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

436 Absorption for most agents is quite high, and concurrent
administration of anticholinergic anti-parkinsonian agents does not
appreciably diminish intestinal absorption. Most orally-disintegrating
tablets (ODT) and liquid preparations provide similar pharmacokinetics
since there is little mucosal absorption and effects depend on
swallowed drug. Asenapine remains the only exception. It is only
available as an ODT preparation administered sublingually, and all
absorption occurs via oral mucosa, with bioavailability of 35% by
this route. If swallowed, the first pass effect is > 98%, indicating that
drug swallowed with oral secretions is not bioavailable.
Intramuscular administration avoids much of the first-pass enteric
metabolism and provides measurable concentrations in plasma
within 15-30 minutes. Most agents are highly protein bound, but this
protein binding may include glycoprotein sites. Kinetic studies indicate
that antipsychotic drugs do not significantly displace other prealbumin-
or albumin-bound medications. Antipsychotic medications
are predominantly highly lipophilic with apparent volumes of distribution
as high as 20 L/kg.
SECTION II
NEUROPHARMACOLOGY
Therapeutic Uses
The use of antipsychotic medications for the treatment
of schizophrenia spectrum disorders, for mania treatment,
and as adjunctive use for treatment-resistant major
depression has been discussed previously. Antipsychotic
agents are also utilized in several nonpsychotic neurological
disorders and as antiemetics.
Anxiety Disorders. There are two anxiety disorders in which double-blind,
placebo-controlled trials have shown benefit of adjunctive
treatment with antipsychotic drugs: obsessive compulsive disorder
(OCD) and post-traumatic stress disorder (PTSD). While SSRI antidepressants
remain the only psychotropic medication with FDA
approval for PTSD treatment, adjunctive low-dose quetiapine, olanzapine,
and particularly risperidone significantly reduce the overall
level of symptoms in SSRI-resistant PTSD (Bartzokis et al., 2005).
OCD patients with limited response to the standard 12-week regimen
of high dose SSRI also benefit from adjunctive risperidone (mean
dose 2.2 mg), even in the presence of comorbid tic disorders
(McDougle et al., 2000). For generalized anxiety disorder, doubleblind
placebo controlled clinical trials demonstrate efficacy for quetiapine
as monotherapy, and for adjunctive low-dose risperidone.
Tourette’s Disorder. The ability of antipsychotic drugs to suppress
tics in patients with Tourette’s disorder has been known for decades,
and relates to reduced D 2
neurotransmission in basal ganglia sites. In
prior decades, the use of low-dose, high-potency typical antipsychotic
agents (e.g., haloperidol, pimozide) was the treatment of
choice, but these nonpsychotic patients were extremely sensitive to
the impact of DA blockade on cognitive processing speed, and on
reward centers. Safety concerns regarding pimozide’s QTc prolongation
and increased risk for ventricular arrhythmias have large
ended its clinical use. While lacking FDA approval for tic disorders,
risperidone and aripiprazole have indications for child and adolescent
schizophrenia and bipolar disorder (acute mania) treatment, and
these agents (as well as ziprasidone) have published data supporting
their use for tic suppression. Given the enormous sensitivity of
preadolescent and teenage patients to antipsychotic-induced weight
gain, aripiprazole has an advantage in this patient population due to
somewhat lower risk for weight gain, and low risk for hyperprolactinemia
or concerns over QTc effects.
Huntington’s Disease. Huntington’s disease is another neuropsychiatric
condition, which, like tic disorders, is associated with basal
ganglia pathology. DA blockade can suppress the severity of
choreoathetotic movements, but is not strongly endorsed due to the
risks associated of excessive DA antagonism that outweigh the marginal
benefit. Inhibition of the vesicular monoamine transporter type 2
(VMAT2) with tetrabenazine has replaced DA receptor blockade in
the management of chorea (Chapter 22).
Autism. Autism is a disease whose neuropathology is incompletely
understood, but in some patients is associated with explosive behavioral
outbursts, and aggressive or self-injurious behaviors that may
be stereotypical. Risperidone has FDA approval for irritability associated
with autism in child and adolescent patients ages 5-16, with
common use for disruptive behavior problems in autism and other
forms of mental retardation. Initial risperidone daily doses are
0.25 mg for patients weighing < 20 kg, and 0.5 mg for others, with
a target dose of 0.5 mg/day in those < 20 kg weight, and 1.0 mg/day
for other patients, with a range 0.5-3.0 mg/day.
Anti-emetic Use. Most antipsychotic drugs protect against the
nausea- and emesis-inducing effects of DA agonists such as apomorphine
that act at central DA receptors in the chemoreceptor trigger
zone of the medulla. Antipsychotic drugs are effective
antiemetics already at low doses. Drugs or other stimuli that cause
emesis by an action on the nodose ganglion, or locally on the GI
tract, are not antagonized by antipsychotic drugs, but potent piperazines
and butyrophenones are sometimes effective against nausea
caused by vestibular stimulation. The commonly used antiemetic
phenothiazines are weak DA antagonists (e.g., prochlorperazine)
without antipsychotic activity, but can be associated with EPS or
akathisia.
Adverse Effects and Drug Interactions
Adverse Effects Predicted by Monoamine
Receptor Affinities
Dopamine D 2
Receptor. With the exception of the D 2
partial
agonist aripiprazole (and the commercially unavailable
agent bifeprunox), all other antipsychotic agents
possess D 2
antagonist properties, the strength of which
determines the likelihood for EPS, akathisia, long-term
tardive dyskinesia risk, and hyperprolactinemia. The
manifestations of EPS are described in Table 16-4,
along with the usual treatment approach. Acute dystonic
reactions occur in the early hours and days of
treatment with highest risk among younger patients
(peak incidence ages 10-19), especially antipsychoticnaïve
individuals, in response to abrupt decreases in
nigrostriatal D 2
neurotransmission. The dystonia typically
involves head and neck muscles, the tongue, and
in its severest form, the oculogyric crisis, extraocular
muscles, and is very frightening to the patient.