Antiseizure drugs are also called antiepileptic drugs (AEDs) or anticonvulsants. The terms seizure and convulsion are often used interchangeably, although they are not the same.
A seizure involves a brief episode of abnormal electrical activity in nerve cells of the brain that may or may not be accompanied by visible changes in appearance or behavior. A convulsion is a tonic-clonic type of seizure characterized by spasmodic contractions of involuntary muscles.
Seizures may occur as single events in response to hypoglycemia, fever, electrolyte imbalances, overdoses of numerous drugs (eg, amphetamine, cocaine, isoniazid, lidocaine,lithium, methylphenidate, antipsychotics, theophylline), and withdrawal of alcohol or sedative-hypnotic drugs. In these instances, treatment of the underlying problem or temporary use of an AED may relieve the seizures.
Epilepsy
When seizures occur in a chronic, recurrent pattern, the disorder is called epilepsy, and drug therapy is usually required.
Epilepsy is characterized by abnormal and excessive electrical discharges of nerve cells. It is diagnosed by clinical signs and symptoms of seizure activity and by the presence of abnormal brain wave patterns on the electroencephalogram.
The cause is unknown in 60% to 80% of children and adolescents and 50% of older adults. When epilepsy begins in infancy, causes include developmental defects, metabolic disease, or birth injury. Fever is a common cause during late infancy and early childhood, and inherited forms usually begin in childhood or adolescence.
When epilepsy begins in adulthood, it is often caused by an acquired neurologic disorder (eg, head injury, stroke, brain tumor) or alcohol and other drug effects.
The incidence of epilepsy is higher in young children and older adults than in other age groups.
Epilepsy is broadly classified as partial and generalized seizures. Partial seizures begin in a specific area of the brain and often indicate a localized brain lesion such as birth injury,trauma, stroke, or tumor.
They produce symptoms ranging from simple motor and sensory manifestations to more complex abnormal movements and bizarre behavior.Movements are usually automatic, repetitive, and inappropriate to the sit-
uation, such as chewing, swallowing, or aversive movements.
Behavior is sometimes so bizarre that the person is diagnosed as psychotic or schizophrenic. In simple partial seizures, consciousness is not impaired; in complex partial seizures, the level of consciousness is decreased.
Generalized seizures are bilateral and symmetric and have no discernible point of origin in the brain. The most common type is the tonic-clonic or major motor seizure. The tonic phase involves sustained contraction of skeletal muscles; abnormal postures, such as opisthotonos; and absence of respiration, during which the person becomes cyanotic. The clonic phase is characterized by rapid rhythmic and symmetric jerking move-
ments of the body. Tonic-clonic seizures are sometimes preceded by an aura, a brief warning, such as a flash of light or a specific sound. In children, febrile seizures (ie, tonic-clonic seizures that occur in the absence of other identifiable causes) are the most common form of epilepsy.
Another type of generalized seizure is the absence seizure, characterized by abrupt alterations in consciousness that last only a few seconds. The person may have a blank, staring expression with or without blinking of the eyelids, twitching of the head or arms, and other motor movements. Other types of
generalized seizures include the myoclonic type (contraction of a muscle or group of muscles) and the akinetic type (absence of movement). Some people are subject to mixed seizures.
Status epilepticus is a life-threatening emergency characterized by generalized tonic-clonic convulsions lasting for several minutes or occurring at close intervals during which the client does not regain consciousness. Hypotension, hypoxia,and cardiac dysrhythmias may also occur. There is a high risk of permanent brain damage and death unless prompt, appropriate treatment is instituted. In a person taking medications
for a diagnosed seizure disorder, the most common cause of status epilepticus is abruptly stopping AEDs. In other clients, regardless of whether they have a diagnosed seizure
disorder, causes of status epilepticus include brain trauma or tumors, systemic or central nervous system (CNS) infections, alcohol withdrawal, and overdoses of drugs (eg, cocaine,theophylline).
ANTISEIZURE DRUGS
Antiseizure drugs can usually control seizure activity but do not cure the underlying disorder. Numerous difficulties, for both clinicians and clients, have been associated with AED therapy, including trials of different drugs, consideration of monotherapy versus two or more drugs, the need to titrate dosage over a period of time, lack of seizure control while drugs are being selected and dosages adjusted, a social stigma and adverse drug effects that often lead to poor client compliance, and undesirable drug interactions among AEDs and between AEDs and other drugs. Attempts to overcome these difficulties have led to the development of several new drugs in recent years.
Drug therapy of epilepsy is rapidly evolving as older, more toxic drugs are virtually eliminated from clinical usage and the roles of newer drugs are being defined.older drugs that are still commonly used (phenytoin, carbamazepine, ethosuximide, phenobarbital, valproate) and newer drugs (gabapentin, lamotrigine, levetiracetam, oxcarbazepine,tiagabine, topiramate, zonisamide) are discussed.
Mechanisms of ActionAlthough the exact mechanism of action is unknown for most AEDs, the drugs are thought to suppress seizures by decreasing movement of ions into nerve cells, altering the activity of neurotransmitters (eg, GABA, glutamate), or a combination of these mechanisms. Because movement of sodium and calcium ions is required for normal conduction of nerve impulses,blocking these ions decreases responsiveness to stimuli and results in stabilized, less excitable cell membranes. Increasing the activity of gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the brain, and decreasing the activity of glutamate, the major excitatory neurotransmitter, also decrease nerve cell excitability. The actions of both sodium channel blockers (eg, phenytoin, oxcarbazine) and GABA enhancers (eg, benzodiazepines and most of the newer AEDs) raise the amount of stimulation required to produce a seizure (called the seizure threshold). Overall, the drugs are thought to stabilize neuronal membranes and decrease neuronal firing in response to stimuli. Some seem able to suppress abnormal neuronal firing without suppressing normal neurotransmission.
Indications for Use
The major clinical indication for AEDs is the prevention or treatment of seizures, especially the chronic recurring seizures of epilepsy. Indications for particular drugs depend on the types and severity of seizures involved. For example, most of the newer drugs are indicated for use with one or two other AEDs to treat more severe seizure disorders that do not respond to a single drug. However, oxcarbazepine is approved for monotherapy and studies indicate that most of the other newer drugs may be effective as monotherapy in some types of seizures.
In addition to maintenance treatment of epilepsy, AEDs also are used to stop acute, tonic-clonic convulsions and status epilepticus. The drug of choice for this purpose is an intravenous (IV) benzodiazepine, usually lorazepam. Once acute seizure activity is controlled, a longer-acting drug, such as phenytoin or fosphenytoin, is given to prevent recurrence.
AEDs also are used prophylactically in clients with brain trauma from injury or surgery.
In addition to treatment of seizure disorders, AEDs are used to treat bipolar disorder (eg, carbamazepine and valproate) although they are not FDA-approved for this purpose.
They are also used in the management of chronic neuropathic pain, although few studies validate their effectiveness for this purpose. Carbamazepine is approved for treatment of the pain associated with trigeminal neuralgia. Gabapentin is also being used, but it is not approved for this indication and is not considered better than carbamazepine. Some of the newer AEDs are being tested for effectiveness in relation to bipolar, neuropathic pain, and other disorders. Because the drugs are being used for other indications than seizure disorders, some people suggest they be called neuromodulators or neurostabilizers rather than AEDs or anticonvulsants.
Contraindications to Use
AEDs are contraindicated or must be used with caution in clients with CNS depression. Phenytoin, carbamazepine, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, tiagabine, topiramate, and valproate are contraindicated in clients who have experienced a hypersensitivity reaction to the particular drug (usually manifested by a skin rash, arthralgia, and other symptoms). Phenytoin, carbamazepine, ethosuximide,lamotrigine, topiramate and zonisamide are contraindicated or must be used cautiously in clients with hepatic or renal impairment. Additional contraindications include phenytoin with sinus bradycardia or heart block; carbamazepine with bone marrow depression (eg, leukopenia, agranulocytosis);and tiagabine and valproic acid with liver disease. All of the drugs must be used cautiously during pregnancy because they are teratogenic in animals.
A seizure involves a brief episode of abnormal electrical activity in nerve cells of the brain that may or may not be accompanied by visible changes in appearance or behavior. A convulsion is a tonic-clonic type of seizure characterized by spasmodic contractions of involuntary muscles.
Seizures may occur as single events in response to hypoglycemia, fever, electrolyte imbalances, overdoses of numerous drugs (eg, amphetamine, cocaine, isoniazid, lidocaine,lithium, methylphenidate, antipsychotics, theophylline), and withdrawal of alcohol or sedative-hypnotic drugs. In these instances, treatment of the underlying problem or temporary use of an AED may relieve the seizures.
Epilepsy
When seizures occur in a chronic, recurrent pattern, the disorder is called epilepsy, and drug therapy is usually required.
Epilepsy is characterized by abnormal and excessive electrical discharges of nerve cells. It is diagnosed by clinical signs and symptoms of seizure activity and by the presence of abnormal brain wave patterns on the electroencephalogram.
The cause is unknown in 60% to 80% of children and adolescents and 50% of older adults. When epilepsy begins in infancy, causes include developmental defects, metabolic disease, or birth injury. Fever is a common cause during late infancy and early childhood, and inherited forms usually begin in childhood or adolescence.
When epilepsy begins in adulthood, it is often caused by an acquired neurologic disorder (eg, head injury, stroke, brain tumor) or alcohol and other drug effects.
The incidence of epilepsy is higher in young children and older adults than in other age groups.
Epilepsy is broadly classified as partial and generalized seizures. Partial seizures begin in a specific area of the brain and often indicate a localized brain lesion such as birth injury,trauma, stroke, or tumor.
They produce symptoms ranging from simple motor and sensory manifestations to more complex abnormal movements and bizarre behavior.Movements are usually automatic, repetitive, and inappropriate to the sit-
uation, such as chewing, swallowing, or aversive movements.
Behavior is sometimes so bizarre that the person is diagnosed as psychotic or schizophrenic. In simple partial seizures, consciousness is not impaired; in complex partial seizures, the level of consciousness is decreased.
Generalized seizures are bilateral and symmetric and have no discernible point of origin in the brain. The most common type is the tonic-clonic or major motor seizure. The tonic phase involves sustained contraction of skeletal muscles; abnormal postures, such as opisthotonos; and absence of respiration, during which the person becomes cyanotic. The clonic phase is characterized by rapid rhythmic and symmetric jerking move-
ments of the body. Tonic-clonic seizures are sometimes preceded by an aura, a brief warning, such as a flash of light or a specific sound. In children, febrile seizures (ie, tonic-clonic seizures that occur in the absence of other identifiable causes) are the most common form of epilepsy.
Another type of generalized seizure is the absence seizure, characterized by abrupt alterations in consciousness that last only a few seconds. The person may have a blank, staring expression with or without blinking of the eyelids, twitching of the head or arms, and other motor movements. Other types of
generalized seizures include the myoclonic type (contraction of a muscle or group of muscles) and the akinetic type (absence of movement). Some people are subject to mixed seizures.
Status epilepticus is a life-threatening emergency characterized by generalized tonic-clonic convulsions lasting for several minutes or occurring at close intervals during which the client does not regain consciousness. Hypotension, hypoxia,and cardiac dysrhythmias may also occur. There is a high risk of permanent brain damage and death unless prompt, appropriate treatment is instituted. In a person taking medications
for a diagnosed seizure disorder, the most common cause of status epilepticus is abruptly stopping AEDs. In other clients, regardless of whether they have a diagnosed seizure
disorder, causes of status epilepticus include brain trauma or tumors, systemic or central nervous system (CNS) infections, alcohol withdrawal, and overdoses of drugs (eg, cocaine,theophylline).
ANTISEIZURE DRUGS
Antiseizure drugs can usually control seizure activity but do not cure the underlying disorder. Numerous difficulties, for both clinicians and clients, have been associated with AED therapy, including trials of different drugs, consideration of monotherapy versus two or more drugs, the need to titrate dosage over a period of time, lack of seizure control while drugs are being selected and dosages adjusted, a social stigma and adverse drug effects that often lead to poor client compliance, and undesirable drug interactions among AEDs and between AEDs and other drugs. Attempts to overcome these difficulties have led to the development of several new drugs in recent years.
Drug therapy of epilepsy is rapidly evolving as older, more toxic drugs are virtually eliminated from clinical usage and the roles of newer drugs are being defined.older drugs that are still commonly used (phenytoin, carbamazepine, ethosuximide, phenobarbital, valproate) and newer drugs (gabapentin, lamotrigine, levetiracetam, oxcarbazepine,tiagabine, topiramate, zonisamide) are discussed.
Mechanisms of ActionAlthough the exact mechanism of action is unknown for most AEDs, the drugs are thought to suppress seizures by decreasing movement of ions into nerve cells, altering the activity of neurotransmitters (eg, GABA, glutamate), or a combination of these mechanisms. Because movement of sodium and calcium ions is required for normal conduction of nerve impulses,blocking these ions decreases responsiveness to stimuli and results in stabilized, less excitable cell membranes. Increasing the activity of gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the brain, and decreasing the activity of glutamate, the major excitatory neurotransmitter, also decrease nerve cell excitability. The actions of both sodium channel blockers (eg, phenytoin, oxcarbazine) and GABA enhancers (eg, benzodiazepines and most of the newer AEDs) raise the amount of stimulation required to produce a seizure (called the seizure threshold). Overall, the drugs are thought to stabilize neuronal membranes and decrease neuronal firing in response to stimuli. Some seem able to suppress abnormal neuronal firing without suppressing normal neurotransmission.
Indications for Use
The major clinical indication for AEDs is the prevention or treatment of seizures, especially the chronic recurring seizures of epilepsy. Indications for particular drugs depend on the types and severity of seizures involved. For example, most of the newer drugs are indicated for use with one or two other AEDs to treat more severe seizure disorders that do not respond to a single drug. However, oxcarbazepine is approved for monotherapy and studies indicate that most of the other newer drugs may be effective as monotherapy in some types of seizures.
In addition to maintenance treatment of epilepsy, AEDs also are used to stop acute, tonic-clonic convulsions and status epilepticus. The drug of choice for this purpose is an intravenous (IV) benzodiazepine, usually lorazepam. Once acute seizure activity is controlled, a longer-acting drug, such as phenytoin or fosphenytoin, is given to prevent recurrence.
AEDs also are used prophylactically in clients with brain trauma from injury or surgery.
In addition to treatment of seizure disorders, AEDs are used to treat bipolar disorder (eg, carbamazepine and valproate) although they are not FDA-approved for this purpose.
They are also used in the management of chronic neuropathic pain, although few studies validate their effectiveness for this purpose. Carbamazepine is approved for treatment of the pain associated with trigeminal neuralgia. Gabapentin is also being used, but it is not approved for this indication and is not considered better than carbamazepine. Some of the newer AEDs are being tested for effectiveness in relation to bipolar, neuropathic pain, and other disorders. Because the drugs are being used for other indications than seizure disorders, some people suggest they be called neuromodulators or neurostabilizers rather than AEDs or anticonvulsants.
Contraindications to Use
AEDs are contraindicated or must be used with caution in clients with CNS depression. Phenytoin, carbamazepine, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, tiagabine, topiramate, and valproate are contraindicated in clients who have experienced a hypersensitivity reaction to the particular drug (usually manifested by a skin rash, arthralgia, and other symptoms). Phenytoin, carbamazepine, ethosuximide,lamotrigine, topiramate and zonisamide are contraindicated or must be used cautiously in clients with hepatic or renal impairment. Additional contraindications include phenytoin with sinus bradycardia or heart block; carbamazepine with bone marrow depression (eg, leukopenia, agranulocytosis);and tiagabine and valproic acid with liver disease. All of the drugs must be used cautiously during pregnancy because they are teratogenic in animals.
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