Etizolam

# Overview
Etizolam (marketed under the brand name Etilaam, Etizest, Etidev,Etizola, Sedekopan, Pasaden or Depas) is a benzodiazepine analog. The etizolam molecule differs from a benzodiazepine in that the benzene ring has been replaced by a thiophene ring, making the drug a thienodiazepine. It possesses amnesic, anxiolytic, anticonvulsant, hypnotic, sedative and skeletal muscle relaxant properties.

# Indications
- Short-term treatment of insomnia
- Short-term treatment of anxiety or panic attacks, if a benzodiazepine is required

# Dosage
- Anxiety disorders associated with depression  : 1 mg two to three times a day (maximum 3 mg per day)
- For panic disorder (associated with agoraphobia): 0.5 mg two times per day (maximum 1 mg per day)
- For insomnia: 12 mg once daily before bedtime
A 1 mg dose of etizolam is approximately equivalent to a 10 mg dose of diazepam, see List of benzodiazepines.

# Side effects
- Blepharospasms with long term use
Very Rare
- Erythema annulare centrifugum skin lesions

# Tolerance, dependence and withdrawal
Abrupt or rapid withdrawal from etizolam, as with benzodiazepines, may result in the appearance of the benzodiazepine withdrawal syndrome, including rebound insomnia. Neuroleptic malignant syndrome, a rare event in benzodiazepine withdrawal, has been documented in a case of abrupt withdrawal from etizolam.
In a study that compared the effectiveness of etizolam, alprazolam, and bromazepam for the treatment of generalized anxiety disorder, all three drugs retained their effectiveness over 2 weeks, but etizolam became more effective from 2 weeks to 4 weeks, a type of reverse tolerance.  Administering .5 mg etizolam twice daily did not induce cognitive deficits over 3 weeks when compared to placebo.
When multiple doses of etizolam, or lorazepam, were administered to rat neurons, lorazepam caused downregulation of alpha-1 benzodiazepine binding sites (tolerance/dependence), while etizolam caused an increase in alpha-2 benzodiazepine binding sites (reverse tolerance to anti-anxiety effects).  Tolerance to the anticonvulsant effects of lorazepam were observed, but no significant tolerance to the anticonvulsant effects of etizolam were observed. Etizolam therefore has a reduced liability to induce tolerance, and dependence, compared with classical benzodiazepines.

# Contraindications and special caution
Etizolam is metabolised by the liver and is contraindicated in those with severely impaired hepatic function. It may impair the ability to drive and operate machinery so caution should be applied. Elderly patients should start on a lower dose as they are more susceptible to the sedative effects of etizolam. It is not recommended to be taken during pregnancy or breastfeeding.
Etizolam can increase the sedative and antidepressant actions of other medication such as neuroleptics, analgesics, anaesthetics, antiepileptics, sedatives and first-generation antihistamines. Co-administration with these medications should be avoided unless instructed by a medical professional. Alcohol should also be avoided.
Drugs inhibiting the enzymes CYP2C19 and CYP3A4, such as fluvoxamine, should not be taken concurrently as etizolam can increase the plasma levels of these enzymes.

# Pharmacology
Etizolam, a thienodiazepine derivative, is absorbed fairly rapidly, with peak plasma levels achieved between 30 minutes and 2 hours. It has a mean elimination half life of about 3.5 hours.  Etizolam possesses potent hypnotic properties, and is comparable with other short-acting benzodiazepines.  Etizolam acts as a full agonist at the benzodiazepine receptor to produce its range of therapeutic and adverse effects. Similar to other benzodiazepines, etizolam binds non-selectively to benzodiazepine receptor subtypes.
In addition, etizolam, unlike most other benzodiazepines (some of which can increase levels of estradiol), has prolactogenic effects, leading to an increase in blood levels of prolactin.
According to the Italian P.I. sheet, etizolam belongs to a new class of diazepines, thienotriazolodiazepines. This new class is easily oxidized, rapidly metabolized, and has a lower risk of accumulation, even after prolonged treatment. Etizolam has an anxiolytic action about 6 times greater than that of diazepam. Etizolam produces, especially at higher dosages, a reduction in time taken to fall asleep, an increase in total sleep time, and a reduction in the number of awakenings. During tests, there were not substantial changes in deep sleep; however, it may reduce REM sleep. In EEG tests of healthy volunteers, etizolam showed some characteristics of tricyclic antidepressants.

# Legal status

## United States
Etizolam is not authorized for medical use in the U.S. However, it currently remains unscheduled and is legal for research purposes. As it is a thienodiazepine, an analog of benzodiazepines, which are Schedule IV drug under Federal Scheduling Guidelines, it does not fall under the Federal Analog Act, which only applies to Schedule I and II drugs.
Etizolam is a controlled substance in the following states: Alabama, Arkansas and Mississippi.

## United Kingdom
Unlike other thienodiazepines such as brotizolam and clotiazepam, etizolam is not controlled under the Misuse of Drugs Act 1971 or licensed as a medicine in the United Kingdom.

## Germany
Etizolam was controlled in Germany in July 2013.

## Poland
Etizolam may be scheduled under the Act on Counteracting Drug Addiction and the State Sanitary Inspection -Article 27c

# Interactions
Itraconazole and fluvoxamine slow down the rate of elimination of etizolam, leading to accumulation of etizolam, therefore increasing its pharmacological effects. Carbamazepine speeds up the metabolism of etizolam, resulting in reduced pharmacological effects.
Etizolam, similarly to other GABAergic agonists including the benzodiazepines has a strong synergistic effect with ethanol and the consequences of co-ingestion of the two drugs can drastically compound the side effects of either drug.Template:Medcn  This can result in (among other effects) anterograde amnesia (blackouts) and severe respiratory depression which in extreme cases can lead to death.Template:Medcn

# Overdose
Cases of intentional suicide by overdose using etizolam have been reported. Although etizolam has a lower LD50 than certain benzodiazepines, the LD50 is still far beyond the prescribed or recommended dose. Many lethal etizolam overdoses were due to drug interactions.

# Abuse
Etizolam is a drug of potential abuse. However, conflicting reports from the World Health Organization, made public in 1991, dispute the abuse claims.
According to the Journal of the American Medical Association, benzodiazepines  either alone or mixed with other drugs  were involved in nearly 30 percent of fatal overdoses in the United States in 2010. A Japanese study published in Forensic Science International revealed that metabolic traces of etizolam were detected in two people who died of lethal drug overdoses. Fast-acting benzodiazepines may produce side effects very quickly, especially if the user is taking other drugs.