DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

leukotrienes. Although glucocorticoids and antihistamines frequently
are administered to patients with severe hypersensitivity reactions,
epinephrine remains the mainstay. Epinephrine auto-injectors
(EPIPEN, others) are employed widely for the emergency self-treatment
of anaphylaxis.
Ophthalmic Uses. Application of various sympathomimetic
amines for diagnostic and therapeutic ophthalmic use is discussed
in Chapter 64.
Narcolepsy and Related Syndromes. Narcolepsy is characterized
by hypersomnia, including attacks of sleep that may occur suddenly
under conditions that are not normally conducive to sleep. Some
patients respond to treatment with tricyclic antidepressants or MAO
inhibitors. Alternatively, CNS stimulants such as amphetamine, dextroamphetamine,
or methamphetamine may be useful. Modafinil
(PROVIGIL), a CNS stimulant, may have benefit in narcolepsy. In the
U.S., it is a schedule IV controlled substance. Its mechanism of
action in narcolepsy is unclear and may not involve adrenergic receptors.
Therapy with amphetamines is complicated by the risk of abuse
and the likelihood of the development of tolerance. Depression, irritability,
and paranoia also may occur. Amphetamines may disturb
nocturnal sleep, which increases the difficulty of avoiding daytime
attacks of sleep in these patients. Armodafinil (NUVIGIL), the R-enantiomer
of modafinil (a mixture of R- and S-enantiomers) is also indicated
for narcolepsy, to improve wakefulness in shift workers, and
to combat excessive sleepiness in patients with obstructive sleep
apnea-hypopnea syndrome.
Narcolepsy in rare individuals is caused by mutations in the
related orexin neuropeptides (also called hypocretins), which are
expressed in the lateral hypothalamus, or in their G protein–coupled
receptors (Mignot, 2004). Although such mutations are not present
in most subjects with narcolepsy, the levels of orexins in the CSF
are markedly diminished, suggesting that deficient orexin signaling
may play a pathogenic role. The association of these neuropeptides
and their cognate GPCRs with narcolepsy provides an
attractive target for the development of novel pharmacotherapies
for this disorder.
Weight Reduction. Obesity arises as a consequence of positive
caloric balance. Optimally, weight loss is achieved by a gradual
increase in energy expenditure from exercise combined with dieting
to decrease the caloric intake. However, this obvious approach has
a relatively low success rate. Consequently, alternative forms of
treatment, including surgery or medications, have been developed
in an effort to increase the likelihood of achieving and maintaining
weight loss. Amphetamine was found to produce weight loss in early
studies of patients with narcolepsy and was subsequently used in the
treatment of obesity. The drug promotes weight loss by suppressing
appetite rather than by increasing energy expenditure. Other anorexic
drugs include methamphetamine, dextroamphetamine (and a prodrug
form, lisdexamfetamine), phentermine, benzphetamine,
phendimetrazine, phenmetrazine, diethylpropion, mazindol, phenylpropanolamine,
and sibutramine (a mixed adrenergic/serotonergic
drug). Phenmetrazine, mazindol, and phenylpropanolamine have
been discontinued in the U.S. In short-term (up to 20 weeks), double-blind
controlled studies, amphetamine-like drugs have been
shown to be more effective than placebo in promoting weight loss;
the rate of weight loss typically is increased by ~ 0.5 pound per week
with these drugs. There is little to choose among these drugs in terms
of efficacy. However, long-term weight loss has not been demonstrated
unless these drugs are taken continuously. In addition, other
important issues have not yet been resolved, including the selection
of patients who might benefit from these drugs, whether the drugs
should be administered continuously or intermittently, and the duration
of treatment. Adverse effects of treatment include the potential
for drug abuse and habituation, serious worsening of hypertension
(although in some patients blood pressure actually may fall, presumably
as a consequence of weight loss), sleep disturbances, palpitations,
and dry mouth. These agents may be effective adjuncts in the
treatment of obesity. However, available evidence does not support
the isolated use of these drugs in the absence of a more comprehensive
program that stresses exercise and modification of diet. β 3
Receptor
agonists have remarkable anti-obesity and anti-diabetic effects in
rodents. However, pharmaceutical companies have not yet succeeded
in developing β 3
receptor agonists for the treatment of these conditions
in humans, perhaps because of important differences in
β 3
receptors between humans and rodents. With the cloning of the
human β 3
receptor, compounds with favorable metabolic effects have
been developed. The use of β 3
agonists in the treatment of obesity
remains a possibility for the future (Fernandez-Lopez et al., 2002;
Robidoux et al., 2004).
Attention-Deficit/Hyperactivity Disorder (ADHD). This syndrome,
usually first evident in childhood, is characterized by excessive
motor activity, difficulty in sustaining attention, and impulsiveness.
Children with this disorder frequently are troubled by difficulties in
school, impaired interpersonal relationships, and excitability.
Academic underachievement is an important characteristic. A substantial
number of children with this syndrome have characteristics
that persist into adulthood, although in modified form. Behavioral
therapy may be helpful in some patients. Catecholamines may be
involved in the control of attention at the level of the cerebral cortex.
A variety of stimulant drugs have been utilized in the treatment of
ADHD, and they are particularly indicated in moderate-to-severe
cases. Dextroamphetamine has been demonstrated to be more
effective than placebo. Methylphenidate is effective in children
with ADHD and is the most common intervention (Swanson and
Volkow, 2003). Treatment may start with a dose of 5 mg of
methylphenidate in the morning and at lunch; the dose is increased
gradually over a period of weeks depending on the response as
judged by parents, teachers, and the clinician. The total daily dose
generally should not exceed 60 mg; because of its short duration of
action, most children require two or three doses of methylphenidate
each day. The timing of doses is adjusted individually in accordance
with rapidity of onset of effect and duration of action.
Methylphenidate, dextroamphetamine, and amphetamine probably
have similar efficacy in ADHD and are the preferred drugs in
this disorder. Sustained-release preparations of dextroamphaetamine,
methylphenidate (RITALIN SR, CONCERTA, META-DATE),
dexmethylphenidate (FOCALIN XR), and amphetamine (ADDERAL XR)
may be used once daily in children and adults. Lisdexamfetamine
(VYVANSE) can be administered once daily and a transdermal formulation
of methylphenidate (DAYTRANA) is marketed for daytime use.
Potential adverse effects of these medications include insomnia,
abdominal pain, anorexia, and weight loss that may be associated
with suppression of growth in children. Minor symptoms may be
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CHAPTER 12
ADRENERGIC AGONISTS AND ANTAGONISTS