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

serum triglycerides may change 70-80 mg/dL during a period
when weight has changed relatively little propelled the search for
adiposity-independent physiological mechanisms to explain this
phenomenon.
In individuals not exposed to antipsychotic drugs, elevated
fasting triglycerides are a direct consequence of insulin resistance
since insulin-dependent lipases in fat cells are normally inhibited by
insulin. As insulin resistance worsens, inappropriately high levels of
lipolysis lead to the release of excess amounts of free fatty acids that
are hepatically transformed into triglyceride particles (Smith, 2007).
Elevated fasting triglyceride levels thus become a sensitive marker
of insulin resistance, leading to the hypothesis that the triglyceride
increases seen during antipsychotic treatment are the result of
derangements in glucose-insulin homeostasis. The ability of antipsychotic
drugs to induce hyperglycemia was first noted during lowpotency
phenothiazine treatment, with chlorpromazine occasionally
exploited for this specific property as adjunctive presurgical treatment
for insulinoma. As atypical antipsychotic drugs found widespread
use, numerous case series documented the association of
new-onset diabetes and diabetic ketoacidosis associated with treatment
with atypical antipsychotic drugs, with most of cases observed
during clozapine and olanzapine therapy (Jin et al., 2002, 2004).
Analysis of the FDA MedWatch database found that reversibility
was high upon drug discontinuation (~78%) for olanzapine- and
clozapine-associated diabetes and ketoacidosis, supporting the contention
of a drug effect. Comparable rates for risperidone and quetiapine
were significantly lower. The mechanism by which
antipsychotic drugs disrupt glucose-insulin homeostasis is not
known, but recent in vivo animal experiments document immediate
dose-dependent effects of clozapine and olanzapine on whole-body
and hepatic insulin sensitivity (Houseknecht et al., 2007).
Antipsychotic-induced weight gain, and other diabetes risk factors
(e.g., age, family history, gestational diabetes, obesity, race, ethnicity,
smoking) all contribute to metabolic dysfunction. There may
also be inherent disease-related mechanisms that increase risk for
metabolic disorders among patients with schizophrenia, but the medication
itself is the primary modifiable risk factor. As a result, all atypical
antipsychotic drugs have a hyperglycemia warning in the drug
label in the U.S., although there is essentially no evidence that asenapine,
iloperidone, aripiprazole, and ziprasidone cause hyperglycemia.
Use of the metabolically more benign agents is
recommended for the initial treatment of all patients where long-term
treatment is expected. Clinicians should obtain baseline metabolic
data, including fasting glucose, lipid panel, and also waist circumference,
given the known association between central obesity and future
type 2 diabetes risk. Ongoing follow-up of metabolic parameters is
commonly built into psychiatric charts and community mental health
clinic procedures to insure that all patients receive some level of metabolic
monitoring. As with weight gain, the changes in fasting glucose
and lipids should prompt reevaluation of ongoing treatment, institution
of measures to improve metabolic health (diet, exercise, nutritional
counseling), and consideration of switching antipsychotic agents.
Adverse Cardiac Effects. Ventricular arrhythmias and
sudden cardiac death (SCD) are a concern with the
use of antipsychotic agents. Most of the older antipsychotic
agents (e.g., thioridazine) inhibit cardiac K +
channels, and all antipsychotic medications marketed
in the U.S. carry a class label warning regarding QTc
prolongation. A black box warning exists for thioridazine,
mesoridazine, pimozide, IM droperidol, and IV
(but not oral or IM) haloperidol due to reported cases of
torsade de pointes and subsequent fatal ventricular
arrhythmias (discussed next and in Chapter 29).
Although the newer atypical agents are thought to have
less effects on heart electrophysiology compared to the
typical agents, a recent retrospective analysis found a
dose-dependent increased risk for SCD among antipsychotic
users of newer and older agents alike compared
to antipsychotic nonusers, with a relative risk of 2 (Ray
et al., 2009).
Cardiac arrhythmia is the most common etiology for SCD,
but it is important to determine whether the arrhythmia is primary or
secondary to structural changes related to cardiomyopathy,
myocarditis, or acute myocardial infarction. Secondary ventricular
arrhythmia is probably the most frequent form of fatal tachyarrhythmia,
but the exact distribution of SCD deaths by etiology among
antipsychotic-treated patients is unclear in the absence of large
autopsy samples. The true incidence of drug-induced ventricular
arrhythmia can only be estimated, due partly to underreporting, and
the fact that drug-induced torsade de pointes is rarely captured with
confirmatory EKG (Nielsen and Toft, 2009).
Multiple ion channels are involved in the depolarization and
repolarization of cardiac ventricular cells, which are discussed in
detail in Chapter 29. Myoycte depolarization is seen as the QRS
complex on EKG, and is primarily mediated by ion channels that
permit rapid Na + influx. Antagonism of these voltage-gated Na +
channels causes QRS widening and an increase in the PR interval,
with increased risk for ventricular arrhythmia. Thioridazine has been
shown to inhibit Na + channels at high dosages, but other antipsychotic
medications have not (Nielsen and Toft, 2009). Repolarization
is mediated in part by K + efflux via two channels: the rapid I kr
and
the slow I ks
channel. The I kr
channel is encoded by the human-ethera-related-go-go
gene (HERG), polymorphisms of which are involved
in the congenital long QT syndrome associated with syncope and
SCD. Many antipsychotic drugs block the I kr
channel to an extent
comparable with that seen in congenital long QT syndrome.
Antagonism of I kr
channels is the mechanism responsible for most
cases of drug-induced QT prolongation, and is the suspected mechanism
for the majority of antipsychotic-induced sudden cardiac
deaths (Nielsen and Toft, 2009).
Aside from individual agents, where anecdotal and pharmacosurveillance
data indicate risk for torsade de pointes (e.g., thioridazine,
pimozide), most of the commonly used newer antipsychotic
agents are associated with known risk for ventricular arrhythmias,
including ziprasidone in overdose up to 12,000 mg. One exception
is sertindole, an agent not available in the U.S. that was withdrawn
in 1998 based on anecdotal reports of torsade de pointes, and then
reintroduced in Europe in 2006 with strict EKG monitoring guidelines
(Nielsen and Toft, 2009). Although in vitro data revealed sertindole’s
affinity for the K + rectifier channel, several epidemiological
studies published over the past decade were unable to confirm an
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