Toxicology A Case-Oriented Approach - part 9 pps

taken on a chronic basis, gastric mucosal erosions occur. Many coffee drinkers
experience heartburn and this symptom arises from a reduction in the tone of the
lower esophageal sphincter that, in turn, leads to acid reflux.
In common with the other methylxanthines, caffeine has a potent effect on the
cardiovascular system. With large ingestions tachycardia, dysrhythmias, and extra-
systoles are noted. The observed increase in heart rate is believed to be associated
with small increases in blood pressure, force of contraction, and cardiac output.
Caffeine toxicity is also manifested by many symptoms. The term “caffeinism”
has been applied to a syndrome of long-term excessive caffeine use. Patients with
this condition exhibit headache, delirium, palpitations, and tachycardia. Often, there
are gastrointestinal complaints, muscle twitches, psychomotor agitation, and possible
arrhythmias. The lethal dose of caffeine is highly variable but 3 g was reported as
a cause of death in at least one case. The commonly published lethal dose is 150 to
200 mg/kg (about 15 g for a 150-lb. man). Blood levels greater than 25

µ

g/mL also
are regarded as in the toxic range, but a good correlation between blood level and
toxicity does not exist.
Although the major exposure of most people to caffeine is in the form of beverage
coffee, caffeine also has at least two medical applications. It is available over-the-
counter as an aid for the prevention of sleep and has been employed for this purpose
by generations of students. Vivarin™ and No-Doz™ are two such products. Some
neonatalogists employ it in the treatment of apnea of prematurity. It is superior to
theophylline in some ways, i.e., a much greater half-life that allows for less frequent
dosing. Caffeine also has a wider therapeutic window; for example, there is a larger
gap between doses that provide therapeutic benefit vs. those associated with toxicity.
Blood levels are of some value in this application and the following guidelines are
recommended:

Caffeine is also sold in many over-the-counter diet pills. What, if any, value it has
in this context has been the object of substantial controversy.

T

HEOPHYLLINE

Theophylline is a methylxanthine that finds its most common medical application
in asthma therapy. It was once thought that it worked by inhibiting cyclic AMP
phosphodiesterase activity. This theory was disproven when it was demonstrated
that the concentrations of drug required to achieve this purpose were not attainable

in vivo

. Further, more potent phosphodiesterase inhibitors have been shown to be
ineffective in asthma treatment. In overdoses, however, part of theophylline’s actions
probably are due to phosphodiesterase inhibition. Currently, the mechanism of action
of theophylline is believed to be antagonism of the activity of adenosine. Because

Therapeutic 8–14

µ

g/mL
Toxic >30

µ

g/mL
Fatal >80

µ

g/mL

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adenosine modulates histamine release and, therefore, causes constriction of respi-
ratory smooth muscle (bronchoconstriction), theophylline, by antagonizing adenos-
ine, causes a bronchial muscle relaxation. Theophylline also causes a release of
catecholamines. Epinephrine and norepinephrine are, therefore, quite elevated in
overdoses with theophylline.
Normal metabolism of theophylline consists of oxidation to 1,3 dimethyluric
acid and/or demethylation to 3-methylxanthine or 1-methyluric acid. A small percent
is eliminated as theophylline. In very young babies theophylline is partly metabolized
to caffeine, a reaction that does not occur in older children or adults. Because of
this, it is advisable to perform analyses for both theophylline and caffeine when
conducting drug monitoring of the very young who are being treated with theophyl-
line. The reactions of theophylline metabolism involve the cytochrome P

450

mixed-
function oxidase system. Therefore, many factors alter theophylline clearance by
changing the available quantities of these enzymes. Cigarette smoking or barbiturates
may shorten theophylline half-life by 50%, whereas some medicines such as eryth-
romycin, ciprofloxacin, and propranolol inhibit theophylline metabolism.
The toxicity of methylxanthines is mainly in association with an excess of their
normal therapeutic actions. Their stimulatory actions can reach the extreme, causing

cardiac and/or respiratory arrest. Theophylline also has a notorious GI irritation
believed to reside in its direct stimulation of the chemoreceptor trigger zone. Thus,
nausea and vomiting are common findings in any level of theophylline overdose.
Restlessness, excitation, and insomnia are symptoms of mild overdose with the
methylxanthines. Perceptual distortions, such as seeing lights or hearing noises, may
be experienced. Headache and dizziness are often reported in overdose. At the
cardiovascular level, tachycardia may progress to ventricular fibrillation and car-
diopulmonary arrest. These are due to the aforementioned excess secretion of cate-
cholamines by theophylline. The catecholamines stimulate the myocardium and this
effect is aggravated by hypokalemia, hypercalcemia, hypophosphatemia, or meta-
bolic acidosis. Convulsions and coma may precede death. One of the unusual
characteristics of theophylline overdose is that major symptoms may be the first
indication of the overdose. Often, nausea and vomiting are the first signs but, on
occasion, generalized seizures occur without any other sign of overdose.
Theophylline overdose is clearly a life-threatening emergency and therapy must
be initiated as promptly and energetically as possible. Ipecac should not be used,
but lavage must be attempted for ingestions that happened during the previous hour.
Activated charcoal with cathartic is usually desirable. Hypotension can be treated
with intravenous fluids. Seizures can be treated with diazepam or phenobarbital.
Lidocaine may be required for arrhythmias. In serious overdoses, hemodialysis is
helpful in enhancing elimination, but charcoal hemoperfusion is three times faster
in reducing the body burden of theophylline. The pharmacokinetics of hemoperfu-
sion are described in a case at the end of this chapter. Blood levels are helpful in
the evaluation and treatment of theophylline overdose. They should be run every
2 hours until a decrease is observed and then every 4 hours until a level of 20

µ

g/mL
is achieved. Interpretation of levels is based on the fact that patients with acute

exposures usually tolerate up to 90

µ

g/mL whereas those with chronic overdose
experience toxicity at lower levels (greater than 40

µ

g/mL). The fact that many

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© 2002 by CRC Press LLC

patients appear to be quite stable mandates the need for blood testing. It indicates
that the patient may be in serious jeopardy despite appearances to the contrary. A
5-year study of 300 patients showed that blood concentration above 80

µ

g/mL is
predictive of major toxicity and suggests that charcoal hemoperfusion should be
started. Another study refined this value and concluded that if theophylline goes
above 60

µ

g/mL or clinical status is deteriorating, then hemoperfusion should be
started while the patient is stable. Supportive therapy must usually be extensive. A
rough correlation exists between blood level and toxicity for the methylxanthines.

For caffeine, blood levels below 15

µ

g/mL usually are not associated with toxicity.
Fatal levels have been reported in the range of 1600

µ

g/mL. For theophylline,
physicians are advised to medicate the patient so that blood concentrations equal
10 to 20

µ

g/mL. Some patients are toxic at these concentrations, so recently this
therapeutic range has been adjusted and 5 to 15

µ

g/mL is now regarded as the
appropriate range for the control of asthma. Theophylline is employed for asthma
therapy because it dilates the bronchi. This effect is presumed to be due to its ability
to relax smooth muscle.

C

AMPHOR

Camphor is a compound with stimulant properties on the cerebral cortex. It is found

in many pharmaceutical products (Table 22.4) because of the many additional prop-
erties that it possesses. Among its uses are as a preservative, antipruritic, topical
rubifacient, cold remedy, and antiseptic.
Camphor is not highly toxic and has a minimum lethal dose of approximately
50 mg/kg. However, because it is widespread in the consumer market, present in
large quantities, and can be absorbed through intact skin, a significant number of
poisonings are found.
Nausea and vomiting are the usual first findings in camphor overdose. From
there the customary findings in stimulant overdose are noted. These include confusion,
restlessness, delirium, and possible hallucinations. Muscular excitability proceeds to

TABLE 22.4
Some Compounds Containing Camphor

Product % Camphor

Absorbine Pain Lotion 10
Ben Gay Children’s Rub 5
Campho-Phenique Liquid 10.85
Heet 3
Mustarole 4
Vick’s VapoRub 4.75
Vick’s Vaposteam 6.2
Sloan’s Liniment 5

Note:

The U.S. FDA ruled in 1983 that medicinal
products may not contain more than 11% of camphor.

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tremors and then epileptic-type seizures. Seizure onset can be sudden, without any
previous signs that seizures are imminent. They can be followed by depression after
the seizure and then coma. If there is a fatal outcome, it is usually due to respiratory
depression. Patients who have been poisoned by camphor can be diagnosed partly
on the basis of the customary signs of stimulant exposure. History may be helpful
if parents or others report an unusual exposure to a pharmaceutical product. Because
such exposures normally are large in amount, the odor of camphor is usually detect-
able in urine or on the breath. This odor has been described as organic and pungent
in nature. If blood testing is conducted, a level of 14.5 mg/L is ominous and suggests
the danger of imminent seizures.
Camphor exposures should be treated with lavage and activated charcoal. Sup-
portive care should include benzodiazepines or barbiturates for seizures. If they are
refractory, then pentobarbital may be effective. Hemodialysis has been shown to be
ineffective in decreasing blood levels; however, hemoperfusion with resins has been
successful in enhancing the rate of camphor elimination.

Questions

1. What are the advantages and disadvantages of treating obesity with sym-
pathomimetic amines?
2. Discuss the use of methylphenidate as treatment for attention deficit
disorder. How can a drug classified as a stimulant cause a depression of
hyperactivity in children?
3. Contrast the use of caffeine and theophylline as treatments for pulmonary
problems in infants. What toxicity is associated with each and how can
laboratory data be helpful in avoiding toxicity?
4. What are the toxic features of camphor and where is this compound found

medically?

Case Study 1: The Hazards of Dieting

An 18-year-old woman ingested eight over-the-counter diet pills. Two hours
later she felt ill and went to an emergency department for evaluation of a
headache and generalized malaise. Her BP was 140/90 and pulse 52. No neu-
rological abnormalities were noted. Because of her history of the diet pill
ingestion, gastric lavage was attempted. She was discharged only to return soon
after with generalized convulsions. She was lethargic but awake and aware of
herself and her surroundings. She was admitted to the hospital and 1 day later
she abruptly lost all brain stem reflexes. A spinal tap revealed that her CSF was
grossly bloody. Evaluation by electroencephalogram resulted in an isoelectric
profile. Carotid angiography revealed that her intracranial vessels were not
filling with blood in a normal manner. She was placed on respiratory support
but, after a long interval of flat brain waves, that support was withdrawn and
she was pronounced dead.

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What is a possible identification for the diet pills?
a) Phenylpropanolamine
b) Diethylpropionate
c) Thyroxine
d) Fenfluramine
All of the suggested answers are marketed alone or in combination with other
agents as diet medicines. Diethylpropionate and fenfluramine, however, were
never sold in the United States as over-the-counter drugs. Because they have a
modest abuse potential, both required a prescription. Fenfluramine was removed

from the market in 1997 when a number of patients were found to have cardiac
injury that appeared to be related to use of fenfluramine. Thyroxine is not a diet
drug although it has been used in that manner by some persons. This is a great
mistake because of thyroxine’s high potency and the fact that any weight loss
it provokes is mainly lean body mass. Thyroxine also requires a prescription.
Phenylpropanolamine is available as an over-the-counter appetite suppres-
sant. It is fairly effective for this purpose but has many side effects including
rapid tolerance, insomnia, and occasional irregularities of cardiac rhythm. On
rare occasions it causes major toxicity as related in the present case.

Questions

Q1. What adverse effects have been reported for phenylpropanolamine?
a) CNS stimulation
b) Hypertension
c) Abuse potential
d) All of the above
Q2. How does phenylpropanolamine resemble amphetamine?
a) Pharmacologically similar but structurally in a different class.
b) Stereoisomers of each other.
c) Optical isomers of each other.
d) Phenylpropanolamine is a hydroxylated form of amphetamine.
Q3. Which of the following items of evidence helps to rule in a drug as the
cause of this patient’s symptoms?
a) Absence of signs of chronic hypertension on autopsy.
b) Brain evaluation did not show a bleeding source such as an aneurysm
or an atrioventricular malformation.
c) Relation of drug use to appearance of symptoms in time.
d) All of the above.

Answers and Discussion

Q1. (Answer = d) Phenylpropanolamine is classified as a sympathomimetic
amine. This is a large class of compounds that includes drugs with very
high abuse potential such as amphetamine and methamphetamine as well

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as numerous analogs of these compounds. They have the classical phar-
macological properties of stimulants. All of the features listed here are
common to this class of drugs.
Q2. (Answer = d) Phenylpropanolamine is very similar to amphetamine and
differs from it merely by the presence of a hydroxyl group on the carbon
adjacent to the benzene ring. However, it does not have the same molecular
formula as amphetamine and is not an isomer of it. (See the structures of
sympathomimetic amines in this text.)
Q3. (Answer = d) It is rare for this particular response to occur in sympath-
omimetic amine usage. Cerebrovascular accidents are usually associated
with hypertension, cerebral malformations, or chronic degenerative dis-
ease in the central nervous system. Therefore, among the probable causes
of this patient’s stroke, phenylpropanolamine overdose is far down the
list. Nevertheless, her death was eventually attributed to phenylpropano-
lamine exposure because no other proximate cause could be determined
and her drug use was close in time to the occurrence of this catastrophic
event. In addition, there are a number of other published cases of stroke
arising from moderate consumption of sympathomimetic amines.

Reference

McDowell, J. and LeBlanc, H., Phenylpropanolamine and cerebral hemorrhage,

West. J.
Med.,

142, 688–691, 1985.

Case Study 2: The Excitable Baby

A 4-month-old baby girl who weighed 10 lbs. was brought to a hospital by her
distraught parents who found the child with an empty bottle of an over-the-
counter medication. The bottle had contained about 30 Tri-Aqua pills. On
evaluation, the child was found to be irritable with elevated breathing and heart
rate. Physical exam revealed hyperresponsiveness to any stimulation with
increased muscle tone and hyperactive deep tendon reflexes. Therapy was started
with the administration of Ipecac. Upon receipt of this emetic the child vomited
coffee ground emesis. Laboratory studies were immediately initiated and they
revealed the following:

pCO

2

18 mm
pH 7.45
K 2.6
HCO

3
–

13
Glucose 323
Theophylline 31
Chest X-ray Normal

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The child was provided IV fluids, NG suction, antacids, and benzodiazepines
for her hyperstimulation status. Dialysis for the elevated theophylline was con-
sidered but was eventually deemed to be unnecessary because it was only
modestly above the therapeutic range. All of the patient’s aberrant laboratory
findings normalized over the following 6 days of hospitalization, although the
hyperexcitability and tachycardia persisted for over 2 days past the time of the
ingestion.
Which of the following drugs was probably in the Tri-Aqua pills?
a) Caffeine
b) Aspirin
c) Morphine
d) Theophylline
The bottle of Tri-Aqua contained caffeine pills each of which contained 98 mg
of caffeine. The symptoms of caffeine overdose are very consistent with the
hyperactive appearance of this patient. Morphine is not possible because it is
not an over-the-counter medication nor does it provoke signs of hyperstimula-
tion. Aspirin does cause some of this child’s findings but the overall picture is,
in many respects, different from aspirin. Theophylline seems to be a likely
suspect because it is a stimulant and the patient had a high theophylline level.
The theophylline level is, however, not impressive and serum concentrations
greater than 40 mg/L or higher would be expected for this degree of hyperstim-

ulation. The observed theophylline arose as a metabolite of caffeine.
During her hospitalization both caffeine and theophylline drug levels were
frequently measured in this patient. Because her physicians were mainly con-
cerned about possible theophylline toxicity, they ordered that theophylline be
tested serially and, if possible, that it be confirmed by a second test method.
The laboratory, accordingly, ran both enzyme immunoassay and high-perfor-
mance liquid chromatography methods. The following data were recorded:
In view of the marked discrepancy between these two methods a third,
different HPLC method was attempted and recovery experiments were run in
an effort to unravel this mystery. The third method gave results of 6.7 and 9.1
mg/L for specimens 2 and 3, respectively. It was eventually determined that the
first two methods were erroneous and the third method, which gave the lowest
answers, was correct.

Specimen Enzyme Immunoassay HPLC
Number (mg/L) (mg/L)

1 9.2 12.4
2 13.6 31
3 13.4 32
4 10.7 24

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Questions

Q1. An erroneously high HPLC result would most likely result from
a) A problem with the instrument detector
b) An interference from a metabolite of the analyte

c) An improperly labeled standard
d) Another medicinal taken at the same time
Q2. What is the best HPLC method modification to prevent co-elution?
a) Change the flow rate
b) Change the type of detector
c) Change the mobile phase
d) Change the column
Q3. Are theophylline and caffeine concentrations valuable in caffeine overdose?
a) Both are critical.
b) Neither is valuable.
c) Only theophylline is needed because it is a more toxic drug.
d) Only caffeine is needed because it is present in larger amounts.
Q4. How did this child’s ingestion compare with a lethal dose of approximately
100 mg/kg?
a) Far below a fatal dose
b) Almost a fatal dose
c) Just above a fatal dose
d) Manyfold greater than the estimated fatal dose

Answers and Discussion

Q1. (Answer = b) Any of these possible answers are feasible but interference
from a metabolite is most likely. Metabolites are structurally similar to
the drug being tested and it is entirely possible, sometimes probable, that
they will react in a manner similar to the test substance. In the case being
discussed, paraxanthine, a metabolite of caffeine, co-eluted with theophyl-
line and contributed to the area under the curve (Figure 22.3). The instru-
ment’s result was effectively equal to paraxanthine plus theophylline.
Also, as a result of its structural similarity, paraxanthine cross-reacted in
the immunoassay with the anti-theophylline antibody. It is quite unusual,

however, for two test methods to be affected to such a large degree. The
erratic HPLC method gave results that were up to 500% too high while
the enzyme immunoassay had errors of up to 380%.
Q2. (Answer = c) Neither the detector nor the flow rate will have any signif-
icant effect on the co-elution of these two compounds. If the column were
changed, it would probably separate the two compounds. Although this
step could be taken, it would be easier to change the mobile phase. In
this case, conversion to a more acidic mobile phase led to a separation of
theophylline from caffeine.
Q3. (Answer = b) Neither serum concentration is of much clinical value. The
correlation between concentration and clinical symptoms is extremely

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© 2002 by CRC Press LLC
Anticholinergic Drugs
CONTENTS
Introduction
Anticholinergic Activity
Antihistamines
Chemistry
Toxicity
Treatment
Antidepressants
Amine Theory of Depression
Therapy for Depressive Illness
Tricyclic Antidepressants (TCA)
Toxicity
Laboratory Testing
Therapeutic Monitoring

Testing for Suspected Overdose
Second-Generation Antidepressants
Toxicity
Third-Generation Antidepressants
Toxicity
Monoamine Oxidase Inhibitors (MAOI)
Toxicity
Antipsychotic Drugs
Terminology
History
Mechanism of Psychosis
Side-Effects
Toxicity
Autonomic Nervous System
Cardiovascular
Central Nervous System
Treatment of Overdose
Laboratory Testing
Questions
INTRODUCTION
This chapter is devoted to drugs that have anticholinergic properties (Table 23.1). This
is a large group of compounds with many pharmaceutical applications. Thus, included
23
© 2002 by CRC Press LLC
Anticholinergic Drugs
CONTENTS
Introduction
Anticholinergic Activity
Antihistamines
Chemistry

Toxicity
Treatment
Antidepressants
Amine Theory of Depression
Therapy for Depressive Illness
Tricyclic Antidepressants (TCA)
Toxicity
Laboratory Testing
Therapeutic Monitoring
Testing for Suspected Overdose
Second-Generation Antidepressants
Toxicity
Third-Generation Antidepressants
Toxicity
Monoamine Oxidase Inhibitors (MAOI)
Toxicity
Antipsychotic Drugs
Terminology
History
Mechanism of Psychosis
Side-Effects
Toxicity
Autonomic Nervous System
Cardiovascular
Central Nervous System
Treatment of Overdose
Laboratory Testing
Questions
INTRODUCTION
This chapter is devoted to drugs that have anticholinergic properties (Table 23.1). This

is a large group of compounds with many pharmaceutical applications. Thus, included
23
© 2002 by CRC Press LLC
Psychedelic Drugs
CONTENTS
Chemistry and Classification
Anticholinergic Psychedelics
Catecholamine Analogs
Mescaline
Other Derivatives
Serotonin-Like Psychedelics
Lysergic Acid Diethylamide (LSD)
DMT Derivatives
Morning Glory Seeds (Ololiuqui)
Psychedelic Anesthetics
Questions
The category of drugs that are thought of as mind expanding are so well-known
today and are composed of such a large variety of compounds that they surely deserve
a separate section for discussion. Some of them are more commonly taken for
euphoria rather than hallucinatory effects. Such drugs are discussed separately under
drugs of abuse. Still others are primarily stimulants that have some hallucinatory
character. They are also discussed separately, in the chapter on stimulants. Those
discussed here are primarily hallucinatory.
Various names have been given to these drugs. They have been called halluci-
nogens. Although the drugs that are the subject of this chapter can cause hallucina-
tions that term is a bit narrow as a designation for these compounds because they
have many other properties. Psychotomimetics is another term used to describe these
drugs because they, on some occasions, produce mind states reminiscent of psychotic
behavior. Here again, however, the term psychotomimetic is neither entirely accurate
nor of sufficient diversity to truly capture the mental states these compounds may

create. Psychedelic is a word that was created specifically to describe the behavioral
reactions these drugs produce. As a new term it can mean whatever its originator
wants. What was intended by it is a concept of agents that alter sensory perception
and also have unique mind-expanding properties. Users of these compounds have
an enhanced awareness of sensation and a self-perception of clarity although with
a decreased control over one’s environment. The personality of the user is often
divided into two persons. One person is a passive spectator who witnesses the divided
persona in the act of receiving the distorted sensory perception. These two parts of
one ego are the observer and the participant. The user believes that he is free from
the doubts and misperceptions of normal mortals and, during the brief period of
2
4