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Drugs for Management of Epilepsy

MBCHB 3 2012

Idiopathic epilepsy
When no specific anatomic cause for the seizure, such as trauma or neoplasm, is evident, a patient may be diagnosed with idiopathic or cryptogenic (primary) epilepsy

These seizures may result from an inherited abnormality in the central nervous system (CNS)
Patients are treated chronically with antiseizure drugs or vagal nerve stimulation Most cases of epilepsy are idiopathic
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Symptomatic epilepsy
A number of causes, such as illicit drug use, tumors, head injury, hypoglycemia, meningeal infection, or rapid withdrawal of alcohol from an alcoholic, can precipitate seizures When two or more seizures occur, then the patient may be diagnosed with symptomatic (secondary) epilepsy Chronic treatment with antiseizure medications, vagal nerve stimulation and surgery are all appropriate treatments and may be used alone or in combination In some cases when the cause of a single seizure can be determined and corrected, therapy may not necessary. For example, a seizure that is caused by transient hypotension or is due to a drug reaction does not require chronic prophylactic therapy. In other situations, antiseizure drugs may be given until the primary cause of the seizures can be corrected
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Classification of Seizure Types

Partial seizures
Simple partial seizures Complex partial seizures Partial seizures secondarily generalized

Generalized seizures
Generalized tonic-clonic (grand mal) seizures Absence (petit mal) seizures Tonic seizures Atonic seizures Clonic and myoclonic seizures Infantile spasms
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Partial
Partial seizures involve only a portion of the brain, typically part of one lobe of one hemisphere. Consciousness is usually preserved Partial seizures may progress, becoming generalized tonic-clonic seizures
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Partial
Simple partial: These seizures are 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 Patient may show abnormal activity of a single limb or muscle group that is controlled by the region of the brain experiencing the disturbance Sensory distortions
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Partial
Complex partial: These seizures exhibit complex sensory hallucinations, mental distortion, and loss of consciousness
Motor dysfunction may involve chewing movements, diarrhea, and/or urination Consciousness is altered Simple partial seizure activity may spread and become complex and then spread to a secondarily generalized convulsion Partial seizures may occur at any age
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Generalized
Generalized seizures may begin locally, producing abnormal electrical discharges throughout both hemispheres of the brain, seizures may be convulsive or non-convulsive, and the patient usually has an immediate loss of consciousness 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 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. This seizure has a very distinct three-per-second spike and wave discharge seen on electroencephalogram
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Generalized
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. This may occur in siblings. The febrile seizures consist of generalized tonic-clonic convulsions of short duration and do not necessarily lead to a diagnosis of epilepsy Status epilepticus: In 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.

Primary Antiepileptic Drugs

Newer drugs have potential advantages in terms of pharmacokinetics, tolerability, and lesser risk for drugdrug interactions when compared with the older agents used to treat epilepsy older antiepileptics: phenobarbital, phenytoin, carbamazepine, ethosuximide, divalproex and valproic acid Second generation: gabapentin, lamotrigine, topiramate, levetiracetam, oxcarbazepine, zonisamide

Second-generation drugs not significantly better with respect to efficacy and adverse effects
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Mechanism of action of antiepileptic drugs

Blockade of voltage-gated channels (Na+ or Ca2+) Enhancement of inhibitory GABAergic impulses

Interference with excitatory glutamate transmission

Anti-epilepsy drugs suppress seizures but do not cure prevent or epilepsy
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Drugs Used in Partial Seizures & Generalized Tonic-Clonic Seizures

Phenytoin Carbamazepine Valproate Barbiturates Newer drugs

lamotrigine, gabapentin, oxcarbazepine, pregabalin, topiramate, vigabatrin
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PHENYTOIN
Phenytoin is the oldest non-sedative antiseizure drug It alters Na+, K+, and Ca2+ conductance, membrane potentials, and the concentrations of amino acids and the neurotransmitters norepinephrine, acetylcholine, and Gammaaminobutyric acid (GABA) Paradoxically causes excitation in some cerebral neurons
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PHENYTOIN
Clinical Use Phenytoin is effective against partial seizures and generalized tonic-clonic seizures Effective against attacks that are either primary or secondary to another seizure type.

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PHENYTOIN
Pharmacokinetics Complete absorption of phenytoin sodium from the gastrointestinal tract in most patients Time to peak may range from 3 to 12 hours Intramuscular injection is not reccommended, and some drug precipitation in the muscle occurs Phenytoin is highly bound to plasma proteins Drug concentration in cerebrospinal fluid is proportionate to the free plasma level. Phenytoin accumulates in brain, liver, muscle, and fat 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 The half-life of phenytoin varies from 12 to 36 hours 15

PHENYTOIN
Adverse Effects Nystagmus occurs early Loss of smooth extraocular pursuit movements Diplopia (may require dose adjustment) Ataxia (may require dose adjustment) Sedation Gingival hyperplasia and hirsutism Mild peripheral neuropathy Skin rash indicate hypersensitivity Fever Skin lesions may be severe and exfoliative

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CARBAMAZEPINE
Closely related to imipramine and other antidepressants, carbamazepine is a tricyclic compound effective in treatment of bipolar depression Initially used for the treatment of trigeminal neuralgia Mechanism of Action The mechanism of action of carbamazepine is similar to that of phenytoin Blocks sodium channels at therapeutic concentrations and inhibits high-frequency repetitive firing in neurons in culture It also acts presynaptically to decrease synaptic transmission
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CARBAMAZEPINE
Clinical Use drug of choice for both partial seizures and generalized tonic-clonic seizures Carbamazepine does not cause sedation at therapeutic doses Effective in patients with trigeminal neuralgia Carbamazepine is also useful in some patients with mania (bipolar disorder)
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CARBAMAZEPINE
Pharmacokinetics Variable absorption rates Peak levels are usually achieved 68 hours after administration Administration after meals slows absorption rate Approximately 70% bound to plasma proteins with no competitive drug displacement Induces microsomal enzymes Half-life of 36 hours, reduces to 812 after continued dosing
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CARBAMAZEPINE
Drug Interactions Drug interactions are to its enzyme-inducing properties The increased metabolic capacity of the hepatic enzymes may cause a reduction in steady-state carbamazepine concentrations Increased rate of metabolism of other drugs, eg, primidone, phenytoin, ethosuximide, valproic acid, and clonazepam Valproic acid may inhibit carbamazepine clearance and increase steady-state carbamazepine blood levels
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CARBAMAZEPINE
Adverse Effects Diplopia Ataxia Mild gastrointestinal upsets Unsteadiness Drowsiness at higher doses Hyponatremia and water intoxication Erythematous skin rash
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PHENOBARBITONE
Mechanism of Action Mechanism of action of phenobarbitone is unknown Enhancement of inhibitory processes and diminution of excitatory transmission may be action associated with antiseizure activity May selectively suppress abnormal neurons, inhibiting the spread and suppressing firing from the foci
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PHENOBARBITAL
Clinical Use Treatment of partial seizures and generalized tonic-clonic seizures Can be added for other seizure types if the attacks are not well controlled Not effective in generalized seizures such as absence, atonic attacks, and infantile spasms

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LAMOTRIGINE
Mechanism of Action Suppresses sustained rapid firing of neurons and produces a voltage- and use-dependent inactivation of sodium channels Lamotrigine also decreases the synaptic release of glutamate

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LAMOTRIGINE
Clinical Use Monotherapy for partial seizures Bipolar disorder Adverse effects Dizziness, headache Diplopia, nausea, somnolence Skin rash
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SODIUM VALPROATE
Clinical Use Effective against absence seizures and is often preferred when the patient has concomitant generalized tonic-clonic attacks Can be used to control myoclonic seizures The drug is effective in generalized tonicclonic seizures, especially those that are primarily generalized Other uses of valproate include management of bipolar disorder and migraine prophylaxis
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SODIUM VALPROATE
Adverse Effects Nausea Vomiting Abdominal pain and heartburn Weight gain, increased appetite Hair loss Hepatotoxicity spina bifida in the offspring of women who took valproate during pregnancy
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Diazepam
Potentiates GABAA responses Well absorbed orally Management of status epilepticus, seizure clusters Adverse Effects: Sedation

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Clonazepam
>80% bioavailability extensively metabolized but no active metabolites Half life of 2050 h Management of absence seizures, myoclonic seizures, infantile spasms Adverse effects similar to diazepam

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Gabapentin
Decreases excitatory transmission by acting on VG Ca2+ channels presynaptically( 2 subunit) Bioavailability 50%, and a half life of 68 h Management of generalized tonic-clonic seizures, partial seizures, generalized seizures Adverse Effects: Somnolence, dizziness, ataxia
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Vigabatrin
Irreversibly inhibits GABA-transaminase 70% bioavailabilty with a half life of 57 h Management of partial seizures, infantile spasms Adverse Effects: Drowsiness, dizziness, psychosis, visual field loss
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Epilepsy in Pregnancy
All women should be on high doses of folic acid prior to conception Barbiturates should be avoided When seizures are controlled, maintenance medication should be reduced, if possible, to the lowest dose that provides control The frequency and severity of seizures may change during pregnancy. Close monitoring is important TERATOGENICITY Phenytoin, phenobarbital and carbamazepine may cause fetal hydantoin syndrome Valproate may cause spina bifida (risk 1%-2%)
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