Nonbenzodiazepine anticonvulsants

Definitions & Key takeaways

Nonbenzodiazepine anticonvulsants are a class of drugs used to treat seizures, headaches, and neuropathic pain. These drugs are also used as mood stabilizers for bipolar disorders. Nonbenzodiazepine anticonvulsants decrease excitatory signals in the brain, primarily by blocking sodium and calcium channels, or by enhancing the actions of GABA. This lead to a decrease in the abnormal electrical activity in the brain responsible for the associated symptoms.

Common examples of nonbenzodiazepine anticonvulsants include carbamazepine, lamotrigine, and valproic acid. Side effects include double vision, ataxia, and liver toxicity for carbamazepine; Stevens Johnson syndrome for lamotrigine; and teratogenic effects like neural tube defects for valproic acid.

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Introduction0:00–0:20

I Anticonvulsants are a type of medication used to treat the various types of seizure disorders. These include benzodiazepines and barbiturates, which increase the activity of inhibitory neurons.
But there are also many other classes of anticonvulsants with different mechanisms that we'll also talk about in this video.

Physiology0:20–2:03

OK, so the cells that make up our brain are called neurons. Neurons communicate with each other through neurotransmitters.
When one neuron is stimulated, it releases excitatory neurotransmitters that bind to receptors on the next neuron. This causes the next neuron to depolarize and release its own excitatory neurotransmitters, propagating the signal throughout the brain.
The main excitatory neurotransmitter in our brain is glutamate, which can bind to several types of receptors that are basically ligandgated ion channels.
which open up and allow sodium and calcium to flow in, and potassium to flow out. In the end, when it's all added up, there's an influx of positive charges that makes the cell less negative, and the neuron becomes depolarized.
This causes nearby voltage-gated sodium channels to open up on the surface of the membrane, causing more sodium to enter.
This in turn triggers other nearby voltage-gated sodium channels to open. So, this series of depolarization travels down the neuron like a wave, and it's called an action potential.
When it reaches the end of the neuron, called the synaptic terminal, it triggers the opening of voltage-gated calcium channels, causing an influx of calcium ions, which stimulates the release of neurotransmitters that are stored in synaptic vesicles.
OK, we also have inhibitory neurons that shut down this chain of events. These neurons release the main inhibitory neurotransmitter called gamma aminobutyric acid, or GABA.
which binds to GABA receptors on other neurons. These GABA receptors are also ligandated ion channels, but they open up to let the negatively charged chlorine into the cell.

Pathology2:03–3:15

The influx of negative ions causes hyperpolarization, where the cell's membrane potential becomes more negative, which means it's much more difficult for it to depolarize and fire off an action potential.
Alright, now there are cases where neurons in the brain start sending out more excitatory signals than normal. This can occur due to either too much excitation or too little inhibition in the brain.
Excessive excitatory signals can cause a variety of disorders, like seizures and epilepsy. Seizures are categorized based on the region of the brain that's affected.
When it's limited to one hemisphere or a single lobe, we call it a focal seizure. And these can cause the person to experience strange sensations, like hearing or tasting something that isn't there, but can also involve jerking movements in specific muscle groups if the neurons controlling these muscles are affected.
A generalized seizure is where both hemispheres of the brain are affected. Tonic-clonic seizures are the most common generalized seizures, where patients experience a tonic phase, where the muscles suddenly tense up, followed by the clonic phase, where the muscles rapidly contract and relax.

Voltage-gated sodium channel inhibitors3:15–7:25

Another type of generalized seizure is absence seizures, where the person has impaired awareness or responsiveness, generally with the only outward sign being that the person looks like they spaced out.
If the seizures themselves last longer than 5 minutes without stopping, or if there are multiple seizures without returning to normal in between, then it's called status epilepticus.
OK, so we can manage seizure disorders by increasing the effect of inhibitory neurons or decreasing the activity of excitatory neurons.
Let's start with a group of voltage-gated sodium channel inhibitors, reducing the ability of excitatory neurons to fire action potentials.
These include carbamazepine, valproic acid, phenytoin, lamotrigine, and topiramate. Keep in mind that some of these medications have additional mechanisms as well.
For example, lamotrigine and topiramate inhibit the release of glutamate. And topiramate also inhibits voltage-gated calcium channels.
Valproic acid inhibits GABA transaminase, which is an enzyme that breaks down GABA in the inhibitory neurons. So, valproic acid inhibits the metabolism of GABA, which increases GABA concentration in the brain and enhances the effect of inhibitory neurons.
All right, now that we know how these voltage-gated sodium channel inhibitors work, let's move on to their indications, which mainly include seizures, bipolar disorder, trigeminal neuralgia, and migraine prophylaxis.
Starting with seizures, carbamazepine, valproic acid, phenytoin, lamotrigine, and topiramate are commonly used for focal and generalized tonic-clonic seizures.
For absence seizures, valproic acid and lamotrigine are used. If seizures progress to status epilepticus and first-line benzodiazepines don't work, phenytoin, it's pro-drug phosphenytoin, or valproic acid can be used as second-line options.
In bipolar disorder, carbamazepine, valproic acid, and lamotrigine act as mood stabilizers. Carbamazepine also serves as the first line treatment for trigeminal neuralgia.
A condition characterized by sharp shooting pain along the trigeminal nerve. Finally, valproic acid and topiramate are used for migraine prophylaxis.
All right, let's move on to side effects. Carbamazepine can cause diplopia or double vision, ataxia, agranulocytosis, liver toxicity, SIADH or syndrome of inappropriate anti-diuretic hormone secretion.
A rare but potentially fatal side effect of carbamazepine is Stevens-Johnson syndrome, which is characterized by rapid desquamation of the skin.
Note also that carbamazepine is not safe for use during pregnancy, because it increases the risk of congenital defects like cleft lip or palate, and neural tube defects such as spina bifida.
Also, carbamazepine induces a class of enzymes called cytochrome P450. These enzymes are involved in the metabolism of various medications like benzodiazepines, phenytoin, quinidine, warfarin, and others.
Increased cytochrome P450 activity can result in these medications being broken down too rapidly, so larger doses are needed to achieve a therapeutic effect.
Up next, common side effects of valproic acid are gastrointestinal symptoms like nausea and vomiting, tremors, sedation, alopecia or loss of hair, weight gain, and blood disorders like a low platelet and white blood cell count.
A rare but life-threatening adverse effect is liver toxicity. Also note that valproic acid should not be used in pregnancy because it causes teratogenic effects like neural tube defects.

Calcium channel blockers7:25–8:18

The side effects of phenytoin include visual disturbances like nystagmus or involuntary eye movement, diplopia, ataxia, hirsutism, or excessive hair growth, and gingival hyperplasia or enlarged gums.
Pheytoin also inhibits the absorption of folate in the small intestine, so it can lead to megaloblastic anemia. In addition, phenytoin induces cytochrome P450, just like carbamazepine.
Rare adverse effects include Stevens-Johnson syndrome and symptoms that mimic systemic lupus erythematosis or SLE-like syndrome.
Keep in mind that phenytoin is not safe for use during pregnancy. Teatogenic effects include intrauterine growth restriction or IUGR, intellectual disability, cleft lip or palate, and congenital heart defects.

GABA inhibitors8:18–8:52

The common side effects of lamotrigine include rash, alopecia, blurred vision, and gastrointestinal symptoms like nausea and vomiting.
Like carbamazepine, Stevens-Johnson syndrome is a rare but possible side effect of lamotrigine as well. Finally, side effects of topiramate include sedation, kidney stones, weight loss, and visual disturbances like blurry vision, diplopia, and glaucoma.
All right, let's move on to GABA-enhancing medications. GABA is the main inhibitory neurotransmitter.

Memory Palace8:52–12:54

Just like valproic acid, vigabatrin inhibits GABA transaminase, increasing the amount of GABA in the brain. Another medication that increases GABA levels is tiagaine, which inhibits GABA reuptake from the synapse back to the neuron, and thus increases GABA concentration.
Both Vigabatrin and tiagaine can be used for the treatment of focal seizures, but what's important is that Vigabatrin can cause permanent bilateral visual loss.
Finally, we have the medications ethosuccimide, gabapentin, and levetiracetam. These don't share a common mechanism, so let's look at them one by one.
Ethosuxamide blocks T-type calcium channels in thalamic neurons and is the drug of choice for absence seizures. Gabapentin, on the other hand, binds to the alpha 2 delta subunit of voltage-gated calcium channels, reducing neurotransmitter release, and is used for focal seizures, neuropathic pain and post-therpetic neuralgia, fibromyalgia, and peripheral neuropathy.
Last, levetiracetam binds to synaptic vesicle protein 2A or SV2A and inhibits the release of excitatory neurotransmitters.
Now, common side effects of ethosuccimide include fatigue, gastrointestinal symptoms, headaches, and itching. Adverse effects of gabapentin include sedation, ataxia, weight gain, and peripheral edema, while adverse effects of levetiracetam include sedation, fatigue, headaches, and changes in personality.
Alright, as a quick recap, non-benzodiazepine anticonvulsants are used for the treatment of seizures, as mood stabilizers for bipolar disorder, and for the treatment of conditions like trigeminal neuralgia, neuropathic pain, and for migraine prophylaxis.
They can decrease excitatory signals in the brain, primarily by blocking sodium channels or calcium channels, or by enhancing the actions of GABA.
Carbamazepine and phenytoin induce cytochrome P450, and like the valproic acid, they're not safe to use during pregnancy.
A rare but fatal side effect of anticonvulsants, and especially of lamotrigine, is Stevens-Johnson syndrome.

Review12:54–13:30

Mind Map13:30–11:16