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Dopaminergic Systems
Five important dopaminergic systems
or pathways are present in CNS. The
first pathwaythe one most closely
related to behavior and psychosisis
the mesolimbic-mesocortical
pathway, which projects from cell
bodies near the substantia nigra to
the limbic system and neocortex.
Phenothiazines
Chlorpromazine, Fluphenazine, Thioridazine
Thioxanthene Derivatives
Thiothixene.
Butyrophenone Derivatives
This group, of which haloperidol is the most
widely used, has a very different structure
from those of the two preceding groups.
Haloperidol, a butyrophenone, is the most
widely used typical antipsychotic drug
Pharmacokinetics
Most antipsychotic drugs are readily but incompletely
absorbed. Furthermore, many undergo significant firstpass metabolism. Thus, oral doses of chlorpromazine and
thioridazine have systemic availability of 2535%,
whereas haloperidol, which has less first-pass metabolism,
has an average systemic availability of about 65%.
Most antipsychotic drugs are highly lipid-soluble and
protein-bound (9299%). They tend to have large volumes
of distribution (usually more than 7 L/kg). They generally
have a much longer clinical duration of action than would
be estimated from their plasma half-lives. This is
paralleled by prolonged occupancy of D2 dopamine
receptors in the brain by the typical antipsychotic drugs.
Clinical uses of
antipsychotic drugs
Behavioural emergencies (e.g. violent
patients with a range of
psychopathologies including mania,
toxic delirium and schizophrenia
classic antipsychotic drugs (e.g.
chlorpromazine, haloperidol) can rapidly
control hyperactive psychotic states
note that the intramuscular dose is lower
than the oral dose of the same drug
because of presystemic metabolism.
Schizophrenia
Many chronic schizophrenic patients are
treated with first generation
antipsychotic drugs. Depot injections
(e.g. flupentixol decanoate) may be
useful for maintenance treatment when
compliance with oral treatment is a
problem. Flupentixol has
antidepressant properties distinct from
its antipsychotic action.
Antipsychotic-induced motor
disturbances
Major problem of antipsychotic drug
treatment.
Two main types of disturbance occur:
acute, reversible dystonias and
Parkinson-like symptoms
slowly developing tardive dyskinesia,
often irreversible.
Aripiprazole, chlorpromazine,
olanzapine, quetiapine,
risperidone, and ziprasidone are
approved by FDA for the treatment of
manic phase of bipolar disorder.
Olanzapine plus fluoxetine in
combination and quetiapine are
approved for the treatment of bipolar
depression.
Side Effects
Tremor is one of the most common adverse
effects of lithium treatment, and it occurs
with therapeutic doses. Propranolol and
atenolol, which have been reported to be
effective in essential tremor, also alleviate
lithium-induced tremor.
Lithium probably decreases thyroid function
in most patients exposed to the drug, but
the effect is reversible or nonprogressive.