflexes

Neurocognitiveeffects:Memory loss,delirium,
ataxia, and/or encephalopathy
V~sualdlsturbantes, paresthesias,andlorataxia
Delirium and/or per~pheralneuropathy
; Encephalopathy and/or peripheral neuropathy
Severe gastromtes~nal
Abdominal pain,vomiting,profusediarrhea
(possibly bloody),and hypotension,
possibly followed by multisystem organ
failure
Inhalation an additional route of exposure;
severe respiratory illness poss~ble
;;
Hypokalemiacommon
Altered mental status (agitation,confusion,
toma),autonom~instabil~ty(tachycardia,
hyper- or hypotension),hyperkinet~c
neuromustular (tremor,tlonus,
hyperreflexia),mydriasis, diaphoresis,
increased bowel motility
Abdominal tramps,diarrhea, lacrimation,
sweating,"goose flesh," yawning,
tachycardia, restlessness, hallucinations

I.,
.
Antihistamines
Alcohol
.,
Anticonvulsants(especialiy
phenytoinand
carbamazepine)

a;

Methemoglobinemia

Cough and decongestant

preparations
Amphetamines
Cocaine
Ecstasy
Theophylline
Tricyclic ant~depressants
Antlparkinsonian drugs
Ant~histamines
Atropine and nightshade
Antispasmod~cs
Phenothiazines
Mushroom poisoning (Amanita
species)
Cytlopentolate eyedrops
Organophosphate insecticides
Drugs for myasthenia gravis (e g ,
pyridostigmine)
Nicotine
Carbamate insect~tides

~ffects

4.
I

5 rur d tuver~'cnem~cal
release bared on hlrror~cuse (I e, Intentional or Inadvertent u

, high iox~c~ry,anoior
ease or avallaoli

Poisonings a 341

Carbon tetrachloride
Ethylene glycol
Methanol
Mushrooms
Oxalates
Aspirin
Theophylline
Corrosives
Fluoride
Boric acid
Iron
Strychnine

Paraquat*
Diquat
Caustics (i.e.,atids and alkalis)
Inorganic mercuric salts
Mustards (e.g.,sulfur)
Cyanide* (e.g, hydrogen cyanic
gas or sodium cyanide)
Sodium monofluoroacetate
(SMFA)"
Carbon monoxide
Hydrogen sulfide
Sodium azide
Methemoglobin-causing agents
Mercury (organic)'
Arsenic (inorganic)*
Thallium
Lead
Acrylamlde

Arsenic"
Ricin*
Colchic~ne
Barium

SSRls,antidepressants,some
oplolds (mependine),
tramadol,St,John's wort,
MAOIs

Cessation of alcohol, barb~turates,

benzodiazepines,narcotics

!. -

involved; it is better to overestimate than to underestimate. Estimates can often be accomplished by counting the remaining
tablets or measuring the remaining volume of liquid. Whatever
amount is missing and cannot be definitively 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 otherwise. These probable overestimates of exposure provide a safety
margin early during the clinical assessment. Estimates can be

refined as the patient is assessed over time and initial laboratory

data become gvailable. 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 concentration 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
pcrssi ble resolution.
T i r n e , d w , For some products, toxic manifestations may
be dclavcd for Ilr or days. Knowing the time lapse between expo-

342

PART VII

Pediatric Drug Therapy

METABOLIC ACIDOSIS (MNEMONIC = MUDPIES)

Methanol." carbon monoxide
Uremia"
Diabetes mellitus*
Paraldehyde." phenformin
Isoniazid, iron
Ethanol," ethylene glycol*
Salicylates, starvation, selzures
HYPOGLYCEMIA
Ethanol
lsonlazid
Insulin
Propranolol
Oral hypoglycemic agents
Sal~cylates
HYPERGLYCEMIA
Salicylates
lsoniaz~d
Iron
Phenothiazines
Sympathom~metics
HYPMALCEMIA
Oxalate
Ethylene glycol
Fluoride
RADIOPAQUE SUBSTANCE ON KUB (MNEMONIC = CHIPPED)
Chloral hydrate, calcium carbonate
Heavy metals (lead,zinc, batlum,arsenic, lithium, bamuth, as In Pepto-Bismol)
Iron
Phenothlaz~nes
Play-Doh, potasslum chloride
Enteric-coated pills
Dental amalgam
"Hyperormolar condition
From KliegmanRM, Mastdanie Kl,Jenson HB (editors)~NeI:on Essenr~airofPed~amcs,5th ed Philadelphia.Elsewer, p 207
KUB. kidney-ureter-bladder rad~oara~h

sure and the onset of symptoms and/or medical evaluation will

markedly influence decisions about obtaining certain diagnostic
testing as well as therapeutic intervention.
Progressha ot-S
Knowing the nature and progression
of cyrnprorns 15 vsr!- liclpiul for assessing the need for immediate
life \upprtrr. the prognosis, and the type of intervention that may
be nccdcd.

MFMCRL RlmORY. tindcrlying diseases may tilake 3 chrld more

s ~ ~ s c e p t ~ti)
h lthe
c rtfccts of .I tosln. Concurrrnr drug therap!- may
also irlirearc susceptihil~rytwcaust. sert.1i11 drugs may intcract
with rhe toxin. I're~n~lncyis 3 commr~riprecipitating tactor in
l
influence the patient cv,~l~raadolescent .;urcicle JttCnlpts d r ~ c can
ticui and trrarrncnt plan. Ar 6 rno ot agv o r younxrr, rt is very
~rnlthrlyrl~ar; l r i i n f ~ n rsoulrl brcornr acc~dcrit~~lly
rsposrd to a
suftisienr quantrry o f .I potcnrlally Iiarrntul prt)clucr in rhr ~ b s c n i c
trt other rxtr.incnus f ~ c t o r sthat require Further ~nvesrigatron
(social c.rlvrrt~nmrnri.

DEMOBRAPHlC 1NFI)WTION. It is parri~ulgclyh p o w t to

obtain dentographic idonnarion regarding thc patient and the
calla Ob-gthe
c a l k ' s filephow number and m e t ad*
is mportant for follow-up and also to allow far dispatch af
emergency personnel if telephone contact 1s disrupted.

change in the ~atient'scondition may alter the decision to remain

at ho>e. ~ h e i i m i n gof follow-up calls depends on the type and
extent of the exposure, combined with a number of clinical variables, including the expectation for when symptoms would begin
to occur and progress. Usually, it is advisable to initiate the 1st
follow-up call 0.5-1.0 hr after the exposure to detect any symptoms that may manifest if the timing, nature, andlor amount of
exposure were different than initially thought; a 2nd follow-up
call should be made 1-3 hr after the first. 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

4, DNgS,AwKiatedwitf~M a j j Modes of Presentation

- - ......- .. ..........- --

. . ........

4mphetamine
Antiarrhythmics
Anticholinergics

Antihistamines
Arsenic
Carbon monoxide
Chloral hydrate
Cocaine
Cyanide
Cyclic ant~depressants
Dig~talis
Freon
Phenothiazrnes
'hysostigmine
'ropranolol
Qu~nine,quinidine
Theophylline
CAUSES OF COMA
Alcohol
Antlcholinetqics
~ntihistami'es
Barbiturates
Carbon monoxide
Ilonidine
Lyanide
:yclic antidepressants
dypoglycemic agents
Lead
Lithium
Vethemoglob~nemia*
Methyldopa
Narcotics
Phencyclidine
Phenothiazlnes
Salicylates
COMMON AGENTS CAUSING SEIZURES (MNEMONIC = CAPS)
Camphor
tarbamazeplne
Carbon monoxide
Cocalne
Cyanide
Aminophylllne
Amphetamine
lnt~cholinergics
4ntidepressants (cyclic)
Pb (lead) [also lithium]
Dest~c~de
(organophosphate)
'hencyclidine
Phenol
Phenoth~az~nes
Propoxyphene

INITIAL MEDICAL CARE

If the patient is managed at home, follow-up assessment calls
should be made at varying times after exposure because any

'Causes of methemogiobinemia.amyl nitrite, aniline dyes, benzota~ne,b~smuthrubntrate, dapsone, prlmaquone,quinoner,

sp~nach,sulfonamider
Fr0mKliegmanRM,MascdanteKl,JensonHB(editors):Ne/sonEssenhairofPed1air1cs,5thedPhiladelph1a,Elsevier,2006,p208

Chapter 58

N-Acetylcysteine (Mucomyst)
-Aterylcysteine (Acetodote)

II

Atropine

BAL ~noil (dimercaprol)

Benztroplne (Cogentin)
Cyanide antidote kit

Dlgoxin-specific
Fab antibodies (Digibind)

DMSA, Chemet)

DTA,calcium (calcium disodium,

Versenate)

Acetaminophen, carbon tetrachloride and

chloroform (experimental)
Acetaminophen
Organophosphateand carbamate pesticides,
bradycardia due to atrioventricular
conduction defects,!.-blocking agents
Arsenc,mertury,other metals
Acute dystonic reactions
Cyan~de
Hydrogen sulfide (nitrites only)

Digitalis glycosides (synthetic or natural)

Lead and probably mercury,arsenic,and

perhaps other metals
Extrapyramidal symptoms,acute dystonic
reactions,allergic reactions
Lead, manganese, nlckel,zlnc,and perhaps
chromium
Methanol, ethylene glycol

'lumazenil (Romaziton)

'omepizole (Cmethylpyrazole,
Antizole)

Ethylene glycol, methanol

Siucagon

p Blockers,calcium channel blockers,

hypoglycemic agents
Methemoglobinemia

Wethylene blue
Yaloxone (Narcan)

3ttreotlde
'hysostigmrne (Anrilirium)

Narcotics
tlonldine (inconsistent response)
Sulfonylureas
Anticholinergic agents

Iralidoxime (2-PAM,Protopam)

Organophosphate insecticides

'yrldoxine (Vitamin B,)

lsoniazid,Gyrom~tramushrooms
Ethylene glycol (investigational)
Carbon monoxide

3xygen

,,,g/kg loading,followed by 70 mglkg q4h for

17 doses
150 mglkg over 30-60 min,followed by 50 mglkg over
4 hrs,followed by 100 mglkg over 16 hrs.
0.05 mglkg repeated q5-10min as needed;dilute in
1-2 mL of NS for ET instiilation
3-5 mglkgldose q4hr,for the 1st day;subsequent dosing
depends on the toxin
0 02-0.05 mglkgldose qd or bid (max,4 mg)
Amyl nitrite: 1 crushable ampule; inhale 30 sec of each min
Sodium nltrite:0.33 mLlkg of 3% solution if hemoglobin
level is not known;otherwise, based on tables with
product
Sodium thiosulfate: 1.6 mL (400 mg)/kg of 25% solution;
mav be reoeated everv 30-60 mln to max of 50 rnL
lnfusioi of 15'mglkglhr imax,6 9/24 hr)
IM. 90 mslkqldose 48h [max, 6 ql24 hr)
1 vial binds 0.6 mg of digitalis gl;tos~de;ingested dose
may be estimated from the serum level (see
table wlth product)
10 mglkgldose q8h for 5 days,then 10 mglkg q12h foi
14 days
5 mglkg divided q8h;max,300 mgl14 hr

1V

Nausea,vomiting,allergic reactions

IVIET

Tachytardia,dry mouth, blurred vision, urinary retention

Deep IIVI

Local injection slte pain and sterile abstess,nausea,

vomiting,fever, salivation, nephrotoxcity
Sedation, blurred vision,dry mouth,tachycardia
Methemoglobinemia
Methemoglobinemia

IVIPO
Inhalation
IV

IV
IV(preferred)
iM

Hypotension (minimized by avoiding rapid infusion rates)

Allergic reactions (rare), return of condition being treated
with digitalis glycoside
Nausea and vomiting, repeated courses may be needed
Sedation or paradoxical agitatlon,ataxia
Nausea,vomiting,fever, hypertension, arthralgias, allergic
reactlons,local inflammation,nephrotoxicity (maintain
adequate hydration)
Nausea, vomiting, sedatron, add falare for methanol

750 mglkg loading dose followed by 80-150 mglkglhr

infusion of 5% or 10% ethanol
0.2 mg over 30 sec;if response is inadequate, repeat qlmin
to 1 mg max

Nausea,vomiting,facial flushing,agltation, headache,

dizziness,seizures, do not use for unknown or
antidepressant ingestions
Note. May not reverse respiratory depression
Infuse slowly over 30 min, increase doses to q4h tf dialysis
18 concurrent
Thiamine and pyridoxine may be helpful
Hyperglycemia,nausea,vomiting

15 mglkg load; 10 mglkg ql2h for 4 doses, 15 mglkg

ql2h until level is <20 mgldL
No specific dose for children
0.05 mglkg bolus followed by infusion of0.05 mglkglhr

Nausea, vomiting, headache, diulness

0 1-0.2 milkg of 1% solution by slaw infusion;rnay be

repeated q30-60min
0.01 mg1kg;if no effect,give 0 1 mgikg;may be repeated
as needed; may give continuous infusion
1-2 pglkg q8hr
0.02 mglkg by slow push;may repeat q5-l0min to 2 mg
max

Acute withdrawal symptoms if given to addicted patlents

lVilM
IV
Inhalation

IVISC

to and monitor poisoning exposures. If the patient requires hospital treatment, the probability of life-threatening symptoms dictates the mode of transportation used (see Chapter 63). After a
decision to transport a patient is made, emergency department
personnel should be notified 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

Poisonings a 343

PO

1-1.5 glm2124 hr in divided doses ql2hfor 5 days

25-50 mglkg over 5-10 min (max,200 mg1m1n);canbe

repeated after 1-2 hr, then qlO-12hr as needed
lsoniazid,dose = dose of ironiazid
Mushrooms:25 mglkg
loo%, hyperbaric

Used in addition to high-dose glucose;may add glucagon

Bradycardia,asystole, seizures, bronchospasm,vomit~ng,
headache
Note-Do not use with cyclic antidepressants
Nausea, diainess, headache, tachycardia,muscle rigidity,
bronchospasm (rapid administration)
Uncommon
Half-life of carboxyhemoglobin 18 5 hr in room air, bur
1 5 hr in 100% 0, and 15-30 min ~n3 atmosphere
hyperbaric
Monitor prothrombin time;give fresh frozen plasma for
acute b1eeding;repeat vitamin K for superwarfarin

primary emphasis an catdiampkatory care. Initial treatment of

s h d , dysthythmias, and seizures isgenerally the same as for any
other critically iU patient (see C b a p 66).
~ Only a s d number
of antidotes exist for only a few poisons (Tables 58-6 and 58-7),
underscoring the importance of thoughtful, b e I y institution and
maintenance of supportive measures, combined with close, contlnuous cl~nrcalmonltorlng.
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).

344

PART VII

Pediatric Drug Therapy

1 ANTDI OTES

lorroderrusantivenin
Botulinantitoxin
Glucagon andlor insulin and glucose
Diphenhydramineandlor benaropine
Cac
lu
i m salts
Prolamine
Fol~nicacid
Crotab-specific fab antibodies

Black wd
i ow spider
Botulism
Cac
lu
i m channel antagonists
Dystonic reactions
Fluoride,calciumchannel blockers
Heparln
Methotrexate,trimethopr~m,
pyrimethamine
Ratlesnake envenomation
%dimchannel blockade (tricyclic ant~depressants
y,pe 1
antiarrhythmits)

Prompt action to remove the toxin and minimize contact with

the absorptive surface is crucial and may prevent the development of major toxicity. Dermal and ocular decontamination can
be accomplished by flushing the affected area with tepid water.
Flushing for a minimum of 1 0 min is recommended for ocular
exposures, although some chemicals, particularly alkaline corronl,iy rcc~urrrrnucli longer pcrloJ\ o t tlushlng. fltteirive
o ~ l l l d 1rrig.ltio11
r
cdrl he lnsr~rl~r'd1,) p o \ l t l o n l r l ~
rrhe patlent'!, t ~ i c
i
i ) t repd w8.tter
uider .I tauicr T O ,~llo\v rnllri ( n o t l o r ~ e t u l\tream
to 1111 tlic \IJC~ >[ ht e rlow and irre.1111 ,lcro\\ thc cyc 2nd dokvn
the il~eel\.It I\ prtrlulll\ advi~.il>lcto prevent the Irrlgarlori tlu~lf
t r o n ~tlluulng trorri I rye dcro\5 to rhr other 2yc. I t i\ hrrtrr to
irrigare I cyc tor 2tl-itl \ e i ; ~ n dthrlr to \ w ~ t i hto lrrlg,ltin!: t h c
(7thc.r ~ f t r . i r r cvc,
~ l .IIIJ $0 torill, tor approxiniarcl\ IO min. For
d c r i ~ i expo\urcs.
~~l
coy~ou\Irrrsatlon. tollo\\:r~lI3y .I n i ~ l Jio,ap
F .~ r rinh.1lr.d rolrnh. drconi,~min,~~~trrl
I\ <Gcn\vasl~.wrl Ilc ~ ~ s c d
n i o v ~ ~(he
i g patient to
c.~..lll!. aciomplicl~cci\1111pl\h! 111111ird1.ltel>Frrsh .ur an~l.~t nrbri.s\,~r-y.atim~nrstcr~ng
oyygrn. Irl n L l ~ l ~ t ~too n
sl\el.

.I

supportive care, a few specific antidotes are used for some specific inhaled toxins.
Several procedures are used to prevent absorption of an
Ingested toxln from the stomach and gastrointest~naltract, and
each has l ~ m ~ t a t ~ oand
n s r~sks.The decls~onto use one particular method over another should be based on whether the technlque chosen 1s l~kelyto be of sufficient value to merit the risk of
ihc proccdurc. 7 ~ n i I ~
\ .In 11n11t.lr111n
~
h t ~ ~ ~m.ln\
l \ c to\111\ '1rt

usual dose administered to a child represents the maximum

tolerated dose. Airway reflexes 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 sorbitol, a cathartic. Flavoring may be added to improve palatability, 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 fluid loss and dehydration. Approximately
2 5 % 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 activated charcoal is more serious than aspiration of gastric contents
alone. If charcoal is given through a gastric tube, placement of
the tube should be carefullv confirmed 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 2 4 hr)
is recommended by some toxicologists for the hospitalized poisoned patient at a dose of approximately 0.25-0.50 glkg every
2-4 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 constipation or intestinal imtlaction. The ~ r i m a r vbenefit 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 nasoeastric
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 aspiration. If the patient cannot tolerate a bolus dose of activated
charcoal via the nasoeastric
tube. the charcoal dose can be
u
administered as a slow continuous drip ( ~ 0 . 2 5glkglhr).
Cathartics. Cathartics have been used in conjunction with activated 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 cathartics 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.

t
r ~ p ~ atl\clrl,ccl
d l ~
trcrn~the \torn,l~li \Y'~th the c.\ceprIr)n ( ~ orall\
isec A c r l ~ ~ t c(d Ii,~rco,tll.
~ d m ~ n ~ x r r r.t~
cc
i t ~ ~ a tLh.lrccr.~l
cil
~ I c c o ~ ~ r ~ l n i i ~pl.orcriurr
~ . l t i ( , i ~ inbt~rurrilahcr the L~~LII: 1 5 ahsorbc~i
po\c.i ~ I E Lto tht~patirr~t\ c ~ r l in o potrnti,~l tor henclit. h l o \ t
I I L ~ L I ~ dr~1.c p r o c l ~ i c t"re
~ a l ~ n i ~ si ~
t ) l l l ~ l i t t . ahsorhcd
ly
thin
3 0 4 . T ni111 0 1 I I I ~ ~ \ ~ I ~ I T~I , n mo\r
~ l r o l ~ d do\age torrn, ;Ire
nbstrrl~t.cl \ v i r l ~ ~1-2
n hr. \krIir.n a I.lrgr ovrrclo\c involve\ sol~il
drr\r t(lrrii\ ir,lhlrt\, powder-tillrd i;lpst~lcs~,
cc~mplsrc~nrcst~rlal
alhorprion i d 1 1 Ilc L]cld\ed h~ ,I\ much
;-(7
hr. anti for drug,
o r toxilns i l ' i t l l dntiihol~~leryc.
~ i ~ i t c ~\low~n,qi
r ~ ~ l ~proprrtlc\,
l
drugs drc
al)st)rprio~~
c..ln I>rdrl,~!-ecl I?!. LIP to 8- I 2 hr. C.c.rr'~~ri
prcd~sposcclti, hci.ir,ir tormntion. \vIi~chnili\r ,ll.;o Ilr ~ o n \ ~ d c r r . ~ l

.I

.I

in the formulation of the patient's initial decontamination and

trrbarmvtlr ~?I.ln\(T,~LllcFS-SI. \Y:li~lrl>ezoari arc rarr. .I hc.7oar
p;ltlent \ v l i i ~h,lr \ytilptonl\ d.i!-\ ,ltrr.r
choulJ hi. \urpcctcrl 111 ~ r i y

..
IDS
\luminumhydroxide

dULK-FORMINGLAXATIVES
Combination laxatives (e g., Perdiem)

Psyllium
EXTENDED-RELEASEPRODUCTS
Nifed~pine
Protainamlde
Verapamil

ION-NCHANGE RESINS
s\.~nl-rtomi.
.~pp.ircii~
i(rmplerc re\olurioll of the a~scri~arcd
Sodlum polystyrene sulfonate
k h W d 1:\n ~ f t c i t ~ \rllran,
i.
fo drcl.r.tsr or prcieiir
Cac
lu
i m polystyrene sulfonate
~ a tc\v clr~rgs.lnd roulls a\ \veil ;I\
the inrrstinal ~ h m r p r l u rot
VITAMIN AND NATURAL PRODUCTS
rilh.-lncr the r11rnin.lrlorl of ~fri~::i.iIre.lJy .ihsorhcd arid prrscnr
Ascorbc
i ac~d
o f ,lcti\-atc~i
within thc z r i t t - ~ I Li l r i u l ~ l i o nI\ or,~l,~~im~n~strari,,n
Ferrous sulfate
; \ i t ~ v , ~ t r C I~ l i , i r ~ 1o5 ~
\pecl,lll!
l
prcp,lred rtr Iia\,r .i very
CII~IT~O~I.
Lecithin
l ~ r g ei i ~ l \ o r p t i \ -\ ~~ i r t x r.lrcA.l. h l ~ r l \but
~ not all. toxin\ .lrc
OTHER MEDICATIONS
adxi)rhccl o!irr>
s~rrt,~ce.
pre\:crlrlng ,~hcorpr~on
trolll 111s
c r c > i ~ ~ t e \ ri i r~>~~* ~~~ tlC ,~ ? I I L >IOSIIIS.
r 1 1 ~ ~ 1 1 i t l r 1l:~<,,i~,?,
1~
~ ~ ~ i ~
1ro)i.
t ~ / s , Carbamazepine
Cholestyramine
IoI~,t11olt~~~11.1r
r ~ , t , ~ ~b~l(,(.~y/~t
lit111111t1.l . ~ y ~ f r o ~ ~ , ~ r~->*.IIII(~~*,
/ i ~ ~ t z s ,ITZJ
,
Enteric-coatedaspirin
hi)ls. ilrc j7a )I s~,yt~~fic.(~~zfly
IJOIIII~~
to t ~ I ~ ~ r ~ - o ~ i l .
Lithlum
Usually, a dose of 10-50 g (=Ig/kg) for a child and 50-100 g
:alicylic acd
i
1,
for an adolescent or an adult is administered. In practice, the
,ucralfate
:I
-

- --

Chapter 58 w Poisonings

Whole Bowel Irrigation. Whole bowel irrigation involves instilling large volumes (30 mUkg/hr) of a nonabsorbed polyethylene
glycol electrolyte solution (e.g., Colyte, GoLYTELY) into the
stomach to flow 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
~ackers).Whole bowel irrirration
can be combined with the use
"
bf activated charcoal, if appropriate (cocaine body packers). It
should be used with caution in young children because of the
possibility of fluid 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 distribution. These techniques are also invasive and associated with risk.
Certain procedures can be used for very specific agents.
Emesis. The emetic used in the past was syrup of ipecac; it contains 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 20-30 min after dosing,
with vomiting occurring in 90-95% of patients. Several episodes
of vomiting usually occur over a 1-2 hr period. The dose is 10
mL for infants 6-12 mo of age, 15-30 mL for children 1-12 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 6-8 oz of water or other clear fluid, with
the actual final volume age- and child-dependent.
The use of ipecac syrup is not recommended for routine ingestions. Emesis with syrup of ipecac removes approximately 1', 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 (acidslbases), 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 flushing with aliquots
of fluid, usually normal saline. Although gastric lavage was used
for many years, objective data do not document or support clinically relevant efficacy, 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 performed, repeated instillation and removal of small volumes of
lavage solution is generally better tolerated, with less risk of aspiration. 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 fluid 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 efficient at removing toxins, peritoneal dialysis is often easier to perform in young children, and
may be sufficient. Few drugs or toxins are removed by dialysis in
amounts sufficient to justify the risks and difficulty of dialysis.
Examples of toxins for which dialysis may be useful include the

345

toxic alcohols, methanol, and ethylene glycol as well as large

symptomatic ingestions of saliqlates, theophylline or lithium.
Hemoperfosim 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, theophylline, and a few other selected agenm. 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 confirming the diagnosis and
formulating the treatment plan. For most intoxicants, qualitative
measurement is not possible or likely to change treatment. Examples include opiold toxicity, in which definitive treatment is based
on symptoms, not serum drug concentrations, and cyanide, in
which treatment must be started rapidly and would be significantly delayed if the clinician were to wait for hboratory coofismation. Comprehensive, qualitative "drug screens" vary widely
in their ability to detect toxins and generally add little infonnation, particularly if the agent is known and the patient's symptoms are consistent with that agent (see Tables 58-3 to 58-5). If

a drug screen is ordered, it is important to know the specific h g a

that can be identified 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 fluid, urine is generally the best fluid 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 toxicologist, or a laboratory technologist and to provide appropriate samples and clinical data so that the most appropriate tests
can be performed and properly interpreted.

SELECTED COMPOUNDS COMMONLY INVOLVED IN

PEDIATRIC POISONINGS
Acetdnopfim is the most widely used 4
6
gcsic and antipyretic in pediatrics, p r h d y Qtle to the h d h g of
s)tadromc and saliqia~s.Cowa relationship between R
qumt~y,aetaminoph~a,2 e h is r
n
*
k in mdtipk h d a tions and &reat stmagths, is d
p maWh in thehome,
where it can be u u b m & d y ingusted by yowg cMdm @mirasing dmable tablets) or taken ia am i n t & ~ i d overdose by
adolescentsand adults. A ~ o p h e p i n ' t o d c ~ t i o na$common
cause of acute llver failure in adolescents and adults.
Pelb#@w.
Acetaminophen toxicity results from the
fomrion gf a highly reactive intermediate metabolite, N-acetylp-bcazaqninonejmine (NAPQI). When therapeutic doses are
administered, only a small amount (4%
of )
a dose is metabo-

lized by the hepatic cgzoehrome WSO aqme dYPZM to

NAF'QI, d i c h is irmnodiady conjugated
glutsthione to
form a hmdm m ~ ~ rarid
i conjugate.
c
~ m h p o t i stmw
c
of glutadtione are depleted to ~ 7 0 %of m r d , die NAFQt
metabolitecan combine with hepatic macrOmo1aclIes t~ p d w
hepatocellular damage. The acute toxlc 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 manufacturer's doslng guidelines and should be aware
of the availability of sustained-release formulations and the drug's
presme in many mmbinatim products.
ck'11dranymmgwdmn6jrrdageatp ~ d y r o h a m e ~ icasl~
toxicity after a singla inge8tioaof-even rdativehy hrp doses
of acetaminophen. Any child with a hist~rpof u sig&k&
in@-

tion should have the pl-

a-ph

--

c ~ ~ t i o n

346 rn PART VII rn Pediatric Drug Therapy

(S.I. Units)
pM per L pg per rnL
-1.00017,I~OO
5,000 -1

4,000
3,000

--

-'

1 i

500 -1

12

16

20

24

Hours Atter Ingestion

K r l r n . ~ ~ k ~ . \ ! . ~ r roc>rilogr.InI
/i(.~
t o r .licr.lmln~phrn I ) ( I I \ ~ I ~ I I I K . d
~ C ~ ~ I I L P ~ plor
. I ~ I T! > I IJ ~ I I~I . I I I ~ I~ ~c t ~ r n ~ !. <~) IoI L~C ~~ ~ l~ J~C Ic< rI I~5~I < [ I I I I C . ( ~ , I L I
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. T h ~ snomogram is not useful for chronic exposures, nor has
lr been val~dated for use after Ingestions involving susta~ned-releaseacetamlnophen products. ( 4 ) The lower solid line 2 5 % below the standard nomogram is included to allow for possible errors in acetaminophen plasma assays
and est~rnatedrime from ingestion of an overdose. (From Rumack BH, Hess
AJ [editors]: Poisindex. Denver, Micromed~x,1995. Adapted from Rumack
BH, Matthew H: Acetammophen poisoning and toxicity. Pediatrrcs 1975;55:
871-876.)

sured and receive treatment with N-acetylcysteine (NAC) if the

plasma concentration falls within the toxic range on the nomogram (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
~nrr-nr1cjn.11ovrrdr)\r. C h r o r ~ ~~cl ~ o l i IngchtlcJr1
ol
i n ~ r c , l s r \thr. rlsk
nt , ~ i r r a r n ~ n t ~ , p hhcer lp a r o r o n ~ i l r \ .Evcn 11 a wrloub <.I\< t ) t h c p , ~ tr>ttr\;tilrjdrvcIop\. rhc mc)rt,ll~t! r31e I, < O . S t ' r , .
rc-tlrirlng rhc

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 nomogram should only be used to evaluate the risk after acute exposure to regular-release products. The nomogram's 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
nomogram's 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 4-6 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 conservative. and more data are needed to better define an o ~ t i m a l
approach to treating patients ingesting sustained-release formulations as well as those with consecutive days of high-dose ingestion. Weighing the real toxicity associated with acetaminophen
intoxication against the definite benefit of treatment with a very
safe antidote, a conservative approach dictates treating if toxicity is suspected, despite the plasma concentration plot on the
treatment nomogram (see Fig. 58-1). These plasma acetaminophen concentrations are most useful for the asymptomatic
patient; symptomatic patients require therapy individualized to
their specific requirements. Liver function studies, including
hepatic enzymes, bilirubin, and prothrombin time, should be followed daily to every other day in all patients with plasma acetaminophen 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 1-2 hr of the ingestion. The
antidote for acetaminophen poisoning is NAC, which serves as a
precursor for hepatic glutathione synthesis, replenishing glutathione stores and preventing the reaction of NAPQI with hepatocytes. NAC therapy is most effective when initiated early in the
course of intoxication (within 8 hr), but may have value even if
started 24-36 hr after the ingestion in severe cases. It is important to note that NAC administration has no effect on the ~ l a s m a
acetaminophen concentration or the drug's 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 ( ~ 3 0 %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 1 7 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

hatcry a ~ i drtticaiv t r i N A C anrrdvrr rher.~py. jc.vcrt.Iy .~tfccr~aJ

parirnrs ma!- r r q u l r r 11vt.r r r . ~ n s p l , t n r a r ~ oIwc.
r ~ C I i ~ p r e r3 h j i .
WilYIW;li*LIIIOIIIL I f ~ ~ n t r c a r e i lp3rlc.nrs
,
w lr)r an, fct~tenverilose mav ml;sth-mrtgh t r h z 4 srnges r l i ~ c t ' t a .
rn~nc~pl~rri
r o s i c ~ ? ilblrlc. F X - Y i . Kei.iusr r.iri\ syrnptr:rrrls arc. n o n .
\prc.~tic. phys~ct.lns tnay nor r i ~ ~ l g ~ l ut hser Ingrsrloli t v i t h o ~ ~,I t

05-24 hr
24-48 hr

gooJ history o r a high ~ r ~ d ot

r z su.;plar:rrl. It a t o s ~ cI r l p c s r l o n is
.;uspcurli, thc plasma aieran1inopht.n c.onccntrar.ic~l~
shcluld hc

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

Ill

72-96 hr

Anorexia, nausea,vomiting, rnala~se,pallor, diaphoresis

Resolution of earl~ersymptoms; r~ghtupper quadrant abdominal
paln and tenderness,elevated bilirub~n,prothrornb~ntlme,
hepatic enzymes,oliguria
Peak liver functlon abnormalities;anorexia, nausea,vomiting,and
maia~semay reappear
Resolution of hepatic dysfunct~onor complete llver failure

Chapter 58 rn Poisonings rn 347

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
8-10 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 15-60 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 situations as well as in cases of acute overdose; the common use of
baby aspirin preparations by parents and grandparents for cardiovascular prophylaxis places the drug in many home environments and thus makes it available for accidental poisoning.
Methyl salicylate is the active ingredient in oil of wintergreen, a
common component in rubefacients. Every 1g of methyl salicylate 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, inhibiting 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 considered >I50 mg/kg for mild symptoms and >300-500 mg/kg for
moderate to severe intoxication.
Clinical and Laboratory Manifestations. The clinical presentation
after acute poisoning differs significantly from that of chronic
toxicity. Chronic toxicity results in signs and symptoms that are
easily attributed to other causes, such as flu or other febrile
illness. Young children are more susceptible to toxic effects
because they are less able to buffer the acid load produced by
salicvlates.
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 sufficient potassium has been lost through the kidneys, an exchange of potassium for hydrogen ion occurs and the urine becomes relatively
acidic. This "paradoxical aciduria" occurs in the presence of continued respiratory alkalosis. Dehydration and progressive metabolic acidosis, caused by the accumulation of lactic acid and other
metabolic acids, eventually develop. Seriously poisoned patients
are >5-10% dehydrated. Patients with chronic salicylate poisoning 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 hemorrhage 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 electrolyte imbalance, or cardiovascular collapse. Hyperpyrexia may
also occur.

Serial serum salicylate concentrations (initially at 4 hr

postingestion and then every 3-4 hr) should be monitored to evaluate for either continued absorption or impairment of excretion.
:\ttrr Lic~rre~ngestior~,
parirnrr" with serum wlicylittr concentrarionc of
nig/dL should unJzrgtl z o ~ ~ r i n ~clbservari~m
ieJ
and
monltorlrlg. Acute wrum ccrncentratrc>nsot >YO-1 00 rnp'dL may
procillcr Ilk-rhrearen~n~
el'feits. Plasma levels do nor always
sorrclate with clinical toxicity. The Done nomogram i s of poor
value and is no longer used. Patients with chronic salicylate toxicity may have a serum concentration within the usual therapeutic range (10-20 mg/dL). Salicylate disposition is characterized by
nonlinear Michaelis-Menten characteristics, where the drug's
body elimination is saturable. The disproportionate increase in
the serum salicylate concentration, but more importantly, the disproportionality of the drug's slow body clearance, particularly in
overdose, should be anticipated and the treatment plan adjusted
~icctordirigly.
Clr~nc pH and \:olume s h o ~ ~ lhe
d rnrasured hourly in all
wricru>l>-poiwneri children. I'lasm;~ pH, glusosc, potasstrim.
~ncfother rlri.trolyrcs shoulil be nion~toredat rcgi~lari~~trrvals.
(.lotrlng \tudirs and liver tuncrinn rrsts shoiild also I>r closely
monitored in all severely poisoned patients.
Treatment. Initial treatment should include gastric decontamination, 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 concentrations continue to rise many hr after ingestion or are persistently elevated. Gastric decontamination is typically not useful
after chronic exposure.
Initial therapy focuses on aggressive rehydration and correction of electrolyte abnormalities (see Chapter 52). Large quantities 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
rlrcrrolvtrs rnd!. hc sevrrely deplered.
L;rrnary rsirction of unmctaholizcd salicylart' hecotnes an
Irriporr,lnr route nt clirnlnarion In ovrrclosc. Clrinay cleara~lier l t
\,IIIL.\ I,irr 15 aitecred hv urine ~ 1 . 1 .Bccausr mrrahnlic acidosis pro~ l l ~ i morr
c < az~drcurrnr, d hlghcr percentage ot filcrred salicylatc
rtXrn,llnsin rile 11n-~onizsdform. which IS etfcctively rcabsorbed.
Urinary salicylate elimination can be increased using "ion trapping" 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 p H increases urinary salicylate clearLiriie 4-tolcl. C'rinr pH > h o ~ ~he
l J increasrd to ar l r a s i 7.0-7.
u,11ig I \ ' h~c~irhonatc.
Thr shift of salicylare to the ic~rii~rd
form
,ilsrn srrvcs to cieirrnse (:NS penetration ~ K C ~ ~ un-io~lized
J S P
drugs
grrirrnII\ c,ross rhc Illcrod-hrarn barrier more cfficirntly. It may hc
J~tt-ii~ilt
t o .ilk;il~zethr urlric without adequately replcnisliing
[ I S ~ L I C<torr\ L-rf p o t a ~ ~ i u.4ceta~ola1nidt'
r~~.
(,Diarnos)should nor
Ilr ubcd In J I I attempt tu achieve urinr alkalizariun.
In wvcrr cases ot salicylate ~nrrjxisat~or~.
dialysis nlay he
rrqu~rcd horh tar remove sal~i\late 2nd t u correct rlrctrolyte
c~I~ntrrm;il~t~rs.
Inci~cat~onstor rxrrac.orpo~.cal rernov.31 ~nclude
> C T U I ~ ISBIIC~I,IIC cclncentratlons o f r 9 0 mg/dI., changes In nsuroIog~i taru us ~drpressrJ Ievd of Lonsclolrsnrss or cfifticult tu
iontrol w~zurcs).respirarory or cardiovnscular instabilir!; r e t r a ~ [or) mrrdt>ol~c.iciJos~s.sevcrr- hypokalrmia, and rrilal failurr.
1 Irrntrcl~dlys~s
is preterred uvcr either per~tnnraldialvsis or charcoal hc.rnopertus~on.Kepcat-do~raztivareri iharcual may aid i n
c~~tiancing
rllr hod! clraranir o t salic.ylatr. Dialysis can hc rffecrlvc In cc~rrccrlng~llcl/ormairltaltlirlg rhc patient's fluid and electrolyte balance.

<.

IBUPROFEN AND OTHER NONSTEROIDAL ANTI-INFLAMMATORY

DRUGS. Ibuprofen and other nonsteroidal anti-inflammatory
drugs (NSAIDs) are often involved in unintentional and intentional overdoses because of their wide distribution and their
common use as analgesics; in particular, ibuprofen is used as an

348

PART VII w Pediatric Drug Therapy

Seizures develop in approximately 15% of cases and can occur

without warning, but are usually brief and resolve without treatment. Adolescents with comparable blood TCA levels have more
significant toxicity than younger children.
irihillitrriy rhc actrv~tyof cyclo-c>xygcnnsc. the prtm.1ry rnzyl-ric
Tachycardia, likely attributed to the anticholinergic actions of
r~.;pclr~rit>letor rhr I>it)iynrhrsis ot prosraglandir~s 'IIIJ crrtnlri
TCAs, is the most common cardiovascular effect, but does not
orher autocolds. T h ~ s d ~ s r u p t ~ o yroduich
n
thc sidr rttects
usually compromise blood pressure. Hypertension may occur
lrrtl.ltion,
rt-porrrd with rhcrdpeuric usc. s l ~ i t i.15 g3stroi1lresr111~I
soon after ingestion, but rarely requires treatment. Hypotension
~.rJuccd renal blor)d tlow, ,inti pl,~relrt d y \ t ~ ~ n i r l o l lS. S A I D
is uncommon, but is a poor prognostic sign. Other cardiac findari,ilogr liavr hccn developed rhar ,ire more ipciltii Icrr rhr
rhc c o r ~ s t ~ t u t l v r ings include slowing of myocardial conduction, multifocal prernrluiiblr ~tjrrn{ r f C:OS (tilt i OX-;! isoiornii
mature ventricular contractions, and ventricular tachycardia or
form, the COX-1 isoform. These drugs attempt to minimize or
fibrillation. In addition to widening of the QRS complex, Q T proreduce the occurrence of therapy-associated adverse effects.
longation occurs with T-wave flattening or inversion, ST segment
Overdose of the more selective COX-2 inhibitors (celecoxib
depression, right bundle branch block, and complete heart block.
[Celebrex]) is treated no differently than for nonspecific COX
Hypoventilation with respiratory arrest may occur without
inhibitors (ibuprofen) because at higher doses, COX-2 selective
warning. Other reported effects include hyperthermia, chora,cr.li[> losr rh1.1r C O S rnhil>~r,rr\ srlrit~vlty. Ihupr1rt~c.11.the
eiform movements, agitation, and twitching. Anticholinergic
prllil.lr\ N.\.\lD used I I I ncd~nrr~c.;.IS \\ell toler.~rcd. c\'zn ;iftrr
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 Q T and Q T c prolongation. QRS duration
and axis deviation and the level of consciousness have been suggested 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 severg ; ~ pnlct.~lrollr J ~ I L I O \ I \ . ion1.1. rrrinslent dpnr.l, rcnal i ~ l ~ l u r r . ity of exposure, but may aid in establishing a diagnosis or assessing the rate of TCA body clearance with therapy.
hLlt ,Ire
~l1.~?O~(.llslu11.
,111d crILLIrc.; i.111 r)iillr \vlth Irlrgc Ov~'r~losrs,
TREATMENT. After general life support measures are instir . 1 ~ ~(hlier
.
r'[)or[~d c t t e c t ~ I I I ~ I U C I ~ . Il).brS~11111S. dlplopla.
< ~ I!r.lll~~crir
IJ
~ l c ~ ~ f ~Rrni~I
i e s . ~ ~ I I I C ~ I O> ~I IL I L ~ I ~ \ tuted, including if indicated, endotracheal intubation, efforts
h c . ~ J ~ c l i rlrinIili\.
t~.
should be undertaken to prevent absorption. Emesis is conand acid-base balance should be monitored after ingestion of
traindicated because of the danger of aspiration from vomiting
large doses.
after the onset of CNS depression (loss of gag reflex) or seizures.
Treatment. Good supportive care is essential in the treatment of
Activated charcoal should be administered. Because of the effects
.1ciirc &.$..\I[)cr\crilo\r o r polsorung. T h c r s 1 5 n o s y r i ~ f i c.~nrlcloof TCAs on slowing intestinal motility, additional doses of acti> Jruc,. L;II~c\I\ I\ o t l~rrlck>r~ietit,bur
t#11r l ~ z r ~ ~t opr \tI11, c l ~ >of
vated charcoal can be administered 4 hr apart, concurrent with
~l
. ~ ~ r i \ ; ~ rsh.~ricral
ctl
call IIC ~ d r n ~ n r s t c r c dt x, t r . ~ ~ o r p o r z .rrl~icr\.rl
a cathartic (sorbitol), if required, based on the patient's bowel
rnrtlii)~l\Ii.~\.crlor h r ~ r iaJrqu,itsly cvnlu.itrd . ~ n darc nor recornmotility status. IV sodium bicarbonate in doses sufficient to
III~IIJC'J.
~ ~ ; l r t ~ ~ ~ rrlleri
~ l . l r lconsldt.ril~g
\.
thr ritcn>ivc dcgrrc to
\$.l~lihrail1 ot t t ~ r an;1l11gs
achieve and maintain a serum p H of 7.45-7.50 should be admin\~
I \ l)ot111c1ro ~il.~\nl.lyrotrrn.
istered to treat and prevent dysrhythmias. IV sodium bicarbonate is one of the most effective therapies in treating andlor
ANTIDEPRESSANTS: TRlCYCLlCS AND SEROTININ-MODULATING
preventing a TCA-induced decrease in cardiac conduction, and it
DRUGS. Tricyclic antidepressants (TCAs) and selective serotoninshould be considered for all TCA-exposed patients with such
reuptake inhibitors (SSRIs) are the 2 most common classes of
O I I EC:I;. L.iJi)cdi~~z
is U S ~
t oJtrcar dysrhyrhniiar
a n r r d r p r r s ~ ~ lol
~ r~i c ~ \ - i i ~31~111fi.lncc.
l ~ g ~ i 1st.r Chaprer 2 7 ) . ."rir~- .1hnor17idI1t1~'5
r h ~ arc
r u n r c s p o r ~ s ~ vt or scrum alkalrzatlon. Qu~nidille3 r d proL ~ C ~ P ~ C \ ~ , L I IIICILIJK
I ~ Y
r ~ ~ ~ ~ ~ t rncrrrrlpryli~ir,
~ ~ t \ I ~ r ,lnJ
~ r ,Irnlpralnlnc..
;lmrillg [rthcrs. \hIil, ~ n i l u d ctluo.;rrinc, s e r ~ r a l ~ l j>.lroszrIIIc.
~r,
i a i n ~ n l i ~ ioer s ~ r n i l ~ iJgrnrs
r
should nor lye used b c i ~ u s rthey
. ~ n dc~r.llr>prarn.;\rlt1tlrprc~s3nrsnot scle~.trvrtor srrorontrl, cr1'tt.n
turrhcr depress cardlac conduction. Hypc~rrnsiorlIila!: respond to

antipyretic in pediatric practice. Fortunately, serious effects after

NSAID overdose are rare.
Pathophysioloyy. '1-hcsc Jrugs ~llhibltp r o s t a g l a ~ i i i tsyr~tlies~s
~~
I>!,

s
tlutd thrrsp!.. although vasopressors, such 3s norcpirctrrrrd r < j .I\ ~ t r l , r > c * l c . r . t r ~ ~st ~~ ~ r i , t r , i r r r r - r t ~ r ( p r L~~tkr(l~~ ~ l ~ r r o r\t.lnciard
/NhJKl.i!. ~niltrdcvrnlatas~nc.,Ijul>rop~on,
d ~ ~ l o x r r i n rnlrr,lL'ipe,
ncplirine, nlay Ilr rrquirej. Scvcre, unrrsponrivc hyporensio~iI S

inc, ,IIILI 11rt.17i)~ione.

Tricyclic Antidepressants
1'1 I t.it )Ill 1 ) \ I { 11 t~ , ) . T ~ I ~ ~ C
, ~I~ I~ ~t ~. J e p r c * \ tilock
\ , ~ ~ l t the
s
rlrurcrnal rcuil~.ikc~ r nt c ~ r e p r n t = p l ~ r ~,rroronln.
r~r.
,Init cloparnlnc
111 t ~ t ~ t lrhc
i
irnrr.11 ,111cl prrlplicr,il liervou\ I;ysrcills. The!- nl\o
prcr~l~lcc
\;lr!.~ng Licgree> o t cc~iarlo~i.
tx-rescptcrr Illock~ng..11)1l
. ~ n t i i t ~ o l i n c r gckteits.
~c
I n l i ~ h i r i o~~r~ta,r
t \crJiurl~ihannrl, In tllc

myocardium leads to the development of cardiac dysrhythmias

and myocardial depression.
CLINICAL AND LABORATORY MANIFESTATIONS. The
pr11t1.1ry orgar, \ysw1115 .~itcirrciI>y I ' C ,A\ Jrt. the CNS JIIJi;lr-

syilrm. Sy~iiproln\CAI] d e i r l o p .I\ c ~ r I \ . 3 0 mln

;11ler lngcillc>ll. iv1t11icrloii\ $y-1nj7roni>L I \ L I ~ J \ ~J\c- \ c l o p ~ ~ \i\g- ~ t l i ~ r i
6 h t o f ingc.<llr)r). In lrirgr Ingcsrlons, pLirlrnr syrnptc~~n.;
In;l\. he
ricl;tyrd !>h-s+ Ilri, r t . i l c i r i ~the
~ ~ . ~ ~ l r ~ i I i r r l ~ n cpropcrtirs
rgii
of
TC:\s 111 \ l r > a ~ i i gga5rrlc. r.tnpt!-lng ,111d I ~ ~ r \ v rm
l o r i l ~ t ~The
~.
pAtrcrn ()i t o x i i i t ~ ,in i h i l i i r c ~15~ illttcrrnr frc~nltti,~tcle.icl.~hcd 111
L~~ll\.d\~~I;lf

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.

.I poor

p r o g ~ i o s t ~sign.
i
Hypertrnslun ~ ~ s ~ ~1a5 lrransirrlr
ly
and
docs nor requlrc trcatrrlerir. Seizures. if they require rrrurtnenr.
~ r u , ~ l lre\ponJ
!
ro hcnzoili~zrpincrhcrapy. 1'hysr)stigrnirw. once
e "TCA roslsiry, IS a Jangcrous Agent
pr0111oted .IS .in - ' ; ~ n r ~ d o ~tor
d
and should I-tor be ~lsecl.
rh,~t(311 C;ILISC' seizures ~ n dysrhythmir~s

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 repeatdose 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 monitored for at least 6 hr after exposure. If any manifestations of
toxicity, including a QRS interval of >I00 msec, conduction
defects, altered mental status, hypotension, or hypoventilation,
develop, the patient should be admitted for continued monitoring in an intensive care unit for 24 hr. Only completely asymptomatic children should be discharged after 6 hr of observation.
Selective Serotonin-Reuptake Inhibitors. Selective serotoninreuptake inhibitors differ from TCAs in that they specifically
inhibit reuptake of serotonin in the CNS. They have little or no

Chapter 58 m Poisonings m 349

-

I
Figurc 58-2. Manifestations of the serotonin syndrome range from mild to life-threatening. The
arrows suggest the approximate point at which each
clinical findinr! mitially. amears in the spectrum of
the disease, but all findings may not be consistently
present in a single patlent. Severe signs may mask
other clinical findings. For example, muscular
hyperton~city can overwhelm tremor and hyperreflexia. (From Boyer EW, Shannon M: The serotonin syndrome. N Engl J Med 2005;352:
1112-1120.)

Mild
symptoms

effect on norepinephrine or dopamine reuptake and minimal, if

any, anticholinergic or a-blocking effects.
Cl_lNICAL JMANIFESI 4 I IONS. 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 asymptomatic. 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 conduction 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
defined.

Tremor
(greater in lower
extremities)

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 interactions (meperidhe, 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, hyperreflexia, tremor, and
~ n u \ i l r~i.g ~ d ~ t('I'ahlr
y
58- 1 UJ.
1 1 < 1 \ 1 \ \ I 1 1 . C,nsrrr~lnresrinal clecorlta~ninatio~~
with acri\ . l t r ~ Ii h . l r c o ~ l is rhc preicrrecl rrcatment nf thc \rrotonir~ syntlronlz; ernr\l\ should not be attcrnpted hccnusr of the rcnl
~ v ' r c n t ~ lor
, ~ l C N \ depression. 'I'rearrncnt depe11ds rm the severity
o t \!-rnprnm-;. h u t rrqLIIrcs re~tioval ot the ~ncitincdrugs a n d
pn'inpt p r ~ ~ v l ~ oi oi ruppr,rtivr
n
carr, nil<lwing rhe severity of rhc

extremities)
Autonomic instability:
often hypertensive

Figure 58-1. Findings in a patient with moderately severe serotonin syndrome. Hyperkinetic neuromuscular findings of tremor or clonus and hyperreflexia 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;352:1112-1120.)

350 w PART VII

Pediatric Drug Therapy

Clinical and Laboratory Manifestations. In clon~d~ne-na~ve

chll-

dfen,symptoms frequently develop within 1 hr of ingstion; rhus,

DRUGS ASSOCIATED WlTH SEROTONIN SYNDROME
Selective serotonin-reuptake inhibiiors:Sertralme, hoxetlne, fluvoxam~ne,paroxetme,cltalopram
Antidepressantdrugs Trazodone, nefazodone, busplrone, clwn~parn~ne,
venlafax~ne
Monoamine axidase inhibitors Phenelme,moclobem~de,clorgll~ne,lsocarboxaz~d
AnticonvulsantrValproate
Analgesia Meperld~ne,fentanyi,tramadol, pentazocrne
Antiemetic agents Ondansetron,gran~setron,metocloprarn~de
Antimigrainedrugs Sumatnptan
Bariatric medications S~butram~ne
Antibiotia Llnezol~de(a rnonoamlne ox~dase~nh~b~tor),
ntonavlr (through lnh~b~t~on
of cytochmme P45
enzyme sof form 3A4)
Over-the-counter cough and cold remedies Dextromethorphan
Drugs of abuse Methylened~oxyrnethamphetam~ne
(MDMA,or"eatasy"), lrerglc acld dlethylam~de
(LSD), 5-rnethoxyd~~sopmpyltryptam~ne
("foxy methmy"), Syrlan rue (contams hanlne and hanallne, b
rnonoamlne oxldase ~nh~b~tors)
Dietary supplementsand herbal products Tryptophan, Hyper~cumperforarum (St John's wort),Pan
g~nseng(gtnseng)
Other Lthlum

rapid recognition and inreruention is m&. Ldargy, ~nimiosis,

bradycardia, and hypotension occur in all age goups. Apnea, respitatory depression, and coma ace common findings in younger
children. Serious symptoms usually resolve within 24 hr of
Ingestion. Serum clon~dineconcentratlons are not readlly available and are of no c l ~ n ~ cvalue.
al

ham- Immediate recognition of an expos~e,with transfa to a health care facility, is of paramount impomnce. Gastric
decomamination is usually of M e value o e g to the s m d quanspmpto,ms.
ingested and tfie rapid onset of

DRUG INTERA(II0NS ASSOCIATED WITH SEVERE SEROTONIN SYNMIWE

Semalrne (loloft), fluoxet~ne(Prozac, Savatem),fluvoxamlne (Luvox),paroxet~ne(Paxll), c~talopram(Celex.
trazodone (Desyrel), nefadozone (Serzone), busplrone (Buspar),clom~prarn~ne
(Anafran~l),venlafax~m
(Effexor), pheneiane (Navd~l),rnociobem~de(Manerex), ~socarboxazrd(Marplan), dlvalproex (Depakote),
meper~dlne(Demerol), flutanyl (Durages~c,Subllmaze),tramadol (Ultram), pentazolclne (Talwln),
ondansetmn (Zoh-an),gran~setron(Kytr~l),metoclopramlde (Reglan),sumatnptun succlnate (Im~trex),
slbutramlne (Mer~d~a),dexfenfluram~ne
(Redux), fenfluramme (Pondlmln), llnezolld (Zyvox),r~tonav~r
(Norv~r),nanylcyprom~ne
(Parnate), lmlpramlne (Tofranll), mlrtazaplne(Remeron)
Phenelzrneand meper~dlne
Tranylcypmm~neand lrnlpramlne
Phenelz~neand selearve serotonin-reuptake ~nhlb~ton
Paroxettne and busplmne
Llnezolldeand c~talopram
Moclobem~deand select~veseroton~n-reuptake~nhlblton
Tramadol, venlafax~ne,and mlrtazaplne
Fmm Bayer ENShannon M The seromnln syndrome NEngll MedHX)5,352 1112-1120

ggresslve supportive care IS Imperative. The ECG, vital slgns,

and blood gases are monitored as symptoms d~ctate.Naloxone
has been used wlth m~xedsuccess to reverse CNS and respiratory
depress~on;its use should not replace aggressive support~vecare.
Because the durat~onof effect of naloxone 1s shorter than that of
clon~d~ne,
repeat doses or adm~n~stration
by continuous infus~on
may be necessary. Extracorporeal removal techn~quesare not of
value.

~atienfssymptoms to direct specific therapies, including benzodiazepine for c ~ o ofl agitation and hyperreflexia or minors.
All patients with moderate to severe symptoms require continuo m cardiac a d body CemPraWe monitoring. Patients whose
muscle effects and resultant h d e r m i a are poorly respomive
to benzodiaae~kesshould be intubated, ventilated, and pharmacoIogicau~ paralyd with a neuromusmk blockkg drugBecaw h e hyperth-ia
is a direct resul of increased muscle
actlvltY, antlPYretlc drugs have no role In the treatment of m-0tonln syndrome. The predominant receptor res~onslblefor seraton111 syndrome may be the S - H T ~ receptor
A
because case reports
have suggested therapeutic benefit In moderate to severe SSRI
lntoxlcatlons wlth the 5-HTZAantagomst cyproheptadlne or
newer atypical ant~psychotic drugs with 5-HTlA antagonlstlc
actlvlty (olanzap~ne).

CU1WNE Clonidine was &st introduced for use as an mtihypertensive, but has found use in amrion-defidt/hyperactivity
disorder and tic syndromes in children (see Chapters 23 and 31).
Increased use for pediatric indications as well as greater populariry of the use of the patch formulation for adults with hyperteasion has reshed in an escalation of acute poisoning and
therapemtic misadventures.
Pathophysiology. The toxlc effects of clon~dineare the direct
result of a2-adrenerg~creceptor lnh~blt~on
In the CNS. Chlldren
are very sensitive to the toxic effects of clonidine, with as little
as 0.1 mg reported KO produce significant toxiciry in young
infants. Serious toxicity has developed after sucking or chewing

on a new or discarded topical patch preparation. It is of paran r ~impomnce

~ ~ t to inform families in which a member uses the
clon~dlnepatch that a substantla1 amount of clon~dlneremalns In
the patch on removal and that the used patch should be folded
by seallng the adhesive surface and then discarded In the trash.

mu. Iron is one of the most common causes of childhood pol-

oning death. Iron-contaming products are common In many

homes, and ~ron-containing v~tamins, whlch often resemble
candy, are frequently freely glven to children by t h e ~ parents.
r
The
potentla1 seventy of exposure IS based on the amount of elemental iron ingested. The amount of elemental iron ingested is cal-

rulated on the basis of thc number of tablets ingested and the

percentage of elemental iron prese~tin the sak form ingested. The
amount of e h e n t a l iron is 20% in ferrous sulfate, 12% in
ferrous gluconate, and 33% h ferrous fu~~laratt~.
Most xridtivitamln products contalnlng iron list on the product label the
amount of lron per tablet as the elemental iron content.

P-ogy.
Iron is corrosive to the gastrointestinal
mucosa and may lead to intestinal ulceration, edema, and occasionally melena, hematmis, and possibly perforation. It also
acamulates in the &ochondria and assues to produrn &dar
damage and s y s t a k m&iv. b n causes vao&kuon and

Increased capillary permeabll~ty,leadlng to hypotension. Early

hypovolem~afrom intestlnal losses, leading to reduced per~pheral
perfus~onand m~tochondr~al
damage, results in lactic and citrlc
acid accurnulat~on,causlng metabol~cac~dosis.Hepat~cnecrosls
develops after serious poisoning, resulting In abnormal h e r functlon test results and coagulopath~es.Drowsiness and coma may
develop as a result of hemodynam~clnstabllity or poss~blyas a
d~recttoxlc effect of Iron In the CNS. Greater than 60 mg/kg of
elemental iron 1s generally considered a toxic dose,
C l i n w and
-QU+
Nausea, vorsi@, dar-

rhea,and

pain reflective of

cofi&ve effects

He

the hallmark of iron polsonlng, and usually develop within 30

mln to 6 hr after ingest~on.Hematemes~sand bloody diarrhea
may develop In more serious poisonings. Gastro~ntestinalsigns
may subslde over 6-12 hr; however, careful observat~on1s warranted because systemlc toxlc~tydue to cellular damage may
ensue, particularly in patlents w ~ t hsevere gastrointestinal slgns,
early h ~ p o t e n s ~ oor
n , drowsiness. All Infants and chlldren with a
history of cIinidy sigaiscant itom ingestion who experience

unprompted emesis should be imm-1y

r e f 4 to a he&
care facility. Because iron is radiopaque, an abdominal radiograph may c o b the i@~*. Repeat radiographs may help
with assessment of the efficiency of gastric deconmnination
metbock. A negative result does not rule out iron ingestion
because only undissolved tablm can be seen. Iron ptesent in cbit&en's chewable multiple viramins is usually not visualized on the
radiograph because of the low concentration of iron md the
r a p ~ dd~ssolutionof the chewed tablet. Gastr~cscarring, pylor~c
stenosis, and intestlnal strictures can develop 2-4 wk after a large
lngestlon or In instances when Iron tablets remaln In prolonged

Chapter 58

contact with the gastrointestinal mucosa. Strictures may be symptomatic and occasionally require surgical intervention.
Serum iron concentrations should be measured and evaluated
in the context of symptoms and should be obtained approximately 4 hr after ingestion. Serum iron concentrations of
4 0 0 pg/dL, measured 4-8 hr after ingestion, indicate a low risk
of significant toxicity. Serum concentrations of >50O~g/dL
indicate that significant toxicity is likely. Serum iron concentrations are of greatest prognostic value in the asymptomatic ironexposed patient. Because of the severe morbidity and mortality
associated with iron intoxication and the time-sensitive variability of serum iron values (best obtained 4-6 hr postingestion),
symptomatic patients with a history of even mild to moderate
exposure should be referred to a health care facility for evaluation 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 >SO0 yg/dL. Further, the
patient's cardiovascular status should be continuously monitored
because early and evolving hypovolemia resulting from gastrointestinal 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 inefficiency, particularly 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 benefit. 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 magnesia) react with iron to form less soluble, poorly absorbed iron
salts; this technique is of very questionable clinical benefit and
should not be attempted. Complexation of iron in the gastrointestinal 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 numerous iron tablets present in the gastrointestinal tract.
Deferoxamine is a specific chelator of iron and is the antidote
for moderate to severe iron intoxication (see Table 58-6). Acute,
transient hypotension, with or without flushing, may be observed
on instituting deferoxamine administration, particularly if a
loading dose is given. These effects associated with deferoxamine administration appear to be due to the drug's ability to induce
histamine release, which often resolves on slowing of the IV infusion rate. Indications for deferoxamine include a serum iron concentration of >SO0 pg/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 continued until the patient is symptom-free. Prolonged deferoxamine 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
rosk), although this is an unreliable indicator of iron excretion
and is rarely observed. Intramuscular deferoxamine administration 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. Specific
agents include nifedipine, diltiazem, verapamil, amlodipine, and
felodipine. They are available as regular-release and sustained-

Poisonings

351

release preparations, as well as in combination with d i u d e s and

other antihypertensives. Their expanding therapeutic we, white
making CCBs the mast c~mmonlypreuibed cardioyii8&
drugs, has also incmased the incidence of poisoning eqmun.
The t o e effeas of t h e drugs iue an extensioEZEZcBpeytic
in thst
antagonize L-type
calcium cfrannds, inhibiting ealcium ia&rx into m y d i a l and

vascular smooth muscle cells; this results in depressed myocardial contcacrility and conduction as w d as peripheral modila-

tion, with subsequent hypotimion and bradydysrhphias.

Galcium Muxis also impaired in the $-islet cells of the pancr~as,
leading to impaired ins& dease and subsequent hyperglycemia. CCBs have a narrow therapeutic index; thus, any dose
greater than the usual maximum daily rherputk dose should
be considered potentially toxic.
Clinical d
.
Y= The oaset of symptoms
may occur within minutes of dre i&on
of a reds-release
product or may be delayed several hr after the ingestion of a sue
tained-release product. All CCBs invariably cause hyporemian,
accompanied by bradycardia, n o d heart rate, m men taxtrycatdia, depending on the a m . Myocardial depmim may lead
to shock in severe cases. One clinical,chara~teristicof CCB o w -

dose IS profound hypotension with preserved consciousness.

Nausea and vomiting are common.
Careful blood pressure and electrocardiographic monitoring is
essential. The electrocardiogram may show varlable 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

&dins

~ P Y .

After appropriate supportive care has been mstimted, absorption should be prevented by early administration of
activated charcoal. Whole bowel irrigation should be considered
if a sustained-release product has been ingested. ~ a a c o t h e r apy should be d b d at maintaming cardiac output and ptriphera1 v a s c t h tone, both of which are impaired in CCB poisonings.

Useful agents indude atropine, cakiciunr, insdin, ghcagon, fluids,

and vasopressors. Atropine is the drug of choice for spmptomadc
bradycardia; a pacernakec shadd be considered for iefcactary

cases.
Administration of IV calcium may reverse myocardial depression,impaired conduction, and hypotcnsion, but it is not consistently effective. Cakiw chloride is preknsd over calcium
gluconate because it cantains a water mount of calcium per
gram. Because calcium salts have a much shorter duration of
acrion &an CCBq administration by coatinuous idmion may be
necessary (see Table 58-7). I i y p e d c d a 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 b e of glucose by the myocardium. Gluaagon
improves cardiac conduction and contractility- by promot&

calcium ion influx rhrough calcium channels i e W y (seeTable

58-7). Its &cacy in the treatment of CC3 overduse is not consistent. Other inotropic agents have also been used with mixed
success. Extsacorporeal membrane oxygenation and cardiac
assist devices have been successfuHy used to support cardiac fanction until the drug is d e a d from the body. Exttacotportd dimination metbods are mt useful for removtn$ CCBs.
V C - 6 &knm as typeITad
dysrhythmic agents, &these drug campe2ithdy block the actioa of
catecholamines at the m a p o r . They are used for the toqhnent
of a wide v h e t y of cardiac and noncardiac problem. Cardiastleahe agents, such as metoproiol, atenolol, and ~ 0 1 0 1 act
,
selectively at the receptorst whereas o & a , such as propra-

352

. .
PART VII

Pediatric Drug Therapy

PI and P2 recep-

system (vagally mediated mechanism), leading to an increased

refractory period, decreased sinus node firing, and slowed conduction through the AV node, with sinus bradycardia, AV block,
Pathol>hyslology 111 c~vrrJose. [j bluikrrs Ir:ld to decrrasrd
or even sinus arrest. The overall effect of digoxin overdose is a
i < l ~ l d ~ ~ t i 311cl
n l i . drcrc:~.ir~iInotrop!,
c h r o n o t r o p ~ .i~npxircd.\I:
~4 1~r.1~lvi~r1l1.1.
I I ~ ~ I Ih-lt~ l i k ;~rtd
, Iiypotrn.iion. I'aric~~ts combination of slowed or blocked conduction and increased
rn,~~iiirsrr-d
ectopy. Digoxin has a very narrow therapeutic index; toxicity can
r11.iy h . 1 sCvt.rc
~~
I ? r o ~ l c l ~ o \ p : i.I\
~nl
n i r h rc;lctlviT .III.\VA\. JICL*,ISC
rcsulr o f IGli1oc.krr to.ilclr!- (the I'll-rncd~,ir~~d
brrrnchod~l,lt~c.)~~develop even from therapeutic doses. The therapeutic plasma
hct~iy h l o c k t ~ \ ~/5:-r~.icp~o~
.
lllc)<kt.r< .ll>o intcrtcrt- \\:ir\~ concentration is 0.5-2.0 ng/mL, whereas levels >2 ng/mL are considered toxic; a digoxin level of >6 ng/mL is considered potenglycogenolysis and gluconeogenesis, impairing the ability to
tially lethal. Digoxin interacts with a wide variety of other drugs,
recover from hypoglycemia.
Cllriical atitl lnl~otatoryManifestations. The onset of symptoms
by a variety of mechanisms, increasing the potential for toxicity
at therapeutic doses.
usr1.11ly occu 1.5 L\ ~ t l i l r i I - 1 111. I r t the ~ngcstionof a regular-release
Clinical and Laboratory Manifestations. Acute toxic effects
p r o ~ l u i to r may l>c clcl.~!.c~ltip I O I 0 hr with a sustained-release
usually occur within 6 hr of ingestion and include gastrointesti~ V C ~ ~ LTlic
I C II l.l o \ t ~ o m l n o r itcatur's c r t st.vt.rt. poisonilip, ,Ire
nal, cardiovascular, and CNS manifestations. Nausea and vomitI,r.id! cardla. li? liotens~on. In\\-outpilr i.lrcl13i I ~ t l u r e ,and i a r ing are invariably associated with acute digoxin toxicity and
J I ~poor
J
myoc.irdl~l
d i r j g e n ~.chock
~
J L I Cro <lcl.l!rd ionci~iiri~lrl
i o n ~ r ~ ~ i t i l i Lilcrcrci
ry.
prc\>urc J I I ~t C ( i rnt)~liioring,lrc e . i ~ c ~ i t i ~ i l . usually represent the presenting symptoms. Cardiovascular mans l turlet~onwith S I I I L I ,
itchtarion> include br.lJyc;~rllin, heart bl(-)ik,a n J vc~~tric.ular
dycTli? t:(:(r m,i> \lie\\ Liccrc;1sed s ~ n c ~ a r r inodc
Iiril~iyt~~lrJ1.1~
S I I I I I \ p.1~1st.s.o r ,111~1s
.lrrcsr. o r ~ l r ~ . r c a s c:\if
d ior1rhythrnins. Rradydysrhythrnias arc mcrrc iornIrion in p r r . v ~ c ~ u s l ~
~ ~ I I L ~ C I \\-it11
OII
v ~ i r i o ~~i \ l r , ~ofr .A\:
~ ~ l>lock.
c ~ I<c5pirs~toryJeprcs51ori
hraltliy hcarrs, w l i e r r ~ s prc.v~oltdy ~ii>eased hcarrs uauall\1s ,l[\rl ionlT11o11, .11011g \vir11 [1rtr11i~1o\pdslll. In susct3prlb1e
Cnnrinuu~is;(:<!I
motiirt~ri~ig
IS
respontl \\rith tacl~ydysrh~thmias.
nolol, sotalol, timolol, and labetalol, block both
tors.

CI

r
digoxin's cficcrs dnd g u l d i n ~r h ~ ~ r a p yblood
.
p.iricllrh. I)cl~riunl. .iltcrcil It)vcl o t consiiou5nes\. eon1,l. ,~ncl cruci.~lt ~ j ,i>\e5sirlg
~
n i ~ ~ i i I i r ~ ~ ~ pressure
ir13 usually preserved despite sig~iibic.lnthmdycardii~.C X S
\c.irr~rrco ~ L i i r\\.it11 m o w l i p ~ ~ p h i .ll~~ec i i t sJ I ~ L\vlth
1 5 . ~ l s o cIi;~r~ictrr~iric
o! p\ t r ~ l ~ i l ~ / i.i Li g~ C I IH~~pogI!~.cnii,l
I~.
m , i n ~ t c s r . ~ r ~ olrrclude
n~
vicual changes. I ~ r a J a c l ~ e ,f'ltiguc,
bl[niktr ~lvcriltisr, C\~L,CI,III:.
in c h ~ l ~ l r ~~* nn. dIilooJ gluzosr
Irth.arg>; ior~fusion..inJ h : i I l ~ c i ~ i ~ t i o rC:hro~lic
is.
cardiac glycrr> ~ < ) L I I L I l ~ nr ~ ( l r ~ i i i r r kr111i1
~J.
lcvrls of 13 Ill~~~ckcrh
arc nor r~>.iJlly s ~ t i ctoxicity IraJs t o .I cornhiii;~tionol vrntriculnr dysrh);rlimi,i.;
~\.;1111blc h )I. l.oll[ltl~.ili111 ~ . i 1iiw. AnJ . I ~ CI ) ( 11 115riul.
.ind ~rnp;tircdA\' conduction. Thc serurn cligorin levcl ~11i)ulclhe
Treatment. Supportive care is essential. Gastrointestinal deconassessed at least 6 hr after ingestion and carefully interpreted in

tamination is very important. Orogastric lavage can be considered in older patients who present within 1hr of ingestion, but
only after atropine administration. Activated charcoal is also rec-

the clinical context because the digoxin level alone is not reflective of the severity of intoxication. The serum potassium level
should be monitored as a useful marker of severe toxicity: It may
~)ii~rilc.l~dccl,
diid \vI~oIt-I>o\vrI irr~g,ltio~l
should lrr c o n s ~ ~ i r r c d be dangerously increased (a poor prognostic sign), although
decreased potassium levels may occur with concomitant use of
x t r ~ rrhc ~ngc\rii)nt)t su\t.li~icd-rrlr.~\~c
yrrparatlon,. I'h,lrm,1coIogii ~licr.ip\ shcrulJ llr JrrccteJ , ~ rm a i n r , i ~ n ~ ncg; l r d ~ . ~ocu r p ~ ~ r . loop diuretics, and hypokalemia enhances digoxin toxicity. Renal
function should also be monitored.
hcLlrr r.lr~.ionrr.lcr~lrt?.. ~ n l ~> I io t ) t l prt.isi~rt..Clsctul Jgrnt\ iricludc
Treatment. Initial treatment includes good general supportive
Litr.c~prnc.tluld hotuses, glui,~gtrii,li~:h-dt,hc ~ n s i ~ l i n.111d
. Y.I\Oprrc\or\. ( I I L I ~ . I ~ O I I 15tlw tirug ot c h o ~ i rtor (j-Iiloil\er polsoril~lg\, care in an intensive care unit and gastric decontamination with

ir4 / j l4:0111\r
c i t r ~ t s.i11~1[hr 1.1ili of i i r i t i e ~ ~ r ~ lplc~rl~cp I i ~ r 3 1
1s rztr.~ctory t o
vL~so~lil.1rrlr!
ctteir,. I t synipttrm,ltli hraclyc,trd~~
f
Ir1casur.c..; dcsirltrr~lc,irl~cr.vcntrici~l~lr
l ~ . l i ~ n\lioi~ld
g
lit.
all ~ l tlic>
corisidcrcd. ,ilthc~ugli ~t (nay not ~lrlpro\-ci,lrdiac output; csrrdcorpabr~~.~l
111r11il~r.1iic
o ~ ~ ~ ~ i oir ,e L~ ~tr c~i i SiLi,\i\t
~~e ~ ~i l c \ . ~ c cI sI I J ~
hc ncLCs*,Ir\ tcjr rc.fr'~cct.)r>111 porrn,lon.
given

.icti\-areil c l l ~ r c o d lit the I ~ ~ C S I I Civ9.i

I I ~ recent. Irnmcd~atcrhcri~py
should .31111 Tor early rect>pn~tiunailJ aggrc5slvc tre;1tmrxnt of
1~.-.t rhrcarrnlng
t
ciitcerh of digoxin toxiciry, iincluiling mounting
hypcrk,llcrnia arid vcntrizi~lardysrhyth~iiias.Hcn~odialysismay
te~nporarilynrtcllunte hyperkalcinid, hut J ~ g o x i ncannor he clinl-

inated in this way, due to its high tissue binding. An antidote for
digoxin, digoxin-specific Fab antibody fragments (Digibind) is
WBOKBI. Dipoxin I \ $1 c,~rdi,iigl\cc)hldr cxtraiiccl trom the lca\rcs
available (see Table 58-6). Digibind binds free digoxin in both
o f D ~ , y / t ~ r/l, ~~ s) l , r t I~) ~I ~: I ~ J I I gI~.cosiJe\
\
,1rc ~ 1 5 0present 111 D I ~ I - the intravascular and the interstitial spaces and facilitates its renal
Effects of Digibind usually begin within 1 hr of admint,llis / ~ f ~ r p r t r , ltosglo\ c!. , \ c , r ~ ~ o nr 1 / ( 3 , 1 1 i t / ~ i, ro l c . ~ ~ ~I.~CiOc Tr ~ ~ , , I ~ / ~ I ) ~ Iclearance.
~I
~r~,l/.zl~s!lil!- 01 (he v,xlley). \~llrri.in gln\eng, .inti wrne t o ~ J \ ' istration. Indications for the use of Digibind include digoxinvtAnclln c U r ~ j r r l ) r i / c i i . ;\c ,I rlicrapr.i~tri,igri~i,digosin i, u ~ t + dIn
related life-threatening dysrhythmias, K+ value of >5 mEq/L in the
ihiliirci~tor 111'. ~rr.ltnlt-nr Ile.lrr t a ~ l u r eand \omc iupravcrlsetting of acute digoxin overdose, significantly altered mental
rl-icular t . ~ i h v i i ~ ~ r l l ! - r I i mrilrhougii
~n~.
Jigosin \\.:I\ o n i r i o n s ~ d - status, renal failure, serum digoxin level of >10 ng/mL, and ingesr~rcti I r ~ til i r ~rncrsr Jangcrou5 poi.iolis. the lnc~clcncr01 digoxin
tion of >4mg in children or >10 mg in adults. In the absence of
ttiyiiit! Iias c1cirrL1crtl, due in p.lrt t o progre5i I I I thr undcrDigibind, ventricular ectopy should be treated with phenytoin,
~
drug i n t ~ ~ r ~ i i t l ocr l~\ ~ in) d which may reverse the digoxin-induced slowed AV conduction
~ t * i ~ ~oti its
d i p~I ~~~~i r r ~ i . l ~I I, CoI~I iI !I I ~JIILI
p.lrt t i ) the .1vail,3ly1l1t>ot .in c t t r c t ~ v c.~rltiJore.;\c~itcc n ~ ~ r J r ) s c and suppress the tachydysrhythmia without diminishing contracITICIV o c c t ~ rfroni ito\111g errors ~r\liec~.ill!-111 !oungcr c l i ~ l ~ l r c ~ i ) .tility. Atropine is the standard therapy for symptomatic bradyfroni ~ i c c i i ~ ~t.)r
~ i ItI ~I ~ ~C Il I ~ I ~ I I ~r11cd1i~1tio1i
II
~ r i v e ~ t ~ oor ri . from
cardia associated with digoxin overdose while Digibind is being
ingr.;ti{rn o t plant ri\.lrcri,il c.r)nr.i~ning d ~ ~ i t . ~ l glysos~clch.
ih
prepared for administration.
('hronii oi ~ . r d o \ eoccur\ mocr trequrntly i l l I ot tht. t o l l o ~ v ~ n3g
<ir.cunisrnliic\: alrc-r,~rion c r t rhc. cligovirl ~ i o s r . Lilrcrnr~oriin
CAUSTICS. Caustics include acids and alkalis as well as a few
J l g t j x ~ ni l c ~ r ~ ~due
r ~ it oc rrn.11 ~rr~p.lirrncnt,c ~ Jr r u g ~ntct.actiim\. cntnrnorl trxidi7rng agents. such 3 5 blench (see C h ~ p r c r324.2).
I,

L.

Pathopt~ysiology. r)ipcrx~n hlocks [he N J ' , K--:\T~I1a\c pllmp,

Pathophysiology Acicls cr~aguliltrprcltcins. causing Incal t ~ s s u c
Icad1r12t o ~ntr~lcrllul.ir
lo\\ o t K- a i ~ dx:~inof Sa ,ind C'.12+, rhils
rlecrosib. wlirch limit? it< tissue prnrtratioll. Alkalis Jigcsr and di\iiiirear~nytlic (.:.I " av;lil.j tlle t o the cor~rractilc.~i~yrrcardium
attcr
\olvt. protcllls, producing transmural I~qu~fairir.)n
nccrr)sis. \vith
rscir.~tion I poritlvc Inorropic cttr'it). '1-he 1ncr~..1scJ111tr-ait.llular
t h ~ .risk o! prrforation if rht. inlurl- ir; I O L ' J ~in~ the ~ntertinal
~11ii111ii
lc:)Js t( r 111cre~icc~l
l i ~ ! ~ o c ~ r ~~I i~~~l l~ t o r ~ i\\71tl1
~ ~ t su
~ h3cc i t ~ - , tract. The severity of the chemical burn produced depends on the
cluc'n~: ~ r r ~ . nodal.
~l,
JIIJV ~ l l t l ' l i ~ l dcctopy.
r
Tlie impaired Na-K
pH, the concentration of the agent, and the length of contact
rscl~angr.~ 1 5 . 0IC,ILI\1 0 dangcrourly high lcvcls of serum porastime. Agents with a pH of <2 or 212 are most likely to produce
sium in thcsc p,~ricnrs.Iligoxin also ~ f t e c r srhc cardiac autonrlrrlii
significant injury.

Chapter 58

Clinical Manifestations. Ingestion of caustic materials may

produce oral burns, visualized as reddened areas or whitish
plaques. Symptoms include pain, drooling, vomiting, and difficulty 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 significant tissue damage.
Treatment. Initial treatment of caustic exposure includes thorough removal of the product from the skin or eye by flushing
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 fluids or solids should be withheld.
The absence of visible oral injury does not preclude significant
esophageal lesions. Endoscopy should be performed in symptomatic patients or those in whom injury is suspected on the basis
of history. The use of corticosteroids and esophageal stents is controversial. Prophylactic antibiotics do not improve outcomes.
METHANOL AND ETHYLENE GLYCOL. Methanol is commonly found
in windshield washer fluids, 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 producing mild toxicity, it is the metabolites of each product that are
responsible for the serious clinical effects that can follow exposure. 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 mitochondria1 respiration. The development of
serious toxic effects is delayed while formic acid is generated and
accumulates in blood and tissues.
CLlNlCAL 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 10-12 hr, and possibly up
to 24 hr, as the parent methanol is undergoing metabolic activation to its toxic metabolites. Visual disturbances include blurred
or cloudy vision, constricted visual fields, 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
significant poisonings, blindness has occasionally been permanent. 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 significant
exposure has occurred is usually a problem. Methanol blood concentrations are usually available and can rule out an exposure;
however, blood concentrations do not correlate well with toxicity. Formic acid concentrations may correlate more closely with
toxicity; however, these blood concentration determinations are

. .
Poisonings

353

not routintly available. If metbanal blood con~pntrationsare not

available, estimation of an asmolar gap has been recommended
as a surrogate. Serum osmohity is measured by the freezhg
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:
Osmolar gap x 3.2 =estimatedmethanol blood concentration (mg/d~)
TREATMENT. Treatment is discussed later.

lEtbylow 61pd

PATHOPf3YSK)LGGY. Ethylene glycol is membolized by

alcohol dehydrogenase m the Liver to glycoaldehyde, which is
further converted to glycolic acid by aldehyde dehydroganase.
Glycolic acid is metabolized to giyoxylic acid and oxalic acid,
which are responsible for most of the observed toxicity. The
development of serious toxic efects is delayed while these acids
are generated and accumulate in b l d and tissues. Oxafic acid
combines with serum and tissue calcium, causing hypodcemia
and the formation of calcium oxalate crystals.

CLINICAL AND LABORATORY MANlFBTATIOXJk As

with acute mehanol consumption, early symptoms asmciated
with ethylene glycol exposure occur 1-12 hr after ingestion and
include gastric irritation, inciudiig nausea and vomiting, and
CNS effects, including drowsiness and inebriation. Metabolic
acidosis begins ro develop. Approximately 12-24 hr after ethylene 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 occut. Renal failure is caused by the deposition of calcium
oxalate uystaIs in renal tubules.
Ethylene glycol blood urncenttations are often ready available, but as with methanol, the values do not correlate well with
toxicity. Glycolic acid and glyoxylic acid concentrations may correlate more closely with ethylene glycol toxicity, but these determinations are not routinely available. Sodium fluorescein is an
additive in many commercial antifreeze products. It k rendly
excreted and may be visualized in urine up to 6 6 after ingestion
when illuminated with a Wood lamp. This simple test may be
used to confirm 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 follow~ngformula:
Osmolar gap x 6.2 =estimatedethylene glycolconcentration(mg/d~)
Calcium oxalate crystals are commonly observed in urine on
but may not be evident early after exposure. Electrolytes, 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 bicarbonate at doses of 1-2 mEq/kg or, if needed, via extracorporeal
hernofiltration. Witb the prompt institution of effedve aeatment
microscopy,

(discussed later), the need for sodium bicarbonate is afren limited.

In patients with moderate to severe systemic metabolic imbalance, hemoatration m dialysis may be far more effective in correcting these abnormalities wide concurrently enhancing body
elimination of h e toxic alcohol and metabolites (discussed later).
Ethanol is considered the classic antidote for both methanol
and ethylene glycol poisoning because it is preferentially metabolized over methanol and ethylene glycol by alcohol dehydrogenase, thus minimizing the formation of toxic metabolites (see
Table 58-6). The parent compounds are then excreted via the

354

PART VII m Pediatric Drug Therapy

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 profile.
Indications for fomepizole or ethanol therapy are a serum ethylene glycol concentration of >25 mg/dL or a serum methanol concentration of >20 mg/dL, a significantly symptomatic patient,
ingestion of >0.4 mUkg of 100% ethylene glycol or methanol,
and systemic acid-base abnormalities.
Hemodialysis effectively removes ethylene glycol, methanol,
the acid metabolites, and any antidote administered (fomeprazole, ethanol). Thus, specific supplemental doses of either antidote 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, supplemental antidote administration in dialyzed patients.

Clinical and Laboratory Manifestations. Transient, mild CNS

depression is common after hydrocarbon ingestion. Aspiration is
characterized by coughing, which usually is the first clinical
finding. Cough usually begins immediately or within 2-5 min of
the aspiration, and persists. Chest radiographs may be normal for
as long as 8-12 hr after aspiration, but more often will be positive 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 patient's 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 2-3 wk after exposure.
Treatment. Emesis is contraindicated because of the risk of aspirartorl. Like\v~\c,gastric lavage is contraindicated, except under
special circumstances of ingestion of highly toxic hydrocarbons
(carbon tetrachloride), because of the risk of vomiting and aspiration. 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

HYDROCARBONS f I~~clroi.irl~c)~is
triclucle ,i \ v ~ d r.lrrily o t il1crn1~ ~ h t ~ n Lto1111el
. c s 111 tho~1~:111el~
of c o r l i r ~ i c r i rprod~rits.
;~~
X1.1ny
.I p.lrr~iul,lrproduit and c s l > o ~ t r wrll
~-r
t;~c.rors~ i r ~ c r r i i u~lirtlirr
~nr
proci~ric5yctrniri roxlirt!. I ( ~ i , l l tnsiirt\., o r both. N c \ ~ r r h c l r \ c .
J\prr.irlotl o t h!.drtrcarllonr I I T ~ Othe lu11g i;ln le'~clt o >cr~cru\,r\'cn
I ( & - r h ~ c ~ ~ r e r irt~n~g\ - l i l tu! ,n d c r \ c c ~ r ~ ~the
r g n r c J tor prompt .lnrn~
rlrlo m ~ A I X ) S patlcnts.
I'Ix rnosr Irtlprrtant .tJ\t.rsr csiiect oi h!sclrocdrhori\; 1 5 .i~pir;it1o11
prlr~rilorirric( C ~ CC h.lprcr iL)-ll. Xhprratrorl
~ ~ ~ i e u ~ i ~dcvclops.
o ~ ~ i t r rcsplratory
c
trcarnmrnr is supprjrrlrc (.;re
r
(.ortrcosrrroids shcruld he avr~idcdI>cc.ausethey arc
ucunlly clL,iur\ .It rllr tinle o t Ingc,rrori, \vlicn ioughrrig ~ n d ~ : l i a p t c 3943.
riot cifecr~ur.ind may rncrrilsr the risk o t inicetion. I'rt~pliylscric
g,lgging arc crlrllrnort. hut ~ . l n.ilstr Ilc- \eioncl.iry r o \rlnilrlng.
\\hicli ic~rnrltoril>.oiilirs .iker rngeStl(rr1. T h e propcns~r!, o t .I
.qnt~hiotrss \houlJ not hr grvrn I~cc'~uschactcr~al p~leurnonia
hydrrliarhcrr\ to e.lll>e ahplr.lrrc)n p n e u n i o n ~ t ~15\ ~nccsrsrly prilociura In only 3 vrr!. S ~ T I A p~ ~~ s ~ t ' n t , l~ig ~L ' J S ~ S .Rcspirarory
porrrnn;>l to it5 \.rscos~ty.C o r ~ i p ~ ) u n i1l~s 1 t hlot\. vrscos~ry.S L I ~ I ~
farlure ha\ hern cuccctsfull! treated horh with srandard vrntilanirn~.ral<pcrlt\, n.lphrh.1, Irero\cnc. g.~scll~ne,
. ~ n dlarrip o r l , spr-c~il tion and with extracorporeal membrane oxygenation.
r.~pidly .lirri\s s ~ ~ r t ~.in'{
c r \ iover I ~ r g rars.1, ot rhr lung, \vhzn
C#OU--lN-G
'l'hc Inc>stcornrnc)nly
I C Io ~t lo\\
~
-\is~.o\rtyIiydro.~\pirii~cci.
0r1Iy s ~ ~ i~ ~~ lLl I ~ I I{-. ~ 1 ~r111.1
~ ~ r i t Pnrur~scelinsecticicfrs .lrc orgn~ir~pllusphiitC\
,lnd iarharrlate\: hotti ;1rc
'.arbon.; ~icccl lw . i \ l ~ ~ r ~t t ~r ~~ >t .r ~o ri l ~ ~\ ~c tg. r ~ ~ f i irlil~lr\~.
1110111r1\ Joc'i not re\uLt tr(111idt'rrii~lah,orpt~on ot liydrt>ic1rhon\ inhibitors of cholinesterase enzymes. Nerve agents used in
warfare are usually organophosphates. Most pediatric poisonings
o r troni irrgcdstlor~ rn the ~l.\rncc of a\prr'1rlon. G,i>olunc .lnd
l ~ l ~as the result of accidental exposure to insecticides in and
k c r o ~ c n c 'iri1 poorly dl>~orllt.C1.Ivrr often i.lLlrc i o r l ~ ~ J e r ~ ~occur
around the home or farm.
gastrointestinal mucosal irritation as they pass through the
intestines.
Pathophysiology. Both organophosphates and carbamates bind
Certain hydrocarbons, most notably, halogen-substituted comto cholinesterase enzymes, preventing the degradation of acetylpounds, can be absorbed after ingestion, inhalation, or dermal
choline, resulting in its accumulation at nerve synapses. Enzymes
contact. Most of these hydrocarbons have anesthetic properties
affected include acetylcholinesterase or red blood cell
and can cause transient CNS depression. Several chlorinated solcholinesterase, pseudocholinesterase (found in plasma), and neuvents, most notably, carbon tetrachloride, can produce hepatic
~ O ~ O S IcZ~ r ~ r . l \(rlervous
r
rystrrli). I t left unrrratrd. organr~pho\toxicity. A few hydrocarbons have also been associated with renal
ph.ltcs forrn a prrnmncnr borld r o thcsc cnzynles, in.~criva~ing
a n d I)rlrlr rn.irrow to\;lilt!-. L \ r n ~ e n rI \ kncnrn to i.lucc cilncer In
g*
ovsr a u ; ~ r ~ a h lpr r r ~ n d ,
rhcm. 'I'hrh procr?.i, i , ~ l l c ~ lg i ~ occurs
but m;iy occur ,I\; soon 3 5 IS hr to 1-.3 J J ~~ F
hurn'311~
.~irt.r Io~ig-rermc-xpowrr. T h e rri'~lrgrianiy rnnir ctrrriI ' I C S exposure. A
rnonly .>-;\clc~atcliw ~ t l itwnxcnc. 1s c ~ ~ ~ i ~i y ri . tl o. g c ~ i oI i~~ L I ~ C ~ I I prriocl
J.
of \vrcks t o rnonth5 i s rrquired t o rcgrnrratc ~nacr~vatccl
Merhylcclc chloride, tound In sori~i.paint rcmo\.rrs, 15 rnct.ilw.
enzymes. In contrast, carbamates form a temporary bond to the
enzymes, allowing regeneration of the enzymes over several
l i d t r l i ~ r l 9 o 1 1niorioxrJr. N~trol~rr~i.r.nc.,
.i~lilrri~,rid rclarrd
~~i~.\.
cornprlir~~ds
cLin prollircc n i c t h c ~ i ~ ~ ) g l o h r ~ i eAlrtlirmoglo\~~ti
hours.
z
1s 31\0 s u g ~ c s r c d
Clinical and Laboratory Manifestations. Clinical manifestations
cdn I ~ c rdzrir~ficd it1 rhr I.lhorarur!.; ~ t prcsrriic
11 J J r c ~ pot hlooel app1ic.J ti) hltcr pLrpcr r c ~ ~ i i ~ hro\\-n
of organophosphate and carbamate toxicity relate to the accui ~ n s . ~ s11
dr~r,. kIrrhc1tio~1ol~rnrrn1.l
1s trcarcd w ~ t h
the .~nriciorcn~rrli!.leri~ mulation of acetylcholine at peripheral nicotinic and muscarinic
synapses and in the CNS (see Table 58-3). Muscarinic signs and
h l ~ r rlsrr T.~l,lr sx-(r!.
symptoms include diaphoresis, emesis, urinary and fecal incontiA number of volatile hydrocarbons, including toluene, propellants, refrigerants, and volatile nitrites, are commonly abused
nrnit., tearing, drool~ng. J i r o ~ ~ ~ I ~ o r.inti
r l ~ th. r~o n i h o s p ~ 1 ~ ~ 1 ,
by inhalation. Some of these substances can sensitize the
d
rnrosis. Iiyporcnsion, and hl-ndysardis. Nicot~nir:signs ~ n sympmyocardium to the effects of endogenous catecholamines, with
tom? inilrldr muscle \vrnkncss, fascicularion<, trerriors. hypuvc~tthe risk of dysrhythmias and sudden death. Chronic abuse of
tll.i~lt>n(di;lphrag111 p ~ r a l p ~ s hypertrnsi~>n.
),
tachycar~lid. a ~ l d
thcsc agents
l e d ro crrt.lir;~l ,rrropliy. nrurolis!~c.hologic.~I
dysrhythm~as.C:liS cttecrs includc n~alalsr,c c ~ n t u s i r c~i~r l~~, r ~ u m ,
ih:lngc\. l~t'npticr,il rlrurop.~rhy, dntl rcnsl disease csrr Cli.lprcr
\c.lzurcs, ;In4 soriia. Sc-rnptams causecl l>y carhamate toxiciry ;irr
I 13.4). All volL~tilc
Iiydroi.~rl)ons.irr lipicl sol\crnrs ancl i;ln causc
usually less scvcrc. than rhosc seen wrth c\rji;lnophosphatcs. A
dcfi~ttlngrlt rlic sk~rr.prodiic.irlg local ~ r r ~ t ~ r 01;i o n\vitl~prolonged
ci)rnrllorll! L I S ~ C I ~iinenionic f o r the tilosr cornmoll 5)-mptonis
rxpohurc, cl~eniicalburr~s.
~:rf ~ h o l ~ n c r g i cscess
c
is D U M B EELS. wliio~ srdnds for

C . I ~i

.-

.-

Chapter 58

diarrhealdefecation, urination, miosis, bronchorrhea, bradycardia, 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 concentrations 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. Significant
symptoms do not generally occur until measured enzyme concentrations fall to <25% of normal. Red blood cell cholinesterase,
although more difficult to measure, is a better reflection of
enzyme activity in the nervous system. Nevertheless, the magnitude and rate of progression of the patient's clinical findings are
of greatest importance in determining the patient's disposition.
These laboratory acetylcholinesterase determinations are of
limited utility in acute exposures, although they may be of value
in confirming 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. Activated charcoal can be used for gastric decontamination, but for
insecticides, it is of limited value because these highly lipidsoluble agents are rapidly absorbed. Basic supportive care should
be provided, including fluid and electrolyte replacement and intubation, with artificial 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 patient's 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 insecticide's 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 significant organophosphate poisonings, 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 treatment, 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 combustion of any carbon-containing fuel. The less efficient the combustion, the greater the amount of CO produced. Wood-burning
stoves, old furnaces, and automobiles are potential sources.
Pathophysiology. Toxicity develops through at least 3 mechanisms. First, it binds to hemoglobin, displacing oxygen-forming
carboxyhemoglobin (COHb), with an affinity 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

Poisonings

-.

mechanisms to CO toxicity is unclear, the net result is tissue

11\-~31~~1~1.
Cl~r~ical
Mid- L

-s.
Synlp~ornsof CO poisoning are usually proportional to the concentration of COHb in
the blood. COHb concentrations can be measured in almost all
hospital laboratories. Early symptoms are nonspecific and include
headache, malaise, and nausea, which are often confused with
[ h i ~ L I . :It hlgher r x p o w r c Icvc.1~. he;lilashcs hecnrnr severe.

dizzirlrsb. visu.11 ihar~gec,and weakncss Inay be present.

~:lli.rry-rr.drnucosnl colorlr~g~ l n dr e t ~ n h~el~ n o r r h a g emay also he
prrwnr. t h l l d r c n riia~;exprricnct. s!-ncopal cpisoclrs as a frsr
.;!rtiprorn. / i t high concrrlrration>, cclrna, scizurcs, respimrory
111,tabillry. .~nci dc,irh may occur (see Chapter 741. Symptom5
~ 1 ~ ~ 1 . 1 1. 1~yp p r a r'11 C'OHh levels of > I S o % . roxicity is prrsrnr nt
ii
arc urliversal a t
I r \ r l \ ot >20'!,,. a n J w v r r r ~ ~ c u r o l o g rftecrs

.~rlil

levels of >40%.
Treatment. 111 addirion r o grncral cupporrivr carc, treiilrnent o f
0 l w i u ~ n ~ nrequires
g
the ad~ninisrrationof 1011?boxygen. High
cor~icnrrnrionsoi oxygen shorten rhc COlHh half-lik 111 rhe blotxl
. I I ~~ I S L I L . ~ . In Iir,~ltlip volunreers, t l ~ ri:Ol-ib 11,llf-life avcrapcs
i-h hr (r.lrige, 2-7 lir). which is dramariially reduced t r ~dpprox~ o nIOl)'k~ osygen dt
trn~tcly 40-hO rni11 by t h r a t i ~ n ~ n ~ s t r a tof
11or11l.ll,~rmosphrricprexsures b\: .I nori-rebrcarhing tace m x k .
111 i i ~ ~ o
sevrrr
r ~ .~nd/or ihrorlii rsposures. 11)-perlmric oxygen
thtrdpy m.ly he rcquirrd, which a t 2.5-3.0 atnl reduces thr
( . < ) I Ih h.llt-l~ir t o .ipproxrmatrly l i - 3 0 I T I I I ~Sevrrrly
.
poisonccl
p,i[~crirshcnrfit iron1 hyprrh~lricoxygen therapy. 11iJ1carion~
tor
hypcrllar~iosygen include nrurolugic symptunls compatllrlr with
( 0 liolsuning arid a OOHh level of >25"% III ihildrrn a11J pregs
n.1nr Lvornrn. After .I significant exposure, sonic p a t i r ~ ~ rmay
r.\prr~t-~ice
J e l ~ y r d - o n s e t neurorosicir!; \vhich m;iy he pcrm;iIlrIlt. Aggrrsslvc rnrly treatnlenr of patienrs with significanr spmp~ l i r i k of ncurotogic scqucltlc.
toms ma!, c i ~ n i i n ~rhr
(

HYDROGEN CYANIDE
Parhophysiology. C:):a~lidc proclucrs toxicity hy intcrfrrrng w ~ r h
o x ) s r n u w in the iytc)cliro~neouldnsr sysrrru, reculring i r i crl1r1I'ir hyr>oxi<l.
al
occur
Clin~caland L a b o m M d b b t h @ . C l ~ n ~ isymptom\
r.lp1~1lv~ l t t e r51gnjh~3rlt
exposure and include hcadachc. agitatior~
L 1 ~ l L 1 cont~~s~t:in.
105s o f co~i~ciousness,
S ~ I ~ V I I ~ S I O Iand
~ S . cardiac
JysrIivrhlnrLih. Szvrrr nirtaholis acidosis occurs rapidly, a n J death
m.ly oiiur. C:yaniJr Icvcls can be mcasurrd in the hlood. hut resrr
.ire not r e a ~ l ~ lavaild1,lc
y
'1nJ levels do not corrclatr. well with
\\mpronl\. Ccvcrr rl~eraholiiacidos~sin 3 pllrlenr with suspected
cyanide esposul-r ( h r c vicrims) shoulcl hc ~ ~ S L I I rIo~ he
C ~i).3111clc
poi\oning.
Treatrt~ent.The cornerstone of treatment is rapid administration
of hlKh coliccnrr.1tior1s nf 0x?~gr11.rogcrhrr with thc r~ccr>f the
1111, i y L ~ n i d ,1ntiJorr
t.
kit. T h r k ~ ril1sluclc.s nltrlrcs [;i~nylnirrire
,ir~'i hodluln n ~ r r i ~uscd
r ) ro prolluce mcthrmr>glohin. which r r i ~ t s
\ v ~ r cyarl~dc.
l~
torrnlnp iyanmt.thrrnoglobin. The kit also ronrairls
IS give11 t o A3srr11 thc mcraholisrt~of
\ c ~ ~ f ~ t rt ri ~n ~ o s u l t a twhlsh
r.
iyanmetllrn~oglob~rlrc, t ~ c r n o ~ l o hand
~ ~ i r h r less ~ o s i crhloi>.lll,lrr. l l y ~ l r o s o s o l ~ ~ l ~(vitanli11
~ r i i ~ ~ iR,:.,), which I-cacrs c r : ~ t l ~
L ! .rni~lst o produce i);a~iocnhalarnm(vitamin UI:l, is an alrer11~1I I V C ~ t ~ t ~ i l obur
t c . 1s rlot currer~tlyavnilirhle In the 11.5.

m.Expobirrc t o plants, hlxh ~nslcicthc horne and o ~ l t s i d e

111

bztcfrortrds 2nd fields, IS r ~ n cu t thr rnost ctlmrnorl causrs o f u~lirrrrrlt~on.ll poisolling in children. Ingrsrion o f most plant parts
~ i ) in mild. st=lf-lim~tl~~g
effccta (T,lhlr
(lc'dic,. SC~CIS, t l o ~ p t ' ~ -rest~lts
58- 1 I ). The rrcurmenr is syti~prnmacicL I I I supportive.
~
Tlrr inherrnr [usiiity t)i the proC1~1ctis SO low that the l~lgestionof ~ r n a l l
rc-I rnode~.arr cluantitirs of plant rnarcrial is unl~kclyro prorli~ct.

t o x ~ csymptoms.
The potential toxicity of a particular plant is highly variable,
depending on the part of the plant involved (flowers are gener-

P A R T VII

356

P e d i a t r i c Drug T h e r a p y

African violet
Aluminum plant
Aralia, false
Aster
Barberry
Begonia specles
Boston fern
Carnation
Chinese evergreen
Christmas cactus
Coleus
Corn plant

Palm
Dracaena
Fern species (not asparagus fern)
Peperomia
Petunia
Fig
Gardenia
Poinsettia
Geranlum
Pokeberries
Pyratantha
Hen and chtcks
Rose
Honeysuckle
Impatlens
Rubber plant
Jade plant
Schefflera
Snake plant
Kalanchoe
Splder plant
Magnolia
Marigold
Violet
Dandelion
Mother-in-law's tongue
Wandering Jew
Daylily
Yucca
Nasturtium
Dogwood
Norfolk Island pine
'The potential for tox~cityIS dependenr on the magnitudeand amount of exposure These agents are cons~derednontoxicor
min~mallytoxic for mild to moderate exposure The potentialfor toxic~tyincreaser with increased amount of exposure.
to the mucora (dermalloroemphageal) andlot may
Further, many plants contaln subslances that can be ~rritat~ng

All parts
Seed ~ngestionis the must common
presentation
dly nightshade (Atropo
Ielladonna)

All parts are poisonous, but berry ingestion

18 the most common presentation

Leaves and broken seeds of the fruit are the

most polsonous parts

ally less toxic than the root or seed), the time of year, growing
conditions, and the route of exposure. Assessment of the potential severity after a plant exposure is also complicated by the difficulty in properly identifying the plant. Many plants are known
by several common names, which may vary between communities. Poison control centers have access to individuals able to
assist in the proper identification 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

SYMPTOMS
Vomiting
Pallor
Dilated pupils
Tachycardia
Dizziness
Dry mouth
Dilated pupils
Hallucinations
Urinary retention
Agitation
Ataxia
Muscle incoordination
Convulsions
Coma
Gastrointestinalupset
Salivation
Flushing
Convulsions
Coma
Arrhythmias

In
trees

All parts of the tree are toxic,except the

pulp of the berry

)dy nightshade (Soionurn

lulcarnara) "Bittersweet"

All parts of the plant are toxic, particularly

unripe fruits

coo pint (Arum maculatum)

'r (Sornbucus n~gra)

All parts ofthe plant are mildly toxic,

part~cularlyunripe berries

tletoe

All parts of the plant are toxic except the

flesh of the berry

barb

The leaves contain oxalates and are toxic

Nausea
Vomiting
Antichollnergic effects
Drowsiness
Bradycardta
Anhyrhmia
Convulsions
Drowsiness
Ataxia
Nausea
Vomiting
Oropharyngeal irr~tation
Mucosal irritation,edema,and occasionally
ulceratlon
Local skin irritation and blistering
Nausea
Vomiting
Dizziness
Tachycardia
Convulsions
Nausea
Vomiting
Diarrhea
Muscle weakness
Pupil dilation
Diuresis
Bradycardia can occur
Symptoms of gastric irritation predomtnate
Oxalares chelate calcium and hypocalcemia
can complicate ingestion
rooms Arch Dis ~ h h d2002; 87 403-406

--

From R~ordanM,Rylance G,Berry K Poi!#nil

old product8,pl

MANAGEMNT
Activated charcoal if>5 seeds ingested
Observation

Activated charcoal if any plant material has been ingested;additional methods of gastric
decontamination if >5 berries ingested; intestinal motility may be impaired and
absorption prolonged
Treatment 18 supportive, physostigmine should be reserved for cases where life-rhreatening
symptoms do not respond to adequate supportive measures
Symptoms can be delayed for up to 12 hr after ingestion
Hospital admission is mandatory
If only the pulp of the berry was eaten, or if stones were swallowed whole, no treatment is
required
Activated charcoal is given if leaves or broken seeds were eaten
Symptoms can be delayed for up to 4 hr
Only toxic in large quantities
Act~vatedcharcoal is given
Asymptomatic children should be observed for 4 hr
Gastric decontamination does not seem to influence outcome
Treatment is supportive
Serious cases are very rare

Activated charcoal is given if >5 ripe berries or any unripe berries have been consumed
Asymptomatic patients should be observed for 8 hr
Treatment is supportive
Treatment is symptomatic
Analgesia and antihistamines
Effects appear rapidly;observation ofasymptomat~cchildren is unnecessary
Consider gastric decontamination if >I0 benies were consumed
Treatment is symptomatic

Symptoms are unlikely if .c3 berries were tonsumed

Treatment is symptomatic;atropine is given for bradycardia
Effects can last for several days

Milk may help to neutralize oxalic acid

Treatment is otherwisesupportive

Chapter 59

nurseries can identify outdoor plants surrounding the child's

primary living environment.

Acetylcysteine (Acetadote) for acetaminophen overdosage. Med Lett Drugs

Ther 2005;47:70-71.
American Academy of Clinical Toxicology & European Association of Poisons
Centres and Clinical Toxicologists: Position paper: Single-dose activated
charcoal. Clin Toxicol 2005;43:61-87.
Bailey B: Glucagon in P-blocker and calcium channel blocker overdoses: A systematic review. J Toxicol Clin Toxicol 2003;41:595-602.
Barry JD: Diagnosis and management of the poisoned child. Pediatr Ann
2005;34:937-946.
Belson MG, Sullivan K, Geller RJ: Beta-adrenergic antagonist exposures in
children. Vet Hum Toxicol 2001;43:361-365.
Bernal W, Donaldson N, Wyncoll D, et al: Blood lactate as an early predictor
of outcome in paracetamol-induced acute liver failure: A cohort study.
Lancet 2002;359:558-562.
Boyer EW, Duic PA, Evans A: Hyperinsulinemia/euglycemia therapy for
calcium channel blocker poisoning. Pediatr Emerg Care 2002;18:36-37.
Boyer EW, Shannon M: The serotonin syndrome. N Engl J Med 2005;
352: 1112-1 120.
Bryant S, Singer J: Management of toxic exposure in children. Emerg Med
Clin North Am 2003;21:101-119.
Centers for Disease Control and Prevention: Nonfatal, unintenrional medication exposures among young children, United States, 2001-03. MMWR
2006;55:1-5.
Centers for Disease Control and Prevention: Recognition of illness associated
with exposure to chemical agents, United States, 2003. MMWR 2003;
52:938-940.
De Silva HA, Fonseka MMD, Pathmeswaran A, et al: Multiple-dose activated
charcoal for treatment of yellow oleander poisoning: A single-blind, randomized, placebo-controlled trial. Lancet 2003;361:1935-1938.
Dugandzic RM, Tierney MG, Dickinson GE, et al: Evaluation of the validity
of the Done nomogram in the management of acute salicylate intoxication.
Ann Emerg Med 1989;18:1186-1190.
Eddleston M, Eyer P, Worek F, et al: Differences between organophosphorus
insecticides in human self-poisoning: A prospective cohort study. Lancet
2005;36:1452-1459.
Eddleston M, Karalliedde L, Buckley N, et al: Pesticide poisoning in the developing world: A minimum pesticides list. Lancet 2002;360:1163-1167.
Eddy 0, Howell JM: Are one or two dangerous? Clonidine and topical imidazolines exposure in toddlers. ] Emerg Med 2003;25:297-302.
Ener RA, Meglathery SB, Van Decker WA, et al: Serotonin syndrome and other
serotonergic disorders. Pain Med 2003;4:63-74.
Eyal D, Molczan KA, Carroll LS: Digoxin toxicity: Pediatric survival after
asystolic arrest. Clin Toxicol (Phila) 2005;43:51-54.
Fugh-Berman A: Herb-drug interactions. Lancet 2000;355:134-138.
Gleyzer A, Traub S, Hoffman RS: Calcium channel blocker ingestions in children. Am ] Emerg Med 2001;19:456457.
Gracia R, Shepherd G: Cyanide poisoning and its treatment. Pharmacotherapy 2004;24:1358-1365.
Henry K, Harris CR: Deadly ingestions. Pediatr Clin North Am 2006;
53:293-315.
Kanabar D, Volans G: Accidental superwarfarin poisoning in children: Less
treatment is better. Lancet 2002;360:963.
Klein-Schwarz W: Trends and toxic effects from pediatric clonidine exposures.
Arch Pediatr Adolesc Med 2002;156:392-396.
Love JN, Enlow B, Howell JM, et al: Electrocardiographicchanges associated
with beta-blocker toxicity. Ann Emerg Med 2002;40:603-610.
Manoguerra AS, Erdman AR, Booze LL, et al: Iron ingestion: An evidencebased consensus guideline for out-of-hospital management. Clin Toxicol
(Phila) 2005;43:553-570.
Michael JB, Sztajnkrycer MD: Deadly pediatric poisons: Nine common agents
that kill at low doses. Emwg Med Clin North Am 2004;22:1019-1050.
Ralston ME. This issue: Managing emergencies part 2. Pediatr Ann 2005;
34:921-923.
Riordan M, Rylance G, Berry K: Poisoning in children 1: General management. Arch Dis Child 2002;87:392-396.
Riordan M, Rylance G, Berry K: Poisoning in children 2: Painkillers. Arch Dis
Child 2002;87:397-399.
Riordan M, Rylance G, Berry K: Poisoning in children 3: Common medicines.
Arch Dis Child 2002;87:400-402.
Riordan M, Rylance G, Berry K: Poisoning in children 4: Household products, plants, and mushrooms. Arch Dis Child 2002;87:403-406.

Herbal Medicines

357

Riordan M, Rylance G, Berry K: Poisoning in children 5: Rare and dangerous

poisons. Arch Dis Child 2002;87:407-410.
Schmidt LE, Knudson TT,Dalhoff K, et al: Effect of acetylcysteine on prothrombin index in paracetamol poisoning without hepatocellular injury.
Lancet 2002;360:1151-1152.
Sinha Y,Cranswick NE: Clonidine poisoning in children: A recent experience.
] Paediatr Child Health 2004;40:678-680.
Spiller HA, Klein-Schwarz W, Kolvin JM, et al: Toxic clonidine ingestions in
children. J Pediatr 2005;146:263-266.
Turrina S, Neri C, De Leo D: Effect of combined exposure to carbon monoxide and cyanides in selected cases. J Clin Forensic Med 2004;11:264-267.
Verhulst L, Waggie Z, Hatherhill M, et al: Presentation and outcome of severe
anticholinesterase insecticide poisoning. Arch Dis Child 2002;86:352-355.
Weaver LK, Hopkins RO, Chan KJ, et al: Hyperbaric oxygen for acute carbon
monoxide poisoning. N Engl J Med 2002;347:1057-1067.
Woolf A, Litovitz T: Progress in the prevention of childhood iron poisoning.
Arch Pediatr Adolesc Med 2005;159:593-595.

ha.1Medicines
)(amper and Peule Bndinn

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 fibrosis, and inflammatory bowel
Ji\c'~\t.. Iwt cvt,n prei-iously healthy children seer1 In prim;~rycare
?rnergenc\ dep.~rtmentstreclucnrly u\r lirrhs, ho111c remedic\,
I \ also ctlnimon among rcrnagcrs; 41'!k o f
a J o l c ~ i e n r 5reported having used hcrbs nnJ supple~ncr~ts.
such a h
c i h ~ n a c e ; ~pnhrng,
,
ginger, Gitrkgo h t l o h ~ .grren rca. ornt.g;1-.?
1.1rry ac~iis,s o y supplenlr~its.St. John's w o r t , valcriun, 01- r i m .
Fc\\rc.r tharl 'I! of p ~ t i r n t sw h o use herhs and rupplcments h d v e
ralkril w ~ t hthrir p h y s ~ c ~ aahour
n
their irw, in part Ixcausr pl~ysiC I . I I I \ have nor rour~nely.lsked pntients and Families a h o ~ i ttheir
11,t. ~ r these
t
prnclllct\.
Hlarhal producrs nrr wtilrly p c r i c ~ v r dss 17eing s a t c hecsusr
rlic\- arc nati~ral.They are also frcqurntly consiclcrcd a5 hav111g
I p
~ t~~ [ d ~ ~ t i .oI ~n) O
s LII
Io\v rht.rapruric ztfiidcy. owlng to a ~ R U C 11i
rlizm 111 \ s ~ r n r i f i ijourni~ls. C:onvCnrlonnl wtsdom may l)r rrllsr.1ker1, rrsulting in r ~ s k sto pnticntr AIIJprovidrrs.
~\lthough rhcY .are generally y a k , llrrhal products can cauw
scrlcru, [oxic~ry.Xiutc hepattc rosicity ;lrid r t r ~ r l im;ly res~ilrt'rr~rn
Ingcsrlon o t even trn;ill Jmounts r>t .4wrrrr~itLr~nushrr~onls:
overd o \ ~ . \of other hcrlx. \LICII as dig~mlih,ephedra, 311d p ~ ' n 1 1 ~ r o ~ a I
2nd

or wpplrmer~rs.llse

can cause life-threatening complications. Ephedra has significant

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
Ii~oricccdn i a u \ e wc'ere licpat~co r renal damage. cailcrr. (or litcrlirc.~te~irnp
clectrol\re d i s t ~ ~ r b a n c eEarl
s . Grry tea causes rnusslc
cr.lrnp.;, p . l r ~ \ r h r s i ~ ~91id
s , blurrcJ c~silxi.whrrcas Japanese s t d r
. i n ~ \ rioittn .I i o ~ i t i i ~ l i i ~ lof
a ~C:h~nesr
it
star anisc) is 3 nelrroroxln.
c
I-:\,ri~~vlicnan hrrlr I S snfc when used cnrrcctly, it car, ~ i u s niil~i

or severe toxicity when used incorrectly. Tea tree oil is safe when
applied to mild fungal infections of the skin, but can cause stinging and irritation when applied to eczema; if taken orally, it can
cause coma in small children. Although peppermint is a commonly used and usually benign gastrointestinal spasmolytic
(included in after-dinner mints and teas and increasingly used to
ease discomfort during colonoscopy), it can exacerbate gastroesophageal reflux in other patients.

358

. .
PART VII

Pediatric Drug Therapy

Coffeeltea

None recently in children

Epidemiologic data suggest fewer

symptoms in coffee drinkers

Tachycardia, ~nsomnia,jltteriness,decreased
appet1te;potential interact~onwith p agonists

Shinpi-to
Salboku-to

None in children
Yes,~nadults

Yes, in historical data

Yes,tortitostero~d-sparingeffects
in adults

Unknown,potent~alinteraction with leukotriene blockers

Unknown;potent~alincrease in corticosteroid adverse effects

Ma huang (Ephedraswica)

Yes

Yes

Licorice (G~yrrhizeglobro)

No
No

Case serles suggest cortitosteroidsparlng effects

Case series in adults

Cardiovascular and central nervous system tox~clty,deaths

reported,potential interacton with p agonists
Pseudohyperaldosteron~sm,hypertension,per~pheraledema,
potential increase in cort~costeroidadverse effects
Unknown

Yes,in adults
No

Yes
Yes, ~na pilot study

Unknown
Unknown

a forskolri
Tylphora ~ndica
Ginkgo biloba

Methylxanthlnes
Increased intratellular CAMP
Bronchodilator
Blocks 5-lipo-oxygenase and phosphollpaseA,
inhibits 11 p-hydroxylase (blocks sterold breakdown)
Blocks 5-lipo-oxygenase
lnhlbits platelet-activating factor
p Agon~st
Bronthodilator
inh~bits11 p-hydroxylase and tortisoi breakdown
Decreased CAMPmetabolism
Bronchodllator
Unknown
Platelet-activating factor antagonist
Ant~oxidant
Blocks leukotriene synthes~s

In vitro and anrmal

Hypersensit~vtty18 rare
data support use
Bee pollen
No
No
Anaphylaxis
r ~ v i p w[nntpmn Ppdrnfr 1W lh.167-195
From Kemper KJ. Lester MR.Alrernat~veasthma therap1es:An ev~depr~-lurpd
eAM~cycl~c
adenos~nemonophosphare,RCT,random~zedcontrolled
ns (ALum cepo)

No

ATlVE HERBS

SCIENTIFIC STUDIES

nan chamomile

In controlled trials, chamomile and its constituents have

positive effects as a m~ldsedative

Hops (Humulus lupulus)

hdvd kava (Piper

methysticum)

Lavender (Lovandulo)

Lemon balm (Melissa

tficmalisi

ionflower (Passifloro
1lato)
Valerian (Voleriona
~fficinalis)
,

c-

I -

POTENTIAL ADVERSE EFFECTS OR INTERACTIONS

Unknown

ADULT DOSE

Tea: 150 mL of boiling water over 3 g fresh flower heads,

Adverse effects: Allerglc reactions
steep for 5-10 min;3 x day
Pregnancyand lactation: No known adverse effects in pregnancy,
lactatlon,and ch~ldhood
Drug interactions: None known
Tea: 0.5-1.0 g dried hops before bed,typicaily in combination
Historical and anecdotal use
Adverse effects: Allergic reactrons,skin irritation
with valerian
Controlled trials have used hopslvalerian combinations; Pregnancy and lactation: No data available
Drug interactions: Sedative activity increasesthe sleeping time
these show improvements in sleep with the
combination
rnduced by pentobarbital
Capsules: 6t-120 mg kava lactones, up to 300 mg of kava
Randomized controlled trials in adults show anxiolytlc
Adverse effects: Drowsiness, 1ethargy;slowed reaction time;
lactones daily to dried rootlrhizome;1.5-3 0 glday in
effects
withdrawal syndrome; chronic use may lead to yellow, dry skin and
red eyes
divided doses
Pregnancyand lactation: Insufficientinformation available
Drug interactions: May potentlate sedative and anxrolytic effects
of other herbs and medications
Massage aromatherapy: 1-10 mL of the essential oil can
Animal data,adult case series,and controlled trials
Advene effects: Allergies with top~caluse; tox~c~flarge doses taken
suggest anticonvulsant and sedative effects
be added to 25 mL of a carrier oil
internally
Bath soak: add '/,-'I2
cup of dried lavender flowers to hot
Pregnancyand lactation: Historically contraindicated during
bath water
pregnancy owing to possible emmenagogue effects; no documented
adverse effects
Drug interactions: May potentiate sedative and anticonvulsant
effects of other drugs
Adverse effects: Allergic reactions are possible
Tea: 2-3 g of dried herb,steeped in water;usually tombrned
Animal data suggest sedatlve hypnotic effects
wtth valerian or lavender
All RCTs have examined lemon balmlvaler~an
Pregnancy and lactation: Insufficient data;generally recognized
combinations; most show enhanced sleep quality
as safe
Drug interactions: None known
Tea: 0 25-1 g (about 1 tsp of crushed dried flowersltup
Case repom and historrcal use; most often combined
Adverse effects: Allergic reactions are posslble
of water)
with other herbs,such as valerian
Pregnancyand lactation: Insufficient data
Solid extract 150-300 mg (sold in capsules) daily
Drug interactions: None known
Random~zeddouble-blind placebo controlled stud~es
Tea: 2-3 g of fresh or dr~edrootlcup; 1-3 x day
Adverse effects: Headaches, insomnia
in adults show decreased sleep latency and
Pregnancyand lactation:Insufficient data
Capsules: 400 mg before bed
improved sleep quality
Drug interactions:Sedatlve activity increases the sleeping time
induced by pentobarbltal
lip Pediatr 2W2;19(2).i
~ndGardiner eKemper K1:HerbsIn pfd~atricand adolescent rnedic~nePediatr Rev 2

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 reflect the contents or the concentrations of ingredients. Herbal products may be unintentionally
contaminated with pesticides, animal wastes, or the wrong
herb that was misidentified during harvesting. Products from
developing countries (e.g., Ayurvedic products from South Asia)

ACTION
Soothinglemollient
Antl-inflammatory
Antiviral
Antibarter~al
Antifungal
iom Gard~nerP, Coles D, Kernper KI: The

HERBISUPPLEMENT FOR TOPICAL USE

Aloe, calendula
Aloe, charnom~le,eveningprimrose otl,lemon balm
Aloe vera,calendula, chamom~le,lemon balm
Aloe vera,calendula,chamomile, lavender, lemon balm, tea tree 011
Lavender,tea tree oil
skinny on herbal remedies for dermatolog~cd~sorderiContemp Ped~on 1
-

aatum (monkshood,
wolfsbane)

Diester alkaloids: Hypaconitine and

aconitine (aconitine increases
permeabil~tyfor sodium ions and
slows down repoarization,leading
to paraiyss ofthe nerve)

Facial neuralgia and sciatica

Headache and migraines
Rheumatic pain,arthritis,gout
Pericarditis sicca

Artemisia obsinthium
(wormwood)

Thujone and isothujone:

Neurotoxins

Anorexia
Dyspeptic conditions
Liver and gallbladder disorders

AtrOpii aeiiaoonno
(deadly nightshade)

Alkaloids: Hyoscyamine (the L-lsomer

of atropl~ne)

Gastrointestinal symptoms
Cardiac insufficiency and
arrhythmia
Asthma

Ayurvedic herbal
remedies
gitolis purpurea
(foxglove)

Contaminated with lead,mercury,or

arsenlc
Cardioactive glycosides: Purpurea
glycos~de,digitox~ngitoxin

Traditional medicine from India,

many purposes
Ulcers, bolls, headaches, abscesses,
paralysis,cardiac insufficiency

Alkaloids: Ephedrine,pseudoephedrine
(stimulates sympathomimetic
receptors and the central nervous
system)

Decongestant for upper respiratory

infection
Asthma
Welght loss
Stimulant

Anisatins; block raminobutyr~c acid

Colic in Latino and Caribbean

populations
Expectorant
Asthma
Spasmolytic
Emetic
To induce mental clarity and a
feeling of well-being

rhedra sinica (ma huang)

Common names.
Miner's tea
Mexican tea
:sert herb

star anise tea)

)behainflata (lobella)

Piperidine alkaloid: i-Lobeline

(stimulates nicotinic receptors)

ngdan xieganwan

Aristolochic acid

Enhance health

lentha puleqium
(pennyroyal)

Pennyroyal oil has a hepatotoxic effect

Acute polsonlng is not found with
proper administration of the
designated therapeutic use of
pennyroyal leaf; however,the drug is
not recommended owing to
hepatotoxicity
lndole alkaloids
Yohimbe: a,-Adrenoreceptor
antagonist

Insect repellent
Respiratory illness
D~gestlvedisorders
Emmenagogue
Abort~fac~ent
Wound treatment
Gout
Sexual disorders
Exhaustion
Improve muscle func [on

Triterpene saponlns (irritate mucous

membranes)
Lectlns (toxic)

Anti-inflammatory
Arthritis
Cancer
Emetic and cathartic
Rheumatism

hytolacca americana
(pokeweed, American
nightshade)

Stramonium folium
(jimsonweed)

Alkaloids: Hyoscyamine (the

L-somer of atropine)

V I ~ album
J ~
(mistletoe)

Alkalo~ds
Viscotoxins (Viscumalbum) cause
hypotension, bradycardia, and
arterial vasoconstriction
Lectins

From GKa'remper

KJ.Herbs for sleep problems.ContempO'rO22,6:98-7

Nausea,vomiting, hypersalivation
Central nervous system: Paresthesias, muscular weakness,
dizziness,ataxia,seizures, coma
Cardiac: Bradycardia, hypotension, rhythm disorders

Mental status changer: Restlessness,vertigo, tremors,

agitation, seizures, headache
Vomiting,stomach and intest~nalcramps
Rhabdomyolysis and renal failure
Anticholinergic reaction: Tachycardia, hyperthermia,
mydriasis, urlnary and bowel retention, restlessness
Nervous system and respiratory depression

Acute or chronic heavy metal toxicity

Supportive care
Gastric lavage
Actlvated charcoal
Treatment of symptoms
Activated charcoal
Benzodiazepine for seizures and sedation
Vasodilators for hypertension
Lidocaine and P blockers for arrhythmias
External cooling if temperature is >lOZF
Hydration therapy

Gastrointestinal:Nausea and vom~ting,abdom~nalpain,

diarrhea
Central nervous system: Anxiety, headache, dizziness,
tremors, seizures, paresthes~as,euphoria
Cardiac: Arrhythmias, bradycardia, transient increase In blood
pressure, decreased respiratory rate
In overdose,lobeline may cause hypotension
D~aphoresis,muscle fasciculations and weakness,tremors,
respiratory depression
Dermat~tis
Renal interstitial fibrosls
End stage renal failure
Renal cell carcinoma
Uterine contractions
Gastrointestinal: Nausea,vomiting, abdominal pain, hepatitis
Neurotoxin: Delirium,dizziness,convulsions,seizures,paralysis,
encephalopathy, coma
Renal failure and hypertension
Shock and disseminated lntravascular coagulation
Contralndicated in pregnancy
Adverse reactions: Dminess, headache,anxlety, hypertension,
ind~gestion,rash, insomnia, tachycardia, tremor,vomiting,
hallucinations, nervousness, paresthesias, hypothermia,
salivation, mydriasis, diarrhea, palpations, tachycardia
Contraindicated in kidney and liver disease
Dizziness, somnolence, nausea, vomiting, diarrhea,tachycardia,
hemorrhagic gastritis, hypotension, lymphocytosis, headache,
respiratory depression,seizures

Supportive care
Gastric emptying
Activated charcoal
Benzodiaze~ines

Antineoplastic adjuvant
Antihv~ertensive
Nervous disorders- calmative agent
Rheumatism
Antispasmodic
and Gardiner li Kemper KJ Herbs ~npedl-I

In high doses, leads to restlessness, manla, hallucinations, delirium

Overdose:Tachycardia,mydriasis,flushing,dry mouth,
decreased sweating, miction, constipation

I
I

Gastric lavage
Physostigmine given in consultation wlth z
poison specialist
External cooling if temperature is >lOZF
Benzodiazepines
Hydration
Depends on heavy metal

Nausea and vomiting, headache, loss of appetite

Cardlac rhythm disorders
Central nervous system: Stupor, confusion, visual
disorders,depression, psychosis, hallucinations
Cardiac: Hypertens~on,card~omyopathy,myocardial
infarction,
arrhythmias
Central nervous system: D~rziness,restlessness, headaches,
anxiety, hallucinations, tremors, seizures, psychosis, strokes
Nausea and vomiting
Contralndicated in diabetes or hypertension,angle-closure
glaucoma,anxiety,prostate adenoma, thyroid disease,
pheochromocytoma
Seizures,tonlc postures, myoclonus, hyperexcitability, irritability

.c

Asthma and cough

Diseases of the autonomic
nervous system

Supportive care
Dioxin-specific antiboaies, unless nistory
e~cludtscardiac glyiosides
Do not give ipecac
Actlvated charcoal and gastric emptying
may help
Avoid type 1 antiarrhythmics
Supportive care
Benzodiazepines

Recovery with supportive care within 48 h

Supportive tare

Supportive care
N-Acetylcysteine

Gastric emptying
Activated charcoal
Antiarrhythm~cs
Hydrat~on
Hydration therapy,electrolyte correction
gastric emptying
Activated charcoal
Electrolyte replacement
Emesis should not be induced if patient is
experiencing symptoms of overdose
Supportive care
Gastric lavage
Decreasing temperature
Physostigmine
Benzodiazepines
Supportive therapy
Data inconciusive for inducing emesis
Activated charcoal

Fever, headaches, nausea,vomiting, d~arrhea,bradycardia,angina,

chanqe in blood pressure,se~zures,confusion, hallucination,
allergic reactions, miosls, mydriasis,chills,coma
2 reported deaths in the last 35 yr;most ingestions lead to
miid reactions
adoiescent rneditine.Ped~atrRev 2OW,21.44''

360

. .
PART VII

Pediatric Drug Therapy

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 30-40%
of Asian patent medicines include potent pharmaceuticals, such
as analgesics, antibiotics, hypoglycemic agents, or corticosteroids; 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. John's 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 subtherapeutic 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-inflammatory effects and adverse effects of glucocorticoid 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 efficacy 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 specific medical conditions, product labels may make "structure-function" claims. A label may claim that a product "promotes 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
FDA's MedWatch program; failure to d o so limits the FDA's
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-

~ERIODICALS PrescribersLeuer. Therapeutic Research Center (209-472-2240)

Review ofNuturolProduas Facts and Comparison (1-800-223-0554)
WEB SITES

AJ0
Azarcon
Azogue
Cebolla
Cenela
Clavo
Com~no
Epasote or Herba Sanctl Mariae
Estafiate
Eucalipto
Granada
iengibre
Limon
Manran~lla

Garlic
Lead tetraox~de
Mercury
Onion
Cinnamon
Cloves
Cumin
Wormseed
Wormwood
Eucalyptus
Pomegranate
Ginger
Lemon
Chamomile

Oregano
Pelos de elote
Sav~la
Siete jarabes

Oregano
Corn silk
Aloe vera
Mixture of syrup of sweet almond,
castor 011,balsam resin, wild cherry,
licorice, cocillana bark, honey
Thyme
Cat's claw
Valerian
Spearmint

Tomillo
Una de gato
Valeriana
Yerba buena

Not a plant
Not a plant
ALum cepa
finnomomurn aromoticum
Eugen~aaromati(a
Cuminum cyminum
Chenopodium anthelm~nti(um
Artemisia absinthium
Eucalyptus globulus
Punlco granarum
Zingiber officinale
fitrus limon
Anthemis nob~lisor
Chomomilla recutito or
Matri(ona charnomillo
Origanum vulgare
Zea mays
Aloe vero

Thymus vulqam
Uncork?tomentoso
Valerianoofficinalis

I I

Academic
Longwood Herbal Task Force: http:l/www.mcphs.edu/MCPHSWeb/herbal
Memorial Sloan-Kettering Cancer Center: hnp://ww.mskcc.org/msktdhtml/l157O.h
University ofTexas M.D. Anderson Cancer Center:
http:l/www.mdanderson,~g/departmentsICIMER/dInde~,ch?pn=6EB86A59EBD9-1 lM-8101M)508BM13A14
Wake Forest University School of Medicine, BestHealth:
hnp:/lww.besthealth.c~mlcam/The~Herbs~S~ppkment~htm
Government
FDA MEOWATCH, monitoring program for reporting adverse effects:
http:/lwww.fda.govlmedwatch (1-800-FDA-1088)
InternationalBibliographic Information on O~etarySupplements (IBIDS):
http://odsad.nih.gov/databases/ibids.html
National Cancer Institute:http:l/www.cancer.gov/cam
National Center for Complementaryand Alternative Medicine:
http://wwwnccam.nih.gov/health/bonle
I
NIG Office of Dietary Supplements: hnp:llodp.ad.n~h.gov
I
US. Department of Agriculture Food and Nutrition Center:
I
http:/lwww.nal.usda.govlfnicletextl0MX)15.html
U.S.Food and Drug Administration Office of Dietary Supplements:
http:llvm.cfsan.fda.gov/-dms/supplmnt.html
Nonprofit
Amer~canBotanicalCouncil: hnp:llwww.herbalgram.org
Children's Hospital and Boston Medical Center:www.holisiukids.org
The Natural Pharmatist:www.tnp.com
Subscription Products
Mitromedex Internet Health Care Series:www.micromedex.com
Natural Medlcine Comprehensive Database~http:/lwww.naturaldatabaserom
Natural Standards:ww.naturalstandards.com
Consumerlabs:www.consumerlabs.com
Toxicology lnformation
Toxicology Information ResourceCenter:
http:/lwww.ornl.govlTechResources/tirclhmepg.html
TOXLINE andTOXNET,from the National Library of Medicine:
http:/lsis.nlm.nih.gov/ToxSearch,htm

I
I

I
I

I
I

- -

tion, St. John's 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 significant analgesia for children with mild to moderate otitis media. Entericcoated 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 7-12 yr of age use 'I2of the adult dose, children 3-6 yr of age use 'I4of 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 0 , Kolrno 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;9:58-61.
Ball SD, Kertesz D, Moyer-Mileur LJ: Dietary supplement use is prevalent
among children with a chronic illness. J Am Diet Assoc 2005;105:78-84.
Centers for Disease Control and Prevention: Suspected moonflower intoxication-Ohio, 2002. M M W R 2003;52:788-791.
De Smet PAGM: Herbal remedies. N Engl J Med 2002;347:2046-2056.

Chapter 59 w Herbal Medicines

Finkel RS: Blue cohosh and perinatal stroke. N Engl J Med 2004;351:
302-303.
Finsterer J: Earl Grey tea intoxication. Lancet 2002;359:1484-1485.
Garrard J, Harms S, Eberly LE, et al: Variations in product choices of frequently purchased herbs. Arch Intern Med 2003;163:2290-2295.
Ize-Ludlow D, Ragone S, Bruck IS, et al: Neurotoxicities in infants seen with
the consumption of star anise tea. Pediatrics 2004;114:e653-e656.
Kline RM, Kline JJ, Di Palma J, et al: Enteric-coated, pH-dependent peppermint oil capsules for the treatment of irritable bowel syndrome in children.
J Pediatr 2001;138:125-128.
Koretz RL, Rotblatt M: Complementary and alternative medicine in gastroenterology: The good, the bad, and the ugly. Clin Gastroenterol Hepatol
2004;2:957-967.
Laing C, Hamour S, Sheaff M, et al: Chinese herbal uropathy and nephropathy. Lancet 2006;368:338-339.
Lanski SL, Greenwald M, Perkins A, et al: Herbal therapy use in a pediatric
emergency department population: Expect the unexpected. Pediatrics
2003;111:981-985.
Markowitz JS, Donovan JL, DeVane CL, et al: Effect of St. John's wort on
drug metabolism by induction of cytochrome P450 3A4 enzyme. JAMA
2003;290:1500-1504.
McBride BF, Karapanos AK, Krudysz A, et al: Electrocardiographic and hemodynamic effects of a multicomponent dietary supplement containing
ephedra and caffeine. JAMA 2004;291:216-221.
Mills E, Montori VM, Wu P, et al: Interaction of St. John's wort with conventional drugs: Systematic review of clinical trials. BMJ 2004;329:27-30.

361

Saper RB, Kales SN, Paquin J, et al: Heavy metal content of Ayurvedic herbal
medicine products. JAMA 2004;292:2868-2873.
Shekelle PG, Hardy ML, Morton SC, et al: Efficacy and safety of ephedra and
ephedrine for weight loss and athletic performance. JAMA 2003;289:
1537-1544.
Sibinga EM, Ottolini MC, Duggan AK, et al: Parent-pediatrician communication about complementary and alternative medicine use for children. Clin
Pediatr (Phila) 2004;43:367-373.
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. ] Pediatr
Gastroenterol Nutr 2001;33:S17-S25.
Taylor JA, Weber W, Standish L, et al: Efficacy and safety of echinacea in treating upper respiratory tract infections in children: A randomized controlled
trial. JAMA 2003;290:2824-2830.
Turner RB, Bauer R, Woelkart K, et al: An evaluation of Echinacea angustifolia in experimental rhinovirus infections. N Engl J Med 2005;353:
341-348.
Wilson KM, Klein JD: Adolescents' use of complementary and alternative
medicine. Ambul Pediatr 2002;2:104-110.
Yussman SM, Ryan SA, Auinger P, et al: Visits to complementary and alternative medicine providers by children and adolescents in the United States.
Ambul Pediatr 2004;4:429435.