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

Drugs

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:

  1. Wheless, JW (November 2008). "History of the ketogenic diet.". Epilepsia. 49 Suppl 8: 3–5. doi:10.1111/j.1528-1167.2008.01821.x. PMID 19049574.
  2. Rang, HP; Dale, MM; Flower, RJ; Henderson, G (2011). Rang & Dale's Pharmacology (7th ed.). Edinburgh, UK: Churchill Livingstone. ISBN 978-0-70-203471-8.
  3. Brunton, L; Chabner, B; Knollman, B (2010). Goodman and Gilman's The Pharmacological Basis of Therapeutics (12th ed.). New York: McGraw-Hill Professional. ISBN 978-0-07-162442-8
  4. Maroon, J; Bost, J; Amos, A; Zuccoli, G (August 2013). "Restricted calorie ketogenic diet for the treatment of glioblastoma multiforme.". Journal of Child Neurology 28 (8): 1002–8. doi:10.1177/0883073813488670. PMID 23670248.
  5. Mobbs, CV; Mastaitis, J; Isoda, F; Poplawski, M (August 2013). "Treatment of diabetes and diabetic complications with a ketogenic diet.". Journal of Child Neurology 28 (8): 1009–14. doi:10.1177/088307381348759. PMID 23680948.
  6. Bueno, NB; de Melo, IS; de Oliveira, SL; da Rocha Ataide, T (October 2013). "Very-low-carbohydrate ketogenic diet v. low-fat diet for long-term weight loss: a meta-analysis of randomised controlled trials.". The British Journal of Nutrition 110 (7): 1178–87. doi:10.1017/S0007114513000548. PMID 23651522.
  7. Kaila, K; Ruusuvuori, E; Seja, P; Voipio, J; Puskarjov, M (November 2013). "GABA actions and ionic plasticity in epilepsy.". Current Opinion in Neurobiology 26C: 34–41. doi:10.1016/j.conb.2013.11.004. PMID 24650502.
  8. Moreau, A; Gosselin-Badaroudine, P; Chahine, M (April 2014). "Biophysics, pathophysiology, and pharmacology of ion channel gating pores." (PDF). Frontiers in Pharmacology 5: 53. doi:10.3389/fphar.2014.00053. PMC 3982104. PMID 24772081.
  9. Winum, JY; Poulsen, SA; Supuran, CT (May 2009). "Therapeutic applications of glycosidic carbonic anhydrase inhibitors.". Medicinal Research Reviews 29 (3): 419–35. doi:10.1002/med.20141. PMID 19058143.
  10. Hübner, CA; Holthoff, K (October 2013). "Anion transport and GABA signaling." (PDF). Frontiers in Cellular Neuroscience 7: 177. doi:10.3389/fncel.2013.00177. PMC 3807543. PMID 24187533.
  11. Aggarwal, M; Kondeti, B; McKenna, R (2013). "Anticonvulsant/antiepileptic carbonic anhydrase inhibitors: a patent review.". Expert Opinion on Therapeutic Patents 23 (6): 717–24. doi:10.1517/13543776.2013.782394. PMID 23514045.
  12. Parsons, MP; Raymond, LA (April 2014). "Extrasynaptic NMDA Receptor Involvement in Central Nervous System Disorders.". Neuron 82 (2): 279–293. doi:10.1016/j.neuron.2014.03.030. PMID 24742457.
  13. Jay, GW; Barkin, RL (January 2014). "Neuropathic pain: etiology, pathophysiology, mechanisms, and evaluations.". Disease-a-Month 60 (1): 6–47. doi:10.1016/j.disamonth.2013.12.001. PMID 24507705.
  14. Wiffen, PJ; Derry, S; Moore, RA; Kalso, EA (April 2014). "Carbamazepine for chronic neuropathic pain and fibromyalgia in adults." (PDF). The Cochrane Database of Systematic Reviews 4: CD005451. doi:10.1002/14651858.CD005451.pub3. PMID 24719027.
  15. Kroenke, K; Krebs, EE; Bair, MJ (May-June 2009). "Pharmacotherapy of chronic pain: a synthesis of recommendations from systematic reviews.". General Hospital Psychiatry 31 (3): 206–19. doi:10.1016/j.genhosppsych.2008.12.006. PMID 19410099
  16. Srivastava, S; Ketter, TA (December 2011). "Clinical relevance of treatments for acute bipolar disorder: balancing therapeutic and adverse effects.". Clinical Therapeutics 33 (12): B40–8. doi:10.1016/j.clinthera.2011.11.020. PMID 22177379.
  17. Smith, DJ; Whitham, EA; Ghaemi, SN (2012). "Bipolar disorder.". Handbook of Clinical Neurology 106: 251–63. doi:10.1016/B978-0-444-52002-9.00015-2. PMID 22608626.
  18. Bauer, M; Ritter, P; Grunze, H; Pfennig, A (May 2012). "Treatment options for acute depression in bipolar disorder.". Bipolar Disorders14 Suppl 2: 37–50. doi:10.1111/j.1399-5618.2012.00991.x. PMID 22510035.
  19. Malhi, GS; Tanious, M; Berk, M (December 2012). "Mania: diagnosis and treatment recommendations.". Current Psychiatry Reports 14 (6): 676–86. doi:10.1007/s11920-012-0324-5. PMID 22986995.
  20. Pfennig, A; Bschor, T; Falkai, P; Bauer, M (February 2013). "The diagnosis and treatment of bipolar disorder: recommendations from the current s3 guideline." (PDF). Deutsches Arzteblatt International 110 (6): 92–100. doi:10.3238/arztebl.2013.0092. PMC 3583180. PMID 23451001.
  21. Geddes, JR; Miklowitz, DJ (May 2013). "Treatment of bipolar disorder." (PDF). Lancet 381 (9878): 1672–82. doi:10.1016/S0140-6736(13)60857-0. PMC 3876031. PMID 23663953.
  22. Renk, K; White, R; Lauer, BA; McSwiggan, M; Puff, J; Lowell, A (2014). "Bipolar Disorder in Children." (PDF). Psychiatry Journal 2014: 928685. doi:10.1155/2014/928685. PMC 3994906. PMID 24800202.
  23. Linde, M; Mulleners, WM; Chronicle, EP; McCrory, DC (June 2013). "Antiepileptics other than gabapentin, pregabalin, topiramate, and valproate for the prophylaxis of episodic migraine in adults." (PDF). The Cochrane Database of Systematic Reviews 6: CD010608. doi:10.1002/14651858.CD010608. PMID 23797674.
  24. Carod-Artal, FJ (2014). "Tackling chronic migraine: current perspectives." (PDF). Journal of Pain Research 7: 185–194. doi:10.2147/JPR.S61819. PMC 3986300. PMID 24748814.
  25. Hornyak, M; Scholz, H; Kohnen, R; Bengel, J; Kassubek, J; Trenkwalder, C (April 2014). "What treatment works best for restless legs syndrome? Meta-analyses of dopaminergic and non-dopaminergic medications.". Sleep Medicine Reviews 18 (2): 153–64. doi:10.1016/j.smrv.2013.03.004. PMID 23746768.
  26. Letterman, L; Markowitz, JS (May 1999). "Gabapentin: a review of published experience in the treatment of bipolar disorder and other psychiatric conditions.". Pharmacotherapy 19 (5): 565–72. doi:10.1592/phco.19.8.565.31521. PMID 10331819.
  27. Blanco, C; Bragdon, LB; Schneier, FR; Liebowitz, MR (February 2013). "The evidence-based pharmacotherapy of social anxiety disorder.". The International Journal of Neuropsychopharmacology 16 (1): 235–49. doi:10.1017/S1461145712000119. PMID 22436306.
  28. Thompson, DF; Brooks, KG (June 2013). "Gabapentin therapy of hiccups.". The Annals of Pharmacotherapy 47 (6): 897–903. doi:10.1345/aph.1S018. PMID 23673537.
  29. Bowden, CL; Singh, V (December 2012). "Lamotrigine (Lamictal IR) for the treatment of bipolar disorder.". Expert Opinion on Pharmacotherapy 13 (17): 2565–71. doi:10.1517/14656566.2012.741590. PMID 23140205.
  30. McIntyre, RS; Cha, DS; Kim, RD; Mansur, RB (December 2013). "A review of FDA-approved treatment options in bipolar depression.". CNS Spectrums. 18 Suppl 1: 4–20; quiz 21. doi:10.1017/S1092852913000746. PMID 24237641.
  31. Reid, JG; Gitlin, MJ; Altshuler, LL (July 2013). "Lamotrigine in psychiatric disorders.". The Journal of Clinical Psychiatry 74 (7): 675–84. doi:10.4088/JCP.12r08046. PMID 23945444.
  32. Vieta, E; Valentí, M (July 2013). "Pharmacological management of bipolar depression: acute treatment, maintenance, and prophylaxis.". CNS Drugs 27 (7): 515–29. doi:10.1007/s40263-013-0073-y. PMID 23749421.
  33. Goff, DC (23 October 2009). "Review: lamotrigine may be an effective treatment for clozapine resistant schizophrenia". Evidence-Based Mental Health 12 (4): 111–111. doi:10.1136/ebmh.12.4.111.
  34. Taylor, CP; Angelotti, T; Fauman, E (February 2007). "Pharmacology and mechanism of action of pregabalin: the calcium channel alpha2-delta (alpha2-delta) subunit as a target for antiepileptic drug discovery.". Epilepsy Research 73 (2): 137–50. doi:10.1016/j.eplepsyres.2006.09.008. PMID 17126531.
  35. Vasudev, K; Macritchie, K; Geddes, J; Watson, S; Young, A (January 2006). "Topiramate for acute affective episodes in bipolar disorder." (PDF). The Cochrane Database of Systematic Reviews (1): CD003384. doi:10.1002/14651858.CD003384.pub2. PMID 16437453.
  36. Johnson, BA (September 2004). "Topiramate-induced neuromodulation of cortico-mesolimbic dopamine function: a new vista for the treatment of comorbid alcohol and nicotine dependence?". Addictive Behaviors 29 (7): 1465–79. doi:10.1016/j.addbeh.2004.06.014. PMID 15345276.
    Jump up
  37. Johnson, BA (2005). "Recent advances in the development of treatments for alcohol and cocaine dependence: focus on topiramate and other modulators of GABA or glutamate function.". CNS Drugs 19 (10): 873–96. doi:10.2165/00023210-200519100-00005. PMID 16185095.
  38. Kenna, GA; Lomastro, TL; Schiesl, A; Leggio, L; Swift, RM (May 2009). "Review of topiramate: an antiepileptic for the treatment of alcohol dependence.". Current Drug Abuse Reviews (2): 135–42. doi:10.2174/1874473710902020135. PMID 19630744.
  39. De Sousa, A (March 2010). "The role of topiramate and other anticonvulsants in the treatment of alcohol dependence: a clinical review.". CNS & Neurological Disorders Drug Targets (1): 45–9. doi:10.2174/187152710790966696. PMID 20201814.
  40. Antel, J; Hebebrand, J (2012). "Weight-reducing side effects of the antiepileptic agents topiramate and zonisamide.". Handbook of Experimental Pharmacology (209): 433–66. doi:10.1007/978-3-642-24716-3_20. PMID 22249827.
  41. Linde, M; Mulleners, WM; Chronicle, EP; McCrory, DC (June 2013). "Valproate (valproic acid or sodium valproate or a combination of the two) for the prophylaxis of episodic migraine in adults." (PDF). The Cochrane Database of Systematic Reviews 6: CD010611. doi:10.1002/14651858.CD010611. PMID 23797677.
  42. Blaheta, RA; Cinatl J, Jr (September 2002). "Anti-tumor mechanisms of valproate: a novel role for an old drug.". Medicinal Research Reviews 22 (5): 492–511. doi:10.1002/med.10017. PMID 12210556.

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 (josephalberteo@gmail.com) i can count on him for a cure for you too.

    ReplyDelete