Central Nervous System
29
29
Stimulants
David A. Taylor
DRUG LI ST
GENERIC NAME PAGE GENERIC NAME PAGE
Amphetamine 350 Pemoline 350
Caffeine 351 Pentylenetetrazol 349
Doxapram 349 Sibutramine 351
Fenfluramine 351 Phentermine 351
Methamphetamine 350 Theobromine 351
Methylphenidate 350 Theophylline 351
Modafenil 351
Central nervous system (CNS) stimulation is the pri- pounds within this category do possess some clinical
mary action of a diverse group of pharmacological utility. Historically, general CNS stimulants were used
agents and an adverse effect associated with the admin- primarily as respiratory stimulants in the treatment of
istration of an even larger group of drugs. CNS stimula- acute overdosage with CNS depressants (e.g., barbitu-
tion consists of a range of behaviors including mild ele- rates). Several factors have contributed to the almost
vation in alertness, increased nervousness and anxiety, complete lack of use of CNS stimulants in this clinical
and convulsions. situation. First, since the stimulants were not specific an-
In general, any hyperexcitability associated with tagonists of the depressant agents, they frequently were
drug administration (as either a desired or an undesired not effective in reversing severe pharmacologically in-
effect) results from an alteration in the fine balance nor- duced CNS depression. Second, the duration of action
mally maintained in the CNS between excitatory and of the CNS stimulant was generally shorter than that of
inhibitory influences. Thus, the bases for CNS stimula- the depressant. Third, the dose of most CNS stimulants
tion by this class of drugs reside in adjusting the inte- required to reverse severe CNS depression was quite
gration of excitatory and inhibitory influences at the close to the dose that produced convulsions and cardiac
level of the individual neuron. An agent that induces arrhythmias. In such cases, the CNS stimulant often ex-
CNS stimulation appears to act by one or more of the acerbated the clinical picture by producing severe life-
following mechanisms: (1) potentiation or enhance- threatening complications. Another factor contributing
ment of excitatory neurotransmission, (2) depression or to the decline in CNS stimulant use for drug-induced
antagonism of inhibitory neurotransmission, and (3) al- CNS depression has been the development of generally
tered presynaptic control of neurotransmitter release. safer procedures for patient management. Supportive
Although the use of CNS stimulants (also known as measures (e.g., maintenance of a patent airway, eleva-
analeptics or convulsants) has declined, certain com- tion of low blood pressure) often provide greater bene-
348
29 Central Nervous System Stimulants 349
brane hyperpolarization and a reduction in the probabil-
Classification of CNS ity of action potential generation (i.e., inhibition of neu-
TABLE 29.1
Stimulants ronal activity). With GABA in particular, the interaction
appears to occur through specific membrane-associated
Analeptic Psychomotor GABAA-receptors that form an integral part of the chlo-
Stimulants Stimulants Methylxanthines ride channel (see Chapter 24). The chloride channel ap-
pears to contain other regulatory sites with high affinity
Doxapram Amphetamine Caffeine
for such agents as the benzodiazepines, picrotoxin, alco-
Nikethamide Methamphetamine Theophylline
hol, neuroactive steroids, and the barbiturates.
Pentylenetetrazol Methylphenidate Theobromine
Strychnine Pemoline Chloride movement across neuronal membranes can
Picrotoxin Ephedrine
be regulated at this ion channel by at least three distinct
Bicuculline Phentermine
molecular entities: (1) a GABA-binding site, (2) a benzo-
Fenfluramine
diazepine-binding site, and (3) a picrotoxin-binding site.
Phenylpropanolamine
GABA and other agonists open the chloride channel
(i.e., increase chloride conductance). Benzodiazepine-
induced facilitation of GABA-mediated increases in
chloride conduction are antagonized by pentylenetetra-
fit to the patient than does the use of analeptic drugs.
zol and possibly by the methylxanthines, while picrotoxin
Tolerance and abuse potential are additional problems
closes the chloride channel. Other agents that appear to
associated with the use of such psychomotor stimulants
promote chloride conductance through this channel in-
as amphetamine and many of its congeners.
clude the barbiturates and alcohol.
Compounds that possess as their primary action the
The existence of the chloride channel as a major site
stimulation of the CNS can be divided into three major
of drug action permits a single molecular event (control
categories (Table 29.1) based on either their proposed
of chloride ion movement) to be involved in the mech-
mechanism of action or their chemical structure. Each
anism of action of a diverse class of agents.
class of compounds is discussed in general terms, and in-
Strychnine is an analeptic stimulant with a well-
dividual drugs are mentioned only as appropriate.
defined mechanism of action that is unrelated to inter-
action with GABA receptors or other sites that modu-
late the activity of the chloride ionophore. Strychnine
ANALEPTIC STIMULANTS
appears to be a specific competitive postsynaptic antag-
onist of glycine. Glycine, like GABA, is a known in-
Chemistry and Pharmacokinetics
hibitory transmitter in the mammalian CNS. Whereas
GABA is likely to be more important in the brain,
The analeptic stimulants are a diverse chemical class of
glycine is more important in the spinal cord. Glycine me-
agents ranging from plant alkaloids, such as picrotoxin
diates inhibition of spinal cord neurons and is intimately
and strychnine, to synthetic compounds, such as
involved in the regulation of spinal cord and brainstem
pentylenetetrazol and doxapram. The wide range of
reflexes. Strychnine directly antagonizes this inhibition,
chemical structures makes this particular class some-
allowing excitatory impulses to be greatly exaggerated.
what difficult to categorize with respect to absorption,
distribution, and metabolism. However, most analeptic
stimulants can be absorbed orally and have short dura-
Clinical Uses
tions of action. The pharmacological effect of most of
As indicated, most of the analeptic stimulants were
these compounds is terminated through hepatic metab-
used as pharmacological treatments for overdosage of
olism rather than renal excretion of unchanged drug.
CNS depressants. Doxapram (Dopram) is sometimes
used to counteract postanesthetic respiratory depression
Mechanism of Action
and as an aid in chronic obstructive pulmonary disease.
Perhaps the most unifying concept concerning the mode Pentylenetetrazol (Metrazol) was used experimentally
of action of these agents comes from studies of the - on rare occasions to  activate the electroencephalo-
aminobutyric acid (GABA) receptor chloride ionophore gram. Strychnine is used almost exclusively in animal
interaction. It has long been recognized that the in- studies as a tool for studying CNS mechanisms because
hibitory action of many amino acid neurotransmitters it is a relatively specific glycine antagonist.
(e.g., GABA) involves an increase in chloride conduc-
tance. Thus, GABA and other inhibitory amino acids ac-
Adverse Effects
tively promote an increase in chloride influx by activation
of the chloride channel in the neuronal membrane.An in- Most of the CNS stimulants produce adverse reactions
crease in chloride conductance generally leads to mem- that are extensions of their therapeutic effect. These
350 IV DRUGS AFFECTING THE CENTRAL NERVOUS SYSTEM
FI GURE 29. 1
Patient in opisthotonos.
agents produce convulsions that can be followed by of untransformed drug is excreted in the urine. Thus, it
coma and death. Convulsions produced by this class of is possible to ion-trap this weak organic base by acidify-
agents (with the exception of strychnine) are usually ing the urine, thereby reducing its reabsorption in the
tonic clonic and are uncoordinated. In some cases, the renal tubules and enhancing its clearance.
convulsions are preceded by marked stimulation of res-
piration, tachycardia, and excessive pressor effects.
Mechanism of Action
The uncontrolled excitation that occurs after acci-
dental or intentional strychnine ingestion (in the ab- There is good evidence that the facilitation of peripheral
sence of normal inhibition) results in characteristic con- sympathetic nervous system transmission produced by
vulsions. In humans, in whom extensor muscles are the amphetamines also occurs in the CNS. The possibility
normally dominant, tonic extension of the body and all that amphetamines act indirectly (i.e., by releasing
limbs is observed. This hyperextension is known as monoamines) at monoaminergic synapses in the brain
opisthotonos; at its extreme, it consists of a characteris- and spinal cord seems likely. However, amphetamine has
tic posture in which the back is arched and only the effects beyond displacement of catecholamines; these in-
back of the head and the heels are touching the surface clude inhibition of neuronal amine uptake, direct stimula-
on which the victim is lying. Figure 29.1 illustrates a pa- tion of dopamine and serotonin receptors, antagonism of
tient in opisthotonos. Under the influence of strychnine, catecholamine action at certain subtypes of adrenocep-
all sensory stimuli produce exaggerated responses. The tors, and inhibition of monoamine oxidase. Interestingly,
primary therapeutic consideration after strychnine poi- none of these actions explains the therapeutic benefit of
soning is to prevent convulsions, which may be fatal. the amphetamines in hyperkinetic children.
Diazepam and clonazepam (see Chapter 33) appear to
be moderately effective in preventing strychnine con-
Clinical Uses
vulsions, and either of these is the agent of choice.
Barbiturates are often used to treat overdoses of all of The therapeutic indications for the psychomotor stimu-
the analeptic stimulants. Generally, however, antidotal lants are quite limited. They are beneficial in the treat-
therapy is not required. ment of the hyperkinetic syndrome (attention deficit
hyperactivity disorder with minimal brain dysfunction).
This is generally a childhood disease characterized by
hyperactivity, inability to concentrate, and impulsive be-
PSYCHOMOTOR STIMULANTS
havior. Amphetamines and the more extensively used
methylphenidate paradoxically are quite effective in
Pharmacokinetics
calming a large proportion of children with this disor-
Many psychomotor stimulants possess activities similar der. Pemoline (Cylert) is also used in the treatment of
to those of amphetamine and have been discussed pre- attention deficit disorder with hyperkinetic behavior.
viously (see Chapter 10). Of primary importance to our The mechanism by which these compounds are effec-
discussion of the psychomotor stimulants are ampheta- tive in this disorder is not known.
mine (Adderall, Benzedrine, Dexedrine), methampheta- Narcolepsy is another medically recognized indica-
mine (Desoxyn), and methylphenidate (Concerta, tion for the use of the psychomotor stimulants. This dis-
Ritalin, Metadate, Methylin). order is characterized by sleep attacks, particularly dur-
All of these compounds are well absorbed after oral ing the day, sudden loss of muscle tone (cataplexy),
administration, leaving injectable forms with few legiti- sleep paralysis, and vivid visual and auditory nightmares
mate applications. Although several catabolic pathways that may persist into the waking state. Drugs that influ-
metabolize the amphetamines, a considerable portion ence the central action of adrenomimetic amines re-
29 Central Nervous System Stimulants 351
markably affect narcolepsy. Monoamine oxidase in- macological properties, there is always a question of
hibitors (e.g., selegiline) and amphetamines are both where most appropriately to discuss them in a pharma-
quite effective in preventing sleep attacks and improv- cology text. The xanthines are clearly CNS stimulants,
ing cataplexy. Modafinil (Provigil) is a nonampheta- although not all have this characteristic equally. While
mine compound whose mechanism of action is not the xanthines have legitimate therapeutic uses, by far
known but that has been shown to be successful in the the greatest public exposure to them is in xanthine-
treatment of narcolepsy. However, amphetamine and containing beverages, including coffee, tea, cocoa, and
methylphenidate are still considered among the drugs cola drinks. The popularity of xanthine-containing
of choice in this disorder. drinks appears to be related to its subtle CNS stimulant
Previously, another use of the amphetamines and effect. It is primarily for this reason that xanthines are
other centrally acting adrenomimetics has been in the listed as CNS stimulants in this text.
management of obesity and weight reduction. Although
the amphetamines have a significant anorexic effect,
Chemistry and Pharmacokinetics
tolerance to this action develops within a few weeks. In
addition, insomnia restricted their use during the latter Three xanthines are pharmacologically important: caf-
part of the day. The combined drawbacks of the devel- feine, theophylline, and theobromine. All three alka-
opment of tolerance and potential for drug abuse have loids, which occur naturally in certain plants, are widely
convinced much of the medical community that the use consumed in the form of beverages (infusions or decoc-
of amphetamines in weight control is inappropriate. tions) derived from these plants. Coffee primarily con-
Fenfluramine (Pondimin) and phentermine (Adipex- tains caffeine (about 100 150 mg per average cup); tea
P, Fastin) are anorexigenic drugs that produce depres- contains caffeine (30 40 mg per cup) and theophylline;
sion of the CNS and at one time were used (Fen-phen) and cocoa contains caffeine (15 18 mg per cup) and
in the treatment of obesity. Sibutramine (Meridia) is also theobromine. Cola drinks also contain significant
available for the treatment of obesity. amounts of caffeine (about 40 mg/12 oz). The CNS
stimulation associated with these beverages is predomi-
nantly due to the caffeine.
Adverse Effects
The xanthines are readily absorbed by the oral and
The acute effects of psychomotor stimulant overdoses
rectal routes. Although these agents can be adminis-
are related to their CNS stimulant properties and may
tered by injection (aminophylline is a soluble salt of
include euphoria, dizziness, tremor, irritability, and in-
theophylline), intravascular administration is indicated
somnia. At higher doses, convulsions and coma may en-
only in status asthmaticus and apnea in premature in-
sue. These drugs are cardiac stimulants and may cause
fants. Intramuscular injection generally produces con-
headache, palpitation, cardiac arrhythmias, anginal
siderable pain at the injection site.
pain, and either hypotension or hypertension. Dextro-
The compounds are extensively metabolized, prima-
amphetamine produces somewhat less cardiac stimula-
rily to uric acid derivatives. There is, however, no indi-
tion. Chronic intoxication, in addition to these symp-
cation that methylxanthines aggravate gout.
toms, commonly results in weight loss and a psychotic
reaction that is often diagnosed as schizophrenia.
Mechanism of Action
These agents produce addiction, including psycholog-
ical dependence, tolerance, and physical dependence.
The mechanism of action of methylxanthine-induced
Psychic dependence also has been seen following high
stimulation of the CNS has been the subject of much in-
doses of methylphenidate.The abstinence syndrome seen
vestigation, and at least two other possible mechanisms
after abrupt discontinuation of amphetamines is neither
of action of the methylxanthines have been suggested.
as dramatic nor as predictable as that observed during
The first derives from the ability of the methylxanthines
withdrawal from the barbiturates or opioids. With the
to act as antagonists of the naturally occurring com-
amphetamines, the abstinence syndrome consists prima-
pound adenosine, a substance that can inhibit both neu-
rily of prolonged sleep, fatigue, and extreme hunger (hy-
ronal activity and behavior through direct postsynaptic
perphagia). These symptoms may be accompanied by
action on neurons and through indirect action involving
profound and long-lasting depression. Amphetamine
presynaptic inhibition of neurotransmitter release. The
abuse is discussed more completely in Chapter 35.
A1 subtype of the purine receptors mediates these ac-
tions of adenosine. Thus, as an equilibrium-competitive
antagonist of adenosine, the methylxanthines may pro-
XANTHINES
duce excitation either by direct blockade of inhibitory
The compounds known as xanthines, methylxanthines, effects of adenosine at the neuron or by an antagonism
or xanthine derivatives constitute a particularly inter- of the presynaptic inhibitory effect of adenosine on the
esting class of drugs. Since they possess diverse phar- release of an excitatory substance (e.g., acetylcholine).
352 IV DRUGS AFFECTING THE CENTRAL NERVOUS SYSTEM
Another suggested mechanism of action involves ure. Theophylline also has shown some benefit in the
the chloride channel. As discussed previously, the chlo- treatment of neonatal apnea syndrome.
ride channel is intimately associated with neuronal inhi-
bition, and its activity appears to be modulated at many
Miscellaneous Uses
different sites. Caffeine can compete for binding at the
Xanthines (usually caffeine) are frequently combined
benzodiazepine site and would therefore be expected to
with aspirin in the treatment of headaches. In combina-
reduce chloride conductance. Thus, caffeine may act
tion with an ergot derivative, methylxanthines have
functionally like the analeptic stimulants that limit chlo-
been used to treat migraine. These effects are likely due
ride channel activation.
to their ability to produce vasoconstriction of cerebral
blood vessels. Aminophylline is useful in the relief of
Clinical Uses
pain due to acute biliary colic.
Central Nervous System
Xanthines, primarily as the intramuscularly adminis-
Adverse Effects
tered combination of caffeine and sodium benzoate,
Toxicity associated with the methylxanthines usually
have been used in the treatment of CNS depressant
takes the form of nervousness, insomnia, and in severe
overdosage. Black coffee has been used to physiologi-
cases, delirium. Cardiovascular stimulation is seen as
cally antagonize alcohol intoxication, although many
tachycardia and extrasystoles. Excessive respiratory
physicians believe that this ineffective therapy simply
stimulation may occur, and diuresis may be prominent.
produces a wide-awake drunk.
The intravenous administration of aminophylline
Many over-the-counter preparations are aimed at
(or theophylline) may present some problems if the
relieving fatigue through CNS stimulation. Such com-
drug is given too rapidly. In such cases, severe headache,
pounds are often referred to as wake-up tablets, but
hypotension, and palpitation accompany drug adminis-
these methylxanthine-containing products do little to
tration. Subsequently the patient may show signs of ex-
offset physical fatigue, so they place individuals using
cessive CNS stimulation, shock, and even death.
them at risk for accidental injuries.
Children appear to be especially prone to this toxicity.
Diuresis
Abuse of Xanthines
All the xanthines, but especially theophylline, are capa-
ble of producing some degree of diuresis in humans.
The use of some xanthine-containing beverages is cus-
This specific action of the methylxanthines is discussed
tomary in most cultures, and moderate use of such bev-
in greater detail in Chapter 21.
erages does not appear to cause problems in most peo-
ple. There is little question, however, that such use is
Bronchial Asthma
habituating. For example, it has been observed that
chronic coffee drinkers who suddenly abstain fre-
Theophylline is frequently used as a bronchodilator in
quently have headaches and a general feeling of fatigue
the treatment of asthma. The importance of the
that may last for several days. Although it has not been
methylxanthines in the management of bronchial
established that these symptoms constitute any kind of
asthma is discussed more fully in Chapter 39. Caffeine
abstinence syndrome, it remains a possibility. There is
as the citrate salt (Cafcit) is used for the short-term
no good evidence for the development of tolerance to
management of apnea in premature infants (28 33
the CNS stimulant effects of caffeine.
weeks of gestational age).
Cardiac Uses Drug Interactions
Theophylline, given as the soluble ethylenediamine salt An interaction of potential clinical significance involves
aminophylline, offers some help in relieving the parox- the xanthines and the coumarin anticoagulants. Xanthines
ysmal dyspnea that is often associated with left heart by themselves shorten clotting time by increasing tissue
failure.A major portion of its efficacy may be due to the prothrombin and factor V and in this regard may be ex-
relief of bronchospasm secondary to pulmonary vascu- pected to antagonize the effectiveness of oral anticoagu-
lar congestion. Theophylline increases myocardial con- lants. However, the usual therapeutic doses of xanthines
tractile force and has occasionally been used in the cause no significant effect on the patient s response to
treatment of refractory forms of congestive heart fail- oral anticoagulants.
29 Central Nervous System Stimulants 353
Study Questi ons
1. Opisthotonos is a convulsive condition that is often (D) Antagonism of muscarinic receptors in the
associated with the ingestion of strychnine. This heart
condition is associated with all of the following (E) Blockade of ganglionic transmission at sympa-
EXCEPT thetic ganglia in the periphery
(A) Antagonism of the inhibitory amino acid neu-
rotransmitter glycine
ANSWERS
(B) The predominance of glycine as an inhibitory
1. C. Glycine is the major inhibitory amino acid trans-
amino acid transmitter in the spinal cord
mitter in the spinal cord, and strychnine is a rela-
(C) Antagonism of the inhibitory amino acid neu-
tively selective antagonist of glycine. Strychnine has
rotransmitter GABA
very little if any action at the GABA receptor
(D) The convulsions lead to tonic extension of the
chloride channel complex.
body and all limbs
2. D. Attention deficit hyperkinetic disorder and at-
2. Which of the following classes of agents is useful
tention deficit disorder are among only a few ap-
in the treatment of attention deficit hyperkinetic
proved uses of the psychomotor stimulants of the
disorder?
amphetamine type.
(A) Analeptic stimulants
3. A. Analeptic stimulants, such as pentylenetetrazol
(B) Benzodiazepines
and picrotoxin, act by inhibiting chloride influx at
(C) Xanthines
the GABAA receptor chloride channel complex.
(D) Psychomotor stimulants
This antagonism can occur through interaction with
(E) Phosphodiesterase inhibitors
one of several binding sites or allosteric modifiers of
3. Which of the following mechanisms of action ac-
receptor channel function.
count for the effects of all analeptic stimulants ex-
4. B. Methylxanthines have been proposed to be in-
cept strychnine?
hibitors of phosphodiesterase, which would elevate
(A) Antagonism of chloride ion influx at the
intracellular levels of cAMP. However, the concen-
GABA receptor chloride channel complex
tration of cAMP that is required for such action is
(B) Increased release of catecholamines from CNS
above the threshold of CNS stimulation. Since the
neurons
methylxanthines are relatively potent antagonists of
(C) Inhibition of cholinesterase leading to in-
adenosine and since adenosine has been shown to
creased acetylcholine levels
be a reasonably potent inhibitor of both central and
(D) Antagonism of CNS adrenoceptors to reduce
peripheral neurons, the most likely mechanism by
inhibition produced by catecholamines
which CNS stimulation occurs is through antago-
(E) Antagonism of nicotinic receptors that inhibit
nism of adenosine receptors.
motor neuron activity
5. B. Psychomotor stimulants such as amphetamine
4. The CNS stimulation produced by methylxanthines,
are also indirectly acting sympathomimetics that in-
such as caffeine, is most likely due to the antago-
crease the release of catecholamines from sympa-
nism of which of the following receptors?
thetic nerve terminals. While amphetamine and
(A) Glycine receptors
other congeners possess additional actions on pe-
(B) Adenosine receptors
ripheral sympathetic nerves, this is the most likely
(C) Glutamate receptors
explanation for the cardiac stimulation observed
(D) GABA receptors
following the administration of these agents.
(E) Cholinergic muscarinic receptors
5. Cardiac stimulation is an adverse effect associated
with the use of the psychomotor stimulants, such as SUPPLEMENTAL READING
amphetamine. Which of the following mechanisms Barnard EA. The molecular biology of GABAA recep-
is most likely responsible for this peripheral effect? tors and their structural determinants. In Biggio C,
(A) Inhibition of vagal tone through an action in Sanna E, and Costa E (eds.). GABAA Receptors
the CNS and Anxiety: From Neurobiology to Treatment.
(B) Indirect sympathomimetic effects in the pe- New York: Raven, 1992.
riphery due to release of norepinephrine Costa E. From GABAA receptor diversity emerges a
(C) Inhibition of a GABA-mediated negative unified vision of GABAergic inhibition. Annu Rev
chronotropic effect at the heart Pharmacol Toxicol 1998;38:321 350.
354 IV DRUGS AFFECTING THE CENTRAL NERVOUS SYSTEM
Daval, J-L, Nehlig A, and Nicolas F. Physiological and Linden J. Structure and function of A1 adenosine recep-
pharmacological properties of adenosine: tors. FASEB J 1991;5:2668 2676.
Therapeutic implications. Life Sci Sieghart W. Structure and pharmacology of -aminobu-
1991;49:1435 1453. tyric acidA receptor subtypes. Pharmacol Rev
Fredholm BB et al. International Union of 1995;47:181 234.
Pharmacology. XXV. Nomenclature and classifica- Smith GB and Olsen RW. Functional domains of
tion of adenosine receptors. Pharmacol Rev GABAA receptors. Trends Pharmacol Sci
2001;53: 527 552. 1995;16:162 168.
Case Study Daytime Sleepiness
. M. is a 55-year-old highly successful busi- abled and unable to continue working. What types
Wnessman who often spends long hours at the of pathological conditions can lead to excessive
office or in his automobile traveling to meet new somnolence? What is the appropriate therapeutic
clients and partners. Since his days in college, W. M. management of these pathological conditions?
has had frequent episodes of daytime somnolence,
ANSWER: Three disorders are most often associated
which he attributed to overwork and fatigue. Over
with EDS. Sleep apnea is characterized by pauses in
the past several years, the number of daytime
respiration during sleep and usually excessive snor-
episodes has begun to increase, and he recently be-
ing. Patients with sleep apnea have EDS but often
gan to lose mobility in his arms and legs during the
awake without feeling rested. Sleep apnea is man-
periods of somnolence. He also barely avoided a
aged by treating the nighttime episodes of apnea.
significant automobile accident for which the local
Narcolepsy is characterized by episodic EDS.
sheriff s deputy cited him for failure to maintain
Patients with this pathology often exhibit periods of
control of his vehicle. During questioning by the po-
irresistible instantaneous REM sleep and may also
lice, W. M. indicated that he had no memory of any
progress to cataplexy, or sudden loss of tone in
of the events surrounding the incident; he tested
skeletal muscles (usually bilaterally). A final type of
negative for any intoxicating substances. As a result
disorder that displays periods of EDS is idiopathic
of this most recent episode, W. M. has come to you,
hypersomnia, in which patients usually have periods
his family physician, to determine the cause of the
of EDS usually associated with non-REM sleep. W.
excessive daytime sleepiness (EDS) and to find a
M. most likely has narcolepsy, which could be more
way to manage this condition. Your examination re-
clearly defined by determining whether he has a
veals an individual who is in otherwise excellent
specific human leukocyte antigen associated with
health and mentation with no apparent significant
the disorder (HLA-DR2). Management of nar-
pathology. He indicates that he has several periods
colepsy is accomplished with psychomotor stimu-
of EDS during the day and that the frequency of
lants of the amphetamine type. Methylphenidate,
these events is beginning to increase. While he feels
modafinil, pemoline, and dextroamphetamine all are
well rested upon waking, he is especially concerned
effective in managing the EDS periods, while
about the recent loss of skeletal muscle function
imipramine and clomipramine can be used to man-
and fears that he may be developing some degener-
age any cataplexy.
ative progressive disease that will leave him dis-