Friday, 9 May 2014

Anticonvulsants, epilepsy and other therapeutic uses of anticonvulsant medications

The anticonvulsants are an interesting little class of medications that are amongst the oldest of synthetic medications currently employed in modern medicine. Their primary use in medicine (and this is where their class name originates from) is in the treatment of epilepsy and other seizure-related disorders. Seizures have plagued mankind since Biblical times and the first effective treatment for epilepsy emerged as early as 500 BC.1 Epilepsy, which is a disorder characterised by repeated seizures, affects about 0.5-1% of people worldwide.2,3

Fasting and dietary changes

Figure 1: Ketone bodies
This effective treatment was fasting; it might seem odd but fasting was proven an effective treatment for epilepsy, in well-designed clinical trials in the 1910s, although its use to relieve the symptoms of epilepsy can be dated back to Ancient Greece. Despite its success it's clearly not ideal to just keep starving people indefinitely so as to control their epilepsy, as they'll eventually develop nutritional deficiencies and die and hence a modern equivalent has been developed and is used in cases of treatment-resistant (refractory) epilepsy, or in kids whom's parents refuse pharmacologic (drug) treatments. This modern equivalent is called the ketogenic diet and it basically consists of a very low-carbohydrate and high fat diet. Its purpose is to force the body to start burning fats for energy (instead of the usual carbohydrates like glucose) and, in so doing, produce a group of compounds called ketones from the body's fat reserves or dietary fats. Ketones, in turn, lower the pH of one's blood and it is believed that it is this action that improves seizure control in people with epilepsy. Despite its efficacy the ketogenic diet has its limitations, especially compliance issues, as many people with refractory epilepsy are kids and kids tend to be picky when it comes to food and most food allowed in the ketogenic diet is very oily and hence not especially palatable. The ketogenic diet can also cause nutritional deficiencies and constipation (due to a lack of fibre in this diet). Plus some people just don't respond to the ketogenic diet. There's also some evidence to suggest that the ketogenic diet might help people with cancer, obesity and diabetes mellitus.1, 4-6


Figure 2: GABA

History and background

The first anticonvulsant drugs were incredibly toxic in cases of even slight overdoses and were the bromides (potassium and sodium salts; first introduced in the late 19th century) which are now largely replaced by safer and more reliable anticonvulsants. Later came phenobarbital (Luminal; first introduced in 1912) and phenytoin (Dilantin; first discovered to have anticonvulsant activity in 1938), which are still widely used to treat epilepsy. Later between 1965 and 1990 other drugs such as other barbiturates (like primidone [Mysoline]) carbamazepine (Tegretol), acetazolamide (Diamox), valproate (Depakote, Epilim, Valpro) and the benzodiazepines (such as clobazam [Frisium], clonazepam [Klonopin, Paxam, Rivotril], diazepam [Valium], midazolam [Hypnovel], nitrazepam [Alodorm, Mogadon]) were introduced as anticonvulsants. Many of these agents work by increasing the activity of a neurotransmitter called γ-aminobutyric acid (GABA), which acts by two receptors  GABAA  and GABAB; both of these receptors suppress the activity of the brain cells on which they're expressed.7 Some act on sodium channels, which are involved in the propagation of action potentials (see this link for an introduction to action potentials that's written for kids so it should be easier for ya to follow).8 Acetazolamide inhibits carbonic anhydrase, which is an enzyme involved in the production of carbonic acid in the blood which regulates blood pH. Hence, by inhibiting this enzyme, it decreases blood pH and this seems to confuse the ion channels found in one's brain; hence interfering with their activity.2,3,8-11
Figure 3: Human Carbonic Anhydrase

Figure 4: Glutamate
Later in the 1990s and 2000s a few extra drugs were introduced as anticonvulsants, such as ethosuximide (Zarontin), felbamate (not marketed in Australia; Felbata, Taloxa), gabapentin (Gabatine, Gantin, Neurontin, Nupentin), lacosamide (Vimpat), lamotrigine (Lamictal, Lamidus, LamogineReedos), levetiracetam (Kepcet, Keppra, Kerron, Levecetam), oxcarbazepine (Trileptal), perampanel (not marketed in Australia; Fycompa), pregabalin (Lyrica), retigabine (not currently marketed in Australia; Potiga, Trobalt), sultiame (Ospolot), topiramate (Epiramax, Tamate, Topamax), vigabatrin (Sabril) and zonisamide (Zonegran). Some of these block calcium channels, which are also involved in signal propagation in the brain; others open potassium channels; while others work on GABA signalling; others work on the neurotransmitter, glutamate, which is basically the opposite to GABA in its actions; the remaining work by inhibiting carbonic anhydrase.2,3,8-12

Table 1: Comparison of anticonvulsants2,3
Drug Pharmacology Intro. Medical uses Structure
Acetazolamide Carbonic anhydrase inhibitor. 1953 Glaucoma and epilepsy.11
BZDs GABAA potentiators. 1960s Anxiety, insomnia and epilepsy.
Carbamazepine Stabilises the inactive form of sodium channels.  1965 Trigeminal neuralgia,13-15 bipolar disorder16-22 and epilepsy.
Ethosuximide Blocks calcium currents in the thalamus. 1960 Epilepsy. 
Felbamate NMDA antagonist/GABAA potentiator 1993 Epilepsy.
Gabapentin α2δ calcium channel blocker 1993 Epilepsy; migraine prevention;23,24 restless legs syndrome;25 anxiety;26,27 hiccups;28 neuropathic pain.13,15
Lacosamide Slowing the inactivation of sodium channels. Also affects collapsin response mediator protein-2, which is involved in neuronal survival. 2008 Epilepsy.
Lamotrigine Sodium channel inactivation delayer; glutamate release inhibitor. 1994 Epilepsy, bipolar depression16,18,29-32 and treatment-resistant schizophrenia.31,33
Levetiracetam Has an action on SV2A, a protein involved in regulating neurotransmitter release.  1999. Epilepsy.
Oxcarbazepine Sodium channel inactivation stabiliser. 2000 Epilepsy.
Perampanel AMPA receptor blocker. 2012 Epilepsy.
Phenobarbital GABAA potentiator. 1912 Epilepsy.
Phenytoin Sodium channel blocker. 1938 Epilepsy.
Pregabalin α2δ calcium channel blocker. 2004 Epilepsy; neuropathic pain; migraine prevention; fibromyalgia; anxiety.34
Primidone GABAA potentiator. 1954 Epilepsy.
Retigabine Potassium channel opener. 2010 Epilepsy.
Sultiame Carbonic anhydrase inhibitor. 1991 Epilepsy
Tiagabine GABA potentiator. 1997 Epilepsy.
Topiramate Blocks voltage-dependent sodium channels; potentiates GABA transmission and glutamate signalling. Carbonic anhydrase inhibitor.  1996 Epilepsy; bipolar disorder (although the evidence is against this use);35 addiction;36-39 obesity;40 migraine prevention;23 Lennox-Gastaut syndrome.
Valproate Voltage-dependent sodium channel blocker. 1978 Epilepsy, bipolar disorder19-22 and migraine prevention.23 May have cancer-fighting effects.42
Vigabatrin Inhibits the breakdown of GABA.  2009 Epilepsy.
Zonisamide Carbonic anhydrase inhibitor; sodium and calcium channel blocker; modulates GABA release; reduces glutamate release.  1989 (Japan) Epilepsy; obesity.40

Additional uses

It's interesting how topiramate and zonisamide can be used to treat obesity; topiramate can also be used to treat drug addictions. It can also be used to treat migraines. Valproate and carbamazepine can be used to treat bipolar disorder as can lamotrigine, although lamotrigine is most effective at treating bipolar depression whereas carbamazepine and valproate are best at treating/preventing mania. Valproate can be used (usually as a last resort) to prevent migraines and has also shown some anticancer activity. Pregabalin and gabapentin can be used to treat neuropathic (nerve injury-related) pain and anxiety disorders. Lamotrigine may also be used to treat schizophrenia in treatment-resistant cases.

Adverse effects/drug interactions

All of these drugs do have their disadvantages, of course, carbamazepine, oxcarbazepine, phenytoin and the barbiturates are notorious for their ability to interact with other drugs and even with themselves (which necessitates regulate monitoring for these medications). These drugs can also precipitate acute attacks in people with porphyria. Most anticonvulsants can cause sedation, drowsiness, memory problems and mood changes, especially early on in treatment. Carbamazepine (especially common with this drug), ethosuximide, lamotrigine, oxcarbazepine, phenytoin, pregabalin, topiramate, valproate and zonisamide can all cause potentially fatal blood disorders, although rarely for most. Some, including carbamazepine, ethosuximide, lamotrigine (especially problematic with this one, which necessitates slow dose increases early on in treatment), levetiracetam, oxcarbazepine, phenytoin, sultiame and zonisamide can cause potentially fatal skin reactions, although rare. These skin effects are more common in those of Asian ancestry. Most other side effects are digestive in nature (like nausea, vomiting, constipation, diarrhoea, loss of appetite, etc.) or psychiatric/neurologic (e.g. headache, dizziness, depression, etc.) in nature. Some can even induce hallucinations or suicidal thoughts. Vigabatrin can also cause visual disturbances which are often irreversible. Many can provoke allergic reactions in some people. Carbonic anhydrase inhibitors can also cause dangerously low blood pH which can cause coma or death; long-term consequences of this action can include brittle bones and kidney stones. Valproate, after long-term use, can also cause brittle bones; it can also cause liver damage (sometimes requiring transplant; which topiramate, carbamazepine and oxcarbazepine can also do) or pancreatitis (swelling of the pancreas). Valproate, vigabatrin, pregabalin, gabapentin and ethosuximide are known to cause weight gain in a number of patients whereas topiramate and zonisamide tend to cause weight loss

Reference list:

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1 comment:

  1. How my daughter was saved from grand mal seizure.
    I am not really a fan of sharing my personal private story on the internet but i decided to do this because this joy is too voluminous for me to hide. My daughter which i took over 8 years after marriage to conceive had her first seizure at age 6 and ever since then it has been from one seizure to another in school, in church, at picnics. This got me worried because she has a bright future that i do not want epilepsy to become a hindrance, i tried several doctors in Texas and none could help with an effective cure. I went on the internet and saw testimonies about a treatment for epilepsy which a doctor offered and i was interested, i got in contact with him and i was able to get the medicine for my daughter which she used for 3 months as he instructed and it has been over 6 months now she is doing just fine without any allergies or aftermath effects. If you are suffering problem try to reach him too on ( i can count on him for a cure for you too.