Antiseizure Drugs

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 evolve.elsevier.com/McCuistion/pharmacology

Millions of people in the United States have active epilepsy, a seizure disorder that results from abnormal electric discharges from the cerebral neurons characterized by a loss or disturbance of consciousness and usually involuntary, uncontrolled movements. The electroencephalogram (EEG), computed tomography (CT), and magnetic resonance imaging (MRI) are useful in diagnosing epilepsy. The EEG records abnormal electric discharges of the cerebral cortex. Of all seizure cases, 75% are considered to be primary, or idiopathic (of unknown cause), and the remainder are secondary to brain trauma, brain anoxia (absence of oxygen), infection, or cerebrovascular disorders (e.g., cerebrovascular accident [CVA], stroke). Epilepsy is a chronic, usually lifelong disorder. The majority of persons with seizure disorder had their first seizure before 20 years of age.
Seizures that are not associated with epilepsy could result from fever, hypoglycemic reaction, electrolyte imbalance (hyponatremia), metabolic imbalance (acidosis or alkalosis), and alcohol or drug use. When these conditions are corrected, the seizures cease. Recurrent seizures may result from birth and perinatal injuries, head trauma, congenital malformations, neoplasms (tumors), or idiopathic, or unknown, causes.

International Classification of Seizures

There are various types of seizures, such as tonic-clonic (formerly known as grand mal), absence (formerly known as petit mal), and psychomotor. The International Classification of Seizures (Table 19.1) describes two seizure categories: generalized and partial. A person may also have mixed seizures that comprise more than one type.

TABLE 19.1

International Classification of Seizures

Category Characteristics
Generalized seizure Seizures involve both cerebral hemispheres of the brain.
Tonic-clonic seizure Also called grand mal seizure, the most common form; in the tonic phase, skeletal muscles contract or tighten in a spasm that lasts 3 to 5 seconds; in the clonic phase, a dysrhythmic muscular contraction occurs with a jerkiness of legs and arms that lasts 2 to 4 minutes.
Tonic seizure Sustained muscle contraction
Clonic seizure Dysrhythmic muscle contraction
Absence seizure Also called petit mal seizure; brief loss of consciousness lasts less than 10 seconds with fewer than three spike waves on the electroencephalogram (EEG) printout. This type usually occurs in children.
Myoclonic seizure Isolated clonic contraction or jerks that last 3 to 10 seconds may be limited to one limb (focal myoclonic) or may involve the entire body (massive myoclonic); may be secondary to a neurologic disorder such as encephalitis or Tay-Sachs disease.
Atonic seizure Head drop, loss of posture, and sudden loss of muscle tone occurs. If lower limbs are involved, the patient could collapse.
Infantile spasms Muscle spasm
Partial seizure Involves one hemisphere of the brain; no loss of consciousness occurs in simple partial seizures, but there is a loss of consciousness in complex partial seizures.
Simple seizure Occurs in motor, sensory, autonomic, and psychic forms; no loss of consciousness occurs.
Motor Formerly called the Jacksonian seizure, this type involves spontaneous movement that spreads; it can develop into a generalized seizure.
Sensory Visual, auditory, or taste hallucinations
Autonomic response Paleness, flushing, sweating, or vomiting
Psychological Personality changes
Complex seizure Loss of consciousness occurs, and the patient does not recall behavior immediately before, during, and immediately after the seizure.
Psychomotor Complex symptoms include automatisms (repetitive behavior such as chewing or swallowing motions), behavioral changes, and motor seizures.
Cognitive Confusion or memory impairment
Affective Bizarre behavior
Compound May lead to generalized seizures such as tonic or tonic-clonic

Antiseizure Drugs

Drugs used for epileptic seizures are called antiseizure drugs, anticonvulsants, or antiepileptic drugs (AEDs). Antiseizure drugs stabilize nerve cell membranes and suppress the abnormal electric impulses in the cerebral cortex. These drugs prevent seizures but do not eliminate the cause or provide a cure. Antiseizure drugs are classified as central nervous system (CNS) depressants.
With the use of antiseizure drugs, seizures are controlled in approximately 70% of patients. These drugs are usually taken throughout the person’s lifetime; however, the health care provider might discontinue the medication if no seizures have occurred after 3 to 5 years in some cases.
Many types of antiseizure drugs are used to treat seizures, including the hydantoins (phenytoin), long-acting barbiturates (phenobarbital, mephobarbital, primidone), succinimides (ethosuximide), benzodiazepines (diazepam, clonazepam), carbamazepine, and valproate (valproic acid). Antiseizure drugs are not indicated for all types of seizures. For example, phenytoin is effective in treating tonic-clonic and partial seizures but is not effective in treating absence seizures.

Pharmacophysiology: Action of Antiseizure Drugs

Antiseizure drugs work in one of three ways: (1) by suppressing sodium influx through the drug binding to the sodium channel when it is inactivated, which prolongs the channel inactivation and thereby prevents neuron firing; (2) by suppressing the calcium influx, which prevents the electric current generated by the calcium ions to the T-type calcium channel; or (3) by increasing the action of gamma-aminobutyric acid (GABA), which inhibits neurotransmitters throughout the brain. The drugs that suppress sodium influx are phenytoin, fosphenytoin, carbamazepine, oxcarbazepine, valproic acid, topiramate, zonisamide, and lamotrigine. Valproic acid and ethosuximide are examples of drugs that suppress calcium influx. Examples of drug groups that enhance the action of GABA are barbiturates, benzodiazepines, and tiagabine. Gabapentin promotes GABA release.

Hydantoins

The first antiseizure drug used to treat seizures was phenytoin, a hydantoin discovered in 1938 and still commonly used for controlling seizures. Hydantoins inhibit sodium influx, stabilize cell membranes, reduce repetitive neuronal firing, and limit seizures. By increasing the electrical stimulation threshold in cardiac tissue, it also acts as an antidysrhythmic. It has a slight effect on general sedation, and it is nonaddicting. However, this drug should not be used during pregnancy because it can have a teratogenic effect on the fetus.
 
icon Patient Safety

Do not confuse:

Cerebyx, a hydantoin antiseizure drug, with Celebrex, a nonsteroidal antiinflammatory drug (NSAID). The names of these drugs look and sound alike but are different in their pharmacology.
Drug dosage for phenytoin and other antiseizure drugs is age related. Newborns, persons with liver disease, and older adults require a lower dosage because of a decrease in metabolism that results in more available drug. Conversely, individuals with an increased metabolic rate, such as children, may require an increased dosage. The drug dosage is adjusted according to the therapeutic plasma or serum level. Phenytoin has a narrow therapeutic range of 10 to 20 mcg/mL, which is generally considered equivalent to 1 to 2 mcg/mL unbound or free phenytoin. The benefits of an antiseizure drug become apparent when the serum drug level is within the therapeutic range. Typically, if the drug level is below the desired range, the patient is not receiving the required drug dosage to control seizure activity. If the drug level is above the desired range, drug toxicity may result. Monitoring the therapeutic serum drug range is of utmost importance to ensure drug effectiveness. Prototype Drug Chart 19.1 lists the pharmacologic data associated with phenytoin.

Pharmacokinetics

Phenytoin is slowly absorbed from the small intestine. It is a highly protein-bound (90% to 95%) drug, therefore a decrease in serum protein or albumin can increase the free phenytoin serum level. With a small to average drug dose, the half-life of phenytoin is approximately 24 hours, but the range can be from 7 to 42 hours. Phenytoin is metabolized to inactive metabolites, and this portion is excreted in the urine.

Pharmacodynamics

The pharmacodynamics of orally administered phenytoin include onset of action within 30 minutes to 2 hours, peak serum concentration in 1.5 to 6 hours, steady state of serum concentration in 7 to 10 days, and a duration of action dependent on the half-life of up to 45 hours. Oral phenytoin is most commonly ordered as a sustained-release (SR) capsule. The peak SR concentration time is 4 to 12 hours.
Intravenous (IV) infusion of phenytoin should be administered by direct injection into a large vein via a central line or peripherally inserted central catheter (PICC). The drug may be diluted in saline solution; however, dextrose solution should be avoided because of drug precipitation. The manufacturer recommends use of an in-line filter when the drug is administered as an infusion. IV phenytoin, 50 mg or a fraction thereof, should be administered over 1 minute for adults and at a rate of 25 mg/min for older adults. Infusion rates of more than 50 mg/min may cause severe hypotension or cardiac dysrhythmias, especially for older and debilitated patients. Local irritation at the injection site may be noted, and sloughing—formation of dead tissue that separates from living tissue—may occur. The IV line should always be flushed with saline before and after each dose to reduce venous irritation. Intramuscular (IM) injection of phenytoin irritates tissues and may cause damage. For this reason, and because of its erratic absorption rate, phenytoin is not given by the IM route.
 
icon PROTOTYPE DRUG CHART 19.1Phenytoin

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