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Nonbenzodiazepine anticonvulsants

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Nonbenzodiazepine anticonvulsants

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Nonbenzodiazepine anticonvulsants

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What is the MOA of the anti-epileptic Vigabatrin?

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A 21-year old G1P0 woman is diagnosed with bipolar disorder and is hospitalized for an acute manic episode that has now resolved. You are asked to design a pharmacologic treatment plan for her, knowing that she is in the second trimester of pregnancy. Which of the following is the best pharmacological option for treatment?

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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 talk about in this video.

Okay, 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 ligand-gated ion channels, which open up and allow Na+ and Ca2+ to flow in, and K+ to flow out.

In the end, when it’s all added up, there’s an influx of positive charge that makes the cell less negative,and the neuron becomes depolarized. This causes nearby voltage-gated Na+ channels to open on the surface of the membrane, causing more Na+ to enter. This in turn triggers other nearby voltage-gated Na+ 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 Ca2+ channels, causing an influx of calcium ions which stimulates the release of neurotransmitters that are stored in synaptic vesicles.

Okay, 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 ligand-gated ion channels, but they open up to let the negatively charged Cl-, into the cell.

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 or partial 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.

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.

Okay, 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 medications that block voltage-gated sodium channels, which inhibit the action potentials in excitatory neurons. These include carbamazepine, valproic acid, phenytoin, lamotrigine, and topiramate. Some of these medications have other mechanisms as well.

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, increases GABA concentration in the brain and enhances the effect of inhibitory neurons.

Okay moving on to indications. Carbamazepine, valproic acid, lamotrigine, topiramate and phenytoin are commonly used for the treatment of partial and generalized tonic-clonic seizures.

In addition, lamotrigine and valproic acid are used for absence seizures.

For the prophylaxis of status epilepticus, phenytoin and its prodrug, fosphenytoin, are considered the medications of choice.

Apart from seizures and epilepsy, carbamazepine, lamotrigine, and valproic acid are also used as mood stabilizers for bipolar disorder.

Note also that carbamazepine is the first line treatment for trigeminal neuralgia which is a disorder characterized by shooting pain in the distribution of the trigeminal nerve.

Finally, valproic acid and topiramate are also used as prophylactic therapy for migraines and cluster headaches.

Alright let’s move on to side effects. Carbamazepine can cause diplopia or double vision, ataxia, agranulocytosis, liver toxicity, and SIADH or syndrome of inappropriate antidiuretic 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 to 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.

Okay, now common side effects of lamotrigine include blurred vision and gastrointestinal symptoms, like nausea and vomiting.

If levels increase, lamotrigine can cause Stevens Johnson syndrome and thus serum levels should be monitored closely.

Now 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.

Phenytoin also inhibits the absorption of folate in the small intestine and 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 erythematosus, or SLE-like syndrome.

Keep in mind that phenytoin is not safe to use during pregnancy.

Teratogenic effects include intrauterine growth restriction or IUGR, intellectual disability, cleft lip or palate, and congenital heart defects.

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.

Sources
  1. "Katzung & Trevor's Pharmacology Examination and Board Review,12th Edition" McGraw-Hill Education / Medical (2018)
  2. "Rang and Dale's Pharmacology" Elsevier (2019)
  3. "Goodman and Gilman's The Pharmacological Basis of Therapeutics, 13th Edition" McGraw-Hill Education / Medical (2017)
  4. "Ethosuximide, sodium valproate or lamotrigine for absence seizures in children and adolescents" Cochrane Database Syst Rev (2017)
  5. "Adverse effects of antiepileptic drugs: a brief overview of important issues" Expert Rev Neurother (2010)
  6. "Antiepileptic action induced by a combination of vigabatrin and tiagabine" Neuroscience (2005)