Ethosuximide

Last updated
Ethosuximide
Ethosuximide.svg
3D Model of Ethosuximide.png
Clinical data
Trade names Zarontin, others
AHFS/Drugs.com Monograph
MedlinePlus a682327
License data
Pregnancy
category
  • AU:D
Routes of
administration 		By mouth (capsules, solution)
ATC code
Legal status
Legal status
  • BR: Class C1 (Other controlled substances) [1]
  • US: ℞-only
  • EU:Rx-only [2]
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability 93% [3]
Metabolism liver (CYP3A4, CYP2E1)
Elimination half-life 53 hours
Excretion kidney (20%)
Identifiers
  • (RS)-3-Ethyl-3-methyl-pyrrolidine-2,5-dione
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.000.954 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C7H11NO2
Molar mass 141.170 g·mol−1
3D model (JSmol)
Chirality Racemic mixture
Melting point 64 to 65 °C (147 to 149 °F)
  • O=C1NC(=O)CC1(C)CC
  • InChI=1S/C7H11NO2/c1-3-7(2)4-5(9)8-6(7)10/h3-4H2,1-2H3,(H,8,9,10) Yes check.svgY
  • Key:HAPOVYFOVVWLRS-UHFFFAOYSA-N Yes check.svgY
   (verify)

Ethosuximide, sold under the brand name Zarontin among others, is a medication used to treat absence seizures. [4] It may be used by itself or with other antiseizure medications such as valproic acid. [4] Ethosuximide is taken by mouth. [4]

Contents

Ethosuximide is usually well tolerated. [5] Common side effects include loss of appetite, abdominal pain, diarrhea, and feeling tired. [4] Serious side effects include suicidal thoughts, low blood cell levels, and lupus erythematosus. [4] [5] It is unclear if it has adverse effects on the fetus during pregnancy. [4] Ethosuximide is in the succinimide family of medications. Its mechanism of action is thought to be due to antagonism of the postsynaptic T-type voltage-gated calcium channel. [6]

Ethosuximide was approved for medical use in the United States in 1960. [7] It is on the World Health Organization's List of Essential Medicines. [8] Ethosuximide is available as a generic medication. [4] As of 2019, its availability was limited in many countries, with concerns about price fixing in the United States. [9] [10] [11]

Medical uses

Ethosuximide is approved for absence seizures, [12] and is considered the first choice medication for treating them, in part because it lacks the idiosyncratic hepatotoxicity of the alternative anti-absence drug, valproic acid. [13]

Adverse effects

As with other anticonvulsants, ethosuximide carries a warning about use during pregnancy. Although a causal relationship with birth defects has not be established, the potential for harm to the baby is weighed against the known harm caused by a mother having even minor seizures. [4]

Central nervous system

Common

Rare

Gastrointestinal

Genitourinary

Blood

The following can occur with or without bone marrow loss:

Skin

Eyes

Drug interactions

Valproates can either decrease or increase the levels of ethosuximide; however, combinations of valproates and ethosuximide had a greater protective index than either drug alone. [14]

It may elevate serum phenytoin levels.

Mechanism of action

The mechanism by which ethosuximide affects neuronal excitability includes block of T-type calcium channels, and may include effects of the drug on other classes of ion channel. The primary finding that ethosuximide is a T-type calcium channel blocker gained widespread support, but initial attempts to replicate the finding were inconsistent. Subsequent experiments on recombinant T-type channels in cell lines demonstrated conclusively that ethosuximide blocks all T-type calcium channel isoforms.[ citation needed ] Significant T-type calcium channel density occurs in dendrites of neurons, and recordings from reduced preparations that strip away this dendritic source of T-type calcium channels may have contributed to reports of ethosuximide ineffectiveness.

In March 1989, Coulter, Huguenard and Prince showed that ethosuximide and dimethadione, both effective anti-absence agents, reduced low-threshold Ca2+ currents in T-type calcium channels in freshly removed thalamic neurons. [15] In June of that same year, they also found the mechanism of this reduction to be voltage-dependent, using acutely dissociated neurons of rats and guinea pigs; it was also noted that valproic acid, which is also used in absence seizures, did not do that. [16] The next year, they showed that anticonvulsant succinimides did this and that the pro-convulsant ones did not. [17] The first part was supported by Kostyuk et al. in 1992, who reported a substantial reduction in current in dorsal root ganglia at concentrations ranging from 7 μmol/L to 1 mmol/L. [18]

That same year, however, Herrington and Lingle found no such effect at concentrations of up to 2.5 mmol/L. [19] The year after, a study conducted on human neocortical cells removed during surgery for intractable epilepsy, the first to use human tissue, found that ethosuximide had no effect on Ca2+ currents at the concentrations typically needed for a therapeutic effect. [20]

In 1998, Slobodan M. Todorovic and Christopher J. Lingle of Washington University reported a 100% block of T-type current in dorsal root ganglia at 23.7 ± 0.5 mmol/L, far higher than Kostyuk reported. [21] That same year, Leresche et al. reported that ethosuximide had no effect on T-type currents, but did decrease noninactivating Na+ current by 60% and the Ca2+-activated K+ currents by 39.1 ± 6.4% in rat and cat thalamocortical cells. It was concluded that the decrease in Na+ current is responsible for the anti-absence properties. [22]

In the introduction of a paper published in 2001, Dr. Juan Carlos Gomora and colleagues at the University of Virginia in Charlottesville pointed out that past studies were often done in isolated neurons that had lost most of their T-type channels. [23] Using cloned α1G, α1H, and α1I T-type calcium channels, Gomora's team found that ethosuximide blocked the channels with an IC50 of 12 ± 2 mmol/L and that of N-desmethylmethsuximide (the active metabolite of mesuximide) is 1.95 ± 0.19 mmol/L for α1G, 1.82 ± 0.16 mmol/L for α1I, and 3.0 ± 0.3 mmol/L for α1H. It was suggested that the blockade of open channels is facilitated by ethosuximide's physically plugging the channels when current flows inward.

Stereochemistry

Ethosuximide is a chiral drug with a stereocenter. Therapeutically, the racemate, the 1: 1 mixture of ( S ) and ( R ) - isomers used. [24]

Enantiomers of ethosuximide
(R)-Ethosuximid Structural Formula V1.svg
CAS-Nummer: 39122-20-8		 (S)-Ethosuximid Structural Formula V1.svg
CAS-Nummer: 39122-19-5

Society and culture

Cost

As of 2019 there were concerns in the United States that the price of ethosuximide was inflated by manufacturers. [11] [25]

Availability

Availability of ethosuximide is limited in many countries. [9] It was marketed under the trade names Emeside and Zarontin. However, both capsule preparations were discontinued from production, leaving only generic preparations available. Emeside capsules were discontinued by their manufacturer, Laboratories for Applied Biology, in 2005. [26] Similarly, Zarontin capsules were discontinued by Pfizer in 2007. [27] Syrup preparations of both brands remained available.

See also

Related Research Articles

<span class="mw-page-title-main">Carbamazepine</span> Anticonvulsant medication

Carbamazepine, sold under the brand name Tegretol among others, is an anticonvulsant medication used in the treatment of epilepsy and neuropathic pain. It is used as an adjunctive treatment in schizophrenia along with other medications and as a second-line agent in bipolar disorder. Carbamazepine appears to work as well as phenytoin and valproate for focal and generalized seizures. It is not effective for absence or myoclonic seizures.

<span class="mw-page-title-main">Valproate</span> Medication used for epilepsy, bipolar disorder and migraine

Valproate are medications primarily used to treat epilepsy and bipolar disorder and prevent migraine headaches. They are useful for the prevention of seizures in those with absence seizures, partial seizures, and generalized seizures. They can be given intravenously or by mouth, and the tablet forms exist in both long- and short-acting formulations.

Anticonvulsants are a diverse group of pharmacological agents used in the treatment of epileptic seizures. Anticonvulsants are also increasingly being used in the treatment of bipolar disorder and borderline personality disorder, since many seem to act as mood stabilizers, and for the treatment of neuropathic pain. Anticonvulsants suppress the excessive rapid firing of neurons during seizures. Anticonvulsants also prevent the spread of the seizure within the brain.

<span class="mw-page-title-main">Topiramate</span> Medication used to treat epilepsy and migraine

Topiramate, sold under the brand name Topamax among others, is a medication used to treat epilepsy and prevent migraines. It has also been used in alcohol dependence and essential tremor. For epilepsy this includes treatment for generalized or focal seizures. It is taken orally.

<span class="mw-page-title-main">Lamotrigine</span> Medication used for bipolar disorder, epilepsy, & many seizure disorders

Lamotrigine, sold under the brand name Lamictal among others, is a medication used to treat epilepsy and stabilize mood in bipolar disorder. For epilepsy, this includes focal seizures, tonic-clonic seizures, and seizures in Lennox-Gastaut syndrome. In bipolar disorder, lamotrigine has not been shown to reliably treat acute depression for all groups except in the severely depressed; but for patients with bipolar disorder who are not currently symptomatic, it appears to reduce the risk of future episodes of depression.

Absence seizures are one of several kinds of generalized seizures. In the past, absence epilepsy was referred to as "pyknolepsy," a term derived from the Greek word "pyknos," signifying "extremely frequent" or "grouped". These seizures are sometimes referred to as petit mal seizures ; however, usage of this terminology is no longer recommended. Absence seizures are characterized by a brief loss and return of consciousness, generally not followed by a period of lethargy. Absence seizures are most common in children. They affect both sides of the brain.

<span class="mw-page-title-main">Oxcarbazepine</span> Anticonvulsant medication

Oxcarbazepine, sold under the brand name Trileptal among others, is a medication used to treat epilepsy. For epilepsy it is used for both focal seizures and generalized seizures. It has been used both alone and as add-on therapy in people with bipolar disorder who have had no success with other treatments. It is taken by mouth.

<span class="mw-page-title-main">Levetiracetam</span> Medication

Levetiracetam, sold under the brand name Keppra among others, is a medication used to treat epilepsy. It is used for partial-onset, myoclonic, or tonic–clonic seizures and is taken either by mouth as an immediate or extended release formulation or by injection into a vein.

<span class="mw-page-title-main">Stiripentol</span> Anticonvulsant medication

Stiripentol, sold under the brand name Diacomit, is an anticonvulsant medication used for the treatment of Dravet syndrome - a serious genetic brain disorder.

<span class="mw-page-title-main">Felbamate</span> Chemical compound

Felbamate is an anticonvulsant used in the treatment of epilepsy. It is used to treat partial seizures in adults and partial and generalized seizures associated with Lennox–Gastaut syndrome in children. However, an increased risk of potentially fatal aplastic anemia and/or liver failure limit the drug's usage to severe refractory epilepsy.

<span class="mw-page-title-main">Mesuximide</span> Chemical compound

Mesuximide is a succinimide anticonvulsant medication. It is sold as a racemate by Pfizer under the tradenames Petinutin (Switzerland) and Celontin. The therapeutic efficacy of methosuximide is largely due to its pharmacologically active metabolite, N-desmethylmethosuximide, which has a longer half-life and attains much higher plasma levels than its parent.

Dravet syndrome (DS), previously known as severe myoclonic epilepsy of infancy (SMEI), is an autosomal dominant genetic disorder which causes a catastrophic form of epilepsy, with prolonged seizures that are often triggered by hot temperatures or fever. It is very difficult to treat with anticonvulsant medications. It often begins before one year of age, with six months being the age that seizures, char­ac­ter­ized by prolonged convulsions and triggered by fever, usually begin.

Childhood absence epilepsy (CAE), formerly known as pyknolepsy, is an idiopathic generalized epilepsy which occurs in otherwise normal children. The age of onset is between 4–10 years with peak age between 5–7 years. Children have absence seizures which although brief, they occur frequently, sometimes in the hundreds per day. The absence seizures of CAE involve abrupt and severe impairment of consciousness. Mild automatisms are frequent, but major motor involvement early in the course excludes this diagnosis. The EEG demonstrates characteristic "typical 3Hz spike-wave" discharges. The presence of any other seizure type at time of diagnosis rules out the diagnose of CAE. Prognosis is usually good in well-defined cases of CAE with most patients "growing out" of their epilepsy.

T-type calcium channels are low voltage activated calcium channels that become inactivated during cell membrane hyperpolarization but then open to depolarization. The entry of calcium into various cells has many different physiological responses associated with it. Within cardiac muscle cell and smooth muscle cells voltage-gated calcium channel activation initiates contraction directly by allowing the cytosolic concentration to increase. Not only are T-type calcium channels known to be present within cardiac and smooth muscle, but they also are present in many neuronal cells within the central nervous system. Different experimental studies within the 1970s allowed for the distinction of T-type calcium channels from the already well-known L-type calcium channels. The new T-type channels were much different from the L-type calcium channels due to their ability to be activated by more negative membrane potentials, had small single channel conductance, and also were unresponsive to calcium antagonist drugs that were present. These distinct calcium channels are generally located within the brain, peripheral nervous system, heart, smooth muscle, bone, and endocrine system.

<span class="mw-page-title-main">Saclofen</span> GABAB receptor antagonist

Saclofen is a competitive antagonist for the GABAB receptor. This drug is an analogue of the GABAB agonist baclofen. The GABAB receptor is heptahelical receptor, expressed as an obligate heterodimer, which couples to the Gi/o class of heterotrimeric G-proteins. The action of saclofen on the central nervous system is understandably modest, because G-proteins rely on an enzyme cascade to alter cell behavior while ionotropic receptors immediately change the ionic permeability of the neuronal plasma membrane, thus changing its firing patterns. These particular receptors, presynaptically inhibit N- and P/Q- voltage-gated calcium channels (VGCCs) via a direct interaction of the dissociated beta gamma subunit of the g-protein with the intracellular loop between the 1st and 2nd domain of the VGCC's alpha-subunit; postsynaptically, these potentiate Kir currents. Both result in inhibitory effects.

<span class="mw-page-title-main">Seletracetam</span> Chemical compound

Seletracetam is a pyrrolidone-derived drug of the racetam family that is structurally related to levetiracetam. It was under development by UCB Pharmaceuticals as a more potent and effective anticonvulsant drug to replace levetiracetam but its development has been halted.

<span class="mw-page-title-main">Lacosamide</span> Anticonvulsant and analgesic medication

Lacosamide, sold under the brand name Vimpat among others, is a medication used for the treatment of partial-onset seizures and primary generalized tonic-clonic seizures. It is used by mouth or intravenously.

Low-threshold spikes (LTS) refer to membrane depolarizations by the T-type calcium channel. LTS occur at low, negative, membrane depolarizations. They often follow a membrane hyperpolarization, which can be the result of decreased excitability or increased inhibition. LTS result in the neuron reaching the threshold for an action potential. LTS is a large depolarization due to an increase in Ca2+ conductance, so LTS is mediated by calcium (Ca2+) conductance. The spike is typically crowned by a burst of two to seven action potentials, which is known as a low-threshold burst. LTS are voltage dependent and are inactivated if the cell's resting membrane potential is more depolarized than −60mV. LTS are deinactivated, or recover from inactivation, if the cell is hyperpolarized and can be activated by depolarizing inputs, such as excitatory postsynaptic potentials (EPSP). LTS were discovered by Rodolfo Llinás and coworkers in the 1980s.

An analgesic adjuvant is a medication that is typically used for indications other than pain control but provides control of pain (analgesia) in some painful diseases. This is often part of multimodal analgesia, where one of the intentions is to minimize the need for opioids.

Antimanic drugs are psychotropic drugs that are used to treat symptoms of mania. Though there are different causes of mania, the majority is caused by bipolar disorder, therefore antimanic drugs are mostly similar to drugs treating bipolar disorder. Since 1970s, antimanic drugs have been used specifically to control the abnormal elevation of mood or mood swings during manic episodes. One purpose of antimanic drugs is to alleviate or shorten the duration of an acute mania. Another objective is to prevent further cycles of mania and maintain the improvement achieved during the acute episode. The mechanism of antimanic drugs has not yet been fully known, it is proposed that they mostly affect chemical neurotransmitters in the brain. However, the usage of antimanic drugs should be consulted with a doctor or pharmacist due to their side effects and interactions with other drugs and food.

References

  1. ↑ Anvisa (2023-03-31). "RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial" [Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese). Diário Oficial da União (published 2023-04-04). Archived from the original on 2023-08-03. Retrieved 2023-08-16.
  2. ↑ "List of nationally authorised medicinal products" (PDF). European Medicines Agency.
  3. ↑ Patsalos PN (November 2005). "Properties of antiepileptic drugs in the treatment of idiopathic generalized epilepsies". Epilepsia. 46 Suppl 9 (s9): 140–8. doi: 10.1111/j.1528-1167.2005.00326.x . PMID   16302888. S2CID   19462889.
  4. 1 2 3 4 5 6 7 8 "Ethosuximide". The American Society of Health-System Pharmacists. Archived from the original on 21 December 2016. Retrieved 8 December 2016.
  5. 1 2 World Health Organization (2009). Stuart MC, Kouimtzi M, Hill SR (eds.). WHO Model Formulary 2008. World Health Organization. pp. 69, 74–75. hdl: 10665/44053 . ISBN   9789241547659.
  6. ↑ Huguenard, John R. (March 2002). "Block of T -Type Ca2+ Channels Is an Important Action of Succinimide Antiabsence Drugs". Epilepsy Currents. 2 (2): 49–52. doi:10.1046/j.1535-7597.2002.00019.x. PMC   320968 . PMID   15309165.
  7. ↑ "Drugs@FDA: FDA-Approved Drugs". U.S. Food and Drug Administration. Retrieved 29 December 2020.
  8. ↑ World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl: 10665/325771 . WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
  9. 1 2 Hempel, Georg (2019). Methods of Therapeutic Drug Monitoring Including Pharmacogenetics. Elsevier. p. 241. ISBN   978-0-444-64067-3.
  10. ↑ "Attorney General Tong leads 44-state coalition in antitrust lawsuit against Teva Pharmaceuticals, 19 other generic drug manufacturers, 15 individuals in conspiracy to fix prices and allocate markets for more than 100 different generic drugs" (Press release). Office of the Attorney General of the State of Connecticut. 12 May 2019. Retrieved 5 April 2020.
  11. 1 2 "States sue generic drug makers, claiming a conspiracy to fix prices". consumeraffairs.com. 14 May 2019. Retrieved 5 April 2020.
  12. ↑ Pharmaceutical Associates, Incorporated (2000). "Ethosuximide Approval Label" (PDF). Label and Approval History. Food and Drug Administration Center for Drug Evaluation and Research. Retrieved 2006-02-05.
  13. ↑ Katzung, B., ed. (2003). "Drugs used in generalized seizures". Basic and Clinical Pharmacology (9th ed.). Lange Medical Books/McGraw-Hill. ISBN   0071410929.
  14. ↑ Bourgeois BF (December 1988). "Combination of valproate and ethosuximide: antiepileptic and neurotoxic interaction". The Journal of Pharmacology and Experimental Therapeutics. 247 (3): 1128–32. PMID   3144596.
  15. ↑ Coulter DA, Huguenard JR, Prince DA (March 1989). "Specific petit mal anticonvulsants reduce calcium currents in thalamic neurons". Neuroscience Letters. 98 (1): 74–8. doi:10.1016/0304-3940(89)90376-5. PMID   2710401. S2CID   13413993.
  16. ↑ Coulter DA, Huguenard JR, Prince DA (June 1989). "Characterization of ethosuximide reduction of low-threshold calcium current in thalamic neurons". Annals of Neurology. 25 (6): 582–93. doi:10.1002/ana.410250610. PMID   2545161. S2CID   20670160.
  17. ↑ Coulter DA, Huguenard JR, Prince DA (August 1990). "Differential effects of petit mal anticonvulsants and convulsants on thalamic neurones: calcium current reduction". British Journal of Pharmacology. 100 (4): 800–6. doi:10.1111/j.1476-5381.1990.tb14095.x. PMC   1917607 . PMID   2169941.
  18. ↑ Kostyuk PG, Molokanova EA, Pronchuk NF, Savchenko AN, Verkhratsky AN (December 1992). "Different action of ethosuximide on low- and high-threshold calcium currents in rat sensory neurons". Neuroscience. 51 (4): 755–8. doi:10.1016/0306-4522(92)90515-4. PMID   1336826. S2CID   41451332.
  19. ↑ Herrington J, Lingle CJ (July 1992). "Kinetic and pharmacological properties of low voltage-activated Ca2+ current in rat clonal (GH3) pituitary cells". Journal of Neurophysiology. 68 (1): 213–32. doi:10.1152/jn.1992.68.1.213. PMID   1325546.
  20. ↑ Sayer RJ, Brown AM, Schwindt PC, Crill WE (May 1993). "Calcium currents in acutely isolated human neocortical neurons". Journal of Neurophysiology. 69 (5): 1596–606. doi:10.1152/jn.1993.69.5.1596. PMID   8389832.
  21. ↑ Todorovic SM, Lingle CJ (January 1998). "Pharmacological properties of T-type Ca2+ current in adult rat sensory neurons: effects of anticonvulsant and anesthetic agents". Journal of Neurophysiology. 79 (1): 240–52. doi:10.1152/jn.1998.79.1.240. PMID   9425195.
  22. ↑ Leresche N, Parri HR, Erdemli G, Guyon A, Turner JP, Williams SR, et al. (July 1998). "On the action of the anti-absence drug ethosuximide in the rat and cat thalamus". The Journal of Neuroscience. 18 (13): 4842–53. doi:10.1523/JNEUROSCI.18-13-04842.1998. PMC   6792570 . PMID   9634550.
  23. ↑ Gomora JC, Daud AN, Weiergräber M, Perez-Reyes E (November 2001). "Block of cloned human T-type calcium channels by succinimide antiepileptic drugs". Molecular Pharmacology. 60 (5): 1121–32. doi:10.1124/mol.60.5.1121. PMID   11641441. S2CID   7098669.
  24. ↑ Rote Liste Service GmbH (Hrsg.): Rote Liste 2017 – Arzneimittelverzeichnis für Deutschland (einschließlich EU-Zulassungen und bestimmter Medizinprodukte). Rote Liste Service GmbH, Frankfurt/Main, 2017, Aufl. 57, ISBN   978-3-946057-10-9, S. 182.
  25. ↑ Staff, WMBF News. "South Carolina joins lawsuit against manufacturers in alleged conspiracy to fix prescription drug prices". wmbfnews.com. Retrieved 5 April 2020.
  26. ↑ "Concern over ethosuximide capsule discontinuation". Pharm J. 275: 539. Oct 29, 2005. Archived from the original on 2008-10-13. Retrieved 2008-08-31. (paywalled archive)
  27. ↑ "Zarontin capsules discontinued". Archived from the original on 2012-06-26. Retrieved 2012-10-24.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.