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

pass many preclinical in vivo assays of antidepressant activity; conversely,
5-HT 2C
antagonists exhibit a similar spectrum of antidepressant
properties, although pure 5-HT 2A
or 5-HT 2C
agents are, by
themselves, not effective antidepressants in human trials (Marek et
al., 2003). Data also indicate that 5-HT 2C
agonism decreases
mesolimbic DA neurotransmission, a mechanism that is being
explored in clinical trials of vabicaserin, a pure 5-HT 2C
agonist. At
the cellular level, stimulation of 5-HT 2A
and 5-HT 1A
receptors causes
depolarization and hyperpolarization, respectively, of cortical pyramidal
cells (Marek et al., 2003). No atypical antipsychotic agent is a
potent agonist of 5-HT 1A
receptors, but several, including clozapine,
ziprasidone and aripiprazole are partial agonists. The extent to which
this contributes to any clinical effect is unknown, but more potent
selective 5-HT 1A
agonists have anxiolytic effects and appear to exert
procognitive effects in schizophrenia patients when added to existing
antipsychotic treatment.
Based upon trials of the selective α 2
adrenergic antagonist
idazoxan, researchers have postulated effects of α 2
blockade on
mood, but ongoing research into this mechanism has not been promising.
Risperidone is the one antipsychotic with relatively high affinity
for α 2
adrenergic receptors, at which it is an antagonist; however,
the clinical correlate of this unique profile is unclear. Any benefit on
major depressive symptoms from low-dose risperidone augmentation
of SSRI antidepressants is more likely conveyed by effects at the
5-HT 2A
receptor, at which risperidone has > 100-fold greater potency
than at α 2
adrenergic receptors.
Tolerance and Physical Dependence. As defined in Chapter 24,
antipsychotic drugs are not addicting; however, tolerance to the
antihistaminic and anticholinergic effects of antipsychotic agents
usually develops over days or weeks. Loss of efficacy with prolonged
treatment is not known to occur with antipsychotic agents;
however, tolerance to antipsychotic drugs and cross-tolerance among
the agents are demonstrable in behavioral and biochemical experiments
in animals, particularly those directed toward evaluation of
the blockade of dopaminergic receptors in the basal ganglia (Tarazi
et al., 2001). This form of tolerance may be less prominent in limbic
and cortical areas of the forebrain. One correlate of tolerance in
striatal dopaminergic systems is the development of receptor supersensitivity
(mediated by upregulation of supersensitive DA receptors)
referred to as D 2
High
receptors (Lieberman et al., 2008). These
changes may underlie the clinical phenomenon of withdrawal-emergent
dyskinesias and may contribute to the pathophysiology of tardive
dyskinesia. This may also partly explain the ability of certain
chronic schizophrenia patients to tolerate high doses of potent DA
antagonists with limited EPS.
Absorption, Distribution, and Elimination. The pharmacokinetic
constants for these drugs may be found in
Appendix II. Table 16–3 outlines the metabolic pathways
of atypical antipsychotic agents available in the
U.S. and selected typical agents in common use. Most
antipsychotic drugs are highly lipophilic, highly
membrane- or protein-bound, and accumulate in the
brain, lung, and other tissues with a rich blood supply.
They also enter the fetal circulation and breast milk.
Despite half-lives that may be short, the biological
effects of single doses of most antipsychotic medications
usually persist for at least 24 hours, permitting
once-daily dosing for many agents once the patient has
adjusted to initial side effects.
Elimination from the plasma may be more rapid than from sites
of high lipid content and binding, notably the CNS, as evidenced by
PET pharmacokinetic studies that demonstrate half-lives in the CNS
that exceed those in plasma. For example, mean single-dose plasma
half-lives of olanzapine and risperidone are 24.2 and 10.3 hours
respectively, whereas a 50% reduction from peak striatal D 2
receptor
occupancy requires 75.2 hours for olanzapine and 66.6 hours for
risperidone (Tauscher et al., 2002). Similar discrepancies are seen
between the time course of plasma levels and occupancy of extrastriatal
D 2
and 5-HT 2A
receptors (Tauscher et al., 2002). Metabolites of
long acting injectable medications have been detected in the urine several
months after drug administration was discontinued. Slow removal
of drug may contribute to the typical delay of exacerbation of psychosis
after stopping drug treatment. Depot decanoate esters of
fluphenazine and haloperidol, paliperidone palmitate, as well as
risperidone-impregnated microspheres, are absorbed and eliminated
much more slowly than are oral preparations. For example, the t 1/2
of
oral fluphenazine is ~20 hours while the IM decanoate ester has a t 1/2
of 14.3 days; oral haloperidol has a t 1/2
of 24-48 hours in CYP2D6-
extensive metabolizers (de Leon et al., 2004), while haloperidol
decanoate has a t 1/2
of 21 days (Altamura et al., 2003); paliperidone
palmitate has a t 1/2
of 25-49 days compared to an oral paliperidone t 1/2
of 23 hours. Clearance of fluphenazine and haloperidol decanoate following
repeated dosing can require 6-8 months. Effects of LAI risperidone
(RISPERDAL CONSTA) are delayed for 4 weeks because of slow
biodegradation of the microspheres and persist for at least 4-6 weeks
after the injections are discontinued (Altamura et al., 2003). The dosing
regimen recommended for starting patients on LAI paliperidone
generates therapeutic levels in the first week, obviating the need for
routine oral antipsychotic supplementation.
With the exception of asenapine, paliperidone and ziprasidone,
all antipsychotic drugs undergo extensive phase 1 metabolism
by CYPs and subsequent phase 2 glucuronidation, sulfation, and
other conjugations (Table 16–3). Hydrophilic metabolites of these
drugs are excreted in the urine and to some extent in the bile. Most
oxidized metabolites of antipsychotic drugs are biologically inactive;
a few (e.g., P88 metabolite of iloperidone, hydroxy metabolite
of haloperidol 9-OH risperidone, N-desmethylclozapine, and dehydroaripiprazole)
are active. These active metabolites may contribute
to biological activity of the parent compound and complicate correlating
serum drug levels with clinical effects. The active metabolite
of risperidone, paliperidone (9-OH risperidone), is already the product
of oxidative metabolism, and 59% is excreted unchanged in urine
with a lesser amount (32%) excreted as metabolites or via phase 2
metabolism (≤ 10%). Ziprasidone’s primary metabolic pathway is
through the aldehyde oxidase system that is neither saturable nor
inhibitable by commonly encountered xenobiotics, with ~ one-third
of ziprasidone’s metabolism through CYP3A4 (Meyer, 2007).
Asenapine is metabolized primarily through glucuronidation
(UGT4), with a minor contribution from CYP1A2. The potential for
drug-drug interactions is covered in “Adverse Effects and Drug
Interactions” later in the chapter.
CHAPTER 16
PHARMACOTHERAPY OF PSYCHOSIS AND MANIA
435