Drugs for epilepsy: how anti-epileptic drugs work
- Anatomy of thalamocortical connectivity
- Basic pathophysiology of epilepsy
- Mechanism of antiepileptic drugs
- Drugs for generalized seizures
- Drugs for absence seizure
- Drugs for partial seizure
- List of most common drugs for epilepsy
- 1. Sodium valproate, valproic acid, divalproex
- 2. Phenobarbital
- 3. Phenytoin
- 4. Fosphenytoin
- 5. Carbamazepine
- 6. Oxcarbazepine
- 7. Ethosuximide
- 8. Benzodiazepines
- 9. Gabapentin
- 10. Pregabalin
- 11. Lamotrigine
- 12. Levetiracetam
- 13. Topiramate and zonisamide
- 14. Tiagabine
- 15. Vigabatrin
If you have an epilepsy problem, you would be on antiepileptic drugs (drugs for epilepsy). You must know how your medications work.
Epilepsy can’t be cured completely, but some medicines can control your seizures effectively. Most people need to continue taking antiepileptic medication for a long time.
According to WHO, up to 70% (7 in 10) of people could stop having seizures with the appropriate use of antiepileptic medicines.
In this post, I am going to cover the basic pharmacology of drugs for epilepsy.
Moreover, we will discuss why neurologists prescribe a particular antiepileptic drug in a specific type of epilepsy.
Let’s move on to discussing drugs for epilepsy.
Anatomy of thalamocortical connectivity
If you will see the structure of the brain. Your brain is generally divided into two hemispheres which contain cortical and subcortical structures.
The superficial (outer) part of your brain contains a cortical structure like the cerebral cortex.
The primary function of the thalamus is to pass motor and sensory signals to the cortex.
Thalamus contains a T-type calcium channel. Whenever your thalamus receives any input signal. Then calcium channels get activated, and the troops of calcium ions start to move into the thalamus.
Due to this calcium ions influx, an action potential is generated in the thalamus.
As soon as action potential propagates in the cortex region, then depolarisation begins around the cortex area via the influx of Na+ ions.
Eventually, the signal goes to a particular group of muscles, and activity gets started.
Basic pathophysiology of epilepsy
To understand the mechanism of antiepileptic drugs, we should know the pathophysiology of epilepsy.
Generalized tonic-clonic seizure (GTCS) and myoclonic seizure
Thalamus is the key structure in generalized epilepsy. It acts as a pacemaker that amplifies repetitive spikes.
Suppose you get generalized epilepsy or myoclonic epilepsy. In that case, the subcortical structure (especially, thalamus) of your brain begins to fire without any reason.
This spontaneous firing generally occurs due to an excessive influx of calcium ions in the thalamus. As a result, an action potential is generated in the thalamus.
Later on, this abnormal action potential passes on to the cortical structure of your brain.
As soon as action potential reaches the cortical structure, it starts to depolarise the rest of the cortical neuron via the influx of sodium ions. After that, they begin to fire in all the segments of the spinal cord.
Eventually, your limbs (hands and legs) will start jerking and shaking vigorously.
So, the main cause of generalized epilepsy is an excessive influx of calcium and sodium ions.
In case of absence seizure, action potential does not spread to the cortical structure. It keeps revolving around the subcortical structure in the thalamus.
In this type of epilepsy, the motor cortex is not involved. So, it does not affect your muscles.
During this absence seizure, you may stare in one direction for a few seconds. It’s just like you freeze for some time.
So, the main cause of absence epilepsy is the only excessive influx of calcium ions.
Focal or partial seizure
Suppose you get any lesion in any particular lobe of your cortical structure; it represents partial or focal epilepsy. The primary cause of partial epilepsy is the excessive influx of sodium ions.
There is no connectivity with your thalamus.
Mechanism of antiepileptic drugs
Drugs for generalized seizures
We have seen that there are two major causes of generalized epilepsy –
- spontaneous firing from thalamus without input signal (excessive influx of calcium ions)
- sudden depolarization (excessive influx of sodium ions)
As soon as it binds to receptors, your nerve cells become electropositive, and it generates too much action potential. These activities may develop into a seizure.
So, you need that drug that inhibits the glutamate pathway.
If you have GTCS or a myoclonic seizure, the first-line drug may be a sodium channel blocker or a calcium channel blocker.
(First-line drug means most suitable drug used in initial level for treating a particular disease.)
Sodium channel blockers – These drugs decrease depolarisation or action potential by inhibiting the sodium channel of your excitatory neurons. For example –
- Sodium valproate, valproic acid, divalproex
Calcium channel blockers – These drugs inhibit the entry of calcium ions into the T- type calcium channel of your thalamus. As a result, it does not propagate to the cortex. For example –
Alpha-2-delta-1 calcium subunit blockers – These drugs prevent calcium entry in the presynaptic neuron by blocking the alpha-2-delta-1 subunit. For example –
Generalized epilepsy may occur due to dysfunction of the GABA-A receptor. Because of this, too little GABA neurotransmitter is released.
So, you may also need that drug that stimulates the GABA pathway. These drugs may be used on second-line drugs or add-on drugs to counter the effect of excessive excitatory impulses (sodium ions).
This type of drug increases the sensitivity of the GABA-A receptor. They help to reduce the action potential via repolarisation (influx of chloride ions).
GABA-A agonist – These drugs directly bind to the GABA-A receptor and increase the concentration of GABA.
- Benzodiazepines – lorazepam, diazepam, midazolam,
GABA reuptake inhibitors – You need more GABA for hyperpolarisation. These drugs prevent the reuptake (or reabsorb) of the GABA into presynaptic neurons, e.g., Tiagabine.
GABA Transaminase inhibitors – When GABA reuptake into the presynaptic neuron. Mostly, GABA gets stored in vesicles, but some GABA molecules convert into Succinic semialdehyde (SSA).
You don’t need this SSA during epilepsy. These drugs inhibit the formation of succinic semialdehyde (SSA) by inhibiting the GABA transaminase enzyme. As a result, you get more GABA molecules.
The classic example of a GABA transaminase inhibitor is vigabatrin.
Drugs for absence seizure
In case of absence seizure, there is no involvement of your motor cortex. It arises from the thalamus.
So, calcium channel blocker is the first-line drug in the absence seizure. For example – ethosuximide, valproate, and zonisamide.
Drugs for partial seizure
Suppose you got a seizure in a particular lobe. In that case, sodium channel blocker is the first-line drug.
For example – sodium valproate, phenytoin, fosphenytoin, carbamazepine, oxcarbazepine, lamotrigine, and topiramate.
List of most common drugs for epilepsy
1. Sodium valproate, valproic acid, divalproex
- Sodium valproate, valproic acid, and Divalproex salts are equivalent in efficacy.
- These drugs may be used in combination to make gastric tolerance better.
- Valproate is a broad-spectrum antiepileptic medicine because it acts by multiple mechanisms – blocking sodium and T-type calcium channel. It also increases the concentration of GABA by blocking the GABA transaminase enzyme.
- It is the best medicine if you are suffering from a partial seizure, GTCS (Generalized Tonic-Clonic Seizure), and absence seizure. Even it is the single best drug of choice in all generalized seizures.
- Valproate is considered a drug of choice in the absence seizure. It is also used in mania, bipolar disease, and migraine.
- It has good oral absorption.
- Valproate acts as a potent CYP 450 enzyme inhibitor. Enzyme inhibitors are those drugs that decrease the metabolic activity of other drugs. Due to this, it increases the efficacy (or concentration) of other medications like clonazepam, carbamazepine, phenytoin, phenobarbitone, and lamotrigine.
- You should strictly avoid valproate if you are pregnant or planning for pregnancy. It may cause congenital disabilities like spina bifida and neural tube defects.
- If you are a liver disease patient, you should avoid this medicine because sodium valproate may cause hepatoxicity by increasing liver enzymes like AST (aspartate aminotransferase), ALT (Alanine aminotransferase), and ALP (Alkaline phosphatase).
- In case of an overdose of valproate, you may have drowsiness, ataxia, and tremor.
- If you are a young girl. In that case, there is a higher chance of PCOD (polycystic ovarian disease) and menstrual irregularities in long-term use of valproate.
- This drug may also cause inflammation in the pancreas and decrease your platelets level.
- Brand name – VALPARIN CHRONO, VALATE CHRONO, EPIVALPRATE
- Phenobarbital was the first antiepileptic drug brought to the market in 1912.
- It is one of the cheapest and minor toxic antiepileptic drugs.
- Phenobarbital belongs to a group of medicine called barbiturates. It acts as a GABA-A agonist.
- The primary mechanism of action of this drug is enhancing the GABA by increasing the sensitivity of the GABA receptor.
- It has a broad-spectrum antiepileptic property in generalized tonic-clonic (GTC), simple partial (SP), and complex partial (CP) seizures.
- It is most commonly used in neonatal seizures and alcohol withdrawal seizures.
- It became less popular after introducing carbamazepine, phenytoin, or valproate into the market.
- The major drawback of this drug is its sedative action.
- The long-term use of phenobarbitone may cause megaloblastic anemia behavioral abnormalities, lack of intelligence, impairment of learning and memory.
- Brand name – GARDENAL, LUMINAL
- Phenytoin prevents and controls your seizures without giving a sedative effect.
- This drug inhibits the voltage-gated sodium channel.
- It is highly effective in the treatment of partial (or focal) and GTCS seizures.
- Although, phenytoin is considered the first-line antiepileptic drug. But it is less commonly used due to its higher side effects.
- Phenytoin may cause gingival hyperplasia (gums grow over the teeth) and hirsutism (excessive growth of dark or coarse hair in a male-like pattern)
- Phenytoin may interfere with your calcium and folate absorption. Due to this, you may have megaloblastic anemia and osteomalacia.
- You should not take this medicine if you are pregnant because it may cause fetal hydantoin syndrome.
- It may also cause severe hypersensitivity problems like Steven Johnson Syndrome (SJS) and DRESS (Drug Rash with Eosinophilia and Systemic Symptoms). During DRESS, you may have a fever, increased eosinophil count, abnormal lymph nodes size, and rash.
- Long-term use of phenytoin may cause peripheral neuropathies and osteoporosis.
- Phenytoin is contraindicated in myoclonic seizures because it may exacerbate the condition.
- Phenytoin is a potent CYP 450 enzyme inducer. This means it decreases the efficacy of other drugs like doxycycline, carbamazepine, digoxin, warfarin, etc.
- It is rarely used intravenously in status epilepsy because of its poor water solubility.
- Brand name – EPTOIN, DILANTIN, PHENYTOS
- To overcome the difficulties in the intravenous administration of phenytoin. Fosphenytoin has been introduced in the market.
- Fosphenytoin is a good water-soluble drug. It is a prodrug of phenytoin, and it is used in the treatment of status epilepticus.
- This fosphenytoin injection controls your seizure by blocking the sodium channel.
- The side effects of this drug are similar to phenytoin.
- Brand name – FOSOLIN
- This drug is popular in the market in a brand of TEGRETOL, VERSITOL, and MAZETOL.
- Carbamazepine is a drug of choice in trigeminal neuralgia.
- It is most commonly used in SPS, CPS, and GTCS.
- This drug also inhibits the influx of sodium ions by blocking voltage-gated sodium channels.
- Sometimes, it also works in mania and bipolar mood disorder.
- Carbamazepine is contraindicated in myoclonic seizures because it may exacerbate your epileptic condition.
- The main side effects of this drug are Steven Johnson Syndrome (SJS) and DRESS.
- You may have problems like aplastic anemia, agranulocytosis, and severe hepatic toxicity.
- Carbamazepine is a potent CYP 450 enzyme inducer. Enzyme inducers are those drugs that increase the metabolic activity of other drugs. Due to this potent enzyme induction, carbamazepine can reduce the efficacy of other drugs like haloperidol, oral contraceptives, lamotrigine, valproate, and topiramate.
- You may have carbamazepine toxicity if you are on enzyme inhibitor drugs like erythromycin, fluoxetine, and isoniazid because these drugs inhibit the metabolism of carbamazepine.
- The carbamazepine may cause dose-related neurotoxicity—sedation, dizziness, hallucination, vertigo, diplopia, and ataxia. This toxicity may occur due to its active metabolite carbamazepine-10,1 1-epoxide (CBZ-E).
- The usual adult dose of carbamazepine is 200–400 mg TDS. The dose in children is 15–30 mg/kg/day.
- Newer congener of carbamazepine.
- Oxcarbazepine does not cause neurotoxicity because it does not convert into epoxide metabolite.
- The primary active metabolite of oxcarbazepine is mono-hydroxy derivative (MHD).
- It is a less potent enzyme inducer than carbamazepine. So, you may not need to worry while taking other drugs.
- The risk of liver toxicity is very less than carbamazepine.
- It has a similar indication as for carbamazepine.
- It is a better-tolerated drug, but it is slightly less potent than carbamazepine.
- Brand name – ZENOXA, OXETOL, OXCARB
- Ethosuximide is considered a first-line drug in the absence seizure. Because clinically, it has seen promising results in absence seizure.
- Ethosuximide is rarely used because of its narrow spectrum activity (only used in absence seizure).
- It reduces the abnormal electrical activity of your brain, which arises from the thalamus. It inhibits the T-type calcium channel.
- Steven Johnson Syndrome is the major side effect of this drug. So, it can be replaced by valproate.
- Brand name – ABSENZ, ZARONTIN
- Lorazepam, diazepam, and midazolam are most commonly benzodiazepines drugs used in epilepsy.
- Benzodiazepines are GABA-A agonist. These drugs help to increase the sensitivity of the GABA-A receptor. Due to this, more chloride ions go into neurons and increase hyperpolarisation. Eventually, it reduces the firing rate by this mechanism.
- These are first-line drugs in status epilepticus and alcohol withdrawal seizures.
- They may use as add-on therapy in GTCS, myoclonic seizures, and partial seizure.
- The major side effects of benzodiazepines are sedation and respiratory depression.
- Diazepam and lorazepam are the first-line drugs to control emergency seizures like status epilepticus, eclampsia, tetanus, and seizure due to drug poisoning.
- Clobazam is generally used as add-on therapy to other antiepileptic drugs like phenytoin, carbamazepine, or valproate in refractory epilepsy (drug-resistant epilepsy).
- Gabapentin is a derivative of GABA.
- It is a lipid-soluble (unionized form) drug that easily crosses your brain and increases GABA release.
- It does not act as an agonist. This means it won’t interfere with to GABA-A receptor.
- This drug reduces the firing rate by preventing the entry of calcium in the presynaptic neuron, especially the alpha-2-delta-1 subunit.
- Gabapentin is a second-line antiepileptic drug because it is used as an add-on drug with other antiepileptic drugs.
- Gabapentin is the first-line drug in neuropathic pain and postherpetic neuralgia (nerve damage due to herpes zoster). Clinically, it has seen some effects in migraines too.
- The starting dose of gabapentin is 300 mg OD. It may increase to 300–600 mg TDS as required.
- Brand name- NEURONTIN, GABAPIN
- Pregabalin is a congener of Gabapentin. So, it has similar mechanism like Gabapentin.
- This drug has proven effects in partial-onset seizures.
- It is particularly used for neuropathic pain, such as diabetic neuropathy, postherpetic neuralgia, fibromyalgia, and certain other types of chronic pain.
- Brand name – PREGABA 75, 150
- Lamotrigine is a newer antiepileptic drug.
- It prevents the release of excess glutamate by blocking the sodium channel.
- This drug is effective in partial seizure, GTCS, and absence seizure.
- Lamotrigine is considered the safest anticonvulsant drug during pregnancy.
- It also acts as a mood stabilizer. Lamotrigine is approved for use in bipolar disorder as well.
- You can be used it in a small dose with valproate during epilepsy treatment.
- It has mild side effects like sedation, pancytopenia, and dizziness.
- The major side effect of this drug is Steven Johnson Syndrome (SJS), especially in children.
- It better-tolerated drug than carbamazepine and phenytoin.
- Brand name – LAMITOR, LAMETEC
- Levetiracetam is a unique antiepileptic drug.
- It prevents the exocytosis of glutamate synaptic vesicles by blocking synaptic vesicle protein SV2A in the neuron. It does not allow the fusion of synaptic vesicles to the plasma membrane of the nerve ending.
- It is entirely well absorbed orally.
- It is mainly used as an add-on drug, and it has good tolerability in CPS, GTCS, and myoclonic epilepsy.
- Levetiracetam is also the safest anticonvulsant drug during pregnancy.
- It is not approved for use in children below four years.
- The dose of levetiracetam is 500 mg twice daily. It may increase up to 1 gm twice. For children, the dose may calculate 10-30 mg/kg/day per body weight.
- Brand name – LEVERA, LEVTAM
13. Topiramate and zonisamide
- These are newer antiepileptic drugs and weak carbonic anhydrase inhibitors.
- Topiramate blocks the sodium channel only. In contrast, zonisamide inhibits the sodium channel and T-type calcium channel.
- Clinically, topiramate is effective in myoclonic epilepsy. In comparison, zonisamide is used as an add-on drug in refractory partial seizures.
- Recently, topiramate has been approved for migraines.
- Brand name – TOPEX, TOPAMATE.
- It is another newer antiepileptic drug.
- This drug inhibits the reuptake of GABA into the presynaptic neuron. It increases the concentration of GABA around GABA-A receptors.
- Tiagabine is only used as add-on therapy in partial seizures.
- Vigabatrin inhibits the formation of succinic semialdehyde (SSA) by inhibiting the GABA transaminase enzyme. Due to this inhibition, the maximum concentration of GABA formed into the vesicles.
- It is approved only for add-on therapy in refractory epilepsy.
- The use of vigabatrin is restricted in many countries due to its side effects like visual disturbance (blurred vision and diplopia).
In this post, I have covered all the important points related to drugs for epilepsy.
You should not take any single drug without consulting your doctor. This is only an informative post for antiepileptic drugs.
These drugs may boost your quality of life if you are dealing with epilepsy.
This blog will help you or your doctor to choose the best medication for epilepsy.
I hope you have got valid information on drugs for epilepsy. If you found this post informative, please share it on social media.
1. Thalamocortical connectivity. Thai epilepsy society.
2. K.D. Tripathi. Essentials of medical pharmacology. 7th edition. Jaypee brothers medical publishers 2013. Chapter -30, antiepileptic drugs, Page- 411-424.
3. Lippincott Williams and Wilkins. Lippincott’s Illustrated Reviews: Pharmacology 5th edition. Wolters Kluwer Health, 2012. Chapter-15, Epilepsy, Page-181 to 191.