Chapter 24: Antiseizure Drugs

Antiseizure drugs are commonly used for long periods of time, and consideration of their pharmacokinetic properties is important for avoiding toxicity and drug interactions. For some of these drugs (eg, phenytoin), determination of plasma levels and clearance in individual patients may be necessary for optimum therapy. In general, antiseizure drugs are well absorbed orally and have good bioavailability. Most antiseizure drugs are metabolized by hepatic enzymes (exceptions include gabapentin and vigabatrin), and in some cases active metabolites are formed. Resistance to antiseizure drugs may involve increased expression of drug transporters at the level of the blood-brain barrier.

Pharmacokinetic drug interactions are common in this drug group. In the presence of drugs that inhibit antiseizure drug metabolism or displace anticonvulsants from plasma protein binding sites, plasma concentrations of the antiseizure agents may reach toxic levels. On the other hand, drugs that induce hepatic drug-metabolizing enzymes (eg, rifampin) may result in plasma levels of the antiseizure agents that are inadequate for seizure control. Several antiseizure drugs are themselves capable of inducing hepatic drug metabolism, especially carbamazepine and phenytoin.

A. Phenytoin

The oral bioavailability of phenytoin is variable because of individual differences in first-pass metabolism. Rapid-onset and extended-release forms are available. Phenytoin metabolism is nonlinear; elimination kinetics shift from first-order to zero-order at moderate to high dose levels. The drug binds extensively to plasma proteins (97–98%), and free (unbound) phenytoin levels in plasma are increased transiently by drugs that compete for binding (eg, carbamazepine, sulfonamides, valproic acid). The metabolism of phenytoin is enhanced in the presence of inducers of liver metabolism (eg, phenobarbital, rifampin) and inhibited by other drugs (eg, cimetidine, isoniazid). Phenytoin itself induces hepatic drug metabolism, decreasing the effects of other antiepileptic drugs including carbamazepine, clonazepam, and lamotrigine. Fosphenytoin is a water-soluble prodrug form of phenytoin that is used parenterally.

B. Carbamazepine

Carbamazepine induces formation of liver drug-metabolizing enzymes that increase metabolism of the drug itself and may increase the clearance of many other anticonvulsant drugs including clonazepam, lamotrigine, and valproic acid. Carbamazepine metabolism can be inhibited by other drugs (eg, propoxyphene, valproic acid). A related drug, oxcarbazepine, is less likely to be involved in drug interactions.

C. Valproic Acid

In addition to competing for phenytoin plasma protein binding sites, valproic acid inhibits the metabolism of carbamazepine, ethosuximide, phenytoin, phenobarbital, and lamotrigine. Hepatic biotransformation of valproic acid leads to formation of a toxic metabolite that has been implicated in the hepatotoxicity of the drug.

D. Other Drugs

Gabapentin, pregabalin, levetiracetam, and vigabatrin are unusual in that they are eliminated by the kidney, largely in unchanged form. These agents have virtually no drug-drug interactions. Tiagabine, topiramate, and zonisamide undergo both hepatic metabolism and renal elimination of intact drug. Lamotrigine is eliminated via hepatic glucuronidation.

The general effect of antiseizure drugs is to suppress repetitive action potentials in epileptic foci in the brain. Many different mechanisms are involved in achieving this effect. In some cases, several mechanisms may contribute to the antiseizure activity of an individual drug. Some of the recognized mechanisms are described next.

A. Sodium Channel Blockade

At therapeutic concentrations, phenytoin, carbamazepine, lamotrigine, and zonisamide block voltage-gated sodium channels in neuronal membranes. This action is rate-dependent (ie, dependent on the frequency of neuronal discharge) and results in prolongation of the inactivated state of the Na⁺ channel and the refractory period of the neuron. Phenobarbital and valproic acid may exert similar effects at high doses.

B. GABA-Related Targets

As described in Chapter 22, benzodiazepines interact with specific receptors on the GABA_A receptor–chloride ion channel macromolecular complex. In the presence of benzodiazepines, the frequency of chloride ion channel opening is increased; these drugs facilitate the inhibitory effects of GABA. Phenobarbital and other barbiturates also enhance the inhibitory actions of GABA but interact with a different receptor site on chloride ion channels that results in an increased duration of chloride ion channel opening.

GABA aminotransaminase (GABA-T) is an important enzyme in the termination of action of GABA. The enzyme is irreversibly inactivated by vigabatrin at therapeutic plasma levels and can also be inhibited by valproic acid at very high concentrations. Tiagabine inhibits a GABA transporter (GAT-1) in neurons and glia prolonging the action of the neurotransmitter. Gabapentin is a structural analog of GABA, but it does not activate GABA receptors directly. Other drugs that may facilitate the inhibitory actions of GABA include felbamate, topiramate, and valproic acid.

C. Calcium Channel Blockade

Ethosuximide inhibits low-threshold (T type) Ca²⁺ currents, especially in thalamic neurons that act as pacemakers to generate rhythmic cortical discharge. A similar action is reported for valproic acid, as well as for both gabapentin and pregabalin, and it may be the primary action of the latter drugs.

D. Other Mechanisms

In addition to its action on calcium channels, valproic acid causes neuronal membrane hyperpolarization, possibly by enhancing K⁺ channel permeability. Although phenobarbital acts on both sodium channels and GABA-chloride channels, it also acts as an antagonist at some glutamate receptors. Felbamate blocks glutamate NMDA receptors. Topiramate blocks sodium channels and potentiates the actions of GABA and may also block glutamate receptors.

1. Which of the mechanisms of action of antiseizure drugs have theoretical implications regarding their activity in cardiac arrhythmias? (See Chapter 14)

2. Recall any clinical uses of antiseizure drugs in the management of cardiac arrhythmias?

The Skill Keeper Answers appear at the end of the chapter.

Diagnosis of a specific seizure type is important for prescribing the most appropriate antiseizure drug (or combination of drugs). Drug choice is usually made on the basis of established efficacy in the specific seizure state that has been diagnosed, the prior responsiveness of the patient, and the anticipated toxicity of the drug. Treatment may involve combinations of drugs, following the principle of adding known effective agents if the preceding drugs are not sufficient.

A. Generalized Tonic-Clonic Seizures

Valproic acid, carbamazepine, and phenytoin are the drugs of choice for generalized tonic-clonic (grand mal) seizures. Phenobarbital (or primidone) is now considered to be an alternative agent in adults but continues to be a primary drug in infants. Lamotrigine and topiramate are also approved drugs for this indication, and several others may be used adjunctively in refractory cases.

B. Partial Seizures

The drugs of first choice are carbamazepine (or oxcarbazepine) or lamotrigine or phenytoin. Alternatives include felbamate, phenolbarbital, topiramate, and valproic acid. Many of the newer anticonvulsants can be used adjunctively, including gabapentin and pregabalin, a structural congener.

C. Absence Seizures

Ethosuximide or valproic acid are the preferred drugs because they cause minimal sedation. Ethosuximide is often used in uncomplicated absence seizures if patients can tolerate its gastrointestinal side effects. Valproic acid is particularly useful in patients who have concomitant generalized tonic-clonic or myoclonic seizures. Clonazepam is effective as an alternative drug but has the disadvantages of causing sedation and tolerance. Lamotrigine, levetiracetam, and zonisamide are also effective in absence seizures.

D. Myoclonic and Atypical Absence Syndromes

Myoclonic seizure syndromes are usually treated with valproic acid; lamotrigine is approved for adjunctive use, but is commonly used as monotherapy. Clonazepam can be effective, but the high doses required cause drowsiness. Levetiracetam, topiramate, and zonisamide are also used as backup drugs in myoclonic syndromes. Felbamate has been used adjunctively with the primary drugs but has both hematotoxic and hepatotoxic potential.

E. Status Epilepticus

Intravenous diazepam or lorazepam is usually effective in terminating attacks and providing short-term control. For prolonged therapy, intravenous phenytoin has often been used because it is highly effective and less sedating than benzodiazepines or barbiturates. However, phenytoin may cause cardiotoxicity (perhaps because of its solvent, propylene glycol), and fosphenytoin (water-soluble) is a safer parenteral agent. Phenobarbital has also been used in status epilepticus, especially in children. In very severe status epilepticus that does not respond to these measures, general anesthesia may be used.

F. Other Clinical Uses

Several antiseizure drugs are effective in the management of bipolar affective disorders, especially valproic acid, which is now often used as a first-line drug in the treatment of mania. Carbamazepine and lamotrigine have also been used successfully in bipolar disorder. Carbamazepine is the drug of choice for trigeminal neuralgia, and its congener oxcarbazepine may provide similar analgesia with fewer adverse effects. Gabapentin has efficacy in pain of neuropathic origin, including postherpetic neuralgia, and, like phenytoin, may have some value in migraine. Topiramate is also used in the treatment of migraine. Pregabalin is also approved for neuropathic pain.

Chronic therapy with antiseizure drugs is associated with specific toxic effects, the most important of which are listed in Table 24–1.

A. Teratogenicity

Children born of mothers taking anticonvulsant drugs have an increased risk of congenital malformations. Neural tube defects (eg, spina bifida) are associated with the use of valproic acid; carbamazepine has been implicated as a cause of craniofacial anomalies and spina bifida; and a fetal hydantoin syndrome has been described after phenytoin use by pregnant women.

B. Overdosage Toxicity

Most of the commonly used anticonvulsants are CNS depressants, and respiratory depression may occur with overdosage. Management is primarily supportive (airway management, mechanical ventilation), and flumazenil may be used in benzodiazepine overdose.

C. Life-Threatening Toxicity

Fatal hepatotoxicity has occurred with valproic acid, with greatest risk to children younger than 2 yr and patients taking multiple anticonvulsant drugs. Lamotrigine has caused skin rashes and life-threatening Stevens-Johnson syndrome or toxic epidermal necrolysis. Children are at higher risk (1–2% incidence), especially if they are also taking valproic acid. Zonisamide may also cause severe skin reactions. Reports of aplastic anemia and acute hepatic failure have limited the use of felbamate to severe, refractory seizure states.

D. Withdrawal

Withdrawal from antiseizure drugs should be accomplished gradually to avoid increased seizure frequency and severity. In general, withdrawal from anti-absence drugs is more easily accomplished than withdrawal from drugs used in partial or generalized tonic-clonic seizure states.

1. A 9-year-old child is having learning difficulties at school. He has brief lapses of awareness with eyelid fluttering that occur every 5–10 min. Electroencephalogram (EEG) studies reveal brief 3-Hz spike and wave discharges appearing synchronously in all leads. Which drug would be effective in this child without the disadvantages of excessive sedation or tolerance development?

   • (A) Clonazepam

   • (B) Diazepam

   • (C) Ethosuximide

   • (D) Gabapentin

   • (E) Phenobarbital

2. Which statement concerning the proposed mechanisms of action of anticonvulsant drugs is inaccurate?

   • (A) Benzodiazepines facilitate GABA-mediated inhibitory actions

   • (B) Ethosuximide selectively blocks potassium ion (K⁺) channels in thalamic neurons

   • (C) Phenobarbital has multiple actions, including enhancement of the effects of GABA, antagonism of glutamate receptors, and blockade of sodium ion (Na⁺) channels

   • (D) Phenytoin prolongs the inactivated state of the Na⁺ channel

   • (E) Zonisamide blocks voltage-gated Na⁺ channels

3. Which drug used in management of seizure disorders is most likely to elevate the plasma concentration of other drugs administered concomitantly?

   • (A) Carbamazepine

   • (B) Clonazepam

   • (C) Phenobarbital

   • (D) Phenytoin

   • (E) Valproic acid

4. A young female patient suffers from absence seizures. Which of the following statements about her proposed drug management is NOT accurate?

   • (A) Ethosuximide and valproic acid are preferred drugs

   • (B) Gastrointestinal side effects are common with ethosuximide

   • (C) The patient should be examined every 2 or 3 mo for deep tendon reflex activity

   • (D) The use of valproic acid in pregnancy may cause congenital malformations

   • (E) Weight gain is common in patients on valproic acid

5. Which statement concerning the pharmacokinetics of antiseizure drugs is accurate?

   • (A) Administration of phenytoin to patients in methadone maintenance programs has led to symptoms of opioid overdose, including respiratory depression

   • (B) To reduce gastrointestinal toxicity, ethosuximide is usually taken twice a day

   • (C) At high doses, phenytoin elimination follows first-order kinetics

   • (D) The administration of phenytoin to patients in methadone maintenance programs has led to symptoms of opioid overdose, including respiratory depression

   • (E) Treatment with vigabatrin reduces the effectiveness of oral contraceptives

   • (F) Valproic acid may increase the activity of hepatic ALA synthase and the synthesis of porphyrins

6. With chronic use in seizure states, the adverse effects of this drug include coarsening of facial features, hirsutism, and gingival hyperplasia.

   • (A) Carbamazepine

   • (B) Ethosuximide

   • (C) Phenytoin

   • (D) Tiagabine

   • (E) Zonisamide

7. Abrupt withdrawal of antiseizure drugs can result in increases in seizure frequency and severity. Withdrawal is most easily accomplished if the patient is treated with

   • (A) Carbamazepine

   • (B) Clonazepam

   • (C) Ethosuximide

   • (D) Phenobarbital

   • (E) Phenytoin

8. The mechanism of antiseizure activity of carbamazepine is

   • (A) Block of sodium ion channels

   • (B) Block of calcium ion channels

   • (C) Facilitation of GABA actions on chloride ion channels

   • (D) Glutamate receptor antagonism

   • (E) Inhibition of GABA transaminase

9. Which statement about phenytoin is accurate?

   • (A) Displaces sulfonamides from plasma proteins

   • (B) Drug of choice in myoclonic seizures

   • (C) Half-life is increased if used with phenobarbital

   • (D) Isoniazid (INH) decreases steady-state blood levels of phenytoin

   • (E) Toxic effects may occur with only small increments in dose

10. A young male patient suffers from a seizure disorder characterized by tonic rigidity of the extremities followed in 15–30 s of tremor progressing to massive jerking of the body. This clonic phase lasts for 1 or 2 min, leaving the patient in a stuporous state. Of the following drugs, which is most suitable for long-term management of this patient?

    • (A) Clonazepam

    • (B) Ethosuximide

    • (C) Felbamate

    • (D) Phenytoin

    • (E) Pregabalin

1. This child suffers from absence seizures, and 2 of the drugs listed are effective in this seizure disorder. Clonazepam is effective but exerts troublesome CNS-depressant effects, and tolerance develops with chronic use. Ethosuximide is not excessively sedating, and tolerance does not develop to its antiseizure activity. Valproic acid (not listed) is also used in absence seizures. The answer is C.

2. The mechanism of action of phenylsuccinimides such as ethosuximide involves blockade of T-type Ca²⁺ channels in thalamic neurons. Ethosuximide does not block K⁺ channels, which in any case would be likely to result in an increase (rather than a decrease) in neuronal excitability. The answer is B.

3. With chronic use, carbamazepine, phenobarbital, and phenytoin can induce the synthesis of hepatic drug-metabolizing enzymes. This action may lead to a decrease in the plasma concentration of other drugs used concomitantly. Valproic acid, an inhibitor of drug metabolism, can increase the plasma levels of many drugs, including those used in seizure disorders such as carbamazepine, lamotrigine, phenobarbital, and phenytoin. Benzodiazepines (including clonazepam and diazepam) as well as gabapentin and vigabatrin have no major effects on the metabolism of other drugs. The answer is E.

4. Ethosuximide and valproic acid are preferred drugs in absence seizures because they cause minimal sedation. However, valproic acid causes gastrointestinal distress and weight gain and is potentially hepatotoxic. In addition, its use in pregnancy has been associated with teratogenicity (neural tube defects). Peripheral neuropathy, including diminished deep tendon reflexes in the lower extremities, occurs with the chronic use of phenytoin, not valproic acid. The answer is C.

5. The enzyme-inducing activity of phenytoin has led to symptoms of opioid withdrawal, presumably because of an increase in the rate of metabolism of methadone. Monitoring of plasma concentration of phenytoin may be critical is establishing and effective dosage because of nonlinear elimination kinetics at high doses. Valproic acid has no effect on porphyrin synthesis. Vigabatrin does not affect the metabolism of oral contraceptives. Twice-daily dosage of ethosuximide reduces the severity of adverse gastrointestinal effects. The answer is B.

6. Common adverse effects of phenytoin include nystagmus, diplopia, and ataxia. With chronic use, abnormalities of vitamin D metabolism, coarsening of facial features, gingival overgrowth and hirsutism may also occur. A major adverse effect of tiagabine and zonisamide is CNS depression. The answer is C.

7. Dose tapering is an important principle in antiseizure drug withdrawal. As a rule, withdrawal from drugs used for absence seizures such as ethosuximide is easier than withdrawal from drugs used for partial and tonic-clonic seizures. Withdrawal is most difficult in patients who have been treated with barbiturates and benzodiazepines. The answer is C.

8. The mechanism of action of carbamazepine is similar to that of phenytoin, blocking sodium ion channels. Ethosuximide blocks calcium channels; benzodiazepines and barbiturates facilitate the inhibitory actions of GABA; topiramate may block glutamate receptors; and vigabatrin inhibits GABA metabolism. The answer is A.

9. Sulfonamides can displace phenytoin from its binding sites, increasing the plasma-free fraction of the drug. Induction of liver drug-metabolizing enzymes by phenobarbital results in a decreased half-life of phenytoin, and isoniazid increases plasma levels of phenytoin by inhibiting its metabolism. Because of the dose-dependent elimination kinetics of phenytoin, some toxicity may occur with only small increments in dose. The answer is E.

10. This patient is suffering from generalized tonic-clonic seizures. For many years, the drugs of choice in this seizure disorder have been carbamazepine or phenytoin or valproic acid. However, many newer drugs are also effective, including gabapentin, lamotrigine, levetiracetem, topiramate, and zonisamide. Clonazepam and ethosuximide are not effective in this type of seizure disorder. Pregabalin is approved for use only in partial seizures. The answer is D.

1. Close similarities of structure and function exist between voltage-gated sodium channels in neurons and in cardiac cells (See Chapter 14). Drugs that exert antiseizure actions via their blockade of sodium channels in the CNS have the potential for a similar action in the heart. Delayed recovery of sodium channels from their inactivated state subsequently slows the rising phase of the action potential in Na⁺-dependent fibers and is characteristic of group I antiarrhythmic drugs. In theory, antiseizure drugs that block calcium ion channels might also have properties akin to those of group IV antiarrhythmic drugs, although neuronal calcium channels differ from those in the heart.

2. In practice, the only antiseizure drug that has been used in cardiac arrhythmias is phenytoin, which has characteristics similar to those of group IB antiarrhythmic drugs. Phenytoin has been used for arrhythmias resulting from cardiac glycoside overdose and for ventricular arrhythmias unresponsive to lidocaine.

When you complete this chapter, you should be able to:

• ❑ List the drugs of choice for partial seizures, generalized tonic-clonic seizures, absence and myoclonic seizures, and status epilepticus.

• ❑ Identify the mechanisms of antiseizure drug action at the levels of specific ion channels or neurotransmitter systems.

• ❑ Describe the main pharmacokinetic features, and list the adverse effects of carbamazepine, phenytoin, and valproic acid.

• ❑ Identify the distinctive toxicities of felbamate, lamotrigine, and topiramate.

• ❑ Indicate why benzodiazepines are rarely used in the chronic therapy of seizure states but are valuable in status epilepticus.