Anticonvulsant

Abstract

Anticonvulsant medications are used in the treatment of epilepsy as neuropathic pain, migraine and psychiatric illness. Anticonvulsants suppress neuronal excitation to reduce the likelihood of seizure activity.

Generally, management is supportive with correction of physiological and metabolic parameters. Drug concentrations may help guide specific treatments such as l-carnitine (for valproate) and multiple dose activated charcoal (for carbamazepine, phenytoin, phenobarbital) Extracorporeal treatments may be used to enhance elimination.

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History

The history of anticonvulsants traces back thousands of years, with early treatments for seizures dating back to ancient civilizations. Some of the earliest known remedies included herbs, minerals, and rituals aimed at warding off evil spirits thought to cause seizures. In the 19th century, the discovery of bromides and phenobarbital marked significant advancements in the pharmacological management of epilepsy. These compounds demonstrated anticonvulsant properties and were widely used for decades.

The mid-20th century saw the introduction of newer anticonvulsants, such as primidone, ethosuximide, and carbamazepine. These medications offered improved efficacy and tolerability compared to earlier options. The late 20th and early 21st centuries witnessed the development of second-generation anticonvulsants, including valproate, lamotrigine, gabapentin, and pregabalin. These drugs offered expanded treatment options and reduced side effects for individuals with epilepsy and other seizure disorders.

Introduction

An anticonvulsant is a medication primarily used to prevent or control seizures in individuals with epilepsy. They work by stabilizing the electrical activity in the brain. Some common anticonvulsants include phenytoin, carbamazepine, valproic acid, and levetiracetam. These medications may also be used to treat other conditions like bipolar disorder and neuropathic pain.

Anticonvulsants are medications used to prevent or reduce the severity and frequency of seizures in people with epilepsy. They work by stabilizing the electrical activity in the brain. They can also be used to treat other conditions like bipolar disorder and neuropathic pain.

Classification

1. Barbiturates: Phenobarbital, Mephobarbital

2. Hydantoins: Phenytoin sodium, ethotoin, mephenytoin.

3. Oxazolidine diones: Trimethadione, Paramethadione

4. Succinimides: Phensuximide, methsuximide, ethosuximide

5. Urea and monoacyl ureas: Phenacemide, Carbamazepine

6. Benzodiazepines: Clonazepam, Diazepam

7. New generation of antiepileptics : Levetiracetam, Gabapentin, Felbamate and Valproic acid.

USES

Antiseizure Medications (Formerly Known as Anticonvulsants) Antiseizure medications (anticonvulsants) help treat epilepsy and other causes of seizures. They can treat other conditions as well, like anxiety and neuropathic pain.

Anti-seizure medications (anticonvulsants) were originally designed to treat people with epilepsy. But the nerve-calming qualities of some of these medications can also help quiet the burning, stabbing or shooting pain often caused by nerve damage.

Therapeutic uses

• Antiseizure: used in the treatment of grand mal epilepsy and tonic-clonic seizure disorders, not in absence seizures.

• Treatment on peripheral neuralgia.

• Antiarrhythmias

Clinical uses

• Absence seizures (petit mal): ethosuximide or valproate. Valproate is used when absence seizures coexist with tonic-clonic seizures, since most drugs used for tonic-clonic seizures may worsen absence seizures.

• Myoclonic seizures: valproate or clonazepam.

• Status epilepticus: must be treated as an emergency, with diazepam intravenously.

Side Effects

Common side effects of anticonvulsants include:

drowsiness, dizziness, headache, nausea, tremor, weight changes, mood changes, hair loss, gum problems and skin rash.

Rare but serious side effects like:

liver problems, suicidal thoughts, birth defects, and severe allergic reactions require immediate medical attention.

To minimize side effects, follow your doctor's instructions, start with a low dose, take the medication with food, avoid driving if drowsy, and discuss potential interactions with other medications.

Talk to your doctor about any concerns regarding the benefits and risks of anticonvulsant use.

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Mechanism of action

Anticonvulsants work by stabilizing the excitable membranes in the brain, which helps reduce the excessive electrical activity that leads to seizures.

They do this by either enhancing the activity of inhibitory neurotransmitters (like GABA) or by reducing the activity of excitatory neurotransmitters (like glutamate).

Each anticonvulsant may have a slightly different mechanism, but they generally target these pathways to prevent or reduce seizure activity.

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Kinetics

Absorption

All antidepressants (AEDs) are available in oral formulations with varying dosing frequencies, with only a few available in intravenous (IV) formulations. IV administration is typically reserved for medical emergencies or when drug therapeutic levels need to be achieved quickly. AEDs with short half-lives are typically administered 3 or 4 times a day, while those with long half-lives are administered once or twice a day. Prolonged-release oral formulations, such as extended-release (ER) or delayed-release tablets or capsules, are designed to prolong absorption of short half-lives.

Current AEDs have different oral bioavailabilities, with most being absorbed by passive diffusion in the gastrointestinal tract. Gabapentin absorption is dependent on a saturable low-capacity L-amino acid transporter in the proximal portion of the small bowel. Strategies to improve or optimize gabapentin bioavailability involve administering smaller doses at more frequent intervals. Gabapentin enacarbil, a recently developed prodrug of gabapentin, has improved bioavailability compared to gabapentin in the fed state.

Coadministration with food can slow the absorption rate of most AEDs, but this does not have a clinically relevant effect on the extent of absorption. Most AEDs can be administered with or without food, and coadministration with food can reduce GI irritation and dose-dependent adverse effects associated with excessive drug peak blood levels.

A study by Yagi et al found that administering phenytoin suspension or gabapentin with antacids containing aluminum, magnesium, and calcium reduces bioavailability. The study found that the AUC of gabapentin decreased by 43% when coadministered with magnesium oxide, indicating a reduction in intestinal absorption. It is recommended that both antacids and phenytoin be taken at least 2 hours apart to ensure adequate absorption and minimize serum concentration fluctuation.

Distribution

The distribution of Antiepileptic Drugs (AEDs) in the body is influenced by individual volume of distribution (Vd), which is used for loading dose calculations. AEDs, such as gabapentin, vigabatrin, and pregabalin, are bound to serum proteins, mainly albumin, to varying degrees. Protein binding is linear, with the percent free fraction being constant within serum concentration. Valproic acid is the only exception, with its free fraction being concentration-dependent.

AEDs with a high protein binding (≥90%) are associated with clinically relevant protein-binding interactions, resulting in significant changes in drug effect. Phenytoin, valproic acid, tiagabine, and perampanel have the greatest plasma protein binding. Phenytoin has the highest risk for protein-binding interactions among all AEDs due to its narrow therapeutic index and nonlinear pharmacokinetics. Perampanel and tiagabine do not seem to have high risk for protein-binding interactions.

Protein binding of valproic acid and phenytoin can be reduced in the presence of decreased serum albumin levels or hypoalbuminemia associated with pregnancy, malnutrition, nephrotic/uremic states, liver disease, or when antiepileptic medication is coadministered with other highly protein-bound medications. Salicylates and certain nonsteroidal anti-inflammatory drugs can significantly displace valproic acid from albumin-binding sites, increasing the free fraction of phenytoin or valproic acid.

To decrease the risk of adverse effects and complications, clinicians should closely monitor for dose-dependent adverse effects and toxicities, adjusting medication doses for altered or unpredictable protein-binding capacity of AEDs.

Metabolism

Most AEDs undergo metabolic conversion to active or inactive metabolites in the liver. This is primarily through hydroxylation via the CYP450 enzyme system and/or conjugation with glucuronide metabolites by uridine glucuronate-glucuronyltranferase (UGT) (Table 2).3-12,14,16,18-21,23-29,31 A large proportion of AEDs are substrates for major CYP450 isoenzymes (including CYP1A2, CYP3A4, CYP2C9, and CYP2C19) and UGT isoenzymes. This makes them more susceptible to drug interaction with agents with induction (eg, rifampin, phenytoin, carbamazepine, phenobarbital, primidone, and St John's wort) or inhibition (eg, cimetidine, azole antifungals, macrolide antibiotics, nondihydropyridine calcium channel blockers, and grapefruit juice) properties of CYP450 and UGT isoenzymes (eg, valproic acid/divalproex sodium/valproate sodium).3-12,14,16,18-21,23-29,31 In order to predict or identify drug-drug interactions, understanding of CYP450 isoenzymes and other major enzyme systems involved in metabolism of individual AEDs is important.

Elimination

The elimination capacity is saturable causing dose dependent kinetics, which again means disproportional changes in plasma level with changes in dose. Great individual variations exist in the rate of metabolism, and several pharmacokinetic drug interactions are known.

Drug-Interactions

PHARMACOKINETIC INTERACTIONS WITH AEDS (Antiepileptic Drug Interactions):

Pharmacokinetic interactions in clinical settings can be categorized into three levels: Level 1 and 2, which involve potentially serious clinical consequences, Level 2 which require cautiousness and possible dosage adjustments, and Level 3 which do not require dosage adjustments.

Older antidepressants (AEDs) are known enzyme inducers or inhibitors, causing interactions with AEDs that can have serious clinical implications. Understanding these interactions can help rationalize therapeutic approaches and avoid unnecessary risks.

However, the clinical significance of some interactions may be questioned if the changes in serum concentrations are minor. Newer AEDs are less susceptible to pharmacokinetic interactions but may be affected by other AEDs or drug classes.

Recently, four new AEDs have been marketed, with lacosamide not being involved in pharmacokinetic interactions. Rufinamide appears to be involved in some interactions, and stiripentol has greater interaction potential, but its use is limited to special pediatric populations.

Tables 1 and 2 illustrate the main metabolic pathways, enzymes, and susceptibility to drug interactions between antiepileptic drugs (AEDs) and other drugs. These interactions can be pharmacokinetic or pharmacodynamic, with pharmacokinetic interactions involving changes in absorption, distribution, or elimination, and pharmacodynamic interactions involving synergism and antagonism at the site of action.

Most clinically important interactions of AEDs result from induction or inhibition of drug metabolism. Carbamazepine, phenytoin, phenobarbital, and primidone are strong inducers of cytochrome P450 and glucuronizing enzymes, which can reduce the efficacy of co-administered medications.

Oxcarbazepine, eslicarbazepine acetate, felbamate, rufinamide, topiramate, and perampanel have weaker inducing properties and a lower propensity to cause interactions mediated by enzyme induction.

Enzyme inhibition results in decreased metabolic clearance of the affected drug, leading to toxic effects.

Pharmacodynamic interactions between AEDs may have potentially beneficial effects, such as the therapeutic synergy of valproic acid combined with lamotrigine, or adverse effects, such as the reciprocal potentiation of neurotoxicity observed in patients treated with a combination of sodium channel blocking antiepileptic drugs.

Table 1

Table 2

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Condition OF Treat

Antiseizure medications (previously known as antiepileptic or anticonvulsant medications) are prescription medications that help treat and prevent seizures. Healthcare providers may prescribe these medications to treat other conditions as well.

A seizure happens when you have a temporary, unstoppable surge of electrical activity in your brain. This overloads the affected areas of your brain.

It can cause a wide range of symptoms, including: