Page 446 - Basic _ Clinical Pharmacology ( PDFDrive )

432 SECTION V Drugs That Act in the Central Nervous System

OTHER DRUGS USED IN that is especially relevant during intense GABA receptor activa-
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MANAGEMENT OF SEIZURES tion, as occurs during seizures, when there is diminution of the
hyperpolarizing chloride gradient. Carbonic anhydrase inhibi-
AND EPILEPSY tion prevents the replenishment of intracellular bicarbonate and
depresses the depolarizing action of bicarbonate.
BENZODIAZEPINES The prototypical carbonic anhydrase inhibitor is the sul-
fonamide acetazolamide (see Chapter 15), which has broad-
Seven benzodiazepines play roles in the treatment of seizures and spectrum antiseizure activity in animal models. In addition,
epilepsy (see also Chapter 22). All produce their functional effects acetazolamide is believed to have clinical antiseizure activity, at
by positive allosteric modulation of GABA receptors; however, least transiently, against most types of seizures including focal
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subtle structural differences among the benzodiazepines result and generalized tonic-clonic seizures and especially general-
in differences in their pharmacokinetic properties. Certain ben- ized absence seizures. However, acetazolamide is rarely used for
zodiazepines are the first-line acute treatment for seizures, either chronic therapy because tolerance develops rapidly, with return
in status epilepticus or acute repetitive seizures (seizure clusters). of seizures usually within a few weeks. The drug is often used
However, two prominent aspects of benzodiazepines limit their in the intermittent treatment of menstrual seizure exacerbations
usefulness in the chronic therapy of epilepsy. The first is their in women. The usual dosage is approximately 10 mg/kg/d to a
pronounced sedative effects; however, in children, there may be a maximum of 1000 mg/d.
paradoxical hyperactivity, as is the case with other sedative agents Another sulfonamide carbonic anhydrase inhibitor, sulthiame,
such as barbiturates. The second problem is tolerance, in which became established in the treatment of focal seizures in the 1950s
seizures may respond initially but recur within a few months. As and has also been reported to be effective in benign focal epilepsy
a result of these limitations, benzodiazepines are infrequently used with centrotemporal spikes (BECTS) and infantile spasms, but
in the chronic treatment of epilepsy. results of controlled trials are not available. Its use has declined in
Diazepam given intravenously is a first-line treatment for status routine practice, other than in a few countries in Europe and in
epilepticus. It is also used in a rectal gel formulation for the treatment Israel. It is not available in the USA.
of acute repetitive seizures (seizure clusters). The drug is occasionally As noted previously, topiramate and zonisamide are sulfur-
given orally on a long-term basis, although it is not considered very containing molecules with weak carbonic anhydrase activity.
effective in this application, because of the development of toler- There is little evidence that this activity is a major factor in their
ance. Lorazepam is more commonly used in the treatment of status therapeutic effects.
epilepticus because it has a more prolonged duration of action after
bolus intravenous injection. There is evidence that intramuscular
midazolam, which is water soluble, is preferred in the out-of- ■ ADDITIONAL TOPICS
hospital treatment of status epilepticus because the delay required to
achieve intravenous access may be avoided. Clonazepam is a long- THERAPEUTIC DRUG MONITORING
acting benzodiazepine that on a milligram basis is one of the most
potent antiseizure agents known. It has documented efficacy in the The pharmacokinetic behavior of most antiseizure drugs varies
treatment of absence, atonic, and myoclonic seizures. As is the case markedly from patient to patient so that dosing must be individu-
for all benzodiazepines, sedation is prominent, especially on initia- alized. Therapeutic drug concentration monitoring is often used
tion of therapy; starting doses should be small. Maximal tolerated as an aid to dosing. Established references ranges are available for
doses are usually in the range of 0.1–0.2 mg/kg/d, but many weeks most of the older antiseizure drugs (Table 24–3). Such ranges are
of gradually increasing daily doses may be needed to achieve these generally not available for newer drugs, although there may be
dosages in some patients. Nitrazepam is not marketed in the USA information on blood levels associated with efficacy. In all cases, the
but is used in many other countries, especially for infantile spasms ranges should be interpreted flexibly given individual variability in
and myoclonic seizures. Clorazepate dipotassium is approved in response. Drug levels can be helpful (1) to guide dose adjustments
the USA for the treatment of focal seizures. Drowsiness and lethargy when there is a change in drug formulation, (2) when breakthrough
are common adverse effects, but as long as the drug is increased seizures occur, (3) when an interacting medication is added to or
gradually, dosages as high as 90 mg/d can be given. Clobazam is removed from a patient’s regimen, (4) during pregnancy, (5) to
described earlier in this chapter under atonic seizures. establish an individual therapeutic concentration range when a
patient is in remission, (6) to determine whether adverse effects are
CARBONIC ANHYDRASE INHIBITORS related to drug levels, and (7) to assess adherence.

Carbonic anhydrases are enzymes that catalyze the interconver- STATUS EPILEPTICUS
sion between CO and bicarbonate (see Chapter 15). Inhibitors
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of carbonic anhydrases, particularly the cytosolic forms CA II and Status epilepticus is clinically defined as abnormally prolonged or
CA VII, exhibit antiseizure activity. Bicarbonate efflux through repetitive seizures. Status epilepticus presents in several forms: (1)
GABA receptors can exert a depolarizing (excitatory) influence convulsive status epilepticus consisting of repeated generalized
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