NCBI Bookshelf. An Introduction to Epilepsy [Internet]. Epilepsy is the tendency to have recurrent seizures unprovoked by systemic or acute neurologic insults. The older term, anticonvulsant drug, is still sometimes used as a synonym for AED, but is less accurate because many seizures do not involve convulsive movements. There is no convincing evidence that AEDs "cure" or alter the natural history of epilepsy.
However, many patients whose seizures have been completely controlled for two or more years can be successfully withdrawn from AEDs. The therapeutic goal is maximizing seizure control while minimizing adverse drug effects, thus improving the patient's quality of life. Slide 3. The first effective AED was potassium bromide, discovered serendipitously in the mid-nineteenth century.
Phenobarbital came into use in the early twentieth century, followed by phenytoin in the late s, the latter resulting from systematic investigations by Merritt and Putnam using an animal seizure model.
Slide 4 Trimethodione, discovered in , was the first AED specific for the treatment of absence seizures. Many of the early AEDs were modifications of these compounds.
The last decade has seen the development of eight new AEDs. Slides 6 and 7 show chemical structures of several AEDs. Most older drugs share a 5- or 6-membered heterocyclic ring which includes one or two nitrogen atoms and a wide variety of side chains, sometimes containing other ring structures.
The shared heterocyclic ring structure may underlie the allergic reactions in some patients to more than one drug.
Structures of the newer drugs possess fewer similarities to the older agents and to each other reflecting perhaps unique mechanisms of drug action. Slide 5. Because AEDs constitute the mainstay of epilepsy therapy, effective treatment requires an understanding of AED pharmacology and pharmacokinetics.
Pharmacology - Antiepileptics
Principles of general pharmacology will be reviewed briefly in the specific context of AED use. Slides 6 — 8.
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A seizure is the clinical manifestation of a hyperexcitable neuronal network, in which the electrical balance underlying normal neuronal activity is pathologically altered—excitation predominates over inhibition see Basic Mechanisms syllabus. Effective seizure treatment generally augments inhibitory processes or opposes excitatory processes.
Since the normal resting neuronal membrane potential is intracellularly negative, inhibitory processes make the neuron more electrically negative, hyperpolarizing the membrane, while excitatory processes make the intracellular potential less negative or more positive, depolarizing the cell. On an ionic level, inhibition is typically mediated by inward chloride or outward potassium currents, and excitation by inward sodium or calcium currents.
Drugs can directly affect specific ion channels or indirectly influence synthesis, metabolism, or function of neurotransmitters or receptors that control channel opening and closing. The most important central nervous system inhibitory neurotransmitter is gamma-amino-butyric acid GABA.
Antiepileptic Drugs, 4th Ed
The most important excitatory neurotransmitter is glutamate , acting through several receptor subtypes. Slide 9.
Table 1 summarizes proposed mechanisms of action of the major AEDs. Blocking voltage-gated sodium channels during rapid rates of neuronal discharge appears to be the primary mechanism of action of several AEDs, particularly the two first-line drugs for partial epilepsies, phenytoin and carbamazepine; this mechanism also appears to be at least partly responsible for the antiepileptic effects of newer drugs such as lamotrigine and topiramate.
This rate-dependent action is crucial, addressing the requirement that AEDs should affect pathologic more than physiologic neuronal excitation, since a drug with similar effects on all excitation would produce deep coma as an inevitable side effect. Slides 10 — Principles of antiepileptic drug action. In Antiepileptic Drugs, Fourth Edition. New York: Raven Press, — Barbiturates and benzodiazepines act directly on subunits of the GABA receptor-chloride channel complex. Barbiturates increase the duration of chloride channel openings, while benzodiazepines increase the frequency of these openings.
Tiagabine inhibits GABA re-uptake from synapses. Vigabatrin, a drug not available in the U. Gabapentin was designed as a lipophilic GABA analogue, but does not function as a receptor agonist; its mechanism of action is unknown. Calcium current into the neuron is another important excitatory mechanism.
There are several different calcium channel types, but nonselective calcium channel blockers have low antiepileptic efficacy. Ethosuximide selectively blocks transient "T-type" calcium currents in thalamic neurons, which inhibits the thalamocortical circuits responsible for generating the EEG spike-wave complex underlying absence seizures. Excitatory neurotransmission mediated by calcium and sodium currents through glutamate receptors has been a tempting target for new AEDs, because these currents may contribute not only to seizure generation but also to neuronal damage from status epilepticus and stroke.
Direct glutamate receptor antagonists are effective against experimental seizures, but frequently cause psychosis and other neuropsychiatric adverse effects, preventing clinical use.
However, several newer, better tolerated drugs, including lamotrigine and topiramate, may act on this system indirectly. This is determined by route of intake. Most AEDs are available for oral administration, although some have formulations that are also available for intravenous, intramuscular or rectal administration. Slide Most AEDs undergo complete or nearly complete absorption when given orally. Most often, administration of AEDs with food slows absorption and can help avert peak dose related side effects.
Calcium containing antacids may interfere with phenytoin absorption. Gabapentin is absorbed by a saturable amino acid transport system and does not get absorbed after a certain dose. Fosphenytoin may be administered intramuscularly if intravenous access cannot be established in cases of frequent repetitive seizures. Diazepam available as a rectal gel has been shown to terminate repetitive seizures and can be administered by family members at home.
This route is used for emergencies.
Phenytoin, fosphenytoin, phenobarbital, diazepam, lorazepam and valproic acid are available as IV preparations see section on status epileptics for side effects related to intravenous use.
Following absorption into the bloodstream, the drug is distributed throughout the body. Lipid solubility and protein binding affect CNS availability. Drugs can displace others from albumin and protein binding is responsible for many pharmacokinetic interactions between AEDs. An example of this is the interaction between phenytoin and valproic acid. If valproic acid is added to a patient who is already taking phenytoin, the phenytoin is displaced from albumin binding sites, resulting in a higher free fraction and toxicity.
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Most AEDs are metabolized in the liver by hydroxylation or conjugation. These metabolites are then excreted by the kidney. Some metabolites are themselves active carbamazepine, oxcarbazepine, primidone. Gabapentin undergoes no metabolism and is excreted unchanged by the kidney. Most AEDs are metabolized by the P enzyme system in the liver. Different AEDs either induce or inhibit certain isoenzymes of this system and can result in changes of the pharmacokinetic properties of different medications Table 2.
In general enzyme inducers decrease the serum concentrations of other drugs metabolized by the system and enzyme inhibitors have the opposite affect.
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Valproic acid is metabolized by a combination of conjugation by uridine glucuronate UDP -Glucuronyltranferase UGT via conjugation and by mitochondrial beta-oxidation. Slides 17 — Adding an enzyme inducer to a substrate decreases the serum concentration of the substrate, while withdrawing an inducer or adding an enzyme inhibitor has the opposite effect.
This changes for some drugs based on serum concentration e. The half-life also determines the dosing frequency required for a drug to be maintained at a steady state in the serum.
Most drugs are eliminated by the kidneys and dosage adjustments are required in cases of renal impairment. AEDs can have a narrow range within which seizures are controlled without toxicity. This concept is quantified as the "therapeutic index" TI. The " therapeutic range " of AED serum concentrations is an attempt to translate the experimental concept of therapeutic index to the clinic. These ranges are broad generalizations which are of limited use and can be misleading when applied to individual patients.
Many patients tolerate and need serum concentrations above the usual therapeutic range, while others achieve complete seizure control, or even experience adverse effects, at concentrations below it. Table 3 shows these ranges for common AEDs, as well as pharmacokinetic parameters relevant to clinical use.
Slides 29 — Drug interactions based on pharmacokinetics, or "what the body does to the drug," must be distinguished from those based on pharmacodynamics, or "what the drug does to the body.
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Gabapentin, for example, has no important pharmacokinetic interactions with other AEDs. Because gabapentin and many other drugs can cause sedation and dizziness, however, pharmacodynamic interactions can occur.
Ideally, drug combinations should produce additive or synergistic supra-additive therapeutic effects and sub-additive toxicities. Drug combinations with different mechanisms of action may help achieve this goal. Slides 35 — Age and systemic conditions can influence pharmacokinetic and pharmacodynamic parameters.
Elimination of many drugs is slower in the elderly, mainly because of reduced hepatic and renal blood flow, which lengthens drug half-life above published values based on young adults. In addition, albumin levels fall with age; this increases the free fraction of drugs that are highly protein bound, thus increasing risk of toxicity, especially for highly protein-bound drugs.
Further, older people are often more sensitive to drug effects at a given free level. In the elderly, AEDs should usually be started at a lower dose and increased at a slower rate than in younger patients. Drug metabolism and disposition in children can differ significantly from that in adults.
Beyond the neonatal period, when protein binding and drug metabolic rates are low, children usually have faster drug elimination rates and reduced serum half-lives relative to adults.
Furthermore, because of shorter pediatric half-lives, most AEDs require at least 3 times daily administration in children 1—10 years of age. Despite frequent drug administration, large swings in peak-to-peak concentrations are possible, especially in young children, because of their fast elimination rates.
Solid oral dosage forms overcome this problem by providing a longer absorption phase that reduces peak and increases trough concentrations.