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

440 health of the patient. Weight gain has effectively replaced concerns
over EPS as the adverse effect causing the most consternation among
patients and clinicians alike. Appetite stimulation is the primary
mechanism involved, with little evidence to suggest that decreased
activity (due to sedation) is a main contributor to antipsychoticrelated
weight gain (Gothelf et al., 2002). Recent animal studies indicate
that medications with significant H 1
antagonism induce appetite
stimulation through effects at hypothalamic sites (Kim et al., 2007).
The low-potency phenothiazine chlorpromazine, and the atypical
antipsychotic drugs olanzapine and clozapine, are the agents of highest
risk, but weight gain of some extent is seen with nearly all
antipsychotic drugs, partly related to the fact that acutely psychotic
patients may lose weight; in placebo-controlled acute schizophrenia
trials, the placebo cohort inevitably loses weight (Meyer, 2001). For
clozapine and olanzapine, massive weight gains of 50 kg or more
are not uncommon, and mean annual weight gains of 13 kg are
reported in schizophrenia clinical trials, with 20% of subjects gaining
≥ 20% of baseline weight. High-potency typical antipsychotic
drugs (e.g., haloperidol, fluphenazine), and newer atypical antipsychotics
asenapine, ziprasidone, and aripiprazole, are associated with
mean annual weight gains < 2 kg in schizophrenia patients, with
mean gains of 2.5-3 kg noted for iloperidone, risperidone, and quetiapine
(Meyer, 2001). For unknown reasons, molindone is associated
with modest weight loss. Younger and antipsychotic drug-naïve
patients are much more sensitive to the weight gain from all antipsychotic
agents, including those which appear roughly weight neutral
in adult studies, leading some to conjecture that DA blockade may
also play a small additive role in weight gain. 5-HT 2C
antagonism is
also thought to play an additive role in promoting weight gain for
medications that possess high H 1
affinities (e.g., clozapine, olanzapine),
but appears to have no effect in the absence of significant
H 1
blockade, as seen with ziprasidone, a weight-neutral antipsychotic
drug with extremely high 5-HT 2C
affinity. Switching to more
weight-neutral medications can achieve significant results; however,
when not feasible or when unsuccessful, behavioral strategies must
be employed, and should be considered for all chronically mentally
ill patients given the high obesity prevalence in this patient population.
SECTION II
NEUROPHARMACOLOGY
M 1
Receptors. Muscarinic antagonism is responsible for
the central and peripheral anticholinergic effects of
medications. Most of the atypical antipsychotic drugs,
including risperidone, paliperidone, asenapine, iloperidone,
ziprasidone, and aripiprazole, have no muscarinic
affinity and no appreciable anticholinergic effects,
while clozapine and low-potency phenothiazines have
significant anticholinergic adverse effects (Table 16–2).
Quetiapine has modest muscarinic affinity, but its active
metabolite norquetiapine is likely responsible for anticholinergic
complaints (Jensen et al., 2008). Clozapine
is particularly associated with significant constipation,
perhaps due to the severely ill population under treatment.
Routine use of stool softeners, and repeated
inquiry into bowel habits are necessary to prevent serious
intestinal obstruction from undetected constipation.
In general, avoidance of anticholinergic medications
obviates the need to secondarily treat problems related
to central or peripheral antagonism. Medications with
significant anticholinergic properties should be particularly
avoided in elderly patients, especially those with
dementia or delirium.
α 1
Receptors. α 1
Adrenergic antagonism is associated
with risk of orthostatic hypotension and can be particularly
problematic for elderly patients who have poor
vasomotor tone. Compared to high-potency typical
agents, low-potency typical agents have significantly
greater affinities for α 1
receptors and greater risk for
orthostasis. While risperidone has a K i
that indicates
greater α 1
-adrenergic affinity than chlorpromazine,
thioridazine, clozapine, and quetiapine, in clinical practice
risperidone is used at 0.01-0.005 times the dosages
of these medications, and thus causes a relatively lower
incidence of orthostasis in non-elderly patients. Since
clozapine-treated patients have few other antipsychotic
options, the potent mineralocorticoid fludrocortisone is
sometimes tried at the dose of 0.1 mg/day as a volume
expander.
Adverse Effects Not Predicted by
Monoamine Receptor Affinities
Adverse Metabolic Effects. Such effects have become the
area of greatest concern during long-term antipsychotic
treatment, paralleling the overall concern for high
prevalence of pre-diabetic conditions and type 2 diabetes
mellitus, and 2-fold greater CV mortality among
patients with schizophrenia (Meyer and Nasrallah,
2009). Aside from weight gain, the two predominant
metabolic adverse seen with antipsychotic drugs are
dyslipidemia, primarily elevated serum triglycerides,
and impairments in glycemic control.
Low-potency phenothiazines were known to elevate serum
triglyceride values, but this effect was not seen with high-potency
agents (Meyer and Koro, 2004). As atypical antipsychotic drugs
became more widely used, significant increases in fasting triglyceride
levels were noted during clozapine and olanzapine exposure,
and to a lesser extent, with quetiapine (Meyer et al., 2008). Mean
increases during chronic treatment of 50-100 mg/dL are common,
with serum triglyceride levels exceeding 7000 mg/dL in some
patients. Effects on total cholesterol and cholesterol fractions are
significantly less, but show expected associations related to agents
of highest risk: clozapine, olanzapine, and quetiapine. Risperidone
and paliperidone have fewer effects on serum lipids, while asenapine,
iloperidone, aripiprazole, and ziprasidone appear to have
none (Meyer and Koro, 2004). Weight gain in general may induce
deleterious lipid changes, but there is compelling evidence to indicate
that antipsychotic-induced hypertriglyceridemia is a weightindependent
adverse event that temporally occurs within weeks
of starting an offending medication, and which similarly resolves
within 6 weeks after medication discontinuation. The finding that