What are antiepileptic drugs

Anti-epileptic drugs also called anticonvulsants, antiepileptic medication and AEDs, are the main type of medications used to manage epilepsy for most people with epilepsy. Up to 70% (7 in 10) of people could stop having seizures with the right antiepileptic drug. Antiepileptic drugs do not stop a seizure once it has started and they cannot cure epilepsy.

Antiepileptic drugs do not cure epilepsy or treat the reason why epilepsy has started. They are taken to try and stop the symptoms of epilepsy – the seizures. Antiepileptic drugs aim to stop seizures from happening. Antiepileptic drugs do not stop a seizure once it has started. Antiepileptic drugs are prophylactic (preventative) and are usually taken either once or twice a day.

The aim of antiepileptic drugs treatment is ‘optimal therapy’. This means taking the fewest types of antiepileptic drugs, at the lowest dose in order to get the best seizure control possible with the fewest side effects. If optimal therapy cannot be found with one particular antiepileptic drug there are usually several others that can be tried, alone or in combination.

Some medications are taken as a ‘course of treatment’ to cure a condition (for example, taking a course of antibiotics for an infection). Antiepileptic drugs are different; they are a preventative medication taken every day to try and stop seizures from happening. Anti-epileptic drugs do this by reducing the excessive electrical activity in the brain that causes seizures. The way they work is not completely understood, and it is likely that different antiepileptic drugs work in slightly different ways.

Some of antiepileptic drugs are also used to treat neuropathic pain, bi-polar disorder and anxiety. Of note, certain antiepileptic drugs have been used off-label for a variety of other indications including but not limited to ¹:

• Anxiolytics: Pregabalin, clonazepam, clobazam
• Migraine relief: Zonisamide, valproic acid, topiramate
• Mood stabilizer: Valproic Acid, lamotrigine, carbamazepine
• Neuropathic pain relief: Pregabalin, gabapentin, carbamazepine
• Weight loss: Zonisamide, topiramate
• Antiparkinsonian agent: Zonisamide.

What are ‘first-line’ and ‘second-line’ antiepileptic drugs?

antiepileptic drugs are licensed to use for controlling particular types of seizures. ‘First-line’ and ‘second-line’ refers to how antiepileptic drugs are selected and used for the treatment of epilepsy and particular types of seizures.

First-line antiepileptic drugs are the antiepileptic drugs that are usually considered first when starting epilepsy treatment. They tend to be used on their own (monotherapy). They include sodium valproate and carbamazepine. Which one is chosen depends on the type of seizures the person has.

Second-line antiepileptic drugs are antiepileptic drugs that are usually taken alongside first-line therapy (also called adjunctive therapy) and therefore they are generally used as polytherapy. They include topiramate and gabapentin. Second-line antiepileptic drugs also include antiepileptic drugs that were used as first-line treatments but that are no longer generally considered as a first treatment option when treatment is started.

However, as treatment with antiepileptic drugs is always individualised, in some cases the neurologist may use his specialist knowledge and decide to put an individual on monotherapy with a second-line rather than first-line drug.

Monotherapy is taking just one drug (mono = one). If you are on monotherapy you usually take a single first-line drug. If you take more than one drug (either more than one first-line drug, or first-line and second-line drugs) this is called polytherapy (poly = many).

Neurologists often use monotherapy at the start of epilepsy treatment. Taking just one antiepileptic drug makes treatment simpler: there are no interactions with other drugs; it reduces the chance of getting side effects; and it is clear to see if the drug works or not. If a single antiepileptic drug does not stop your seizures the options are to try a different first-line drug, or to add-on a second drug.

Taking more than one drug (polytherapy) means that there may be different side effects from each of the different drugs. Your neurologist will have to consider which side effects may be from which drug. He (or she) will also need to be aware of possible interactions between the drugs, and, if your seizures become better controlled, may find it hard to see which drug is working best.

Antiepileptic drugs mechanism of action

Anti-epileptic drugs are numerous, with different mechanisms of action, and some antiepileptic drug has multiple mechanisms of action.

Antiepileptic drugs act primarily through one, or a combination of five, mechanisms. These mechanisms and common medications that act on these mechanisms include ²:

1. Inhibition of sodium channels: carbamazepine, lacosamide, lamotrigine, oxcarbazepine, phenytoin, valproic acid, topiramate, zonisamide
2. Inhibition of calcium conductance: ethosuximide, zonisamide, valproic acid, pregabalin, gabapentin
3. Inhibition of excitatory neurotransmitter N-methyl-D-aspartate (NMDA): perampanel, felbamate, lamotrigine, topiramate
4. Stimulation of Inhibitory neurotransmitter gamma-aminobutyric acid (GABA): benzodiazepines, phenobarbital, tiagabine, vigabatrin
5. Interaction with synaptic vesicle protein 2A (SV2A) proteins: levetiracetam

Some antiepileptic drugs act on the sodium channels by either blocking their repetitive activation (phenytoin, carbamazepine) or by enhancing their slow inactivation (lacosamide) ¹. Others work on calcium channels by blocking either T-calcium channels (ethosuximide, valproic acid) or the N and L calcium channels (zonisamide). Lamotrigine works by blocking sodium channels, N and L calcium channel, and modulating H-current. Topiramate works by blocking sodium channels, alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors, and by inhibiting carbonic anhydrase. Other mechanisms through which antiepileptic drugs act are by enhancing gamma-aminobutyric acid (GABA)–A receptors (phenobarbital, benzodiazepines), blocking N -methyl-D-aspartic acid (NMDA) receptors (felbamate), and opening neuronal potassium channels (ezogabine) ³.

Sodium ion channels

Sodium channels are the parts of the neurone that affect how electrical signals or messages are passed along the length of a neurone. ‘Action potentials’ are events that cause the cell membrane of the neurone to depolarize and repolarize (when the balance of ions inside and outside the neurone changes, which causes the electrical charge of the neurone to change). This is because they change the amount of ions inside and outside the cell, which then changes the electrical charge of the cell. This is how messages travel along a neurone”. Sodium channels affect how ‘excitable’ neurones are and how easily messages are sent from one brain cell to another.

Some antiepileptic drugs (such as phenytoin, lamotrigine and carbamazepine) work by affecting the sodium channels of neurons. Antiepileptic drugs that bind or attach themselves to the sodium channels, affect how ions flow through the channels and stop the channel becoming activated or creating an action potential. This slows down how fast and how well the sodium channels work, which effectively stops the neuron from sending repeated messages.

Calcium ion channels

Calcium ions, like sodium ions, are involved in sending electric messages through the brain. Calcium channel are particularly involved with sending a message from one neurone to another, by affecting the release of neurotransmitters (chemicals that help to send messages from one neuron to another) across the synapse, where two neurones meet and the movement of calcium ions in the receiving neuron.

Antiepileptic drugs that target calcium channels (such as lamotrigine and topiramate) work by blocking the calcium channels. This prevents messages being sent across the synapse from one neuron to another either by stopping the release of neurotransmitters or by preventing calcium entering the second neuron.

One particular type of calcium channel, called the T-type channel, is involved in keeping the normal rhythm of brain activity. This channel is also involved in the specific brain activity that happens in absence seizures. antiepileptic drugs that specifically target, and block, the T-type calcium channel (such as ethosuximide), work specifically on reducing absence seizures.

GABA system and receptor agonists

GABA (gamma amino butyric acid) is a type of inhibitory neurotransmitter in the brain, which effectively stops brain messages from continuing to be sent (switches messages off). GABA helps chloride ions pass into neurons, which affects the resting membrane potential of the cell and makes it difficult for the neuron to send messages.

Antiepileptic drugs that work on the GABA system and its receptors are agonists (a substance that helps another substance to work better), and effectively increase the movement of chloride into cells, and increase the ‘switching off’ of messages.

Antiepileptic drugs such as gabapentin work by increasing the production of GABA, and sodium valproate and vigabatrin work by decreasing the breakdown of GABA, both of which result in an increased amount of GABA.

Antiepileptic drugs such as benzodiazepines (including clonazepam and clobazam) increase how often GABA receptors open, and barbiturates (such as phenobarbitone) increase how long the receptors are open for, again affecting the release and movement of GABA.

Increasing the making of GABA, reducing its breakdown, and increasing its movement, all results in increases its inhibitory effect (more GABA means more prevention of messages being sent).

Glutamate receptor antagonists

Glutamate is a type of amino acid, and is a major excitatory neurotransmitter in the brain. Messages are sent from one neuron to another in excitation, due to the movement of sodium and calcium ions into cells, and potassium out of cells. This movement of ions through the cell membranes is helped by glutamate, which binds to different receptors on the cell membrane.

Drugs that effect and prevent glutamate uptake (antagonists) prevent glutamate from helping the movement of ions through the cell membrane and so prevent the spread of the messages from one neuron to another.

The antiepileptic drug perampanel works specifically on glutamate receptors, while some other antiepileptic drugs (such as topiramate) work on glutamate receptors as well as other targets.

Different antiepileptic drugs use different targets, or a combination of targets. For some it is known which targets they use, but for others it is not yet known.

Antiepileptic drugs classification

Antiepileptic drugs can be divided into two groups according to when they where developed and how long they have been around for.

Newer drugs (licensed after 1989) include lamotrigine, gabapentin and topiramate. Older drugs (licensed before 1989) include phenytoin, carbamazepine and sodium valproate.

When you compare the older and newer antiepileptic drugs it is not as simple as ‘newer drugs are better because they have been developed more recently’ or that ‘older drugs are better because they have stood the test of time and are still used’. Again, like most things in the treatment of epilepsy, there are positives and negatives to each.

The positives and negatives about older antiepileptic drugs include:

• Because they have been used over may years the longer-term benefits and side effects are better known
• Doctor know more about how they work and what seizures they are likely to work for
• They are known to be very effective for some people (through many years of experience using them)
• Some have serious side effects or interactions with other drugs.

The positives and negatives about newer antiepileptic drugs include:

• They often have fewer side effects
• They are less likely to interact with other drugs
• They are more expensive (see section on licensing)
• Doctors don’t have the years of experience to know what types of seizures they work best for.

So the decision about which antiepileptic drugs to choose is more complicated than their age alone.

Choosing antiepileptic drugs depends on:

• The type of seizures you have
• The antiepileptic drug that is known to work best for that type of seizure
• Your lifestyle. Some side effects are more important to some people than others: for a student, avoiding an antiepileptic drug that affects their concentration may be important, but for a man, taking an antiepileptic drug that can cause menstrual problems won’t be a problem.

With regard to epilepsy and antiepileptic drugs, weighing up the risks and benefits of taking or not taking treatments can include the following issues:

• the possible risks of taking antiepileptic drugs, including side effects
• the possible benefits of taking antiepileptic drugs, including stopping seizures
• the possible risks of not taking antiepileptic drugs, including continuing to have seizures (and accidents and injuries because of them)
• the possible benefits of not taking antiepileptic drugs, including not having side effects.

How important these risks and benefits are will vary from one person to another and will depend on individual circumstances: the risk of accidents or injuries due to seizures will depend on the type of seizures you have, how often they happen, and how they affect you; the effects of taking antiepileptic drugs will vary depending on the antiepileptic drug and how your body responds to it. Ultimately the decision is yours, but having the input and support from your doctors can help you to weigh up these points and come to a decision that you are happy with. Taking part in making this choice may also help you to feel more in control, which might be important if your epilepsy makes you feel you have lost some control over your life.

Antiepileptic drugs list

List of anti-epileptic drugs:

• Acetazolamide
• Brivaracetam available as Briviact
• Carbamazepine also available as Carbagen, Tegretol, Tegretol Prolonged Release
• Clobazam also available as Frisium, Perizam, Tapclob, Zacco
• Clonazepam
• Eslicarbazepine acetate available as Zebinix
• Ethosuximide
• Everolimus also available as Votubia
• Gabapentin also available as Neurontin
• Lacosamide available as Vimpat
• Lamotrigine also available as Lamitcal
• Levetiracetam also available as Desitrend, Keppra
• Oxcarbazepine also available asTrileptal
• Perampanel available as Fycompa
• Phenobarbital
• Phenytoin also available as Epanutin, Phenytoin Sodium Flynn
• Piracetam available as Nootropil
• Pregabalin also available as Alzain, Axalid, Lecaent, Lyrica, Rewisca
• Primidone
• Rufinamide available as Inovelon
• Sodium valproate als available as Epilim, Epilim Chrono, Epilim Chronosphere, Episenta, Epival
• Stiripentol also available as Diacomit
• Tiagabine available as Gabitril
• Topiramate also available as Topamax
• Valproic acid available as Convulex, Epilim Chrono, Epilim Chronosphere
• Vigabatrin available as Sabril
• Zonisamide also available as Zonegran

Valproate: Sodium valproate and Valproic acid must NOT be used in females of childbearing potential unless the conditions of the Pregnancy Prevention Program are met and alternative treatments are ineffective or not tolerated. This is because of the risk of birth defects and developmental disorders for an unborn baby. During pregnancy, sodium valproate and valproic acid must not be used for epilepsy unless it is the only possible treatment.

Antiepileptic drugs in pregnancy

Valproate products include valproate sodium (Depacon), divalproex sodium (Depakote, Depakote CP, and Depakote ER), valproic acid (Depakene and Stavzor), and their generics must NOT be used in females of childbearing potential unless the conditions of the Pregnancy Prevention Program are met and alternative treatments are ineffective or not tolerated. Valproate products are assigned to Pregnancy Category D. This is because of the risk of birth defects and developmental disorders for an unborn baby. During pregnancy, sodium valproate and valproic acid must not be used for epilepsy unless it is the only possible treatment. Sodium valproate is an epilepsy drug prescribed for all seizure types including absence, myoclonus and tonic clonic seizures. It is also prescribed to a lesser degree for bipolar disorders. It is known under different brand names including Epilim, Epival, Episenta and Convulex.

Pregnancy Prevention Program. This means that if your doctor decides, in collaboration with you and/or your parent or legal guardian, that sodium valproate is the only medication that will effectively control your seizures, they must also discuss the need to use effective contraception to prevent you from getting pregnant. Depending on the type of contraception that you and your doctor consider to be best, regular pregnancy tests might be needed to make sure you are not pregnant. Your epilepsy specialist or family doctor must also invite you for a review of your epilepsy and medication at least once a year. This is an important opportunity to review your treatment and discuss the risks around the medication. You and your doctor will both need to sign a form acknowledging that you have discussed and understand the risks. Make an appointment to talk to your doctor or specialist and arrange to have a review if you haven’t already been invited for one.

If a baby is exposed to sodium valproate and valproic acid during pregnancy, there is a risk of it being born with physical disabilities and developmental issues. This applies whether valproate is taken alone or in combination with other medicines. The risk of disabilities such as spina bifida is approximately 10 per cent while studies show that up to 30-40 per cent of babies exposed to sodium valproate or valproic acid in the womb experience delays in their early development such as talking, and/or walking, have low intellectual abilities, poor language skills and memory problems.

Several published epidemiological studies have indicated that children exposed to valproate in utero have lower cognitive test scores than children exposed to either another antiepileptic drug in utero or to no antiepileptic drugs in utero. The largest of these studies is a prospective cohort study conducted in the United States and United Kingdom that found children with prenatal exposure to valproate throughout pregnancy had lower Differential Ability Scale scores at age 3 (92) than children with prenatal exposure to the other evaluated antiepileptic drug monotherapy treatments: lamotrigine (101), carbamazepine (98) and phenytoin (99) ⁴. The Differential Ability Scale, which has a mean score of 100 (SD = 15), is a battery of cognitive tests designed for children 2.5 to 17 years of age. The Differential Ability Scale is a measure of cognitive development performed in children who are too young to undergo IQ testing, and generally correlates with IQ scores later in childhood. Although all of the available studies have methodological limitations, the weight of the evidence supports the conclusion that valproate exposure in utero causes subsequent adverse effects on cognitive development in offspring.

During pregnancy your body may use up more of your antiepileptic drugs than usual. This means the amount of antiepileptic drug you normally take may not be enough to stop your seizures from happening. This is especially true for the antiepileptic drug lamotrigine (Lamictal).

Although routine monitoring of antiepileptic drug levels in pregnancy is not generally necessary, your neurologist might ask you to have blood tests to make sure that the amount of antiepileptic drug you take is at the right level for you and your baby throughout your pregnancy, especially if your seizures increase or are likely to increase. Testing the levels of the antiepileptic drug in your blood helps your neurologist decide if the dose needs to be changed. If your dose needs to be changed, it will usually be slowly reduced back to its original level after you give birth. However if the higher dose has led to better seizure control after birth, and there is no evidence that this increased dose is causing you problems, then you and your neurologist may decide to leave your antiepileptic drugs at this new dose.

What should happen if you are prescribed sodium valproate?

• your doctor should talk to you about the risks to babies during pregnancy and the importance of using an effective contraception
• they should ensure you have seen a specialist in the last year
• they should offer you an updated patient information booklet for more information
• both you and your doctor should sign a risk acknowledgement form showing that you have been informed of and understand risks associated with valproate.

When you receive your medication, your pharmacist should:

• show you the warning on the packaging that contains your medication
• make sure you have the patient card and leaflet about sodium valproate
• check that you have seen your doctor to discuss risks and measures for women and girls.

Should you stop taking sodium valproate straight away?

You should never stop taking your epilepsy medication without first consulting your doctor. This also applies if you are pregnant. In some circumstances seizures can cause miscarriage, trauma related to falls and may harm your baby. Even if you are not pregnant, seizures can pose a risk to your well being. It is important to seek the advice of your doctor and look at changing slowly to a different medication.

Can antiepileptic drugs affect an unborn baby?

If the baby’s father has epilepsy and takes antiepileptic drugs, these will not affect the baby’s development because the baby will not come into contact with the father’s antiepileptic drugs.

For a woman with epilepsy who takes antiepileptic drugs during her pregnancy, her baby will be exposed to antiepileptic drugs in the womb. Although while she is pregnant a mother’s bloodstream is kept separate from her unborn baby’s, some substances can pass from her blood into her baby’s blood via the placenta. These substances include nutrients, oxygen, alcohol and medication, including antiepileptic drugs. Some antiepileptic drugs can affect how the baby grows and develops in the womb, particularly so in the first 12 weeks of pregnancy when the baby’s main organs and skeleton are developing.

What should you do if you are not planning to start a family?

It is still important to take effective contraception to ensure that you do not become pregnant. As above, you must have an annual review with your specialist. Depending on the type of contraception you use you may also need to take a regular pregnancy test and sign a risk acknowledgement form.

What should you do if you are planning to start a family?

Make an appointment to see your doctor as early as possible and discuss your treatment options. Never stop taking your sodium valproate or contraception but discuss with your doctor the safest options to ensure your safety and that of any future babies.

What should you do if you are pregnant?

Do not stop taking your medication but make an appointment to see your doctor immediately. You will be able to discuss together the best form of treatment to safeguard the well being of both you and your baby. In some circumstances you may not be able to switch to another medication and your doctor will provide you with more information. You will be closely monitored to ensure you have the best seizure control and to check how your baby is developing.

Antiepileptic drugs administration

After the diagnosis of epilepsy, choosing of an antiepileptic drug is largely dependent on the classification of the seizure type. In the most general sense, seizures can be classified as either partial or generalized. Partial seizures can be further broken down into those that do not affect awareness (simple partial) or those that do (complex partial).

Simple partial seizures affect focal areas of the brain that, in turn, cause focal neurological findings like loss of motor function in one limb, sensory dysfunction in a specific body region, or changes to vision or speech, without affecting awareness of the event. Complex partial seizures are similar but do include brief moments of confusion that quickly resolve once the seizure has ended.

Generalized seizures affect the entire body and can exist as tonic-clonic seizures (where muscles stiffen initially, which is followed by jerking and spasming of the body), absence seizures (where individuals may stare off into space, and there is a brief lapse in awareness, often confused with daydreaming), and atonic seizures (where there is a sudden loss of muscle tone, frequently resulting in falls).

The International League Against Epilepsy recommends that epilepsy be diagnosed when any of the following exist: a history of two unprovoked seizures at least 24 hours apart, or an unprovoked seizure when the risk for a subsequent seizure is greater than 60% after two unproved seizures over the subsequent 10 years, or seizures that are part of an epilepsy syndrome.

Initiation of antiepileptic drugs

antiepileptic drugs can be broken down into two categories: broad-spectrum and narrow-spectrum. Broad-spectrum antiepileptic drugs treat a wide variety of seizure types, as the name suggests, and are a good initial choice, especially when the classification of seizure type is uncertain. These antiepileptic drugs include but are not limited to levetiracetam, lamotrigine, zonisamide, topiramate, valproic acid, clonazepam, perampanel, clobazam, and rufinamide.

Narrow spectrum antiepileptic drugs primarily are for the treatment of focal or partial seizures. These include but are not limited to lacosamide, pregabalin, gabapentin, carbamazepine, oxcarbazepine, ezogabine, phenytoin, and vigabatrin.

Monotherapy is the ideal pathway for the treatment of seizures, but newer antiepileptic drugs have had difficulty obtaining FDA approval as a monotherapy agent due to the difficulty of achieving approval requirements. However, anecdotally, and by examining the current evidence base, second-generation antiepileptic drugs appear to be an appropriate choice, as they have demonstrated similar efficacy when compared to older antiepileptic drugs and may be better tolerated.

One large randomized trial, the Standard and New Antiepileptic Drugs trial, demonstrated some comparative advantages of certain antiepileptic drugs when treating focal or generalized epilepsy. In the end, when comparing valproate, lamotrigine, or topiramate for generalized seizures, they recommended valproic acid as their first line choice. Additionally, when comparing carbamazepine, gabapentin, lamotrigine, oxcarbazepine, and topiramate for focal seizures, lamotrigine was cited as the first line choice.

Of note, regarding partial onset seizures specifically, perampanel, lacosamide, brivaracetam, and eslicarbazepine acetate are a few of the recently FDA-approved seizure medications for monotherapy.

How often should antiepileptic drugs be taken each day?

How often you take an antiepileptic drug (once, twice or possibly three times each day) depends on its half-life. The half-life of a drug is the length of time it takes for the original amount of the drug to reduce by half. The half-life is used to measure the concentration of the drug in the blood, which is not exactly the same as the dose of drug you take.

When you take a drug it takes time to be absorbed into your blood. When it is in your blood the amount can be measured; this is expressed as the drug’s ‘concentration’ or ‘level’, which relates to how much of the active ingredient of the drug is available to work. Once the drug has done its work it becomes metabolized (broken down) and eliminated (removed) from the body. In simple terms, when the drug reaches its half-life half of it is still in the blood and half of it has been metabolized and eliminated.

The aim of taking antiepileptic drugs regularly is to keep the level in the blood as stable as possible. Some antiepileptic drugs have a half-life of 24 hours so they are taken once a day. Those that have a half-life of 12 hours are taken twice a day, and those with a half-life of eight hours are taken three times a day. The shorter the half-life of the antiepileptic drug the more often it is taken.

What is the average dose range of an antiepileptic drug?

When considering how much medication someone takes we look at two different things. Firstly, we look at their ‘average’ dose — this is a measure of the number of tablets they take and how much active ingredient each tablet contains. For example, for an adult an average dose range for carbamazepine is 600–2000 mg per day and for sodium valproate it is 400–2000 mg per day. But how helpful is this? These figures are a very general guide but they are not individualized to each person: some people may have their seizures controlled on a dose lower than the bottom dose or higher than the top dose.

The second way of monitoring medication is to look at the amount of an antiepileptic drug in the blood and compare this to a reference range. The reference range is a range of concentrations of an antiepileptic drug within which most people will get a benefit from the drug (that is, it will stop the seizures). Below the reference range the drug is unlikely to work (that is, it will not stop the seizures) whereas above it, toxic effects (that is, reactions because the dose is too high) are likely to happen. Again, this is a general guide and not specific to an individual.

By monitoring drug levels in an individual and seeing what amount of an antiepileptic drug gives them the best seizure control, it is possible to work out an individualized therapeutic range for them. This range will vary from one person to another but will often fall within the general reference range for that antiepileptic drug.

Monitoring of antiepileptic drugs

Once administered, monitoring of serum medication levels is recommended to establish a therapeutic baseline and assess for toxicity. If the patient remains stable, these levels can be checked yearly, along with a complete blood count, a comprehensive metabolic panel, and liver function testing.

What is ‘blood-level testing’?

Blood-level testing, or therapeutic drug monitoring, is a system of monitoring the antiepileptic drug levels in an individual to help manage their epilepsy treatment.

Therapeutic drug monitoring involves taking blood samples to measure the amount of the drug in the blood that is ‘available’ to work (its bioavailability). So this is a good way of measuring how much of the drug your body is getting. This is not the same as looking at how much of the drug you take (that is, your daily dose), although they are connected: the higher the dose you take the more you would expect to be in your blood.

Although doctors call it ‘blood-level’ testing it is sometimes also referred to as ‘plasma-level’ or ‘serum-level’ testing because the drug is measured in the liquid part of the blood (the plasma or serum) and not the blood cells.

At the moment blood-level testing is not done very often, but there are many situations in which it can help to manage epilepsy treatment. For example, it can be used to see if you are getting the right amount of a drug for you, or if you are taking toxic amounts of drugs, or to monitor how different situations affect your medication (for example, if you are a woman and you become pregnant, or you start taking medication for another condition which might affect your antiepileptic drugs).

When you increase a dose, how long does it take to start working?

This varies from one antiepileptic drug to another and depends on the half-life of the drug. Generally, you can see the effect of an increase in five half-lives’ time, so if the half-life of the antiepileptic drug is 24 hours you will see the effect five days (that is, 5 x 24 hours) later. If the half-life is 12 hours you will see the effect two-and-a-half days (that is, 5 x 12 hours) later.

Discontinuation of antiepileptic drugs

When to discontinue antiepileptic drugs is less clear. In children, consensus recommendations appear to be after two years of remaining seizure free. However, in adults, some research has estimated the risk of seizure recurrence immediately after cessation of antiepileptic drugs at the 2-year mark at 30%. The risk appears to diminish with time if an individual continues without further seizures. Taking this into account, it is apparent why guidelines in adults are more conservative and recommend a seizure-free period of 2 to 5 years while advising against driving for three months after antiepileptic drug cessation.

Antiepileptic drugs contraindications

A contraindication to most medications, in general, is a prior history of hypersensitivity or allergic reaction to that medication. Other contraindications exist but are more drug-specific, including hepatic failure, certain blood diseases, narrow-angle glaucoma, and familial short QT syndrome to name a few.

Valproic acid and felbamate are associated with hepatotoxicity, and therefore, contraindicated in patients with hepatic failure. The liver metabolizes many others, and dosage adjustments need to be made before initiation.

Similarly, those with renal impairments need to adjust dosing with antiepileptic drugs excreted by the kidneys, primarily by using the glomerular filtration rate. Hemodialysis also may require dosing adjustment to ensure the medication remains in the respective therapeutic range.

Likewise, because of variability in metabolism and excretion rates, caution must be exercised in children and the elderly.

While in pregnancy, guidelines proffered by the American Academy of Neurology in 2009 report that women should remain on their current antiepileptic drug, as switching medications increase the risk of breakthrough seizure, and adding another antiepileptic drug increases the risk of congenital disabilities. Folic acid should be supplemented for any woman of childbearing age, and especially those considering becoming pregnant. If possible, optimization of the medication regimen, by identifying the lowest effective dose with the least amount of medications, is ideal. Women who experience their first seizure during pregnancy should follow the same management strategy as if she was not pregnant.

Through the duration of the pregnancy, serum drug levels should regularly be monitored, and dosages titrated or adjusted to within therapeutic ranges.

Unfortunately, there is insufficient research into comparative efficacy and teratogenicity for recommendations of specific antiepileptic drugs in pregnancy. However, valproic acid deserves special mention as it is contraindicated in pregnancy due to consistent evidence of teratogenicity, including dose-dependent effects on IQ, adaptive functioning, increased risk of ADHD, and increased risk of major congenital malformations.

As benefits are believed to outweigh risks, the consensus remains that antiepileptic drugs can continue to be taken while breastfeeding. However, measurable levels can be found in breastmilk, and available research has not determined what risk this poses to newborns ⁵.

Antiepileptic drugs side effects

According to the American Academy of Neurology, antiepileptic drugs side effects also called adverse drug reactions may range from 7% to 31%, but are mostly mild and reversible ¹. In general, it is important to review the specific medication insert for a complete list of side effects ⁶.

Antiepileptic drugs can impact cognition and learning either positively or negatively. Where medications successfully control the seizures, they are reducing the abnormal activity in the brain which can affect learning, therefore improving the child’s ability to learn.

Sometimes medications may negatively affect the child’s ability to learn. This can be related to the dose of the medication, length of time taking the medication, the type of medication or combination of medications.

Some common unwanted side effects of antiepileptic drugs include:

• Poor concentration, short term memory loss
• Hyperactivity, drowsiness, or fatigue
• Visual problems – blurred or double vision
• Speech problems
• Poor coordination and balance, dizziness and unsteadiness
• Nausea, vomiting, weight gain or loss
• Depression, aggressiveness, anti-social behaviors

The challenge is to control the seizures while not compromising the child’s learning. Sometimes this will be difficult. It is best to speak with your child’s neurologist about possible side effects, and if they are being experienced, and discuss alternative options for treatment.

Of the more mild and common side effects, patients should be advised to monitor for headaches, fatigue, dizziness, blurry vision, nausea, weight gain or loss, mood disorders and neurocognitive problems. The potential for allergic reactions is present amongst all medications and should be monitored with initiation.

With chronic use, many antiepileptic drugs carries a side effect of osteoporosis, and general recommendations are to supplement diets with calcium and vitamin D, as well as to encourage routine exercise habits.

Of the more serious side effects, Stevens-Johnson syndrome, agranulocytosis, aplastic anemia, hepatic failure, pancytopenia, multiorgan hypersensitivity, psychosis, and lupus syndrome have all been reported. Although the risk for suicidality is low, the U.S. Food Drug and Administration (FDA) has required all antiepileptic drugs to carry a suicide warning.

Also of concern are drug-drug interactions, which occur most commonly with the older generation of antiepileptic drug’s, as they can affect hepatic enzymes. If these hepatic enzymes are induced, it can lead to rapid metabolism of other medications, potentially leading to their subtherapeutic levels in the body. If, on the other hand, hepatic enzymes are inhibited, toxic levels of medications can be reached due to impaired breakdown through the liver.

Both are inducing and inhibiting medications can raise significant concern when managing certain comorbid conditions where therapeutic doses of medications are of the utmost importance, including HIV, cancer, endocrine disorders, and cardiovascular disease.

Why do side effects happen?

When you take a prescribed drug you are obviously taking it for a reason, which is to make something happen such as preventing a condition or treating a symptom. The aim of antiepileptic drugs is to stop seizures happening. But when you take a drug — any drug — there is also a possibility of side effects.

Medication usually needs to get into your body, and around it, in your bloodstream to reach the area it needs to work on (called the site of action) before it is removed from the body. As the medication makes this journey it can have other, sometimes unwelcome, effects.

Do side effects always happen?

The list of side effects for any drug, including antiepileptic drugs, can be very long and quite off-putting. But side effects are only possible effects: they do not always happen. Generally, most people take drugs without having serious side effects (that is, side effects that mean they want, or need, to stop taking the drug). Whether these side effects happen or not depends on the individual because different people can respond differently to the same drug.

Patient information leaflets use terms like ‘common’ and ‘rare’. But what do these terms actually mean?

These terms are the same for all drugs and refer to the likelihood that a side effect will happen. This likelihood is shown by how many people will get it:

• Very common means that more than one-in-10 people will get it
• Common means that one-in-100 to one-in-10 people will get it
• Occasional means that one-in-1,000 to one-in-100 people will get it
• Rare means that less than one-in-1,000 people will get it
• Very rare means that less than one-in-10,000 people will get it
• Extremely rare means that less than one-in-100,000 people will get it

These terms tell you how many people are likely to get the side effect, but they cannot tell you how likely you are to get it.

Knowing what these terms actually mean may help you to put side effects into perspective. This can be helpful when you are making decisions about taking – or not taking – medication.

Are side effects the same for all antiepileptic drugs?

No, they vary from one drug to another. When drugs are developed they are tested on many people and the common side effects are listed on the patient information leaflet that comes with each drug. If the side effects are very serious the drug may not continue to be developed.

Although the tests are done on many people, once a drug is licensed and prescribed it may be used by thousands of people over long periods of time. Some side effects, particularly those that are extremely rare or ‘idiosyncratic’ (that is, unique to you) may not have come to light during the trials and may not be seen until the drug is being widely used. Also, some side effects only happen if the drug is taken over a very long period of time, possibly over many years or decades, and so will not be seen during the trials.

Antiepileptic drugs toxicity

Toxic symptoms in antiepileptic drugs are idiosyncratic and are believed to occur more frequently in the first-generation antiepileptic drugs. One such example is carbamazepine, a commonly implicated first-generation antiepileptic drug in acute or chronic toxicity. Possible symptoms may include ataxia, dystonia, sinus tachycardia, hyperthermia, coma, arrhythmias, respiratory depression, and death. Another example is valproic acid, which can have toxic effects that include metabolic and hematological disruption, pancreatitis, central nervous system (CNS) depression, optic nerve atrophy, respiratory depression, cardiopulmonary arrest, brain edema, and coma ⁷.

Treatment can range from supportive measures to high-flow hemodialysis, plasmapheresis, or charcoal hemoperfusion.

Patients should be educated before initiating any antiepileptic drug to alert treating physicians when adverse events are encountered. It is also important to note that therapeutic reference ranges are considered guidelines, and levels outside of the range do not necessarily indicate toxicity or a need to adjust dosing. However, if clinical picture correlates with elevated serum drug levels, then, indeed, treatment is warranted.

References

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