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

Therapeutic Use. A double-blind, placebo-controlled study of children
with Lennox-Gastaut syndrome demonstrated that rufinamide
reduced tonic-atonic seizure frequency to a greater extent than
placebo.
Vigabatrin
VIGABATRIN
Vigabatrin (SABRIL) was approved by the FDA in 2009
as adjunctive therapy of refractory partial complex
seizures in adults. In addition, vigabatrin is designated
as an orphan drug for treatment of infantile spasms
(described in the subsequent “Therapeutic Use” section).
Due to progressive and permanent bilateral vision
loss, vigabatrin must be reserved for patients who have
failed several alternative therapies; its availability is
restricted under the conditions of the SHARE special
distribution program.
Pharmacological Effects and Mechanism of Action. Vigabatrin is
a structural analog of GABA that irreversibly inhibits the major
degradative enzyme for GABA, GABA-transaminase, thereby leading
to increased concentrations of GABA in the brain. Its mechanism
of action is thought to involve enhancement of GABA-mediated
inhibition.
Therapeutic Use. A 2-week, randomized, single masked clinical
trial of vigabatrin for infantile spasms in children < 2 years old
revealed time- and dose-dependent increases in responders, evident
as freedom from spasms for 7 consecutive days. The subset of children
in whom infantile spasms were caused by tuberous sclerosis
was particularly responsive to vigabatrin.
Acetazolamide
Acetazolamide, the prototype for the carbonic anhydrase inhibitors,
is discussed in Chapter 25. Its anti-seizure actions have been discussed
in previous editions of this textbook. Although it is sometimes
effective against absence seizures, its usefulness is limited by the
rapid development of tolerance. Adverse effects are minimal when
it is used in moderate dosage for limited periods.
GENERAL PRINCIPLES AND CHOICE
OF DRUGS FOR THE THERAPY
OF THE EPILEPSIES
Early diagnosis and treatment of seizure disorders with
a single appropriate agent offers the best prospect of
achieving prolonged seizure-free periods with the lowest
risk of toxicity. An attempt should be made to determine
the cause of the epilepsy with the hope of discovering a
correctable lesion, either structural or metabolic. The
drugs commonly used for distinct seizure types are listed
in Table 21–1. The efficacy combined with the unwanted
effects of a given drug determine which particular drug
is optimal for a given patient.
The first decision to make is whether and when to
initiate treatment (French and Pedley, 2008). For example,
it may not be necessary to initiate anti-seizure therapy
after an isolated tonic-clonic seizure in a healthy
young adult who lacks a family history of epilepsy and
who has a normal neurological exam, a normal EEG,
and a normal brain MRI scan. The odds of seizure recurrence
in the next year (15%) are similar to the risk of a
drug reaction sufficiently severe to warrant discontinuation
of medication (Bazil and Pedley, 1998). On the
other hand, a similar seizure occurring in an individual
with a positive family history of epilepsy, an abnormal
neurological exam, an abnormal EEG, and an abnormal
MRI carries a risk of recurrence approximating 60%,
odds that favor initiation of therapy.
Unless extenuating circumstances such as status
epilepticus exist, only monotherapy should be initiated.
Initial dosing should target steady-state plasma drug
concentrations within at least the lower portion of the
range associated with clinical efficacy. At the same time
the initial dose should be as low as possible to minimize
dose-related adverse effects. Dosage is increased
at appropriate intervals as required for control of
seizures or as limited by toxicity. Such adjustment
should be assisted by monitoring of drug concentrations
in plasma. Compliance with a properly selected, single
drug in maximal tolerated dosage results in complete
control of seizures in ~50% of patients. If a seizure
occurs despite optimal drug levels, the physician should
assess the presence of potential precipitating factors
such as sleep deprivation, a concurrent febrile illness, or
drugs (e.g., large amounts of caffeine or over-the-counter
medications that can lower the seizure threshold).
If compliance has been confirmed yet seizures
persist, another drug should be substituted. Unless serious
adverse effects of the drug dictate otherwise,
dosage always should be reduced gradually to minimize
risk of seizure recurrence. In the case of partial seizures
in adults, the diversity of available drugs permits selection
of a second drug that acts by a different mechanism
(see Table 21–2). Among previously untreated
patients, 47% became seizure free with the first drug
and an additional 14% became seizure free with a second
or third drug (Kwan and Brodie, 2000).
If therapy with a second single drug also is inadequate,
combination therapy is warranted. This decision
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CHAPTER 21
PHARMACOTHERAPY OF THE EPILEPSIES