Carbonic anhydrases are enzymes that catalyze the interconversion between CO2 and bicarbonate (see Chapter 15). Inhibitors of carbonic anhydrases, particularly the cytosolic forms CA II and CA VII, exhibit antiseizure activity. Bicarbonate efflux through GABAA receptors can exert a depolarizing (excitatory) influence that is especially relevant during intense GABAA receptor activation, as occurs during seizures, when there is diminution of the hyperpolarizing chloride gradient. Carbonic anhydrase inhibition prevents the replenishment of intracellular bicarbonate and depresses the depolarizing action of bicarbonate.
The prototypical carbonic anhydrase inhibitor is the sulfonamide acetazolamide (see Chapter 15), which has broad-spectrum antiseizure activity in animal models. In addition, acetazolamide is believed to have clinical antiseizure activity, at least transiently, against most types of seizures including focal and generalized tonic-clonic seizures and especially generalized absence seizures. However, acetazolamide is rarely used for chronic therapy because tolerance develops rapidly, with return of seizures usually within a few weeks. The drug is often used in the intermittent treatment of menstrual seizure exacerbations in women. The usual dosage is approximately 10 mg/kg/d to a maximum of 1000 mg/d.
Another sulfonamide carbonic anhydrase inhibitor, sulthiame, became established in the treatment of focal seizures in the 1950s and has also been reported to be effective in benign focal epilepsy with centrotemporal spikes (BECTS) and infantile spasms, but results of controlled trials are not available. Its use has declined in routine practice, other than in a few countries in Europe and in Israel. It is not available in the USA.
As noted previously, topiramate and zonisamide are sulfur-containing molecules with weak carbonic anhydrase activity. There is little evidence that this activity is a major factor in their therapeutic effects.
The pharmacokinetic behavior of most antiseizure drugs varies markedly from patient to patient so that dosing must be individualized. Therapeutic drug concentration monitoring is often used as an aid to dosing. Established references ranges are available for most of the older antiseizure drugs (Table 24–3). Such ranges are generally not available for newer drugs, although there may be information on blood levels associated with efficacy. In all cases, the ranges should be interpreted flexibly given individual variability in response. Drug levels can be helpful (1) to guide dose adjustments when there is a change in drug formulation, (2) when breakthrough seizures occur, (3) when an interacting medication is added to or removed from a patient’s regimen, (4) during pregnancy, (5) to establish an individual therapeutic concentration range when a patient is in remission, (6) to determine whether adverse effects are related to drug levels, and (7) to assess adherence.
Status epilepticus is clinically defined as abnormally prolonged or repetitive seizures. Status epilepticus presents in several forms: (1) convulsive status epilepticus consisting of repeated generalized for some antiseizure drugs.
1These data are provided only as a general guideline. Many patients will respond better at different levels, and some patients may have drug-related adverse events within the listed reference ranges.2Monohydroxy metabolites (combination of eslicarbazepine and R-licarbazepine).3Not well established. 4Not well established; values given were associated with positive response.