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
calcium channels such as Valproic acid and Zonisamide as a side note here keep
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