Drugs for Epilepsy
Approximately 10% of the population will have at least one seizure in their lifetime.Epilepsy is a heterogeneous symptom complex—a chronic disorder characterized by recurrent seizures.
Seizures are finite episodes of brain dysfunction resulting from abnormal discharge of cerebral neurons.
The causes of seizures are many and include the full range of neurologic diseases—from infection to neoplasm and head injury.
Classification Of Seizures
Seizures have been classified into two broad groups: focal( partial) and generalized.
Focal: Focal seizures involve only a portion of the brain, typically part of one lobe of one hemisphere. The symptoms of each seizure type depend on the site of neuronal discharge and on the extent to which the electrical activity spreads to other neurons in the brain. Focal seizures may progress to become generalized tonic–clonic seizures.
Simple partial: These seizures are caused by a group of hyperactive neurons exhibiting abnormal electrical activity and are confined to a single locus in the brain. The electrical discharge does not spread, and the patient does not lose consciousness or awareness. The patient often exhibits abnormal activity of a single limb or muscle group that is controlled by the region of the brain experiencing the disturbance.
Complex partial: These seizures exhibit complex sensory hallucinations and mental distortion. Motor dysfunction may involve chewing movements, diarrhea, and/or urination. Consciousnessnis altered.
Generalized: Generalized seizures may begin locally and then progress to include abnormal electrical discharges throughout both hemispheres of the brain.
Tonic–clonic: These seizures result in loss of consciousness, followed by tonic (continuous contraction) and clonic (rapid contraction and relaxation) phases.
Absence: These seizures involve a brief, abrupt, and self limiting loss of consciousness. The onset generally occurs in patients at 3 to 5 years of age and lasts until puberty or beyond. The patient stares and exhibits rapid eye-blinking, which lasts for 3 to 5 seconds.
Myoclonic: These seizures consist of short episodes of muscle contractions that may recur for several minutes.
Clonic: These seizures consist of short episodes of muscle contractions that may closely resemble myoclonic seizures. Consciousness is more impaired with clonic seizures as compared to myoclonic.
Tonic: These seizures involve increased tone in the extension muscles and are generally less than 60 seconds long.
Atonic: These seizures are also known as drop attacks and are characterized by a sudden loss of muscle tone.
Drugs Used In Partial Seizures & Generalized Tonic-Clonic Seizures
The classic major drugs for partial and generalized tonic-clonic seizures are phenytoin (and congeners), carbamazepine, valproate, and the barbiturates. While the newer drugs involve eslicarbazepine, lamotrigine, levetiracetam, gabapentin, oxcarbazepine, pregabalin, retigabine, topiramate, vigabatrin, lacosamide, and zonisamide
Phenytoin :Phenytoin is the oldest nonsedative antiseizure drug, introduced in 1938
Mechanism of Action:
Blocks voltage-gated sodium channels by selectively binding to the channel in the inactive state and slowing its rate of recovery so that phenytoin blocks sustained high-frequency repetitive firing of action potentials.
phenytoin inhibit a variety of calcium-induced secretory processes, including release of hormones and neurotransmitters, this occur as a result of phenytoin ability to reduce calcium permeability, with inhibition of calcium influx across the cell membrane
Clinical Uses:
Phenytoin is effective against partial seizures and generalized tonic-clonic seizures.
Pharmacokinetics
Absorption of phenytoin is highly dependent on the formulation of the dosage form. Particle size and pharmaceutical additives affect both the rate and the extent of absorption.
Absorption of phenytoin sodium from the gastrointestinal tract is nearly complete in most patients, although the time to peak may range from 3 to 12 hours.
Absorption after intramuscular injection is unpredictable. In contrast, fosphenytoin, a more soluble phosphate prodrug of phenytoin, is well absorbed after intramuscular administration.
Phenytoin is highly bound to plasma proteins.
Phenytoin is metabolized to inactive metabolites that are excreted in the urine.
The elimination of phenytoin is dose-dependent. At very 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 phenytoin is approached. Further increases in dosage, though relatively small, may produce very large changes in phenytoin concentrations
Toxicity
Dose-related adverse effects caused by phenytoin are often similar to those caused by other antiseizure drugs in this group,
Nystagmus occurs early
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;
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,
MEPHENYTOIN, & ETHOTOIN
mephenytoin and ethotoin, like phenytoin, appear to be most effective against generalized tonic-clonic seizures and partial seizures.
Ethotoin may be recommended for patients who are hypersensitive to phenytoin, but larger doses are required.
The adverse effects and toxicity are generally less severe than those associated with phenytoin, but the drug appears to be less effective.
Both ethotoin and mephenytoin share with phenytoin the property of saturable metabolism within the therapeutic dosage range. Careful monitoring of the patient during dosage alterations with either drug is essential.
CARBAMAZEPINE
Closely related to imipramine and other antidepressants, carbamazepine is a tricyclic compound effective in treatment of bipolar depression. It was initially marketed for the treatment of trigeminal neuralgia but has proved useful for epilepsy as well.
Mechanism of Action
Carbamazepine, like phenytoin, blocks Na+ channels at therapeutic concentrations and inhibits high-frequency repetitive firing in neurons in culture. It also acts presynaptically to decrease synaptic transmission. Potentiation of a voltage-gated K+ current has also been described.
Clinical Uses
Although carbamazepine has long been considered a drug of choice for both partial seizures and generalized tonic-clonic seizures, some of the newer antiseizure drugs are beginning to displace it from this role.
The drug is also very effective in some patients with trigeminal neuralgia.
Carbamazepine is also useful for controlling mania in some patients with bipolar disorder.
Pharmacokinetics
The rate of absorption of carbamazepine varies widely among patients, although almost complete absorption apparently occurs in all.
Peak levels are usually achieved 6–8 hours after administration.
Slowing absorption by giving the drug after meals helps the patient tolerate larger total daily doses.
Carbamazepine has a notable ability to induce microsomal enzymes. 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 also alters the clearance of other drugs eg, primidone, phenytoin, ethosuximide, valproic acid, and clonazepam
Carbamazepine is completely metabolized in humans to several derivatives.
Toxicity
The most common dose-related adverse effects of carbamazepine are diplopia and ataxia.
Other dose-related complaints include mild gastrointestinal upsets, unsteadiness, and, at much higher doses, drowsiness.
Hyponatremia and water intoxication have occasionally occurred and may be dose related.
idiosyncratic blood dyscrasias, including fatal cases of aplastic anemia and agranulocytosis.
The most common idiosyncratic reaction is an erythematous skin rash
OXCARBAZEPINE
Oxcarbazepine is closely related to carbamazepine and is useful in the same seizure types, but it may have an improved toxicity profile. Oxcarbazepine is less potent than carbamazepine
ESLICARBAZINE
Eslicarbazepine acetate (ESL) is a prodrug that has been approved as adjunctive therapy in adults with partial-onset seizures, with or without secondary generalization. The mechanism of action of carbamazepine, oxcarbazepine, and ESL appears to be the same, ie, blocking of voltage-gated Na+ channels. Clinically, the drug is similar to carbamazepine and oxcarbazepine in its spectrum of action
PHENOBARBITAL
Clinical Uses
Phenobarbital is useful in the treatment of partial seizures and generalized tonic-clonic seizures, although the drug is often tried for virtually every seizure type, especially when attacks are difficult to control.
There is little evidence for its effectiveness in generalized seizures such as absence, atonic attacks, and infantile spasms; it may worsen certain patients with these seizure types.
PRIMIDONE
primidone was metabolized to phenobarbital and phenylethylmalonamide (PEMA). All three compounds are active anticonvulsants
Although primidone is converted to phenobarbital, the mechanism of action of primidone itself may be more like that of phenytoin
Primidone, like its metabolites, is effective against partial seizures and generalized tonic-clonic seizures and may be more effective than phenobarbital
FELBAMATE
Felbamate appears to have multiple mechanisms of action. It produces a use-dependent block of the NMDA receptor; It also produces a barbiturate-like potentiation of GABAA receptor responses.
Although it is effective in some patients with partial seizures, the drug causes aplastic anemia and severe hepatitis at unexpectedly high rates and has been relegated to the status of a third-line drug for refractory cases.
Felbamate has a half-life of 20 hours
metabolized by hydroxylation and conjugation
A significant percentage of the drug is excreted unchanged in the urine. When added to treatment with other antiseizure drugs, felbamate increases plasma phenytoin and valproic acid levels but decreases levels of carbamazepine
GABAPENTIN & PREGABALIN
Gabapentin is an amino acid, an analog of GABA, that is effective against partial seizures. Pregabalin is another GABA analog, closely related to gabapentin, and has been approved for both antiseizure activity and for its analgesic properties
Mechanism of Action
In spite of their close structural resemblance to GABA, gabapentin and pregabalin do not act directly on GABA receptors.
They may, however, modify the synaptic or nonsynaptic release of GABA. An increase in brain GABA concentration is observed in patients receiving gabapentin.
Gabapentin and pregabalin bind avidly to the α2δ subunit of voltage-gated N-type Ca2+ channels. This appears to underlie the main mechanism of action, which is decreasing Ca2+ entry, with a predominant effect on presynaptic channels. A decrease in the synaptic release of glutamate provides the antiepileptic effect.
Clinical Uses
Gabapentin is effective as an adjunct against partial seizures and generalized tonic-clonic seizures at dosages that range up to 2400 mg/d
Gabapentin has also been promoted for the treatment of neuropathic pain and is now indicated for postherpetic neuralgia in adults at doses of 1800 mg and above.
Pregabalin is approved for the adjunctive treatment of partial seizures, with or without secondary generalization
Pregabalin is also approved for use in neuropathic pain, including painful diabetic peripheral neuropathy and postherpetic neuralgia. It is the first drug in the USA approved for fibromyalgia.
It is also approved for generalized anxiety disorder.
LACOSAMIDE
Lacosamide is an amino acid-related compound that has been studied in both pain syndromes and partial seizures.
Lacosamide enhances slow inactivation of voltage-gated Na+ channels (in contrast to the prolongation of fast inactivation shown by other AEDs).
Lacosamide is approved as adjunctive therapy in the treatment of partial-onset seizures with or without secondary generalization in patients with epilepsy who are age 16–17 years and older.
Adverse effects were dizziness, headache, nausea, and diplopia.
LAMOTRIGINE
Lamotrigine, like phenytoin, suppresses sustained rapid firing of neurons and produces a voltage- and use-dependent blockade of Na+ channels. This action probably explains lamotrigine’s efficacy in focal epilepsy.
It appears likely that lamotrigine also inhibits voltage-gated Ca2+ channels, which would account for its efficacy in primary generalized seizures in childhood, including absence attacks.
Lamotrigine also decreases the synaptic release of glutamate.
Clinical Uses
It is effective as monotherapy for partial seizures, and lamotrigine is now widely prescribed for this indication.
The drug is also active against absence and myoclonic seizures in children and is approved for seizure control in the Lennox-Gastaut syndrome. Lamotrigine is also effective for bipolar disorder.
Adverse effects
Dizziness, headache, diplopia, nausea, somnolence, and skin rash. The rash is considered a typical hypersensitivity reaction.
LEVETIRACETAM.
Levetiracetam modifies the synaptic release of glutamate and GABA through an action on vesicular function.
Levetiracetam inhibits N-type calcium channels and inhibits calcium release from intracellular stores.
Levetiracetam is marketed for the adjunctive treatment of partial seizures in adults and children for primary generalized tonic-clonic seizures and for the myoclonic seizures of juvenile myoclonic epilepsy.
Adverse effects include somnolence, asthenia, ataxia, and dizziness.
RETIGABINE (EZOGABINE)
Retigabine is approved for the adjunctive treatment of partial-onset seizures in adults.
It is a potassium-channel facilitator and unique in its mechanism of action.
Absorption is not affected by food and kinetics are linear; drug interactions are minimal.
adverse effects are dose-related and include dizziness, somnolence, blurred vision, confusion, and dysarthria. Bladder dysfunction, mostly mild and related to the drug’s mechanism of action, was observed in 8-9% of patients
TIAGABINE
Tiagabine is an inhibitor of GABA uptake in both neurons and glia. It prolongs the inhibitory action of synaptically released GABA
Tiagabine is indicated for the adjunctive treatment of partial seizures
Minor adverse events are dose related and include nervousness, dizziness, tremor, difficulty in concentrating, and depression. Excessive confusion, somnolence, or ataxia may require discontinuation.
TOPIRAMATE
Mechanism of Action
Topiramate block voltage-gated Na+ channels.
It also acts on high-voltage activated (L-type) Ca2+ channels.
Topiramate potentiates the inhibitory effect of GABA, acting at a site different from the benzodiazepine or barbiturate sites.
It also depresses the excitatory action of kainate on glutamate receptors.
Clinical Uses and adverse effect
topiramate as monotherapy demonstrated efficacy against partial and generalized tonic-clonic seizures.
The drug is also approved for the Lennox-Gastaut syndrome, and may be effective in infantile spasms and even absence seizures.
Topiramate is also approved for the treatment of migraine headaches.
dose-related adverse effects occur most frequently in the first 4 weeks and include somnolence, fatigue, dizziness, cognitive slowing, paresthesias, nervousness, and confusion.
VIGABATRIN
Vigabatrin is an irreversible inhibitor of GABA aminotransferase (GABA-T), the enzyme responsible for the degradation of GABA. It may also inhibit the vesicular GABA transporter.
Vigabatrin is useful in the treatment of partial seizures and infantile spasms. The half-life is approximately 6–8 hours, but considerable evidence suggests that the pharmacodynamic activity of the drug is more prolonged and not well correlated with the plasma half-life.
Typical toxicities include drowsiness, dizziness, and weight gain.
long-term therapy with vigabatrin has been associated with development of peripheral visual field defects in 30–50% of patients.
ZONISAMIDE
Zonisamide is a sulfonamide derivative. Its primary site of action appears to be the Na+ channel; it also acts on T-type voltage-gated Ca2+ channels. The drug is effective against partial and generalized tonic-clonic seizures and may also be useful against infantile spasms and certain myoclonias.
Adverse effects include drowsiness, cognitive impairment, and potentially serious skin rashes
DRUGS USED IN GENERALIZED SEIZURES
ETHOSUXIMIDE
Ethosuximide has an important effect on Ca2+ currents, reducing the low-threshold (T-type) current.
ethosuximide is particularly effective against absence seizures
Data continue to show that ethosuximide and valproate are the drugs of choice for absence seizures and are more effective than lamotrigine.
The most common dose-related adverse effect of ethosuximide is gastric distress, including pain, nausea, and vomiting.
Other dose-related adverse effects are transient lethargy or fatigue and, much less commonly, headache, dizziness, hiccup, and euphoria.
VALPROIC ACID & SODIUM VALPROATE
Like phenytoin and carbamazepine, valproate blocks sustained high-frequency repetitive firing of neurons in culture at therapeutically relevant concentrations.
Blockade of NMDA receptor-mediated excitation may also be important.
Valproate is very effective against absence seizures and is often preferred to ethosuximide when the patient has concomitant generalized tonic-clonic attacks.
Valproate is unique in its ability to control certain types of myoclonic seizures; in some cases the effect is very dramatic.
The drug is effective in tonic-clonic seizures, especially those that are primarily generalized.
Other uses of valproate include management of bipolar disorder and migraine prophylaxis.
Food may delay absorption, and decreased toxicity may result if the drug is given after meals.
Valproic acid is 90% bound to plasma proteins
The most common dose-related adverse effects of valproate are nausea, vomiting, and other gastrointestinal complaints such as abdominal pain and heartburn
OTHER DRUGS USED IN MANAGEMENT OF EPILEPSY
Some drugs not classifiable by application to seizure type are discussed in this section.
BENZODIAZEPINES
Six benzodiazepines play prominent roles in the therapy of epilepsy
Diazepam given intravenously or rectally is highly effective for stopping continuous seizure activity, especially generalized tonic-clonic status epilepticus
Lorazepam appears in some studies to be more effective and longer acting than diazepam in the treatment of status epilepticus and is preferred by some experts.
Clonazepam is a long-acting drug with documented efficacy against absence seizures; on a milligram basis, it is one of the most potent antiseizure agents known. It is also effective in some cases of myoclonic seizures and has been tried in infantile spasms.
Nitrazepam is used for infantile spasms and myoclonic seizures. It is less potent than clonazepam
Clorazepate dipotassium is approved as an adjunct to treatment of complex partial seizures in adults.
ACETAZOLAMIDE
Acetazolamide is a diuretic whose main action is the inhibition of carbonic anhydrase
Mild acidosis in the brain may be the mechanism by which the drug exerts its antiseizure activity
Acetazolamide has been used for all types of seizures but is severely limited by the rapid development of tolerance, with return of seizures usually within a few weeks.
The drug may have a special role in epileptic women who experience seizure exacerbations at the time of menses; seizure control may be improved and tolerance may not develop because the drug is not administered continuously.