Benzoctamine

Last updated

Benzoctamine
Benzoctamine.svg
Clinical data
Trade names Tacitin
Routes of
administration 		Oral, intravenous
ATC code
Legal status
Legal status
  • BR: Class C1 (Other controlled substances) [1]
  • In general: legal
Pharmacokinetic data
Bioavailability Oral: 90%
Metabolism Hepatic
Elimination half-life 2 to 3 hours
Excretion Renal
Identifiers
  • N-Methyl-9,10-ethanoanthracene-9(10H)-methanamine
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
Formula C18H19N
Molar mass 249.357 g·mol−1
3D model (JSmol)
  • c1ccc3c(c1)C4c2ccccc2C3(CC4)CNC
  • InChI=1S/C18H19N/c1-19-12-18-11-10-13(14-6-2-4-8-16(14)18)15-7-3-5-9-17(15)18/h2-9,13,19H,10-12H2,1H3 Yes check.svgY
  • Key:GNRXCIONJWKSEA-UHFFFAOYSA-N Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Benzoctamine is a drug that possesses sedative and anxiolytic properties. Marketed as Tacitin by Ciba-Geigy, it is different from most sedative drugs because in most clinical trials it does not produce respiratory depression, but actually stimulates the respiratory system. As a result, when compared to other sedative and anxiolytic drugs such as benzodiazepines like diazepam, it is a safer form of tranquilizing. However, when co-administered with other drugs that cause respiratory depression, like morphine, it can cause increased respiratory depression.

Contents

Medically, benzoctamine is used as a treatment for anxious outpatients to control aggression, [2] enuresis, [3] fear, and minor social maladjustment in children. [2] Its anxiolytic effects are most similar to diazepam, another anxiolytic, but unlike diazepam, benzoctamine has antagonistic effects on epinephrine and norepinephrine, and appears to increase serotonin levels. While little is understood about how it carries out its effects, studies point to reduced serotonin, epinephrine, and norepinephrine as partial causes of its pharmacologic and behavioral effects.

Animal studies have shown sedative hypnotic drugs tend to show dependency in animals, but benzoctamine has been shown to not be addictive. Other animal studies also point to the drug as a possible mechanism by which to reduce blood pressure through the adrenergic system.

Chemically, benzoctamine belongs to the class of compounds called dibenzobicyclo-octadienes. It is a tetracyclic compound, consisting of four rings in a three dimensional configuration, and is very closely related structurally to the tetracyclic antidepressant (TeCA) maprotiline, differing only in the length of their side chain.

Medical uses

Anxiety

Benzoctamine's main clinical use is for the treatment of anxiety, and evidence points to it being as effective as other clinical anxiety drugs, in particular diazepam. [4] In the treatment of symptoms of mild anxiety due to psychoneurosis, a daily dosage of 30 to 80 mg of benzoctamine was shown to be just as effective as 6–20 mg of diazepam. [4] In another study one group of patients were given 10 mg of benzoctamine three times a day, while another group was given 5 mg of diazepam, and the treatments were equivalent. [4] While these studies point to higher doses of benzoctamine being needed to exert the same pharmacological effects, the drug is still popular because of its ability to act as an anxiolytic without producing the common respiratory depression associated with other sedative drugs. Some studies have even shown that it stimulates the respiratory system. [5]

Benzoctamine and sodium amylobarbitone

In a study used to compare benzoctamine to sodium amylobarbitone as a sleep promoter, it was found that during administration of both drugs, patients reported that their sleep was less restless, and drowsiness was diminished. [6] The study further showed that while sodium amylobarbitone caused withdrawal rebound symptoms, benzoctamine did not. [6] It was also found that benzoctamine reduced plasma corticosteroid hormone levels. [6] There is a relationship between anxiety and adreno-corticosteroid activity, with raised levels commonly being reported as an indication of stress. [6] The study showed that benzoctamine, a drug reported to reduce anxiety, was also able to reduce the hormones that potentially cause it. [6] This points to a phenomenon often seen within pharmacology where drugs intended for other uses often have far-reaching and rarely considered effects.

Benzoctamine vs. chlordiazepoxide in anxiety neurosis

Benzoctamine has been found to have the same efficacy as chlordiazepoxide when treating anxiety neurosis. [7]

Sleep sedation

While benzoctamine was made to be an alternative to the benzodiazepine line of anxiolytic drugs, other uses for the drug have been discovered. Due to benzoctamine's ability to tranquilize without causing respiratory depression, scientists are moving forward with studies that test its sedative effects in patients with respiratory failure. In one study that used benzoctamine in a clinical setting, researchers showed that the use of benzoctamine for sedation did not result in changes in forced expiratory volume in one second or carbon dioxide partial pressure (pCO2). [8] This confirmed previous statements that claimed the drug did not cause respiratory failure. The main goal of this clinical study was to confirm the findings of another study that showed benzoctamine did not reduce CO2 responsiveness, but instead increased the ventilatory response to CO2. [9]

There are usually many risks associated with using sedatives on patients who are suffering from respiratory failure, which has made it difficult to administer tranquillizing medications in situations when they are desirable. It is not known why this drug is safe and its benzodiazepine cousins are not, but a possible explanation for this phenomenon might come from its similarity in structure to tricyclic antidepressants, which have also been shown to not cause respiratory failure. [8] While further experimentation is necessary, this study points to benzoctamine's possible consideration for sedation in respiratory failure patients.

Other uses

Hypertension

A possible treatment for hypertension is blocking peripheral vascular seretonergic neurons or alpha-adrenergic neurons on postsynaptic cell sites. [10] One study showed that benzoctamine, a serotonin and alpha-adrenergic antagonist, does not reduce blood pressure through a seretonin mechanism but does reduce blood pressure by antagonizing alpha-adrenergic receptors in rats. [10] Rats were given 10 mg of benzoctamine and drops in their blood pressure were approximately 30mm Hg. [10] The researchers further confirmed that serotonin antagonism was not sufficient to reduce blood pressure by using the highly selective serotonin antagonist 1-(1-naphthyl)piperazine, which was not able to decrease the blood pressure of the rats. [10] These studies have yet to be repeated in humans.

Side effects

Common side effects

Common side effects include drowsiness (incidence of 9%), gastro-intestinal upset, dry mouth, headache, and dizziness (incidence of 1-2% each). [11]

Serotonin turnover

Studies have shown that benzoctamine increases level of serotonin. [12] Scientists confirmed these results and proposed that the method of action was inhibition of serotonin uptake since the drug also blocked the serotonin depleting action of extra-neuronal monoamine transporters (EMT). [13] This would lead to increased stimulation of serotonin receptors through a negative feed back mechanism, eventually decreasing serotonin out put. However, the study points out that other studies have shown that drugs combined with EMT cause a lowering of body temperature that in fact results in a decrease in serotonin turnover. [13] This means that body temperature effects cannot be ruled out.

Pharmacology

Not much is understood about how benzoctamine produces its anti-anxiety effects, but rat studies have shown that the possible mechanism of action is by way of increased turnover of catecholamines. [14] In addition to serotonin it has also been shown to decrease epinephrine, dopamine, and norepinephrine turnover by antagonizing their receptors. [13] When given intravenously in doses of 20–40 mg there are no significant differences in efficacy. [15] Oral doses exceeding 10 mg three times daily do not increase the effects of the drug. [4] Assuming serotonin postsynaptic antagonism is the main mechanism by which benzoctamine carries out its effects, studies have shown it to have an IC50 value of 115 mM at the serotonin receptor. [16]

Pharmacokinetics

Benzoctamine can be injected directly into the blood or given as tablets. When given as tablets, it is given in doses of 10 mg three times daily. [4] And when given intravenously, patients are given the drug at a rate of 5 mg/minute until 20–40 mg of drug has been injected. [15] Benzoctamine can be analyzed as the 3H acetyl derivative and N-methyl metabolite it gets broken down into using radioactive analysis. [17] Benzoctamine has a half-life of 2–3 hours, [5] with a bioavailability of around >90% when given orally. [18] The average time to achieve peak plasma concentrations is 1 hour [5] and the volume of distribution for a 70 kg person is 1–2 L/kg. [5]

See also

Related Research Articles

An anxiolytic is a medication or other intervention that reduces anxiety. This effect is in contrast to anxiogenic agents which increase anxiety. Anxiolytic medications are used for the treatment of anxiety disorders and their related psychological and physical symptoms.

<span class="mw-page-title-main">Benzodiazepine</span> Class of depressant drugs

Benzodiazepines, colloquially known as "benzos", are a class of depressant drugs whose core chemical structure is the fusion of a benzene ring and a diazepine ring. They are prescribed to treat conditions such as anxiety disorders, insomnia, and seizures. The first benzodiazepine, chlordiazepoxide (Librium), was discovered accidentally by Leo Sternbach in 1955, and was made available in 1960 by Hoffmann–La Roche, which followed with the development of diazepam (Valium) three years later, in 1963. By 1977, benzodiazepines were the most prescribed medications globally; the introduction of selective serotonin reuptake inhibitors (SSRIs), among other factors, decreased rates of prescription, but they remain frequently used worldwide.

<span class="mw-page-title-main">Diazepam</span> Benzodiazepine sedative

Diazepam, sold under the brand name Valium among others, is a medicine of the benzodiazepine family that acts as an anxiolytic. It is used to treat a range of conditions, including anxiety, seizures, alcohol withdrawal syndrome, muscle spasms, insomnia, and restless legs syndrome. It may also be used to cause memory loss during certain medical procedures. It can be taken orally, as a suppository inserted into the rectum, intramuscularly, intravenously or used as a nasal spray. When injected intravenously, effects begin in one to five minutes and last up to an hour. When taken by mouth, effects begin after 15 to 60 minutes.

<span class="mw-page-title-main">Lorazepam</span> Benzodiazepine medication

Lorazepam, sold under the brand name Ativan among others, is a benzodiazepine medication. It is used to treat anxiety, trouble sleeping, severe agitation, active seizures including status epilepticus, alcohol withdrawal, and chemotherapy-induced nausea and vomiting. It is also used during surgery to interfere with memory formation, to sedate those who are being mechanically ventilated, and, along with other treatments, for acute coronary syndrome due to cocaine use. It can be given orally, transdermally, intravenously (IV), or intramuscularly When given by injection, onset of effects is between one and thirty minutes and effects last for up to a day.

<span class="mw-page-title-main">Clonazepam</span> Benzodiazepine medication

Clonazepam, sold under the brand name Klonopin among others, is a benzodiazepine medication used to prevent and treat anxiety disorders, seizures, bipolar mania, agitation associated with psychosis, obsessive–compulsive disorder (OCD), and akathisia. It is a long-acting tranquilizer of the benzodiazepine class. It possesses anxiolytic, anticonvulsant, sedative, hypnotic, and skeletal muscle relaxant properties. It is typically taken orally but is also used intravenously. Effects begin within one hour and last between eight and twelve hours in adults.

<span class="mw-page-title-main">Clobazam</span> Benzodiazepine class medication

Clobazam, sold under the brand names Frisium, Onfi and others, is a benzodiazepine class medication that was patented in 1968. Clobazam was first synthesized in 1966 and first published in 1969. Clobazam was originally marketed as an anxioselective anxiolytic since 1970, and an anticonvulsant since 1984. The primary drug-development goal was to provide greater anxiolytic, anti-obsessive efficacy with fewer benzodiazepine-related side effects.

<span class="mw-page-title-main">Nordazepam</span> Benzodiazepine derivative medication

Nordazepam is a 1,4-benzodiazepine derivative. Like other benzodiazepine derivatives, it has amnesic, anticonvulsant, anxiolytic, muscle relaxant, and sedative properties. However, it is used primarily in the treatment of anxiety disorders. It is an active metabolite of diazepam, chlordiazepoxide, clorazepate, prazepam, pinazepam, and medazepam.

<span class="mw-page-title-main">Clorazepate</span> Benzodiazepine medication

Clorazepate, sold under the brand name Tranxene among others, is a benzodiazepine medication. It possesses anxiolytic, anticonvulsant, sedative, hypnotic, and skeletal muscle relaxant properties. Clorazepate is an unusually long-lasting benzodiazepine and serves as a prodrug for the equally long-lasting desmethyldiazepam, which is rapidly produced as an active metabolite. Desmethyldiazepam is responsible for most of the therapeutic effects of clorazepate.

<span class="mw-page-title-main">Alpidem</span> Anxiolytic medication

Alpidem, sold under the brand name Ananxyl, is a nonbenzodiazepine anxiolytic medication which was briefly used to treat anxiety disorders but is no longer marketed. It was previously marketed in France, but was discontinued due to liver toxicity. Alpidem is taken by mouth.

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

Camazepam is a benzodiazepine psychoactive drug, marketed under the brand names Albego, Limpidon and Paxor. It is the dimethyl carbamate ester of temazepam, a metabolite of diazepam. While it possesses anxiolytic, anticonvulsant, skeletal muscle relaxant and hypnotic properties it differs from other benzodiazepines in that its anxiolytic properties are particularly prominent but has comparatively limited anticonvulsant, hypnotic and skeletal muscle relaxant properties.

<span class="mw-page-title-main">Etizolam</span> Benzodiazepine analog drug

Etizolam is a thienodiazepine derivative which is a benzodiazepine analog. The etizolam molecule differs from a benzodiazepine in that the benzene ring has been replaced by a thiophene ring and triazole ring has been fused, making the drug a thienotriazolodiazepine.

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

Bretazenil (Ro16-6028) is an imidazopyrrolobenzodiazepine anxiolytic drug which is derived from the benzodiazepine family, and was invented in 1988. It is most closely related in structure to the GABA antagonist flumazenil, although its effects are somewhat different. It is classified as a high-potency benzodiazepine due to its high affinity binding to benzodiazepine binding sites where it acts as a partial agonist. Its profile as a partial agonist and preclinical trial data suggests that it may have a reduced adverse effect profile. In particular bretazenil has been proposed to cause a less strong development of tolerance and withdrawal syndrome. Bretazenil differs from traditional 1,4-benzodiazepines by being a partial agonist and because it binds to α1, α2, α3, α4, α5 and α6 subunit containing GABAA receptor benzodiazepine receptor complexes. 1,4-benzodiazepines bind only to α1, α2, α3 and α5GABAA benzodiazepine receptor complexes.

<span class="mw-page-title-main">Chlordiazepoxide</span> Benzodiazepine medication

Chlordiazepoxide, sold under the brand name Librium among others, is a sedative and hypnotic medication of the benzodiazepine class. It is used to treat anxiety, insomnia and symptoms of withdrawal from alcohol, benzodiazepines, and other drugs.

<span class="mw-page-title-main">Benzodiazepine withdrawal syndrome</span> Signs and symptoms due to benzodiazepine discontinuation in physically dependent persons

Benzodiazepine withdrawal syndrome is the cluster of signs and symptoms that may emerge when a person who has been taking benzodiazepines as prescribed develops a physical dependence on them and then reduces the dose or stops taking them without a safe taper schedule.

<span class="mw-page-title-main">Delorazepam</span> Benzodiazepine medication

Delorazepam, also known by the synonyms chlordesmethyldiazepam and nordiclazepam, is a drug which is a benzodiazepine and a derivative of desmethyldiazepam. It is marketed in Italy, where it is available under the trade name EN and Dadumir. Delorazepam (chlordesmethyldiazepam) is also an active metabolite of the benzodiazepine drugs diclazepam and cloxazolam. Adverse effects may include hangover type effects, drowsiness, behavioural impairments and short-term memory impairments. Similar to other benzodiazepines delorazepam has anxiolytic, skeletal muscle relaxant, hypnotic and anticonvulsant properties.

<span class="mw-page-title-main">Alcohol detoxification</span> Abrupt cessation of alcohol intake

Alcohol detoxification is the abrupt cessation of alcohol intake in individuals that have alcohol use disorder. This process is often coupled with substitution of drugs that have effects similar to the effects of alcohol in order to lessen the symptoms of alcohol withdrawal. When withdrawal does occur, it results in symptoms of varying severity.

<span class="mw-page-title-main">Fosazepam</span> Benzodiazepam

Fosazepam is a drug belonging to the benzodiazepine class, which are primarily anti-anxiety and sedative-hypnotic agents. It is a water soluble derivative of diazepam which has been substituted with a dimethylphosphoryl group to improve solubility in water. At equipotent doses, it possesses sedative and anxiolytic properties that are qualitatively and quantitatively similar to the effects of diazepam, with equal sedative-hypnotic, anti-convulsive, and muscle relaxant effects. In comparison to an equipotent dose of nitrazepam, its effects tended to be of noticeably milder magnitude.

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

Metaclazepam is a drug which is a benzodiazepine derivative. It is a relatively selective anxiolytic with less sedative or muscle relaxant properties than other benzodiazepines such as diazepam or bromazepam. It has an active metabolite N-desmethylmetaclazepam, which is the main metabolite of metaclazepam. There is no significant difference in metabolism between younger and older individuals.

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

Premazepam is a Pyrrolodiazepine class of drug. It is a partial agonist of benzodiazepine receptors and was shown in 1984 to possess both anxiolytic and sedative properties in humans but was never marketed.

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

Flutemazepam was initially first synthesized in 1965, but was not further described until a team at Stabilimenti Chimici Farmaceutici Riuniti SpA in the mid-1970s. It is a short-acting fluorinated analogue of temazepam that has powerful hypnotic, sedative, amnesiac, anxiolytic, anticonvulsant and skeletal muscle relaxant properties. As a result, flutemazepam has been shown to have similar pharmacological properties to temazepam. It has been found to be effective for the treatment of the most severe states of anxiety, panic attacks, and insomnia. Furthermore, it is potent with 1 mg of flutemazepam being equivalent to 10 mg of diazepam. Flutemazepam is highly effective for acute psychotic states, especially stimulant psychosis, violent behaviour, and aggression.

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. 1 2 Rickels K, Downing RW, Case WG, Feldman HS, Pereira-Ogan JA, Weise CC (March 1973). "Benzoctamine and Chlordiazepoxide in Anxiety: Some Predictors of Improvement". Journal of International Medical Research. 1 (3): 184–187. doi:10.1177/030006057300100308. ISSN   0300-0605.
  3. ↑ Robson WL (2022-05-19). Cendron M (ed.). "Enuresis Treatment & Management: Approach Considerations, Initial Management, Alarm Therapy". MedScape.
  4. 1 2 3 4 5 Goldstein BJ, Weer DM (May–Jun 1970). "Comparative evaluation of benzoctamine and diazepam in treatment of anxiety". The Journal of Clinical Pharmacology and the Journal of New Drugs. 10 (3): 194–198. doi:10.1177/009127007001000308. PMID   4392683. S2CID   44552044.
  5. 1 2 3 4 Utting HJ, Pleuvry BJ (September 1975). "Benzoctamine-a study of the respiratory effects of oral doses in human volunteers and interactions with morphine in mice". British Journal of Anaesthesia. 47 (9): 987–992. doi: 10.1093/bja/47.9.987 . PMID   1103919. S2CID   39957236.
  6. 1 2 3 4 5 Ogunremi OO, Adamson L, Brezinová V, Hunter WM, Maclean AW, Oswald I, et al. (April 1973). "Two anti-anxiety drugs: a psychoneuroendocrine study". British Medical Journal. 2 (5860): 202–205. doi:10.1136/bmj.2.5860.202. PMC   1589389 . PMID   4349414.
  7. ↑ Lo WH, Lo T (January 1973). "Clinical trial of benzoctamine versus chlordiazepoxide in anxiety neurosis". The Journal of Clinical Pharmacology and New Drugs. 13 (1): 48–53. doi:10.1002/j.1552-4604.1973.tb00069.x. PMID   4566124.
  8. 1 2 Clark TJ, Collins JV (January 1973). "Use of benzoctamine as sedative in patients with respiratory failure". British Medical Journal. 1 (5845): 75–76. doi:10.1136/bmj.1.5845.75. PMC   1588741 . PMID   20791872.
  9. ↑ Geisler L, Rost HD (1970). Respiratory stimulation. Proceedings of International Symposium on Anxiety and Tension-New Therapeutic Aspects. St. Moritz. p. 57.
  10. 1 2 3 4 Cohen ML, Fuller RW, Kurz KD (Sep–Oct 1983). "Evidence that blood pressure reduction by serotonin antagonists is related to alpha receptor blockade in spontaneously hypertensive rats". Hypertension. 5 (5): 676–681. doi: 10.1161/01.hyp.5.5.676 . PMID   6311738.
  11. ↑ Forrest WA (November 1972). "Anxiety with Depressed Mood in General Practice: A survey of 3,000 Patients treated with Benzoctamine: A Report of a Monitored Release Study". Journal of International Medical Research. 1 (1): 37–44. doi:10.1177/030006057200100110. ISSN   0300-0605.
  12. ↑ "Benzoctamine". go.drugbank.com. Retrieved 2024-02-09.
  13. 1 2 3 Lippmann W, Pugsley TA (August 1974). "Effects of benzoctamine and chlordiazepoxide on turnover and uptake of 5-hydroxytryptamine in the brain". British Journal of Pharmacology. 51 (4): 571–575. doi:10.1111/j.1476-5381.1974.tb09676.x. PMC   1778070 . PMID   4480288.
  14. ↑ Maître L, Staehelin M, Bein HJ (November 1970). "Effects of benzoctamine (30803-Ba, TACITIN), a new psychoactive drug, on catecholamine metabolism". Biochemical Pharmacology. 19 (11): 2875–2892. doi:10.1016/0006-2952(70)90027-4. PMID   5512696.
  15. 1 2 Goodwin NM, Brock-Utne JG, Downing JW, Coleman AJ (November 1974). "Benzoctamine. A preliminary report on a new sedative drug". Anaesthesia. 29 (6): 715–720. doi:10.1111/j.1365-2044.1974.tb00758.x. PMID   4479725. S2CID   221427437.
  16. ↑ Suzuki-Nishimura T, Sano T, Uchida MK (August 1989). "Effects of benzodiazepines on serotonin release from rat mast cells". European Journal of Pharmacology. 167 (1): 75–85. doi:10.1016/0014-2999(89)90749-8. PMID   2550260.
  17. ↑ Flanagan RJ (September 1995). "The poisoned patient: the role of the laboratory". British Journal of Biomedical Science. 52 (3): 202–213. PMID   8527998.
  18. ↑ Rang HP, Dale MM, Ritter JM, Moore PK (2003). Pharmacology (5th ed.). Edinburgh [u.a.]: Churchill Livingstone. p. 103. ISBN   0-443-07145-4.
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