Antiseizure Drugs.

Antiseizure Drugs

Introduction Globally epilepsy is the third most common neurologic disorder after cerebrovascular and Alzheimer's disease The term seizure refers to a transient alteration of behaviour due to the disordered, synchronous, and rhythmic firing of populations of brain neurons Epilepsy is a heterogeneous symptom complex—a chronic disorder characterized by recurrent, periodic, and unpredictable seizures originating from several mechanisms that have in common the sudden, excessive, and synchronous discharge of cerebral neurons

Introduction Often, there is no recognisable cause, although it may develop after brain damage, such as trauma, stroke, infection or tumour growth, or other kinds of neurological disease, including various inherited neurological syndromes This abnormal electrical activity may result in a variety of events, including loss of consciousness, abnormal movements, atypical or odd behavior, or distorted perceptions that are of limited duration but recur if untreated

Introduction Seizures are thought to arise from the cerebral cortex, and not from other central nervous system (CNS) structures such as the thalamus, brainstem, or cerebellum The behavioral manifestations of a seizure are determined by the functions normally served by the cortical site at which the seizure arises

Introduction The clinical classification of epilepsy is done on the basis of the characteristics of the seizure rather than on the cause or underlying pathology The clinical classification of epilepsy defines two major categories, namely partial and generalised seizures Either form is classified as simple (if consciousness is not lost) or complex (if consciousness is lost)

Partial seziures Partial seizures are those in which the discharge begins locally and often remains localised 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 The symptoms depend on the brain region or regions involved, and include involuntary muscle contractions, abnormal sensory experiences or autonomic discharge, or effects on mood and behaviour

Partial seziures Consciousness is usually preserved. Partial seizures may progress, becoming generalized tonic-clonic seizures

Partial seziures Simple partial
Caused by a group of hyperactive neurons exhibiting abnormal electrical activity, which are confined to a single locus in the brain The electrical discharge does not spread, and the patient does not lose consciousness 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 lasting approximating seconds

Partial seziures Complex partial
Exhibit complex sensory hallucinations, mental distortion, and impaired consciousness lasting 30 seconds to 2 minutes with purposeless movements such as lip smacking or hand wringing Motor dysfunction may involve chewing movements, diarrhea, and/or urination

Generalized seziures Generalized seizures may begin locally, producing abnormal electrical discharges throughout both hemispheres of the brain Primary generalized seizures may be convulsive or nonconvulsive The patient usually has an immediate loss of consciousness

Generalized seziures Tonic-clonic:
Seizures result in loss of consciousness, followed by tonic (continuous contraction) and clonic (rapid contraction and relaxation) phases The seizure may be followed by a period of confusion and exhaustion due to the depletion of glucose and energy stores

Generalized seziures 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

Generalized seziures Myoclonic: These seizures consist of short episodes of muscle contractions that may reoccur for several minutes. They generally occur after wakening and exhibit as brief jerks of the limbs. Myoclonic seizures occur at any age but usually begin around puberty or early adulthood Febrile seizures: Young children may develop seizures with illness accompanied by high fever. The febrile seizures consist of generalized tonic-clonic convulsions of short duration and do not necessarily lead to a diagnosis of epilepsy

Generalized seziures Status epilepticus: two or more seizures recur without recovery of full consciousness between them. These may be partial or primary generalized, convulsive or nonconvulsive. Status epilepticus is life-threatening and requires emergency treatment

Seizure type Features Partial seizures Simple partial Diverse manifestations determined by the region of cortex activated by the seizure (e.g., if motor cortex representing left thumb, clonic jerking of left thumb results; if somatosensory cortex representing left thumb, paresthesia of left thumb results), lasting approximating seconds. Key feature is preservation of consciousness Complex partial Impaired consciousness lasting 30 seconds to 2 minutes, often associated with purposeless movements such as lip smacking or hand wringing Partial with secondarily generalized tonic-clonic seizure Simple or complex partial seizure evolves into a tonic-clonic seizure with loss of consciousness and sustained contractions (tonic) of muscles throughout the body followed by periods of muscle contraction alternating with periods of relaxation (clonic), typically lasting 1-2 minutes Generalized Seizures Absence seizure Abrupt onset of impaired consciousness associated with staring and cessation of ongoing activities typically lasting less than 30 seconds Myoclonic seizure A brief (perhaps a second), shocklike contraction of muscles that may be restricted to part of one extremity or may be generalized Tonic-clonic seizure As described earlier in table for partial with secondarily generalized tonic-clonic seizures except that it is not preceded by a partial seizure

Neural mechanisms of epliepsy
The underlying neuronal abnormality in epilepsy is poorly understood In general, excitation will naturally tend to spread throughout a network of interconnected neurons but is normally prevented from doing so by inhibitory mechanisms

The pivotal role of synapses in mediating communication among neurons in the mammalian brain suggested that defective synaptic function might lead to a seizure: a reduction of inhibitory synaptic activity or enhancement of excitatory synaptic activity might be expected to trigger a seizure The neurotransmitters mediating the bulk of synaptic transmission in the mammalian brain are γ-aminobutyric acid (GABA) and glutamate

Neurons from which the epileptic discharge originates display an unusual type of electrical behaviour termed the paroxysmal depolarising shift (PDS), during which the membrane potential suddenly decreases by about 30 mV and remains depolarised for up to a few seconds before returning to normal

Electrophysiological analyses of individual neurons during a partial seizure demonstrate that the neurons undergo depolarization and fire action potentials at high frequencies Inhibition of the high-frequency firing is thought to be mediated by reducing the ability of Na+ channels to recover from inactivation

Activation of the GABAA receptor inhibits the postsynaptic cell by increasing the inflow of Cl– ions into the cell, which tends to hyperpolarize the neuron Clinically relevant concentrations of both benzodiazepines and barbiturates enhance GABAA receptor–mediated inhibition through distinct actions on the GABAA receptor

In contrast to partial seizures, which arise from localized regions of the cerebral cortex, generalized-onset seizures arise from the reciprocal firing of the thalamus and cerebral cortex Thalamic neurons is pivotally involved in the generation of the 3-Hz spike-and-wave discharges is a particular type of Ca2+ current, the low threshold ("T-type") current

T-type Ca2+ channels are activated at a much more negative membrane potential "low threshold" than most other voltage-gated Ca2+ channels expressed in the brain T-type currents amplify thalamic membrane potential oscillations and bursts of action potentials in thalamic neurons are mediated by activation of the T-type currents

Antiseziure Drugs Current antiseizure drugs are palliative rather than curative; therapy is symptomatic in that available drugs inhibit seizures, but neither effective prophylaxis nor cure is available Choice of drug treatment is based on the classification of the seizures being treated, patient specific variables (for example, age, comorbid medical conditions, lifestyle, and other preferences), and characteristics of the drug, including cost and interactions with other medications

Antiseziure Drugs The ideal anti-seizure drug would suppress all seizures without causing any unwanted effects Unfortunately, the drugs used currently not only fail to control seizure activity in some patients, but frequently cause unwanted effects that range in severity from minimal impairment of the CNS to death from aplastic anemia or hepatic failure

Antiseziure Drugs An awareness of the antiepileptic drugs available, including their mechanisms of action, pharmacokinetics, potential for drug-drug interactions, and adverse effects, is essential for successful therapy Measurement of drug concentrations in plasma facilitates optimizing anti-seizure medication, especially when therapy is initiated, after dosage adjustments, in the event of therapeutic failure, when toxic effects appear, or when multiple-drug therapy is instituted

Antiseziure Drugs In newly diagnosed patients, monotherapy is instituted with a single agent until seizures are controlled or toxicity occurs If seizures are not controlled with the first drug, monotherapy with an alternate antiepileptic drug(s) However, multiple-drug therapy may be required, especially when two or more types of seizure occur in the same patient

Antiseziure Drugs Drugs that are effective in seizure reduction accomplish this by a variety of mechanisms: Enhancement of inhibitory GABAergic impulses Interference with excitatory glutamate transmission Modification of ionic conductances: Inhibition of sodium channel function Inhibition of calcium channel function

Inhibition of sodium channel function
Agents: phenytoin, carbamazepine, oxcarbazepine, topiramate, valproic acid, zonisamide, and lamotrigine The sodium channel exists in three main conformations: a resting (R) or activatable state, an open (0) or conducting state, and an inactive (I) or nonactivatable state The anticonvulsant drugs bind preferentially to the inactive form of the channel reducing the rate of recovery of Na+ channels from inactivation would limit the ability of a neuron to fire at high frequencies

Inhibition of sodium channel function
Inhibiting voltage-gated ion channels is a common mechanism of action among anti-seizure drugs with anti–partial-seizure activity

Phenytoin Phenytoin is the oldest nonsedative antiseizure drug
Phenytoin is the most important member of the hydantoin group of compounds, which are structurally related to the barbiturates Phenytoin is a valuable agent for the treatment of generalized tonic–clonic seizures and for the treatment of partial seizures with complex symptoms

Phenytoin Mechanism of action
Phenytoin blocks voltage-gated sodium channels by selectively binding to the channel in the inactive state and slowing its rate of recovery At concentrations 5- to 10-fold higher, multiple effects of phenytoin are evident, including reduction of spontaneous activity and enhancement of responses to GABA administration.

Phenytoin Pharmacokinetics
Phenytoin absorption is slow but usually complete, and it occurs primarily in the duodenum 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 Phenytoin sodium should never be given IM because it can cause tissue damage and necrosis Fosphenytoin is a prodrug and is rapidly converted to phenytoin in the blood that can be administered IM

The pharmacokinetic characteristics of phenytoin are influenced markedly by its binding to serum proteins, by the nonlinearity of its elimination kinetics, and by its metabolism by CYPs Phenytoin is extensively bound (about 90%) to serum proteins, mainly albumin The majority (95%) of phenytoin is metabolized principally in the hepatic endoplasmic reticulum by CYP2C9/10 and to a lesser extent CYP2C19

The elimination of phenytoin is dose-dependent: At very low blood levels, phenytoin metabolism follows first-order kinetics 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, the half-life of the drug increases markedly, & steady state is not achieved

Phenytoin Drug interactions
Drug interactions involving phenytoin are primarily related to protein binding or to metabolism Highly bound drugs, such as salicylates, valproate, phenylbutazone and sulfonamides, can competitively displace phenytoin from its binding site The protein binding of phenytoin is decreased in the presence of renal disease, neonate, in patients with hypoalbuminemia

Phenytoin Drug interactions
Phenytoin induces microsomal enzymes responsible for metabolism of a number of drugs (e.g. oral anticoagulants) Treatment with phenytoin can enhance the metabolism of oral contraceptives and lead to unplanned pregnancy The metabolism of phenytoin itself can be either enhanced or competitively inhibited by various drug metabolized by CYP2C9 or CYP2C10 Carbamazepine, which may enhance the metabolism of phenytoin, causes a well-documented decrease in phenytoin concentration Interaction between phenytoin and phenobarbital is variable

Phenytoin Adverse effects
Dose-depedent: usually result from overdosage Characterized by nystagmus, ataxia, vertigo, and diplopia (cerebellovestibular dysfunction) Higher doses lead to altered levels of consciousness and cognitive Gingival hyperplasia occurs in about 20% of all patients during chronic therapy and is probably the most common manifestation of phenytoin toxicity in children and young adolescents

Figure 1. A 17-year-old boy had generalized tonic–clonic seizures for four years. When the seizures began, a computed tomographic scan of his brain and an electroencephalogram were normal. Treatment with 300 mg of phenytoin per day was subsequently begun and continued unsupervised for a period of two years. Examination revealed coarsening of facial features and severe gingival hyperplasia (Panel A), brisk deep-tendon reflexes, and cerebellar ataxia. Withdrawal of phenytoin was followed by marked regression of the gingival hyperplasia within three months (Panel B); however, ataxia persisted.

Dose-depedent: Endocrine side effects: Inhibition of release of anti-diuretic hormone (ADH) in patients with inappropriate ADH secretion Hyperglycemia and glycosuria due to inhibition of insulin secretion Osteomalacia, with hypocalcemia and elevated alkaline phosphatase activity, due to both altered metabolism of vitamin D and the attendant inhibition of intestinal absorption of Ca2+

Idiosyncratic reactions (Hypersensitivity reactions): seen shortly after therapy has begun. rash in 2-5% of patients and occasionally more serious skin reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis Systemic lupus erythematosus and potentially fatal hepatic necrosis have been reported rarely

Phenytoin Teratogenicity
Phenytoin has been implicated in a specific syndrome called fetal hydantoin syndrome The symptoms of this disorder may include abnormalities of the skull and facial features, growth deficiencies, underdeveloped nails of the fingers and toes, and/or mild developmental delays

Carbamazepine It is one of the most widely used antiepileptic drugs, is chemically derived from the tricyclic antidepressant drugs The mechanism of action of carbamazepine appears to be similar to that of phenytoin Clinical Uses DOC for partial seizures, also used for generalized tonic-clonic seizures Peripheral neuropathy, e.g. trigeminal neuralgia In some patients with mania (bipolar disorder)

Carbamazepine Pharmacokinetics
Carbamazepine is absorbed slowly and erratically after oral administration The drug 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- 10,11-epoxide is a pharmacologically active metabolite with significant anticonvulsant effects of its own

Carbamazepine Drug interactions
Phenobarbital, phenytoin, and valproate may increase the metabolism of carbamazepine by inducing CYP3A4 Carbamazepine may enhance the metabolism of phenytoin Concurrent administration of carbamazepine may lower concentrations of valproate, lamotrigine, tiagabine, and topiramate The metabolism of carbamazepine may be inhibited by propoxyphene, erythromycin, cimetidine, fluoxetine, and isoniazid

Carbamazepine Side effects
Dose-dependent Diplopia and ataxia: most common Mild gastrointestinal upsets, unsteadiness, and, at much higher doses, drowsiness Hyponatremia and water intoxication

Carbamazepine Side effects
Dose-independent The most common idiosyncratic reaction is an erythematous skin rash Transient, mild leukopenia occurs in ~10% of patients during initiation of therapy and usually resolves within the first 4 months of continued treatment Idiosyncratic blood dyscrasias, including fatal cases of aplastic anemia and agranulocytosis Transient elevation of hepatic transaminases in plasma in 5-10% of patients

Oxcarbazepine It is a keto analog of carbamazepine
Oxcarbazepine is a prodrug that is almost immediately converted to its main active metabolite, a 10-monohydroxy derivative Its mechanism of action is similar to that of carbamazepine Oxcarbazepine is less potent than carbamazepine: clinical doses of oxcarbazepine may need to be 50% higher than those of carbamazepine to obtain equivalent seizure control

Oxcarbazepine Oxcarbazepine is a less potent enzyme inducer than carbamazepine Oxcarbazepine does not induce the hepatic enzymes involved in its own degradation Most adverse effects that occur with oxcarbazepine are similar in character to reactions reported with carbamazepine Hyponatremia may occur more commonly with oxcarbazepine than with carbamazepine

Lamotrigine Lamotrigine, like phenytoin, suppresses sustained rapid firing of neurons and produces a voltage- and use-dependent blockade of Na+ channels Lamotrigine also inhibits voltage-gated Ca2+ channels, particularly the N- and P/Q-type channels, which would account for its efficacy in primary generalized seizures in childhood, including absence attacks Lamotrigine also decreases the synaptic release of glutamate

Lamotrigine Clinical Uses
Partial seizures, absence and myoclonic seizures in children, and for seizure control in the Lennox-Gastaut syndrome Lamotrigine is also effective for bipolar disorder

Lamotrigine Lamotrigine is almost completely absorbed and has a
The drug has linear kinetics and is metabolized primarily by glucuronidation to the 2-N-glucuronide, which is excreted in the urine Lamotrigine has a half-life of approximately 24 hours Administration of phenytoin, carbamazepine, or phenobarbital reduces the t1/2 and plasma concentrations of lamotrigine Valproate causes a twofold increase in the drug's half-life

Lamotrigine The most common adverse effects are dizziness, ataxia, blurred or double vision, nausea, vomiting, and rash when lamotrigine was added to another anti-seizure drug A few cases of Stevens-Johnson syndrome and disseminated intravascular coagulation have been reported The incidence of serious rash in pediatric patients is higher than in the adult population

Topirmate Topiramate main mechanism of action nis likely to involve blocking of voltage-gated Na+ channels It also acts on high-voltage activated (L-type) Ca2+ channels It potentiates the inhibitory effect of GABA, acting at a site different from the benzodiazepine or barbiturate sites Topiramate also depresses the excitatory action of kainate on glutamate receptors

Topirmate Clinical uses: partial and generalized tonic-clonic seizures
Lennox-Gastaut syndrome Infantile spasms Absence seizures Treatment of migraine headaches

Topirmate Topiramate is well tolerated
The most common adverse effects are somnolence, fatigue, weight loss, and nervousness It can precipitate renal calculi, which is most likely due to inhibition of carbonic anhydrase Topiramate has been associated with cognitive impairment and patients may complain about a change in the taste of carbonated beverages

Zonisamide Zonisamide primary site of action appears to be the Na+ channel it also acts on T-type voltage-gated Ca2+ channels It 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 Zonisamide does not interact with other antiseizure drugs

Valproic Acid & Sodium Valproate
Mechanism of action Like phenytoin and carbamazepine, it prolongs the recovery of voltage-activated Na+ channels from inactivatioI It increases the levels of GABA in the brain: it stimulates the activity of the GABA synthetic enzyme, glutamic acid decarboxylase, and inhibit GABA degradative enzymes, GABA transaminase and succinic semialdehyde dehydrogenase Blockade of NMDA receptor-mediated excitation Reductions of T-type Ca2+ currents in the thalamus

Clinical uses Valproate is a broad-spectrum anti-seizure drug effective in the treatment of absence, myoclonic, partial, and tonic-clonic seizures Intravenous formulations are occasionally used to treat status epilepticus Management of bipolar disorder Migraine prophylaxis

Valproate is well absorbed after an oral dose, with bioavailability greater than 80% Food may delay absorption, and decreased toxicity may result if the drug is given after meals Valproic acid is 90% bound to plasma The vast majority of valproate (95%) undergoes hepatic metabolism, with < 5% excreted unchanged in urine Its hepatic metabolism occurs mainly by UGT enzymes (20%) and β-oxidation

Dose-dependent GIT: nausea, vomiting, abdominal pain, and heartburn Sedation if valproate is added to phenobarbital Weight gain Increased appetite Hair loss

Idiosyncratic Thrombocytopenia Acute pancreatitis Hyperammonemia Elevation of hepatic transaminases in plasma is observed in up to 40% of patients and often occurs asymptomatically during the first several months of therapy

Idiosyncratic Hepatotoxicity: Risk is greatest for patients under 2 years of age and for those taking multiple medications Most fatalities have occurred within 4 months after initiation of therapy Careful monitoring of liver function is recommended when starting the drug Hepatotoxicity is reversible in some cases if the drug is withdrawn

Valproic Acid & Sodium Valproate Teratogenicity
Valproic acid use during pregnancy can produce teratogenic effects : Neural tube defects: spina bifida Cardiovascular, orofacial, and digital abnormalities

Valproic Acid & Sodium Valproate D/D interactions
Valproate displaces phenytoin from plasma proteins Valproate inhibits the metabolism of several drugs that are substrates for CYP2C9, including phenytoin and phenobarbital, and UGT , including the metabolism of lamotrigine and lorazepam

Enhancement of inhibitory GABAergic impulses
Several antiepileptic drugs (e.g. phenobarbital and benzodiazepines) enhance the activation of GABAA receptors, thus facilitating the GABA-mediated opening of chloride channels Enhancement of the action of GABA as an inhibitory transmitter: Vigabatrin acts by inhibiting the enzyme GABA transaminase, which is responsible for inactivating GABA Tiagabine inhibits GABA uptake

Phenobarbital It has relatively low toxicity, is inexpensive, and is still one of the more effective and widely used drugs Phenobarbital, exert maximal anti-seizure action at doses below those required for hypnosis, which determines their clinical utility as anti-seizure agents

Phenobarbital Mechanism of Action
Phenobarbital increased the GABAA receptor–mediated current by increasing the duration of bursts of GABAA receptor–mediated currents At higher concentrations: blocks some Ca2+ currents (L-type & N-type), suppresses high-frequency repetitive firing in neurons through an action on Na+ conductance, and decrease glutamate release

Phenobarbital Pharmacokinetics
Oral absorption of phenobarbital is complete but somewhat slow Up to 25% of a dose is eliminated by pH-dependent renal excretion of the unchanged drug; the remainder is inactivated by hepatic microsomal enzymes, principally CYP2C9

Phenobarbital Anti-seizure properties
It is often tried for virtually every seizure type, especially when attacks are difficult to control It is useful in the treatment of partial seizures and generalized tonic-clonic seizures, although the drug

Phenobarbital D/D interactions
Interactions between phenobarbital and other drugs usually involve induction of the hepatic CYPs by phenobarbital The interaction between phenytoin and phenobarbital is variable Concentrations of phenobarbital in plasma may be elevated by as much as 40% during concurrent administration of valproic acid

Phenobarbital D/D interactions
Phenobarbital induces uridine diphosphate-glucuronosyltransferase (UGT) enzymes as well as the CYP2C and CYP3A subfamilies Drugs metabolized by these enzymes can be more rapidly degraded when co-administered with phenobarbital; importantly, oral contraceptives are metabolized by CYP3A4

Primidone A prodrug converted to phenobarbital & phenylethylmalonamide (PEMA): all three compounds are active anticonvulsants It is effective against partial seizures and more generalized tonic-clonic seizures The dose-related adverse effects of primidone are similar to those of its metabolite, phenobarbital, except that drowsiness occurs early in treatment and may be prominent if the initial dose is too large

Vigabatrin Vigabatrin is an irreversible inhibitor of GABA aminotransferase (GABA-T), the enzyme responsible for the degradation of GABA Vigabatrin may also inhibit the vesicular GABA transporter Vigabatrin is useful in the treatment of partial seizures and infantile spasms refractory to other treatments ADEs: drowsiness, dizziness, weight gain, & visual field defects in 30–50% of patients

Tiagabine Tiagabine is an inhibitor of GABA transporter, GAT-1, and thereby reduces GABA uptake into neurons and glia Tiagabine is indicated for the adjunctive treatment of partial seizures ADRs: dose-dependent nervousness, dizziness, tremor, difficulty in concentrating, and depression, and idiosyncratic rash

Benzodiazepines At therapeutically relevant concentrations, benzodiazepines act at subsets of GABAA receptors and increase the frequency, but not duration, of openings at GABA-activated Cl– channels At higher concentrations, diazepam and many other benzodiazepines can reduce sustained high-frequency firing of neurons, similar to the effects of phenytoin, carbamazepine, and valproate

Benzodiazepines Diazepam given intravenously or rectally is highly effective for stopping continuous seizure activity, especially generalized tonic-clonic status epilepticus. However, its short duration of action is a disadvantage Lorazepam is longer acting than diazepam in the treatment of status epilepticus and is sometime preferred

Benzodiazepines Clonazepam is useful in the therapy of absence seizures as well as myoclonic seizures in children. However, tolerance to its anti-seizure effects usually develops after 1-6 months of administration

Other antiepileptic drugs

Ethosumximide It reduces low threshold Ca2+ currents (T-type currents) in thalamic neurons Ethosuximide has a very narrow spectrum of clinical activity & is particularly effective against absence seizures Administration of ethosuximide with valproic acid results in a decrease in ethosuximide clearance and higher steady-state concentrations owing to inhibition of metabolism

Ethosumximide The most common dose-related side effects are GIT complaints (nausea, vomiting, and anorexia) and CNS effects (drowsiness, lethargy, euphoria, dizziness, headache, and hiccough)

Felbamate It produces a use-dependent block of the NMDA receptor, with selectivity for the NR1-2B subtype It also produces a barbiturate-like potentiation of GABAA receptor responses it is effective in some patients with partial seizures and it is effective in patients with Lennox-Gastaut syndrome However, it causes aplastic anemia and severe hepatitis at unexpectedly high rates and therefore has been relegated to the status of a third-line drug for refractory cases

Gabapentin & Pregabalin
Analogs of GABA Gabapentin and pregabalin bind avidly to the α2δ subunit of N-type Ca2+ channels, which decrease Ca2+ entry Are absorbed after oral administration and are not metabolized in humans, and are excreted unchanged, mainly in the urine They do not induce hepatic enzymes and drug-drug interactions are negligible

Gabapentin & Pregabalin
Gabapentin and pregabalin are effective for partial seizures, with and without secondary generalization, when used in addition to other anti-seizure drugs Most common adverse effects of somnolence, dizziness, ataxia, and fatigue

Levetiracetam Levetiracetam modifies the synaptic release of glutamate and GABA through an action on synaptic vesicle protein (SV2A) It neither induces nor is a high-affinity substrate for CYP isoforms or glucuronidation enzymes and thus is devoid of known interactions with other antiseizure drugs, oral contraceptives, or anticoagulants

Levetiracetam It is approved for adjunct therapy of partial seizures in adults and children for primary generalized tonic-clonic seizures and for the myoclonic seizures of juvenile myoclonic epilepsy Side effects most often reported include dizziness, sleep disturbances, headache, and weakness

Acetazolamide Carbonic anhydrase inhibitor Mechanism of action:
Mild acidosis in the brain may be the mechanism Diminishing the depolarizing action of bicarbonate ions moving out of neurons via GABA receptor ion channels Its usefulness is 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

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