Antiepileptic Drugs

Antiepileptic Drugs


Seizures are episodes of abnormal electrical activity in the brain that cause involuntary movements, sensations, or thoughts. Seizures can result from head trauma, stroke, brain tumors, hypoxia, hypoglycemia, fever, chronic alcohol withdrawal, and other conditions that alter neuronal function. Recurrent seizures that cannot be attributed to any proximal cause are seen in patients with epilepsy. In some patients, epilepsy appears to have a genetic basis. Environmental perturbations (e.g., intrauterine or neonatal complications) have also been implicated in the development of epilepsy. In the United States, epilepsy affects 1% to 2% of the population and is the second most common neurologic disease after stroke.

Classification of Seizures

The two main categories of seizures are partial (focal) seizures and generalized seizures (Table 20-1). A partial seizure originates in one cerebral hemisphere, and the patient does not lose consciousness during the seizure. A generalized seizure arises in both cerebral hemispheres and involves loss of consciousness. Seizures are accompanied by characteristic changes in the electroencephalogram (EEG), as shown in Figure 20-1. Most seizures are self-limited and last from about 10 seconds to 5 minutes. Some seizures are preceded by an aura, which is a sensation or mood that may help identify the anatomic location of the seizure focus.

About 60% of epileptic seizures are partial seizures. Electroencephalographic abnormalities are seen in one or more lobes of a cerebral hemisphere, and the patient may exhibit motor, sensory, and autonomic symptoms. In simple partial seizures, consciousness is not altered. In complex partial seizures, however, patients have an altered consciousness and exhibit repetitive behaviors (automatisms). Complex partial seizures often originate in the temporal lobe, in which case the disorder is called either temporal lobe epilepsy or psychomotor epilepsy. Some partial seizures progress along anatomic lines as the electrical discharges spread across the cortex. For example, a seizure may first involve the fingers, then the hand, and finally the entire arm. This is characteristic of jacksonian epilepsy, or “jacksonian march.” Partial seizures can also evolve into generalized seizures.

The two main types of generalized seizures are tonic-clonic seizures and absence seizures. Generalized tonic-clonic seizures, which were formerly called grand mal seizures, begin with a brief tonic phase that is followed by a clonic phase with muscle spasms lasting 3 to 5 minutes, and they conclude with a postictal period of drowsiness, confusion, and a glazed look in the eyes. Status epilepticus is a condition in which patients experience recurrent episodes of tonic-clonic seizures without regaining consciousness or normal muscle movement between episodes. Generalized absence seizures, or petit mal seizures, are characterized by abrupt loss of consciousness and decreased muscle tone, and they can include a mild clonic component, automatisms, and autonomic effects. On the EEG, generalized absence seizures exhibit a synchronous 3-Hz (three cycles per second) spike-and-dome pattern that usually lasts 10 to 15 seconds.

Less-common types of generalized seizures include myoclonic seizures and atonic seizures (see Table 20-1).

Neurobiology of Seizures

Epileptic seizures are caused by synchronous neuronal discharges within a particular group of neurons, or seizure focus, which is often located in the cerebral cortex but can be found in other areas of the brain. Once initiated, the abnormal discharges spread to other parts of the brain and produce abnormal movements, sensations, or thoughts. The neuronal mechanisms that initiate a seizure are not fully understood, but growing evidence indicates the involvement of excessive excitatory neurotransmission mediated by glutamate (Fig. 20-2). Investigators believe that excessive activation by glutamate of N-methyl-D-aspartate (NMDA) receptors displaces Mg2+ ions from the NMDA receptor–calcium ion channel and thereby facilitates calcium entry into neurons. Calcium contributes to the long-term potentiation of excitatory glutamate neurotransmission by activating the synthesis of nitric oxide.

Nitric oxide is a gas that can diffuse backward to the presynaptic neuron, where it facilitates glutamate release via stimulation of a G protein that activates the synthesis of cyclic guanosine monophosphate. These actions further increase NMDA receptor activation and calcium influx, which are believed to contribute to the depolarization shift that is observed in seizure foci. The depolarization shift consists of abnormally prolonged action potentials (depolarizations) that have spikelets. The shift recruits and synchronizes depolarizations by surrounding neurons and thereby initiates a seizure.

Several other mechanisms can be involved in seizures. One is the suppression of inhibitory neurotransmission of γ-aminobutyric acid (GABA), and another is an increase in calcium influx via T-type calcium channels in thalamic neurons.

Mechanisms of Antiepileptic Drugs

Antiepileptic drugs are believed to suppress the formation or spread of abnormal electrical discharges in the brain. As shown in Table 20-2, the currently available drugs accomplish these actions via three mechanisms: (1) inhibition of the sodium or calcium influx responsible for neuronal depolarization, (2) augmentation of inhibitory GABA neurotransmission, and (3) inhibition of excitatory glutamate neurotransmission.

Effects on Ion Channels

Under normal circumstances, voltage-sensitive (voltage-gated) sodium channels are rapidly opened when the neuronal membrane potential (voltage) reaches its threshold. This causes rapid depolarization of the membrane and the conduction of an action potential along the neuronal axon. When the action potential reaches the nerve terminal, it evokes the release of a neurotransmitter. After the neuronal membrane is depolarized, the sodium channel is inactivated by closure of the channel’s inactivation gate. The inactivation gate must be opened before the next action potential can occur.

Many antiepileptic drugs, including carbamazepine, lamotrigine, phenytoin, and topiramate, prolong the time that the sodium channel’s inactivation gate remains closed, and this delays the formation of the next action potential. These drugs bind to the channel when it is opened. Because rapidly firing neurons are opened a greater percentage of the time than are slowly firing neurons, the drugs exhibit use-dependent blockade. For this reason, the drugs suppress abnormal repetitive depolarizations in a seizure focus more than they suppress normal neuronal activity. By these actions, carbamazepine and other drugs prevent the spread of abnormal discharges in a seizure focus to other neurons.

A few drugs, such as ethosuximide and valproate, block T-type (low-threshold) calcium channels that are located in thalamic neurons and participate in the initiation of generalized absence seizures.

Effects on GABAergic Systems

Antiepileptic drugs facilitate GABA neurotransmission by various means. Benzodiazepines, such as clonazepam, and barbiturates, such as phenobarbital, enhance GABA activation of the GABAA receptor–chloride ion channel (see Chapter 19). Topiramate also activates the GABAA receptor. Gabapentin increases GABA release, whereas valproate inhibits GABA degradation. Drugs that augment GABA may serve to counteract the excessive excitatory neurotransmission responsible for initiating and spreading abnormal electrical discharges.

Treatment of Seizure Disorders

As indicated in the box at the beginning of this chapter, some of the listed drugs are active against only one or two types of seizures. In contrast, valproate has a broad spectrum of activity and is active against most types of seizures. The newer agents, such as lamotrigine, topiramate, tiagabine, levetiracetam, zonisamide, pregabalin, lacosamide, and ezogabine, are considered adjunct agents and are primarily used in combination with older drugs for the treatment of partial seizures. These newer agents are particularly useful because complex partial seizures are more resistant to treatment than are other types of seizures.

The pharmacologic properties of antiepileptic drugs are described in the following sections, whereas the mechanisms of action, adverse effects, contraindications, and drug interactions are given in Tables 20-2, 20-3, and 20-4. With regard to adverse effects, the results of recent U.S. Food and Drug Administration (FDA) studies showed an increased risk of suicidal thoughts and behavior with all antiepileptic agents.

TABLE 20-3

Adverse Effects, Contraindications, and Pregnancy Risk Data for Select Antiepileptic Drugs

Carbamazepine Aplastic anemia (rare); ataxia, drowsiness, and other symptoms of central nervous system (CNS) depression; gastrointestinal reactions; and nausea Hypersensitivity Category C; increased risk of birth defects, abnormal facial features, neural tube defects such as spina bifida, reduced head size, and other anomalies
Clonazepam Arrhythmia, CNS depression, drug dependence, hypotension, and mild respiratory depression Acute angle-closure glaucoma, hypersensitivity, and severe liver disease Category C; apnea in newborns, increased risk of birth defects
Clorazepate Confusion, drowsiness, drug tolerance, and lethargy Hypersensitivity Category D; increased risk of birth defects
Diazepam Same as clonazepam Same as clonazepam Category D; increased risk of birth defects
Ethosuximide Dizziness, drowsiness, gastric distress, lethargy, and nausea Hypersensitivity Category C
Felbamate Aplastic anemia, fatigue, gastrointestinal reactions, headache, hepatic toxicity, and insomnia Bone marrow depression, hepatic disease, and hypersensitivity Category C
Gabapentin Ataxia, dizziness, drowsiness, nystagmus, and tremor Hypersensitivity Category C
Lamotrigine Ataxia, diplopia, dizziness, drowsiness, headache, nausea, rash, and Stevens-Johnson syndrome
Risk of aseptic meningitis
Hypersensitivity: use cautiously in patients who are taking valproate or have hepatic or renal disease. Category C; may reduce folate levels
Levetiracetam Somnolence, asthenia (weakness), infection, and dizziness Hypersensitivity Category C; levetiracetam produced evidence of developmental toxicity at doses similar to or greater than human therapeutic doses
Lorazepam Same as clonazepam Same as clonazepam Category D; increased risk of birth defects
Phenobarbital Ataxia, cognitive impairment, dizziness, drowsiness, drug dependence, rash, and respiratory depression Hypersensitivity, porphyria, respiratory depression, and severe liver disease Category D; bleeding at birth, minor congenital defects
Phenytoin Cerebellar symptoms, gastrointestinal disturbances, gingival hyperplasia, hirsutism, megaloblastic anemia and other blood cell deficiencies, osteomalacia, and psychiatric changes Bradycardia, hypersensitivity, and severe atrioventricular block or sinoatrial dysfunction; Asians with polymorphism in human leukocyte antigen (HLA) allele at higher risk for skin reactions. Category D; may reduce folate levels, two to three times increased risk of birth defects, fetal hydantoin syndrome
Primidone Same as phenobarbital Hypersensitivity Category D
Tiagabine Dizziness, somnolence, nausea, nervousness, abdominal pain, and difficulty with concentration or attention Hypersensitivity Category C; adverse effects on embryo-fetal development, including teratogenic effects at doses greater than the human therapeutic dose
Topiramate Ataxia, dizziness, drowsiness, nystagmus, paresthesia, and psychomotor impairment Hypersensitivity; use cautiously during pregnancy, during lactation, or in the presence of hepatic or renal disease. Category D; recent data showed increase incidence of cleft palate.
Valproate Drowsiness, gastrointestinal disturbances, hepatic toxicity (rare), pancreatitis (rare), nausea, and weight gain Hepatic disease and hypersensitivity Category D; may reduce folate levels; teratogenic during the first trimester; neural tube defects such as spina bifida; decreased cognitive development
Vigabatrin Amnesia, blurred vision, blue-yellow color blindness, decreased vision or other vision changes, eye pains, increase in seizures (rare) Hypersensitivity Category C; studies in rabbits have shown that vigabatrin causes birth defects.
Zonisamide Somnolence, anorexia, dizziness, headache, nausea, and agitation or irritability; metabolic acidosis in younger patients Hypersensitivity Category C; teratogenic in mice, rats, and dogs and embryolethal in monkeys when administered during the period of organogenesis at zonisamide dosage and maternal plasma levels similar to or lower than therapeutic levels in humans
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Jul 23, 2016 | Posted by in PHARMACY | Comments Off on Antiepileptic Drugs

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