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Basic Pharmacology of Antiseizure Drugs
Chemistry
Until 1990, approximately 16
antiseizure drugs were available, and 13 of them can be classified into
five very similar chemical groups: barbiturates, hydantoins,
oxazolidinediones, succinimides, and acetylureas. These groups have in
common a similar heterocyclic ring structure with a variety of
substituents (Figure 24–3). For drugs with this basic structure, the
substituents on the heterocyclic ring determine the pharmacologic class,
either anti-MES or antipentylenetetrazol. Very small changes in structure
can dramatically alter the mechanism of action and clinical properties of
the compound. The remaining drugs in this older group—carbamazepine,
valproic acid, and the benzodiazepines—are structurally dissimilar, as
are the newer compounds marketed since 1990, ie, felbamate, gabapentin,
lacosamide, lamotrigine, levetiracetam, oxcarbazepine, pregabalin,
tiagabine, topiramate, vigabatrin, and zonisamide.
Pharmacokinetics
The antiseizure drugs exhibit
many similar pharmacokinetic properties—even those whose structural and
chemical properties are quite diverse—because most have been selected for
oral activity and all must enter the central nervous system. Although
many of these compounds are only slightly soluble, absorption is usually
good, with 80–100% of the dose reaching the circulation. Most antiseizure
drugs (other than phenytoin and valproic acid) are not highly bound to
plasma proteins.
Antiseizure drugs are cleared
chiefly by hepatic mechanisms, although they have low extraction ratios
(see Chapter 3). Many are converted to active metabolites that are also
cleared by the liver. These drugs are predominantly distributed into
total body water. Plasma clearance is relatively slow; many antiseizure
drugs are therefore considered to be medium- to long-acting. Some have
half-lives longer than 12 hours. Many of the older antiseizure drugs are
potent inducers of hepatic microsomal enzyme activity. Compliance is
better with less frequent administration; thus extended-release
formulations permitting once- or twice-daily administration may offer an
advantage.
Drugs Used in Partial Seizures
& Generalized Tonic-Clonic Seizures
The classic major drugs for
partial and generalized tonic-clonic seizures are phenytoin (and
congeners), carbamazepine, valproate, and the barbiturates. However, the
availability of newer drugs—lamotrigine, levetiracetam, gabapentin,
oxcarbazepine, pregabalin, topiramate, vigabatrin, lacosamide, and
zonisamide—is altering clinical practice in countries where these
compounds are available.
Phenytoin
Phenytoin is the oldest
nonsedative antiseizure drug, introduced in 1938 after a systematic
evaluation of compounds such as phenobarbital that altered electrically
induced seizures in laboratory animals. It was known for decades as diphenylhydantoin.
Chemistry
Phenytoin is a
diphenyl-substituted hydantoin with the structure shown. It has much
lower sedative properties than compounds with alkyl substituents at the 5
position. A more soluble prodrug of phenytoin, fosphenytoin, is
available for parenteral use; this phosphate ester compound is rapidly
converted to phenytoin in the plasma.
Mechanism of Action
Phenytoin has major effects on
several physiologic systems. It alters Na+, K+, and
Ca2+ conductance, membrane potentials, and the concentrations
of amino acids and the neurotransmitters norepinephrine, acetylcholine,
and  -aminobutyric
acid (GABA). Studies with neurons in cell culture show that phenytoin
blocks sustained high-frequency repetitive firing of action potentials
(Figure 24–4). This effect is seen at therapeutically relevant concentrations.
It is a use-dependent effect (see Chapter 14) on Na+
conductance, arising from preferential binding to—and prolongation of—the
inactivated state of the Na+ channel. This effect is also seen
with therapeutically relevant concentrations of carbamazepine,
lamotrigine, and valproate and probably contributes to their antiseizure
action in the electroshock model and in partial seizures.
In addition, phenytoin
paradoxically causes excitation in some cerebral neurons. A reduction of
calcium permeability, with inhibition of calcium influx across the cell
membrane, may explain the ability of phenytoin to inhibit a variety of
calcium-induced secretory processes, including release of hormones and
neurotransmitters. Recording of excitatory and inhibitory postsynaptic
potentials show that phenytoin decreases the synaptic release of
glutamate and enhances the release of GABA. The mechanism of phenytoin's
action probably involves a combination of actions at several levels. At
therapeutic concentrations, the major action of phenytoin is to block
sodium channels and inhibit the generation of rapidly repetitive action
potentials. Presynaptic actions on glutamate and GABA release probably
arise from actions other than those on voltage-gated Na+
channels.
Clinical Use
Phenytoin is effective against
partial seizures and generalized tonic-clonic seizures. In the latter, it
appears to be effective against attacks that are either primary or
secondary to another seizure type.
Pharmacokinetics
Absorption of phenytoin is
highly dependent on the formulation of the dosage form. Particle size and
pharmaceutical additives affect both the rate and the extent of
absorption. Absorption of phenytoin sodium from the gastrointestinal
tract is nearly complete in most patients, although the time to peak may
range from 3 to 12 hours. Absorption after intramuscular injection is
unpredictable, and some drug precipitation in the muscle occurs; this
route of administration is not recommended for phenytoin. In contrast,
fosphenytoin, a more soluble phosphate prodrug of phenytoin, is well
absorbed after intramuscular administration.
Phenytoin is highly bound to
plasma proteins. The total plasma level decreases when the percentage
that is bound decreases, as in uremia or hypoalbuminemia, but correlation
of free levels with clinical states remains uncertain. Drug concentration
in cerebrospinal fluid is proportionate to the free plasma level.
Phenytoin accumulates in brain, liver, muscle, and fat.
Phenytoin is metabolized to
inactive metabolites that are excreted in the urine. Only a very small
proportion of the dose is excreted unchanged.
The elimination of phenytoin is
dose-dependent. At very low blood levels, phenytoin metabolism follows
first-order kinetics. However, as blood levels rise within the
therapeutic range, the maximum capacity of the liver to metabolize
phenytoin is approached. Further increases in dosage, though relatively
small, may produce very large changes in phenytoin concentrations (Figure
24–5). In such cases, the half-life of the drug increases markedly,
steady state is not achieved in routine fashion (since the plasma level
continues to rise), and patients quickly develop symptoms of toxicity.
The half-life of phenytoin
varies from 12 to 36 hours, with an average of 24 hours for most patients
in the low to mid therapeutic range. Much longer half-lives are observed
at higher concentrations. At low blood levels, it takes 5–7 days to reach
steady-state blood levels after every dosage change; at higher levels, it
may be 4–6 weeks before blood levels are stable.
Therapeutic Levels & Dosage
The therapeutic plasma level of
phenytoin for most patients is between 10 and 20 mcg/mL. A loading dose
can be given either orally or intravenously; the latter, using
fosphenytoin, is the method of choice for convulsive status epilepticus
(discussed later). When oral therapy is started, it is common to begin
adults at a dosage of 300 mg/d, regardless of body weight. This may be
acceptable in some patients, but it frequently yields steady-state blood
levels below 10 mcg/mL, which is the minimum therapeutic level for most
patients. If seizures continue, higher doses are usually necessary to
achieve plasma levels in the upper therapeutic range. Because of its
dose-dependent kinetics, some toxicity may occur with only small
increments in dosage. The phenytoin dosage should be increased each time
by only 25–30 mg in adults, and ample time should be allowed for the new
steady state to be achieved before further increasing the dosage. A
common clinical error is to increase the dosage directly from 300 mg to
400 mg/d; toxicity frequently occurs at a variable time thereafter. In
children, a dosage of 5 mg/kg/d should be followed by readjustment after
steady-state plasma levels are obtained.
Two types of oral phenytoin
sodium are currently available in the USA, differing in their respective
rates of dissolution; one is absorbed rapidly and one more slowly. Only
the slow-release extended-action formulation can be given in a single
daily dosage, and care must be used when changing brands (see
Preparations Available). Although a few patients being given phenytoin on
a long-term basis have been proved to have low blood levels from poor
absorption or rapid metabolism, the most common cause of low levels is
poor compliance. Fosphenytoin sodium is available for intravenous or
intramuscular use and replaces intravenous phenytoin sodium, a much less
soluble form of the drug.
Drug Interactions &
Interference with Laboratory Tests
Drug interactions involving
phenytoin are primarily related to protein binding or to metabolism.
Since phenytoin is 90% bound to plasma proteins, other highly bound
drugs, such as phenylbutazone and sulfonamides, can displace phenytoin
from its binding site. In theory, such displacement may cause a transient
increase in free drug. A decrease in protein binding—eg, from
hypoalbuminemia—results in a decrease in the total plasma concentration
of drug but not the free concentration. Intoxication may occur if efforts
are made to maintain total drug levels in the therapeutic range by
increasing the dose. The protein binding of phenytoin is decreased in the
presence of renal disease. The drug has an affinity for thyroid-binding
globulin, which confuses some tests of thyroid function; the most
reliable screening test of thyroid function in patients taking phenytoin
appears to be measurement of thyroid-stimulating hormone (TSH).
Phenytoin has been shown to
induce microsomal enzymes responsible for the metabolism of a number of
drugs. Autostimulation of its own metabolism, however, appears to be
insignificant.
Toxicity
Dose-related adverse effects
caused by phenytoin are often similar to those caused by other
antiseizure drugs in this group, making differentiation difficult in
patients receiving multiple drugs. Nystagmus occurs early, as does loss
of smooth extraocular pursuit movements, but neither is an indication for
decreasing the dose. Diplopia and ataxia are the most common dose-related
adverse effects requiring dosage adjustment; sedation usually occurs only
at considerably higher levels. Gingival hyperplasia and hirsutism occur
to some degree in most patients; the latter can be especially unpleasant
in women. Long-term use is associated in some patients with coarsening of
facial features and with mild peripheral neuropathy, usually manifested
by diminished deep tendon reflexes in the lower extremities. Long-term
use may also result in abnormalities of vitamin D metabolism, leading to
osteomalacia. Low folate levels and megaloblastic anemia have been
reported, but the clinical importance of these observations is unknown.
Idiosyncratic reactions to
phenytoin are relatively rare. A skin rash may indicate hypersensitivity
of the patient to the drug. Fever may also occur, and in rare cases the
skin lesions may be severe and exfoliative. Lymphadenopathy may be
difficult to distinguish from malignant lymphoma, and although some
studies suggest a causal relationship between phenytoin and Hodgkin's
disease, the data are far from conclusive. Hematologic complications are
exceedingly rare, although agranulocytosis has been reported in
combination with fever and rash.
Mephenytoin, Ethotoin, &
Phenacemide
Many congeners of phenytoin have
been synthesized, but only three have been marketed in the USA, and one
of these (phenacemide) has been withdrawn. The other two congeners,
mephenytoin and ethotoin, like phenytoin, appear to be most effective
against generalized tonic-clonic seizures and partial seizures. No
well-controlled clinical trials have documented their effectiveness. The
incidence of severe reactions such as dermatitis, agranulocytosis, or
hepatitis is higher for mephenytoin than for phenytoin.
Ethotoin may be recommended for
patients who are hypersensitive to phenytoin, but larger doses are
required. The adverse effects and toxicity are generally less severe than
those associated with phenytoin, but the drug appears to be less
effective.
Both ethotoin and mephenytoin
share with phenytoin the property of saturable metabolism within the
therapeutic dosage range. Careful monitoring of the patient during dosage
alterations with either drug is essential. Mephenytoin is metabolized to
5,5-ethylphenylhydantoin via demethylation. This metabolite, nirvanol,
contributes most of the antiseizure activity of mephenytoin. Both
mephenytoin and nirvanol are hydroxylated and undergo subsequent
conjugation and excretion. Therapeutic levels for mephenytoin range from
5 mcg/mL to 16 mcg/mL, and levels above 20 mcg/mL are considered toxic.
Therapeutic blood levels of
nirvanol are between 25 and 40 mcg/mL. A therapeutic range for ethotoin
has not been established.
Carbamazepine
Closely related to imipramine
and other antidepressants, carbamazepine is a tricyclic compound
effective in treatment of bipolar depression. It was initially marketed
for the treatment of trigeminal neuralgia but has proved useful for
epilepsy as well.
Chemistry
Although not obvious from a
two-dimensional representation of its structure, carbamazepine has many
similarities to phenytoin. The ureide moiety (–N–CO–NH2) in
the heterocyclic ring of most antiseizure drugs is also present in
carbamazepine. Three-dimensional structural studies indicate that its
spatial conformation is similar to that of phenytoin.
Mechanism of Action
The mechanism of action of
carbamazepine appears to be similar to that of phenytoin. Like phenytoin,
carbamazepine shows activity against maximal electroshock seizures.
Carbamazepine, like phenytoin, blocks sodium channels at therapeutic
concentrations and inhibits high-frequency repetitive firing in neurons
in culture (Figure 24–4). It also acts presynaptically to decrease
synaptic transmission. These effects probably account for the
anticonvulsant action of carbamazepine. Binding studies show that
carbamazepine interacts with adenosine receptors, but the functional
significance of this observation is not known.
Clinical Use
Although carbamazepine has long
been considered a drug of choice for both partial seizures and
generalized tonic-clonic seizures, some of the newer antiseizure drugs
are beginning to displace it from this role. Carbamazepine is not
sedative in its usual therapeutic range. The drug is also very effective
in some patients with trigeminal neuralgia, although older patients may
tolerate higher doses poorly, with ataxia and unsteadiness. Carbamazepine
is also useful in some patients with mania (bipolar disorder).
Pharmacokinetics
The rate of absorption of
carbamazepine varies widely among patients, although almost complete
absorption apparently occurs in all. Peak levels are usually achieved 6–8
hours after administration. Slowing absorption by giving the drug after
meals helps the patient tolerate larger total daily doses.
Distribution is slow, and the
volume of distribution is roughly 1 L/kg. The drug is approximately 70%
bound to plasma proteins; no displacement of other drugs from protein
binding sites has been observed.
Carbamazepine has a very low
systemic clearance of approximately 1 L/kg/d at the start of therapy. The
drug has a notable ability to induce microsomal enzymes. Typically, the
half-life of 36 hours observed in subjects after an initial single dose
decreases to as little as 8–12 hours in subjects receiving continuous
therapy. Considerable dosage adjustments are thus to be expected during
the first weeks of therapy. Carbamazepine also alters the clearance of
other drugs (see below).
Carbamazepine is completely
metabolized in humans to several derivatives. One of these,
carbamazepine-10,11-epoxide, has been shown to have anticonvulsant
activity. The contribution of this and other metabolites to the clinical
activity of carbamazepine is unknown.
Therapeutic Levels & Dosage
Carbamazepine is available only
in oral form. The drug is effective in children, in whom a dosage of 15–25
mg/kg/d is appropriate. In adults, daily doses of 1 g or even 2 g are
tolerated. Higher dosage is achieved by giving multiple divided doses
daily. Extended-release preparations permit twice-daily dosing for most
patients. In patients in whom the blood is drawn just before the morning
dose (trough level), the therapeutic level is usually 4–8 mcg/mL.
Although many patients complain of diplopia at drug levels above 7
mcg/mL, others can tolerate levels above 10 mcg/mL, especially with
monotherapy.
Drug Interactions
Drug interactions involving
carbamazepine are almost exclusively related to the drug's
enzyme-inducing properties. As noted previously, the increased metabolic
capacity of the hepatic enzymes may cause a reduction in steady-state
carbamazepine concentrations and an increased rate of metabolism of other
drugs, eg, primidone, phenytoin, ethosuximide, valproic acid, and
clonazepam. Other drugs such as propoxyphene, troleandomycin, and
valproic acid may inhibit carbamazepine clearance and increase steady-state
carbamazepine blood levels. Other anticonvulsants, however, such as
phenytoin and phenobarbital, may decrease steady-state concentrations of
carbamazepine through enzyme induction. No clinically significant
protein-binding interactions have been reported.
Toxicity
The most common dose-related
adverse effects of carbamazepine are diplopia and ataxia. The diplopia
often occurs first and may last less than an hour during a particular
time of day. Rearrangement of the divided daily dose can often remedy
this complaint. Other dose-related complaints include mild
gastrointestinal upsets, unsteadiness, and, at much higher doses,
drowsiness. Hyponatremia and water intoxication have occasionally
occurred and may be dose-related.
Considerable concern exists
regarding the occurrence of idiosyncratic blood dyscrasias with
carbamazepine, including fatal cases of aplastic anemia and
agranulocytosis. Most of these have been in elderly patients with
trigeminal neuralgia, and most have occurred within the first 4 months of
treatment. The mild and persistent leukopenia seen in some patients is
not necessarily an indication to stop treatment but requires careful
monitoring. The most common idiosyncratic reaction is an erythematous
skin rash; other responses such as hepatic dysfunction are unusual.
Oxcarbazepine
Oxcarbazepine is closely related
to carbamazepine and is useful in the same seizure types, but it may have
an improved toxicity profile. Oxcarbazepine has a half-life of only 1–2
hours. Its activity, therefore, resides almost exclusively in the
10-hydroxy metabolite, to which it is rapidly converted and which has a
half-life similar to that of carbamazepine, ie, 8–12 hours. The drug is
mostly excreted as the glucuronide of the 10-hydroxy metabolite.
Oxcarbazepine is less potent
than carbamazepine, both in animal models of epilepsy and in epileptic
patients; clinical doses of oxcarbazepine may need to be 50% higher than
those of carbamazepine to obtain equivalent seizure control. Some studies
report fewer hypersensitivity reactions to oxcarbazepine, and
cross-reactivity with carbamazepine does not always occur. Furthermore,
the drug appears to induce hepatic enzymes to a lesser extent than
carbamazepine, minimizing drug interactions. Although hyponatremia may
occur more commonly with oxcarbazepine than with carbamazepine, most
adverse effects that occur with oxcarbazepine are similar in character to
reactions reported with carbamazepine.
Phenobarbital
Aside from the bromides,
phenobarbital is the oldest of the currently available antiseizure drugs.
Although it has long been considered one of the safest of the antiseizure
agents, the use of other medications with lesser sedative effects has
been urged. Many consider the barbiturates the drugs of choice for
seizures only in infants.
Chemistry
The four derivatives of
barbituric acid clinically useful as antiseizure drugs are phenobarbital,
mephobarbital, metharbital, and primidone. The first three are so similar
that they are considered together. Metharbital is methylated barbital,
and mephobarbital is methylated phenobarbital; both are demethylated in
vivo. The pKas of these three weak acid compounds range from 7.3 to 7.9.
Slight changes in the normal acid-base balance, therefore, can cause
significant fluctuation in the ratio of the ionized to the un-ionized
species. This is particularly important for phenobarbital, the most
commonly used barbiturate, whose pKa is similar to the plasma pH of 7.4.
The three-dimensional
conformations of phenobarbital and N-methylphenobarbital are
similar to that of phenytoin. Both compounds possess a phenyl ring and
are active against partial seizures.
Mechanism of Action
The exact mechanism of action of
phenobarbital is unknown, but enhancement of inhibitory processes and
diminution of excitatory transmission probably contribute significantly.
Recent data indicate that phenobarbital may selectively suppress abnormal
neurons, inhibiting the spread and suppressing firing from the foci. Like
phenytoin, phenobarbital suppresses high-frequency repetitive firing in
neurons in culture through an action on Na+ conductance, but
only at high concentrations. Also at high concentrations, barbiturates
block some Ca2+ currents (L-type and N-type). Phenobarbital
binds to an allosteric regulatory site on the GABAA receptor,
and it enhances the GABA receptor-mediated current by prolonging the
openings of the chloride channels. Phenobarbital can also decrease
excitatory responses. An effect on glutamate release is probably more
significant than blockade of AMPA (see Chapter 21). Both the enhancement
of GABA-mediated inhibition and the reduction of glutamate-mediated
excitation are seen with therapeutically relevant concentrations of
phenobarbital.
Clinical Use
Phenobarbital is useful in the
treatment of partial seizures and generalized tonic-clonic seizures,
although the drug is often tried for virtually every seizure type,
especially when attacks are difficult to control. There is little
evidence for its effectiveness in generalized seizures such as absence,
atonic attacks, and infantile spasms; it may worsen certain patients with
these seizure types.
Some physicians prefer either
metharbital or mephobarbital—especially the latter—to phenobarbital
because of supposed decreased adverse effects. Only anecdotal data are
available to support such comparisons.
Pharmacokinetics, Therapeutic
Levels, & Dosage
For pharmacokinetics, drug
interactions, and toxicity of phenobarbital, see Chapter 22.
The therapeutic levels of
phenobarbital in most patients range from 10 mcg/mL to 40 mcg/mL.
Documentation of effectiveness is best in febrile seizures, and levels
below 15 mcg/mL appear ineffective for prevention of febrile seizure
recurrence. The upper end of the therapeutic range is more difficult to
define because many patients appear to tolerate chronic levels above 40
mcg/mL.
Primidone
Primidone, or
2-desoxyphenobarbital (Figure 24–6), was first marketed in the early
1950s. It was later reported that primidone was metabolized to
phenobarbital and phenylethylmalonamide (PEMA). All three compounds are
active anticonvulsants.
Mechanism of Action
Although primidone is converted
to phenobarbital, the mechanism of action of primidone itself may be more
like that of phenytoin.
Clinical Use
Primidone, like its metabolites,
is effective against partial seizures and generalized tonic-clonic
seizures and may be more effective than phenobarbital. It was previously
considered to be the drug of choice for complex partial seizures, but
later studies of partial seizures in adults strongly suggest that
carbamazepine and phenytoin are superior to primidone. Attempts to
determine the relative potencies of the parent drug and its two
metabolites have been conducted in newborn infants, in whom
drug-metabolizing enzyme systems are very immature and in whom primidone
is only slowly metabolized. Primidone has been shown to be effective in
controlling seizures in this group and in older patients beginning
treatment with primidone; older patients show seizure control before
phenobarbital concentrations reach the therapeutic range. Finally,
studies of maximal electroshock seizures in animals suggest that primidone
has an anticonvulsant action independent of its conversion to
phenobarbital and PEMA (the latter is relatively weak).
Pharmacokinetics
Primidone is completely
absorbed, usually reaching peak concentrations about 3 hours after oral
administration, although considerable variation has been reported.
Primidone is generally distributed in total body water, with a volume of
distribution of 0.6 L/kg. It is not highly bound to plasma proteins;
approximately 70% circulates as unbound drug.
Primidone is metabolized by
oxidation to phenobarbital, which accumulates very slowly, and by
scission of the heterocyclic ring to form PEMA (Figure 24–6). Both
primidone and phenobarbital also undergo subsequent conjugation and
excretion.
Primidone has a larger clearance
than most other antiseizure drugs (2 L/kg/d), corresponding to a
half-life of 6–8 hours. PEMA clearance is approximately half that of
primidone, but phenobarbital has a very low clearance. The appearance of
phenobarbital corresponds to the disappearance of primidone.
Phenobarbital therefore accumulates very slowly but eventually reaches
therapeutic concentrations in most patients when therapeutic doses of
primidone are administered. During chronic therapy, phenobarbital levels
derived from primidone are usually two to three times higher than
primidone levels.
Therapeutic Levels & Dosage
Primidone is most efficacious
when plasma levels are in the range of 8–12 mcg/mL. Concomitant levels of
its metabolite, phenobarbital, at steady state usually vary from 15 mcg/mL
to 30 mcg/mL. Dosages of 10–20 mg/kg/d are necessary to obtain these
levels. It is very important, however, to start primidone at low doses
and gradually increase over days to a few weeks to avoid prominent
sedation and gastrointestinal complaints. When adjusting doses of the
drug, it is important to remember that the parent drug reaches steady
state rapidly (30–40 hours), but the active metabolites phenobarbital (20
days) and PEMA (3–4 days) reach steady state much more slowly.
Toxicity
The dose-related adverse effects
of primidone are similar to those of its metabolite, phenobarbital,
except that drowsiness occurs early in treatment and may be prominent if
the initial dose is too large. Gradual increments are indicated when
starting the drug in either children or adults.
Vigabatrin
Current investigations that seek
drugs to enhance the effects of GABA include efforts to find GABA
agonists and prodrugs, GABA transaminase inhibitors, and GABA uptake
inhibitors. Vigabatrin (-vinyl-GABA)
is one of these drugs and has been registered in many countries but not
in the USA.
Mechanism of Action
Vigabatrin is an irreversible
inhibitor of GABA aminotransferase (GABA-T), the enzyme responsible for
the degradation of GABA. It may also inhibit the vesicular GABA transporter.
Vigabatrin produces a sustained increase in the extracellular
concentration of GABA in the brain. This leads to some desensitization of
synaptic GABAA receptors but prolonged activation of
nonsynaptic GABAA receptors that provide tonic inhibition. A
decrease in brain glutamine synthetase activity is probably secondary to
the increased GABA concentrations. It is effective in a wide range of
seizure models. Vigabatrin is marketed as a racemate; the S(+)
enantiomer is active and the R(–) enantiomer appears to be
inactive.
Clinical Use
Vigabatrin is useful in the
treatment of partial seizures and West's syndrome. The half-life is
approximately 6–8 hours, but considerable evidence suggests that the
pharmacodynamic activity of the drug is more prolonged and not well
correlated with the plasma half-life. In adults, vigabatrin should be
started at an oral dosage of 500 mg twice daily; a total of 2–3 g (rarely
more) daily may be required for full effectiveness. Typical toxicities
include drowsiness, dizziness, and weight gain. Less common but more
troublesome adverse reactions are agitation, confusion, and psychosis;
preexisting mental illness is a relative contraindication. The drug was
delayed in its worldwide introduction by the appearance in rats and dogs of
a reversible intramyelinic edema; this phenomenon may have been recently
detected in infants taking the drug; the clinical significance is
unknown. In addition, long-term therapy with vigabatrin has been
associated with development of visual field defects in up to one third of
patients. This adverse effect is usually not reversible, and vigabatrin
is therefore relegated to use in patients—such as those with infantile
spasms—who are refractory to other treatments.
Lamotrigine
Lamotrigine was developed when
some investigators thought that the antifolate effects of certain
antiseizure drugs (eg, phenytoin) may contribute to their effectiveness.
Several phenyltriazines were developed, and although their antifolate
properties were weak, some were active in seizure screening tests.
Mechanism of Action
Lamotrigine, like phenytoin,
suppresses sustained rapid firing of neurons and produces a voltage- and
use-dependent inactivation of sodium channels. This action probably
explains lamotrigine's efficacy in focal epilepsy. It appears likely that
lamotrigine also inhibits voltage-gated Ca2+ channels,
particularly the N- and P/Q-type channels, which would account for its
efficacy in primary generalized seizures in childhood, including absence
attacks. Lamotrigine also decreases the synaptic release of glutamate.
Clinical Use
Although most controlled studies
have evaluated lamotrigine as add-on therapy, some suggest that the drug
is effective as monotherapy for partial seizures, and the drug is now
widely prescribed for this indication. Some authorities feel that the
drug is also active against absence and myoclonic seizures in children.
Lamotrigine is also prescribed for bipolar disorder. Adverse effects
include dizziness, headache, diplopia, nausea, somnolence, and skin rash.
The rash is considered a typical hypersensitivity reaction. Although the
risk of rash may be diminished by introducing the drug slowly, pediatric
patients are at high risk; some studies suggest that a potentially
life-threatening dermatitis will develop in 1–2% of pediatric patients.
Pharmacokinetics & Dosage
Lamotrigine is almost completely
absorbed and has a volume of distribution in the range of 1–1.4 L/kg.
Protein binding is only about 55%. The drug has linear kinetics and is
metabolized primarily by glucuronidation to the 2-N-glucuronide,
which is excreted in the urine. Lamotrigine has a half-life of
approximately 24 hours in normal volunteers; this decreases to 13–15
hours in patients taking enzyme-inducing drugs. Lamotrigine is effective
against partial seizures in adults, with dosages typically between 100
and 300 mg/d and with a therapeutic blood level near 3 mcg/mL. Valproate
causes a twofold increase in the drug's half-life; in patients receiving
valproate, the initial dosage of lamotrigine must be reduced to 25 mg
every other day.
Felbamate
Felbamate has been approved and
marketed in the USA and in some European countries. Although it is
effective in some patients with partial seizures, the drug causes
aplastic anemia and severe hepatitis at unexpectedly high rates and has
been relegated to the status of a third-line drug for refractory cases.
Felbamate appears to have multiple
mechanisms of action. It produces a use-dependent block of the NMDA
receptor, with selectivity for the NR1-2B sub-type. It also potentiates
GABAA receptor responses. Felbamate has a half-life of 20
hours (somewhat shorter when administered with either phenytoin or
carbamazepine) and is metabolized by hydroxylation and conjugation; a
significant percentage of the drug is excreted unchanged in the urine.
When added to treatment with other antiseizure drugs, felbamate increases
plasma phenytoin and valproic acid levels but decreases levels of
carbamazepine.
In spite of the seriousness of
the adverse effects, thousands of patients worldwide remain on the
medication. Usual dosages are 2000–4000 mg/d in adults, and effective
plasma levels range from 30 mcg/mL to 100 mcg/mL. In addition to its
usefulness in partial seizures, felbamate has proved effective against
the seizures that occur in Lennox-Gastaut syndrome.
Gabapentin & Pregabalin
Gabapentin is an amino acid, an
analog of GABA, that is effective against partial seizures. Originally
planned as a spasmolytic, it was found to be more effective as an
antiseizure drug. Pregabalin is another GABA analog, closely related to
gabapentin. This drug has been approved for both antiseizure activity and
for its analgesic properties.
Mechanism of Action
In spite of their close
structural resemblance to GABA, gabapentin and pregabalin do not act
directly on GABA receptors. They may, however, modify the synaptic or
nonsynaptic release of GABA. An increase in brain GABA concentration is
observed in patients receiving gabapentin. Gabapentin is transported into
the brain by the L-amino acid
transporter. Gabapentin and pregabalin bind avidly to the  2
subunit of voltage-gated Ca2+ channels. This appears to
underlie the main mechanism of action, which is decreasing Ca2+
entry, with a predominant effect on presynaptic N-type channels. A
decrease in the synaptic release of glutamate provides the antiepileptic
effect. Gabapentin and pregabalin also act presynaptically to decrease
the release of glutamate; this effect is probably dependent on reduced
presynaptic entry of Ca2+ via voltage-activated channels.
Clinical Use & Dosage
Gabapentin is effective as an
adjunct against partial seizures and generalized tonic-clonic seizures at
dosages that range up to 2400 mg/d in controlled clinical trials. Open
follow-up studies permitted dosages up to 4800 mg/d, but data are
inconclusive on the effectiveness or tolerability of such doses.
Monotherapy studies also document some efficacy. Some clinicians have
found that very high dosages are needed to achieve improvement in seizure
control. Effectiveness in other seizure types has not been well
demonstrated. Gabapentin has also been promoted for the treatment of
neuropathic pain and is now indicated for postherpetic neuralgia in
adults at doses of 1800 mg and above. The most common adverse effects are
somnolence, dizziness, ataxia, headache, and tremor.
Pregabalin is approved for the
adjunctive treatment of partial seizures, with or without secondary
generalization; controlled clinical trials have documented its
effectiveness. It is available only in oral form, and the daily dose
ranges from 150 to 600 mg/d, usually in two or three divided
administrations. Pregabalin is also approved for use in neuropathic pain,
including painful diabetic peripheral neuropathy and postherpetic
neuralgia.
Pharmacokinetics
Gabapentin is not metabolized
and does not induce hepatic enzymes. Absorption is nonlinear and
dose-dependent at very high doses, but the elimination kinetics are
linear. The drug is not bound to plasma proteins. Drug-drug interactions
are negligible. Elimination is via renal mechanisms; the drug is excreted
unchanged. The half-life is relatively short, ranging from 5 to 8 hours;
the drug is typically administered two or three times per day.
Pregabalin, like gabapentin, is
not metabolized and is almost entirely excreted unchanged in the urine.
It is not bound to plasma proteins and has virtually no drug-drug
interactions, again resembling the characteristics of gabapentin.
Likewise, other drugs do not affect the pharmacokinetics of pregabalin.
The half-life of pregabalin ranges from about 4.5 hours to 7.0 hours,
thus requiring more than once-per-day dosing in most patients.
Lacosamide
Lacosamide is an amino
acid-related compound that has been studied in both pain syndromes and
partial seizures. The drug was approved in Europe and the USA in 2008 for
the treatment of partial seizures.
Mechanism of Action
Two effects relevant to the
mechanism of action of lacosamide as an antiseizure drug have been
described. Lacosamide enhances slow inactivation of voltage-gated Na+
channels. It also binds to the collapsin-response mediator protein,
CRMP-2, thereby blocking the effect of neurotrophic factors such as BDNF
and NT3 on axonal and dendritic growth.
Clinical Use & Dosage
Lacosamide is approved as
adjunctive therapy in the treatment of partial-onset seizures with or
without secondary generalization in patients with epilepsy 16 years and
older. Clinical trials include three multicenter, randomized
placebo-controlled studies with more than 1300 patients. Treatment was
effective at both 200 and 400 mg/d. Adverse effects were dizziness,
headache, nausea, and diplopia. In the open-label follow-up study, using
doses ranging from 100 to 800 mg/d, many patients continued for 24 to 30
months of lacosamide treatment. The drug is typically administered twice
daily, beginning with 50-mg doses and increasing by 100 mg increments
weekly.
Pharmacokinetics
Oral lacosamide is rapidly and
completely absorbed in adults, with no food effect. Bioavailability is
nearly 100%. The plasma concentrations are proportional up to 800 mg
orally. Peak concentrations occur from 1 to 4 hours after oral dosing,
with an elimination half-life of 13 hours. There are no active
metabolites and protein binding is minimal. Lacosamide does not induce or
inhibit cytochrome P450 isoenzymes, so drug interactions are negligible.
Levetiracetam
Levetiracetam is a piracetam
analog that is ineffective against seizures induced by maximum
electroshock or pentylenetetrazol but has prominent activity in the
kindling model. This is the first major drug with this unusual
preclinical profile that is effective against partial seizures.
Mechanism of Action
Levetiracetam binds selectively
to the synaptic vesicular protein SV2A. The function of this
protein is not understood but it is likely that levetiracetam modifies
the synaptic release of glutamate and GABA through an action on vesicular
function.
Clinical Use
Levetiracetam is marketed for
the adjunctive treatment of partial seizures in adults and children for
primary generalized tonic-clonic seizures and for the myoclonic seizures
of juvenile myoclonic epilepsy. Adult dosing can begin with 500 or 1000
mg/d. The dosage can be increased every 2–4 weeks by 1000 mg to a maximum
dosage of 3000 mg/d. The drug is dosed twice daily. Adverse effects
include somnolence, asthenia, ataxia, and dizziness. Less common are
complaints of agitation or anxiety. Idiosyncratic reactions are rare.
Drug interactions are minimal; levetiracetam is not metabolized by
cytochrome P450. Both oral and intravenous preparations are available.
Pharmacokinetics
Oral absorption of levetiracetam
is nearly complete; it is rapid and unaffected by food, with peak plasma
concentrations in 1.3 hours. Kinetics are linear. Protein binding is less
than 10%. The plasma half-life is 6–8 hours and may be longer in the
elderly. Two thirds of the drug is excreted unchanged in the urine, and
no active metabolites have been found.
Tiagabine
Tiagabine is a derivative of
nipecotic acid and was "rationally designed" as an inhibitor of
GABA uptake (as opposed to discovery through random screening).
Mechanism of Action
Tiagabine is an inhibitor of
GABA uptake in both neurons and glia. It preferentially inhibits the
transporter isoform 1 (GAT-1) rather than GAT-2 or GAT-3 and increases
extracellular GABA levels in the forebrain and hippocampus. It prolongs
the inhibitory action of synaptically released GABA, but its most
significant effect may be potentiation of tonic inhibition. In rodents,
it is potent against kindled seizures but weak against the maximum
electroshock model, consistent with its predominant action in the
forebrain and hippocampus.
Clinical Use
Tiagabine is indicated for the
adjunctive treatment of partial seizures and is effective in doses
ranging from 16 to 56 mg/d. Divided doses as often as four times per day
are sometimes required. Some patients appear to do well with tiagabine
monotherapy, which is generally well tolerated. Minor adverse events are
dose-related and include nervousness, dizziness, tremor, difficulty in
concentrating, and depression. Excessive confusion, somnolence, or ataxia
may require discontinuation. Psychosis occurs rarely. The drug can cause
seizures in some patients, notably those taking the drug for other
indications. Rash is an uncommon idiosyncratic adverse effect. Laboratory
studies are usually normal.
Pharmacokinetics
Tiagabine is 90–100%
bioavailable, has linear kinetics, and is highly protein-bound. The
half-life is 5–8 hours and decreases in the presence of enzyme-inducing
drugs. Food decreases the peak plasma concentration but not the area
under the concentration curve (see Chapter 3). Hepatic impairment causes a
slight decrease in clearance (and may necessitate a lower dose), but the
drug does not cause inhibition or induction of hepatic enzymes. The drug
is oxidized in the liver by CYP3A. Elimination is primarily in the feces
(60–65%) and urine (25%).
Topiramate
Topiramate is a substituted
monosaccharide that is structurally different from all other antiseizure
drugs.
Mechanism of Action
Topiramate blocks repetitive
firing of cultured spinal cord neurons, as do phenytoin and
carbamazepine. Its mechanism of action, therefore, is likely to involve
blocking of voltage-gated sodium channels. Topiramate also appears to
potentiate the inhibitory effect of GABA, acting at a site different from
the benzodiazepine or barbiturate sites. Topiramate also depresses the
excitatory action of kainate on glutamate receptors. The multiple effects
of topiramate may arise through a primary action on kinases altering the
phosphorylation of voltage-gated and ligand-gated ion channels.
Clinical Use
Clinical trials of topiramate as
monotherapy demonstrated efficacy against partial and generalized
tonic-clonic seizures. Good evidence suggests that the drug has a broader
spectrum, with effectiveness against Lennox-Gastaut syndrome, West's
syndrome, and even absence seizures. Topiramate is also approved for the
treatment of migraine headaches. Dosages typically range from 200 to 600
mg/d, with a few patients tolerating dosages higher than 1000 mg/d. Most
clinicians begin at a low dose (50 mg/d) and increase slowly to prevent
adverse effects. Several studies have used topiramate in monotherapy with
encouraging results. Although no idiosyncratic reactions have been noted,
dose-related adverse effects occur most frequently in the first 4 weeks
and include somnolence, fatigue, dizziness, cognitive slowing,
paresthesias, nervousness, and confusion. Acute myopia and glaucoma may
require prompt drug withdrawal. Urolithiasis has also been reported.
However, the discontinuation rate is apparently only about 15%. The drug
is teratogenic in animal models, and hypospadias has been reported in
male infants exposed in utero to topiramate. However, no causal
relationship could be established.
Pharmacokinetics
Topiramate is rapidly absorbed
(about 2 hours) and is 80% bioavailable. There is no food effect on
absorption, minimal (15%) plasma protein binding, and only moderate
(20–50%) metabolism; no active metabolites are formed. The drug is primarily
excreted unchanged in the urine. The half-life is 20–30 hours. Although
increased levels are seen with renal failure and hepatic impairment,
there is no age or gender effect, no autoinduction, no inhibition of
metabolism, and kinetics are linear. Drug interactions do occur and can
be complex, but the major effect is on topiramate levels rather than on
the levels of other antiseizure drugs. Birth control pills may be less
effective in the presence of topiramate, and higher estrogen doses may be
required.
Zonisamide
Zonisamide is a sulfonamide
derivative. Its primary site of action appears to be the sodium channel;
it may also act on voltage-gated calcium channels. The drug is effective
against partial and generalized tonic-clonic seizures and may also be
useful against infantile spasms and certain myoclonias. It has good
bioavailability, linear kinetics, low protein-binding, renal excretion,
and a half-life of 1–3 days. Doses range from 100 to 600 mg/d in adults
and from 4 to 12 mg/d in children. Adverse effects include drowsiness,
cognitive impairment, and potentially serious skin rashes. Zonisamide
does not interact with other antiseizure drugs.
Rufinamide
Rufinamide is a new triazole
derivative with little similarity to other antiseizure drugs. It is approved
for use in Lennox-Gastaut syndrome and preliminary evidence suggests that
it may also be useful in other difficult-to-treat epilepsy syndromes.
Drugs Used in Generalized
Seizures
Ethosuximide
Ethosuximide was introduced in
1960 as the third of three marketed succinimides in the USA. Ethosuximide
has very little activity against maximal electroshock but considerable
efficacy against pentylenetetrazol seizures; it was introduced as a
"pure petit mal" drug.
Chemistry
Ethosuximide is the last
antiseizure drug to be marketed whose origin is in the cyclic ureide
structure. The three antiseizure succinimides marketed in the USA are
ethosuximide, phensuximide, and methsuximide. Methsuximide and
phensuximide have phenyl substituents, whereas ethosuximide is 2-ethyl-2-methylsuccinimide.
Mechanism of Action
Ethosuximide has an important
effect on Ca2+ currents, reducing the low-threshold (T-type)
current. This effect is seen at therapeutically relevant concentrations
in thalamic neurons. The T-type calcium currents are thought to provide a
pacemaker current in thalamic neurons responsible for generating the
rhythmic cortical discharge of an absence attack. Inhibition of this
current could therefore account for the specific therapeutic action of
ethosuximide.
Clinical Use
As predicted from its activity
in laboratory models, ethosuximide is particularly effective against
absence seizures, but has a very narrow spectrum of clinical activity.
Documentation of its effectiveness in human absence seizures was achieved
with long-term electroencephalographic recording techniques.
Pharmacokinetics
Absorption is complete following
administration of the oral dosage forms. Peak levels are observed 3–7
hours after oral administration of the capsules. Ethosuximide is not
protein-bound.
Ethosuximide is completely
metabolized, principally by hydroxylation, to inactive metabolites. The
drug has a very low total body clearance (0.25 L/kg/d). This corresponds
to a half-life of approximately 40 hours, although values from 18 to 72
hours have been reported.
Therapeutic Levels & Dosage
Therapeutic levels of 60–100
mcg/mL can be achieved in adults with dosages of 750–1500 mg/d, although
lower or higher dosages and blood levels (up to 125 mcg/mL) may be
necessary and tolerated in some patients. Ethosuximide has a linear
relationship between dose and steady-state plasma levels. The drug might
be administered as a single daily dose were it not for its adverse
gastrointestinal effects; twice-a-day dosage is common.
Drug Interactions
Administration of ethosuximide
with valproic acid results in a decrease in ethosuximide clearance and
higher steady-state concentrations owing to inhibition of metabolism. No
other important drug interactions have been reported for the
succinimides.
Toxicity
The most common dose-related
adverse effect of ethosuximide is gastric distress, including pain,
nausea, and vomiting. When an adverse effect does occur, temporary dosage
reductions may allow adaptation. Other dose-related adverse effects are
transient lethargy or fatigue and, much less commonly, headache,
dizziness, hiccup, and euphoria. Behavioral changes are usually in the
direction of improvement.
Non–dose-related or
idiosyncratic adverse effects of ethosuximide are extremely uncommon.
Phensuximide & Methsuximide
Phensuximide and methsuximide
are phenylsuccinimides that were developed and marketed before ethosuximide.
They are used primarily as anti-absence drugs. Methsuximide is generally
considered more toxic, and phensuximide less effective, than
ethosuximide. Unlike ethosuximide, these two compounds have some activity
against maximal electroshock seizures, and methsuximide has been used for
partial seizures by some investigators.
Valproic Acid & Sodium
Valproate
Sodium valproate, also used as
the free acid, valproic acid, was found to have antiseizure properties
when used as a solvent in the search for other drugs effective against
seizures. It was marketed in France in 1969 but was not licensed in the
USA until 1978. Valproic acid is fully ionized at body pH, and for that
reason the active form of the drug may be assumed to be the valproate ion
regardless of whether valproic acid or a salt of the acid is
administered.
Chemistry
Valproic acid is one of a series
of fatty carboxylic acids that have antiseizure activity; this activity
appears to be greatest for carbon chain lengths of five to eight atoms.
The amides and esters of valproic acid are also active antiseizure
agents.
Mechanism of Action
The time course of valproate's
anticonvulsant activity appears to be poorly correlated with blood or
tissue levels of the parent drug, an observation giving rise to
considerable speculation regarding both the active species and the
mechanism of action of valproic acid. Valproate is active against both pentylenetetrazol
and maximal electroshock seizures. Like phenytoin and carbamazepine,
valproate blocks sustained high-frequency repetitive firing of neurons in
culture at therapeutically relevant concentrations. Its action against
partial seizures may be a consequence of this effect on Na+
currents. Blockade of NMDA receptor-mediated excitation may also be
important. Much attention has been paid to the effects of valproate on
GABA. Several studies have shown increased levels of GABA in the brain
after administration of valproate, although the mechanism for this
increase remains unclear. An effect of valproate to facilitate glutamic
acid decarboxylase (GAD), the enzyme responsible for GABA synthesis, has
been described. An inhibitory effect on the GABA transporter GAT-1 may
contribute. At very high concentrations, valproate inhibits GABA
transaminase in the brain, thus blocking degradation of GABA. However, at
the relatively low doses of valproate needed to abolish pentylenetetrazol
seizures, brain GABA levels may remain unchanged. Valproate produces a
reduction in the aspartate content of rodent brain, but the relevance of
this effect to its anticonvulsant action is not known.
Valproic acid is a potent
inhibitor of histone deacetylase and through this mechanism changes the
transcription of many genes. A similar effect, but to a lesser degree, is
shown by some other antiseizure drugs (topiramate, carbamazepine, and a
metabolite of levetiracetam).
Clinical Use
Valproate is very effective
against absence seizures and is often preferred when the patient has
concomitant generalized tonic-clonic attacks. Valproate is unique in its
ability to control certain types of myoclonic seizures; in some cases the
effect is very dramatic. The drug is effective in generalized tonic-clonic
seizures, especially those that are primarily generalized. A few patients
with atonic attacks may also respond, and some evidence suggests that the
drug is effective in partial seizures.
Other uses of valproate include
management of bipolar disorder and migraine prophylaxis.
Pharmacokinetics
Valproate is well absorbed after
an oral dose, with bioavailability greater than 80%. Peak blood levels
are observed within 2 hours. Food may delay absorption, and decreased
toxicity may result if the drug is given after meals.
Valproic acid is 90% bound to
plasma proteins, although the fraction bound is somewhat reduced at blood
levels greater than 150 mcg/mL. Since valproate is both highly ionized
and highly protein-bound, its distribution is essentially confined to
extracellular water, with a volume of distribution of approximately 0.15
L/kg. At higher doses, there is an increased free fraction of valproate,
resulting in lower total drug levels than expected. It may be clinically
useful, therefore, to measure both total and free drug levels. Clearance
for valproate is low and dose-dependent; its half-life varies from 9 to
18 hours. Approximately 20% of the drug is excreted as a direct conjugate
of valproate.
The sodium salt of valproate is
marketed in Europe as a tablet and is quite hygroscopic. In Central and
South America, the magnesium salt is available, which is considerably
less hygroscopic. The free acid of valproate was first marketed in the
USA in a capsule containing corn oil; the sodium salt is also available
in syrup, primarily for pediatric use. An enteric-coated tablet of
divalproex sodium is also marketed in the USA. This improved product, a
1:1 coordination compound of valproic acid and sodium valproate, is as
bioavailable as the capsule but is absorbed much more slowly and is
preferred by many patients. Peak concentrations following administration
of the enteric-coated tablets are seen in 3–4 hours. Various
extended-release preparations are available; not all are bioequivalent
and may require dosage adjustment.
Therapeutic Levels & Dosage
Dosages of 25–30 mg/kg/d may be
adequate in some patients, but others may require 60 mg/kg/d or even
more. Therapeutic levels of valproate range from 50 to 100 mcg/mL.
Drug Interactions
Valproate displaces phenytoin
from plasma proteins. In addition to binding interactions, valproate
inhibits the metabolism of several drugs, including phenobarbital,
phenytoin, and carbamazepine, leading to higher steady-state
concentrations of these agents. The inhibition of phenobarbital
metabolism, for example, may cause levels of the barbiturate to rise
steeply, causing stupor or coma. Valproate can dramatically decrease the
clearance of lamotrigine.
Toxicity
The most common dose-related
adverse effects of valproate are nausea, vomiting, and other
gastrointestinal complaints such as abdominal pain and heartburn. The
drug should be started gradually to avoid these symptoms. Sedation is
uncommon with valproate alone but may be striking when valproate is added
to phenobarbital. A fine tremor is frequently seen at higher levels.
Other reversible adverse effects, seen in a small number of patients,
include weight gain, increased appetite, and hair loss.
The idiosyncratic toxicity of
valproate is largely limited to hepatotoxicity, but this may be severe;
there seems little doubt that the hepatotoxicity of valproate has been
responsible for more than 50 fatalities in the USA alone. The risk is
greatest for patients under 2 years of age and for those taking multiple
medications. Initial aspartate aminotransferase values may not be
elevated in susceptible patients, although these levels do eventually
become abnormal. Most fatalities have occurred within 4 months after
initiation of therapy. Some clinicians recommend treatment with oral or
intravenous L-carnitine as soon as
severe hepatotoxicity is suspected. Careful monitoring of liver function
is recommended when starting the drug; the hepatotoxicity is reversible
in some cases if the drug is withdrawn. The other observed idiosyncratic
response with valproate is thrombocytopenia, although documented cases of
abnormal bleeding are lacking. It should be noted that valproate is an
effective and popular antiseizure drug and that only a very small number
of patients have had severe toxic effects from its use.
Several epidemiologic studies of
valproate have confirmed an increased incidence of spina bifida in the
offspring of women who took valproate during pregnancy. In addition, an
increased incidence of cardiovascular, orofacial, and digital
abnormalities has been reported. These observations must be strongly
considered in the choice of drugs during pregnancy.
Oxazolidinediones
Trimethadione, the first
oxazolidinedione (Figure 24–3), was introduced as an antiseizure drug in
1945 and remained the drug of choice for absence seizures until the
introduction of succinimides in the 1950s. Use of the oxazolidinediones
(trimethadione, paramethadione, and dimethadione) is now very limited.
These compounds are active
against pentylenetetrazol-induced seizures. Trimethadione raises the
threshold for seizure discharges after repetitive thalamic stimulation.
It—or, more notably, its active metabolite dimethadione—has the same
effect on thalamic Ca2+ currents as ethosuximide (reducing the
T-type calcium current). Thus, suppression of absence seizures is likely
to depend on inhibiting the pacemaker action of thalamic neurons.
Trimethadione is rapidly
absorbed, with peak levels reached within 1 hour after drug
administration. It is not bound to plasma proteins. Trimethadione is
completely metabolized in the liver by demethylation to dimethadione,
which may exert the major antiseizure activity. Dimethadione has an
extremely long half-life (240 hours).
The therapeutic plasma level
range for trimethadione has never been established, although
trimethadione blood levels higher than 20 mcg/mL and dimethadione levels
higher than 700 mcg/mL have been suggested. A dosage of 30 mg/kg/d of
trimethadione is necessary to achieve these levels in adults.
The most common and bothersome
dose-related adverse effect of the oxazolidinediones is sedation.
Trimethadione has been associated with many other toxic adverse effects,
some of which are severe. These drugs should not be used during
pregnancy.
Other Drugs Used in Management
of Epilepsy
Some drugs not classifiable by
application to seizure type are discussed in this section.
Benzodiazepines
Six benzodiazepines play
prominent roles in the therapy of epilepsy (see also Chapter 22).
Although many benzodiazepines are similar chemically, subtle structural
alterations result in differences in activity. They have two mechanisms
of antiseizure action, which are shown to different degrees by the six
compounds. This is evident from the fact that diazepam is relatively more
potent against electroshock and clonazepam against pentylenetetrazol (the
latter effect correlating with an action at the GABA-benzodiazepine
allosteric receptor sites). Possible mechanisms of action are discussed
in Chapter 22.
Diazepam given
intravenously or rectally is highly effective for stopping continuous
seizure activity, especially generalized tonic-clonic status epilepticus
(see below). The drug is occasionally given orally on a long-term basis,
although it is not considered very effective in this application,
probably because of the rapid development of tolerance. A rectal gel is
available for refractory patients who need acute control of bouts of
seizure activity. Lorazepam appears in some studies to be more
effective and longer acting than diazepam in the treatment of status
epilepticus and is preferred by some experts.
Clonazepam is a
long-acting drug with documented efficacy against absence seizures; on a
milligram basis, it is one of the most potent antiseizure agents known.
It is also effective in some cases of myoclonic seizures and has been
tried in infantile spasms. Sedation is prominent, especially on
initiation of therapy; starting doses should be small. Maximal tolerated
doses are usually in the range of 0.1–0.2 mg/kg, but many weeks of
gradually increasing daily doses may be needed to achieve these dosages
in some patients. Nitrazepam is not marketed in the USA but is
used in many other countries, especially for infantile spasms and
myoclonic seizures. It is less potent than clonazepam, and superiority to
that drug has not been documented.
Clorazepate dipotassium is
approved in the USA as an adjunct to treatment of complex partial
seizures in adults. Drowsiness and lethargy are common adverse effects,
but as long as the drug is increased gradually, dosages as high as 45
mg/d can be given.
Clobazam is not available
in the USA but is marketed in most countries and is widely used in a
variety of seizure types. It is a 1,5-benzodiazepine (other marketed
benzodiazepines are 1,4-benzodiazepines) and reportedly has less sedative
potential than benzodiazepines marketed in the USA. Whether the drug has
significant clinical advantages is not clear. It has a half-life of 18
hours and is effective at dosages of 0.5–1 mg/kg/d. It does interact with
some other antiseizure drugs and causes adverse effects typical of the
benzodiazepines; efficacy, in some patients, is limited by the
development of tolerance.
Pharmacokinetics
See Chapter 22.
Limitations
Two prominent aspects of
benzodiazepines limit their usefulness. The first is their pronounced
sedative effect, which is unfortunate both in the treatment of status
epilepticus and in chronic therapy. Children may manifest a paradoxical
hyperactivity, as with barbiturates. The second problem is tolerance, in
which seizures may respond initially but recur within a few months. The
remarkable antiseizure potency of these compounds often cannot be
realized because of these limiting factors.
Acetazolamide
Acetazolamide is a diuretic
whose main action is the inhibition of carbonic anhydrase (see Chapter
15). Mild acidosis in the brain may be the mechanism by which the drug
exerts its antiseizure activity; alternatively, the depolarizing action
of bicarbonate ions moving out of neurons via GABA receptor ion channels
may be diminished by carbonic anhydrase inhibition. Acetazolamide has
been used for all types of seizures but is severely limited by the rapid
development of tolerance, with return of seizures usually within a few
weeks. The drug may have a special role in epileptic women who experience
seizure exacerbations at the time of menses; seizure control may be
improved and tolerance may not develop because the drug is not
administered continuously. The usual dosage is approximately 10 mg/kg/d
to a maximum of 1000 mg/d.
Another carbonic anhydrase
inhibitor, sulthiame, was not found to be effective as an
anticonvulsant in clinical trials in the USA. It is marketed in some
other countries.
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