Carbamazepine is a prototype of the antiseizure drugs primarily used in the treatment of focal onset seizures. In addition to being effective in the treatment of focal seizures, carbamazepine is indicated for the treatment of tonic-clonic (grand mal) seizures. This indication derives from studies in patients whose focal onset seizures progressed to bilateral tonic-clonic seizures (previously called “secondarily generalized tonic-clonic seizures”). Drugs like carbamazepine exacerbate certain seizure types in idiopathic generalized epilepsies, including myoclonic and absence seizures, and are generally avoided in patients with such a diagnosis. There is evidence from anecdotal reports and small studies indicating that carbamazepine, phenytoin, and lacosamide may be effective and safe in the treatment of generalized tonic-clonic seizures in idiopathic generalized epilepsies. The most popular drugs for the treatment of focal seizures are carbamazepine, lamotrigine, phenytoin, and lacosamide; levetiracetam is also commonly used. Phenobarbital is useful if cost is an issue. Vigabatrin and felbamate are third-line drugs because of risk of toxicity.
Carbamazepine is one of the most widely used antiseizure drugs despite its limited range of activity as a treatment for focal (partial onset) and focal-to-bilateral tonic-clonic seizures. It was initially marketed for the treatment of trigeminal neuralgia, for which it is highly effective; it is usually the drug of first choice for this condition. In addition, carbamazepine is a mood stabilizer used to treat bipolar disorder.
Structurally, carbamazepine is an iminostilbene (dibenzazepine)—a tricyclic compound consisting of two benzene rings fused to an azepine group. The structure of carbamazepine is similar to that of tricyclic antidepressants such as imipramine, but unlike the tricyclic antidepressants, carbamazepine does not inhibit monoamine (serotonin and norepinephrine) transporters with high affinity; therefore, carbamazepine is not used as an antidepressant despite its ability to treat bipolar disorder.
Carbamazepine is a prototypical sodium channel-blocking antiseizure drug that is thought to protect against seizures by interacting with the voltage-gated sodium channels (Nav1) responsible for the rising phase of neuronal action potentials (see Chapters 14 and 21). In the normal state, when neurons are depolarized to action potential threshold, the sodium channel protein senses the depolarization and, within a few hundred microseconds, undergoes a conformational change (gating) that converts the channel from its closed (resting) nonconducting state to the open conducting state that permits sodium flux (Figure 24–2). Then, within less than a millisecond, the channel enters the inactivated state, terminating the flow of sodium ions. The channel must then be repolarized before it can be activated again by a subsequent depolarization. Brain sodium channels can rapidly cycle through the resting, open, and inactivated states, allowing neurons to fire high-frequency trains of action potentials.
(A1) Voltage-gated sodium channels mediate the upstroke of action potentials in brain neurons. Fast inactivation of sodium channels (along with the activation of potassium channels) terminates the action potential. (A2) Voltage-clamp recording of sodium channel current following depolarization, illustrating the time course of sodium channel gating. (B) Schematic illustration of the voltage-dependent gating of sodium channels between closed, open, and inactivated states. (C1) Primary structures of the subunits of sodium channels. The main α subunit, consisting of four homologous repeats (I–IV), is shown flanked by the two auxiliary β subunits. Cylinders represent α-helical transmembrane segments. Blue α-helical segments (S5, S6) form the pore region. +, S4 voltage sensors; grey circles, inactivation particle in inactivation gate loop; III-S6 and IV-S6 (red) are regions of antiseizure drug binding. (C2) Schematic illustration of the sodium channel pore composed of the homologous repeats arrayed around the central channel pore through which sodium flows into the neuron. The S5 and S6 transmembrane α-helical segments from each homologous repeat (I–IV) form the four walls of the pore. The outer pore mouth and ion selectivity filter are formed by re-entrant P-loops. The key α-helical S6 segments in repeat III and IV, which contain the antiseizure drug binding sites, are highlighted. A lamotrigine molecule is illustrated in association with its binding site.
Sodium channels are multimeric protein complexes, composed of (1) a large α subunit that forms four subunit-like homologous domains (designated I–IV) and (2) one or more smaller β subunits. The ion-conducting pore is contained within the α subunit, as are the elements of the channel that undergo conformational changes in response to membrane depolarization. Carbamazepine and other sodium channel-blocking antiseizure drugs such as phenytoin and lamotrigine bind preferentially to the channel when it is in the inactivated state, causing it to be stabilized in this state. During high-frequency firing, sodium channels cycle rapidly through the inactivated state, allowing the block to accumulate. This leads to a characteristic use-dependent blocking action in which high-frequency trains of action potentials are more effectively inhibited than are either individual action potentials or the firing at low frequencies (see Chapter 14, Figures 14–9 and 14–10). In addition, sodium channel-blocking antiseizure drugs exhibit a voltage dependence to their blocking action because a greater fraction of sodium channels exist in the inactivated state at depolarized potentials. Thus, action potentials, which are superimposed on a depolarized plateau potential as characteristically occurs with seizures, are effectively inhibited. The use dependence and voltage dependence of the blocking action of drugs like carbamazepine provide the ability to preferentially inhibit action potentials during seizure discharges and to less effectively interfere with ordinary ongoing action potential firing (Figure 24–3). Such action is thought to allow such drugs to prevent the occurrence of seizures without causing unacceptable neurologic impairment. It is noteworthy that sodium channel-blocking antiseizure agents act mainly on action potential firing; the drugs do not directly alter excitatory or inhibitory synaptic responses. However, the effect on action potentials translates into reduced transmitter output at synapses.
(A) Selective effect of a clinically relevant concentration of lamotrigine (50 μM) on action potentials and epileptic-like discharges in rat hippocampal neurons as assessed with intracellular recording. In normal recording conditions, lamotrigine has no effect on action potentials or on the evoked excitatory postsynaptic potentials (EPSPs) that elicit the action potential. In epileptic-like conditions (low magnesium), activation elicits initial spikes followed by repetitive epileptiform spike firing (afterdischarge). Lamotrigine inhibits the pathologic discharge but not the initial spikes. EPSPs were elicited by stimulation of the Schaffer collateral/commissural fibers (triangles). (B) Voltage and use dependence of block of human Nav1.2 voltage-activated sodium channels. Sodium currents elicited by depolarization from a holding potential of –90 mV (where there is little inactivation) are minimally affected by 100 μM of lamotrigine, whereas there is strong block of current elicited from –60 mV (where there is more substantial inactivation). Trains of 0.7-millisecond (ms) duration pulses from –90 mV (minimal inactivation) are minimally blocked in a use-dependent fashion by 100 μM of lamotrigine, whereas 20-ms pulses (marked inactivation) show substantial use dependence. (Adapted, with permission, from Xie X, Hagan RM: Cellular and molecular actions of lamotrigine: Possible mechanisms of efficacy in bipolar disorder. Neuropsychobiology 1998;38:119.)
Carbamazepine is effective for the treatment of focal and focal-to-bilateral tonic-clonic seizures. As noted earlier, there is anecdotal evidence that carbamazepine may be effective in the treatment of generalized tonic-clonic seizures in idiopathic generalized epilepsies but must be used with caution as it can exacerbate absence and myoclonic seizures. Carbamazepine is also effective for the treatment of trigeminal and glossopharyngeal neuralgia, and mania in bipolar disorder.
Carbamazepine has nearly 100% oral bioavailability, but the rate of absorption varies widely among patients. Peak levels are usually achieved 6–8 hours after administration. Slowing absorption by giving the drug after meals causes a reduction in peak levels and helps the patient tolerate larger total daily doses. Extended-release formulations may also decrease the incidence of adverse effects.
Distribution is slow, and the volume of distribution is approximately 1 L/kg. Plasma protein binding is approximately 70%. 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 its own metabolism, often causing serum concentrations to fall after a few weeks of treatment. 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 is metabolized in the liver, and only about 5% of the drug is excreted unchanged. The major route of metabolism is conversion to carbamazepine-10,11-epoxide, which has been shown to have antiseizure activity. This reaction is primarily catalyzed by CYP3A4, although CYP2C8 also plays a role and CYP3A5 may be involved. The contribution of this and other metabolites to the clinical activity of carbamazepine is unknown.
Dosage Recommendations & Therapeutic Levels
Carbamazepine is available in oral forms (tablets and suspensions), and an intravenous formulation is available for temporary replacement of oral therapy. The drug is effective in children, in whom a dosage of 15–25 mg/kg/d is appropriate. In adults, the typical daily maintenance dose is 800–1200 mg/d, and the maximum recommended dose is 1600 mg/d, but rarely patients have required doses up to 2400 mg/d. 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), therapeutic concentrations are 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 initiation should be slow, with gradual increases in dose.
Carbamazepine stimulates the transcriptional up-regulation of CYP3A4 and CYP2B6. This autoinduction leads not only to a reduction in steady-state carbamazepine concentrations but also to an increased rate of metabolism of concomitant antiseizure drugs including primidone, phenytoin, ethosuximide, valproic acid, and clonazepam. Some antiseizure drugs such as valproic acid may inhibit carbamazepine clearance and increase steady-state carbamazepine blood levels. Other antiseizure drugs, notably phenytoin and phenobarbital, may decrease steady-state concentrations of carbamazepine through enzyme induction. These interactions may require dosing changes. No clinically significant protein-binding interactions have been reported.
Carbamazepine may cause dose-dependent mild gastrointestinal discomfort, dizziness, blurred vision, diplopia, or ataxia; sedation occurs only at high doses, and rarely, weight gain can occur. 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. A benign leukopenia occurs in many patients, but there is usually no need for intervention unless neutrophil count falls below 1000/mm3. Rash and hyponatremia are the most common reasons for discontinuation. Stevens-Johnson syndrome is rare, but the risk is significantly higher in patients with the HLA-B*1502 allele. It is recommended that Asians, who have a 10-fold higher incidence of carbamazepine-induced Stevens-Johnson syndrome compared to other ethnic groups, be tested before starting the drug.
Oxcarbazepine is the 10-keto analog of carbamazepine. Unlike carbamazepine, it cannot form an epoxide metabolite. Although it has been hypothesized that the epoxide is associated with carbamazepine’s adverse effects, little evidence is available to document the claim that oxcarbazepine is better tolerated. Oxcarbazepine is thought to protect against seizures by blocking voltage-gated sodium channels in the same way as carbamazepine. Oxcarbazepine itself has a half-life of only 1–2 hours; its antiseizure activity resides almost exclusively in the active 10-hydroxy metabolites, S(+)- and R(–)-licarbazepine (also referred to as monohydroxy derivatives or MHDs), to which oxcarbazepine is rapidly converted and both of which have half-lives similar to that of carbamazepine (8–12 hours). The bulk (80%) of oxcarbazepine is converted to the S(+) form. The drug is mostly excreted as the glucuronide of the 10-hydroxy metabolite.
Oxcarbazepine is less potent than carbamazepine, both in animal tests and in 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 of oxcarbazepine are similar to those of carbamazepine.
Eslicarbazepine acetate, a prodrug of S(+)-licarbazepine, provides an alternative to oxcarbazepine, with some minor differences. Like oxcarbazepine, eslicarbazepine acetate is converted to eslicarbazepine but the conversion occurs more rapidly and it is nearly completely to the S(+) form, with only a small amount of the R(−) isomer (5%) formed by chiral inversion. Whether there is a benefit to the more selective conversion to S(+)-licarbazepine is uncertain, especially since both enantiomers act similarly on voltage-gated sodium channels. The effective half-life of S(+)-licarbazepine following oral administration of eslicarbazepine acetate is 20–24 hours so the prodrug can be administered once daily, which is a potential advantage. The drug is administered at a dosage of 400–1600 mg/d; titration is typically required for the higher doses. S(+)-Licarbazepine is eliminated primarily by renal excretion; dose adjustment is therefore required for patients with renal impairment. Minimal pharmacokinetic effects are observed with coadministration of carbamazepine, levetiracetam, lamotrigine, topiramate, and valproate. The dose of phenytoin may need to be decreased if used concomitantly with eslicarbazepine acetate. Oral contraceptives may be less effective with concomitant eslicarbazepine acetate administration.
Lacosamide is a sodium channel-blocking antiseizure drug approved for the treatment of focal seizures. It has favorable pharmacokinetic properties and good tolerability. The drug is widely prescribed.
Early studies suggested that lacosamide enhances a poorly understood type of sodium channel inactivation called slow inactivation. Recent studies, however, contradict this view and indicate that the drug binds selectively to the fast inactivated state of sodium channels—as is the case for other sodium channel-blocking antiseizure drugs, except that the binding is much slower.
Lacosamide is approved for the treatment of focal onset seizures in patients age 17 years and older. In clinical trials with more than 1300 patients, lacosamide was effective at doses of 200 mg/d and had greater and roughly similar overall efficacy at 400 and 600 mg/d, respectively. Although the overall efficacy was similar at 400 and 600 mg/d, the higher dose may provide better control of focal-to-bilateral tonic-clonic (secondarily generalized) seizures; however, this dose is associated with a greater incidence of adverse effects. Adverse effects include dizziness, headache, nausea, and diplopia. The drug is typically administered twice daily, beginning with 50-mg doses and increasing by 100-mg increments weekly. An intravenous formulation provides short-term replacement for the oral drug. The oral solution contains aspartame, which is a source of phenylalanine and could be harmful in people with phenylketonuria.
Oral lacosamide is rapidly and completely absorbed in adults, with no food effect. Bioavailability is nearly 100%. The plasma concentrations are proportional to oral dosage up to 800 mg. 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 minimal.
Phenytoin, first identified to have antiseizure activity in 1938, is the oldest nonsedating drug used in the treatment of epilepsy. It is prescribed for the prevention of focal seizures and generalized tonic-clonic seizures and for the acute treatment of status epilepticus. Phenytoin was identified by testing in laboratory animals in a search for better tolerated barbiturates.
Phenytoin, sometimes referred to as diphenylhydantoin, is the 5,5-diphenyl-substituted analog of hydantoin. Hydantoin is a five-membered ring molecule similar structurally to barbiturates, which are based on a six-member ring. Phenytoin free base (pKa = 8.06–8.33) is poorly water soluble, but phenytoin sodium does dissolve in water (17 mg/mL). Phenytoin is most commonly prescribed in an extended-release capsule containing phenytoin sodium and other excipients to provide a slow and extended rate of absorption with peak blood concentrations from 4 to 12 hours. This form differs from the prompt phenytoin sodium capsule form that provides rapid rate of absorption with peak blood concentration from 1.5 to 3 hours. In addition, the free base is available as an immediate-release suspension and chewable tablets. Phenytoin is available as an intravenous solution containing propylene glycol and alcohol adjusted to a pH of 12. Absorption after intramuscular injection is unpredictable, and some drug precipitation in the muscle occurs; this route of administration is not recommended.
With intravenous administration, there is a risk of the potentially serious “purple glove syndrome” in which a purplish-black discoloration accompanied by edema and pain occurs distal to the site of injection. Fosphenytoin is a water-soluble prodrug of phenytoin that may have a lower incidence of purple glove syndrome. This phosphate ester compound is rapidly converted to phenytoin in the plasma and is used for intravenous administration and treatment of status epilepticus. Fosphenytoin is well absorbed after intramuscular administration, but this route is rarely appropriate for the treatment of status epilepticus.
Phenytoin is a sodium channel-blocking antiseizure drug that acts in a similar fashion to carbamazepine and other agents in the class.
Phenytoin is effective in preventing focal onset seizures and also tonic-clonic seizures, whether they are focal-to-bilateral tonic-clonic (secondarily generalized) or occurring in the setting of an idiopathic generalized epilepsy syndrome. Phenytoin may worsen other seizure types in primary generalized epilepsies, including absence epilepsy, juvenile myoclonic epilepsy, and Dravet’s syndrome.
Pharmacokinetics & Drug Interactions
Absorption of phenytoin is highly dependent on the formulation. Particle size and pharmaceutical additives affect both the rate and the extent of absorption. Therefore, while absorption from the gastrointestinal tract is nearly complete in most patients, the time to peak may range from 3 to 12 hours. Phenytoin is extensively (~90%) bound to serum albumin and is prone to displacement in response to a variety of factors (eg, hyperbilirubinemia or drugs such as warfarin or valproic acid), which can lead to toxicity. Also, low plasma albumin (such as in liver disease or nephrotic syndrome) can result in abnormally high free concentrations and toxicity. Small changes in the bound fraction dramatically affect the amount of free (active) drug. Increased proportions of free drug are also present in the neonate and in the elderly. Some agents such as valproic acid, phenylbutazone, and sulfonamides can compete with phenytoin for binding to plasma proteins. Valproic acid also inhibits phenytoin metabolism. The combined effect can result in marked increases in free phenytoin. In all of these situations, patients may exhibit signs of toxicity when total drug levels are within the therapeutic range. Because of its high protein binding, phenytoin has a low volume of distribution (0.6–0.7 L/kg in adults).
Phenytoin is metabolized by CYP2C9 and CYP2C19 to inactive metabolites that are excreted in the urine. Only a small proportion of the dose is excreted unchanged. The elimination of phenytoin depends on the dose. At 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 the drug is approached (saturation kinetics). Even small increases in dose may be associated with large changes in phenytoin serum concentrations (Figure 24–4). 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.
Relationship between dose and exposure for antiseizure drugs (ASDs). Most antiseizure drugs follow linear (first-order) kinetics, in which a constant fraction per unit time of the drug is eliminated (elimination is proportional to drug concentration). In the case of phenytoin, as the dose increases, there is saturation of metabolism and a shift from first-order to zero-order kinetics, in which a constant quantity per unit time is metabolized. A small increase in dose can result in a large increase in concentration. Orally administered gabapentin also exhibits zero-order kinetics, but in contrast to phenytoin where metabolism can be saturated, in the case of gabapentin, gut absorption, which is mediated by the large neutral amino acid system L transporter, is susceptible to saturation. The bioavailability of gabapentin falls at high doses as the transporter is saturated so that increases in blood levels do not keep pace with increases in dose.
The half-life of phenytoin in most patients varies from 12 to 36 hours, with an average of 24 hours in the low to mid therapeutic range. Much longer half-lives are observed at higher concentrations. At low blood levels, 5–7 days are needed to reach steady-state blood levels after every dosage change; at higher levels, it may be 4–6 weeks before blood levels are stable. Phenytoin—like carbamazepine, phenobarbital, and primidone—is a major enzyme-inducing antiseizure drug that stimulates the rate of metabolism of many coadministered antiseizure drugs, including valproic acid, tiagabine, ethosuximide, lamotrigine, topiramate, oxcarbazepine and MHDs, zonisamide, felbamate, many benzodiazepines, and perampanel. Autoinduction of its own metabolism, however, is insignificant.
Therapeutic Levels & Dosing
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, with either fosphenytoin sodium injection (preferred) or phenytoin sodium injection. 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 μg/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 the kinetic factors discussed earlier, toxic levels may occur with only small increments in dosage. The phenytoin dosage should be increased in increments of no more than 25–30 mg/d 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/d 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 are currently available in the USA, differing in their respective rates of dissolution. The predominant form is the sodium salt in an extended-release pill intended for once- or twice-a-day use. In addition, the free acid is available as an immediate-release suspension and chewable tablets. 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. As noted, fosphenytoin sodium is available for intravenous or intramuscular use and usually replaces intravenous phenytoin sodium, a much less soluble form of the drug.
Early signs of phenytoin administration include nystagmus and loss of smooth extraocular pursuit movements; 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 rarely occur; this must be distinguished from malignant lymphoma. 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 focal and generalized tonic-clonic seizures. No well-controlled clinical trials have documented their effectiveness, and the drugs are rarely used. The incidence of severe reactions such as dermatitis, agranulocytosis, or hepatitis is higher for mephenytoin than for phenytoin. Mephenytoin is metabolized to 5-ethyl-5-phenyl-hydantoin (nirvanol) via demethylation; nirvanol contributes most of the antiseizure activity of mephenytoin.
Gabapentin and pregabalin, known as “gabapentinoids,” are amino acid-like molecules that were originally synthesized as analogs of GABA but are now known not to act through GABA mechanisms. They are used in the treatment of focal seizures and various nonepilepsy indications, such as neuropathic pain, restless legs syndrome, and anxiety disorders.
Despite their close structural resemblance to GABA, gabapentin and pregabalin do not act through effects on GABA receptors or any other mechanism related to GABA-mediated neurotransmission. Rather, gabapentinoids bind avidly to α2δ, a protein that serves as an auxiliary subunit of voltage-gated calcium channels but may also have other functions. The precise way in which binding of gabapentinoids to α2δ protects against seizures is not known but may relate to a decrease in glutamate release at excitatory synapses.
Gabapentin and pregabalin are effective in the treatment of focal seizures; there is no evidence that they are efficacious in generalized epilepsies. Indeed, gabapentin may aggravate absence seizures and myoclonic seizures. Gabapentin is usually started at a dose of 900 mg/d (in three divided doses), but starting doses as high as 3600 mg/d can be used if a rapid response is required. Some clinicians have found that even higher dosages are needed to achieve improvement in seizure control. The recommended starting dose of pregabalin is 150 mg/d, but a lower starting dose (50–75 mg/d) may avoid adverse effects that can occur on drug initiation; the effective maintenance dose range is 150 to 600 mg/d. Although comparative studies are lacking, gabapentinoids are generally considered less effective than other antiseizure drugs for the treatment of focal seizures. Gabapentinoids are frequently used in the treatment of neuropathic pain conditions, including postherpetic neuralgia and painful diabetic neuropathy, and in the treatment of anxiety disorders. Pregabalin is also approved for the treatment of fibromyalgia. Gabapentin and pregabalin are generally well tolerated. The most common adverse effects are somnolence, dizziness, ataxia, headache, and tremor. These adverse effects are most troublesome at initiation of therapy and often resolve with continued dosing. Both gabapentinoids can cause weight gain and peripheral edema.
Gabapentin and pregabalin are not metabolized and do not induce hepatic enzymes; they are eliminated unchanged in the urine. Both drugs are absorbed by the L-amino acid transport system, which is found only in the upper small intestine. The oral bioavailability of gabapentin decreases with increasing dose because of saturation of this transport system. In contrast, pregabalin exhibits linear absorption within the therapeutic dose range. This is explained, in part, by the fact that pregabalin is used at much lower doses than gabapentin so it does not saturate the transport system. Also, pregabalin may be absorbed by mechanisms other than the L-amino acid transport system. Because of dependence on the transport system, absorption of gabapentin shows patient-to-patient variability and dosing requires individualization. Pregabalin bioavailability exceeds 90% and is independent of dose so that it may produce a more predictable patient response. Gabapentinoids are not bound to plasma proteins. Drug-drug interactions are negligible. The half-life of both drugs is relatively short (ranging from 5 to 8 hours for gabapentin and 4.5 to 7.0 hours for pregabalin); they are typically administered two or three times per day. Sustained-release, once-a-day preparations of gabapentin are available. The gabapentin prodrug gabapentin enacarbil is also available in an extended-release formulation. This prodrug is actively absorbed by high-capacity nutrient transporters, which are abundant throughout the intestinal tract, and then converted to gabapentin presumably within the intestine, so there is dose-proportional systemic gabapentin exposure over a wide dose range.
Tiagabine, a selective inhibitor of the GAT-1 GABA transporter, is a second-line treatment for focal seizures. It is contraindicated in generalized onset epilepsies.
Tiagabine is a lipophilic, blood-brain barrier-permeant analog of nipecotic acid, a GABA uptake inhibitor that is not active systemically. The chemical structure of tiagabine consists of the active moiety—nipecotic acid—and a lipophilic anchor that allows the molecule to cross the blood-brain barrier. Tiagabine is highly selective for the GAT-1 GABA transporter isoform, the most abundant GABA transporter expressed in brain, and has little or no activity on the other sodium- and chloride-dependent GABA transporters, GAT-2, GAT-3, or BGT-1. The action of the GABA that is released by inhibitory neurons is normally terminated by reuptake into the neuron and surrounding glia by these transporters. Tiagabine inhibits the movement of GABA from the extracellular space—where the GABA can act on neuronal receptors—to the intracellular compartment, where it is inactive. This action of tiagabine causes prolongation of GABA-mediated inhibitory synaptic responses and potentiation of tonic inhibition; the latter is caused by the action of GABA on extrasynaptic GABA receptors. Tiagabine is considered a “rationally designed” antiseizure drug because it was developed with the understanding that potentiation of GABA action in the brain is a possible antiseizure mechanism.
Tiagabine is indicated for the adjunctive treatment of focal seizures, with or without secondary generalization. In adults, the recommended initial dose is 4 mg/d with weekly increments of 4–8 mg/d to total doses of 16–56 mg/d. Initial dosages can be given twice a day, but a change to three times a day is recommended above 30–32 mg/d. Divided doses as often as four times daily are sometimes required. Adverse effects and apparent lack of efficacy limit the use of this drug. Minor adverse events are dose related and include nervousness, dizziness, tremor, difficulty 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.
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). To avoid adverse effects, the drug should be taken with food. Hepatic impairment causes a slight decrease in clearance and may necessitate a lower dose. The drug is oxidized in the liver by CYP3A. Elimination is primarily in the feces (60–65%) and urine (25%).
Retigabine (US Adopted Name: ezogabine), a potassium channel opener, is a third-line treatment for focal seizures. Because retigabine causes pigment discoloration of the retina and skin, its use is limited to those who have failed to respond to other agents.
Retigabine is an allosteric opener of KCNQ2-5 (Kv7.2-Kv7.5) voltage-gated potassium channels, which are localized, in part, in axons and nerve terminals. Opening KCNQ potassium channels in presynaptic terminals inhibits the release of various neurotransmitters, including glutamate, which may be responsible for the seizure protection.
Doses of retigabine range from 600 to 1200 mg/d, with 900 mg/d expected to be the most common. The drug is administered in three divided doses, and the dose must be titrated beginning at 300 mg/d. Most adverse effects are dose-related and include dizziness, somnolence, blurred vision, confusion, and dysarthria. Urinary symptoms, including retention, hesitation, and dysuria, believed to be due to effects of the drug on KCNQ potassium channels in detrusor smooth muscle, may occur. They are generally mild and usually do not require drug discontinuation. In 2013, reports began to appear of blue pigmentation, primarily on the skin and lips, but also on the palate, sclera, and conjunctiva. The skin dyspigmentation is due to the presence of coarse melanin granules within dermal cells and not to deposition of the drug within the tissue. The skin discoloration has not been associated with more serious adverse effects but may be of cosmetic significance. In addition, however, retinal pigment abnormalities can occur independent of skin changes. Of particular concern are postmarketing reports of macular abnormalities characterized as vitelliform lesions, such as those seen in macular degeneration or dystrophy. Decreased visual acuity has been reported, but documentation is lacking. Nevertheless, because of the ophthalmologic adverse reactions, regulatory agencies have recommended use of retigabine only in cases where other antiseizure drugs are not adequate or not tolerated.
Absorption of retigabine is not affected by food, and kinetics are linear; drug interactions are minimal. The major metabolic pathways in humans are N-glucuronidation and N-acetylation. The drug neither inhibits nor induces the major CYP enzymes involved in drug metabolism.