Introduction
Fluclotizolam is a thienotriazolodiazepine derivative which was first synthesised in 1979, but was never marketed.
Background
It has subsequently been sold as a designer drug, first being definitively identified in 2017.
Tag: Medication
What is Flubrotizolam?
Introduction
Flubrotizolam (2-bromo-4-(2-fluorophenyl)-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine) is a thienotriazolodiazepine derivative with potent sedative and anxiolytic effects, which has been sold as a designer drug.
What is Flubromazepam?
Introduction
Flubromazepam is a benzodiazepine derivative which was first synthesized in 1960, but was never marketed and did not receive any further attention or study until late 2012 when it appeared on the grey market as a novel designer drug.
It is a structural analogue of phenazepam in which the chlorine atom has been replaced by a fluorine atom.
An alternative isomer, 5-(2-bromophenyl)-7-fluoro-1,3-dihydro-2H-1,4-benzodiazepin-2-one or “iso-flubromazepam”, may have been sold under the same name.
Legal Status
United Kingdom
In the UK, flubromazepam has been classified as a Class C drug by the May 2017 amendment to The Misuse of Drugs Act 1971 along with several other designer benzodiazepine drugs.
United States
Flubromazepam, clonazolam, and flubromazolam are Schedule I controlled substances under Virginia State Law.
What is Fluadinazolam?
Introduction
Fluadinazolam is a benzodiazepine derivative developed in 1973, with sedative and anxiolytic effects.
Background
It is a derivative of the never commercially marketed benzodiazepine adinazolam and has similarly been sold as a designer drug.
What is Delorazepam?
Introduction
Delorazepam, also known as 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.
Indications
Delorazepam is mainly used as an anxiolytic because of its long elimination half-life; showing superiority over the short-acting drug lorazepam. In comparison with the antidepressant drugs, paroxetine and imipramine, delorazepam was found to be more effective in the short-term but after 4 weeks the antidepressants showed superior anti-anxiety effects.
Delorazepam is also used as a premedication for dental phobia for its anxiolytic properties. High doses of Delorazepam may be administered the night before a dental (or other medical) procedure in order to provide relief from anxiety-associated insomnia that night with the effects persisting long enough to sufficiently treat anxiety the next day.
Delorazepam has also demonstrated effectiveness in treating alcohol withdrawal.
Availability
Delorazepam is available in tablet and liquid drop formulations. The liquid drop formulation is absorbed more quickly and has improved bioavailibility.
Pharmacology
Delorazepam is well absorbed after administration, reaching peak plasma levels within 1-2 hours. It has a very long elimination half-life and can still be detected 72 hours after dosing. Bioavailability is about 77%. Peak plasma levels occur at just over one hour after administration. Significant accumulation occurs of delorazepam due to its slow metabolism; the elderly metabolise delorazepam and its active metabolite slower than younger individuals, resulting in a dose of delorazepam accumulating faster and peaking at a higher plasma concentration than an equal dose administered to a younger individual. The elderly also have a poorer response to the therapeutic effects and a higher rate of adverse effects. The elimination half-life of delorazepam is 80-115 hours. The active metabolite of delorazepam is lorazepam and represents about 15-24% of the parent drug (delorazepam). The pharmacokinetics of delorazepam are not altered if it is taken with food, except for some slowing of absorption. Delorazepams potency is approximately equal to that of lorazepam, being ten times more potent by weight than diazepam (1 mg delorazepam = 1 mg lorazepam = 5 mg diazepam), typical doses range from 0.5 mg-2 mg. Treatment is generally initiated at 1 mg for healthy adults and 0.5 mg in paediatric and geriatric patients and patients with mild renal impairment, treatment is contraindicated in patients with moderate or severe renal impairment.
Side Effects and Contraindications
Delorazepam hosts all the classic side-effects of GABAA full agonists (such as most benzodiazepines). These include sedation/somnolence, dizziness/ataxia, amnesia, reduced inhibition, increased talkativeness/sociability, euphoria, impaired judgement, hallucinations, and respiratory depression. Paradoxical reactions including increased anxiety, excitation, and aggression may occur and are more common in elderly, paediatric, and schizophrenic patients. In rare instances, delorazepam may cause suicidal ideation and actions.
Long term use of delorazepam (as well as all other benzodiazepines) has been found to increase long term cognitive deficits (persisting longer than sixth months) which some researchers claim to be permanent. Short term use may occasionally cause depression and the risk of depressive symptoms occurring increases considerably with longer terms of use, delorazepam is not intended to be used for more than 2-4 weeks unless it used only occasionally on an as-needed basis. When being used on an as-needed basis the need for delorazepam therapy should be re-evaluated each time a new prescription for delorazepam is issued, and alternative medications should be considered if patients begin to take delorazepam habitually (many days in a row).
The most serious effect of long term delorazepam use is dependence, with withdrawal symptoms which mimic delirium tremens presenting when delorazepam use is discontinued. Although the withdrawal effects from delorazepam are generally less severe than its shorter-acting counterparts, they can be life-threatening. Slow de-titration of delorazepam over a period of weeks or months is generally suggested to minimise the severity of withdrawal. Psychological effects of withdrawal such as rebound anxiety and insomnia have been known to persist for months after physical dependence has been successfully treated.
Delorazepam is contraindicated in those with severe schizophrenia or schizo-affective disorders, those with a known allergy or hypersensitivity to delorazepam or related benzodiazepines, and those with moderate to severe renal impairment (delorazepam is sometimes administered at a reduced dose to patients with mild renal impairment). Delorazepam is generally considered to be contraindicated in patients with severe acute or chronic illnesses but is occasionally used in the palliative care of terminal patients during their last days/weeks of life.
Patients with a history of substance and/or alcohol use are believed to have an increased risk of abusing delorazepam (as well as all other benzodiazepines), this must be considered when a physician prescribes delorazepam to such patients. Although all patients being treated with delorazepam should be routinely monitored for signs of use and diversion of medication, increased monitoring of patients with a history of substance and/or alcohol use is always warranted. Non-medical benzodiazepine use in patients who have them prescribed on an as-needed basis for chronic/refractory anxiety, insomnia, and intermittent muscle spasms has occurred and generally occurs very slowly, becoming evident only after months or years since the initiation of therapy. Monitoring of patients actively using delorazepam should never be discontinued even if the patients has been stable on the medication for many months or years.
Caution must be used when delorazepam is administered alongside other sedative medications (ex. opiates, barbiturates, z-drugs, and phenothiazines) due to an increased risk of sedation, ataxia, and (potentially fatal) respiratory depression. Although overdoses of benzodiazepines alone rarely result in death, the combination of benzodiazepines and other sedatives (particularly other gabaminergic drugs such as barbiturates and alcohol) is far more likely to result in death.
Special Cautions
People with renal failure on haemodialysis have a slow elimination rate and a reduced volume of distribution of the drug. Liver disease has a profound effect on the elimination rate of delorazepam, resulting in the half-life almost doubling to 395 hours, whereas healthy patients showed an elimination half-life of 204 hours on average. Caution is recommended when using delorazepam in patients with liver disease.
What is Antipsychotic Switching?
Introduction
Antipsychotic switching refers to the process of switching out one antipsychotic for another antipsychotic.
There are multiple indications for switching antipsychotics, including inadequate efficacy and drug intolerance. There are several strategies that have been theorised for antipsychotic switching, based upon the timing of discontinuation and tapering of the original antipsychotic and the timing of initiation and titration of the new antipsychotic. Major adverse effects from antipsychotic switching may include supersensitivity syndromes, withdrawal, and rebound syndromes.
Rationale
Antipsychotics may be switched due to inadequate efficacy, drug intolerance, patient/guardian preference, drug regimen simplification, or for economic reasons.
| Rationale | Outline |
|---|---|
| Inadequate Efficacy | 1. An inadequate treatment response to an antipsychotic, assuming that the lack of efficacy is due to an otherwise adequately dosed regimen for an appropriate duration, can result from failure to achieve therapeutic goals in any major treatment domain. 2. For example, this can refer to a patient who becomes acutely psychotic after being stable previously. 3. Other failures include persistent symptoms of schizophrenia, either positive or negative, problems with mood (including suicidality), or problems with cognition. Inadequate efficacy may be due to nonadherence to therapy, which can influence treatment decisions. 4. For example, long acting injectable (LAI) antipsychotics are often indicated in the setting of medication nonadherence. |
| Drug Intolerance | 1. Adverse effects can contribute to drug intolerance, potentially necessitating antipsychotic switching. 2. Adverse effects that threaten serious harm, aggravate other medical conditions, or make a person want to stop taking their medications are all examples of drug intolerance. 3. Certain drug interactions can cause adverse effects as well. |
| Patient/Guardian Preference | 1. A patient or caregiver may prefer a different antipsychotic. 2. This may be due to misinformation regarding the antipsychotic, including its side effects, a lack of insight into the importance of the medication and the severity of the disease, or overestimating the therapeutic effect. |
| Drug Regimen Simplification | 1. Adherence to medication therapy is inversely related to the frequency of dosing. 2. The antipsychotic quetiapine is typically dosed two to three times daily for the management of schizophrenia. 3. A simpler regimen would be a once daily administered antipsychotic. 4. For example, risperidone can be administered once daily. 5. A lack of adherence can lead to poor health outcomes, as well as unnecessary financial burden. |
| Economics | 1. A patient or caregiver may request antipsychotic switching to reduce medication costs. 2. The following is an estimate of the direct costs of living with schizophrenia per patient across select countries (annual direct costs in US$): a. Belgium: 12,050. b. People’s Republic of China: 700. c. South Korea: 2,600. d. Taiwan: 2,115. e. UK: 3,420. f. US: 15,464. |
Contraindications
In general, contraindications to antipsychotic switching are cases in which the risk of switching outweighs the potential benefit. Contraindications to antipsychotic switching include effective treatment of an acute psychotic episode, patients stable on a LAI antipsychotic with a history of poor adherence, and stable patients with a history of self-injurious behaviour, violent behaviour, or significant self-neglect or other symptoms.
Strategies
There are multiple strategies available for switching antipsychotics. An abrupt switch involves abruptly switching from one antipsychotic to the other without any titration. A cross-taper is accomplished by gradually discontinuing the pre-switch antipsychotic while simultaneously up-titrating the new antipsychotic. An overlap and discontinuation switch involves maintaining the pre-switch antipsychotic until the new antipsychotic is gradually titrated up, then gradually titrating down on the pre-switch antipsychotic. Alternatively, in an ascending taper switch, the pre-switch antipsychotic can be abruptly discontinued. Another alternative, known as the descending taper switch, involves slowly discontinuing the pre-switch antipsychotic while abruptly starting the new antipsychotic. These switching strategies can be further subdivided by the inclusion or exclusion of a plateau period.
See the figure below for a graphic visualisation of the five main antipsychotic switching strategies discussed above.
Due to differences in how individual antipsychotics work, even within each generation, the process of switching between antipsychotics has become more complex.
Adverse Effects
The three major adverse effects of antipsychotic switching are supersensitivity syndromes, withdrawal, and rebound syndromes.
Supersensitivity Syndromes
Antipsychotics work by antagonising the dopamine receptor D2 (D2R) in the mesolimbic pathway of the brain. When the D2R is suppressed, the neurons may become sensitised to the effect of an endogenous ligand (i.e. dopamine) by up-regulating the production of postsynaptic D2Rs. If the D2 receptors are not subsequently suppressed at previous levels after an abrupt discontinuation of an antipsychotic (e.g. after switching to weak D2R antagonists quetiapine or clozapine), a rebound/supersensitivity psychosis may occur due to the overwhelming effect of endogenous dopamine on sensitised neurons. Supersensitivity psychosis, also called rapid-onset psychosis, must be distinguished from a relapse or exacerbation of the underlying disease (e.g. schizophrenia). Dopamine supersensitivity psychosis generally occurs around 6 weeks after an oral antipsychotic is discontinued, or 3 months after a LAI antipsychotic is discontinued. In addition, supersensitivity psychosis is generally easier to reverse by reintroducing D2R antagonism (i.e. restarting the discontinued drug), whereas a relapsed schizophrenia is more difficult to control.
Rebound Syndromes
The second-generation antipsychotic olanzapine is thought to have a rebound-induced hyperthermia, which may be mediated by serotonin receptors. Hyperthermia, or elevated core body temperature, is associated with neuroleptic malignant syndrome, a potentially lethal syndrome that commonly occurs due to excessive D2R antagonism (As a point of contrast, hypothermia, or low core body temperature, has most frequently occurred in the presence of olanzapine, risperidone, or haloperidol).
In general, rebound D2R activity may induce rebound parkinsonism and rebound akathisia.
Withdrawal
D2 receptor activity withdrawal may induce withdrawal dyskinesia. This late-onset, hypersensitivity-type dyskinesia is in contrast to the early-onset dyskinesia that can occur due to an over-compensatory dopamine release associated with abrupt dopamine antagonist withdrawal. Other symptoms of dopamine withdrawal include difficulty sleeping, anxiety, and restlessness.
Alternatives
An alternative to antipsychotic switching, in the setting of a person that is not responding to the initial dose of an antipsychotic, is to increase the dose of antipsychotic prescribed. A 2018 Cochrane review compared the evidence between the two strategies, but the authors were unable to draw any conclusions about whether either method was preferable due to limited evidence.
What is an Atypical Antidepressant?
Introduction
An atypical antidepressant is any antidepressant medication that acts in a manner that is different from that of most other antidepressants.
Refer to Second-Generation Antidepressant, Tricyclic Antidepressant, and Tetracyclic Antidepressant.
Background
Atypical antidepressants include agomelatine, bupropion, mianserin, mirtazapine, nefazodone, opipramol, tianeptine, and trazodone. The agents vilazodone and vortioxetine are partly atypical. Typical antidepressants include the SSRIs, SNRIs, TCAs, and MAOIs, which act mainly by increasing the levels of the monoamine neurotransmitters serotonin and/or norepinephrine. Among TCAs, trimipramine is an atypical agent in that it appears not to do this. In August 2020, Esketamine (JNJ-54135419) was approved by the US Food and Drug Administration (FDA) for the treatment for treatment-resistant depression with the added indication for the short-term treatment of suicidal thoughts.
Buprenorphine/Samidorphan (ALKS-5461) is an antidepressant with a novel mechanism of action which is under development and is considered an atypical antidepressant. They act faster than available antidepressants.
What is a Second-Generation Antidepressant?
Introduction
The second-generation antidepressants are a class of antidepressants characterised primarily by the era of their introduction, approximately coinciding with the 1970s and 1980s, rather than by their chemical structure or by their pharmacological effect. As a consequence, there is some controversy over which treatments actually belong in this class.
Refer to Atypical Antidepressant, Tricyclic Antidepressant, and Tetracyclic Antidepressant.
The term “third generation antidepressant” is sometimes used to refer to newer antidepressants, from the 1990s and 2000s, often selective serotonin reuptake inhibitors (SSRIs) such as; fluoxetine (Prozac), paroxetine (Paxil) and sertraline (Zoloft), as well as some non-SSRI antidepressants such as mirtazapine, nefazodone, venlafaxine, duloxetine and reboxetine. However, this usage is not universal.
Examples
This list is not exhaustive, and different sources vary upon which items should be considered second-generation.
- Amineptine.
- Amoxapine.
- Bupropion.
- Iprindole.
- Maprotiline.
- Medifoxamine.
- Mianserin.
- Nomifensine.
- Tianeptine.
- Trazodone.
- Venlafaxine.
- Viloxazine.
What is Phenobarbital?
Introduction
Phenobarbital, also known as phenobarbitone or phenobarb, or by the trade name Luminal, is a medication of the barbiturate type.
It is recommended by the World Health Organisation (WHO) for the treatment of certain types of epilepsy in developing countries. In the developed world, it is commonly used to treat seizures in young children, while other medications are generally used in older children and adults. It may be used intravenously, injected into a muscle, or taken by mouth. The injectable form may be used to treat status epilepticus. Phenobarbital is occasionally used to treat trouble sleeping, anxiety, and drug withdrawal and to help with surgery. It usually begins working within five minutes when used intravenously and half an hour when administered by mouth. Its effects last for between four hours and two days.
Side effects include a decreased level of consciousness along with a decreased effort to breathe. There is concern about both abuse and withdrawal following long-term use. It may also increase the risk of suicide. It is pregnancy category B or D (depending on how it is taken) in the United States and category D in Australia, meaning that it may cause harm when taken by pregnant women. If used during breastfeeding it may result in drowsiness in the baby. A lower dose is recommended in those with poor liver or kidney function, as well as elderly people. Phenobarbital, like other barbiturates works by increasing the activity of the inhibitory neurotransmitter GABA.
Phenobarbital was discovered in 1912 and is the oldest still commonly used anti-seizure medication. It is on the WHO’s List of Essential Medicines.
Brief History
The first barbiturate drug, barbital, was synthesized in 1902 by German chemists Emil Fischer and Joseph von Mering and was first marketed as Veronal by Friedr. Bayer et comp. By 1904, several related drugs, including phenobarbital, had been synthesized by Fischer. Phenobarbital was brought to market in 1912 by the drug company Bayer as the brand Luminal. It remained a commonly prescribed sedative and hypnotic until the introduction of benzodiazepines in the 1960s.
Phenobarbital’s soporific, sedative and hypnotic properties were well known in 1912, but it was not yet known to be an effective anti-convulsant. The young doctor Alfred Hauptmann gave it to his epilepsy patients as a tranquiliser and discovered their seizures were susceptible to the drug. Hauptmann performed a careful study of his patients over an extended period. Most of these patients were using the only effective drug then available, bromide, which had terrible side effects and limited efficacy. On phenobarbital, their epilepsy was much improved: The worst patients suffered fewer and lighter seizures and some patients became seizure-free. In addition, they improved physically and mentally as bromides were removed from their regimen. Patients who had been institutionalised due to the severity of their epilepsy were able to leave and, in some cases, resume employment. Hauptmann dismissed concerns that its effectiveness in stalling seizures could lead to patients suffering a build-up that needed to be “discharged”. As he expected, withdrawal of the drug led to an increase in seizure frequency – it was not a cure. The drug was quickly adopted as the first widely effective anti-convulsant, though World War I delayed its introduction in the US.
In 1939, a German family asked Adolf Hitler to have their disabled son killed; the five-month-old boy was given a lethal dose of Luminal after Hitler sent his own doctor to examine him. A few days later 15 psychiatrists were summoned to Hitler’s Chancellery and directed to commence a clandestine programme of involuntary euthanasia.
In 1940, at a clinic in Ansbach, Germany, around 50 intellectually disabled children were injected with Luminal and killed that way. A plaque was erected in their memory in 1988 in the local hospital at Feuchtwanger Strasse 38, although a newer plaque does not mention that patients were killed using barbiturates on site. Luminal was used in the Nazi children’s euthanasia programme until at least 1943.
Phenobarbital was used to treat neonatal jaundice by increasing liver metabolism and thus lowering bilirubin levels. In the 1950s, phototherapy was discovered, and became the standard treatment.
Phenobarbital was used for over 25 years as prophylaxis in the treatment of febrile seizures. Although an effective treatment in preventing recurrent febrile seizures, it had no positive effect on patient outcome or risk of developing epilepsy. The treatment of simple febrile seizures with anticonvulsant prophylaxis is no longer recommended.
Medical Uses
Phenobarbital is used in the treatment of all types of seizures, except absence seizures. It is no less effective at seizure control than phenytoin, however phenobarbital is not as well tolerated. Phenobarbital may provide a clinical advantage over carbamazepine for treating partial onset seizures. Carbamazepine may provide a clinical advantage over phenobarbital for generalised onset tonic-clonic seizures. Its very long active half-life (53-118 hours) means for some people doses do not have to be taken every day, particularly once the dose has been stabilised over a period of several weeks or months, and seizures are effectively controlled.
The first-line drugs for treatment of status epilepticus are benzodiazepines, such as lorazepam or diazepam. If these fail, then phenytoin may be used, with phenobarbital being an alternative in the US, but used only third-line in the UK. Failing that, the only treatment is anaesthesia in intensive care. The WHO gives phenobarbital a first-line recommendation in the developing world and it is commonly used there.
Phenobarbital is the first-line choice for the treatment of neonatal seizures. Concerns that neonatal seizures in themselves could be harmful make most physicians treat them aggressively. No reliable evidence, though, supports this approach.
Phenobarbital is sometimes used for alcohol detoxification and benzodiazepine detoxification for its sedative and anti-convulsant properties. The benzodiazepines chlordiazepoxide (Librium) and oxazepam (Serax) have largely replaced phenobarbital for detoxification.
Phenobarbital is useful for insomnia and anxiety.
Other Uses
Phenobarbital properties can effectively reduce tremors and seizures associated with abrupt withdrawal from benzodiazepines.
Phenobarbital is a cytochrome P450 inducer, and is used to reduce the toxicity of some drugs.
Phenobarbital is occasionally prescribed in low doses to aid in the conjugation of bilirubin in people with Crigler-Najjar syndrome, type II,[26] or in people with Gilbert’s syndrome. Phenobarbital can also be used to relieve cyclic vomiting syndrome symptoms.
Phenobarbital is a commonly used agent in high purity and dosage for lethal injection of “death row” criminals.
In infants suspected of neonatal biliary atresia, phenobarbital is used in preparation for a 99mTc-IDA hepatobiliary (HIDA; hepatobiliary 99mTc-iminodiacetic acid) study that differentiates atresia from hepatitis or cholestasis.
Phenobarbital is used as a secondary agent to treat newborns with neonatal abstinence syndrome, a condition of withdrawal symptoms from exposure to opioid drugs in utero.
In massive doses, phenobarbital is prescribed to terminally ill people to allow them to end their life through physician-assisted suicide.
Like other barbiturates, phenobarbital can be used recreationally, but this is reported to be relatively infrequent.
Side Effects
Sedation and hypnosis are the principal side effects (occasionally, they are also the intended effects) of phenobarbital. Central nervous system effects, such as dizziness, nystagmus and ataxia, are also common. In elderly patients, it may cause excitement and confusion, while in children, it may result in paradoxical hyperactivity.
Phenobarbital is a cytochrome P450 hepatic enzyme inducer. It binds transcription factor receptors that activate cytochrome P450 transcription, thereby increasing its amount and thus its activity. Due to this higher amount of CYP450, drugs that are metabolised by the CYP450 enzyme system will have decreased effectiveness. This is because the increased CYP450 activity increases the clearance of the drug, reducing the amount of time they have to work.
Caution is to be used with children. Among anti-convulsant drugs, behavioural disturbances occur most frequently with clonazepam and phenobarbital.
Contraindications
Acute intermittent porphyria, hypersensitivity to any barbiturate, prior dependence on barbiturates, severe respiratory insufficiency (as with chronic obstructive pulmonary disease), severe liver failure, pregnancy, and breastfeeding are contraindications for phenobarbital use.
Overdose
Refer to Barbiturate Overdose.
Phenobarbital causes a depression of the body’s systems, mainly the central and peripheral nervous systems. Thus, the main characteristic of phenobarbital overdose is a “slowing” of bodily functions, including decreased consciousness (even coma), bradycardia, bradypnea, hypothermia, and hypotension (in massive overdoses). Overdose may also lead to pulmonary oedema and acute renal failure as a result of shock, and can result in death.
The electroencephalogram (EEG) of a person with phenobarbital overdose may show a marked decrease in electrical activity, to the point of mimicking brain death. This is due to profound depression of the central nervous system, and is usually reversible.
Treatment of phenobarbital overdose is supportive, and mainly consists of the maintenance of airway patency (through endotracheal intubation and mechanical ventilation), correction of bradycardia and hypotension (with intravenous fluids and vasopressors, if necessary), and removal of as much drug as possible from the body. In very large overdoses, multi-dose activated charcoal is a mainstay of treatment as the drug undergoes enterohepatic recirculation. Urine alkalisation (achieved with sodium bicarbonate) enhances renal excretion. Haemodialysis is effective in removing phenobarbital from the body, and may reduce its half-life by up to 90%. No specific antidote for barbiturate poisoning is available.
Mechanism of Action
Phenobarbitol is as an allosteric modulator which extends the amount of time the chloride ion channel is open by interacting with GABAA receptor subunits. Through this action, phenobarbital increases the flow of chloride ions into the neuron which decreases the excitability of the post-synaptic neuron. Hyperpolarising this post-synaptic membrane leads to a decrease in the general excitatory aspects of the post-synaptic neuron. By making it harder to depolarise the neuron, the threshold for the action potential of the post-synaptic neuron will be increased. Phenobarbital stimulates GABA to accomplish this hyperpolarisation. Direct blockade of excitatory glutamate signalling is also believed to contribute to the hypnotic/anticonvulsant effect that is observed with the barbiturates.
Pharmacokinetics
Phenobarbital has an oral bioavailability of about 90%. Peak plasma concentrations (Cmax) are reached eight to 12 hours after oral administration. It is one of the longest-acting barbiturates available – it remains in the body for a very long time (half-life of two to seven days) and has very low protein binding (20 to 45%). Phenobarbital is metabolized by the liver, mainly through hydroxylation and glucuronidation, and induces many isozymes of the cytochrome P450 system. Cytochrome P450 2B6 (CYP2B6) is specifically induced by phenobarbital via the CAR/RXR nuclear receptor heterodimer. It is excreted primarily by the kidneys.
Veterinary Uses
Phenobarbital is one of the initial drugs of choice to treat epilepsy in dogs, as well as cats. It is also used to treat feline hyperesthesia syndrome in cats when anti-obsessional therapies prove ineffective.
It may also be used to treat seizures in horses when benzodiazepine treatment has failed or is contraindicated.
Society and Culture
Names
Phenobarbital is the INN and phenobarbitone is the BAN.
Synthesis
Barbiturate drugs are obtained via condensation reactions between a derivative of diethyl malonate and urea in the presence of a strong base. The synthesis of phenobarbital uses this common approach as well but differs in the way in which this malonate derivative is obtained. The reason for this difference is due to the fact that aryl halides do not typically undergo nucleophilic substitution in Malonic ester synthesis in the same way as aliphatic organosulfates or halocarbons do. To overcome this lack of chemical reactivity two dominant synthetic approaches using benzyl cyanide as a starting material have been developed:
- The first of these methods consists of a Pinner reaction of benzyl cyanide, giving phenylacetic acid ethyl ester. Subsequently, this ester undergoes cross Claisen condensation using diethyl oxalate, giving diethyl ester of phenyloxobutandioic acid. Upon heating this intermediate easily loses carbon monoxide, yielding diethyl phenylmalonate. Malonic ester synthesis using ethyl bromide leads to the formation of α-phenyl-α-ethylmalonic ester. Finally a condensation reaction with urea gives phenobarbital.
- The second approach utilises diethyl carbonate in the presence of a strong base to give α-phenylcyanoacetic ester. Alkylation of this ester using ethyl bromide proceeds via a nitrile anion intermediate to give the α-phenyl-α-ethylcyanoacetic ester. This product is then further converted into the 4-iminoderivative upon condensation with urea. Finally acidic hydrolysis of the resulting product gives phenobarbital.
Regulation
The level of regulation includes Schedule IV non-narcotic (depressant) (ACSCN 2285) in the United States under the Controlled Substances Act 1970—but along with a few other barbiturates and at least one benzodiazepine, and codeine, dionine, or dihydrocodeine at low concentrations, it also has exempt prescription and had at least one exempt OTC combination drug now more tightly regulated for its ephedrine content.[63] The phenobarbitone/phenobarbital exists in subtherapeutic doses which add up to an effective dose to counter the overstimulation and possible seizures from a deliberate overdose in ephedrine tablets for asthma, which are now regulated at the federal and state level as: a restricted OTC medicine and/or watched precursor, uncontrolled but watched/restricted prescription drug & watched precursor, a Schedule II, III, IV, or V prescription-only controlled substance & watched precursor, or a Schedule V (which also has possible regulations at the county/parish, town, city, or district as well aside from the fact that the pharmacist can also choose not to sell it, and photo ID and signing a register is required) exempt Non-Narcotic restricted/watched OTC medicine.[64]
Selected Overdoses
The Japanese officers aboard the German submarine U-234 killed themselves with phenobarbital while the German crew members were on their way to the US to surrender (but before Japan had surrendered).
A mysterious woman, known as the Isdal Woman, was found dead in Bergen, Norway, on 29 November 1970. Her death was caused by some combination of burns, phenobarbital, and carbon monoxide poisoning; many theories about her death have been posited, and it is believed that she may have been a spy.
British veterinarian Donald Sinclair, better known as the character Siegfried Farnon in the “All Creatures Great and Small” book series by James Herriot, committed suicide at the age of 84 by injecting himself with an overdose of phenobarbital. Activist Abbie Hoffman also committed suicide by consuming phenobarbital, combined with alcohol, on 12 April 1989; the residue of around 150 pills was found in his body at autopsy. Also dying from an overdose was British actress Phyllis Barry in 1954 and actress/model Margaux Hemingway in 1996.
Thirty-nine members of the Heaven’s Gate UFO religious group committed mass suicide in March 1997 by drinking a lethal dose of phenobarbital and vodka “and then lay down to die” hoping to enter an alien spacecraft.
What is Phenazolam?
Introduction
Phenazolam, (Clobromazolam, DM-II-90, BRN 4550445) is a benzodiazepine derivative which acts as a potent sedative and hypnotic drug.
Background
It was first invented in the early 1980s, but was never developed for medical use. It has been sold over the internet as a designer drug, first being identified in seized samples by a laboratory in Sweden in March 2016.
Legality
Clobromazolam was made illegal in Serbia in May 2019, and in Italy in March 2020.
Mental Health Matters 
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