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

dopamine D 2
receptor–blocking actions in the same
molecule (Meltzer and Huang, 2008). Risperidone
(RISPERDAL, others), for example, is a potent 5-HT 2A
and
D 2
receptor antagonist. Low doses of risperidone have
been reported to attenuate negative symptoms of schizophrenia
with a low incidence of extrapyramidal side
effects. Extrapyramidal effects are commonly seen,
however, with doses of risperidone in excess of 6 mg/day.
Other atypical antipsychotic agents—quetiapine (SERO-
QUEL) and olanzapine (ZYPREXA)—act on multiple
receptors, but their antipsychotic properties are thought
to be due to antagonism of DA and 5-HT.
Cyproheptadine. The structure of cyproheptadine
resembles that of the phenothiazine histamine H 1
receptor
antagonists, and indeed, cyproheptadine is an effective
H 1
receptor antagonist. Cyproheptadine also has
prominent 5-HT blocking activity on smooth muscle
by virtue of its binding to 5-HT 2A
receptors. In addition,
it has weak anticholinergic activity and possesses
mild CNS depressant properties.
CYPROHEPTADINE
Cyproheptadine shares the properties and uses of
other H 1
receptor antagonists (Chapter 32). In allergic
conditions, the action of cyproheptadine as a 5-HT
receptor antagonist is irrelevant, since 5-HT 2A
receptors
are not involved in human allergic responses. The
5-HT blocking actions of cyproheptadine explain its
value in the off-label uses for postgastrectomy dumping
syndrome, intestinal hypermotility of carcinoid, and
migraine prophylaxis. Cyproheptadine is not, however,
a preferred treatment for these conditions.
Methysergide. Methysergide (SANSERT; 1-methyl-dlysergic
acid butanolamide) is a congener of methylergonovine
(Figure 13–5). It has both agonist and
antagonist activities at multiple 5-HT receptors. For
details, see “Ergot and the Ergot Alkaloids”, above.
Clinical Manipulation of 5-HT Levels:
Serotonin Syndrome
The clinical uses of drugs that alter 5-HT content in the
CNS are discussed in Chapter 15. Excessive elevation
of 5-HT levels in the body can cause serotonin syndrome,
a constellation of symptoms sometimes
observed in patients starting new or increased antidepressant
therapy or combining an SSRI with a NE reuptake
inhibitor or a triptan (for migraine), and others.
Symptoms (from mild to major) include restlessness,
confusion, shivering, tachycardia, diarrhea, muscle
twitches/rigidity, fever, seizures, loss of consciousness,
and death. Serotonin syndrome and its treatment are
discussed in Chapter 15.
DOPAMINE
History. Dopamine (DA) was first synthesized in 1910. Later that
year, Henry Dale characterized the biological properties of DA in
the periphery, and described it as a weak, adrenaline-like substance.
In the 1930s, DA was recognized as a transitional compound in the
synthesis of NE and epinephrine, but was believed to be little more
than a biosynthetic intermediate. Not until the early 1950s were
stores of DA were found in tissues, suggesting DA had a signaling
function of its own. By decade’s end, Carlsson and Montagu had
each identified DA stores in the brain. Soon thereafter, Hornykiewicz
discovered the DA deficit in the parkinsonian brain, fueling interest
in the role of DA in neurological diseases and disorders (see
Hornykiewicz, 2002).
Sources and Chemistry. DA consists of a catechol moiety linked to
an ethyl amine, leading to its classification as a catecholamine. DA
is closely related to melanin, a pigment that is formed by oxidation
of DA, tyrosine, or L-DOPA. Melanin exists in the skin and cuticle
and gives the substantia nigra its namesake dark color. Both DA and
L-DOPA are readily oxidized by non-enzymatic pathways to form
cytotoxic reactive oxygen species and quinones. DA- and DOPAquinones
form adducts with α-synuclein, a major constituent of Lewy
bodies in Parkinson disease (Chapter 22). DA is a polar molecule that
does not readily cross the blood-brain barrier.
Synthesis and Metabolism of DA. The synthesis of DA
is similar to the 5-HT biosynthetic pathway (Figure
13–6). The amino acids phenylalanine and tyrosine are
the precursors of DA. For the most part, mammals convert
dietary phenylalanine to tyrosine by phenylalanine
hydroxylase (predominantly located in the liver).
Diminished levels of this enzyme lead to high levels
of phenylalanine, a condition known as phenylketonuria,
which must be controlled by dietary restrictions
in order to avoid intellectual impairment.
Tyrosine crosses readily into the brain through uptake;
however, unlike tryptophan, normal brain levels of
tyrosine are typically saturating. Conversion of tyrosine
to L-DOPA (3,4-dihydroxyphenylalanine) by the
enzyme tyrosine hydroxylase is the rate-limiting step
in the synthesis of DA. Tyrosine hydroxylase is a
mixed-function enzyme that requires iron and a
biopterin co-factor; enzyme activity is regulated by
phosphorylation and by end-product inhibition
351
CHAPTER 13
5-HYDROXYTRYPTAMINE (SEROTONIN) AND DOPAMINE