Antiseizure Drugs

Introduction Globally epilepsy is the third most common neurologic disorder after cerebrovascular and Alzheimer's disease Epilepsy affects 0.5-1% of the population

Introduction 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 The term seizure refers to a transient alteration of behaviour due to the disordered, synchronous, and rhythmic firing of populations of brain 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 In some subgroups, heredity Single gene defects, usually of an autosomal dominant nature involving genes coding voltage-gated ion channels or GABAA receptors has proved to be a predominant factor. This abnormal electrical activity may result in a variety of events, including loss of consciousness, abnormal movements, atypical or odd behaviour, 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 Partial seizures with no loss of consciousness are classified as simple PS Partial seizures with an alteration of consciousness are classified as complex PS Partial seizures may progress, becoming generalized tonic-clonic seizures

Partial seziures Simple partial The electrical discharge does not spread, and the patient is completely aware of the attack and can describe it in detail 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 20-60 seconds

Partial seziures Complex partial It has a localized onset, but the discharge becomes more widespread (usually bilateral) and almost always involves the limbic system 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 (automatism)

Partial seziures Complex partial After 30–120 seconds, the patient makes a gradual recovery to normal consciousness but may feel tired or ill for several hours after the attack

Generalized seziures 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 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 (petit mal): 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 without overt signs of neurologic deficit 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

Generalized seziures Atonic seizures: Are those in which the patient has sudden loss of postural tone. If standing, the patient falls suddenly to the floor and may be injured. If seated, the head and torso may suddenly drop forward Most often seen in children

Generalized seziures 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

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 (25-35% of 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

? 20 15 Number of Licensed Antiepileptic Drugs 10 5 1840 1860 1880 Retigabine ? Rufinamide Lacosamide Brivaracetam 20 Pregabalin Zonisamide Levetiracetam Oxcarbazepine Tiagabine 15 Fosphenytoin Topiramate Lamotrigine Gabapentin Number of Licensed Antiepileptic Drugs 10 Felbamate Sodium Valproate Carbamazepine Ethosuximide Benzodiazepines 5 Phenytoin Primidone Phenobarbital Bromide 1840 1860 1880 1900 1920 1940 1960 1980 2000 Calendar Year

Pregabalin Zonisamide Levetiracetam Oxcarbazepine Tiagabine Topiramate 20 Pregabalin 10 Zonisamide Levetiracetam Number of Licensed Antiepileptic Drugs Oxcarbazepine Tiagabine Topiramate Fosphenytoin 5 Lamotrigine Gabapentin Felbamate 1990 2000 Calendar Year

Antiseziure Drugs Mechanism of action 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

Voltage-gated sodium channel Open Inactivated Na+ Na+ X I I Carbamazepine Phenytoin Lamotrigine Valproate Na+ Na+ A = activation gate I = inactivation gate Goodman & Gilman’s. 12th ed. 2012

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 a valuable agent for the treatment of generalized tonic–clonic seizures and for the treatment of partial seizures with complex symptoms

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

Phenytoin Pharmacokinetics 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

Phenytoin Pharmacokinetics 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

A) Nonlinear Pharmacokinetics: (Michaelis-Menten type) Clearance decreases as dose increases A) Nonlinear B) Linear PHT C) Nonlinear pharmacokinetics: Ave. Serum Conc. (mg/L) C) Nonlinear Clearance increases with dose CBZ Daily Dose (mg/kg/day) Cloyd and Birnbaum, 1995

Daily Dose (mg/kg) as PHT Acid Phenytoin Concentration (mg/L) 8 6 4 2 10 20 30 40 50 60 Daily Dose (mg/kg) as PHT Acid Phenytoin Concentration (mg/L) Elderly (aged 65-79 years)1 Vmax=5.5 mg/kg/day Km=5.8 mg/L Nonelderly (aged 19-64 years)2 Vmax=8.45 mg/kg/day Km=6.25 mg/L 1. Bauer LA, Blouin RA. Clin Pharmacol Ther. 1982;31:301-304. 2. Cloyd J, et al. Presented at: 10th Epilepsy International Symposium; 1978; Vancouver, British Columbia.

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 PTN 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

Phenytoin Drug interactions 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. http://content.nejm.org/cgi/content/full/342/5/325

Phenytoin Adverse effects 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+

Phenytoin Adverse effects 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

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 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

Anti-seizure drug-induced reduction of current through T-type Ca2+ channels Agents: valporate and ethusximide They reduce the flow of Ca2+ through T-type Ca2+ channels thus reducing the pacemaker current that underlies the thalamic rhythm in spikes and waves seen in generalized absence seizures

X Ca+2 Ca+2 I Ca+2 Ethusuximide Valproate Goodman & Gilman’s. 12th ed. 2012

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)

Valproic Acid & Sodium Valproate Mechanism of action Like phenytoin and carbamazepine, it prolongs the recovery of voltage-activated Na+ channels from inactivation 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

Valproic Acid & Sodium Valproate 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

Valproic Acid & Sodium Valproate 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

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

Valproic Acid & Sodium Valproate 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

Valproic Acid & Sodium Valproate 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 by: Inhibiting the enzyme GABA transaminase, which is responsible for inactivating GABA: vigabatrin Inhibiting GABA uptake: tiagabine

Cl- Vigabatrin Valproate Tiagabine Ca2+ GABA Na+ metabolites GAT-1 Succinic Semialdehyde Valproate SSD metabolites Tiagabine GAT-1 GABA recognition site Cl- Barbiturates Benzodiazepine

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

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

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

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

Gabapentin Gabapentin is not metabolized and does not induce hepatic enzymes Absorption is nonlinear and dose- dependent at very high doses The drug is not bound to plasma proteins Drug-drug interactions are negligible Elimination is via renal mechanisms The half-life is relatively short (5-8 hrs)