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

344 suppressant in the management of obesity. The drug is
converted to two active metabolites that contribute to
its therapeutic effects. The relative importance of
effects on single or multiple neurotransmitters in sibutramine’s
anti-obesity action is unclear. Sibutramine is
classified as a selective serotonin/ norepinephrine
reuptake inhibitor (SNRI). Other SNRIs include duloxetine
(CYMBALTA; approved for depression, anxiety,
peripheral neuropathy, and fibromyalgia), venlafaxine
(EFFEXOR; approved for the treatment of depression,
anxiety, and panic disorders), desvenlafaxine (PRISTIQ;
approved for depression), and milnacipran (SAVELLA;
approved for fibromyalgia).
Nonselective treatments that alter 5-HT levels
include MAO inhibitors (e.g., phenelzine [NARDIL],
tranylcypromine [PARNATE, others], and isocarboxazid
[MARPLAN]) and reserpine. MAO inhibitors block the
principal route of degradation, thereby increasing levels
of 5-HT, whereas reserpine, a VMAT2 inhibitor,
depletes intraneuronal stores of 5-HT. These treatments
profoundly alter levels of 5-HT throughout the body.
Because reserpine and MAO inhibitors also cause comparable
changes in the levels of catecholamines, the
drugs are of limited utility as research tools. Both
agents have been used in the treatment of mental diseases:
reserpine as an antipsychotic drug (Chapter 16)
and MAO inhibitors as antidepressants (Chapter 15).
SECTION II
NEUROPHARMACOLOGY
Experimental strategies for evaluating the role of 5-HT
depend on techniques that manipulate tissue levels of 5-HT or block
5-HT receptors. Until recently, manipulation of the levels of endogenous
5-HT was the more commonly used strategy, because the
actions of 5-HT receptor antagonists were poorly understood.
Tryptophan hydroxylase is the rate-limiting enzyme in 5-HT
synthesis, and manipulation of its catalytic flux provides useful ways
to alter 5-HT levels. A diet low in tryptophan reduces the concentration
of brain 5-HT; conversely, ingestion of a tryptophan load
increases levels of 5-HT in the brain. An acute decrease in brain 5-HT
can be achieved by oral administration of an amino acid mixture
devoid of tryptophan, a valuable tool for human studies of the role
of 5-HT. In addition, administration of a tryptophan hydroxylase
inhibitor causes a profound depletion of 5-HT. The most widely used
selective tryptophan hydroxylase inhibitor is p-chlorophenylalanine,
which acts irreversibly to produce long-lasting depletion of 5-HT
levels with no change in levels of catecholamines.
p-Chloroamphetamine and other halogenated amphetamines
promote the release of 5-HT from platelets and neurons. A rapid
release of 5-HT is followed by a prolonged and selective depletion of
5-HT in brain. The mechanism of 5-HT release involves reversal of
5-HT transporter, analogous to the mechanism of the catecholaminereleasing
action of amphetamine. The halogenated amphetamines are
valuable experimental tools and two of them, fenfluramine and dexfenfluramine,
were used clinically to reduce appetite; the once popular
diet drug regimen, “fen-phen,” combined fenfluramine and phentermine.
Fenfluramine (PONDIMIN) and dexfenfluramine (REDUX) were
withdrawn from the U.S. market in the late 1990s after reports of lifethreatening
heart valve disease and pulmonary hypertension associated
with their use. This toxicity may be secondary to 5-HT 2B
receptor activation
(Roth, 2007). The mechanism for long-term depletion of brain
5-HT by the halogenated amphetamines remains controversial. A profound
reduction in levels of 5-HT in the brain lasts for weeks and is
accompanied by an equivalent loss of proteins (5-HT transporter and
tryptophan hydroxylase) selectively localized in 5-HT neurons, suggesting
that the halogenated amphetamines have a neurotoxic action.
Despite these long-lasting biochemical deficits, neuroanatomical signs
of neuronal death are not readily apparent. Another class of compounds,
ring-substituted tryptamine derivatives such as 5,7-dihydroxytryptamine
(Figure 13–1) produces unequivocal degeneration of 5-HT neurons.
In adult animals, 5,7-dihydroxytryptamine selectively destroys
serotonergic axon terminals; the remaining intact cell bodies allow
eventual regeneration of axon terminals. In newborn animals, degeneration
is permanent because 5,7-dihydroxytryptamine destroys serotonergic
cell bodies as well as axon terminals.
5-HT RECEPTOR AGONISTS
AND ANTAGONISTS
5-HT Receptor Agonists
Direct-acting 5-HT receptor agonists have widely different
chemical structures, as well as diverse pharmacological
properties (Table 13–5), as might be predicted
from the multiplicity of 5-HT receptor subtypes. 5-HT 1A
receptor–selective agonists have helped elucidate the
functions of this receptor in the brain and have resulted
in a new class of antianxiety drugs including buspirone
(BUSPAR, others) and the investigational agents, gepirone
and ipsapirone (Chapter 15). 5-HT 1B/1D
receptor–selective
agonists, such as sumatriptan, have unique properties
that result in constriction of intracranial blood vessels
that are effective in the treatment of acute migraine
attacks. A number of 5-HT 4
receptor–selective agonists
have been developed or are being developed for the
treatment of disorders of the GI tract (Chapter 46).
These classes of selective 5-HT receptor agonists are
discussed in more detail in the chapters that deal directly
with treatment of the relevant pathological conditions.
5-HT Receptor Agonists and Migraine. Migraine
headache afflicts 10-20% of the population. Although
migraine is a specific neurological syndrome, the manifestations
vary widely. The principal types are
migraine without aura (common migraine); migraine
with aura (classic migraine, which includes subclasses
of migraine with typical aura, migraine with prolonged
aura, migraine aura without headache, and migraine
with acute-onset aura), and several rarer types.
Premonitory aura may begin as long as 24 hours
before the onset of pain and often is accompanied by