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

598 displacement of phenytoin from albumin. The concurrent administration
of valproate and clonazepam has been associated with the
development of absence status epilepticus; however, this complication
appears to be rare.
Therapeutic Uses. Valproate is a broad-spectrum antiseizure
drug effective in the treatment of absence,
myoclonic, partial, and tonic-clonic seizures. The initial
daily dose usually is 15 mg/kg, increased at weekly
intervals by 5-10 mg/kg per day to a maximum daily
dose of 60 mg/kg. Divided doses should be given when
the total daily dose exceeds 250 mg. The therapeutic
uses of valproate in epilepsy are discussed further at the
end of this chapter.
SECTION II
NEUROPHARMACOLOGY
BENZODIAZEPINES
The benzodiazepines are used primarily as sedativeanti-anxiety
drugs; their pharmacology is described in
Chapters 14 and 17. Discussion here is limited to their
use in the therapy of the epilepsies. A large number of
benzodiazepines have broad anti-seizure properties, but
only clonazepam (KLONOPIN, others) and clorazepate
(TRANXENE, others) have been approved in the U.S. for
the long-term treatment of certain types of seizures.
Midazolam was designated an orphan drug in 2006 for
intermittent treatment of bouts of increased seizure
activity in refractory patients with epilepsy who are on
stable regimens of anti-seizure drugs. Diazepam (VAL-
IUM, DIASTAT; others) and lorazepam (ATIVAN, others) have
well-defined roles in the management of status epilepticus.
The structures of the benzodiazepines are shown
in Chapter 17.
Anti-Seizure Properties. In animal models, inhibition of
pentylenetetrazol-induced seizures by the benzodiazepines is much
more prominent than is their modification of the maximal electroshock
seizure pattern. Clonazepam is unusually potent in
antagonizing the effects of pentylenetetrazol, but it is almost
without action on seizures induced by maximal electroshock.
Benzodiazepines, including clonazepam, suppress the spread of kindled
seizures and generalized convulsions produced by stimulation
of the amygdala, but do not abolish the abnormal discharge at the
site of stimulation.
Mechanism of Action. The anti-seizure actions of the benzodiazepines,
as well as other effects that occur at nonsedating doses,
result in large part from their ability to enhance GABA-mediated
synaptic inhibition. Molecular cloning and study of recombinant
receptors have demonstrated that the benzodiazepine receptor is an
integral part of the GABA A
receptor (Chapter 17). At therapeutically
relevant concentrations, benzodiazepines act at subsets of GABA A
receptors and increase the frequency, but not duration, of openings
at GABA-activated Cl – channels (Twyman et al., 1989). At higher
concentrations, diazepam and many other benzodiazepines can
reduce sustained high-frequency firing of neurons, similar to the
effects of phenytoin, carbamazepine, and valproate. Although these
concentrations correspond to concentrations achieved in patients
during treatment of status epilepticus with diazepam, they are considerably
higher than those associated with anti-seizure or anxiolytic
effects in ambulatory patients.
Pharmacokinetic Properties. Benzodiazepines are well absorbed
after oral administration, and concentrations in plasma are usually
maximal within 1-4 hours. After intravenous administration, they are
redistributed in a manner typical of that for highly lipid-soluble
agents. Central effects develop promptly, but wane rapidly as the
drugs move to other tissues. Diazepam is redistributed especially
rapidly, with a t 1/2
of redistribution of ~1 hour. The extent of binding
of benzodiazepines to plasma proteins correlates with lipid solubility,
ranging from ~99% for diazepam to ~85% for clonazepam
(Appendix II).
The major metabolite of diazepam, N-desmethyl-diazepam,
is somewhat less active than the parent drug and may behave as a
partial agonist. This metabolite also is produced by the rapid decarboxylation
of clorazepate following its ingestion. Both diazepam and
N-desmethyl-diazepam are slowly hydroxylated to other active
metabolites, such as oxazepam. The t 1/2
of diazepam in plasma is
between 1 and 2 days, while that of N-desmethyl-diazepam is
~60 hours. Clonazepam is metabolized principally by reduction of
the nitro group to produce inactive 7-amino derivatives. Less than
1% of the drug is recovered unchanged in the urine. The t 1/2
of clonazepam
in plasma is ~23 hours. Lorazepam is metabolized chiefly by
conjugation with glucuronic acid; its t 1/2
in plasma is ~14 hours.
Toxicity. The principal side effects of long-term oral
therapy with clonazepam are drowsiness and lethargy.
These occur in ~50% of patients initially, but tolerance
often develops with continued administration. Muscular
incoordination and ataxia are less frequent. Although
these symptoms usually can be kept to tolerable levels
by reducing the dosage or the rate at which it is
increased, they sometimes force drug discontinuation.
Other side effects include hypotonia, dysarthria, and dizziness.
Behavioral disturbances, especially in children, can be very
troublesome; these include aggression, hyperactivity, irritability, and
difficulty in concentration. Both anorexia and hyperphagia have been
reported. Increased salivary and bronchial secretions may cause difficulties
in children. Seizures are sometimes exacerbated, and status
epilepticus may be precipitated if the drug is discontinued abruptly.
Other aspects of the toxicity of the benzodiazepines are discussed
in Chapter 17. Cardiovascular and respiratory depression may occur
after the intravenous administration of diazepam, clonazepam, or
lorazepam, particularly if other anti-seizure agents or central depressants
have been administered previously.
Plasma Drug Concentrations. Because tolerance affects the relationship
between drug concentration and drug anti-seizure effect,
plasma concentrations of benzodiazepines are of limited value.
Therapeutic Uses. Clonazepam is useful in the therapy of absence
seizures as well as myoclonic seizures in children. However, tolerance
to its anti-seizure effects usually develops after 1-6 months of
administration, after which some patients will no longer respond to