Acetazolamide, the prototype for the carbonic anhydrase inhibitors, is discussed in Chapter 25. Its antiseizure 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.
Ezogabine is a first-in-class K+ channel opener, known as retigabine in the E.U. Ezogabine enhances transmembrane K+ currents mediated by the KCNQ family of ion channels (i.e., Kv7.2–Kv7.5). Through its activation of the KCNQ channels, ezogabine may stabilize the resting membrane potential and reduce neuronal excitability. In vitro studies suggested that ezogabine may also enhance GABA-mediated currents.
Dosing in adults is typically initiated at 300 mg per day and gradually titrated to 600–1200 mg/d over several weeks. Ezogabine is rapidly absorbed after oral administration, and absorption is not affected by food. Ezogabine is approximately 80% protein bound in plasma. Ezogabine is metabolized by glucuronidation and acetylation and has a t1/2 of 7–11 h; it and its metabolites are excreted in the urine. Thus, ezogabine generally requires dosing thrice daily. Concomitant administration of phenytoin or carbamazepine may reduce plasma concentrations of ezogabine; consequently, an increase in ezogabine dosage should be considered when adding phenytoin or carbamazepine.
Ezogabine was approved in the U.S. as adjunctive treatment of focal-onset seizures in patients aged 18 years and older with inadequate response to alternative ASDs and for whom the benefits outweigh the risk of retinal abnormalities and potential visual acuity deficits. However, the FDA issued a warning for ezogabine citing safety concerns, including blue discoloration and retinal abnormalities. In response, the manufacturer announced that production of ezogabine would cease in June, 2017.
Adverse Effects and Toxicity
The most common adverse effects associated with ezogabine include dizziness, somnolence, fatigue, confusion, and blurred vision. Vertigo, diplopia, memory impairment, gait disturbance, aphasia, dysarthria, and balance problems also may occur. Serious side effects include skin discoloration, QT prolongation, and neuropsychiatric symptoms, including suicidal thoughts and behavior, psychosis, and hallucinations. Due to the presence of Kv7.2–Kv7.5 in the bladder uroepithelium, ezogabine is also associated with urinary retention. Blue pigmentation of skin and lips occurs in as many as one-third of patients maintained on long-term ezogabine therapy. Chronic treatment with ezogabine may cause retinal abnormalities, independent of changes in skin coloration. The FDA has changed the labeling of ezogabine to warn about the risks serious adverse effects, all of which may be permanent. Ezogabine should thus be discontinued if clinical benefit is not achieved after careful titration; however, the discontinuation of ezogabine should be done gradually, while under the care of a physician. In additon, the FDA recommends that all patients taking ezogabine should have baseline and periodic (every 6 months) systemic visual monitoring by an opthalmic professional, which includes both visual acuity and dilated fundus photography.
Felbamate is not indicated as a first-line therapy for any type of seizure activity. Rather, felbamate is FDA-approved for focal seizures in patients who have inadequately responded to alternative ASDs and in patients for whom the severity of their epilepsy outweighs the substantial risk of drug-induced aplastic anemia or liver failure. The potential for such serious and life-threatening adverse effects has limited the clinical utility of felbamate.
Clinically relevant concentrations of felbamate inhibit NMDA-evoked responses and potentiate GABA-evoked responses in whole-cell, voltage-clamp recordings of cultured rat hippocampal neurons (Rho et al., 1994). This dual action on excitatory and inhibitory transmitter responses may contribute to the wide spectrum of action of the drug in seizure models; however, the mechanism(s) by which felbamate exerts its anticonvulsant activity remain unknown.
Despite the potential serious adverse effects, felbamate is used at doses ranging from 1 to 4 g/d. Clinical studies demonstrate the efficacy of felbamate in patients with poorly controlled focal and secondarily generalized seizures (Sachdeo et al., 1992) and in patients with Lennox-Gastaut syndrome (Felbamate Study Group in Lennox-Gastaut Syndrome, 1993). The clinical efficacy of this unique compound, which inhibits responses to NMDA while potentiating GABAergic neurotransmission, underscores the potential therapeutic value of identifying additional ASDs with novel mechanisms of action.
Gabapentin and Pregabalin
Gabapentin and pregabalin are ASDs that consist of a GABA molecule covalently bound to a lipophilic cyclohexane ring or isobutane, respectively. Gabapentin was designed to be a centrally active GABA agonist, with its high lipid solubility aimed at facilitating its transfer across the blood-brain barrier; the actual mechanism of action is notably different (see below).
Gabapentin inhibits tonic hind limb extension in the electroshock seizure model. Interestingly, gabapentin also inhibits clonic seizures induced by pentylenetetrazol. Its efficacy in both of these tests parallels that of valproate and distinguishes it from phenytoin and carbamazepine. Despite their design as GABA agonists, neither gabapentin nor pregabalin mimics GABA when iontophoretically applied to neurons in primary culture. Rather, these compounds bind with high affinity to a protein in cortical membranes with an amino acid sequence identical to that of the Ca2+ channel subunit α2δ-1 (Gee et al., 1996). This interaction with the α2δ-1 protein may mediate the anticonvulsant effects of gabapentin, but whether and how the binding of gabapentin to the α2δ-1 subunit regulates neuronal excitability remains unclear. Pregabalin binding is reduced but not eliminated in mice carrying a mutation in the α2δ-1 protein (Field et al., 2006). Analgesic efficacy of pregabalin is eliminated in these mice; whether the anticonvulsant effects of pregabalin are also eliminated was not reported.
Gabapentin and pregabalin are absorbed after oral administration and are not metabolized in humans. These compounds are not bound to plasma proteins and are excreted unchanged, mainly in the urine. Their half-lives, when used as monotherapy, approximate 6 h. These compounds have no known interactions with other ASDs.
Gabapentin and pregabalin are effective for focal onset seizures, with and without progression to bilateral tonic-clonic seizures, when used in addition to other ASDs. Gabapentin is also indicated for the management of the neuropathic pain associated with postherpetic neuralgia in adults. Pregabalin is FDA-approved as an adjunctive therapy for adults with focal onset seizures. It is also indicated for the management of fibromyalgia and the neuropathic pain associated diabetic peripheral neuropathy, postherpetic neuralgia, or spinal cord injury.
In double-blind, placebo-controlled trials of adults with refractory focal seizures, addition of gabapentin or pregabalin to other ASDs is superior to placebo (French et al., 2003; Sivenius et al., 1991). Gabapentin monotherapy (900 or 1800 mg/d) is equivalent to carbamazepine (600 mg/d) for newly diagnosed focal or generalized epilepsy (Chadwick et al., 1998).
Gabapentin usually is effective in doses of 900–1800 mg daily in three doses, although 3600 mg may be required in some patients to achieve reasonable seizure control. Therapy usually is begun with a low dose (300 mg once on the first day), which is increased in daily increments of 300 mg until an effective dose is reached. In comparison, pregabalin is generally initiated at 50 mg three times a day (150 mg/day) and increase within 1 week to 300 mg/day based on efficacy and tolerability. Since both gabapentin and pregabalin are eliminated by renal excretion, appropriate dose adjustments are necessary in patients with reduced renal function.
Overall, gabapentin is well tolerated, with the most common adverse effects of somnolence, dizziness, ataxia, and fatigue. These effects usually are mild to moderate in severity but resolve within 2 weeks of onset during continued treatment. Gabapentin and pregabalin are both listed in pregnancy category C.
Lacosamide is a stereoselective enantiomer of the amino acid, L-serine. This functionalized amino acid is FDA approved as adjunctive therapy for focal-onset seizures in patients older than 17 years. The FDA assigned lacosamide a Controlled Substance Act (CSA) schedule V designation, meaning it has a low potential for abuse.
Lacosamide is the first ASD to enhance (prolong) the slow inactivation of voltage-gated Na+ channels and to limit sustained repetitive firing, the neuronal firing pattern characteristic of focal seizures. Lacosamide also binds collapsin response mediator protein-2 (CRMP-2), a phosphoprotein involved in neuronal differentiation and axon outgrowth, but the contribution of CRMP-2 to lacosamide’s antiseizure efficacy remains unclear. Lacosamide was extensively evaluated by the ETSP and found to be highly effective in numerous preclinical animal models of seizures and epilepsy, including maximal electroshock, hippocampal kindling, Frings and 6-Hz models, giving lacosamide a unique preclinical profile compared to other Na+ channel blockers.
Peak lacosamide plasma concentrations occur about 1–4 h after oral administration, and food consumption does not affect the absorption. Lacosamide has a t1/2 of 12–16 h; 95% is excreted in the urine, about half of which is the unchanged parent compound. The major metabolite, O-desmethyl-lacosamide, is inactive.
Lacosamide is approved for both monotherapy and add-on therapy for focal-onset seizures in patients 17 years and older. As a monotherapy for the treatment of focal seizures, the initial recommended dose is 50–100 mg twice daily and, depending on patient response, may be increased at weekly intervals by 50 mg twice daily to a recommended maintenance dose of 100 mg to 200 mg twice daily, or 200–400 mg/d. The pharmacological profile is advantageous for hospitalized patients because it is available in an intravenous formulation, has minimal hepatic metabolism, and has no adverse respiratory effects. In addition, double-blind, placebo-controlled studies of adults with refractory focal seizures suggest that addition of lacosamide to other ASDs is superior to the addition of placebo.
Lacosamide is generally well tolerated. Although it has been associated with a brief (6-ms) prolongation of the PR interval, well-controlled studies in healthy patients suggested lacosamide does not prolong the QT interval. However, patients who are taking concomitant agents that prolong the PR internal should have a baseline electrocardiogram before starting lacosamide and be closely monitored due to a risk of AV block or bradycardia. Patients with renal impairment or hepatic impairment who are taking inhibitors of CYP3A4 or CYP2C9 may experience a significant increase in lacosamide exposure. No major adverse effects have been reported, although minor adverse effects include headache, dizziness, double vision, nausea, vomiting, fatigue, tremor, loss of balance, and somnolence. Like most currently available ASDs, lacosamide may contribute to suicidal ideations and suicide. As a consequence, the FDA has mandated a black-box warning for this agent.
Lamotrigine is a phenyltriazine derivative initially developed as an antifolate agent, based on the incorrect idea that reducing folate would effectively combat seizures. Structure-activity studies have since indicated that its effectiveness as an ASD is unrelated to its antifolate properties (Macdonald and Greenfield, 1997).
Lamotrigine suppresses tonic hind limb extension in the maximal electroshock model and focal and secondarily generalized seizures in the kindling model, but does not inhibit clonic motor seizures induced by pentylenetetrazol. Lamotrigine blocks sustained repetitive firing of mouse spinal cord neurons and delays the recovery from inactivation of recombinant Na+ channels, mechanisms similar to those of phenytoin and carbamazepine (Xie et al., 1995). This may well explain lamotrigine’s actions on focal and secondarily generalized seizures. However, as mentioned below, lamotrigine is effective against a broader spectrum of seizures than are phenytoin and carbamazepine, suggesting that lamotrigine may have actions in addition to regulating recovery from inactivation of Na+ channels. One possibility, supported by basic research, is that lamotrigine inhibits synaptic release of glutamate by acting at Na+ channels themselves.
Lamotrigine is completely absorbed from the GI tract. The drug is metabolized primarily by glucuronidation, yielding a plasma t1/2 of a single dose of 24–30 h. Administration of phenytoin, carbamazepine, or phenobarbital reduces the t1/2 and plasma concentrations of lamotrigine. Conversely, addition of valproate markedly increases plasma concentrations of lamotrigine, likely by inhibiting glucuronidation. Addition of lamotrigine to valproate produces a reduction of valproate concentrations by about 25% over a few weeks. Concurrent use of lamotrigine and carbamazepine is associated with increases of the 10,11-epoxide of carbamazepine and clinical toxicity in some patients.
Lamotrigine is useful for monotherapy and add-on therapy of focal and secondarily generalized tonic-clonic seizures in adults and Lennox-Gastaut syndrome in both children and adults. Lennox-Gastaut syndrome is a disorder of childhood characterized by multiple seizure types, mental retardation, and refractoriness to antiseizure medication.
Lamotrigine monotherapy in newly diagnosed focal or generalized tonic-clonic seizures is equivalent to monotherapy with carbamazepine or phenytoin (Brodie et al., 1995; Steiner et al., 1999). Addition of lamotrigine to existing ASDs is effective against tonic-clonic seizures and drop attacks in children with the Lennox-Gastaut syndrome (Motte et al., 1997). Lamotrigine is also superior to placebo in children with newly diagnosed absence epilepsy (Frank et al., 1999).
Patients who are already taking a CYP-inducing ASD (e.g., carbamazepine, phenytoin, phenobarbital, or primidone, but not valproate) should be given lamotrigine initially at 50 mg/d for 2 weeks. The dose is increased to 50 mg twice per day for 2 weeks and then increased in increments of 100 mg/d each week up to a maintenance dose of 300–500 mg/d divided into two doses. For patients taking valproate in addition to an enzyme-inducing ASD, the initial dose should be 25 mg every other day for 2 weeks, followed by an increase to 25 mg/d for 2 weeks; the dose then can be increased by 25–50 mg/d every 1–2 weeks up to a maintenance dose of 100–150 mg/d divided into two doses.
The most common adverse effects are dizziness, ataxia, blurred or double vision, nausea, vomiting, and rash when lamotrigine is added to another ASD. A few cases of Stevens-Johnson syndrome and disseminated intravascular coagulation have been reported. The incidence of serious rash in pediatric patients (~0.8%) is higher than in the adult population (0.3%).
Levetiracetam and Brivaracetam
Levetiracetam is a pyrrolidine, the racemically pure S-enantiomer of α-ethyl-2-oxo-1-pyrrolidineacetamide, and is FDA-approved for adjunctive therapy for myoclonic, focal-onset, and generalized onset tonic-clonic seizures in adults and children as young as 4 years old. Brivaracetam, an analogue of levetiracetam, was FDA-approved in 2016 as an adjunctive therapy for focal-onset seizures in patients aged 16 years and older with epilepsy.
Levetiracetam exhibits a novel pharmacological profile: It inhibits focal and secondarily generalized tonic-clonic seizures in the kindling model, yet is ineffective against maximum electroshock- and pentylenetetrazol-induced seizures, findings consistent with clinical effectiveness against focal and secondarily generalized tonic-clonic seizures. The mechanism by which levetiracetam exerts these antiseizure effects is not fully understood. However, the correlation between binding affinity of levetiracetam and its analogues and their potency toward audiogenic seizures suggests that the synaptic vesicle protein SV2A mediates the anticonvulsant effects of levetiracetam (Rogawski and Bazil, 2008). SV2A is an integral transmembrane glycoprotein; expression of human SV2A in hexose transport-deficient yeast shows that SV2A can function as a galactose transporter (Madeo et al, 2014). The neuronal function of the SV2A protein is not fully understood, but binding of levetiracetam to SV2A might affect neuronal excitability by modifying the release of glutamate and GABA through an action on vesicular function. In mice, a missense mutation in SV2A is reportedly associated with disruption of action-potential invoked GABA release in limbic regions (Ohno and Tokudome, 2017). Other workers have suggested that SV2A may play a role in vesicle recycling following exocytosis of neurotransmitter (Bartolome, et al., 2017). In addition, levetiracetam inhibits N-type Ca2+ channels and Ca2+ release from intracellular stores.
Brivaracetam binds with high affinity to SV2A and inhibits neuronal voltage-gated Na+ channels (Kenda et al., 2004; Zona et al., 2010); preclinical studies suggested a broad spectrum of anticonvulsant protection (Matagne et al., 2008).
Levetiracetam is rapidly and almost completely absorbed after oral administration and is not bound to plasma proteins. The plasma t1/2 is 6–8 h, but may be longer in elderly patients. Ninety-five percent of the drug and its inactive metabolite are excreted in the urine, 65% of which is unchanged drug; 24% of the drug is metabolized by hydrolysis of the acetamide group. Because levetiracetam neither induces nor is a high-affinity substrate for CYPs or glucuronidation enzymes, it is devoid of known interactions with other ASDs, oral contraceptives, or anticoagulants.
Brivaracetam is rapidly absorbed and well tolerated, with an elimination t1/2 of approximately 7–8 h.
Levetiracetam is marketed for the adjunctive treatment of focal seizures in adults and children, for primary onset tonic-clonic seizures, and for myoclonic seizures of JME. It is available in tablet (10, 25, 50, 75, or 100 mg), oral solution (10 mg/mL), or injectable form (50 mg/5 mL). Adult dosing is initiated at 500–1000 mg/d and increased every 2–4 weeks by 1000 mg to a maximum dose of 3000 mg/d. The drug is administered twice daily. In adults with either refractory focal seizures or uncontrolled generalized tonic-clonic seizures associated with idiopathic generalized epilepsy, addition of levetiracetam to other antiseizure medications is superior to placebo. Levetiracetam also has efficacy as adjunctive therapy for refractory generalized myoclonic seizures (Andermann et al., 2005). Insufficient evidence is available about its use as monotherapy for focal or generalized epilepsy.
The recommended starting dose for brivaracetam is 50 mg twice daily, which may be adjusted to either 25 mg twice daily or 100 mg twice daily, based on patient response and tolerability.
Both levetiracetam and brivaracetam are well tolerated. The most frequently reported adverse effects associated with levetiracetam are somnolence, asthenia, ataxia, and dizziness. Behavioral and mood changes are serious, but less common. For brivaracetam, the most common adverse effects are similarly mild and include somnolence, sedation, dizziness, and GI upset. In patients with hepatic insufficiency, dose adjustment may be required with brivaracetam to 25 mg twice daily and a maximal dosage of 75 mg twice daily. Hypersensitivity reactions may occur.
Perampanel is a first-in class selective, noncompetitive antagonist of the AMPA-type ionotropic glutamate receptor (Bialer and White, 2010; Stephen and Brodie, 2011). Unlike NMDA antagonists, which shorten the duration of repetitive discharges, AMPA receptor antagonists prevent repetitive neuronal firing. Preclinical studies demonstrated a broad spectrum of activity in both acute and chronic seizure models, indicating that perampanel reduces fast excitatory signaling critical to the seizure generation (Tortorella et al., 1997) and spread (Namba et al., 1994; Rogawski and Donevan, 1999). Perampanel seems to have a greater inhibitory effect on seizure propagation than on seizure initiation (Hanada et al., 2011).
ADME and Drug Interactions
Perampanel is absorbed well after oral administration with a plasma t1/2 of about 105 h, permitting once-daily administration. The drug is 95% bound to plasma protein, mainly albumin, and is metabolized by hepatic oxidation and glucuronidation. A linear relationship between perampanel dose and plasma concentration has been reported over the dose range of 2–12 mg/d.
Primary metabolism is mediated by hepatic CYP3A; thus, specific drug interactions and dose adjustments need to be considered. For example, perampanel may decrease the effectiveness of progesterone-containing hormone contraceptives, carbamazepine, clobazam, lamotrigine, and valproate, but it may increase the level of oxcarbazepine. Furthermore, serum perampanel may be decreased when taken with carbamazepine, oxcarbazepine, and topiramate.
Perampanel is FDA-approved as an adjunctive therapy for the treatment of focal-onset seizures in patients 12 years and older with or without secondarily generalized seizures. The recommended oral starting dose is 2 mg once daily, titrated to a maximal dose of 4–12 mg/d at bedtime.
Common adverse effects include somnolence, anxiety, confusion, imbalance, double vision, dizziness, GI distress or nausea, and weight gain. Rare, but serious, adverse behavioral reactions, including hostility, aggression, and suicidal thoughts and behaviors, independent of clinical history of psychiatric disorder, have also been reported.
Rufinamide, a triazole derivative, is structurally unrelated to other marketed ASDs. It is FDA-approved for adjunctive treatment of seizures related to Lennox-Gastaut syndrome in children more than 4 years old and adults.
Rufinamide prolongs slow inactivation of voltage-gated Na+ channels and limits sustained repetitive firing, the firing pattern characteristic of focal seizures. The complete mechanism of action of rufinamide remains unclear.
Rufinamide is well absorbed orally, binds minimally to plasma proteins, and reaches peak plasma concentrations about 4–6 h after oral administration. The t1/2 is 6–10 h. Rufinamide is metabolized independent of CYPs and then excreted in the urine.
Rufinamide has been shown to be effective against all seizure phenotypes in Lennox-Gastaut syndrome. In adults, 400–800 mg/d rufinamide is initially administered in two equal doses. Doses are then titrated upward every other day by 10 mg/kg to a maximum of the lesser of 45 mg/kg/d or 3200 mg/d. Children are initiated at 10 mg/kg/d divided into two equal daily doses, increasing to a maximum of the lesser of 45 mg/kg/d or 3200 mg/d.
Common adverse effects include headache, dizziness, somnolence, fatigue, and nausea.
Stiripentol is an aromatic alcohol, structurally unrelated to any other ASDs. Stiripentol was granted orphan drug status for the treatment of Dravet syndrome in 2008 but has not received FDA approval due its complex pharmacokinetic and pharmacodynamic interactions with other drugs.
Although the exact nature of its antiseizure mechanism is not clear, stiripentol may increase CNS levels of the inhibitory transmitter GABA by inhibition of synaptosomal uptake of GABA or by inhibition of GABA transaminase. In model systems, stiripentol also enhances GABAA receptor–mediated neurotransmission and increases the mean open duration of GABAA receptor chloride channels in a barbiturate-like fashion (Fisher, 2011; Quilichini et al., 2006).
ADME and Drug Interactions
Stiripentol is quickly absorbed, reaching a peak Cp in about 1.5 h; the drug is highly bound to plasma proteins. Stiripentol’s elimination kinetics are nonlinear, with a t1/2 ranging from 4 to 13 h. Plasma clearance decreases markedly at high doses and after repeated administration, probably due to inhibition or saturation of the CYPs responsible for stiripentol metabolism. Metabolites are excreted in the urine.
Stiripentol has diverse pharmacokinetic and pharmacodynamic interactions with concomitantly administered drugs. It is a potent inhibitor of CYPs 3A4, 1A2, and 2C19. Thus, adjunctively administered ASDs, such as carbamazepine, valproate, phenytoin, phenobarbital, and benzodiazepines, may require dose adjustments due to the potent inhibition of CYPs involved in their hepatic metabolism. Concomitant stiripentol can increase clobazam and valproate concentrations by 2- to 3-fold, and dose reduction of either or both ASDs may be necessary to avoid toxicity.
Stiripentol is used clinically in conjunction with clobazam and valproate as an adjunctive therapy for refractory generalized tonic-clonic seizures in patients with severe myoclonic epilepsy in infancy (Dravet syndrome) whose seizures are not adequately controlled with clobazam and valproate (Aneja and Sharma, 2013; Plosker, 2012). Adjunctive stiripentol in children with Dravet syndrome who fail to respond to valproate and clobazam have a 71% response rate (Chiron et al., 2000; Nabbout and Chiron, 2012). Stiripentol also reduces the frequency and severity of tonic-clonic seizures as well as status epilepticus in infants and children with a variety of epilepsy syndromes (Inoue et al., 2009; Perez et al., 1999; Rey et al., 1999).
Use of stiripentol is replete with potential drug interactions (see the section on ADME) that must be considered. Initiation of adjunctive therapy with stiripentol should be undertaken gradually, with frequent plasma monitoring for both the parent ASDs and their active metabolites. Plasma monitoring is important to inform reductions in concomitant ASDs as needed, based on patient response.
The most commonly reported adverse effects in patients on stiripentol include anorexia, weight loss, insomnia, drowsiness, ataxia, hypotonia, and dystonia.
Tiagabine is a derivative of nipecotic acid and is FDA-approved as adjunct therapy for focal seizures in adults.
Tiagabine inhibits the GABA transporter GAT-1 and thereby reduces GABA uptake into neurons and glia and prolongs the dwell time of GABA in the synaptic space. In CA1 neurons of the hippocampus, tiagabine increases the duration of inhibitory synaptic currents, findings consistent with prolonging the effect of GABA at inhibitory synapses through reducing its reuptake by GAT-1. Tiagabine inhibits maximum electroshock seizures and both limbic and secondarily generalized tonic-clonic seizures in the kindling model, results suggestive of clinical efficacy against focal and tonic-clonic seizures.
Tiagabine is rapidly absorbed after oral administration, extensively bound to serum proteins, and metabolized mainly in the liver, predominantly by CYP3A. Its t1/2 of about 8 h is shortened by 2–3 h when coadministered with CYP-inducing drugs such as phenobarbital, phenytoin, or carbamazepine.
Tiagabine is efficacious as add-on therapy for refractory focal seizures with or without secondary generalization. Its efficacy as monotherapy for newly diagnosed or refractory focal and generalized epilepsy has not been established.
Adverse Effects and Precautions
The principal adverse effects include dizziness, somnolence, and tremor; they are mild to moderate in severity and appear shortly after initiation of therapy. Tiagabine and other drugs that enhance effects of synaptically released GABA can facilitate spike-and-wave discharges in animal models of absence seizures. Case reports suggest that tiagabine treatment of patients with a history of spike-and-wave discharges causes exacerbations of their EEG abnormalities. Thus, tiagabine may be contraindicated in patients with generalized absence epilepsy. Paradoxically, tiagabine has been associated with the occurrence of seizures in patients without epilepsy; thus, off-label use of the drug is discouraged.
Topiramate is a sulfamate-substituted monosaccharide that is FDA-approved as initial monotherapy (in patients at least 10 years old) and as adjunctive therapy (for patients as young as 2 years) for focal-onset or primary generalized tonic-clonic seizures, for Lennox-Gastaut syndrome in patients 2 years of age and older, and for migraine headache prophylaxis in adults.
Topiramate reduces voltage-gated Na+ currents in cerebellar granule cells and may act on the inactivated state of the channel similarly to phenytoin. In addition, topiramate activates a hyperpolarizing K+ current, enhances postsynaptic GABAA receptor currents, and limits activation of the AMPA-kainate subtype(s) of glutamate receptors. The drug is a weak inhibitor of carbonic anhydrase. Topiramate inhibits maximal electroshock and pentylenetetrazol-induced seizures as well as focal and secondarily generalized tonic-clonic seizures in the kindling model, findings predictive of a broad spectrum of antiseizure actions clinically.
Topiramate is rapidly absorbed after oral administration, exhibits little (10%–20%) binding to plasma proteins, and is excreted largely unchanged in the urine. A small fraction undergoes metabolism by hydroxylation, hydrolysis, and glucuronidation, with no single metabolite accounting for more than 5% of an oral dose. Its t1/2 is about 1 day. Reduced estradiol plasma concentrations occur with concurrent topiramate, suggesting the need for higher doses of oral contraceptives when coadministered with topiramate.
Topiramate is equivalent to valproate and carbamazepine in children and adults with newly diagnosed focal and primary generalized epilepsy (Privitera et al., 2003). The agent is effective as monotherapy for refractory focal epilepsy (Sachdeo et al., 1997) and refractory generalized tonic-clonic seizures (Biton et al., 1999). Topiramate is significantly more effective than placebo against both drop attacks and tonic-clonic seizures in patients with Lennox-Gastaut syndrome (Sachdeo et al., 1999).
Topiramate is well tolerated. The most common adverse effects are somnolence, fatigue, weight loss, and nervousness. It may precipitate renal calculi (kidney stones), probably due to inhibition of carbonic anhydrase. Topiramate has been associated with cognitive impairment, and patients may complain about a change in the taste of carbonated beverages.
The antiseizure properties of valproic acid were discovered serendipitously when it was employed as a vehicle for other compounds that were being screened for antiseizure activity. Valproate (n-dipropylacetic acid) is a simple branched-chain carboxylic acid. Certain other branched-chain carboxylic acids have potencies similar to that of valproic acid in antagonizing pentylenetetrazol-induced seizures. However, increasing the number of carbon atoms to nine introduces marked sedative properties. Straight-chain carboxylic acids have little or no activity.
Valproate is strikingly different from phenytoin or ethosuximide in that it is effective in inhibiting seizures in a variety of models. Like phenytoin and carbamazepine, valproate inhibits tonic hind limb extension in maximal electroshock seizures and kindled seizures at nontoxic doses. Like ethosuximide, valproate at subtoxic doses inhibits clonic motor seizures induced by pentylenetetrazol. Its efficacy in diverse models parallels its efficacy against absence as well as focal and generalized tonic-clonic seizures in humans.
Valproate produces effects on isolated neurons similar to those of phenytoin and ethosuximide. At therapeutically relevant concentrations, valproate inhibits sustained repetitive firing induced by depolarization of mouse cortical or spinal cord neurons (McLean and Macdonald, 1986b). The action is similar to that of phenytoin and carbamazepine (Table 17–2) and appears to be mediated by a prolonged recovery of voltage-activated Na+ channels from inactivation. Valproate does not modify neuronal responses to iontophoretically applied GABA. In neurons isolated from the nodose ganglion, valproate also produces small reductions of T-type Ca2+ currents (Kelly et al., 1990) at clinically relevant concentrations that are slightly higher than those that limit sustained repetitive firing; this effect on T-type currents is similar to that of ethosuximide in thalamic neurons (Coulter et al., 1989). Together, these actions of limiting sustained repetitive firing and reducing T-type currents may contribute to the effectiveness of valproate against focal and tonic-clonic seizures and absence seizures, respectively.
In model systems, valproate can increase brain content of GABA, stimulate GABA synthesis (by glutamate decarboxylase), and inhibit GABA degradation (by GABA transaminase and succinic semialdehyde dehydrogenase). Such data notwithstanding, it has been difficult to relate the increased GABA levels to the antiseizure activity of valproate. Valproate is also a potent inhibitor of histone deacetylase. Thus, some of its antiseizure activity may be due to its ability to modulate gene expression through this mechanism.
Valproate is absorbed rapidly and completely after oral administration. Peak Cp occurs in 1 to 4 h, although this can be delayed for several hours if the drug is administered in enteric-coated tablets or is ingested with meals. Its extent of binding to plasma proteins is usually about 90%, but the fraction bound is reduced as the total concentration of valproate is increased through the therapeutic range. Although concentrations of valproate in CSF suggest equilibration with free drug in the blood, there is evidence for carrier-mediated transport of valproate both into and out of the CSF.
Valproate undergoes hepatic metabolism (95%), with less than 5% excreted unchanged in urine. Its hepatic metabolism occurs mainly by UGTs and β-oxidation. Valproate is a substrate for CYPs 2C9 and 2C19, but these enzymes account for a relatively minor portion of its elimination. Some of the drug’s metabolites, notably 2-propyl-2-pentenoic acid and 2-propyl-4-pentenoic acid, are nearly as potent antiseizure agents as the parent compound; however, only the former accumulates in plasma and brain to a potentially significant extent. The t1/2 of valproate is about 15 h but is reduced in patients taking other antiseizure drugs.
Plasma Drug Concentrations
Valproate plasma concentrations associated with therapeutic effects are about 30–100 μg/mL. However, there is a poor correlation between the plasma concentration and efficacy. There appears to be a threshold at about 30–50 μg/mL, the concentration at which binding sites on plasma albumin begin to become saturated.
Valproate is a broad-spectrum ASD effective in the treatment of absence, myoclonic, focal, and tonic-clonic seizures. The initial daily dose usually is 15 mg/kg, increased at weekly intervals by 5–10 mg/kg/d 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.
Adverse Effects and Drug Interactions
The most frequent side effects are transient GI symptoms, including anorexia, nausea, and vomiting (~16%). Effects on the CNS include sedation, ataxia, and tremor; these symptoms occur infrequently and usually respond to a decrease in dosage. Rash, alopecia, and stimulation of appetite have been observed occasionally; weight gain has been seen with chronic valproate treatment in some patients. Elevation of hepatic transaminases in plasma is observed in up to 40% of patients and often occurs asymptomatically during the first several months of therapy.
A rare but frequently fatal complication is fulminant hepatitis. Children below 2 years of age with other medical conditions who were given multiple ASDs were especially likely to suffer fatal hepatic injury; there were no deaths reported for patients over the age of 10 years who received only valproate (Dreifuss et al., 1989). Acute pancreatitis and hyperammonemia have been frequently associated with the use of valproate. This agent can also produce teratogenic effects, such as neural tube defects.
Valproate inhibits the metabolism of drugs that are substrates for CYP2C9, including phenytoin and phenobarbital. Valproate also inhibits UGTs and thus inhibits the metabolism of lamotrigine and lorazepam. The high molar concentrations of valproate used clinically result in valproate’s displacing phenytoin and other drugs from albumin. With respect to phenytoin in particular, valproate’s inhibition of that drug’s metabolism is exacerbated by displacement of phenytoin from albumin. The concurrent administration of valproate and clonazepam is associated with the development of absence status epilepticus; however, this complication appears to be rare.
Vigabatrin is FDA-approved as adjunct therapy of refractory focal seizures with impaired awareness in adults. In addition, vigabatrin is designated as an orphan drug for treatment of infantile spasms (described in the Therapeutic Use section that follows).
Vigabatrin, a structural analogue of GABA, irreversibly inhibits the major degradative enzyme for GABA, GABA transaminase, thereby leading to increased concentrations of GABA in the brain. This effect is hypothesized to result in increased extracellular GABA at its receptors and enhanced GABAergic transmission.
An oral dose is well absorbed, reaching a maximal Cp within 1 h; the presence of food prolongs absorption but does not reduce the area under the curve. Vigabatrin is excreted unmetabolized by the kidney, and the dose must be reduced for patients with renal impairment. Although vigabatrin has a t1/2 of only 6–8 h, the pharmacodynamic effects are prolonged and do not correlate well with plasma t1/2 or the Cp. Such kinetics would be expected due to the irreversible nature of the drug’s inhibition of GABA transaminase and a recovery period that reflects the rate of enzyme resynthesis rather than the rate of drug elimination. Vigabatrin induces CYP2C9.
Adult dosing is generally initiated orally at 500 mg twice daily and then increased in 500-mg increments weekly to 1.5 g twice daily.
A 2-week, randomized, single masked clinical trial of vigabatrin for infantile spasms in children younger than 2 years revealed time- and dose-dependent increases in responders, evident as freedom from spasms for 7 consecutive days. Children in whom infantile spasms were caused by tuberous sclerosis were particularly responsive to vigabatrin. As with other ASDs, vigabatrin should be withdrawn slowly, not stopped abruptly.
Toxicity, Adverse Effects, and Precautions
Due to progressive and permanent bilateral vision loss (FDA box warning), vigabatrin must be reserved for patients who have failed several alternative therapies. A patient’s vision must be professionally monitored at the beginning of therapy and regularly throughout and after a therapeutic course. Due to this serious toxicity, vigabatrin is available only through SHARE (1-888-45-SHARE), a restricted distribution program.
The most common side effects (>10% patients) include weight gain, concentric visual field constriction, fatigue, somnolence, dizziness, hyperactivity, and seizures. Data in animal models suggest that vigabatrin may harm a developing fetus, and the drug is classified in pregnancy category C. Vigabatrin is excreted in the milk of nursing mothers.
Zonisamide is FDA-approved as adjunctive therapy of focal seizures in adults 12 years or older.
Zonisamide inhibits the sustained, repetitive firing of spinal cord neurons, presumably by prolonging the inactivated state of voltage-gated Na+ channels in a manner similar to actions of phenytoin and carbamazepine and by preventing neurotransmitter release. In addition, zonisamide inhibits T-type Ca2+ currents and reduces the influx of calcium. Zonisamide can also inhibit carbonic anhydrase and scavenge free radicals; whether and how these actions may contribute to the drug’s neuroprotective effects are unknown.
Zonisamide is almost completely absorbed after oral administration, has a long t1/2 (~60 h), is about 40% bound to plasma protein, and has linear kinetics at doses ranging from 100 to 400 mg. Approximately 85% of an oral dose is excreted in the urine, principally as unmetabolized zonisamide and a glucuronide of sulfamoylacetyl phenol, the product of metabolism by CYP3A4. Thus, phenobarbital, phenytoin, and carbamazepine will decrease the plasma concentration/dose ratio of zonisamide, whereas lamotrigine will increase this ratio. Zonisamide has little effect on the plasma concentrations of other ASDs.
The addition of zonisamide to other drugs is superior to placebo. There is insufficient evidence for zonisamide’s efficacy as monotherapy for newly diagnosed or refractory epilepsy.
Overall, zonisamide is well tolerated. The most common adverse effects include somnolence, dizziness, cognitive impairment, ataxia, anorexia, nervousness, and fatigue. Potentially serious skin rashes are rare but may occur. Approximately 1% of individuals develop renal calculi during treatment, which may relate to inhibition of carbonic anhydrase by zonisamide. As a carbonic anhydrase inhibitor, zonisamide may also cause metabolic acidosis. Thus, patients with predisposing conditions (e.g., renal disease, severe respiratory disorders, diarrhea, surgery, ketogenic diet) may be at greater risk for metabolic acidosis while taking zonisamide, a risk that appears to be more frequent and severe in younger patients. Measurement of serum bicarbonate prior to initiating therapy and periodically thereafter, even in the absence of symptoms, is recommended. Last, spontaneous abortions and congenital abnormalities have been reported at twice the rate (7%) of the healthy, control population (2%–3%) in female patients of childbearing age receiving polytherapy including zonisamide.