Drugs Used to Treat Epilepsy Epilepsy It is a family of different recurrent seizure disorders that have in common the

sudden, excessive, and disorderly discharge of cerebral neurons which results in abnormal movements or perceptions that are of short duration but tend to recur. Seizures Finite episodes of brain dysfunction resulting from abnormal discharge of cerebral neurons. Etiology of Seizures Birth and perinatal injuries Vascular insults Head trauma Congenital malformations Metabolic disturbances Drugs or alcohol, including withdrawal from barbiturates and CNS depressants Neoplasia Infection Hyperthermia in children Classification According to Etiology Primary or idiopathic epilepsy No specific anatomical cause for the seizure. May be produced by an inherited abnormality in the CNS. Treatment chronically with anti-epileptic drugs for life. Secondary epilepsy When seizures are triggered by a number of reversible disturbances, such as tumors, head injury, hypoglycemia, meningeal infection, or rapid withdrawal of alcohol in an alcoholic. Anti-epileptic drugs are given until the primary cause can be corrected. Classification According to Its Nature Partial or focal seizures Arise in a part of one cerebral hemisphere and are accompanied by focal EEG abnormalities. 1. Simple partial 2. Complex partial

Generalized onset seizures
Simultaneous involvement of all or large part of both cerebral hemispheres seen by EEG or clinically. 1. Tonic-clonic (grand mal) 2. Absence (petit mal) 3. Others, including myoclonic, atonic

Febrile Seizures

Occur

in young children, 3 months to 5 years of age, accompanying an illness with a high temperature. Consists of a generalized tonic-clonic convulsions of short duration. Drug of choice: Phenobarbital. Status Epilepticus When seizures recur with increasing frequency such that baseline consciousness is not regained between seizures. Lasts at least 30 minutes. Leads to hypoxia, acidemia, hyperpyrexia, CV collapse, renal shutdown. A medical emergency with mortality of 15% or less. Seizure Sequence Focal epileptogenesis (Initiation) Abnormal voltage-operated ion channel. Abnormal receptor-operated channels. 1. Decreased GABA-ergic inhibition that causes neural excitation and depolarization 2. Increased excitatory neurotransmission by glutamate receptor as NMDA (N-methyl-D-aspartate) Synchronization of surrounding neurons Abnormal receptor-operated channel. Alterations in extracellular ionic environment (increased K+, decreased Ca++). Recruitment of normal neurons via anatomical circuits. Propagation of seizure discharge to other areas of the brain. Alterations in extracellular ionic environment leading to neuronal excitability Recruitment of normal neurons via anatomical circuits Goal of Therapy To keep the patient free of seizures without causing any unwanted effects that might interfere with his normal function.
Monodrug

1. 2. 3. 4.

therapy Low incidence of adverse effects. Avoidance of drug interactions. Improved patient compliance. Lower medical cost.

Success with monotherapy depends on: 1. Correct seizure classification and diagnosis. 2. Appropriate drug choice for the seizure type. 3. Optimal drug administration and serum monitoring. Mechanisms of Drug Action Use-dependent blockade of sodium channels, reducing the repetitive firing of neurons. Phenytoin, Primidone, Carbamazepine, Lamotrigine

Increasing

the inhibitory activity of GABA that causes increased influx of chloride ions that, in turn, decreases neural excitation by hyperpolarization and elevated seizure threshold. Clonazepam, Valproic acid, Phenobarbital, Vigabatrin, Tiagabine, Felbamate, Gabapentin, Pregabalin, Topiramate Reducing the propagation of abnormal electrical activity in the brain by inhibiting the T-type calcium channels. Ethosuximide Primary Drugs for Epilepsy Clonazepam(Rivotril) A BZD which suppresses seizure spread from the epileptogenic foci by enhancing GABA action. Valproic acid (Depakene) A carboxylic acid derivative that acts by increasing the inhibitory activity of GABA by inhibiting 2 enzymes that inactivates GABA: (1) GABAtransaminase and (2) succinic semialdehyde dehydrogenase. Phenytoin (Dilantin) Also known as diphenylhydantoin or DPH. Oldest non-sedating drug that acts by inhibiting sodium channel function and increasing GABA action. Phenobarbital (Luminal) A derivative of barbituric acid that inhibits initiation of discharge, elevates seizure threshold, and potentiates inhibitory pathways in the brain by enhancing GABA action. Drug of choice for neonatal and febrile seizures. Primidone (Mysoline) Also known as 2-desoxyphenobarbital. A derivative of barbituric acid which is metabolized to active anticonvulsants: phenobarbital and phenylethylmalonamide (PEMA). Acts by inhibition of sodium channel function. Carbamazepine (Tegretol) A tricyclic compound used also in treating bipolar depression. Acts by inhibiting sodium channel function, thus inhibiting the generation of repetitive action potentials in the epileptic focus. Ethosuximide (Zarontin) A succinimide, pure petit mal drug. Reduces the propagation of abnormal electrical activity in the brain by inhibiting the T-type calcium channels. Newer Anti-epileptic drugs Vigabatrin ♦gamma-vinyl-substituted analogue of GABA. ¨Irreversibly inhibits the GABA metabolizing enzyme, GABA aminotransferase (GABA-T), thereby enhancing the inhibitory effect of GABA. Lamotrigine Acts by inhibiting sodium channels. Felbamate

MOA: 1. Use-dependent blockade of the NMDA receptor; 2. Potentiation of GABA receptor responses. Gabapentin and Pregabalin Analogue of GABA that increases the synaptic release of GABA  increased GABA concentration. Tiagabine Blocks GABA uptake into the presynaptic neuron, permitting more GABA to be available for receptor binding, thus causing enhanced inhibitory activity. Topiramate A chemical relative of fructose that causes blockade of the sodium channels, increased GABA activity at GABA receptors, and blockade of some glutamate receptors. Levetiracetam A piracetam analogue effective against seizures induced by maximum electroshock or pentylenetetrazole. Modifies the synaptic release of glutamate and GABA. Zonisamide A sulfonamide derivative that inhibits the sodium channel and the voltage-gated calcium channels.

Secondary Drugs for Epilepsy Methosuximide (Celontin) Acetazolamide (Diamox) Mephobarbital (Mebaral) Mephenytoin (Mesantoin) Phensuximide (Milontin) Paramethadione (Paradione) Ethotoin (Peganone) Phenacemide (Phenurone) Tridione (Trimethadione) Chlorazepate (Tranxene) Drugs for Status Epilepticus Lorazepam (Ativan) Diazepam (Valium) Chemistry of Anti-epileptic drugs Phenyl group at the R1 position produces activity against partial seizures. Alkyl group at the R1 position produces activity against certain generalized seizures. Pharmacokinetics Absorption is good following oral administration. They cross the BBB, hence have the potential of producing neurologic toxicity. They are not highly protein-bound except Phenytoin, BZD, and Valproic acid which may displace other drugs owing to their being highly protein-bound. They are cleared chiefly by hepatic mechanism.

Interactions Among Anti-epileptic Drugs Carbamazepine With Phenobarbital: Increased metabolism to epoxide, thus decreasing Carbamazepine effect. With Phenytoin: Increased metabolism, thus decreasing Carbamazepine effect. Phenytoin With Primidone: Increased conversion of Primidone into Phenobarbital, thus increasing the blood conc. Valproic acid With Clonazepam: Precipitate convulsive status epilepticus. With Phenobarbital: Decreased metabolism of Phenobarbital, thus producing toxicity. With Phenytoin: Increased Phenytoin toxicity due to displacement from binding. Interactions with Other Drugs Antibiotics: Increased serum conc. of Phenytoin, Phenobabrbital, or Carbamazepine that may cause toxicity. Anticoagulants: Decreased effect of Coumadin because of increased metabolism by Phenytoin or Phenobarbital. Cimetidine: Increased BZD effect due to its displacement from binding. Isoniazid: Increased toxicity of Phenytoin because its metabolism is reduced. Oral contraceptives: Increased failure rate because of increased metabolism. Salicylates: Phenobarbital or Valproic acid toxicity because they are displaced from binding. Theophylline: Carbamazepine and Phenytoin decrease its effects. Adverse Drug Reactions Carbamazepine Mild GI upset, drowsiness, granulocyte suppression and aplastic anemia in the elderly, diplopia and ataxia, erythematous skin rashes. Phenytoin Ataxia and nystagmus (dose-related), cognitive impairment and sedation, osteomalacia due to an abnormality in vit. D metabolism. Hirsutism, gingival hyperplasia, coarsening of facial features, and peripheral neuropathy on long-term use. Phenobarbital and Primidone Sedation and cognitive impairment, behavioral changes (hyperactivity and short-term memory), induction of liver enzymes. Valproic acid Tremors; GI symptoms (NAV, abd. pain, heartburn); hepatotoxicity; spina bifida; CV, orofacial, and digital abnormalities in offsprings of mothers taking this drug. Ethosuximide Gastric distress, NAV, transient lethargy or fatigue, headache, dizziness, hiccup. Clonazepam

Sedation and lethargy, ataxia, tolerance to anti-epileptic effects.

Withdrawal from Anti-epileptic Treatment Withdrawal of these drugs can cause increased seizure frequency and severity. In general, withdrawal of anti-absence drugs is easier than withdrawal of drugs for partial of grand mal types. Barbiturates and BZD are the most difficult to discontinue, requiring weeks or months with very gradual dosage decrements. Children whose seizures have always been infrequent and whose EEG are normal are candidates for gradual removal of drugs after 4 seizure-free years. Anti-epileptic therapy and pregnancy 1. The rates of stillbirth and infant mortality are higher for epileptic mothers. 2. Children of epileptic mothers who received anticonvulsant medications during the early months of pregnancy have an increased incidence of a variety of birth defects. 3. Formation of epoxide intermediates during the metabolism of carbamazepine and phenytoin may induce fetal malformations. 4. Valproic acid is cited as causing neural tube defects in 1-2% of offsprings of epileptic mothers. 5. Phenytoin is implicated in fetal hydantoin syndrome characterized by cleft lip, cleft palate, congenital heart disease, slowed growth, and mental deficiency. 6. The incidence of malformations is increased with the combination of carbamazepine, valproic acid, and phenytoin or phenobarbital. General Principles for Therapy Early diagnosis and treatment of seizure disorders with a single appropriate agent offers the best prospect of achieving prolonged seizure-free periods with the lowest risk of toxicity. Complete control of seizures can be achieved in up to 50% of cases and that another 25% can improve significantly. An attempt should be made to ascertain the cause of the epilepsy with the hope of discovering a correctable lesion, either structural or metabolic. The degree of success is greater in newly-diagnosed cases and is dependent on the type of seizure, family history, and extent of associated neurological abnormalities. The goal of therapy is to keep the patient free of seizures without interfering with normal function. Medication should be initiated with a single dose. Dosage is increased gradually at appropriate intervals as required for control of seizures or decreased in the presence of toxicity, and such adjustment is preferably assisted by monitoring the drug concentration in the plasma. If a single drug fails to provide adequate control of seizures, substitution with a second drug is generally preferred to the concurrent administration of another drug. Dosage should always be reduced gradually when drug is to be discontinued in order to minimize risk of precipitating status epilepticus. No drug should be discarded as useless unless toxicity prevents increased dosage.

The

frequency and severity of toxicity are reduced by avoiding regimens with 2 or more drugs. However, multiple drug therapy may be required especially when 2 or more types of seizures occur in the same patient. Most crucial for successful management is the regularity of medication since faulty compliance is the most frequent cause of failure in therapy. Measurement of plasma drug concentrations at appropriate intervals greatly facilitates the initial adjustment of dosage to minimize dose-related adverse effects without sacrificing seizure control. Many patients appear to be resistant to medications or develop unnecessary side effects because the medications chosen are not appropriate for the kind of seizure or are not in the optimum doses.

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