Pharmacology - ANTIEPILEPTIC DRUGS (MADE EASY)

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