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

358 receptor agonist and a weak D 1
antagonist. Pergolide is a partial agonist
of D 1
receptors and a strong D2-family agonist with high affinity
for both D 2
and D 3
receptor subtypes. Ergot derivatives are
commonly reported to cause unpleasant side effects, including nausea,
dizziness, and hallucinations. Pergolide was removed from the
U.S. market as therapy for PD after it was associated with an
increased risk for valvular heart disease.
Ergot Alkaloids in the Treatment of Hyperprolactinemia. Despite the
contraindications for PD, ergot-based DA agonists are still used in
the treatment of hyperprolactinemia. Like bromocriptine, cabergoline
(DOSTINEX) is a strong agonist at D 2
receptors, and has lower
affinity for D 1
, 5-HT, and α adrenergic receptors. The therapeutic
utility of bromocriptine and cabergoline in hyperprolactinemia is
derived from their properties as DA receptor agonists: they activate
D 2
receptors in the pituitary to reduce prolactin secretion. The risk
of valvular heart disease in ergot therapy is associated with higher
doses of drug (necessary for PD treatment), but not with the lower
doses used in treating hyperprolactinemia. The use of bromocriptine
and cabergoline in the management of hyperprolactinemia is
described in Chapter 38.
SECTION II
NEUROPHARMACOLOGY
D1/D2 Receptor Agonists (Non-Ergot Alkaloids). Apomorphine
(APOKYN), a derivative of morphine, is approved for the treatment of
PD. Apomorphine binds with the order of potence D 4
>D 2
>D 3
>D 5
.
Apomorphine also binds with lower affinity to D 1
, α-adrenergic, 5-
HT 1A
, and 5-HT 2
receptors. The therapeutic benefits of apomorphine
in PD are likely due to its higher affinity and efficacy at DA receptors,
especially D2-family receptors. Apomorphine is most commonly
used in combination with L-DOPA to surmount the sudden
“off” periods that can occur after long-term L-DOPA treatment.
Rotigotine is offered in a transdermal patch (NEUPRO) for
the treatment of PD. Rotigotine preferentially binds to D 2
and D 3
receptors and has much lower affinity for D 1
receptors. In addition,
rotigotine is an agonist at 5-HT 1A
and 5-HT 2
receptors, and an
antagonist at α 2
adrenergic receptors. Due to problems with patch
release, rotigotine is currently not sold in the U.S., but is available
in Europe.
D2 Family Receptor Agonists (Non-Ergot Alkaloids). Based on
the role of DA in PD and the initial therapeutic utility of ergot compounds,
more selective D2 dopaminergic agonists were developed
for PD treatment. Pramipexole (MIRAPEX) and ropinirole (REQUIP)
are agonists at all D2 family receptors and, notably, bind with highest
affinity to the D 3
receptor subtype. Interestingly, pramipexole is
reported to have neuroprotective properties when administered
before MPTP or 6-OHDA in animal models of PD (Joyce and
Millan, 2007); agonist activity at the D 3
receptor may be the underlying
neuroprotective mechanism.
Ropinirole in the Treatment of Restless Leg Syndrome (RLS). In addition
to its utility in the treatment of PD, ropinirole has also been FDAapproved
as pharmacotherapy for RLS. Mild dopaminergic hypofunction
has been noted in patients with RLS. Somnolence and other side
effects reported for PD therapy are less pronounced in the treatment of
RLS, presumably due to the lower dose required for RLS therapy.
D 4
Receptor Agonists and Attention Deficit-Hyperactivity
Disorder (ADHD). The D 4
receptor is known to be significant in
ADHD; an association has been reproducibly demonstrated between
the seven-repeat D 4
VNTR variant and patients with ADHD. Recent
preclinical testing has uncovered potential therapeutic benefits of the
selective D 4
agonist, A-412997, in cognitive tasks and animal models
of ADHD. Animals treated with A-412997 showed cognitive
improvements well below hyperlocomotive doses and, importantly,
A-412997 did not show potential for abuse at any dose tested
(Woolley et al., 2008). This is in marked contrast to the currently
available drug therapies for ADHD treatment that have high abuse
potential. While all published studies to date are preclinical, D 4
-
selective agonists show significant promise for the next generation
of ADHD therapy.
DA Receptor Antagonists
Just as enhancing DA neurotransmission is clinically
important, inhibiting an over-active dopaminergic system
can be useful. As with the DA receptor agonists, a
lack of subtype-specific antagonists has limited the
therapeutic utility of this group of ligands. Recent
advances in defining GPCR structure, along with ligand-binding
modeling, have advanced rational drug
design, and selective antagonists are now available as
experimental tools (Table 13–7). Many subtype-selective
antagonists are in early stages of preclinical testing
for therapeutic utility.
DA Receptor Antagonists and Schizophrenia. DA receptor antagonists
are a mainstay in the pharmacotherapy of schizophrenia.
While many neurotransmitter systems likely contribute to the complex
pathology of schizophrenia (Chapter 16), DA dysfunction is
considered the basis of this disorder. The DA hypothesis of schizophrenia
has its origins in the characteristics of the drugs used to treat
this disorder: all antipsychotic compounds used clinically have high
affinity for DA receptors. Moreover, psychostimulants that increase
extracellular DA levels can induce or worsen psychotic symptoms in
schizophrenic patients. The advent of neuroimaging techniques for
visualization of DA in human brain regions has led to new insights
into the role of specific DA systems. DA hyperfunction in subcortical
regions, most notably the striatum, has been associated with the
positive symptoms of schizophrenia that respond well to antipsychotic
treatment. In contrast, the prefrontal cortex of schizophrenic
patients exhibits dopaminergic hypofunction, which has been associated
with the more treatment-refractory negative/cognitive symptoms.
The drugs currently used to treat schizophrenia are classified
as either typical (also referred to as first generation) or atypical (second
generation) antipsychotics. This nomenclature stems from the
high efficacy and lack of extrapyramidal side effects observed with
atypical antipsychotics. Some of the newer drugs in development do
not fit into this classification scheme, including the D1-selective agonist,
dihydrexidine. Dihydrexidine shows great promise to improve
the refractory negative symptoms of schizophrenia, and may be especially
useful in combination therapy with current antipsychotics that
preferentially reduce positive symptoms by antagonizing D2 receptors
(Mu et al., 2007).
Antipsychotic Agents
Typical Antipsychotics. The first antipsychotic drug used to treat
schizophrenia was chlorpromazine (THORAZINE). Despite its affinity
for a wide array of neurotransmitter receptors, the antipsychotic