Convulsant

Short description: Drug that induces convulsions

A convulsant is a drug which induces convulsions and/or epileptic seizures, the opposite of an anticonvulsant. These drugs generally act as stimulants at low doses, but are not used for this purpose due to the risk of convulsions and consequent excitotoxicity. Most convulsants are antagonists (or inverse agonists) at either the GABAA or glycine receptors, or ionotropic glutamate receptor agonists.[1] Many other drugs may cause convulsions as a side effect at high doses (e.g. bupropion, tramadol, pethidine, dextropropoxyphene, clomipramine) but only drugs whose primary action is to cause convulsions are known as convulsants.[2] Nerve agents such as sarin, which were developed as chemical weapons, produce convulsions as a major part of their toxidrome, but also produce a number of other effects in the body and are usually classified separately.[3][4][5][6] Dieldrin which was developed as an insecticide blocks chloride influx into the neurons causing hyperexcitability of the CNS and convulsions.[7] The Irwin observation test and other studies that record clinical signs are used to test the potential for a drug to induce convulsions.[8] Camphor, and other terpenes given to children with colds can act as convulsants (sympathomimetics, piperazine derivatives, theophylline, antihistamines, etc.) in children who have had febrile seizures.[9]

## Contents

* 1 Uses
* 2 Examples
* 2.1 GABAA receptor antagonists, inverse agonists or negative allosteric modulators
* 2.2 GABA synthesis inhibitors
* 2.3 Glycine receptor antagonists
* 2.4 Ionotropic glutamate receptor agonists
* 2.5 Acetylcholine receptor agonists
* 3 Advantages
* 4 Risks/Complications
* 5 History
* 6 References

## Uses

Some convulsants such as pentetrazol and flurothyl were previously used in shock therapy in psychiatric medicine, as an alternative to electroconvulsive therapy.[10] Others such as strychnine and tetramethylenedisulfotetramine are used as poisons for exterminating pests.[11] Bemegride and flumazenil are used to treat drug overdoses (of barbiturates and benzodiazepines respectively), but may cause convulsions if the dose is too high.[12][13] Convulsants are also widely used in scientific research, for instance in the testing of new anticonvulsant drugs. Convulsions are induced in captive animals, then high doses of anticonvulsant drugs are administered.[14][15][16] For example, kainic acid can lead to status epilepticus in animals as it is a cyclic analog of l-glutamate and an agonist for kainate receptors in the brain which makes it a potent neurotoxin and excitant.[17]

## Examples

### GABAA receptor antagonists, inverse agonists or negative allosteric modulators

GABAA receptor antagonists are drugs that bind to GABAA receptors but do not activate them and inhibit the action of GABA. Thus it blocks both the endogenous and exogenous actions of GABAA receptor agonists.[18][19]

* Bemegride
* Bicuculline
* Cicutoxin
* Cyclothiazide
* DMCM
* FG-7142
* Fipronil
* Flumazenil
* Flurothyl
* Gabazine
* IPTBO
* Laudanosine
* Oenanthotoxin
* Pentylenetetrazol (Metrazol)
* Phenylsilatrane
* Picrotoxin
* Sarmazenil
* Securinine
* Sinomenine
* TBPO
* TBPS
* Tetramethylenedisulfotetramine
* Thujone

### GABA synthesis inhibitors

GABA synthesis inhibitors are drugs that inhibit the action of GABA.[20]

* 3-Mercaptopropionic acid
* Allylglycine

### Glycine receptor antagonists

Glycine receptor antagonists are drugs which inactivates the glycine receptors.[21]

* Bicuculline
* Brucine
* Colubrine
* Diaboline
* Gelsemine
* Hyenandrine
* Laudanosine
* Oripavine
* RU-5135 (also GABA antagonist)
* Sinomenine
* Strychnine
* Thebaine
* Tutin

### Ionotropic glutamate receptor agonists

Ionotropic glutamate receptor agonists are drugs that activate the ionotropic glutamate receptors in the brain.[22]

* AMPA
* Domoic acid
* Kainic acid
* NMDA
* Quinolinic acid
* Quisqualic acid
* Tetrazolylglycine

### Acetylcholine receptor agonists

Acetylcholine receptor agonists are drugs that activate the acetylcholine receptors.[23]

* Anatoxin-a
* Pilocarpine

## Advantages

Camphor injections for psychiatric treatment were inefficient and were replaced by pentylenetetrazol. Seizures induced by chemicals like flurothyl were clinically effective as electric convulsions with lesser side effects on memory retention. Therefore, considering flurothyl induced seizures in modern anesthesia facilities is encouraged to relieve medication treatment resistant patients with psychiatric illnesses like mood disorders and catatonia.[24]

## Risks/Complications

Convulsants like pentylenetetrazol and flurothyl were effective in psychiatric treatment but difficult to administer. Flurothyl was not widely being used due to the persistence of the ethereal aroma and fears in the professional staff that they might seize.[25]

## History

In 1934, camphor-induced and pentylenetetrazol-induced brain seizures were first used to relieve psychiatric illnesses. But camphor was found ineffective. In 1957, inhalant anesthetic flurothyl was tested and found to be clinically effective in the induction of seizures, even though certain risks persisted.[26]

## References

1. ↑ "Convulsant Agent - an overview | ScienceDirect Topics". https://www.sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-science/convulsant-agent.
2. ↑ Chen, Hsien-Yi; Albertson, Timothy E.; Olson, Kent R. (March 2016). "Treatment of drug-induced seizures: Treatment of drug-induced seizures". British Journal of Clinical Pharmacology 81 (3): 412–419. doi:10.1111/bcp.12720. PMID 26174744.
3. ↑ "Excitatory aminoacids and epileptic seizures in immature brain". Physiological Research 53 Suppl 1: S115-24. 2004. doi:10.33549/physiolres.930000.53.S115. PMID 15119942.
4. ↑ "Modulation of the epileptic seizure threshold: implications of biphasic dose responses". Critical Reviews in Toxicology 38 (6): 543–56. 2008. doi:10.1080/10408440802014261. PMID 18615309.
5. ↑ "Advantages of an antagonist: bicuculline and other GABA antagonists". British Journal of Pharmacology 169 (2): 328–36. May 2013. doi:10.1111/bph.12127. PMID 23425285.
6. ↑ "Exposure to nerve agents: from status epilepticus to neuroinflammation, brain damage, neurogenesis and epilepsy". Neurotoxicology 33 (6): 1476–1490. December 2012. doi:10.1016/j.neuro.2012.09.001. PMID 23000013.
7. ↑ "Dieldrin - an overview | ScienceDirect Topics". https://www.sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-science/dieldrin.
8. ↑ "Convulsant Agent - an overview | ScienceDirect Topics". https://www.sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-science/convulsant-agent.
9. ↑ Galland, M. C.; Griguer, Y.; Morange-Sala, S.; Jean-Pastor, M. J.; Rodor, F.; Jouglard, J. (September–October 1992). "[Febrile convulsions: should some drugs be contraindicated?"]. Thérapie 47 (5): 409–414. PMID 1363740. https://pubmed.ncbi.nlm.nih.gov/1363740/.
10. ↑ Cooper, K.; Fink, M. (October 2014). "The chemical induction of seizures in psychiatric therapy: were flurothyl (indoklon) and pentylenetetrazol (metrazol) abandoned prematurely?". Journal of Clinical Psychopharmacology 34 (5): 602–607. doi:10.1097/JCP.0000000000000173. PMID 25029329. https://pubmed.ncbi.nlm.nih.gov/25029329/.
11. ↑ "Convulsant Agent - an overview | ScienceDirect Topics". https://www.sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-science/convulsant-agent.
12. ↑ Kang, Michael; Galuska, Michael A.; Ghassemzadeh, Sassan (2021-07-26) (in en). Benzodiazepine Toxicity. StatPearls. PMID 29489152. https://www.ncbi.nlm.nih.gov/books/NBK482238/.
13. ↑ Suddock, Jolee T.; Cain, Matthew D. (2022), "Barbiturate Toxicity", StatPearls (Treasure Island (FL): StatPearls Publishing), PMID 29763050, http://www.ncbi.nlm.nih.gov/books/NBK499875/, retrieved 2022-01-18
14. ↑ "Animal models of epilepsy for the development of antiepileptogenic and disease-modifying drugs. A comparison of the pharmacology of kindling and post-status epilepticus models of temporal lobe epilepsy". Epilepsy Research 50 (1–2): 105–23. June 2002. doi:10.1016/s0920-1211(02)00073-6. PMID 12151122.
15. ↑ "Preclinical assessment of proconvulsant drug activity and its relevance for predicting adverse events in humans". European Journal of Pharmacology 610 (1–3): 1–11. May 2009. doi:10.1016/j.ejphar.2009.03.025. PMID 19292981.
16. ↑ "In vivo experimental models of epilepsy". Central Nervous System Agents in Medicinal Chemistry 10 (4): 298–309. December 2010. doi:10.2174/187152410793429746. PMID 20868357.
17. ↑ "Kainic Acid - an overview | ScienceDirect Topics". https://www.sciencedirect.com/topics/neuroscience/kainic-acid.
18. ↑ "GABA-A Receptor Antagonists - MeSH - NCBI". https://www.ncbi.nlm.nih.gov/mesh/68058787.
19. ↑ "GABAA Receptor Agonists - an overview | ScienceDirect Topics". https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/gabaa-receptor-agonists.
20. ↑ George, Kevin; Sadiq, Nazia M. (2022), "GABA Inhibitors", StatPearls (Treasure Island (FL): StatPearls Publishing), PMID 31424814, http://www.ncbi.nlm.nih.gov/books/NBK545230/, retrieved 2022-01-18
21. ↑ "Glycine Receptor Antagonist - an overview | ScienceDirect Topics". https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/glycine-receptor-antagonist.
22. ↑ Celli, Roberta; Fornai, Francesco (2021). "Targeting Ionotropic Glutamate Receptors in the Treatment of Epilepsy". Current Neuropharmacology 19 (6): 747–765. doi:10.2174/1570159X18666200831154658. ISSN 1875-6190. PMID 32867642.
23. ↑ "Acetylcholine receptor anatomy" (in en-US). https://www.openanesthesia.org/acetylcholine-receptor-anatomy/.
24. ↑ Cooper, Kathryn (October 2014). "The chemical induction of seizures in psychiatric therapy: were flurothyl (indoklon) and pentylenetetrazol (metrazol) abandoned prematurely?". Journal of Clinical Psychopharmacology 34 (5): 602–607. doi:10.1097/JCP.0000000000000173. PMID 25029329. https://pubmed.ncbi.nlm.nih.gov/25029329/.
25. ↑ Cooper, Kathryn (October 2014). "The chemical induction of seizures in psychiatric therapy: were flurothyl (indoklon) and pentylenetetrazol (metrazol) abandoned prematurely?". Journal of Clinical Psychopharmacology 34 (5): 602–607. doi:10.1097/JCP.0000000000000173. PMID 25029329. https://pubmed.ncbi.nlm.nih.gov/25029329/.
26. ↑ Cooper, Kathryn (October 2014). "The chemical induction of seizures in psychiatric therapy: were flurothyl (indoklon) and pentylenetetrazol (metrazol) abandoned prematurely?". Journal of Clinical Psychopharmacology 34 (5): 602–607. doi:10.1097/JCP.0000000000000173. PMID 25029329. https://pubmed.ncbi.nlm.nih.gov/25029329/.

* v
* t
* e

Convulsants

GABA receptor antagonists|

* Picrotoxin
* Gabazine
* Tetramethylenedisulfotetramine
* Cicutoxin
* Phenylsilatrane
* Tutin
* Pentylenetetrazol
* Thujone
* Endosulfan
* Bicuculline
* Oenanthotoxin
* Fipronil
* EBOB
* BIDN
* Dihydropicrotoxinin
* DMCM
* FG-7142
* Chlorophenylsilatrane
* Bicyclic phosphates (TBPS, TBPO, IPTBO)

GABA synthesis inhibitors|

* Allylglycine
* Crimidine
* Ginkgotoxin
* Toxopyrimidine
* Isoniazid
* 3-Mercaptopropionic acid
* 4-Deoxypyridoxine

Glycine receptor antagonists|

* Strychnine
* Tutin
* Picrotoxin
* Dendrobine

Glutamate receptor agonists|

* AMPA
* NMDA
* Kainic acid
* Domoic acid
* Quisqualic acid
* Tetrazolylglycine

Other|

* Methyl fluoroacetate
* Fluoroethyl fluoroacetate
* Nitrocyclohexane
* Methionine sulfoximine

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