Convulsant

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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

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]

GABA synthesis inhibitors

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

Glycine receptor antagonists

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

Ionotropic glutamate receptor agonists

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

Acetylcholine receptor agonists

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

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. [10]

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. [10]

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. [10]

Related Research Articles

<span class="mw-page-title-main">GABA receptor</span> Receptors that respond to gamma-aminobutyric acid

The GABA receptors are a class of receptors that respond to the neurotransmitter gamma-aminobutyric acid (GABA), the chief inhibitory compound in the mature vertebrate central nervous system. There are two classes of GABA receptors: GABAA and GABAB. GABAA receptors are ligand-gated ion channels ; whereas GABAB receptors are G protein-coupled receptors, also called metabotropic receptors.

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

Bicuculline is a phthalide-isoquinoline compound that is a light-sensitive competitive antagonist of GABAA receptors. It was originally identified in 1932 in plant alkaloid extracts and has been isolated from Dicentra cucullaria, Adlumia fungosa, and several Corydalis species. Since it blocks the inhibitory action of GABA receptors, the action of bicuculline mimics epilepsy; it also causes convulsions. This property is utilized in laboratories around the world in the in vitro study of epilepsy, generally in hippocampal or cortical neurons in prepared brain slices from rodents. This compound is also routinely used to isolate glutamatergic receptor function.

GABA<sub>A</sub> receptor Ionotropic receptor and ligand-gated ion channel

The GABAA receptor (GABAAR) is an ionotropic receptor and ligand-gated ion channel. Its endogenous ligand is γ-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system. Accurate regulation of GABAergic transmission through appropriate developmental processes, specificity to neural cell types, and responsiveness to activity is crucial for the proper functioning of nearly all aspects of the central nervous system (CNS). Upon opening, the GABAA receptor on the postsynaptic cell is selectively permeable to chloride ions (Cl−) and, to a lesser extent, bicarbonate ions (HCO3−).

Molecular neuroscience is a branch of neuroscience that observes concepts in molecular biology applied to the nervous systems of animals. The scope of this subject covers topics such as molecular neuroanatomy, mechanisms of molecular signaling in the nervous system, the effects of genetics and epigenetics on neuronal development, and the molecular basis for neuroplasticity and neurodegenerative diseases. As with molecular biology, molecular neuroscience is a relatively new field that is considerably dynamic.

<span class="mw-page-title-main">Kainate receptor</span> Class of ionotropic glutamate receptors

Kainate receptors, or kainic acid receptors (KARs), are ionotropic receptors that respond to the neurotransmitter glutamate. They were first identified as a distinct receptor type through their selective activation by the agonist kainate, a drug first isolated from the algae Digenea simplex. They have been traditionally classified as a non-NMDA-type receptor, along with the AMPA receptor. KARs are less understood than AMPA and NMDA receptors, the other ionotropic glutamate receptors. Postsynaptic kainate receptors are involved in excitatory neurotransmission. Presynaptic kainate receptors have been implicated in inhibitory neurotransmission by modulating release of the inhibitory neurotransmitter GABA through a presynaptic mechanism.

GABAB receptors (GABABR) are G-protein coupled receptors for gamma-aminobutyric acid (GABA), therefore making them metabotropic receptors, that are linked via G-proteins to potassium channels. The changing potassium concentrations hyperpolarize the cell at the end of an action potential. The reversal potential of the GABAB-mediated IPSP is –100 mV, which is much more hyperpolarized than the GABAA IPSP. GABAB receptors are found in the central nervous system and the autonomic division of the peripheral nervous system.

<span class="mw-page-title-main">Progabide</span> Pharmaceutical drug

Progabide is an analogue and prodrug of γ-aminobutyric acid (GABA) used in the treatment of epilepsy. Via conversion into GABA, progabide behaves as an agonist of the GABAA, GABAB, and GABAA-ρ receptors.

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

Kainic acid, or kainate, is an acid that naturally occurs in some seaweed. Kainic acid is a potent neuroexcitatory amino acid agonist that acts by activating receptors for glutamate, the principal excitatory neurotransmitter in the central nervous system. Glutamate is produced by the cell's metabolic processes and there are four major classifications of glutamate receptors: NMDA receptors, AMPA receptors, kainate receptors, and the metabotropic glutamate receptors. Kainic acid is an agonist for kainate receptors, a type of ionotropic glutamate receptor. Kainate receptors likely control a sodium channel that produces excitatory postsynaptic potentials (EPSPs) when glutamate binds.

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

Gabazine (SR-95531) is a drug that acts as an antagonist at GABAA receptors. It is used in scientific research and has no role in medicine, as it would be expected to produce convulsions if used in humans.

<span class="mw-page-title-main">Analeptic</span> Drug class

An analeptic, in medicine, is a central nervous system stimulant. The term "analeptic" typically refers to respiratory stimulants. Analeptics are central nervous system (CNS) stimulants that include a wide variety of medications used to treat depression, attention deficit hyperactivity disorder (ADHD), and respiratory depression. Analeptics can also be used as convulsants, with low doses causing patients to experience heightened awareness, restlessness, and rapid breathing. The primary medical use of these drugs is as an anesthetic recovery tool or to treat emergency respiratory depression. Other drugs of this category are prethcamide, pentylenetetrazole, and nikethamide. Nikethamide is now withdrawn due to risk of convulsions. Analeptics have recently been used to better understand the treatment of a barbiturate overdose. Through the use of agents, researchers were able to treat obtundation and respiratory depression.

<span class="mw-page-title-main">Succinic semialdehyde dehydrogenase deficiency</span> Rare disorder involving deficiency in GABA degradation

Succinic semialdehyde dehydrogenase deficiency (SSADHD) is a rare autosomal recessive disorder of the degradation pathway of the inhibitory neurotransmitter γ-aminobutyric acid, or GABA. The disorder has been identified in approximately 350 families, with a significant proportion being consanguineous families. The first case was identified in 1981 and published in a Dutch clinical chemistry journal that highlighted a number of neurological conditions such as delayed intellectual, motor, speech, and language as the most common manifestations. Later cases reported in the early 1990s began to show that hypotonia, hyporeflexia, seizures, and a nonprogressive ataxia were frequent clinical features as well.

GABA gamma-aminobutyric acid (GABA) is a key chemical messenger or a neurotransmitter in the central nervous system, that significantly inhibits neuronal transmission. GABA calms the brain and controls several physiological processes, such as stress, anxiety, and sleep. GABAA receptors are a class of ionotropic receptors that are triggered by GABA. They are made up of five subunits that are assembled in various configurations to create distinct receptor subtypes. The direct influx of chloride ions causes rapid inhibitory responses. GABAB receptors are another type of metabotropic receptor that modifies intracellular signaling pathways to provide slower, sustained inhibitory responses. At synapses, GABAA receptors facilitate rapid inhibitory neurotransmission, whereas GABAB receptor which comprise GABA B1 and GABA B2 subunits—control neurotransmitter release and cellular excitability over a longer period of time. These unique qualities help explain the various ways that GABAergic neurotransmission controls brain communication and neuronal function.

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

Loreclezole is a sedative and an anticonvulsant which acts as a GABAA receptor positive allosteric modulator. The binding site of loreclezole has been shown experimentally to be shared by valerenic acid, an extract of the root of the valerian plant. Structurally, loreclezole is a triazole derivative. In animal seizure models, loreclezole is protective against pentylenetetrazol seizures but is less active in the maximal electroshock test. In addition, at low, nontoxic doses, the drug has anti-absence activity in a genetic model of generalized absence epilepsy. Consequently, loreclezole has a profile of activity similar to that of benzodiazepines. A potential benzodiazepine-like interaction with GABA receptors is suggested by the observation that the anticonvulsant effects of loreclezole can be reversed by benzodiazepine receptor inverse agonists. The benzodiazepine antagonist flumazenil, however, fails to alter the anticonvulsant activity of loreclezole, indicating that loreclezole is not a benzodiazepine receptor agonist. Using native rat and cloned human GABA-A receptors, loreclezole strongly potentiated GABA-activated chloride current. However, activity of the drug did not require the presence of the γ-subunit and was not blocked by flumazenil, confirming that loreclezole does not interact with the benzodiazepine recognition site.

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

Flurothyl (Indoklon) is a volatile liquid drug from the halogenated ether family, related to inhaled anaesthetic agents such as diethyl ether, but having the opposite effects, acting as a stimulant and convulsant. A clear and stable liquid, it has a mild ethereal odor whose vapors are non-flammable. It is excreted from the body by the lungs in an unchanged state.

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

Pentylenetetrazol, also known as pentylenetetrazole, leptazol, metrazol, pentetrazol (INN), pentamethylenetetrazol, Corazol, Cardiazol, Deumacard, or PTZ, is a drug formerly used as a circulatory and respiratory stimulant. High doses cause convulsions, as discovered by Hungarian-American neurologist and psychiatrist Ladislas J. Meduna in 1934. It has been used in convulsive therapy, and was found to be effective—primarily for depression—but side effects such as uncontrolled seizures were difficult to avoid. In 1939, pentylenetetrazol was replaced by electroconvulsive therapy, which is easier to administer, as the preferred method for inducing seizures in England's mental hospitals. In the US, its approval by the Food and Drug Administration was revoked in 1982. It is used in Italy as a cardio-respiratory stimulant in combination with codeine in a cough suppressant drug.

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

Quisqualamine is the α-decarboxylated analogue of quisqualic acid, as well as a relative of the neurotransmitters glutamate and γ-aminobutyric acid (GABA). α-Decarboxylation of excitatory amino acids can produce derivatives with inhibitory effects. Indeed, unlike quisqualic acid, quisqualamine has central depressant and neuroprotective properties and appears to act predominantly as an agonist of the GABAA receptor and also to a lesser extent as an agonist of the glycine receptor, due to the facts that its actions are inhibited in vitro by GABAA antagonists like bicuculline and picrotoxin and by the glycine antagonist strychnine, respectively. Mg2+ and DL-AP5, NMDA receptor blockers, CNQX, an antagonist of both the AMPA and kainate receptors, and 2-hydroxysaclofen, a GABAB receptor antagonist, do not affect quisqualamine's actions in vitro, suggesting that it does not directly affect the ionotropic glutamate receptors or the GABAB receptor in any way. Whether it binds to and acts upon any of the metabotropic glutamate receptors like its analogue quisqualic acid however is unclear.

A channel modulator, or ion channel modulator, is a type of drug which modulates ion channels. They include channel blockers and channel openers.

<span class="mw-page-title-main">GABA analogue</span> Class of drugs

A GABA analogue is a compound which is an analogue or derivative of the neurotransmitter gamma-Aminobutyric acid (GABA).

A GABAA receptor negative allosteric modulator is a negative allosteric modulator (NAM), or inhibitor, of the GABAA receptor, a ligand-gated ion channel of the major inhibitory neurotransmitter γ-aminobutyric acid (GABA). They are closely related and similar to GABAA receptor antagonists. The effects of GABAA receptor NAMs are functionally the opposite of those of GABAA receptor positive allosteric modulators (PAMs) like the benzodiazepines, barbiturates, and ethanol (alcohol). Non-selective GABAA receptor NAMs can produce a variety of effects including convulsions, neurotoxicity, and anxiety, among others.

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

Willardiine (correctly spelled with two successive i's) or (S)-1-(2-amino-2-carboxyethyl)pyrimidine-2,4-dione is a chemical compound that occurs naturally in the seeds of Mariosousa willardiana and Acacia sensu lato. The seedlings of these plants contain enzymes capable of complex chemical substitutions that result in the formation of free amino acids (See:#Synthesis). Willardiine is frequently studied for its function in higher level plants. Additionally, many derivates of willardiine are researched for their potential in pharmaceutical development. Willardiine was first discovered in 1959 by R. Gmelin, when he isolated several free, non-protein amino acids from Acacia willardiana (another name for Mariosousa willardiana) when he was studying how these families of plants synthesize uracilyalanines. A related compound, Isowillardiine, was concurrently isolated by a different group, and it was discovered that the two compounds had different structural and functional properties. Subsequent research on willardiine has focused on the functional significance of different substitutions at the nitrogen group and the development of analogs of willardiine with different pharmacokinetic properties. In general, Willardiine is the one of the first compounds studied in which slight changes to molecular structure result in compounds with significantly different pharmacokinetic properties.

References

  1. ↑ "Convulsant Agent - an overview | ScienceDirect Topics". www.sciencedirect.com. Retrieved 2022-01-15.[ vague ]
  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. PMC   4767205 . PMID   26174744.
  3. ↑ Mares P, Folbergrová J, Kubová H (2004). "Excitatory aminoacids and epileptic seizures in immature brain". Physiological Research. 53 (Suppl 1): S115-24. doi: 10.33549/physiolres.930000.53.S115 . PMID   15119942. S2CID   28716793.
  4. ↑ Calabrese EJ (2008). "Modulation of the epileptic seizure threshold: implications of biphasic dose responses". Critical Reviews in Toxicology. 38 (6): 543–56. doi:10.1080/10408440802014261. PMID   18615309. S2CID   5081215.
  5. ↑ Johnston GA (May 2013). "Advantages of an antagonist: bicuculline and other GABA antagonists". British Journal of Pharmacology. 169 (2): 328–36. doi:10.1111/bph.12127. PMC   3651659 . PMID   23425285.
  6. ↑ de Araujo Furtado M, Rossetti F, Chanda S, Yourick D (December 2012). "Exposure to nerve agents: from status epilepticus to neuroinflammation, brain damage, neurogenesis and epilepsy". Neurotoxicology. 33 (6): 1476–1490. doi:10.1016/j.neuro.2012.09.001. PMID   23000013.
  7. ↑ "Dieldrin - an overview | ScienceDirect Topics". www.sciencedirect.com. Retrieved 2022-01-20.[ vague ]
  8. ↑ "Convulsant Agent - an overview | ScienceDirect Topics". www.sciencedirect.com. Retrieved 2022-01-20.[ vague ]
  9. ↑ Galland, M. C.; Griguer, Y.; Morange-Sala, S.; Jean-Pastor, M. J.; Rodor, F.; Jouglard, J. (1992). "Convulsions fébriles : faut-il contre-indiquer certains médicaments ?" [Febrile convulsions: should some drugs be contraindicated?]. Thérapie (in French). 47 (5): 409–414. PMID   1363740. INIST   3915621.
  10. 1 2 3 4 Cooper, Kathryn; Fink, Max (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. S2CID   23735035.
  11. ↑ "Convulsant Agent - an overview | ScienceDirect Topics". www.sciencedirect.com. Retrieved 2022-01-15.[ vague ]
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  13. ↑ Suddock, Jolee T.; Kent, Kristen J.; Cain, Matthew D. (2024). "Barbiturate Toxicity". StatPearls. StatPearls Publishing. PMID   29763050.
  14. ↑ Löscher W (June 2002). "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. doi:10.1016/s0920-1211(02)00073-6. PMID   12151122. S2CID   5930079.
  15. ↑ Löscher W (May 2009). "Preclinical assessment of proconvulsant drug activity and its relevance for predicting adverse events in humans". European Journal of Pharmacology. 610 (1–3): 1–11. doi:10.1016/j.ejphar.2009.03.025. PMID   19292981.
  16. ↑ Rubio C, Rubio-Osornio M, Retana-Márquez S, Verónica Custodio ML, Paz C (December 2010). "In vivo experimental models of epilepsy". Central Nervous System Agents in Medicinal Chemistry. 10 (4): 298–309. doi:10.2174/187152410793429746. PMID   20868357.
  17. ↑ "Kainic Acid - an overview | ScienceDirect Topics". www.sciencedirect.com. Retrieved 2022-01-15.[ vague ]
  18. ↑ "GABA-A Receptor Antagonists". Medical Subject Headings . National Library of Medicine . Retrieved 18 February 2024.
  19. ↑ "GABAA Receptor Agonists - an overview | ScienceDirect Topics". www.sciencedirect.com. Retrieved 2022-01-18.[ vague ]
  20. ↑ George, Kevin; Preuss, Charles V.; Sadiq, Nazia M. (2024). "GABA Inhibitors". StatPearls. StatPearls Publishing. PMID   31424814.
  21. ↑ "Glycine Receptor Antagonist - an overview | ScienceDirect Topics". www.sciencedirect.com. Retrieved 2022-01-18.[ vague ]
  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. PMC   8686308 . PMID   32867642.
  23. ↑ "Acetylcholine receptor anatomy". www.openanesthesia.org. Retrieved 2022-01-18.
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