Antiepileptic Drugs Flashcards
Partial Seizures
SIMPLE PARTIAL SEIZURES
The patient doesn’t lose consciousness; often exhibits abnormal activity of a single limb or muscle group that is controlled by the region of the brain experiencing the disturbance. The patient may also show sensory distortions. Simple partial seizures may occur at any age. Duration: 20-60 seconds.
COMPLEX PARTIAL SEIZURES
Seizures exhibit complex sensory hallucinations, mental distortion, and loss of consciousness. Motor dysfunction may involve chewing movements, diarrhea, urination. The majority of complex partial seizures originate from the temporal lobe. Duration: 30-120 seconds.
PARTIAL WITH SECONDARILY GENERALIZED TONIC-CLONIC SEIZURES
Simple or complex partial seizure evolves into a tonic-clonic seizure with loss of consciousness and sustained contractions of muscles throughout the body followed by periods of muscle contraction alternating with periods of relaxation, typically lasting 1-2 minutes.
Generalized Seizures
GENERALIZED SEIZURES
There is no evidence of localized onset. They may be convulsive or nonconvulsive; the patient usually has an immediate loss of consciousness.
TONIC-CLONIC SEIZURES (GRAND MAL)
Most commonly encountered and most dramatic form of epilepsy. Seizures result in loss of consciousness, followed by tonic, then clonic phases. Seizure is followed by a period of confusion and exhaustion.
ABSENCE SEIZURES (PETIT MAL)
These seizures involve a brief, abrupt and self-limiting loss of consciousness. The onset occurs in patients at ages 3-5 years and lasts until puberty. The patient stares and exhibits rapid eye-blinking. Duration: usually less than 10 seconds and rarely more than 45 seconds. The EEG shows a 3-Hz spike-and-wave pattern that emerges abruptly and ceases after a few seconds.
ATYPICAL ABSENCE SEIZURES
They are marked by more intense muscle involvement and a longer recovery time. Atypical absence seizures respond poorly to treatment and are often associated with severe neurologic impairment.
ATONIC SEIZURES
The patient has sudden loss of postural tone. Although most often seen in children, this seizure type is not unusual in adults.
TONIC SEIZURES
In tonic seizures, the muscles contract and consciousness is altered for about 10 seconds, but the seizures do not progress to the clonic or jerking phase.
MYOCLONIC SEIZURES
Short (perhaps one second) episodes of muscle contractions that may reoccur for several minutes. Myoclonic seizures are rare, occur at any age, and are often a result of permanent damage acquired as a result of hypoxia, uremia, encephalitis or drug poisoning.
STATUS EPILEPTICUS
STATUS EPILEPTICUS
Repeated seizure, or a seizure prolonged for at least 5 minutes. It may be convulsive (tonic-clonic), nonconvulsive (absence or complex partial), partial (epilepsia partialis continuans), or subclinical (electrographic status epilepticus). The most common type, generalized tonic-clonic status epilepticus, is a life-threatening emergency, requiring immediate cardiovascular, respiratory and metabolic management, as well as pharmacologic therapy.
DRUGS THAT BLOCK VOLTAGE-GATED ION CHANNELS
DRUGS THAT BLOCK VOLTAGE-GATED ION CHANNELS
Drugs that block Voltage-Gated Na+ Channels
Voltage-gated sodium channel blockade is thought to be the principal mechanism of action of phenytoin, carbamazepine, oxcarbazepine, lamotrigine and zonisamide. It may also contribute to the effects of phenobarbital, valproate, and topiramate.
Note: Primidone is metabolized to phenobarbital and phenylethylmalonamide. Primidone and both its metabolites have anticonvulsant activity.
Drugs that block T-type Ca2+ Channels
Absence seizures involve oscillatory neuronal activity between thalamus and cortex. A low-threshold calcium current (the T-type Ca2+ current) governs oscillatory responses in thalamic neurons. Reduction of this current by ethosuximide and valproate is thought to explain the effect of these compounds in absence seizures.
DRUGS THAT AFFECT SYNAPTIC TRANSMISSION
Drugs that enhance GABAergic neurotransmission
• Postsynaptically:
Direct action on the GABAA receptor: benzodiazepines, barbiturates and topiramate
• Presynaptically:
Inhibition of reuptake of GABA: Tiagabine.
Inhibition of degradation of GABA: Vigabatrin is an irreversible inhibitor of GABA aminotransferase (GABA-T), the enzyme responsible for degradation of GABA. As a consequence, the amount of GABA released at synaptic sites is increased.
Drugs that reduce glutamatergic neurotransmission
• Postsynaptically:
Phenobarbital and topiramate inhibit excitatory responses induced by glutamate by blocking glutamate receptors.
• Presynaptically:
Gabapentin and pregabalin act presynaptically to decrease glutamate release; this effect is a consequence of blockade of presynaptic voltage- gated Ca2+ channels.
Levetiracetam binds to synaptic vesicle glycoprotein 2A (SV2A). The exact mechanism of its anticonvulsant action is unknown. It is likely that levetiracetam modifies the synaptic release of glutamate and GABA through an action on vesicular function.
Ethosuximide and Valproate
ABSENCE SEIZURES
The drugs of choice for absence seizures are ethosuximide and valproate.
If tonic-clonic seizures are present or emerge during therapy, valproate is the drug of choice since it is effective in both conditions. Valproate is also preferred for atypical absence seizures.
Lamotrigine is probably effective.
Partial and Generalized Seizures Treatment
PARTIAL AND SECONDARILY GENERALIZED TONIC-CLONIC SEIZURES
• The main drugs used include: Carbamazepine, oxcarbazepine, levetiracetam, zonisamide, phenytoin, valproate, lamotrigine, topiramate, and phenobarbital.
GENERALIZED SEIZURES
TONIC-CLONIC SEIZURES
• The main drugs used include: Carbamazepine, oxcarbazepine, valproate, lamotrigine, phenytoin, and topiramate.
MYOCLONIC SEIZURES
Valproate is the drug of choice for myoclonic seizures.
Topiramate is also used.
Levetiracetam is approved for adjunctive therapy.
ATONIC SEIZURES
Atonic seizures are often refractory to all available medications.
Valproate and lamotrigine may be beneficial.
Febrile Convulsions Treatment
Febrile convulsions are defined as seizures associated with an elevated temperature greater than 38oC, in a child younger than 6 years of age, with no CNS infection or inflammation, no acute systemic metabolic abnormality that may produce convulsions, and no history of previous afebrile seizures. Febrile convulsions are not considered to be a form of epilepsy.
Treatment is supportive if seizures last < 15 minutes. Seizures lasting > 15 minutes require pharmacological treatment to prevent possible brain damage resulting from continued seizure activity, although such effect appears to be rare. Treatment is with diazepam given IV or as a rectal solution.
Treatment of Status Epilepticus
There are many forms of status epilepticus. The most common, generalized tonic-clonic status epilepticus is a life-threatening emergency. The goal of treatment is rapid termination of seizure activity. Drugs should be given IV only.
Initial treatment is usually with a benzodiazepine. Diazepam has been widely used, but IV lorazepam is now preferred for first-line treatment in most protocols, since it appears to be more effective and has a much longer duration of antiepileptic action: lorazepam’s lower liposolubility prevents rapid redistribution from the brain and accounts for its longer duration of action.
If seizures continue IV phenytoin or fosphenytoin are given. Fosphenytoin is a water- soluble phosphate ester prodrug of phenytoin, available for parenteral use. Fosphenytoin is rapidly converted to phenytoin in plasma by nonspecific phosphatases. Use of fosphenytoin allows more rapid administration of large IV loading doses with less risk of injection site complications. Note: some protocols recommend routine administration of phenytoin (or fosphenytoin) after termination of seizures with a benzodiazepine.
If benzodiazepines and phenytoin fail IV phenobarbital is recommended. Respiratory depression is a common complication, especially if benzodiazepines have already been given, and intubation and ventilation should be instituted.
Status epilepticus that does not respond to a benzodiazepine, phenytoin or phenobarbital is considered refractory. At this point general anesthesia should be instituted. Continuous IV infusions with midazolam, propofol or barbiturates (thiopental or pentobarbital) are the most useful treatments.
BREAKTHROUGH SEIZURES
Breakthrough seizures are seizures experienced by epileptic patients who are on antiepileptic therapy. They are intermittent and periodic episodes of markedly increased seizure activity. Diazepam rectal gel (Diastat AcuDial) is FDA-approved for use in the treatment of increased seizure activity in patients on a stable regimen of antiepileptic agents. Supplied as a pre-filled syringe. It is recommended that diazepam rectal gel be used to treat no more than five episodes per month and no more than one episode every five days.
Lamotrigine
Note: Antiepileptic drugs most often associated with skin rashes are: Phenytoin, lamotrigine, phenobarbital and carbamazepine. Lamotrigine carries a black box warning about life-threatening skin reactions. Lamotrigine should be discontinued at the first sign of rash.
OVERDOSE TOXICITY
Antiepileptic drugs are common agents taken in intentional drug overdoses. They are CNS depressants but are rarely lethal. Very high blood levels are usually necessary before overdoses can be considered life-threatening. The most dangerous effect of antiseizure drugs after large overdoses is respiratory depression, which may be potentiated by other agents, such as alcohol. Treatment of antiseizure drug overdose is supportive; stimulants should not be used. Efforts to hasten removal of antiseizure drugs like alkalinization of the urine (phenytoin is a weak acid) are usually ineffective.
ANTIEPILEPTIC DRUGS AND PREGNANCY
TERATOGENICITY
There is good evidence of an increased risk of congenital malformations in infants born of women taking antiseizure drugs.
Most pregnant patients exposed to antiepileptic drugs deliver normal infants. However, fetal exposure to older antiepileptic drugs, particularly valproate and phenobarbital, is associated with congenital anomalies. Valproate is associated with the highest risk of congenital malformations, and with developmental delay.
Polytherapy carries a significantly higher risk of congenital malformations than monotherapy. In order to minimize fetal risks antiepileptic drugs should be used as monotherapy, and at the lowest possible doses.
Valproate has been implicated in spina bifida.
Phenobarbital has been associated with a higher risk of cardiac defects and oral clefts.
Phenytoin has been implicated in a syndrome called fetal hydantoin syndrome.
Available data suggest that newer antiepileptic drugs such as lamotrigine, levetiracetam and gabapentin are associated with lower rates of major malformations.
Topiramate appears to increase the risk of oral cleft.
Folate supplementation has been recommended by the U.S. Public Health Service for all women of childbearing age to reduce the likelihood of neural tube defects, and this is appropriate for epileptic women as well.
NEWBORN HEMORRHAGIC DISEASE
Enzyme-inducing antiepileptic drugs, such as phenytoin, phenobarbital, primidone and carbamazepine can cause postnatal bleeding in the newborn infant. These drugs cross the placenta and may increase the rate of oxidative degradation of vitamin K in the fetus.
Consequently, vitamin K supplementation is recommended for the mother in the final month of pregnancy and for the newborn.
NONPHARMACOLOGIC THERAPIES
VAGUS NERVE STIMULATION
Intermittent electrical stimulation of the left vagus nerve with an implanted pacemaker- like device reduces the number of partial seizures by 1⁄3. The patient can activate the device when they sense a seizure is imminent. Vagus nerve stimulation is used as an adjunct to anticonvulsant therapy.
SURGERY
For most patients whose seizures originate from a local area of abnormal brain, function improves markedly when the epileptic focus is resected. Some patients remain seizure- free, but most still require anticonvulsants.
THE KETOGENIC DIET
It is considered a safe and effective alternative therapy for children and adults with refractory epilepsy. The traditional ketogenic diet consists of four parts fat to one part protein and carbohydrate. The high fat content and extremely low carbohydrate content produce a persistent ketosis, which appears to have a direct antiseizure effect. How the ketogenic diet suppresses seizures remains unclear.
