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).
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.
GNE
ENtYMEITARGET
DRUG
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
....
- - - - - - . .....- -
..
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)
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
323
Treatment Outcome
fi
Success
Failure
Treat w~thalternat~ve
drug
'Dlug
*-c
324
. .
PART V I I
.-
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
325
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
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
328
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-
Chapter 56
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
I
t
Myelosuppression
wt/mut
I I I
wvwt
L Toxicity
1'Risk of relapse
330
W MC
- 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
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
rlic rrlc,iw
~c\mpo[~~
.~frc.r
i c l Illtr'lvc.nollc
d r ~ .~I L ~yI T I I I I -
I\tr.trlc>li
332
. .
PART VII
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
Increasing
Drug concentration
filtration rate.
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
65
35-44
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
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.
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 / ~ )
-.
(0.693)(Vd)
t1/2
ADDITIONAL CONSIDERATIONS
METHOD OF DRUG ADMINISTRATION. Intravenous administration
of a drug is not always rapid or complete. The length of time nec-
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).
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
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
.: -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)
-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
-1 Absorption'
I'r'
::
.1Digoxin effect
'T' Digoxin toxicity
I I
'
Digoxin
7' Anticoagulation
c p
ADVERSE EFFECT
UOROQUINOLONES
[acids
?ophylline
11,*
'
IITERA(T1NG AGENT
.
.
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
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
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
THEOPHYLLINE
Barbiturates
0-Adrenergic blockers
I l ! , I1 I
..
' '
Neurotoxicny
Cimetdine effect
1'Cyclosporine toxicity
-1 Absorption
1'Sedation
.;'
-If.
, -
Megaloblastic anemia
.1Blockade
1'Phenytoin toxicity
I
I
Chapter 58
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
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%)
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&.
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
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
Mydriasis
CARDIAC SIGNS
Tachycardia
Bradycardia
Hypertension
Hypotension
RESPIRATORY SIGNS
Depressed respiration
Increased respiration
Pulmonary edema
CNS SIGNS
Ataxla
Coma
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
-
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
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
It/
I.,
.
Antihistamines
Alcohol
.,
Anticonvulsants(especialiy
phenytoinand
carbamazepine)
a;
Methemoglobinemia
~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
!. -
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
342
PART VII
. . ........
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
Chapter 58
N-Acetylcysteine (Mucomyst)
-Aterylcysteine (Acetodote)
II
Atropine
Benztroplne (Cogentin)
Cyanide antidote kit
Dlgoxin-specific
Fab antibodies (Digibind)
DMSA, Chemet)
'lumazenil (Romaziton)
'omepizole (Cmethylpyrazole,
Antizole)
Siucagon
Wethylene blue
Yaloxone (Narcan)
3ttreotlde
'hysostigmrne (Anrilirium)
Narcotics
tlonldine (inconsistent response)
Sulfonylureas
Anticholinergic agents
Iralidoxime (2-PAM,Protopam)
Organophosphate insecticides
lsoniazid,Gyrom~tramushrooms
Ethylene glycol (investigational)
Carbon monoxide
3xygen
1V
Nausea,vomiting,allergic reactions
IVIET
Deep IIVI
IVIPO
Inhalation
IV
IV
IV(preferred)
iM
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
344
PART VII
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)
.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
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
..
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
a-ph
--
c ~ ~ t i o n
(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
05-24 hr
24-48 hr
Ill
72-96 hr
<.
348
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
.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
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
Tremor
(greater in lower
extremities)
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.)
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
~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
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
rhea,and
pain reflective of
cofi&ve effects
He
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
vascular smooth muscle cells; this results in depressed myocardial contcacrility and conduction as w d as peripheral modila-
&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.
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&
352
. .
PART VII
PI and P2 recep-
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
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.
Chapter 58
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
lEtbylow 61pd
354
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
-.
-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.
.~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.
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)
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
tletoe
barb
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
--
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
Chapter 59
Herbal Medicines
357
ha.1Medicines
)(amper and Peule Bndinn
or wpplrmer~rs.llse
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
Coffeeltea
Tachycardia, ~nsomnia,jltteriness,decreased
appet1te;potential interact~onwith p agonists
Shinpi-to
Salboku-to
None in children
Yes,~nadults
Ma huang (Ephedraswica)
Yes
Yes
Licorice (G~yrrhizeglobro)
No
No
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
No
ATlVE HERBS
SCIENTIFIC STUDIES
nan chamomile
Lavender (Lovandulo)
ionflower (Passifloro
1lato)
Valerian (Voleriona
~fficinalis)
,
c-
I -
Unknown
ADULT DOSE
ACTION
Soothinglemollient
Antl-inflammatory
Antiviral
Antibarter~al
Antifungal
iom Gard~nerP, Coles D, Kernper KI: The
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)
Artemisia obsinthium
(wormwood)
Anorexia
Dyspeptic conditions
Liver and gallbladder disorders
AtrOpii aeiiaoonno
(deadly nightshade)
Gastrointestinal symptoms
Cardiac insufficiency and
arrhythmia
Asthma
Ayurvedic herbal
remedies
gitolis purpurea
(foxglove)
Alkaloids: Ephedrine,pseudoephedrine
(stimulates sympathomimetic
receptors and the central nervous
system)
ngdan xieganwan
Aristolochic acid
Enhance health
lentha puleqium
(pennyroyal)
Insect repellent
Respiratory illness
D~gestlvedisorders
Emmenagogue
Abort~fac~ent
Wound treatment
Gout
Sexual disorders
Exhaustion
Improve muscle func [on
Anti-inflammatory
Arthritis
Cancer
Emetic and cathartic
Rheumatism
hytolacca americana
(pokeweed, American
nightshade)
Stramonium folium
(jimsonweed)
V I ~ album
J ~
(mistletoe)
Alkalo~ds
Viscotoxins (Viscumalbum) cause
hypotension, bradycardia, and
arterial vasoconstriction
Lectins
From GKa'remper
Nausea,vomiting, hypersalivation
Central nervous system: Paresthesias, muscular weakness,
dizziness,ataxia,seizures, coma
Cardiac: Bradycardia, hypotension, rhythm disorders
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
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
I
I
Gastric lavage
Physostigmine given in consultation wlth z
poison specialist
External cooling if temperature is >lOZF
Benzodiazepines
Hydration
Depends on heavy metal
.c
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
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
360
. .
PART VII
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
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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
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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
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