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

antimuscarinic activity, but is rarely used due to concerns over QTc
prolongation and risk of torsade de pointes. Several potent phenothiazine
antipsychotic compounds have a piperazine group in the side
chain (fluphenazine, perphenazine, and trifluoperazine) and have
reduced affinity for H 1
, M, and α 1
receptors. Those with a free
hydroxyl can also be esterified to long-chain fatty acids to produce
LAI antipsychotic medications (e.g., fluphenazine decanoate).
Thioxanthenes also have aliphatic or piperazine side-chain substituents.
Piperazine-substituted thioxanthenes include the high
potency agent thiothixene. Since thioxanthenes have an olefinic double
bond between the central-ring C10 and the side chain, geometric
isomers exist. The cis isomers are more active. The antipsychotic phenothiazines
and thioxanthenes have three carbon atoms interposed
between position 10 of the central ring and the first amino nitrogen
atom of the side chain at this position; the amine is always tertiary.
Antihistaminic phenothiazines (e.g., promethazine) or strongly anticholinergic
phenothiazines have only two carbon atoms separating
the amino group from position 10 of the central ring. Metabolic N-
dealkylation of the side chain or increasing the size of amino N-alkyl
substituents reduces antidopaminergic and antipsychotic activity.
Additional tricyclic antipsychotic agents are the benzepines, containing
a 7-member central ring, of which loxapine (a dibenzoxazepine)
and clozapine (a dibenzodiazepine) are available in the U.S.
Clozapine-like atypical antipsychotic agents may lack a substituent
on the aromatic ring (e.g., quetiapine, a dibenzothiazepine), have an
analogous methyl substituent (olanzapine), or have an electron-donating
substituent at position 8 (e.g., clozapine). In addition to their moderate
potencies at DA receptors, clozapine-like agents interact with
varying affinities at several other classes of receptors (α 1
and α 2
adrenergic, 5-HT 1A
, 5-HT 2A
, 5-HT 2C
, M, H 1
). The prototypical butyrophenone
(phenylbutylpiperidine) antipsychotic is haloperidol, originally
developed as a substituted derivative of the phenylpiperidine
analgesic meperidine. An analogous compound, droperidol, is a very
short-acting and highly sedating agent that was used almost exclusively
for emergency sedation and anesthesia until QTc and torsade
de pointes concerns substantially curtailed its use and the use of the
related diphenylbutylpiperidine pimozide. Several other classes of
heterocyclic compounds have antipsychotic effects, of which only
the indole molindone has generated any interest due to its unusual
association with modest weight loss (Sikich et al., 2008a). The enantiomeric,
substituted benzamides are another group of heterocyclic
compounds that are relatively selective antagonists at central D 2
receptors and have antipsychotic activity. Examples (not available in
the U.S.) include sulpiride and its congener, amisulpride.
The introduction of clozapine stimulated research into agents
with antipsychotic activity and low EPS risk. This search led to a
series of atypical antipsychotic agents with certain pharmacological
similarities to clozapine: namely lower affinity for D 2
receptors than
typical antipsychotic drugs and high 5-HT 2
antagonist effects. The
currently available atypical antipsychotic medications include the
structurally related olanzapine, quetiapine, and clozapine; the benzisoxazoles
risperidone, its active metabolite paliperidone, and
iloperidone; ziprasidone (a benzisothiazolpiprazinylindolone derivative);
asenapine (a dibenzo-oxepino pyrrole), and aripiprazole (a
quinolinone derivative). Table 16–1.
Presently, antipsychotic agents include many different
chemical structures with a range of activities at
different neurotransmitter receptors (e.g., 5-HT 2A
antagonism,
5-HT 1A
partial agonism). As a result, structurefunction
relationships that were relied upon in the past
have become less important. Instead, receptor-function
relationships and functional assays are more clinically
relevant. Aripiprazole represents a good example of
how an examination of the structure provides little
insight into its mechanism, which is based on dopamine
partial agonism (discussed later). Detailed knowledge
of receptor affinities (Table 16–2) and the functional
effect at specific receptors (e.g., full, partial or inverse
agonism or antagonism) can provide important insight
into the therapeutic and adverse effects of antipsychotic
agents. Nevertheless, there are limits. For example, it
is not known which properties are responsible for clozapine’s
unique effectiveness in refractory schizophrenia,
although many hypotheses exist. Other notable antipsychotic
properties not fully explained by receptor parameters
include the reduced seizure threshold, the
unexpected extent of prolactin elevation for risperidone
and paliperidone, the effects of antipsychotic agents on
metabolic function, and the increased risk for cerebrovascular
events and mortality among dementia
patients (see “Adverse Effects and Drug Interactions”
later in the chapter).
Mechanism of Action. While emerging data indicate
that stimulation of glutamate or muscarinic receptors
may confer antipsychotic properties, no clinically
available effective antipsychotic is devoid of D 2
antagonistic
activity. This reduction in dopaminergic neurotransmission
is presently achieved through one of two
mechanisms: D 2
antagonism or partial D 2
agonism, of
which aripiprazole is the only current example. Another
partial agonist, bifeprunox, completed clinical trials but
failed to gain FDA approval.
Aripiprazole has an affinity for D 2
receptors only slightly less
than DA itself, but its intrinsic activity is ~25% that of dopamine. As
depicted in Figure 16–3, when dopamine is given in increasing concentrations
in an in vitro model, 100% stimulation of the available
D 2
receptors occurs (as measured by forskolin-stimulated cyclic
AMP accumulation). In the absence of DA, aripiprazole produces a
maximal level of D 2
activity ~25% that of DA (Burris et al., 2002).
The potent D 2
antagonist haloperidol is capable of reducing
dopamine’s effect to zero, but when DA is incubated with increasing
concentrations of aripiprazole, maximal inhibition of D 2
activity did
not exceed 25% of the DA response, that is, the level of agonism
provided by aripiprazole. Aripiprazole’s capacity to stimulate D 2
receptors in brain areas where synaptic DA levels are limited (e.g.,
PFC neurons) or decrease dopaminergic activity when dopamine
concentrations are high (e.g., mesolimbic cortex) is thought to be
the basis for its clinical effects in schizophrenia. Evidence for its
partial DA agonist properties is seen clinically as a reduction in
CHAPTER 16
PHARMACOTHERAPY OF PSYCHOSIS AND MANIA
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