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On This Day … 20 August

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People (Births)

  • 1913 – Roger Wolcott Sperry, American neuropsychologist and neurobiologist, Nobel Prize laureate (d. 1994).

People (Deaths)

  • 1985 – Donald O. Hebb, Canadian psychologist and academic (b. 1904).

Roger Wolcott Sperry

Roger Wolcott Sperry (20 August 1913 to 17 April 1994) was an American neuropsychologist, neurobiologist and Nobel laureate who, together with David Hunter Hubel and Torsten Nils Wiesel, won the 1981 Nobel Prize in Physiology and Medicine for his work with split-brain research. A Review of General Psychology survey, published in 2002, ranked Sperry as the 44th most cited psychologist of the 20th century.

Education

Sperry went to Hall High School in West Hartford, Connecticut, where he was a star athlete in several sports, and did well enough academically to win a scholarship to Oberlin College. At Oberlin, he was captain of the basketball team, and he also took part in varsity baseball, football, and track. He also worked at a café on campus to help support himself. Sperry was an English major, but he took an Intro to Psychology class taught by a Professor named R.H. Stetson who had worked with William James, the father of American Psychology. This class sparked Sperry’s interest in the brain and how it can change. Stetson was disabled and had trouble getting around so Sperry would help him out by driving him to and from wherever he needed to go. This included taking Stetson to lunch with his colleagues. Sperry would just sit at the end of the table and listen to Stetson and his colleagues discuss their research and other psychological interests. This increased Sperry’s interest in Psychology even more and after he received his undergraduate degree in English from Oberlin he decided to stay and get his master’s degree in Psychology. He received his bachelor’s degree in English in 1935 and a master’s degree in psychology in 1937. He received his Ph.D. in zoology from the University of Chicago in 1941, supervised by Paul A. Weiss. Sperry then did postdoctoral research with Karl Lashley at Harvard University though most of his time was spent with Lashley at the Yerkes Primate Research Centre in Orange Park, Florida.

Career

In 1942, Sperry began work at the Yerkes Laboratories of Primate Biology, then a part of Harvard University. There he focused on experiments involving the rearranging of motor and sensory nerves. He left in 1946 to become an assistant professor, and later associate professor, at the University of Chicago. In 1949, during a routine chest x-ray, there was evidence of tuberculosis. He was sent to Saranac Lake in the Adironack Mountains in New York for treatment. It was during this time when he began writing his concepts of the mind and brain, and was first published in the American Scientist in 1952. In 1952, he became the Section Chief of Neurological Diseases and Blindness at the National Institutes of Health and finished out the year at the Marine Biology Laboratory in Coral Gables, Florida. Sperry went back to The University of Chicago in 1952 and became an Associate Professor of Psychology. He was not offered tenure at Chicago and planned to move to Bethesda, Maryland but was held up by a delay in construction at the National Institutes of Health. During this time Sperry’s friend Victor Hepburn invited him to lecture about his research at a symposium. There were professors from the California Institute of Technology in the audience of the symposium who, after listening to Sperry’s lecture, were so impressed with him they offered him a job as the Hixson Professor of Psychobiology. In 1954, he accepted the position as a professor at the California Institute of Technology (Caltech as Hixson Professor of Psychobiology) where he performed his most famous experiments with Joseph Bogen, MD and many students including Michael Gazzaniga.

Under the supervision of Paul Weiss while earning his Ph.D. at the University of Chicago, Sperry became interested in neuronal specificity and brain circuitry and began questioning the existing concepts about these two topics. He asked the simple question first asked in his Introduction to Psychology class at Oberlin: Nature or nurture? He began a series of experiments in an attempt to answer this question. Sperry crosswired the motor nerves of rats’ legs so the left nerve controlled the right leg and vice versa. He would then place the rats in a cage that had an electric grid on the bottom separated into four sections. Each leg of the rat was placed into one of the four sections of the electric grid. A shock was administered to a specific section of the grid, for example the grid where the rat’s left back leg was located would receive a shock. Every time the left paw was shocked the rat would lift his right paw and vice versa. Sperry wanted to know how long it would take the rat to realize he was lifting the wrong paw. After repeated tests Sperry found that the rats never learned to lift up the correct paw, leading him to the conclusion that some things are just hardwired and cannot be relearned. In Sperry’s words, “no adaptive functioning of the nervous system took place.” During Sperry’s postdoctoral years with Karl Lashley at Harvard and at the Yerkes Laboratories of Primate Biology in Orange Park, Florida, he continued his work on neuronal specificity that he had begun as a doctoral student and initiated a new series of studies involving salamanders. The optic nerves were sectioned and the eyes rotated 180 degrees. The question was whether vision would be normal after regeneration or would the animal forever view the world as “upside down” and right-left reversed. Should the latter prove to be the case, it would mean that the nerves were somehow “guided” back to their original sites of termination. Restoration of normal vision (i.e. “seeing” the world in a “right-side-up” orientation) would mean that the regenerating nerves had terminated in new sites, quite different from the original ones. The animals reacted as though the world was upside down and reversed from right to left. Furthermore, no amount of training could change the response. These studies, which provided strong evidence for nerve guidance by “intricate chemical codes under genetic control” (1963) culminated in Sperry’s chemoaffinity hypothesis (1951).

Sperry later served on the Board of Trustees and as Professor of Psychobiology Emeritus at California Institute of Technology. The Sperry Neuroscience Building at Oberlin College was named in his honour in 1990.

Donald O. Hebb

Donald Olding Hebb FRS (22 July 1904 to 20 August 1985) was a Canadian psychologist who was influential in the area of neuropsychology, where he sought to understand how the function of neurons contributed to psychological processes such as learning. He is best known for his theory of Hebbian learning, which he introduced in his classic 1949 work The Organisation of Behaviour. He has been described as the father of neuropsychology and neural networks. A Review of General Psychology survey, published in 2002, ranked Hebb as the 19th most cited psychologist of the 20th century. His views on learning described behaviour and thought in terms of brain function, explaining cognitive processes in terms of connections between neuron assemblies.

What is Fletazepam?

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Introduction

Fletazepam is a drug which is a benzodiazepine derivative. It has sedative and anxiolytic effects similar to those produced by other benzodiazepine derivatives, but is mainly notable for its strong muscle relaxant properties.

Fletazepam is most closely related to other N-trifluoroethyl substituted benzodiazepines such as halazepam and quazepam.

What is Clobazam?

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Introduction

Clobazam, sold under the brand name Frisium among 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.

Refer to Triflubazam.

Brief History

Clobazam was discovered at the Maestretti Research Laboratories in Milan and was first published in 1969; Maestretti was acquired by Roussel Uclaf which became part of Sanofi.

Medical Uses

Clobazam is used for its anxiolytic effect, and as an adjunctive therapy in epilepsy.

Clobazam is approved in Canada for add-on use in tonic-clonic, complex partial, and myoclonic seizures. Clobazam is approved for adjunctive therapy in complex partial seizures, certain types of status epilepticus, specifically the mycolonic, myoclonic-absent, simple partial, complex partial, and tonic varieties, and non-status absence seizures. It is also approved for the treatment of anxiety.

In India, clobazam is approved for use as an adjunctive therapy in epilepsy, and in acute and chronic anxiety. In Japan, clobazam is approved for adjunctive therapy in treatment-resistant epilepsy featuring complex partial seizures. In New Zealand, clobazam is marketed as Frisium In the United Kingdom clobazam (Frisium) is approved for short-term (2-4 weeks) relief of acute anxiety in patients who have not responded to other drugs, with or without insomnia and without uncontrolled clinical depression. It was not approved in the United States until 25 October 2011, when it was approved for the adjunctive treatment of seizures associated with Lennox-Gastaut syndrome in patients 2 years of age or older.

As an adjunctive therapy in epilepsy, it is used in patients who have not responded to first-line drugs and in children who are refractory to first-line drugs. It is unclear if there are any benefits to clobazam over other seizure medications for children with Rolandic epilepsy or other epileptic syndromes. It is not recommended for use in children between the ages of six months and three years, unless there is a compelling need. In addition to epilepsy and severe anxiety, clobazam is also approved as a short-term (2-4 weeks) adjunctive agent in schizophrenia and other psychotic disorders to manage anxiety or agitation.

Clobazam is sometimes used for refractory epilepsies. However, long-term prophylactic treatment of epilepsy may have considerable drawbacks, most importantly decreased antiepileptic effects due to drug tolerance which may render long-term therapy less effective. Other antiepileptic drugs may therefore be preferred for the long-term management of epilepsy. Furthermore, benzodiazepines may have the drawback, particularly after long-term use, of causing rebound seizures upon abrupt or over-rapid discontinuation of therapy forming part of the benzodiazepine withdrawal syndrome.

Contraindications

Clobazam should be used with great care in patients with the following disorders:

  • Myasthenia gravis.
  • Sleep apnoea.
  • Severe liver diseases such as cirrhosis and hepatitis.
  • Severe respiratory failure.

Benzodiazepines require special precaution if used in the elderly, during pregnancy, in children, alcohol or drug-dependent individuals, and individuals with comorbid psychiatric disorders.

Side Effects

In September 2020, the US Food and Drug Administration (FDA) required the boxed warning be updated for all benzodiazepine medicines to describe the risks of abuse, misuse, addiction, physical dependence, and withdrawal reactions consistently across all the medicines in the class.

Refer to Effects of Long-Term Benzodiazepine Use.

Common

Common side effects include fever, drooling, and constipation.

Post-Marketing Experience

  • Hives.
  • Rashes.

Warnings and Precautions

In December 2013, the FDA added warnings to the label for clobazam, that it can cause serious skin reactions, Stevens-Johnson syndrome, and toxic epidermal necrolysis, especially in the first eight weeks of treatment.

Drug Interactions

  • Alcohol increases bioavailability by 50%; compounded depressant effect may precipitate life-threatening toxicity.
  • Cimetidine increases the effects of clobazam.
  • Valproate.

Overdose

Overdose and intoxication with benzodiazepines, including clobazam, may lead to CNS depression, associated with drowsiness, confusion, and lethargy, possibly progressing to ataxia, respiratory depression, hypotension, and coma or death. The risk of a fatal outcome is increased in cases of combined poisoning with other CNS depressants, including alcohol.

Abuse Potential and Addiction

Refer to Benzodiazepine Use Disorder.

Classic (non-anxioselective) benzodiazepines in animal studies have been shown to increase reward-seeking behaviours which may suggest an increased risk of addictive behavioural patterns. Clobazam abuse has been reported in some countries, according to a 1983 World Health Organisation (WHO) report.

Dependence and Withdrawal

In humans, tolerance to the anticonvulsant effects of clobazam may occur and withdrawal seizures may occur during abrupt or over rapid withdrawal.

Clobazam as with other benzodiazepine drugs can lead to physical dependence, addiction, and what is known as the benzodiazepine withdrawal syndrome. Withdrawal from clobazam or other benzodiazepines after regular use often leads to withdrawal symptoms which are similar to those seen during alcohol and barbiturate withdrawal. The higher the dosage and the longer the drug is taken, the greater the risk of experiencing unpleasant withdrawal symptoms. Benzodiazepine treatment should only be discontinued via a slow and gradual dose reduction regimen.

Pharmacology

Clobazam is predominantly a positive allosteric modulator at the GABAA receptor with some speculated additional activity at sodium channels and voltage-sensitive calcium channels.

Like other 1,5-benzodiazepines (for example, arfendazam, lofendazam, or CP-1414S), the active metabolite N-desmethylclobazam has less affinity for the α1 subunit of the GABAA receptor compared to the 1,4-benzodiazepines. It has higher affinity for α2 containing receptors, where it has positive modulatory activity.

In a double-blind placebo-controlled trial published in 1990 comparing it to clonazepam, 10 mg of clobazam was shown to be less sedative than either 0.5 mg or 1 mg of clonazepam.

The α1 subtype of the GABAA receptor, was shown to be responsible for the sedative effects of diazepam by McKernan et al. in 2000, who also showed that its anxiolytic and anticonvulsant properties could still be seen in mice whose α1 receptors were insensitive to diazepam.

In 1996, Nakamura et al. reported that clobazam and its active metabolite, N-desmethylclobazam (norclobazam), work by enhancing GABA-activated chloride influx at GABAA receptors, creating a hyperpolarizing, inhibitory postsynaptic potential. It was also reported that these effects were inhibited by the GABA antagonist flumazenil, and that clobazam acts more efficiently in GABA-deficient brain tissue.

Metabolism

Clobazam has two major metabolites: N-desmethylclobazam and 4′-hydroxyclobazam, the former of which is active. The demethylation is facilitated by CYP2C19, CYP3A4, and CYP2B6 and the 4-hydroxyclobazam by CYP2C18 and CYP2C19.

Chemistry

Clobazam is a 1,5-benzodiazepine, meaning that its diazepine ring has nitrogen atoms at the 1 and 5 positions (instead of the usual 1 and 4).

It is not soluble in water and is available in oral form only.

What is Halazepam?

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Introduction

Halazepam is a benzodiazepine derivative that was marketed under the brand names Paxipam in the United States, Alapryl in Spain, and Pacinone in Portugal.

Medical Uses

Halazepam was used for the treatment of anxiety.

Adverse Effects

Adverse effects include drowsiness, confusion, dizziness, and sedation. Gastrointestinal side effects have also been reported including dry mouth and nausea.

Pharmacokinetics and Pharmacodynamics

Pharmacokinetics and pharmacodynamics were listed in Current Psychotherapeutic Drugs published on 15 June 1998 as follows:

  • Onset of action: Intermediate to slow.
  • Plasma half life: 14 hours for parent drug and 30-100 hours for its metabolite.
  • Peak plasma levels: 1-3 hours for parent drug and 3-6 hours for its metabolite.
  • Metabolism: Metabolised into desmethyldiazepam and 3-hydroxyhalazepam (in the liver).
  • Excretion: Excreted through kidneys.
  • Protein binding: 98% bound to plasma protein.

Regulatory Information

Halazepam is classified as a schedule 4 controlled substance with a corresponding code 2762 by the Drug Enforcement Administration (DEA).

Commercial Production

Halazepam was invented by Schlesinger Walter in the US. It was marketed as an anti-anxiety agent in 1981. However, Halazepam is not commercially available in the United States because it was withdrawn by its manufacturer for poor sales.

What is Imidazenil?

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Introduction

Imidazenil is an experimental anxiolytic drug which is derived from the benzodiazepine family, and is most closely related to other imidazobenzodiazepines such as midazolam, flumazenil, and bretazenil.

Outline

Imidazenil is a highly potent benzodiazepine receptor partial agonist with an unusual profile of effects, producing some of the effects associated with normal benzodiazepines such as anticonvulsant and anxiolytic effects, yet without any notable sedative or amnestic effects. In fact, imidazenil blocks the sedative effects of diazepam, yet without lowering the convulsion threshold, and so potentially could be a more flexible antidote than the antagonist flumazenil which is commonly used to treat benzodiazepine overdose at present.

As of August 2021, Imidazenil has not yet been developed commercially for use in humans, however it has been suggested as a safe and effective treatment for anxiety, a potent yet non-sedating anticonvulsant which might be particularly useful in the treatment of poisoning with organophosphate nerve agents, and as a novel treatment for schizophrenia.

Who was Heather Ashton?

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Introduction

Heather Ashton FRCP (11 July 1929 to 15 September 2019) was a British psychopharmacologist and physician. She is best known for her clinical and research work on benzodiazepene dependence.

Biography

Chrystal Heather Champion was born in Dehradun, northern India, to Harry Champion, a British silviculturalist, and Chrystal (Parsons) Champion, a secretary. From the age of six, she attended a boarding school in Swanage, Dorset, England. When WWII began, she was evacuated to West Chester, Pennsylvania; during the crossing, her ship was attacked by a U-boat.

Ashton went on to study Medicine at Somerville College, Oxford, graduating with a First Class Honours Degree (BA) in Physiology in 1951. She earned her medical degree (DM) in 1956. She completed professional training at Middlesex Hospital. She was elected as a Fellow of the Royal College of Physicians, London, in 1975.

In 1965, Ashton joined the faculty at Newcastle University, first in the Department of Pharmacology and later in the Department of Psychiatry. From 1982 to 1994, she ran a benzodiazepine withdrawal clinic at the Royal Victoria Infirmary in Newcastle. She was on the executive committee of the North East Council on Addictions. Ashton also helped set up the British organisation Victims of Tranquillisers (VOT). She also gave evidence to British government committees on tobacco smoking, cannabis and benzodiazepines.

Ashton died on 15 September 2019 at her home in Newcastle upon Tyne, at age 90.

Research

Ashton’s developed her expertise in the effects of psychoactive drugs and the effects of substances such as nicotine and cannabis on the brain.

During the 1960s, benzodiazepines, like diazepam and temazepam, had become popular and were seen as safe and effective treatments for anxiety or insomnia. One study found that the overdose death rate among patients taking both benzodiazepines and opioids was 10 times higher than among those who only took opioids.

Ashton’s research on these drugs found that they could be used in the short term, but could lead to physical dependence over the long-term. She also recognised that this benzodiazepine withdrawal syndrome was very different from those addicted to illegal drugs. This led to her writing an important manual to help those who were trying to stop their prescribed benzodiazepine. This manual is now used all over the world. This book, Benzodiazepines: How They Work and How to Withdraw, was first published in 1999; it has become known as the Ashton Manual and has been translated into 11 languages. Ashton’s research was influential, leading to changes in prescribing practices and guidelines recommended for benzodiazepines in 2013. Her research on psychotropic drugs led to over 200 journal articles, chapters and books, including over 50 papers concerning benzodiazepines alone.

What is Loprazolam?

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Introduction

Loprazolam (triazulenone) marketed under many brand names is a benzodiazepine medication.

It possesses anxiolytic, anticonvulsant, hypnotic, sedative and skeletal muscle relaxant properties. It is licensed and marketed for the short-term treatment of moderately-severe insomnia.

It was patented in 1975 and came into medical use in 1983.

Medical Uses

Insomnia can be described as a difficulty falling asleep, frequent awakening, early awakenings or a combination of each. Loprazolam is a short-acting benzodiazepine and is sometimes used in patients who have difficulty in maintaining sleep or have difficulty falling asleep. Hypnotics should only be used on a short-term basis or in those with chronic insomnia on an occasional basis.

Dose

The dose of loprazolam for insomnia is usually 1 mg but can be increased to 2 mg if necessary. In the elderly a lower dose is recommended due to more pronounced effects and a significant impairment of standing up to 11 hours after dosing of 1 mg of loprazolam. The half-life is much more prolonged in the elderly than in younger patients. A half-life of 19.8 hours has been reported in elderly patients. Patients and prescribing physicians should, however, bear in mind that higher doses of loprazolam may impair long-term memory functions.

Side Effects

Side effects of loprazolam are generally the same as for other benzodiazepines such as diazepam.[5] The most significant difference in side effects of loprazolam and diazepam is it is less prone to day time sedation as the half-life of loprazolam is considered to be intermediate whereas diazepam has a very long half-life. The side effects of loprazolam are the following:

  • Drowsiness.
  • Paradoxical increase in aggression.
  • Lightheadedness.
  • Confusion.
  • Muscle weakness.
  • Ataxia (particularly in the elderly).
  • Amnesia.
  • Headache.
  • Vertigo.
  • Hypotension.
  • Salivation changes.
  • Gastro-intestinal disturbances.
  • Visual disturbances.
  • Dysarthria.
  • Tremor.
  • Changes in libido.
  • Incontinence.
  • Urinary retention.
  • Blood disorders and jaundice.
  • Skin reactions.
  • Dependence and withdrawal reactions.

Residual ‘hangover’ effects after night-time administration of loprazolam such as sleepiness, impaired psychomotor and cognitive functions may persist into the next day which may increase risks of falls and hip fractures.

Tolerance, Dependence and Withdrawal

Loprazolam, like all other benzodiazepines, is recommended only for the short-term management of insomnia in the UK, owing to the risk of serious adverse effects such as tolerance, dependence and withdrawal, as well as adverse effects on mood and cognition. Benzodiazepines can become less effective over time, and patients can develop increasing physical and psychological adverse effects, e.g. agoraphobia, gastrointestinal complaints, and peripheral nerve abnormalities such as burning and tingling sensations.

Loprazolam has a low risk of physical dependence and withdrawal if it is used for less than 4 weeks or very occasionally. However, one placebo-controlled study comparing 3 weeks of treatment for insomnia with either loprazolam or triazolam showed rebound anxiety and insomnia occurring 3 days after discontinuing loprazolam therapy, whereas with triazolam the rebound anxiety and insomnia was seen the next day. The differences between the two are likely due to the differing elimination half-lives of the two drugs. These results would suggest that loprazolam and possibly other benzodiazepines should be prescribed for 1-2 weeks rather than 2-4 weeks to reduce the risk of physical dependence, withdrawal, and rebound phenomenon.

Withdrawal Symptoms

Slow reduction of the dosage over a period of months at a rate that the individual can tolerate greatly minimises the severity of the withdrawal symptoms. Individuals who are benzodiazepine dependent often cross to an equivalent dose of diazepam to taper gradually, as diazepam has a longer half-life and small dose reductions can be achieved more easily.

  • Anxiety and panic attacks.
  • Sweating.
  • Nightmares.
  • Insomnia.
  • Headache.
  • Tremor.
  • Nausea and vomiting.
  • Feelings of unreality.
  • Abnormal sensation of movement.
  • Hypersensitivity to stimuli.
  • Hyperventilation.
  • Flushing.
  • Sweating.
  • Palpitations.
  • Dimensional distortions of rooms and television pictures.
  • Paranoid thoughts and feelings of persecution.
  • Depersonalisation.
  • Fears of going mad.
  • Heightened perception of taste, smell, sound, and light; photophobia.
  • Agoraphobia.
  • Clinical depression.
  • Poor memory and concentration.
  • Aggression.
  • Excitability.
  • Somatic symptoms.
  • Numbness.
  • Altered sensations of the skin.
  • Pain.
  • Stiffness.
  • Weakness in the neck, head, jaw, and limbs.
  • Muscle fasciculation, ranging from twitches to jerks, affecting the legs or shoulders.
  • Ataxia.
  • Paraesthesia.
  • Influenza-like symptoms.
  • Blurred double vision.
  • Menorrhagia.
  • Loss of or dramatic gain in appetite.
  • Thirst with polyuria.
  • Urinary incontinence.
  • Dysphagia.
  • Abdominal pain.
  • Diarrhoea.
  • Constipation.

Major complications can occur after abrupt or rapid withdrawal, especially from high doses, producing symptoms such as:

  • Psychosis.
  • Confusion.
  • Visual and auditory hallucinations.
  • Delusions.
  • Epileptic seizures (which may be fatal).
  • Suicidal thoughts or actions.
  • Abnormal, often severe, drug seeking behaviour.

It has been estimated that between 30% and 50% of long-term users of benzodiazepines will experience withdrawal symptoms. However, up to 90% of patients withdrawing from benzodiazepines experienced withdrawal symptoms in one study, but the rate of taper was very fast at 25% of dose per week. Withdrawal symptoms tend to last between 3 weeks to 3 months, although 10-15% of people may experience a protracted benzodiazepine withdrawal syndrome with symptoms persisting and gradually declining over a period of many months and occasionally several years.

Contraindications and Special Caution

Benzodiazepines require special precaution if used in the elderly, during pregnancy, in children, alcohol or drug-dependent individuals and individuals with comorbid psychiatric disorders. Loprazolam, similar to other benzodiazepines and nonbenzodiazepine hypnotic drugs causes impairments in body balance and standing steadiness in individuals who wake up at night or the next morning. Falls and hip fractures are frequently reported. The combination with alcohol increases these impairments. Partial, but incomplete tolerance develops to these impairments.

Mechanism of Action

Loprazolam is a benzodiazepine, which acts via positively modulating the GABAA receptor complex via a binding to the benzodiazepine receptor which is situated on alpha subunit containing GABAA receptors. This action enhances the effect of the neurotransmitter GABA on the GABAA receptor complex by increasing the opening frequency of the chloride ion channel. This action allows more chloride ions to enter the neuron which in turn produces such effects as; muscle relaxation, anxiolytic, hypnotic, amnesic and anticonvulsant action. These properties can be used for therapeutic benefit in clinical practice. These properties are also sometimes used for recreational purposes in the form of drug abuse of benzodiazepines where high doses are used to achieve intoxication and or sedation.

Pharmacokinetics

After oral administration of loprazolam on an empty stomach, it takes 2 hours for serum concentration levels to peak, significantly longer than other benzodiazepine hypnotics. This delay brings into question the benefit of loprazolam for the treatment of insomnia when compared to other hypnotics (particularly when the major complaint is difficulty falling asleep instead of difficulty maintaining sleep for the entire night), although some studies show that loprazolam may induce sleep within half an hour, indicating rapid penetration into the brain. The peak plasma delay of loprazolam, therefore, may not be relevant to loprazolam’s efficacy as a hypnotic. If taken after a meal it can take even longer for loprazolam plasma levels to peak and peak levels may be lower than normal. Loprazolam significantly alters electrical activity in the brain as measured by EEG, with these changes becoming more pronounced as the dose increases. Roughly half of each dose is metabolized in humans to produce an active metabolite, (a piperazine with lesser potency), the other half is excreted unchanged. The half-life of the active metabolite is about the same as the parent compound loprazolam.

What is a GABA Receptor?

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Introduction

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 (also known as ionotropic receptors); whereas GABAB receptors are G protein-coupled receptors, also called metabotropic receptors.

Ligand-Gated Ion Channels

Ionotropic GABA receptors (iGABARs) are ligand-gated ion channel of the GABA receptors class which are activated by gamma-aminobutyric acid (GABA), and include:

  • GABAA receptors.
  • GABAA-ρ receptors.

The GABAB receptor, a G protein-coupled receptor, is the only metabotropic GABA receptor and its mechanism of action differs significantly from the ionotropic receptors. Functionally, in mature organisms, activation of these receptors typically results in neural inhibition, primarily via the influx of chloride ions, although exceptions to this general principle exist, such as during early development. Structurally, iGABARs are pentameric transmembrane ion channels, meaning they are made up of five subunits. Since there are several classes of subunits and a variety of genes encoding many members of these classes, a wide variety of structurally, and therefore functionally, distinct channels of iGABARs is observed.

GABAA Receptor

It has long been recognised that the fast response of neurons to GABA that is stimulated by bicuculline and picrotoxin is due to direct activation of an anion channel. This channel was subsequently termed the GABAA receptor. Fast-responding GABA receptors are members of a family of Cys-loop ligand-gated ion channels. Members of this superfamily, which includes nicotinic acetylcholine receptors, GABAA receptors, glycine and 5-HT3 receptors, possess a characteristic loop formed by a disulfide bond between two cysteine residues.

In ionotropic GABAA receptors, binding of GABA molecules to their binding sites in the extracellular part of the receptor triggers opening of a chloride ion-selective pore. The increased chloride conductance drives the membrane potential towards the reversal potential of the Cl¯ ion which is about -75 mV in neurons, inhibiting the firing of new action potentials. This mechanism is responsible for the sedative effects of GABAA allosteric agonists. In addition, activation of GABA receptors lead to the so-called shunting inhibition, which reduces the excitability of the cell independent of the changes in membrane potential.

There have been numerous reports of excitatory GABAA receptors. According to the excitatory GABA theory, this phenomenon is due to increased intracellular concentration of Cl¯ ions either during development of the nervous system or in certain cell populations. After this period of development, a chloride pump is upregulated and inserted into the cell membrane, pumping Cl− ions into the extracellular space of the tissue. Further openings via GABA binding to the receptor then produce inhibitory responses. Over-excitation of this receptor induces receptor remodelling and the eventual invagination of the GABA receptor. As a result, further GABA binding becomes inhibited and inhibitory postsynaptic potentials are no longer relevant.

However, the excitatory GABA theory has been questioned as potentially being an artefact of experimental conditions, with most data acquired in in-vitro brain slice experiments susceptible to un-physiological milieu such as deficient energy metabolism and neuronal damage. The controversy arose when a number of studies have shown that GABA in neonatal brain slices becomes inhibitory if glucose in perfusate is supplemented with ketone bodies, pyruvate, or lactate, or that the excitatory GABA was an artefact of neuronal damage. Subsequent studies from originators and proponents of the excitatory GABA theory have questioned these results, but the truth remained elusive until the real effects of GABA could be reliably elucidated in intact living brain. Since then, using technology such as in-vivo electrophysiology/imaging and optogenetics, two in-vivo studies have reported the effect of GABA on neonatal brain, and both have shown that GABA is indeed overall inhibitory, with its activation in the developing rodent brain not resulting in network activation, and instead leading to a decrease of activity.

GABA receptors influence neural function by coordinating with glutamatergic processes.

GABAA-ρ Receptor

A subclass of ionotropic GABA receptors, insensitive to typical allosteric modulators of GABAA receptor channels such as benzodiazepines and barbiturates, was designated GABAС receptor. Native responses of the GABAC receptor type occur in retinal bipolar or horizontal cells across vertebrate species.

GABAС receptors are exclusively composed of ρ (rho) subunits that are related to GABAA receptor subunits. Although the term “GABAС receptor” is frequently used, GABAС may be viewed as a variant within the GABAA receptor family. Others have argued that the differences between GABAС and GABAA receptors are large enough to justify maintaining the distinction between these two subclasses of GABA receptors. However, since GABAС receptors are closely related in sequence, structure, and function to GABAA receptors and since other GABAA receptors besides those containing ρ subunits appear to exhibit GABAС pharmacology, the Nomenclature Committee of the IUPHAR has recommended that the GABAС term no longer be used and these ρ receptors should be designated as the ρ subfamily of the GABAA receptors (GABAA-ρ).

G Protein-Coupled Receptors

GABAB Receptor

A subclass of ionotropic GABA receptors, insensitive to typical allosteric modulators of GABAA receptor channels such as benzodiazepines and barbiturates, was designated GABAС receptor. Native responses of the GABAC receptor type occur in retinal bipolar or horizontal cells across vertebrate species.

GABAС receptors are exclusively composed of ρ (rho) subunits that are related to GABAA receptor subunits. Although the term “GABAС receptor” is frequently used, GABAС may be viewed as a variant within the GABAA receptor family. Others have argued that the differences between GABAС and GABAA receptors are large enough to justify maintaining the distinction between these two subclasses of GABA receptors. However, since GABAС receptors are closely related in sequence, structure, and function to GABAA receptors and since other GABAA receptors besides those containing ρ subunits appear to exhibit GABAС pharmacology, the Nomenclature Committee of the IUPHAR has recommended that the GABAС term no longer be used and these ρ receptors should be designated as the ρ subfamily of the GABAA receptors (GABAA-ρ).

GABA Receptor Gene Polymorphisms

Two separate genes on two chromosomes control GABA synthesis – glutamate decarboxylase and alpha-ketoglutarate decarboxylase genes – though not much research has been done to explain this polygenic phenomenon. GABA receptor genes have been studied more in depth, and many have hypothesized about the deleterious effects of polymorphisms in these receptor genes. The most common single nucleotide polymorphisms (SNPs) occurring in GABA receptor genes rho 1, 2, and 3 (GABBR1, GABBR2, and GABBR3) have been more recently explored in literature, in addition to the potential effects of these polymorphisms. However, some research has demonstrated that there is evidence that these polymorphisms caused by single base pair variations may be harmful.

It was discovered that the minor allele of a single nucleotide polymorphism at GABBR1 known as rs1186902 is significantly associated with a later age of onset for migraines, but for the other SNPs, no differences were discovered between genetic and allelic variations in the control vs. migraine participants. Similarly, in a study examining SNPs in rho 1, 2, and 3, and their implication in essential tremor, a nervous system disorder, it was discovered that there were no differences in the frequencies of the allelic variants of polymorphisms for control vs. essential tremor participants. On the other hand, research examining the effect of SNPs in participants with restless leg syndrome found an “association between GABRR3rs832032 polymorphism and the risk for RLS, and a modifier effect of GABRA4 rs2229940 on the age of onset of RLS” – the latter of which is a modifier gene polymorphism. The most common GABA receptor SNPs do not correlate with deleterious health effects in many cases, but do in a few.

One significant example of a deleterious mutation is the major association between several GABA receptor gene polymorphisms and schizophrenia. Because GABA is integral to the release of inhibitory neurotransmitters which produce a calming effect and play a role in reducing anxiety, stress, and fear, it is not surprising that polymorphisms in these genes result in more consequences relating to mental health than to physical health. Of an analysis on 19 SNPs on various GABA receptor genes, five SNPs in the GABBR2 group were found to be significantly associated with schizophrenia, which produce the unexpected haplotype frequencies not found in the studies mentioned previously.

Several studies have verified association between alcohol use disorder and the rs279858 polymorphism on the GABRA2 gene e, and higher negative alcohol effects scores for individuals who were homozygous at six SNPs. Furthermore, a study examining polymorphisms in the GABA receptor beta 2 subunit gene found an association with schizophrenia and bipolar disorder, and examined three SNPs and their effects on disease frequency and treatment dosage. A major finding of this study was that functional psychosis should be conceptualised as a scale of phenotypes rather than distinct categories.

What is Flumazenil?

Published on by Andrew Marshall12 Comments

Introduction

Flumazenil (also known as flumazepil, code name Ro 15-1788) is a selective GABAA receptor antagonist administered via injection, otic insertion, or intranasally. Therapeutically, it acts as both an antagonist and antidote to benzodiazepines (particularly in cases of overdose), through competitive inhibition.

It was first characterised in 1981, and was first marketed in 1987 by Hoffmann-La Roche under the trade name Anexate. However, it did not receive US Food and Drug Administration (FDA) approval until 20 December 1991. The developer lost its exclusive patent rights in 2008; so at present, generic formulations of this drug are available. Intravenous flumazenil is primarily used to treat benzodiazepine overdoses and to help reverse anaesthesia. Administration of flumazenil by sublingual lozenge and topical cream has also been tested.

Medical Uses

Flumazenil benefits patients who become excessively drowsy after use of benzodiazepines for either diagnostic or therapeutic procedures.

The drug has been used as an antidote in the treatment of benzodiazepine overdoses. It reverses the effects of benzodiazepines by competitive inhibition at the benzodiazepine (BZ) recognition site on the GABA/benzodiazepine receptor complex. There are many complications that must be taken into consideration when used in the acute care setting. These include lowered seizure threshold, agitation, and anxiousness. Flumazenil’s short half-life requires multiple doses. Because of the potential risks of withdrawal symptoms and the drug’s short half-life, patients must be carefully monitored to prevent recurrence of overdose symptoms or adverse side effects.

Flumazenil is also sometimes used after surgery to reverse the sedative effects of benzodiazepines. This is similar to naloxone’s application to reverse the effect of opiates and opioids following surgery. Administration of the drug requires careful monitoring by an anaesthesiologist due to potential side effects and serious risks associated with over-administration. Likewise, post-surgical monitoring is also necessary because flumazenil can mask the apparent metabolisation (“wearing off”) of the drug after removal of patient life-support and monitoring equipment.

Flumazenil has been effectively used to treat overdoses of non-benzodiazepine hypnotics, such as zolpidem, zaleplon and zopiclone (also known as “Z-drugs”).

It may also be effective in reducing excessive daytime sleepiness while improving vigilance in primary hypersomnias, such as idiopathic hypersomnia.

The drug has also been used in hepatic encephalopathy. It may have beneficial short‐term effects in people with cirrhosis, but there is no evidence for long-term benefits.

The onset of action is rapid, and effects are usually seen within one to two minutes. The peak effect is seen at six to ten minutes. The recommended dose for adults is 200 μg every 1-2 minutes until the effect is seen, up to a maximum of 3 mg per hour. It is available as a clear, colourless solution for intravenous injection, containing 500 μg in 5 mL.

Many benzodiazepines (including midazolam) have longer half-lives than flumazenil. Therefore, in cases of overdose, repeat doses of flumazenil may be required to prevent recurrent symptoms once the initial dose of flumazenil wears off.

It is hepatically metabolised to inactive compounds which are excreted in the urine. Individuals who are physically dependent on benzodiazepines may suffer benzodiazepine withdrawal symptoms, including seizure, upon rapid administration of flumazenil.

It is not recommended for routine use in those with a decreased level of consciousness.

In terms of drug enforcement initiatives, diversion control programs and required post-marketing surveillance of adverse events, orders for flumazenil may trigger a prescription audit to the search for benzodiazepine misuse and for clinically significant adverse reactions related to their use.

PET Radioligand

Radiolabeled with the radioactive isotope carbon-11, flumazenil may be used as a radioligand in neuroimaging with positron emission tomography to visualize the distribution of GABAA receptors in the human brain.

Treatment for Benzodiazepine Dependence & Tolerance

Epileptic patients who have become tolerant to the anti-seizure effects of the benzodiazepine clonazepam became seizure-free for several days after treatment with 1.5 mg of flumazenil. Similarly, patients who were dependent on high doses of benzodiazepines (median dosage 333 mg diazepam-equivalent) were able to be stabilised on a low dose of clonazepam after 7-8 days of treatment with flumazenil.

Flumazenil has been tested against placebo in benzo-dependent subjects. Results showed that typical benzodiazepine withdrawal effects were reversed with few to no symptoms. Flumazenil was also shown to produce significantly fewer withdrawal symptoms than saline in a randomised, placebo-controlled study with benzodiazepine-dependent subjects. Additionally, relapse rates were much lower during subsequent follow-up.

In vitro studies of tissue cultured cell lines have shown that chronic treatment with flumazenil enhanced the benzodiazepine binding site where such receptors have become more numerous and uncoupling/down-regulation of GABAA has been reversed. After long-term exposure to benzodiazepines, GABAA receptors become down-regulated and uncoupled. Growth of new receptors and recoupling after prolonged flumazenil exposure has also been observed. It is thought this may be due to increased synthesis of receptor proteins.[20]

Flumazenil was found to be more effective than placebo in reducing feelings of hostility and aggression in patients who had been free of benzodiazepines for 4–266 weeks. This may suggest a role for flumazenil in treating protracted benzodiazepine withdrawal symptoms.

Low-dose, slow subcutaneous flumazenil administration is a safe procedure for patients withdrawing from long-term, high-dose benzodiazepine dependency. It has a low risk of seizures even amongst those who have experienced convulsions when previously attempting benzodiazepine withdrawal.

In Italy, the gold standard for treatment of high-dose benzodiazepine dependency is 8-10 days of low-dose, slowly infused flumazenil. One addiction treatment centre in Italy has used flumazenil to treat over 300 patients who were dependent on high doses of benzodiazepines (up to 70 times higher than conventionally prescribed) with physicians being among the clinic’s most common patients.

Clinical Pharmacology

Flumazenil, an imidazobenzodiazepine derivative, antagonizes the actions of benzodiazepines on the central nervous system. Flumazenil competitively inhibits the activity at the benzodiazepine recognition site on the GABA/benzodiazepine receptor complex. It also exhibits weak partial agonism of GABAA receptor complexes that contain α6-type monomers; the clinical relevance of this is unknown.

Flumazenil does not antagonize all of the central nervous system effects of drugs affecting GABA-ergic neurons by means other than the benzodiazepine receptor (including ethanol, barbiturates, and most anaesthetics) and does not reverse the effects of opioids. It will however antagonize the action of non-benzodiazepine z-drugs, such as zolpidem and zopiclone, because they act via the benzodiazepine site of the GABA receptor – it has been used to successfully treat z-drug overdose.

Pharmacodynamics

Intravenous flumazenil has been shown to antagonize sedation, impairment of recall, psychomotor impairment and ventilatory depression produced by benzodiazepines in healthy human volunteers.

The duration and degree of reversal of sedative benzodiazepine effects are related to the dose and plasma concentrations of flumazenil.

Availability

Flumazenil is sold under a wide variety of brand names worldwide like Anexate, Lanexat, Mazicon, Romazicon. In India it is manufactured by Roche Bangladesh Pharmaceuticals and USAN Pharmaceuticals.