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1 st gen antiphsychotics

PHARMACOLOGY First-generation antipsychotics (FGAs) are characterized by


strong antagonism of dopamine D2 receptors in both cortical and striatal areas .
Their dopamine D2 binding is highly correlated with clinical potency. The nonspecific
localization of their dopamine binding is consistent with their risk of movement
disorders and prolactinemia.
PHARMACOKINETICS First-generation antipsychotics (FGAs) are lipophilic,
highly protein and tissue-bound compounds with large volumes of distribution ( table
2 ). Most have prolonged half-lives (20 to 40 hours) that permit once or twice daily
dose administration after the dose has been stabilized. All FGAs are subject to
extensive metabolism via cytochrome P450 (CYP) -2D6, -3A4, -1A2 and/or other
enzymes, and several have active metabolites. Their oral absorption tends to be
somewhat erratic and several of the FGAs undergo extensive first-pass metabolism
by the liver, yielding low or variable oral bioavailability. Pharmacokinetics and
selected drug interactions of the FGAs are listed in the table ( table 2 ).
Therapeutic blood levels have not been established for haloperidol , the most widely
studied of these drugs [ 5,6 ]. Positron emission tomography (PET) studies have
found a 65 percent occupancy of dopamine D2 receptors to be correlated with
antipsychotic activity, and about 80 percent occupancy with onset of EPS [ 7 ] has
given rise to the possibility that PET scanning may prove useful in establishing and
monitoring drug levels. However, more research is needed.
Haloperidol Haloperidol is a butyrophenone, IM,IV,oral route of administration.
Haloperidol is readily absorbed orally, but extensive first-pass hepatic metabolism
reduces its bioavailability to 60 percent. The drug is cleared by the liver and its
cytochrome P450 isoenzymes CYP3A4 and CYP2D6, and glucuronidation, with a half
life of about 20 hours . Haloperidol can interact with potent inhibitors or inducers of
CYP3A4 and 2D6, giving elevated serum levels with fluoxetine , paroxetine ,
and bupropion , and decreased levels with carbamazepine . In most instances, these
interactions can be adequately addressed with dose adjustments. Clinically
significant interactions can occur with lithium , metoclopramide , and drugs that also
prolong the QTc interval or lower the seizure threshold.
The recommended dose of haloperidol has decreased steadily over the past 20 years.
Most recent guidelines recommend a maximum daily dose of 20 to 30 milligrams.
Analysis of two large randomized trials comparing different dosing levels of oral
haloperidol, concluded that the optimal daily dose was between 10 and 20 milligrams
per day . It is increasingly common for patients to receive daily doses less than 10
mg.
Intramuscular injection of antipsychotics is used, particularly on inpatient psychiatric
units, to treat agitation associated with psychosis. The usual intramuscular dose
of haloperidol for short-term treatment of acute agitation is 2 to 10 mg, as often as
every 30 minutes. Intramuscular administration results in a peak serum
concentration after 20 minutes.
Intravenous (IV) haloperidol is commonly used in intensive care units to treat
agitation associated with delirium in the US and other countries. This route of
administration has not been approved by the United States (US) Food and Drug
Administration (FDA). As in the case of oral dosing, IV doses of haloperidol in excess
of 100 mg/day for schizophrenia have been reported, but there is little evidence that
doses higher than 20 to 30 mg/day are beneficial, and the risk of cardiac conduction
abnormalities increases above 35 mg/day [ 11 ]. Although oral and intramuscular
dosing of haloperidol have been associated with minimal change in QT interval,
intravenous (IV) haloperidol has an elevated risk of prolonged QTc interval and
torsades de pointes [ 11,12,16 ]. Continuous cardiac monitoring is recommended
during acute IV drug administration and for two to three hours thereafter [ 16,30 ]
and IV dosing should be avoided in patients with pre-existing QT prolongation, other
cardiac abnormalities, electrolyte imbalance, or who are taking other drugs known to
increase QT interval [ 12,30 ]. (See "Sedative-analgesic medications in critically ill
patients: Properties, dosage regimens, and adverse effects", section on
'Neuroleptics'.)
Haloperidol is available as a decanoate preparation for depot administration, which is
cleared with a half life of about 21 days ( table 5 ). The usual dose of haloperidol
decanoate is 50 to 200 mg intramuscularly every two to four weeks [ 31 ]. The depot
formulation is used in maintenance treatment, particularly when adherence to daily
oral administration is poor. Although atypical agents are also available for depot
injection, the lower cost of the conventional depot drugs makes their use common.
(See "Pharmacotherapy for schizophrenia: Acute and maintenance phase treatment",
section on 'Maintenance treatment' .)
Although generally considered to be metabolically more benign than newer
drugs, haloperidol s major advantage is primarily overolanzapine [ 22,23 ], with
only a slight difference in risk compared with risperidone [ 23 ]. Even so, haloperidol
has long been associated with a moderate risk of weight gain [ 32 ] and diabetes
[ 33 ]. As such, in this regard, it should not be considered a safer alternative to
atypical medications ( table 1 ).
SIDE EFFECTS Common side effects associated with first-generation
antipsychotic antipsychotics (FGAs) include extrapyramidal symptoms (EPS), tardive
dyskinesia, hyperprolactinemia, neuroleptic malignant syndrome, QT prolongation,
sudden death, and an increased risk of mortality when used to treat psychiatric
symptoms associated with dementia in elderly patients

EPS: