Effects on ion channels
A critical mechanism for preventing seizures is the stabilization of neuronal membranes through the blockade of voltage-gated ion channels.
Sodium channel blockade These drugs act on the presynaptic membrane, preventing the propagation of pathological excitation and suppressing high-frequency discharge generation. This group includes phenytoin, carbamazepine, lamotrigine, and, partially, valproic acid.
Calcium channel modulation Medications can act at both presynaptic and postsynaptic levels:
- T-type channels are located postsynaptically (especially in thalamic neurons, which is critical for the development of absence seizures). They are specifically blocked by ethosuximide and valproic acid.
- High-voltage channels are located on the presynaptic membrane. Their blockade reduces calcium influx into the terminal and decreases the release of the excitatory neurotransmitter glutamate. A key drug with this mechanism is gabapentin, which binds to the specific $\alpha_2\delta$-subunit of the channel.
Interference with neurotransmission
The second global strategy is altering the balance between the inhibitory and excitatory systems of the central nervous system.
Enhancement of GABAergic transmission GABA (gamma-aminobutyric acid) is the main inhibitory neurotransmitter. Its activity can be pharmacologically increased in three ways:
- Direct receptor action: allosteric modulation of GABA receptors on the postsynaptic membrane enhances chloride ion influx into the cell, causing hyperpolarization. This is how benzodiazepines and phenobarbital work.
- Reuptake inhibition: inhibition of GABA transporters increases the concentration of the neurotransmitter in the synaptic cleft (tiagabine).
- Metabolism inhibition: irreversible blockade of the enzyme GABA transaminase (GABA-T) in glial cells prevents the destruction of the inhibitory neurotransmitter (vigabatrin).
Suppression of glutamatergic transmission Drugs can directly decrease the activity of the excitatory system. For example, felbamate acts as an antagonist of postsynaptic NMDA receptors, blocking the action of glutamate and glycine.
Drug selection based on seizure type
The clinical use of antiepileptic drugs strictly depends on the form of epilepsy:
- Major convulsive seizures (generalized tonic-clonic): main drugs are used (carbamazepine, valproic acid, phenytoin, lamotrigine), barbiturates (phenobarbital, benzobarbital, primidone), as well as topiramate and vigabatrin.
- Minor seizures (absence seizures): the specific drug of choice is ethosuximide. Broad-spectrum agents (valproic acid, lamotrigine) and clonazepam are also effective.
- Myoclonic epilepsy: valproic acid, clonazepam, lamotrigine.
- Partial (focal) seizures: broad-spectrum agents overlapping with major seizure therapy are used, plus adjunct drugs (gabapentin, topiramate, vigabatrin, clonazepam).
- Status epilepticus: requires emergency therapy. First-line drugs are intravenous benzodiazepines (diazepam, lorazepam, clonazepam). Phenobarbital and phenytoin are used as alternatives or additions.
Features of phenytoin
Phenytoin (INN, also known as diphenylhydantoin) is a hydantoin derivative. Historically, it is the first anticonvulsant agent introduced into clinical practice back in 1938.
Its key pharmacodynamic feature lies in the principle of frequency dependence (use-dependent). The drug binds to sodium channels exclusively in their inactivated state and slows their reactivation. The degree of binding directly depends on the frequency of channel opening. This means that the more hyperactive the neuron is (within the epileptic focus), the stronger the effect of phenytoin on it. It is this selective action on pathological discharges that allows the drug to control seizures without general CNS depression and without a hypnotic effect.
In addition to its antiepileptic action (prevention of partial and major seizures, termination of status epilepticus), phenytoin exhibits antiarrhythmic properties, especially in digitalis glycoside toxicity, and analgesic effects, which have found application in the treatment of trigeminal neuralgia.
Briefly: answers to topical questions
What side effects are characteristic of phenytoin?
Phenytoin is characterized by a wide range of side effects affecting various body systems.
- Neurotoxicity — dizziness, agitation, tremor, nystagmus, ataxia, diplopia.
- Skin and connective tissue manifestations — hyperplastic gingivitis (gingival hyperplasia) and hirsutism.
- Metabolic disorders — folate deficiency with the development of megaloblastic anemia and impaired vitamin D metabolism (osteomalacia).
- Gastrointestinal tract — nausea and vomiting.
- Other effects — allergic reactions, hypersensitivity reactions, and teratogenic effects (fetal hydantoin syndrome).
Which antiepileptic drugs suppress glutamatergic transmission?
Glutamatergic transmission is suppressed by several antiepileptic drugs with different mechanisms of action.
- Felbamate — acts as an antagonist of NMDA receptors on the postsynaptic membrane, blocking the action of glutamate and glycine.
- Topiramate — blocks excitatory amino acid receptors (kainate subtype glutamate receptors).
- Gabapentin — reduces calcium ion influx into the presynaptic terminal, which decreases the release of excitatory neurotransmitters, notably glutamate.
Which antiepileptic drugs have teratogenic effects?
The following antiepileptic drugs have teratogenic effects posing a danger during pregnancy:
- Phenytoin (Phenytoinum) — causes fetal hydantoin syndrome, which represents a risk of fetal malformations when taken during pregnancy.
- Carbamazepine — carries a risk of teratogenic effects, and therefore is prescribed during pregnancy only for life-saving indications.
Which antiepileptic drugs are hepatic microsomal enzyme inducers?
The following antiepileptic drugs are hepatic microsomal enzyme inducers:
- Phenytoin (Phenytoinum) — a potent inducer that accelerates the metabolism and decreases the concentration of other drugs.
- Carbamazepine — induces hepatic enzymes, lowering the concentration of other drugs, and also causes autoinduction, accelerating its own metabolism.
- Barbiturates (e.g., phenobarbital) — cause enzyme induction, leading to a decrease in the concentration of other drugs in the blood.
To remember the unique mechanism of valproic acid: it has a "mixed" action and hits three targets at once — it blocks sodium channels, blocks T-type calcium channels, and increases GABA levels.
Class and exam questions
Why doesn't phenytoin cause pronounced drowsiness during treatment?
Phenytoin exhibits the property of use-dependence. It selectively blocks only those sodium channels that operate in a hyperactive mode (in the epileptic focus) without affecting normally functioning neurons, and therefore does not exert a sedative effect.
Which drug is specific for the treatment of absence seizures?
The drug of choice for the prevention of minor seizures (absences) is ethosuximide. It works by blocking postsynaptic T-type calcium channels.
What is the mechanism of action of gabapentin?
Gabapentin blocks high-voltage calcium channels of the presynaptic membrane by binding to their alpha-2-delta subunit. This leads to a decrease in calcium ion influx and a reduction in glutamate release into the synaptic cleft.
How do tiagabine and vigabatrin affect inhibitory neurotransmission?
Tiagabine inhibits GABA reuptake from the synaptic cleft, while vigabatrin irreversibly blocks the enzyme GABA transaminase in glia, preventing the degradation of this inhibitory neurotransmitter.
What else to study on this topic
- Detailed pharmacodynamics of benzodiazepines in status epilepticus
- Comparison of sodium channel blockers (phenytoin, carbamazepine, lamotrigine)
- Morphological differences between T-type calcium channels and high-voltage-activated channels
- Clinical use of phenytoin in cardiology (antiarrhythmic effect)
- Pharmacological effects of NMDA receptor blockade by felbamate
Master the entire topic in the «Pharmacology» course
This is a summary. The course covers everything tested in classes and exams.
- Complete study guide on "Antiepileptic Drugs" and another 5,304 pages of the subject
- Assignments and quizzes after every topic — just like in a colloquium
- AI tutor answers questions on the topic anytime
- 116 video lessons on the subject
Other topics in the section "Agents Used in Psychiatry and Neurology"
Free video lessons: pharmacologyShort lessons with study notes — no registration required.
Prepared by WhiteCoat Pro faculty in accordance with the medical school curriculum. For educational purposes only.