Antiepileptic drugs
- prevent or control epilepsy commonly known as seizure
- seizure is a sudden burst of uncontrolled electrical activity in the brain
- occurs when neurons become excessively active
- generally classified into two major groups:
- Focal seizures: affect initially only a portion of the brain typically one hemisphere
- may occur with or without impairment of awareness
- Generalized seizures: affect both sides of the brain at the same time
- almost always cause loss of consciousness
- seizures can be viewed as the result of an imbalance between inhibitory and excitatory processes in the brain
- either too little inhibition or too much excitation
Content:
1. Excitatory synapse
2. Basic mechanism underlying seizures
3. Side-effects
4. Reference
2. Basic mechanism underlying seizures
3. Side-effects
4. Reference
1. Excitatory synapse
Excitatory neuron when at rest,
- inside is slightly more negative than the outside
- an action potential starts when voltage-gated sodium channels open allowing positively charged sodium ions to rush into the cell
- thus reversing the polarization of the membrane
- consequently membrane depolarization leads to opening of high-voltage-activated calcium channels
- allow positively charged calcium ions enter the neuron
- triggering release of glutamate from the vesicles into the synaptic cleft
- glutamate binds to two types of receptors on the postsynaptic neuron
- AMPA receptors: binding of glutamate open and permit entry of sodium ions
- NMDA receptors: open and permit entry of calcium ions
- calcium may enter through low-voltage-activated calcium channels also known as t-type calcium channels
- t-type calcium channels open in response to small depolarizations at or below resting membrane potential
- All this influx of positive ions again leads to depolarization and propagation of action potential
If there is too much glutamate, neurons can become hyperexcitable and a seizure may result.
But this normally doesn't happen because we also have inhibitory neurons.
- inhibitory neurons release neurotransmitter GABA
- GABA binds to GABA-A receptors on the excitatory neuron
- causes them to open and allow negatively charged chloride ions to enter
- causes the membrane potential to be more negative on the inside
- thus limiting the neurons ability to respond to further stimulation
- once GABA dissociates from the GABA-A receptor, it becomes removed from the synaptic cleft by reuptake through the GABA-transporter-1 (GAT-1)
- degraded by an enzyme gamma-aminobutyric acid aminotransferase (GABA-T)
Hence, with excess of glutamate, too little GABA can also allow neurons to become hyperexcitable which may lead to seizures.
2. Basic mechanism underlying seizures
Main goal of therapeutic interventions: lower neuronal excitability and or enhance neuronal inhibition
Prevent excessive firing of an action potential in neurons👉blocking voltage-gated sodium channels
- block sodium channels and thus reduce the amount of sodium that enters the neuron
- Drug:
- Carbamazepine
- Oxcarbazepine
- Lamotrigine
- Phenytoin
- Topiramate
- Valproic acid
- Zonisamide
Slow down hyperactive neurons👉blocking calcium channels
- inhibit high-voltage-activated calcium channels
- Drug:
- Lamotrigine
- Topiramate
- inhibit low-voltage-activated t-type calcium channels
- Drug:
- Valproic acid
- Zonisamide
Many of the antiepileptic drugs act on multiple targets
- Lamotrigine Topiramate Valproic acid and Zonisamide 👉 inhibit both calcium channels and sodium channels
- Topiramate 👉 inhibit excitatory neurotransmission by blocking AMPA receptors
Gabapentin and Pregabalin
- interacting with high-voltage-activated calcium channels
- bind to an accessory subunit of the high-voltage-activated calcium channel called alpha-2-delta-1
- because the presynaptic channels that contain this specific subunit appear to modulate the release of excitatory neurotransmitters, eg, glutamate
- Inhibition of alpha-2-delta-1 containing calcium channels speculated to be one of the main reasons for their antiepileptic effect
Levetiracetam
- high-voltage-activated calcium channel blocker
- its ability to bind to the SV2A protein found in the walls of vesicles that contain glutamate
- appears to impair the synaptic release of glutamate
- thus decrease neuronal excitability
Felbamate
- inhibits excitatory neurotransmission by blocking NMDA receptors
Drugs that act on the GABA system
- Benzodiazepines and Barbiturates
- work by binding to GABA-A receptor
- thus prolonging the opening of the channel
- permitting greater influx of negatively charged chloride ions into the neuron
Review: 【Pharmacology】Anxiolytic and hypnotic drugs
Tiagabine
- selective inhibitor of the GABA transporter
- blocks GABA reuptake
- permitting more GABA to be available for receptor binding on the postsynaptic neurons
Vigabatrin
- irreversibly inhibits GABA-aminotransferase
- the enzyme responsible for catabolism of GABA
- effectively increasing the concentrations of GABA in the brain
3. Side-effects
- Sedation
- Dizziness
- Hyponatremia (Carbamazepine and Oxcarbazepine)
- Visual field loss (Vigabatrin)
- Double vision (Lamotrigine and Phenytoin)
- Gingival hyperplasia (Phenytoin)
- Hirsutism cognitive problems (Topiramate and Zonisamide)
- Weight loss (Topiramate)
- Weight gain (Valproic acid)
- Peripheral edema (Gabapentin and Pregabalin)
- Liver toxicity (Valproic acid and Felbamate)
- Aplastic anemia (Felbamate)
4. Reference
https://youtu.be/xFUHE9gX6W8
NEXT:
PREVIOUS:
Comments
Post a Comment