29.33 Valproate
1045
dosage of a TCA. Nortriptyline is unique in its association with
a therapeutic window—that is, plasma concentrations below
50 ng/mL or above 150 ng/mL may reduce its efficacy.
Plasma concentrations may be useful in confirming com-
pliance, assessing reasons for drug failures, and documenting
effective plasma concentrations for future treatment. Clinicians
should always treat the person and not the plasma concentra-
tion. Some persons have adequate clinical responses with seem-
ingly subtherapeutic plasma concentrations, and other persons
only respond at supratherapeutic plasma concentrations with-
out experiencing adverse effects. The latter situation, however,
should alert the clinician to monitor the person’s condition with,
for example, serial EKG recordings.
Overdose Attempts
Overdose attempts with TCAs are serious and can often be fatal.
Prescriptions for these drugs should be nonrefillable and for no
longer than 1 week at a time for patients at risk for suicide.
Amoxapine may be more likely than the other TCAs to result
in death when taken in overdose. The newer antidepressants are
safer in overdose.
Symptoms of overdose include agitation, delirium, con-
vulsions, hyperactive deep tendon reflexes, bowel and blad-
der paralysis, dysregulation of BP and temperature, and
mydriasis. The patient then progresses to coma and perhaps
respiratory depression. Cardiac arrhythmias may not respond
to treatment. Because of the long half-lives of TCAs, the
patients are at risk of cardiac arrhythmias for 3 to 4 days after
the overdose, so they should be monitored in an intensive care
medical setting.
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▲▲
29.33 Valproate
Valproate (Depakene, Depakote), or valproic acid, is approved
for the treatment of manic episodes associated with bipolar I
disorder and is one of the most widely prescribed mood stabiliz-
ers in psychiatry. It has a rapid onset of action and is well toler-
ated, and numerous studies suggest that it reduces the frequency
and intensity of recurrent manic episodes over extended periods
of time.
Chemistry
Valproate is a simple-chain branch carboxylic acid. It is called
valproic acid because it is rapidly converted to the acid form
in the stomach. Multiple formulations of valproic acid are
marketed. These include valproic acid (Depakene); divalproex
sodium (Depakote), an enteric-coated delayed-release 1:1 mix-
ture of valproic acid and sodium valproate available in tablet
and sprinkle formulation (can be opened and spread on food);
and sodium valproate injection (Depacon). An extended-release
preparation is also available. Each of these is therapeutically
equivalent because at physiologic pH, valproic acid dissociates
into valproate ion.
Pharmacologic Actions
Regardless of how it is formulated, valproate is rapidly and
completely absorbed 1 to 2 hours after oral administration,
with peak concentrations occurring 4 to 5 hours after oral
administration. The plasma half-life of valproate is 10 to 16
hours. Valproate is highly protein bound. Protein binding
becomes saturated at higher dosages, and concentrations of
therapeutically effective free valproate increase at serum con-
centrations above 50 to 100
m
g/mL. The unbound portion of
valproate is considered to be pharmacologically active and can
cross the blood–brain barrier. The extended-release preparation
produces lower peak concentrations and higher minimum con-
centrations and can be given once a day. Valproate is metabo-
lized primarily by hepatic glucuronidation and mitochondrial
b
oxidation.
The biochemical basis of valproate’s therapeutic effects
remains poorly understood. Postulated mechanisms include
enhancement of GABA activity, modulation of voltage-sensitive sodium channels, and action on extrahypothalamic
neuropeptides.
