Abnormal and excessive electrical discharges in a group of nerve cells affecting brain function Abnormality in neuronal plasma membranes results in increased permeability and responsiveness to stimuli Diagnosed by clinical signs and symptoms of seizure activity and by abnormal brain wave patterns on the EEG patterns on the EEG 3
1-2 % of the world's population has epilepsy, the second most common neurologic disorder after stroke. Epilepsy is a chronic disorder characterized by recurrent seizures. Seizures are finite episodes of brain dysfunction resulting from abnormal discharge of cerebral neurons because of: All neurologic diseases Infection Neoplasm Head injury Heredity
Hypoglycemia, fever, electrolyte imbalances, overdoses of drugs, withdrawal of alcohol or sedative-hypnotic drugs or as a result of epilepsy Cause is idiopathic in 60-80% of children Seizures occur in a chronic, recurrent pattern 8
Partial seizures Simple partial Complex partial Secondarily generalized Generalized seizures Generalized tonic-clonic (grand mal) Generalized tonic-clonic (grand mal) Generalized tonic-clonic (grand mal) Absence (petit mal) Absence (petit mal) Absence (petit mal) Tonic Atonic Clonic and myoclonic Infantile spasms Minimal spread of the abnormal discharge Tonic rigidity of all extremities for seconds. The clonic phase with massive jerking of the body slows over seconds Clonic jerking of the eyelids or extremities and automatisms may occur. involves the limbic system with automatisms limbic systemlimbic system
Tonic-clonic. Tonic phase is sustained skeletal contraction, clonic phase is rapid and rhythmic jerking movements. Absence—abrupt alterations in consciousness that last only seconds Status Epilepticus—life-threatening, generalized tonic-clonic convulsions lasting for several minutes or at close intervals. Hypotension, hypoxia and cardiac dysrhythmias may occur. 13
14 Antiepileptic drugs
A drug which decreases the frequency and/or severity of seizures in people with epilepsy Treats the symptom of seizures, not the underlying epileptic condition Goal—maximize quality of life by minimizing seizures and adverse drug effects 15
Drugs act by one of the three mechanisms:three mechanisms Enhancement of gabaergic (inhibitory) transmission Diminution of excitatory (glutamatergic) transmission Modification of ionic conductances (Na + or Ca 2+ ) Drugs used in partial & generalized tonic-clonic seizures are the same. Refractory cases may respond to vagus-nerve stimulation (VNS) for partial seizures.
First effective antiseizure agent Mechanism: GABA A receptor mediated Continued use – sedation effect lost but not anticonvulsant action Raises seizure threshold and limits spread Phenobarbital: Uses Partial and generalized tonic-clonic seizures Promotes sleep and sedation Drug of choice: No longer drugs of choice – need monitoring Can be used as 2 nd -line in all forms of epilepsy Adverse effects: D ependence, Nystagmus, Ataxia, CNS depression
The major action is to block sodium channels and inhibit the generation of rapidly repetitive action potentials.repetitive action potentials Metabolism is dose-dependent with saturation kinetics.dose-dependent Some drug precipitation after intramuscular injection occurs so IM route is not recommended. It takes 7 days (at low blood levels) or 6 weeks (at higher levels) to reach steady-state after every dosage change.
Phenytoin induces microsomal enzymes.microsomal enzymes Toxicity: Nystagmus occurs early, but is not an indication for decreasing the dose. Diplopia & ataxia (the most common adverse effects requiring dosage adjustment) Gingival hyperplasia Gingival hyperplasia Coarsening of facial features, HirsutismHirsutism megaloblastic anaemia, osteomalacia
Decreases effect of oral contraceptives, warfarin, glucocorticoids Phenytoin level can be increased if used with diazepam, isoniazid (tuberculosis drug), cimetidine, alcohol, valproic acid 28
Considered drug of choice for tonic clonic seizures, partial seizures Also used for cardiac arrhythmias & trigeminal neuralgic 29
Are similar to phenytoin. Ethotoin is recommended for patients hypersensitive to phenytoin. The toxicity of ethotoin is generally less severe than phenytoin, but the drug is less effective.
Drug of choice for : Simple absence seizures Also used for: Myoclonic, atypical absences, atonic Adverse effects: GI upset, drowsiness, dizziness, ataxia, allergic reactions, drug-induced SLE MOA: Blocks low threshold, “transient” (T-type) Ca channels in thalamic neurons 32
Blocks sodium channels It is not sedative. Is very effective in patients with trigeminal neuralgia.
Considered a drug of choice for tonic clonic seizures partial seizures trigeminal neuralgia prophylaxis of manic depressive illness Potent inducer of hepatic enzymes own half life reduces over 2-3 weeks increases metabolism of theophylline, warfarin.. complex drug interactions with other anticonvulsants 34
Diplopia & ataxia are the most common dose related adverse effects. Idiosyncratic blood dyscrasias, including fatal cases of aplastic anemia and agranulocytosis. Most have been in elderly patients with trigeminal neuralgia. Most have occurred within the first 4 months of treatment.
Is less potent than carbamazepine. It may have an improved toxicity profile. The drug appears to induce hepatic enzymes to a lesser extent than carbamazepine.
Most too sedative for clinical use Clonazepam and clobazam are used clinically effectiveness wanes on long term therapy Adverse effects: Sedation, Hypotonia, impaired co-ordination 37
Seizures associated with Lennox-Gastaut syndrome (a severe form of epilepsy) Akinetic seizures (known as atonic seizures), characterized by a sudden loss of muscle tone, causing "drop attacks" Myoclonic seizures (brief muscle jerks) Absence seizures, characterized by brief periods of decreased awareness or "spacing out."
Drug of choice if the patient has concomitant absence seizures & generalized tonic-clonic attacks. The most common adverse effects are nausea, vomiting and abdominal pain. A pregnant woman taking valproate has a 1-2% risk of having a child with spina bifida. The idiosyncratic toxicity is hepatotoxicity More than 50 fatalities in the USA alone The risk is greatest under the age of 2 years Most fatalities within 4 months after therapy Although it is important to minimize exposure to antiseizure drugs, it is also important not to allow maternal seizures to go unchecked.
MOA: May enhance GABA transmission Blocks voltage-dependent Na channels Does not induce drug metabolism Adverse effects Thinning and curling of hair in 10% Rare hepatic and pancreatic disorders Coagulopathy (inhibition of platelet aggregation) Increased appetite and weight gain 40
Gabapentin is an analog of GABA which is effective against partial seizures. In spite of its structural resemblance to GABA, gabapentin does not act directly on GABA receptors. Gabapentin increases GABA concentration in the brain. Gabapentin is effective as an adjunct against partial seizures and generalized tonic-clonic seizures.
Widely used to relieve pain, especially neuropathic pain. Well tolerated in most patients With mild side-effect profile, and passes through the body unmetabolized. 42
Suppresses sodium and Ca 2+ channels and decreases the release of glutamate. Lamotrigine is effective as monotherapy for partial seizures, and is widely prescribed for this indication. Primary and secondary tonic- clonic seizures, bipolar disorder. A potentially life-threatening dermatitis will develop in 1-2% of pediatric patients.
Not a first line antiepileptic drug Only in patients who respond inadequately to alternative treatments and whose epilepsy is so severe that a substantial risk of aplastic anemia and/or liver failure is deemed acceptable. MOA: Unknown 44
An analogue of GABA. It is irreversible inhibitor of 4-aminobutyrate transaminase It is used as an adjunctive treatment in treatment resistant epilepsy, complex partial seizures, secondary generalized seizures 45
It is used as an adjunctive treatment for partial seizures in ages 12 and up. It is also used in the treatment for panic disorder, anxiety disorders and neuropathic pain 46 A selective GABA reuptake inhibitor.
Used for the treatment and control of partial seizures and severe tonic-clonic (grand mal) seizures and also for the prevention of migraine headaches. In children it is also used for treatment of Lennox-Gastaut syndrome. 47
It blocks sodium channels. It ihibits carbonic anydrase. It also affects GABA and Glutamate receptors Acute myopia and glaucoma may require prompt drug withdrawal.
Blocks voltage-dependent Na channels at high firing frequencies Increases frequency at which GABA opens Cl- channels (different site than benzodiazepines) Antagonizes glutamate action at AMPA/kainate receptor subtype 49
for treatment of grand mal and partial seizures in adults and children Can also be prescribed off-label to treat certain types of tremors. Works by preventing abnormal electrical activity from starting and spreading to other parts of the brain.
Initiation of therapy Aim for monotherapy (efficacious and safe) Start with low dose - escalate over about a month Should control 80% of patients on one agent If unable to achieve control change to new agent of different class OR add a second agent of a different class About 3 months treatment required to determine efficacy 99
The Sodium Channel: A. Resting State B. Arrival of Action Potential causes depolarization and channel opens allowing sodium to flow in. C. Refractory State, Inactivation – reduce the rate of recovery. Na + Sustain channel in this conformation Anticonvulsant mechanism – contd. m gate h gate