Medical Pharmacology Topics   

CNS Pharmacology: Anticonvulsants

Epileptic syndromes are classified as isolated or provoked seizures, generalized epilepsies and localization-related epilepsies. Examples of isolated or provoked seizures include febrile seizures, hypoglycemic seizures and alcohol withdrawal seizures. Such seizures are not controlled by anticonvulsants but by treating the undelying pathology.

Generalized epilepsies are events of abnormal electrical activity in the whole brain. The treatment goal for generalized epilepsies is to normalize the EGG, i.e. brain function. Generalized epilepsies may be primary or secondary. Patients with primary generalized epilepsies usually have otherwise normal neurological and cognitive function. Examples of generalized primary epilepsies are absence epilepsy and juvenile myoclonic epilepsy. Secondary generalized epilepsies, for example Lenox-Gastaut epilepsy, are associated with diffuse brain disfunction. Patients with secondary generalized epilepsies have other cognitive or neurological problems and are often refractory to medications.

Localization-related epilepsies are more common than generalized epilepsies in the adult population. The seizure starts at a focal point in the cortex (?) and can result in focal, complex partial or secondary generalized seizures. The treatment goal for localization-related epilepsies is to prevent generalization.

Many different classes of drugs are used to treat seizures depending on the type of epilepsy. Drugs used to treat generalized seizures include benzodiazepines, ethosuximide and felbamate. Drugs used to treat localized seizures include the carbamazepines, gabapentin, levetiracetam, tiagabine, and zonisamide. Valproate, phenytoin/fosphenytoin, phenobarbital, lamotrigine and topiramate are used in the treatment of both generalized and localized seizures.

Status epilepticus is treated first with IV benzodiazepines. If the patient is not responsive to the benzodiazepines, fosphenytoin is administered. If the seizures continue, phenobarbital is used. If none of the drugs are succesful, paralysis and coma are induced in order to protect the patient from neurological damage.

Agents Used for Localized and Generalized Epilepsies

Phenobarbital has been used for the treatmnt of epilepsy since 1912 and is effective used orally or parenterally. It is used for the treatment of seizures in neonates and young children, and is currently most commonly used in the very sick adults or to treat status epilepticus.

Phenobarbital prolongs the length of time GABA-activated Cl channels remain open, blocks N-type voltage-gated Na channels and has direct inhibitory action on NMDA-type glutamate receptors. It's half-life is 60-110 hours. Adverse effects include somnolence, depression, behavioral problems and hyperactivity in children, and idiosyncratic reactions including rash and a lupus-like syndrome.

Phenytoin is used orally or parenterally to treat localization-related epilepsies and parenterally in status epilepticus (if benzodiazepines are not effective). It stabilizes voltage-gated Na channels in their inactivated conformation, inhibits voltage-gated Ca channels and stimulates Na/K ATPase activity.

Phenytoin has non-linear pharmacokinetics, so that small changes in dose lead to significant changes in plasma concentrations. It is 90% protein bound, but only the free fraction is active. Most tests for blood levels measure the bound form, which usually has a 10:1 ration with the free form.

Phenytoin can cause nystagmus, ataxia, and gingival hyperplasia. Idiosyncratic reactions include rash and blood diacrasias. Parenteral administration can cause skin necrosis and cardiac arrythmias due to the formulation used to dissolve the drug. These adverse effects can be avoided by using the pro-drug formulation fosphenytoin.

Lamotrigine is used alone or in combination with other drugs. It stabilizes voltage-gated Na channels in the inactivated state, inhibits glutamate release and blocks t-type Ca currents. Lamotrigine is metabolized in the liver and may cause a severe and life-threatening rash especially when used in conjnction with valproate. This rash is more common in children and can be avoided in most cases by slow titration.

Topiramate is used as an adjuvant treatment. It has direct potentiating action on GABA receptors at a unique site and inactivates voltage-gated Na channels. The predominant elimination route is renal (~80%), although it also undergoes hepatic metabolism. Common adverse effects include psychomotor slowing (cognitive), fatigue, nausea, parasthesias and weigth loss. There is an increased occurrence of kidney stones with the use of this drug.

Valproate inhibits the metabolism of GABA, inactivates volatage-gated Na channels and blocks t-type Ca channels. It is one of only two drugs effective for absence epilepsy. Common dose-related adverse effects include weight gain, hair loss and tremor. Idiosyncratic reactions include liver failure, pancreatitis and thrombocytopenia.

Treatment of Generalized Epilepsies

Intravenous administration of benzodiazepines like diazepam and lorazepam is used in the acute treatment of prolonged generalized seizures or status epilepticus, regardless of how the seizure came to be. Clonazepam is a long-acting benzodiazepine used orally to prevent generalized epilepsies. The benzodiazepines act by enhancing GABA binding to its GABA-A receptor. Adverse effects include sedation and respiratory depression.

Ethosuximide blocks t-type Ca channels, and is the main drug indicated to prevent absence epilepsy. It is metabolized in the liver and adverse effects include nausea, hiccups, anorexia, rash and a lupus-like syndrome.

Felbamate is used to treat otherwise refractory epilepsies. Although it is a very effective drug its use is restricted because of its association with aplastic anemia and liver failure. Felbamate binds to the NMDA receptor and prevents calcium influx.

Treatment of Localized Epilepsies

The carbamazepines, carbamazepine and oxcarbazepine, are used orally. Since their half-life is short, seizures may come back if one of the three daily doses is missed. Carbamezapine is also indicated to treat trigeminal neuralgia. These drugs stabilize voltage-gated Na channels in their inactive conformation and decrease voltage-gated Ca conductance.

Both carbamezapine and oxcarbazepine are metabolized to similar active compounds. Carbamazepine has an epoxide metabolite that causes more difficulty with rapid titration (?). The carbamezapines will worsen generalized epilepsies and may cause double vision, dizziness, nausea and headaches (less so with oxcarbazepine), and hyponatremia (more wih oxcarbazepine). Leukopenia and rash can occur not related to the dose.

Gabapentin was designed as a GABA receptor agonist, but has no action at that receptor. It does bind to Ca channels and enhances GABA synthesis. Gabapentin is used as adjunctive therapy to treat localized epilepsies and post-herpetic neuralgia. Adverse effects include nausea, somnolence and lightheadedness. It is excreted unmetabolized in the urine.

Levetiracetam is used as adjuvant in the treatment of localization-related epilepsies. Its mechanism of action is unknown and it is renally excreted unchanged. Levetiracetam is generally well tolerated but can causes somnolence, weakness, headache and behavioral difficulties.

Tiagabine inhibits GABA reuptake. It is metabolized in the liver and may cause tremor, dizziness, nervousness, difficulty concentrating and somnolence.

The mechanism of action of zonisamide is likely to be similar to that of topiramate: has direct potentiating action on GABA receptors at a unique site and inactivates voltage-gated Na channels. It is metabolized mostly renally and common adverse effect include psychomotor slowing, fatigue, nausea, paresthesias, weight loss, and an increased incidence of kidney stones.

Drug Interactions

Many anticonvulsants induce P450 enzymes and/or are metabolized by P450 enzymes. This is the source of major interactions among anticonvulsant drugs and between anticonvulsants and other drug types that either induce or inhibit P450. Inducers of P450 will decrease the half-life of the drug, while P450 inhibitors will increase the half-life and the effect of the anticonvulsant.

Carbamezapine, oxcarbazepine, phenytoin and phenobarbital are P450 inducers. They will decrease the half-life, and the effectiveness, of each other if given together, as well as the half-life of other anticonvulsants metabolized by P450: valproate, ethosuximide, lamotrigine and topiramate. These drugs also decrease the half-life and effectivenes of other drugs like warfarin, theophilline, oral contraceptives and protease inhibitors. The clearance of drugs metabolized by P450 is inhibited by macrolides, cimetidine, Ca channel blockers and serotonin reuptake inhibitors.

Benzodiazepines have minimal interaction with other anticonvulsants. Anticonvulsant drugs excreted mostly renally (zonisamide, gabapentin, levetiracetam) have no interaction with other anticonvulsants.

Carbamazapines also decrease levels of benzodiazepines and valproate (how?). Valproate prolongs the half-life of lamotrigine, phenobarbital and carbamezapine (how?).

Treatment of Fertile Women

The seizure threshold is lowered during prenancy. Stillbirths occur twice as often in women with epilepsy who have a seizure during pregnancy than in women that do not have a seizure during pregnacy.

Valproate and the carbamezapines increase the incidence of neural tube defects in the fetus. The risk is 0.5%-1% for carbamazepine and 1-2% with valproate, compared to 0.1% for the general population. Other abnormalities associated with the use of anticonvulsants during pregnancy are early hemorrhagic disease of the newborn and congenital malformations.

In many cases, neural tube defects can be corrected by surgery. Education of the patient is important to ensure adequate family planning and folate supplementation. Oral contraceptives would be ineffective when using carbamezapine, oxcarbazepine, phenytoin and phenobarbital, therefore other forms of contraceptions should be used.

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