Katzung & Trevor's Pharmacology Examination and Board Review, 9th Edition

Chapter 24. Antiseizure Drugs

Antiseizure Drugs: Introduction

Epilepsy comprises a group of chronic syndromes that involve the recurrence of seizures (ie, limited periods of abnormal discharge of cerebral neurons). Effective antiseizure drugs have, to varying degrees, selective depressant actions on such abnormal neuronal activity. However, they vary in terms of their mechanisms of action and in their effectiveness in specific seizure disorders.

High-Yield Terms to Learn

Seizures Finite episodes of brain dysfunction resulting from abnormal discharge of cerebral neurons Partial seizures, simple Consciousness preserved; manifested variously as convulsive jerking, paresthesias, psychic symptoms (altered sensory perception, illusions, hallucinations, affect changes), and autonomic dysfunction Partial seizures, complex Impaired consciousness that is preceded, accompanied, or followed by psychological symptoms Tonic-clonic seizures, generalized Tonic phase (less than 1 min) involves abrupt loss of consciousness, muscle rigidity, and respiration arrest; clonic phase (2-3 min) involves jerking of body muscles, with lip or tongue biting, and fecal and urinary incontinence; formerly called grand mal Absence seizures, generalized Impaired consciousness (often abrupt onset and brief), sometimes with automatisms, loss of postural tone, or enuresis; begin in childhood (formerly, petit mal) and usually cease by age 20 yrs Myoclonic seizures Single or multiple myoclonic muscle jerks Status epilepticus A series of seizures (usually tonic-clonic) without recovery of consciousness between attacks; it is a life-threatening emergency

Pharmacokinetics

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 that 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.

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 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.

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.

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.

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. Topiramate and zonisamide undergo both hepatic metabolism and renal elimination of intact drug. Lamotrigine is eliminated via hepatic glucuronidation.

Mechanisms of Action

The general effect of antiseizure drugs is to suppress repetitive action potentials in epileptic foci in the brain. Different mechanisms are involved in achieving this effect. In some drugs, many mechanisms may contribute to their antiseizure activities. Some of the recognized mechanisms are described next.

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.

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.

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 both for gabapentin and pregabalin, and it may be the primary action of the latter drugs.

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.

Skill Keeper: Antiarrhythmic Drug Actions

(See Chapter 14)

1. Which of the mechanisms of action of antiseizure drugs have theoretical implications regarding their activity in cardiac arrhythmias?

2. Can you recall any clinical uses of antiseizure drugs in the management of cardiac arrhythmias?

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

Clinical Uses

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.

Generalized Tonic-Clonic Seizures

Valproic acid, or carbamazepine, or 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.

Partial Seizures

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

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.

Myoclonic & 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.

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.

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.

Toxicity

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

TABLE 24-1 Adverse effects and complications of antiepileptic drugs.

Antiepileptic Drug Adverse Effects Benzodiazepines Sedation, tolerance, dependence Carbamazepine Diplopia, cognitive dysfunction, drowsiness, ataxia; rare occurrence of severe blood dyscrasias and Stevens-Johnson syndrome; teratogenic potential Ethosuximide Gastrointestinal distress, lethargy, headache, behavioral changes Felbamate Aplastic anemia, hepatic failure Gabapentin Dizziness, sedation, ataxia, nystagmus; does not affect drug metabolism (Pregabalin is similar) Lamotrigine Dizziness, ataxia, nausea, rash, rare Stevens-Johnson syndrome Levetiracetam Dizziness, sedation, weakness, irritability, hallucinations, and psychosis have occurred Oxcarbazepine Similar to carbamazepine, but hyponatremia is more common; unlike carbamazepine, does not induce drug metabolism Phenobarbital Sedation, cognitive dysfunction, tolerance, dependence, induction of hepatic drug metabolism; primidone is similar Phenytoin Nystagmus, diplopia, sedation, gingival hyperplasia, hirsutism, anemias, peripheral neuropathy, osteoporosis, induction of hepatic drug metabolism Tiagabine Abdominal pain, nausea, dizziness, tremor, asthenia; drug metabolism is not induced Topiramate Drowsiness, dizziness, ataxia, psychomotor slowing and memory impairment; paresthesias, weight loss, acute myopia Valproic acid Drowsiness, nausea, tremor, hair loss, weight gain, hepatotoxicity (infants), inhibition of hepatic drug metabolism Vigabatrin Sedation, dizziness, weight gain; visual field defects with long-term use, which may not be reversible Zonisamide Dizziness, confusion, agitation, diarrhea, weight loss, rash, Stevens-Johnson syndrome

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.

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.

Life-Threatening Toxicity

Fatal hepatotoxicity has occurred with valproic acid, with greatest risk to children younger than 2 yrs 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.

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.

Skill Keeper Answers: Antiarrhythmic Drug Actions

(See Chapter 14)

1. Close similarities of structure and function exist between voltage-gated sodium channels in neurons and in cardiac cells. 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.

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.

Checklist

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 and/or neurotransmitter systems.

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

 Identify the distinctive toxicities of new antiseizure drugs.

 Describe the important pharmacokinetic and pharmacodynamic considerations relevant to the long-term use of antiseizure drugs.

Drug Summary Table: Antiseizure Drugs

Subclass Mechanism of Action Clinical Applications Pharmacokinetics and Interactions Toxicities Cyclic ureides Phenytoin Blocks voltage-gated Na+ channels

Generalized tonic-clonic and partial seizures Varable absorption, dose-dependent elimination; protein binding; many drug interactions Ataxia,diplopia, gingival hyperplasia, hirsutism, neuropathy Phenobarbital Enhances GABA A receptor responses

Same as above Long half-life, inducer of P450; many interactions Sedation, ataxia Ethosuximide Decreases Ca2+ currents (T-type)

Absence seizures Long half-life GI distress, dizziness, headache Tricyclics Carbamazepine Blocks voltage-gated Na+ channels and decreases glutamate release

Generalized tonic-clonic and partial seizures Well absorbed, active metabolite; many drug interactions Ataxia, diplopia, headache, nausea Benzodiazepines Diazepam Enhance GABAA receptor responses

Status epilepticus See Chapter 22 Sedation Clonazepam Absence and myoclonic seizures, infantile spasms Similar to above Similar to above GABA derivatives Gabapentin Blocks Ca2+ channels

Generalized tonic-clonic and partial seizures Variable bioavailability; renal elimination Ataxia, dizziness, somnolence Pregabalin Same as above Partial seizures Renal elimination Same as above Vigabatrin Inhibits GABA transaminase Same as above Renal elimination Drowsiness, dizziness, psychosis, ocular effects Miscellaneous Valproate  Blocks high-frequency firing Generalized tonic-clonic, partial and myoclonic seizures Extensive protein binding and metabolism; many drug interactions Nausea, alopecia, weight gain, teratogenic Lamotrigine Blocks Na+ and Ca2+ channels, decreases glutamate

Generalized tonic-clonic, partial, myoclonic and absence seizures Not protein-bound, extensive metabolism; many drug interactions Dizzines, diplopia, headache, rash Leveliracetam Binds synaptic protein Generalized tonic-clonic and partial seizures Well absorbed, extensive metabolism; some drug interactions Dizziness, nervousness, depression, seizures Tiagabine Blocks GABA reuptake Partial seizures Extensive protein binding and metabolism; some drug interactions Dizziness, nervousness, depression, seizures Topiramate Unknown Generalized tonic-clonic, absence and partial seizures, migraine Both hepatic and renal clearance Sleepiness, cognitive slowing, confusion, paresthesias Zonisamide Blocks Na+ channels

Generalized tonic-clonic, partial and myoclonic seizures Both hepatic and renal clearance Sleepiness, cognitive slowing, poor concentration, paresthesias



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