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 20-60 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

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

Neural mechanisms of epliepsy • 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

Neural mechanisms of epliepsy • 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

Neural mechanisms of epliepsy • 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

Neural mechanisms of epliepsy • 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

Neural mechanisms of epliepsy • 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

Neural mechanisms of epliepsy • 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

PhenytoinMechanism 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

PhenytoinPharmacokinetics • 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

PhenytoinPharmacokinetics • 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

PhenytoinPharmacokinetics • 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

PhenytoinDrug 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

PhenytoinDrug 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

PhenytoinAdverse 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

PhenytoinAdverse effects • Dose-depedent:Endocrine side effects: • Inhibition of release of anti-diuretic hormone (ADH) in patients with inappropriate ADH secretion • Hyperglycemiaand 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+

PhenytoinAdverse 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

PhenytoinTeratogenicity • 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)

CarbamazepinePharmacokinetics • 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

CarbamazepineDrug 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

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

CarbamazepineSide 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

Antiseizure Drugs