A Review of Pharmacodynamics and Pharmacokinetics in Seizure Management.
Pharmacological management of seizures aims to decrease the severity and frequency of the abnormal neuronal activity that characterize seizures. In general, antiepileptic drugs (AEDs) either block the initiation of electrical discharges from a hyperirritable focus or, more commonly, prevent the spread of abnormal electrical discharges to adjacent brain areas. Seizures can be completely controlled with medication in approximately 50% of epileptic patients, and meaningful improvement is attained in an additional 25% of remaining patients.
Pharmacologic management of seizures is not benign. Patients must be closely monitored for therapeutic, toxic and adverse effects, especially during initiation of therapy, during regimen changes, when intercurrent illness occurs and in the presence of factors that predispose the patient to recurrent seizures. In general, the goal of pharmacologic management of epilepsy is to achieve the best seizure control possible with the least adverse effects and amount of drugs. Also, patients must have information about medications and the rationale for ongoing drug treatment. By understanding the effective site of action for AEDs and being familiar with absorption, distribution and elimination of these drugs, the nurse is better able to monitor patient response to therapy, anticipate or treat toxic and adverse effects, and inform patients about treatment to enhance compliance. This article reviews the pharmacodynamics and pharmacokinetics for commonly prescribed AEDs.
There are five classes of agents typically used to control seizures: hydantoins, barbiturates, benzodiazepines, succinamides and diones. There are five additional unique drugs that complete the listing of main pharmacological treatments for epilepsy: carbamazepine, valproic acid, gabapentin, lamotrigine and topiramate. Treatment regimens vary by seizure classification (Table 1). To decrease adverse effects and toxicity, seizures are initially treated with a single drug. When seizures are not controlled with a single drug, adjunctive or alternative agents may be used. For patients with several different types of seizures or refractory seizures, several drugs may be required. The pharmacodynamics of the drugs in Table 1 are detailed below.
Table 1. Classification and Pharmacologic Management of Seizures Seizure First Line Agents New/Alternative Agents Simple Partial phenytoin primidone carbamazepine phenobarbital valproic acid gabapentin lamotrigine felbamate topiramate ethotoin mephenytoin Complex partial phenytoin primidone carbamazepine valproic acid phenobarbital mephobarbital gabapentin lamotrigine felbamate topiramate amobarbital Absence clonazepam methsuximide ethosuximide phensuximide valproic acid lamotrigine trimethadione Myoclonic valproic acid clonazepam Tonic Clonic phenytoin/fosphenytoin phenobarbital carbamazepine primidone valproic acid topiramate Stares epilepticus phenytoin/fosphenytoin diazepam lorazepam phenobarbital diazepam secobarbital pentobarbital
Hydantoins are used to control major motor and complex partial seizures. Because phenytoin is the most commonly prescribed of hydantoin drugs, it is discussed in detail. Phenytoin stabilizes neuronal membranes at the cell body, axon and synapse. It does this by decreasing the influx of sodium ions into neurons in the resting state and during depolarization. Significantly, both voltage- and use-dependent sodium channels are blockaded. Further, phenytoin also reduces the influx of calcium ions during depolarization. At the synapse, phenytoin decreases post-tetanic potentiation and repetitive after-discharge.[1,9] Further, hydantoins have an effect on the cerebellum, activating inhibitory pathways that extend to the cerebral cortex.[1,3,5,9] Thus, phenytoin and other hydantoins block the initiation of electrical discharge by altering cellular depolarization. Phenytoin also inhibits the spread of the abnormal discharge to adjacent brain areas by interfering with synaptic transmission of abnormal impulses. This duality of cellular action helps explain the effectiveness of phenytoin in treating seizures.
The absorption, distribution and elimination of the hydantoins are not equivalent. Phenytoin has a slow and variable gastrointestinal (GI) and intramuscular (IM) absorption. GI absorption is significantly slowed by concurrent oral or gastric administration of folic acid, calcium, vitamin D and enteral feedings.[2,5,9] Intravenous (IV) phenytoin absorption is rapid. Fosphenytoin is a watersoluble prodrug of phenytoin; its actions and kinetics are the same as phenytoin once converted from its prodrug form in the liver. Because fosphenytoin is water soluble and has a more neutral pH compared to phenytoin, it is more rapidly and less painfully absorbed when given via the IV or IM route.[5,9] Ethotoin and mephenytoin, second line AEDs in this class, are rapidly absorbed through the gastrointestinal (GI) system. Once absorbed, rapid distribution to cerebrospinal fluid, saliva, semen, GI fluid, breast milk and across the placenta occurs for all hydantoins. These drugs are bound to plasma proteins and undergo hepatic biotransformation. All hydantoins induce production of liver microsomal enzymes (the cytochrome P-450 system), thereby accelerating the metabolism of concomitantly administered drugs. The half-life of ethotoin is 3-9 hours. The half-life of mephenytoin is about 7 hours with biotransformation yielding an active metabolite, nirvanol, which has its own half-life of 95-144 hours. The apparent half-life of phenytoin varies by dose and serum concentration. This is due to the saturation of the liver enzyme system responsible for metabolizing phenytoin. To explain, as the dosage of phenytoin increases, the hydroxylation system which metabolizes phenytoin becomes loaded and is unable to process additional phenytoin volume. Therefore, small increases in dose produce a large increase in serum concentration as a constant (rather than increased) amount of the drug is metabolized, resulting in drug-induced toxicity. Variable GI absorption may also cause extended half-life, resulting in potential, unexpected toxicity. Hydantoins are eliminated via the renal system primarily as metabolites; excretion is enhanced by alkaline urine. Significant adverse reactions and drug-drug interactions in this class lead to difficulty in establishing an effective dosing regimen. Seven to ten days are required to attain therapeutic serum levels when used to treat chronic (nonstatus epilepticus) seizures.
Barbiturates are effective AEDs which nonselectively suppress CNS activity. Recent studies suggest that barbiturates increase the threshold for electrical stimulation of the motor cortex, possibly by enhancing or mimicking the inhibitory synaptic action of gamma-aminobutyric acid (GABA). Thus, barbiturates limit the spread of seizure activity through central nervous system activity suppression and raise the seizure threshold by rendering a hyperirritable foci less irritable. Phenobarbital is the most commonly prescribed drug in this class. Therapeutic doses should not induce excessive sedative or hypnotic effects, although these are adverse effects commonly reported by patients, especially at induction.[2,4,5,9] Phenobarbital is well absorbed orally although it may take as long as 15 minutes to reach therapeutic levels in the brain after IV administration as it is not particularly lipid-soluble.[8,9] Phenobarbital is a long-acting barbiturate with a half-life of 96 hours. Other barbiturates prescribed in this class are pentobarbital and secobarbitol; their short onset and duration of 3-8 hours limit their use to treatment of status epilepticus. Mephobarbital, primidone and amobarbitol may also be used in combination with other AEDs. This class of drugs is metabolized by the hepatic microsomal system and eliminated via the renal system.
Several benzodiazepines show antiepileptic activity. Diazepam and lorazepam are used in the acute treatment of status epilepticus. Clonazepam is useful for the chronic treatment of absence and myoclonic seizures and clorazepate is effective in partial seizures when used with other AEDs. Benzodiazepines bind to GABA-A receptors in the brain, increasing opening of chloride channels, leading to an inhibitory effect on cell firing. By enhancing presynaptic inhibition, benzodiazpines suppress the spread of seizure activity.[2,5,8,9] They may also increase the seizure threshold of epileptigenic foci. Other neurotransmitters such as serotonin and norepinepherine may be affected, contributing to the therapeutic effects of this class of agents.
The benzodiazepines are lipophilic, rapidly absorbed through the GI tract and distributed throughout the body. The long-acting benzodiazepines, diazepam (clonazepam and clorazepate) form active metabolites which prolong the duration of drug action beyond 1-3 days. Further, steady dosing of these long-acting agents causes accumulation of parent and metabolite compounds which are slowly eliminated over days-to-weeks. Benzodiazepines used to control seizures are metabolized by the hepatic microsomal system and excreted in the urine.[2,5,8,9] Tolerance, sedation and multiple drug-drug interactions limit their use as first-line agents.
The succinimides consist of ethosuximide, methsuximide and phensuximide. These medications are effective in treating absence seizures. The mechanism of action is poorly defined. They are thought to increase the seizure threshold by either directly modifying cell membrane function or altering chemically mediated neurotransmission. There is some evidence that ethosuximide affects slow some calcium channels, resulting in suppressing of abnormal neuronal discharge) These agents are generally rapidly and completely absorbed through the GI tract and freely distributed to all body tissues except fat. Biotransformation is undertaken in the liver; methsuximide is metabolized to an active metabolite, significantly prolonging it's half-life of 1-3 hours.[2,5,9] The half-life of ethosuximide is 50-60 hours in adults and 30-36 hours in children). Phensuxamide has a half-life of 1-4 hours).
Trimethadione is the only dione available in the United States; paramethadione is used overseas and in Canada for absence seizures. Diones, also known as oxazolidinediones, reduce T-type calcium currents in thalamic neurons. This reduction raises the threshold for repetitive activity in the thalamus and inhibits corticothalamic relay transmission, reducing absence seizure activity. They are rapidly absorbed, biotransformed in the liver to active metabolites and slowly eliminated via the renal system.[2,5,8,9] The half-life of trimethadione is 11-16 hours; its active metabolite, dimethadione, has a half-life of about 10 days. The drugs in this class have serious adverse effects including blood dyscrasias and hepatic impairment and are typically used as second-line, or even third-line, agents.
Carbamazepine blocks voltage and used-dependent sodium channels, inhibiting the generation of repetitive post-synaptic activity, thus reducing the propagation of abnormal impulses in the central nervous system.[6,9] Further, blocking presynaptic sodium channels may block release of neurotransmitters and reduce the irritability of an epileptogenic focus. It is a first line agent for all partial seizures and effective in tonic-clonic seizures. Slowly and variably absorbed following oral administration, it is lipid soluble and widely distributed. Carbamazepine induces the metabolizing enzymes in the liver, and its half-life decreases with chronic dosing. Because of its variable absorption, long half-life of 25- 65 hours and autoinduction of metabolism, levels may fluctuate widely during trial dosing. Once stable serum levels are achieved, the half-life is 12-17 hours as a result of autoinduction of metabolism. A stable therapeutic concentration may require a month to achieve.[5,8,9]
Valproic acid is the most effective agent for myoclonic seizures. It can also be used as a second-line drug for absence as well as adjunct medication for tonic-clonic seizures and partial seizures. The mechanism of action is thought to be related to direct or secondary increases in concentrations of GABA, possibly by altering the metabolism of GABA or decreasing the re-uptake of GABA in brain tissue) Alternatively, valproic acid may mimic or enhance the inhibitory action of GABA.[3,4] In animal studies, valproic acid blocks sustained neuronal bursting response by reducing the amplitude of sodium-dependent action potentials. In any case, valproic acid reduces the propagation of abnormal electrical activity. It is rapidly absorbed orally, although absorption can be slowed by the presence of food. It is protein-bound, metabolized by the liver, and excreted via the kidneys. Some metabolites have active or toxic activity. Its half-life varies from six to 16 hours, depending on age and administration of enzyme-inducing medications.
Gabapentin is indicated as an adjunct medication in treatment of partial seizures. Gabapentin is a structural analog of GABA but does not interact with GABA receptors, is not metabolized to GABA and does not inhibit or enhance GABA transmission. There is some evidence that it alters the transport or metabolism of amino acids in the CNS in animal models. Gabapentin is well-absorbed by the GI system, in part via the Lamino transport system. There is limited information about gabapentin's distribution; clearly it penetrates the blood-brain barrier. It's half-life in the presence of normal renal function is 5-7 hours. It is eliminated unchanged in the urine, minimizing drug-drug interactions.[8,9]
Lamotrigine is another relatively new adjunct medication for partial seizures. Its approved use is for those over 16 years of age. Lamotrigine appears to stabilize neuronal membranes and inhibit presynaptic release of neurotransmitters (principally glutamate) by blocking sodium sensitive channels. These actions block the propagation of abnormal impulses. Lamotrigine may also directly inhibit high-frequency sustained repetitive firing of sodium-dependent action potentials. It is rapidly absorbed and widely distributed in body tissues. It undergoes metabolism in the liver; there are conflicting data about whether autoinduction is present. Lamotrigine has a half-life of 15-35 hours; half-life varies with concurrent administration of other anticonvulsants. The half-life is reduced with enzyme-inducing AEDs like the hydantoins and increased with valproic acid. Elimination is primarily via the renal system with less than 2% eliminated through feces.
Topiramate is a relatively new AED approved for adjunct therapy of refractory partial seizures. It is a weak anhydrase inhibitor and appears to act by blocking the spread of seizure activity rather than by raising the seizure threshold.[2,7] Its specific mechanism of action is not known. The half-life of topiramate is 21 hours. It is well absorbed and excreted unchanged primarily in urine. The safety and efficacy of the last three agents (gabapentin, lamotrigine and topiramate) have not been established in children.
Drug therapy is the most widely effective mode of treatment for epilepsy. Knowledge about the mechanisms of action and metabolism for antiepileptic medications has grown significantly in the past decade as understanding of neurotransmitters and cell physiology has evolved. This knowledge has resulted in engineering of new seizure controlling drugs. Understanding the pharmacological actions and pharmacokinetics of AEDs assists the advanced practice nurse in prescriptive decision-making and all nurses in monitoring patient response to therapy. This knowledge can also assist nurses to provide accurate information to patients receiving antiepileptic drugs.
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[4.] Ozuna J: Pharmacologic management of epilepsy: An update. J Neuroscience Nurs 1997; 29; 330-335.
[5.] Mycek MJ, Harvey RA, Champe PC: Pharmacology, 2nd ed. Lippincott-Raven, 1997.
[6.] Natsch S: Newer anticonvulsant drugs, role of pharmacology, drug interactions and adverse reactions in drug choice. Drug Safety 1997; 25; 228-240.
[7.] Privitera MD: Topiramate: A new antiepleptic drug. Ann Pbarmacotber 1997; 31; 1164-1173.
[8.] Smith CM, Reynard AM: Textbook of Pharmacology. WB Saunders, 1992.
[9.] United States Pharmcopeial Drug Information for the Health Care Professional, 18th ed. US Pharmacopeial Convention, 1998.
Chris Winkelman, RN, MSN, 2287 Loyola Road, University Heights, Ohio 44118. She is a staff nurse trauma/critical care float pool at MetroHealth Medical Center and a lecturer at France Payne Bolton School of Nursing, Case Western Reserve University in Cleveland, Ohio.