in this lecture we are going to cover the pharmacology of antiepileptic drugs

so let's get right into it the primary use of antiepileptic drugs is to

prevent or control epilepsy commonly known as seizure a seizure is a sudden

burst of uncontrolled electrical activity in the brain that occurs when

neurons become excessively active seizures can be generally classified

into two major groups depending on where they begin in the brain first focal

seizures affect initially only a portion of the brain typically one hemisphere

and may occur with or without impairment of awareness second generalized seizures

affect both sides of the brain at the same time and almost always cause loss

of consciousness now simplistically seizures can be

viewed as the result of an imbalance between inhibitory and excitatory processes

in the brain that produces either too little inhibition or too much excitation

in order to gain better understanding of how this happens we need to take a

closer look at how neurons pass signals to one another so as you probably already

know the main form of communication among neurons occurs through the

travelling wave of electrical excitation known as an action potential an action

potential is orchestrated by the synchronized opening and closing of ion

channels now if we look at the simple excitatory neuron when at rest the 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 which then allow positively charged calcium ions

enter the neuron thereby triggering release of glutamate from the vesicles

into the synaptic cleft next glutamate binds to two types of

receptors on the postsynaptic neuron first the AMPA receptors that upon binding

of glutamate open and permit entry of sodium ions and the second NMDA

receptors that open and permit entry of calcium ions

in addition to that calcium may enter through low-voltage-activated calcium

channels also known as t-type calcium channels which open in response to small

depolarizations at or below resting membrane potential

so all this influx of positive ions again leads to depolarization and propagation

of action potential now as you can imagine if there is too much glutamate

around neurons can become hyperexcitable and a seizure may result

but this normally doesn't happen because we also have inhibitory neurons around

that put brakes on excitatory impulses these inhibitory neurons release

neurotransmitter GABA which binds to GABA-A receptors on the excitatory neuron

causes them to open and allow negatively charged chloride ions to enter in this

causes the membrane potential to be more negative on the inside relative to the

outside thus limiting the neurons ability to respond to further

stimulation finally once GABA dissociates from the GABA-A receptor it

becomes removed from the synaptic cleft by reuptake through the GABA-transporter-1

GAT-1 for short and then degraded by an enzyme gamma-aminobutyric acid

aminotransferase GABA-T for short so again as you can see just like with excess of

glutamate too little GABA can also allow neurons to become hyperexcitable which

may lead to seizures now that we covered the basic mechanism underlying seizures

let's move on to discussing pharmacology of antiepileptic drugs so the main goal

of therapeutic interventions is to simply lower neuronal excitability and

or enhance neuronal inhibition one way antiepileptic drugs may prevent

excessive firing of an action potential in neurons is simply by blocking

voltage-gated sodium channels antiepileptics that block sodium channels and

thus reduce the amount of sodium that enters the neuron include Carbamazepine

Oxcarbazepine Lamotrigine Phenytoin Topiramate Valproic acid and

Zonisamide now another way antiepileptics can slow

down hyperactive neurons is by blocking calcium channels this task gets done by

drugs that inhibit high-voltage-activated calcium channels such as

Lamotrigine and Topiramate and drugs that inhibit low-voltage-activated t-type

in mind that many of the antiepileptic drugs act on multiple targets so as you

can see Lamotrigine Topiramate Valproic acid and Zonisamide can inhibit both

calcium channels and sodium channels furthermore Topiramate has been shown to

also inhibit excitatory neurotransmission by blocking AMPA receptors now couple

other antiepileptic drugs namely Gabapentin and Pregabalin also exert

their effects by interacting with high-voltage-activated calcium channels

however unlike the other agents Gabapentin and Pregabalin 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 such as

glutamate inhibition of alpha-2-delta-1 containing calcium channels by

Gabapentin and Pregabalin is speculated to be one of the main

reasons for their antiepileptic effect another high-voltage-activated calcium

channel blocker with unique mechanism of action is Levetiracetam one of the major

mechanisms that is speculated to be responsible for antiseizure activity of

Levetiracetam is its ability to bind to the so called

SV2A protein found in the walls of vesicles that contain glutamate this

binding appears to impair the synaptic release of glutamate and thus decrease

neuronal excitability next we have antiepileptic drug called Felbamate that

inhibits excitatory neurotransmission by blocking NMDA receptors and finally

we have drugs that act on the GABA system the two major classes of drugs

that target this system are Benzodiazepines and Barbiturates which

work by binding to GABA-A receptor thus prolonging the opening of the channel

and permitting greater influx of negatively charged chloride ions into

the neuron for more detailed explanation of their mechanism of action

check out my recent video about Benzodiazepines and Barbiturates next we

have drug called Tiagabine which is a selective inhibitor of the GABA

transporter in a nutshell Tiagabine simply blocks GABA reuptake thereby

permitting more GABA to be available for receptor binding on the postsynaptic

neurons last but not least we have drug called Vigabatrin which

irreversibly inhibits GABA-aminotransferase the enzyme responsible for

catabolism of GABA thereby effectively increasing the concentrations of GABA in

the brain now when it comes to side-effects sedation and dizziness

can occur with all antiepileptic drugs hyponatremia can occur with the use of

Carbamazepine and Oxcarbazepine visual field loss can occur with the use of

Vigabatrin while double vision can occur with the use of Lamotrigine

and Phenytoin additionally Phenytoin is known for

causing gingival hyperplasia and hirsutism cognitive problems can occur

with the use of Topiramate and Zonisamide Topiramate is also known for

causing weight loss weight gain on the other hand can occur most frequently

with the use of Valproic acid although it has also been reported with the use

of Gabapentin and Pregabalin which also happen to cause peripheral edema in

addition to that both Valproic acid and Felbamate can cause liver toxicity in

rare cases the use of Felbamate can also lead to rare but serious condition

called aplastic anemia and with that I wanted to thank you for watching I hope

you enjoyed this video and as always stay tuned for more