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

442 increased risk of sudden death due to sertindole exposure, thereby
providing justification for its reintroduction. Aside from sertindole,
the apparent safety of newer antipsychotic medications appears at
odds with retrospective findings of SCD among antipsychotic users
(Ray et al., 2009), thus confronting the clinician with contradictory
information regarding antipsychotic drug-related SCD risk, and leading
to conflicting clinical recommendations. Currently, there are no
data that would suggest a benefit of routine EKG monitoring for
prevention of SCD among antipsychotic drug users.
SECTION II
NEUROPHARMACOLOGY
Other Adverse Effects. Seizure risk is an unusual adverse effect of
antipsychotic drugs, with anecdotal reports of uncertain causality
present for many agents. In the U.S., there is a class label warning for
seizure risk on all antipsychotic agents, with reported incidences well
below 1%. Among commonly used newer antipsychotic drugs, only
clozapine has a dose-dependent seizure risk, with an incidence of
3-5% per year. The structurally related olanzapine had an incidence
of 0.9% in premarketing studies. Seizure disorder patients who commence
antipsychotic treatment must receive adequate prophylaxis,
with consideration given to avoiding carbamazepine and phenytoin
due to their capacity to induce CYPs and P-glycoprotein.
Carbamazepine is also contraindicated during clozapine treatment
due to its bone marrow effects, particularly leucopenia. Redistribution
and increased spacing of doses to minimize high peak serum clozapine
levels can help, but patients may eventually require antiseizure
medication. Valproic acid derivatives (e.g., divalproex sodium) are
often used, but will compound clozapine-associated weight gain.
Clozapine possesses a host of unusual adverse effects aside
from seizure induction, the most concerning of which is agranulocytosis.
Clozapine’s introduction in the U.S. was based on its efficacy
in refractory schizophrenia, but came with FDA-mandated CBC
monitoring that is overseen by industry-created registries. Now that
several generic forms of clozapine are available in addition to proprietary
CLOZARIL, clinicians must verify with each manufacturer the
history of prior exposure. The overall agranulocytosis incidence is
slightly under 1%, with highest risk during the initial 6 months of
treatment, peaking at months 2-3 and diminishing rapidly thereafter.
The mechanism is immune mediated, and patients who have verifiable
clozapine-related agranulocytosis should not be rechallenged.
Increased risk is associated with certain HLA types and advanced
age. An extensive algorithm guiding clinical response to agranulocytosis,
and lesser forms of neutropenia, is available from manufacturer
web sites, and must be followed, along with the current
recommended CBC monitoring frequency.
While rarely used due to its risk of QTc prolongation, thioridazine
is also associated with pigmentary retinopathy at daily doses
≥ 800 mg/day. Low-potency phenothiazines are associated with the
development of photosensitivity, which necessitated warnings
regarding sun exposure. Phenothiazines are also associated with
development of a cholestatic picture on laboratory assessments (e.g.,
elevated alkaline phosphatase), and rarely elevations in hepatic
transaminases.
Increased Mortality in Dementia Patients. Perhaps the least understood
adverse effect is the increased risk for cerebrovascular events
and all-cause mortality among elderly dementia patients exposed to
antipsychotic medications. All antipsychotic agents carry a mortality
warning in the drug label regarding their use in dementia patients.
The cerebrovascular adverse event rates in 10-week dementia trials
range from 0.4-0.6% for placebo to 1.3-1.5% for risperidone,
olanzapine and aripiprazole (Jeste et al., 2008). The mortality warning
indicates a 1.6-1.7 fold increased mortality risk for drug versus
placebo. Mortality is due to heart failure, sudden death, or pneumonia.
The underlying etiology for antipsychotic-related cerebrovascular
and mortality risk is unknown, but the finding of
virtually equivalent mortality risk for typical agents compared to
atypical antipsychotic drugs (including aripiprazole) suggests an
impact of reduced D 2
signaling regardless of individual antipsychotic
mechanisms.
Overdose with typical antipsychotic agents is of
particular concern with low-potency agents (e.g., chlorpromazine)
due to the risk of torsades de pointes, sedation,
anticholinergic effects, and orthostasis. Patients
who overdose on high-potency typical antipsychotic
drugs (e.g., haloperidiol) and the substituted benzamides
are at greater risk for EPS due to the high D 2
affinity, but also must be observed for EKG changes.
Overdose experience with newer agents, including
ziprasidone, indicates a much lower risk for torsade de
pointes ventricular arrhythmias compared to older
antipsychotic medications; however, combinations of
antipsychotic agents with other medications can lead to
fatality, primarily through respiratory depression
(Ciranni et al., 2009).
Drug-Drug Interactions. Antipsychotic agents are not
significant inhibitors of CYP enzymes with a few
notable exceptions (chlorpromazine, perphenazine, and
thioridazine inhibit CYP 2D6) (Otani and Aoshima,
2000). The plasma half-lives of a number of these
agents are altered by induction or inhibition of hepatic
CYPs and by genetic polymorphisms that alter specific
CYP activities (Table 16–3). While antipsychotic drugs
are highly protein bound, there is no evidence of significant
displacement of other protein bound medications,
so dosage adjustment is not required for
anticonvulsants, warfarin, or other agents with narrow
therapeutic indices. With respect to drug-drug interactions,
it is important to consider the effects of environmental
exposures (smoking, nutraceuticals, grapefruit
juice), and changes in these behaviors.
Changes in smoking status can be especially problematic for
clozapine-treated patients, and will alter serum levels by 50% or
more. Within 2 weeks of smoking discontinuation (e.g., hospitalization
in nonsmoking environment), the absence of aryl hydrocarbons
will cause upregulated CYP1A2 activity to return to baseline levels,
with a concomitant rise in serum clozapine concentrations (Rostami-
Hodjegan et al., 2004). For smoking patients with high serum clozapine
levels, this loss of enzyme induction may result in nonlinear
increases in clozapine levels, with potentially catastrophic results.
Conversely, patients discharged from nonsmoking wards to the community
will be expected to resume smoking behavior, with an
expected 50% decrease in clozapine levels. Monitoring of serum
clozapine concentrations, anticipation of changes in smoking habits,