By: Aya Alrmah
Understanding how antiepileptic drugs (AEDs) work is not only crucial for individuals living with epilepsy but also for society as a whole. Epilepsy affects millions of people worldwide, and AEDs play a vital role in managing the condition and reducing the frequency and severity of seizures. By gaining a deeper understanding of how these medications exert their effects on the brain, people with epilepsy can empower themselves with knowledge about their treatment options. Exploring the mechanisms through which AEDs modulate neuronal activity offers insights into the underlying causes of seizures and helps individuals make informed decisions about their healthcare.
First and foremost, epilepsy is a chronic neurological condition that disrupts the electrical impulses of the brain, resulting in seizures and irregular behavior. Seizures occur due to the hyperexcitability of the nervous system, and thus, their suppression involves minimizing excess electrical activity. To treat this condition, the aim is to depress specific neurological impulses, depending on the type of epilepsy.
Let’s delve into how certain AEDs work and gain a better understanding of their mechanism of action. Currently, there are three major mechanisms that AEDs follow. The first mechanism involves regulating voltage-gated channels, which are responsible for initiating electrical impulses in neurons and other cells. The second mechanism involves utilizing inhibitory neurotransmitters such as γ-Aminobutyric acid (GABA) to reduce excessive electrical activity, while the third mechanism involves attenuating glutamate-mediated excitatory neurotransmission.
Regulation of voltage-gated channels:
AEDs that target voltage-gated channels aim to block the channels and reduce the frequency of electrical impulses. Among these channels, sodium channels are the primary focus for a major group of AEDs. Sodium channels operate through three phases: resting to open, open to inactivated, and inactivated to resting. The channel is unable to respond to further electrical impulses until it returns to the resting state.
Drugs in this group bind to the sodium channel during its inactivated state, slowing down the cycle and inhibiting the cell’s ability to respond to additional electrical impulses. Some common drugs that target sodium channels include phenytoin and carbamazepine, which serve as prototypes for many new AEDs.
Inhibitory neurotransmitter GABA:
GABA neurotransmitters help decrease the excitability of neurons, making their potentiation desirable in epilepsy cases. Enhancing GABA’s efficacy can be achieved by increasing its concentration, enhancing its effect by binding to its receptors, or decreasing its metabolism and prolonging its life.
Barbiturates like phenobarbital and benzodiazepines such as diazepam bind to the GABA-A receptor, enhancing GABA’s inhibitory effects. Another AED, tiagabine, inhibits the uptake of GABA, prolonging its presence in circulation.
Decreasing glutamate-mediated excitatory neurotransmission:
Perampanel works by targeting alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, which are found on glutamate-gated channels. By binding to the receptor meant for glutamate, perampanel prevents glutamate from binding to the channel and exerting its effect.
Gaining insight into the mechanisms of action of antiepileptic drugs is a critical step toward developing effective treatment strategies for epilepsy. By targeting voltage-gated channels, enhancing inhibitory neurotransmitters like GABA, and attenuating glutamate-mediated excitatory neurotransmission, these medications aim to reduce abnormal electrical activity in the brain and reduce the frequency of seizures. Continued research and advancements in understanding the intricate workings of the brain hold promise for the development of innovative antiepileptic drugs, leading to improved management and quality of life for individuals living with epilepsy.
Resources:
Science Direct (n.d.). GABA Reuptake Inhibitor. Science Direct. Retrieved from: https://www.sciencedirect.com/topics/neuroscience/gaba-reuptake-inhibitor
Science Direct (2018). AMPA Receptor. AMPA receptors (AMPARs) are heteromeric protein receptors consisting of combinations of four different subunits GluA1, GluA2, GluA3, and GluA4 (formerly GluR1-4) (Xue et.al., 2017). Science Direct. Retrieved from: https://www.sciencedirect.com/topics/neuroscience/ampa-receptor#:~:text=AMPA%20receptors%20are%20glutamate%2Dgated,critical%20for%20normal%20brain%20function.
Sills, G.J. (n.d.). Mechanisms of action of antiepileptic drugs. Department of Molecular and Clinical Pharmacology, University of Liverpool. Retrieved from: https://epilepsysociety.org.uk/sites/default/files/2020-08/Chapter25Sills2015.pdf
World Health Organization (2019). Epilepsy: Report by the Director-General. World Health Organization. Retrieved from:https://apps.who.int/gb/ebwha/pdf_files/EB146/B146_12-en.pdf
