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

symptoms of psychosis. The behavioral effects and the
time course of antipsychotic response parallel the rise in
D 2
occupancy and include calming of psychomotor agitation,
decreased hostility, decreased social isolation,
and less interference from disorganized or delusional
thought processes and hallucinations.
Levels of central D 2
occupancy estimated by positron emission
tomography (PET) brain imaging in patients treated with
antipsychotic drugs support conclusions arising from laboratory studies
that receptor occupancy predicts clinical efficacy, EPS, and serum
level-clinical response relationships. Occupation of > 78% of D 2
receptors in the basal ganglia is associated with a risk of EPS across
all dopamine antagonist antipsychotic agents, while occupancies in
the range of 60-75% are associated with antipsychotic efficacy
(Figure 16–2) (Kapur et al., 2000b). With the exception of aripiprazole,
all atypical antipsychotic drugs at low doses have much greater
occupancy of 5-HT 2A
receptors (e.g., 75-99%) than typical agents
(Table 16–2). Among atypical agents, clozapine has the highest ratio
of 5-HT 2A
/D 2
binding. Clozapine’s D 2
occupancy 12-hours post-dose
ranges from 51-63% (Kapur et al., 1999), providing evidence for its
limited EPS risk. The trough D 2
occupancy for quetiapine is even
lower (< 30%), but PET studies obtained 2-3 hours after dosing reveal
D 2
receptor occupancies in the expected therapeutic range (54-64%),
albeit transiently. Ziprasidone absorption is sensitive to the presence
of food, but PET studies demonstrate that clinical efficacy occurs
when D 2
occupancy exceeds 60%, which corresponds to a minimum
daily dose of 120 mg (with food) (Mamo et al., 2004).
Among the typical antipsychotic drugs, receptor occupancy is
best studied for haloperidol. Haloperidol has complex metabolism and
is susceptible to modulation by CYP inhibitors, inducers, and CYP
polymorphisms (Table 16–3), complicating the establishment of doseresponse
relationships in patients. Nonetheless, the use of serum levels
can predict D 2
occupancy (Fitzgerald et al., 2000):
% D 2
receptor occupancy = 100 × (Plasma haloperidol
ng/mL)/(0.40 ng/mL + Plasma haloperidol ng/mL)
Similar formulas also exist for several atypical antipsychotic
drugs, although their plasma concentrations are rarely measured in
the clinical setting.
D 3
and D 4
Receptors in the Basal Ganglia and Limbic System. The
discovery that D 3
and D 4
receptors are preferentially expressed in
limbic areas has led to efforts to identify selective inhibitors for these
receptors that might have antipsychotic efficacy and low EPS risk.
As previously noted, clozapine has modest selectivity for D 4
receptors,
which are preferentially localized in cortical and limbic brain
regions in relatively low abundance, and are up-regulated after
repeated administration of most typical and atypical antipsychotic
drugs (Tarazi et al., 2001). These receptors may contribute to clinical
antipsychotic actions, but agents that are D 4
selective (e.g.,
sonepiprazole) or mixed D 4
/5-HT 2A
antagonists (e.g., fananserin)
lack antipsychotic efficacy in clinical studies. In contrast to effects
on D 2
and D 4
receptors, long-term administration of typical and atypical
antipsychotic drugs does not alter D 3
receptor levels in rat forebrain
regions (Tarazi et al., 2001). These findings suggest that D 3
receptors are unlikely to play a pivotal role in antipsychotic drug
actions, perhaps because their avidity for endogenous DA prevents
their interaction with antipsychotic agents. The subtle and atypical
functional activities of cerebral D 3
receptors suggest that D 3
agonists
rather than antagonists may have useful psychotropic effects,
particularly in antagonizing stimulant-reward and dependence
behaviors. Aripiprazole possesses affinity and intrinsic activity at D 3
receptors equivalent to that at D 2
; the clinical advantage of this property
is not readily apparent, although preclinical data suggest some
effects on substance use.
The Role of Non-Dopamine Receptors for Atypical Antipsychotic
Agents. The concept of atypicality was initially based on clozapine’s
absence of EPS within the therapeutic range, combined with a prominent
role of 5-HT 2
receptor antagonism. As subsequent agents were
synthesized using clozapine’s 5-HT 2
/D 2
ratio as a model, most of
which possessed greater D 2
affinity and EPS risk than clozapine, there
has been considerable debate on the definition of an atypical antipsychotic
agent and its necessary properties. Aripiprazole in particular is
problematic for the model based on ratios of 5-HT 2
to D 2
, since its
action as partial agonist necessitates very high D 2
affinity. Loxapine
is another problematic agent for the model since its receptor pharmacology
suggests atypical properties based on 5-HT 2
/D 2
ratio; however,
in clinical practice its use was associated with the expected
higher level of EPS characteristic of typical antipsychotic drugs, perhaps
related to the additive D 2
antagonist properties of the active
metabolite amoxapine. These dilemmas have lead some to suggest
abandonment or modification of the atypical/typical antipsychotic
terminology, perhaps in lieu of the designation by generation (e.g.,
first, second, etc.), as is used with antibiotics, or some other organizing
scheme (Gründer et al., 2009). Nonetheless, the term “atypical”
persists in common usage and designates lesser (but not absent) EPS
risk and other decreased effects of excessive D 2
antagonism, or more
accurately, reduction in D 2
-mediated neurotransmission.
The neuropharmacology and behavioral pharmacology
of 5-HT 2
antagonism provide insights into the
advantageous properties of medications with these
effects (Marek et al., 2003). Antipsychotic agents with
appreciable 5-HT 2
affinity have significant effects at
both 5-HT 2A
and 5-HT 2C
receptors with individual medications
varying in their relative potencies at each subtype
(Tarazi et al., 2002). As discussed previously,
atypical antipsychotic agents exhibit potent functional
antagonism at both subtypes of 5-HT 2
receptors, but
in vitro assays suggest that these effects result from
inverse agonism at these G-coupled receptors.
5-HT 2A
receptors are widely distributed, but antagonism
exerts the greatest effect on prefrontal and basal ganglia DA release
and midbrain noradrenergic outflow, with recent data implicating
5-HT 2A
receptor polymorphisms in differential antidepressant
response (McMahon et al., 2006). There are significant interrelationships
between serotonin receptors, with evidence from animal studies
that stimulation of either 5-HT 1A
or 5-HT 2C
receptors antagonizes
the behavioral effects of 5-HT 2A
agonists (Marek et al., 2003). This
can be seen with agents that have direct effects on 5-HT 2A
activity
and also in studies of NMDA antagonists where there are opposing
modulatory effects of 5-HT 2A
and 5-HT 2C
stimulation. By virtue
of their impact on noradrenergic neurotransmission, 5-HT 2A
antagonists
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PHARMACOTHERAPY OF PSYCHOSIS AND MANIA
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