Tag: GABAA

What is Bretazenil?

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Introduction

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 α5 GABAA benzodiazepine receptor complexes.

Brief History

Bretazenil was originally developed as an anti-anxiety drug and has been studied for its use as an anticonvulsant but has never commercialised. It is a partial agonist for GABAA receptors in the brain. David Nutt from the University of Bristol has suggested bretazenil as a possible base from which to make a better social drug, as it displays several of the positive effects of alcohol intoxication such as relaxation and sociability, but without the bad effects such as aggression, amnesia, nausea, loss of coordination, liver disease and brain damage. The effects of bretazenil can also be quickly reversed by the action of flumazenil, which is used as an antidote to benzodiazepine overdose, in contrast to alcohol for which there is no effective and reliable antidote.

Traditional benzodiazepines are associated with side effects such as drowsiness, physical dependence and abuse potential. It was hoped that bretazenil and other partial agonists would be an improvement on traditional benzodiazepines which are full agonists due to preclinical evidence that their side effect profile was less than that of full agonist benzodiazepines. For a variety of reasons however, bretazenil and other partial agonists such as pazinaclone and abecarnil were not clinically successful. However, research continues into other compounds with partial agonist and compounds which are selective for certain GABAA benzodiazepine receptor subtypes.

Tolerance and Dependence

In a study in rats, cross-tolerance between the benzodiazepine drug chlordiazepoxide and bretazenil has been demonstrated. In a primate study bretazenil was found to be able to replace the full agonist diazepam in diazepam dependent primates without precipitating withdrawal effects, demonstrating cross tolerance between bretazenil and benzodiazepine agonists, whereas other partial agonists precipitated a withdrawal syndrome. The differences are likely due to differences in intrinsic properties between different benzodiazepine partial agonists. Cross-tolerance has also been shown between bretazenil and full agonist benzodiazepines in rats. In rats tolerance is slower to develop to the anticonvulsant effects compared to the benzodiazepine site full agonist diazepam. However, tolerance developed to the anticonvulsant effects of bretazenil partial agonist more quickly than they developed to imidazenil.

Pharmacology

Bretazenil has a more broad spectrum of action than traditional benzodiazepines as it has been shown to have low affinity binding to α4 and α6 GABAA receptors in addition to acting on α1, α2, α3 and α5 subunits which traditional benzodiazepine drugs work on. The partial agonist imidazenil does not, however, act at these subunits. 0.5mg of bretazenil is approximately equivalent in its psychomotor-impairing effect to 10 mg of diazepam. Bretazenil produces marked sedative-hypnotic effects when taken alone and when combined with alcohol. This human study also indicates that bretazenil is possibly more sedative than diazepam. The reason is unknown, but the study suggests the possibility that a full-agonist metabolite may be generated in humans but not animals previously tested or else that there are significant differences in benzodiazepine receptor population in animals and humans.

In a study of monkeys bretazenil has been found to antagonize the effects of full agonist benzodiazepines. However, bretazenil has been found to enhance the effects of neurosteroids acting on the neurosteroid binding site of the GABAA receptor. Another study found that bretazenil acted as an antagonist provoking withdrawal symptoms in monkeys who were physically dependent on the full agonist benzodiazepine triazolam.

Partial agonists of benzodiazepine receptors have been proposed as a possible alternative to full agonists of the benzodiazepine site to overcome the problems of tolerance, dependence and withdrawal which limits the role of benzodiazepines in the treatment of anxiety, insomnia and epilepsy. Such adverse effects appear to be less problematic with bretazenil than full agonists. Bretazenil has also been found to have less abuse potential than benzodiazepine full agonists such as diazepam and alprazolam, however long-term use of bretazenil would still be expected to result in dependence and addiction.

Bretazenil alters the sleep EEG profile and causes a reduction in cortisol secretion and increases significantly the release of prolactin. Bretazenil has effective hypnotic properties but impairs cognitive ability in humans. Bretazenil causes a reduction in the number of movements between sleep stages and delays movement into REM sleep. At a dosage of 0.5 mg of bretazenil REM sleep is decreased and stage 2 sleep is lengthened.

What is Barbiturate Dependence?

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Introduction

Barbiturate dependence develops with regular use of barbiturates. This in turn may lead to a need for increasing doses of the drug to get the original desired pharmacological or therapeutic effect.

Refer to Barbiturate Overdose.

Background

Barbiturate use can lead to both addiction and physical dependence, and as such they have a high potential for excess or non-medical use, however, it does not affect all users. Management of barbiturate dependence involves considering the affected person’s age, comorbidity and the pharmacological pathways of barbiturates.

Psychological addiction to barbiturates can develop quickly. The patients will then have a strong desire to take any barbiturate-like drug. The chronic use of barbiturates leads to moderate degradation of the personality with narrowing of interests, passivity and loss of volition. The somatic signs include hypomimia, problems articulating, weakening of reflexes, and ataxia.

The GABAA receptor, one of barbiturates’ main sites of action, is thought to play a pivotal role in the development of tolerance to and dependence on barbiturates, as well as the euphoric “high” that results from their use. The mechanism by which barbiturate tolerance develops is believed to be different from that of ethanol or benzodiazepines, even though these drugs have been shown to exhibit cross-tolerance with each other and poly drug administration of barbiturates and alcohol used to be common.

The management of a physical dependence on barbiturates is stabilisation on the long-acting barbiturate phenobarbital followed by a gradual titration down of dose. People who use barbiturates tend to prefer rapid-acting barbiturates (amobarbital, pentobarbital, secobarbital) rather than long-acting barbiturates (barbital, phenobarbital). The slowly eliminated phenobarbital lessens the severity of the withdrawal syndrome and reduces the chances of serious barbiturate withdrawal effects such as seizures. A cold turkey withdrawal can in some cases lead to death. Antipsychotics are not recommended for barbiturate withdrawal (or other CNS depressant withdrawal states) especially clozapine, olanzapine or low potency phenothiazines e.g. chlorpromazine as they lower the seizure threshold and can worsen withdrawal effects; if used extreme caution is required. The withdrawal symptoms after ending barbiturate consumption are quite severe and last from 4 to 7 days.

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 Zolpidem?

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Introduction

Zolpidem, sold under the brand name Ambien, among others, is a medication primarily used for the short-term treatment of sleeping problems. Guidelines recommend that it be used only after cognitive behavioural therapy (CBT) for insomnia and behavioural changes, such as sleep hygiene, have been tried. It decreases the time to sleep onset by about fifteen minutes and at larger doses helps people stay asleep longer. It is taken by mouth and is available in conventional tablets, sublingual tablets, or oral spray.

Common side effects include daytime sleepiness, headache, nausea, and diarrhoea. Other side effects include memory problems, hallucinations, and substance abuse. The previously recommended dose was decreased in 2013, by the US Food and Drug Administration (FDA), to the immediate-release 10 mg for men, and 5 mg for women, in an attempt to reduce next-day somnolence. Newer extended-release formulations include the 6.25 mg for women, and 12.5 mg or 6.25 mg for men, which also cause next-day somnolence when used in higher doses. Additionally, driving the next morning is not recommended with either higher doses or the long-acting formulation. While flumazenil, a GABAA-receptor antagonist, can reverse zolpidem’s effects, usually supportive care is all that is recommended in overdose.

Zolpidem is a nonbenzodiazepine Z drug which acts as a sedative and hypnotic. Zolpidem is a GABAA receptor agonist of the imidazopyridine class. It works by increasing GABA effects in the central nervous system by binding to GABAA receptors at the same location as benzodiazepines. It generally has a half-life of two to three hours. This, however, is increased in those with liver problems.

Zolpidem was approved for medical use in the United States in 1992. It became available as a generic medication in 2007. Zolpidem is a Schedule IV controlled substance under the Controlled Substances Act of 1970 (CSA). More than ten million prescriptions are filled a year in the United States, making it one of the most commonly used treatments for sleeping problems. In 2018, it was the 60th most commonly prescribed medication in the United States, with more than 12 million prescriptions.

Brief History

Zolpidem was used in Europe starting in 1988, and was brought to market there by Synthelabo. Synthalabo and Searle collaborated to bring it to market in the US, and it was approved in the United States in 1992 under the brand name “Ambien”. It became available as a generic medication in 2007.

In 2015, the American Geriatrics Society said that zolpidem, eszopiclone, and zaleplon met the Beers criteria and should be avoided in individuals 65 and over “because of their association with harms balanced with their minimal efficacy in treating insomnia.” The AGS stated the strength of the recommendation that older adults avoid zolpidem is “strong” and the quality of evidence supporting it is “moderate.”

Medical Uses

Zolpidem is labelled for short-term (usually about two to six weeks) treatment of insomnia at the lowest possible dose. It may be used for both improving sleep onset, sleep onset latency, and staying asleep.

Guidelines from the UK’s National Institute for Health and Care Excellence (NICE), the European Sleep Research Society, and the American College of Physicians recommend medication for insomnia (including possibly zolpidem) only as a second line treatment after non-pharmacological treatment options have been tried (e.g. CBT for insomnia). This is based in part on a 2012 review which found that zolpidem’s effectiveness is nearly as much due to psychological effects as to the medication itself.

A lower-dose version (3.5 mg for men and 1.75 mg for women) is given as a tablet under the tongue and used for middle-of-the-night awakenings. It can be taken if there are at least 4 hours between the time of administration and when the person must be awake.

Contraindications

Zolpidem should not be taken by people with obstructive sleep apnoea, myasthenia gravis, severe liver disease, respiratory depression; or by children, or people with psychotic illnesses. It should not be taken by people who are or have been addicted to other substances.

Use of zolpidem may impair driving skills with a resultant increased risk of road traffic accidents. This adverse effect is not unique to zolpidem, but also occurs with other hypnotic drugs. Caution should be exercised by motor vehicle drivers. In 2013, the FDA recommended the dose for women be reduced and that prescribers should consider lower doses for men due to impaired function the day after taking the drug.

Zolpidem should not be prescribed to older people, who are more sensitive to the effects of hypnotics including zolpidem and are at an increased risk of falls and adverse cognitive effects, such as delirium and neurocognitive disorder.

Zolpidem has not been assigned to a pregnancy category by the FDA. Animal studies have revealed evidence of incomplete ossification and increased intrauterine foetal death at doses greater than seven times the maximum recommended human dose or higher; however, teratogenicity was not observed at any dose level. There are no controlled data in human pregnancy. In one case report, zolpidem was found in cord blood at delivery. Zolpidem is recommended for use during pregnancy only when benefits outweigh risks.

Adverse Effects

The most common adverse effects of:

  • Short-term use include headache (reported by 7% of people in clinical trials), drowsiness (2%), dizziness (1%), and diarrhoea (1%); and
  • Long-term use included drowsiness (8%), dizziness (5%), allergy (4%), sinusitis (4%), back pain (3%), diarrhoea (3%), drugged feeling (3%), dry mouth (3%), lethargy (3%), sore throat (3%), abdominal pain (2%), constipation (2%), heart palpitations (2%), lightheadedness (2%), rash (2%), abnormal dreams (1%), amnesia (1%), chest pain (1%), depression (1%), flu-like symptoms (1%), and sleep disorder (1%).

Zolpidem increases risk of depression, falls and bone fracture, poor driving, suppressed respiration, and has been associated with an increased risk of death. Upper and lower respiratory infections are also common (experienced by between 1 and 10% of people).

Residual ‘hangover’ effects, such as sleepiness and impaired psychomotor and cognitive function, may persist into the day following night-time administration. Such effects may impair the ability of users to drive safely and increase risks of falls and hip fractures. Around 3% of people taking zolpidem are likely to break a bone as a result of a fall due to impaired coordination caused by the drug.

Some users have reported unexplained sleepwalking while using zolpidem, as well as sleep driving, night eating syndrome while asleep, and performing other daily tasks while sleeping. Research by Australia’s National Prescribing Service found these events occur mostly after the first dose taken, or within a few days of starting therapy. In February 2008, the Australian Therapeutic Goods Administration attached a boxed warning concerning this adverse effect.

Tolerance, Dependence, and Withdrawal

As zolpidem is associated with drug tolerance and substance dependence, its prescription guidelines are only for severe insomnia and short periods of use at the lowest effective dose. Tolerance to the effects of zolpidem can develop in some people in just a few weeks. Abrupt withdrawal may cause delirium, seizures, or other adverse effects, especially if used for prolonged periods and at high doses. When drug tolerance and physical dependence to zolpidem develop, treatment usually entails a gradual dose reduction over a period of months to minimise withdrawal symptoms, which can resemble those seen during benzodiazepine withdrawal. Failing that, an alternative method may be necessary for some people, such as a switch to a benzodiazepine equivalent dose of a longer-acting benzodiazepine drug, as for diazepam or chlordiazepoxide, followed by a gradual reduction in dose of the long-acting benzodiazepine. In people who are difficult to treat, an inpatient flumazenil administration allows for rapid competitive binding of flumazenil to GABAA-receptor as an antagonist, thus stopping (a effectively detoxifying) zolpidem from being able to bind as an agonist on GABAA-receptor; slowly drug dependence or addiction to zolpidem will wane.

Alcohol has cross tolerance with GABAA receptor positive allosteric modulators, such as the benzodiazepines and the nonbenzodiazepine drugs. For this reason, alcoholics or recovering alcoholics may be at increased risk of physical dependency or abuse of zolpidem. It is not typically prescribed in people with a history of alcoholism, recreational drug use, physical dependency, or psychological dependency on sedative-hypnotic drugs. A 2014 review found evidence of drug-seeking behaviour, with prescriptions for zolpidem making up 20% of falsified or forged prescriptions.

Rodent studies of the tolerance-inducing properties have shown that zolpidem has less tolerance-producing potential than benzodiazepines, but in primates, the tolerance-producing potential of zolpidem was the same as seen with benzodiazepines.

Overdose

Overdose can lead to coma or death. When overdose occurs, there are often other drugs in the person’s system.

Zolpidem overdose can be treated with the GABAA receptor antagonist flumazenil, which displaces zolpidem from its binding site on the GABAA receptor to rapidly reverse the effects of the zolpidem. It is unknown if dialysis is helpful.

Detection in Body Fluids

Zolpidem may be quantitated in blood or plasma to confirm a diagnosis of poisoning in people who are hospitalized, to provide evidence in an impaired driving arrest, or to assist in a medicolegal death investigation. Blood or plasma zolpidem concentrations are usually in a range of 30-300 μg/l in persons receiving the drug therapeutically, 100-700 μg/l in those arrested for impaired driving, and 1000-7000 μg/l in victims of acute overdosage. Analytical techniques, in general, involve gas or liquid chromatography.

Pharmacology

Mechanism of Action

Zolpidem is a ligand of high-affinity positive modulator sites of GABAA receptors, which enhances GABAergic inhibition of neurotransmission in the central nervous system. It selectively binds to α1 subunits of this pentameric ion channel. Accordingly, it has strong hypnotic properties and weak anxiolytic, myorelaxant, and anticonvulsant properties. Opposed to diazepam, zolpidem is able to bind to binary αβ GABA receptors, where it was shown to bind to the α1–α1 subunit interface. Zolpidem has about 10-fold lower affinity for the α2- and α3- subunits than for α1, and no appreciable affinity for α5 subunit-containing receptors. ω1 type GABAA receptors are the α1-containing GABAA receptors and are found primarily in the brain, the ω2 receptors are those that contain the α2-, α3-, α4-, α5-, or α6 subunits, and are found primarily in the spine. Thus, zolpidem favours binding to GABAA receptors located in the brain rather the spine. Zolpidem has no affinity for γ1 and γ3 subunit-containing receptors and, like the vast majority of benzodiazepine-like drugs, it lacks affinity for receptors containing α4 and α6. Zolpidem modulates the receptor presumably by inducing a receptor conformation that enables an increased binding strength of the orthosteric agonist GABA towards its cognate receptor without affecting desensitization or peak currents.

Like zaleplon, zolpidem may increase slow wave sleep but cause no effect on stage 2 sleep. A meta-analysis that compared benzodiazepines against nonbenzodiazepines has shown few consistent differences between zolpidem and benzodiazepines in terms of sleep onset latency, total sleep duration, number of awakenings, quality of sleep, adverse events, tolerance, rebound insomnia, and daytime alertness.

Interactions

People should not consume alcohol while taking zolpidem, and should not be prescribed opioid drugs nor take such illicit drugs recreationally. Opioids can also increase the risk of becoming psychologically dependent on zolpidem. Use of opioids with zolpidem increases the risk of respiratory depression and death. the FDA is advising that the opioid addiction medications buprenorphine and methadone should not be withheld from patients taking benzodiazepines or other drugs that depress the central nervous system (CNS).

Next day sedation can be worsened if people take zolpidem while they are also taking antipsychotics, other sedatives, anxiolytics, antidepressant agents, antiepileptic drugs, and antihistamines. Some people taking antidepressants have had visual hallucinations when they also took zolpidem.

Cytochrome P450 inhibitors, particularly CYP3A4 and CYP1A2 inhibitors, fluvoxamine and ciprofloxacin will increase the effects of a given dose of zolpidem.

Cytochrome P450 activators like St. John’s Wort may decrease the activity of zolpidem.

Chemistry

Three syntheses of zolpidem are common. 4-methylacetophenone is used as a common precursor. This is brominated and reacted with 2-amino-5-methylpyridine to give the imidazopyridine. From here the reactions use a variety of reagents to complete the synthesis, either involving thionyl chloride or sodium cyanide. These reagents are challenging to handle and require thorough safety assessments. Though such safety procedures are common in industry, they make clandestine manufacture difficult.

A number of major side-products of the sodium cyanide reaction have been characterised and include dimers and mannich products.

Society and Culture

Prescriptions in the US for all sleeping pills (including zolpidem) steadily declined from around 57 million tablets in 2013, to around 47 million in 2017, possibly in relation to concern about prescribing addictive drugs in the midst of the opioid crisis.

Military Use

The United States Air Force uses zolpidem as one of the hypnotics approved as a “no-go pill” (with a six-hour restriction on subsequent flight operation) to help aviators and special duty personnel sleep in support of mission readiness. (The other hypnotics used are temazepam and zaleplon.) “Ground tests” are required prior to authorization issued to use the medication in an operational situation.

Recreational Use

Zolpidem has potential for either medical misuse when the drug is continued long term without or against medical advice, or for recreational use when the drug is taken to achieve a “high”. The transition from medical use of zolpidem to high-dose addiction or drug dependence can occur with use, but some believe it may be more likely when used without a doctor’s recommendation to continue using it, when physiological drug tolerance leads to higher doses than the usual 5 mg or 10 mg, when consumed through inhalation or injection, or when taken for purposes other than as a sleep aid. Recreational use is more prevalent in those having been dependent on other drugs in the past, but tolerance and drug dependence can still sometimes occur in those without a history of drug dependence. Chronic users of high doses are more likely to develop physical dependence on the drug, which may cause severe withdrawal symptoms, including seizures, if abrupt withdrawal from zolpidem occurs.

Other drugs, including the benzodiazepines and zopiclone, are also found in high numbers of suspected drugged drivers. Many drivers have blood levels far exceeding the therapeutic dose range, suggesting a high degree of excessive-use potential for benzodiazepines, zolpidem and zopiclone. US Congressman Patrick J. Kennedy says that he was using zolpidem (Ambien) and promethazine (Phenergan) when caught driving erratically at 3 a.m. “I simply do not remember getting out of bed, being pulled over by the police, or being cited for three driving infractions,” Kennedy said.

Nonmedical use of zolpidem is increasingly common in the US, Canada, and the UK. Some users have reported decreased anxiety, mild euphoria, perceptual changes, visual distortions, and hallucinations. Zolpidem was used by Australian Olympic swimmers at the London Olympics in 2012, leading to controversy.

Regulation

For the stated reason of its potential for recreational use and dependence, zolpidem (along with the other benzodiazepine-like Z-drugs) is a Schedule IV substance under the Controlled Substances Act in the US. The United States patent for zolpidem was held by the French pharmaceutical corporation Sanofi-Aventis.

Use in Crime

The Z-drugs including zolpidem have been used as date rape drugs. Zolpidem is available legally by prescription, and broadly prescribed unlike other date rape drugs: gamma-hydroxybutyrate (GHB), which is used to treat a rare form of narcolepsy, or flunitrazepam (Rohypnol), which is only prescribed as a second-line choice for insomnia. Zolpidem can typically be detected in bodily fluids for 36 hours, though it may be possible to detect it by hair testing much later, which is due to the short elimination half-life of 2.5-3 hours. This use of the drug was highlighted during proceedings against Darren Sharper, who was accused of using the tablets he was prescribed to facilitate a series of rapes.

Sleepwalking

Zolpidem received widespread media coverage in Australia after the death of a student who fell 20 metres (66 ft) from the Sydney Harbour Bridge while under the influence of zolpidem.

Brands

As of September 2018, zolpidem was marketed under many brands: Adorma, Albapax, Ambien, Atrimon, Belbien, Bikalm, Cymerion, Dactive, Dalparan, Damixan, Dormeben, Dormilam, Dormilan, Dormizol, Eanox, Edluar, Flazinil, Fulsadem, Hypnogen, Hypnonorm, Intermezzo, Inzofresh, Ivadal, Ivedal, Le Tan, Lioram, Lunata, Medploz, Mondeal, Myslee, Nasen, Niterest, Nocte, Nottem, Noxidem, Noxizol, Nuo Bin, Nytamel, Nyxe, Olpitric, Onirex, Opsycon, Patz, Polsen, Sanval, Semi-Nax, Sleepman, Somex, Somidem, Somit, Somnil, Somnipax, Somnipron, Somno, Somnogen, Somnor, Sonirem, Sove, Soza, Stilnoct, Stilnox, Stilpidem, Stimin, Sublinox, Sucedal, Sumenan, Vicknox, Viradex, Xentic, Zasan, Zaviana, Ziohex, Zipsoon, Zodem, Zodenox, Zodium, Zodorm, Zolcent, Zoldem, Zoldorm, Zoldox, Zolep, Zolfresh, Zolip, Zolman, Zolmia, Zolnox, Zolnoxs, Zolodorm, Zolnyt, Zolpeduar, Zolpel, Zolpi, Zolpi-Q, Zolpic, Zolpidem, Zolpidem tartrate, Zolpidemi tartras, Zolpidemtartraat, Zolpidemtartrat, Zolpidemum, Zolpigen, Zolpihexal, Zolpimist, Zolpineo, Zolpinox, Zolpirest, Zolpistar, Zolpitop, Zolpitrac, Zolpium, Zolprem, Zolsana, Zolta, Zoltar, Zolway, Zomnia, Zonadin, Zonoct, Zopid, Zopidem, Zopim, and Zorimin.

Research

While cases of zolpidem improving aphasia in people with stroke have been described, use for this purpose has unclear benefit. Zolpidem has also been studied in persistent vegetative states with unclear effect. A 2017 systematic review concluded that while there is preliminary evidence of benefit for treating disorders of movement and consciousness other than insomnia (including Parkinson’s disease), more research is needed. More recent research has found zolpidem treatment to be effective in the short term, but only in a small proportion of cases (estimated at around 5%) and only when the brain injury is of a specific type. Tolerance to the beneficial effects also develops rapidly, and so for these reasons while zolpidem may sometimes be used as a “last resort” treatment, it has numerous disadvantages and research continues into novel treatments that might provide the same kind of benefits in a larger proportion of patients, and with a more sustained benefit.

Animal studies in FDA files for zolpidem showed a dose dependent increase in some types of tumours, although the studies were too small to reach statistical significance. Some observational epidemiological studies have found a correlation between use of benzodiazepines and certain hypnotics including zolpidem and an increased risk of getting cancer, but others have found no correlation; a 2017 meta-analysis of such studies found a correlation, stating that use of hypnotics was associated with a 29% increased risk of cancer, and that “zolpidem use showed the strongest risk of cancer” with an estimated 34% increased risk, but noted that the results were tentative because some of the studies failed to control for confounders like cigarette smoking and alcohol use, and some of the studies analysed were case-controls, which are more prone to some forms of bias. Similarly, a meta-analysis of benzodiazepine drugs also shows their use is associated with increased risk of cancer.

What is Gamma-Aminobutyric Acid?

Published on by Andrew Marshall38 Comments

Introduction

gamma-Aminobutyric acid (or γ-aminobutyric acid or GABA), is the chief inhibitory neurotransmitter in the developmentally mature mammalian central nervous system. Its principal role is reducing neuronal excitability throughout the nervous system.

GABA is sold as a dietary supplement in many countries. It has been traditionally thought that exogenous GABA (i.e. taken as a supplement) does not cross the blood-brain barrier, however data obtained from more current research indicates that it may be possible.

Brief History

In 1883, GABA was first synthesized, and it was first known only as a plant and microbe metabolic product.

In 1950, GABA was discovered as an integral part of the mammalian central nervous system.

In 1959, it was shown that at an inhibitory synapse on crayfish muscle fibres GABA acts like stimulation of the inhibitory nerve. Both inhibition by nerve stimulation and by applied GABA are blocked by picrotoxin.

Function

Neurotransmitter

Refer to GABA Receptor.

Two general classes of GABA receptor are known:

  • GABAA in which the receptor is part of a ligand-gated ion channel complex; and
  • GABAB metabotropic receptors, which are G protein-coupled receptors that open or close ion channels via intermediaries (G proteins).

Neurons that produce GABA as their output are called GABAergic neurons, and have chiefly inhibitory action at receptors in the adult vertebrate. Medium spiny cells are a typical example of inhibitory central nervous system GABAergic cells. In contrast, GABA exhibits both excitatory and inhibitory actions in insects, mediating muscle activation at synapses between nerves and muscle cells, and also the stimulation of certain glands. In mammals, some GABAergic neurons, such as chandelier cells, are also able to excite their glutamatergic counterparts.

Release, Reuptake, and Metabolism Cycle of GABA.

GABAA receptors are ligand-activated chloride channels: when activated by GABA, they allow the flow of chloride ions across the membrane of the cell. Whether this chloride flow is depolarising (makes the voltage across the cell’s membrane less negative), shunting (has no effect on the cell’s membrane potential), or inhibitory/hyperpolarising (makes the cell’s membrane more negative) depends on the direction of the flow of chloride. When net chloride flows out of the cell, GABA is depolarising; when chloride flows into the cell, GABA is inhibitory or hyperpolarising. When the net flow of chloride is close to zero, the action of GABA is shunting. Shunting inhibition has no direct effect on the membrane potential of the cell; however, it reduces the effect of any coincident synaptic input by reducing the electrical resistance of the cell’s membrane. Shunting inhibition can “override” the excitatory effect of depolarising GABA, resulting in overall inhibition even if the membrane potential becomes less negative. It was thought that a developmental switch in the molecular machinery controlling the concentration of chloride inside the cell changes the functional role of GABA between neonatal and adult stages. As the brain develops into adulthood, GABA’s role changes from excitatory to inhibitory.

Brain Development

While GABA is an inhibitory transmitter in the mature brain, its actions were thought to be primarily excitatory in the developing brain. The gradient of chloride was reported to be reversed in immature neurons, with its reversal potential higher than the resting membrane potential of the cell; activation of a GABA-A receptor thus leads to efflux of Cl− ions from the cell (that is, a depolarising current). The differential gradient of chloride in immature neurons was shown to be primarily due to the higher concentration of NKCC1 co-transporters relative to KCC2 co-transporters in immature cells. GABAergic interneurons mature faster in the hippocampus and the GABA signalling machinery appears earlier than glutamatergic transmission. Thus, GABA is considered the major excitatory neurotransmitter in many regions of the brain before the maturation of glutamatergic synapses.

In the developmental stages preceding the formation of synaptic contacts, GABA is synthesized by neurons and acts both as an autocrine (acting on the same cell) and paracrine (acting on nearby cells) signalling mediator. The ganglionic eminences also contribute greatly to building up the GABAergic cortical cell population.

GABA regulates the proliferation of neural progenitor cells, the migration and differentiation the elongation of neurites and the formation of synapses.

GABA also regulates the growth of embryonic and neural stem cells. GABA can influence the development of neural progenitor cells via brain-derived neurotrophic factor (BDNF) expression. GABA activates the GABAA receptor, causing cell cycle arrest in the S-phase, limiting growth.

Beyond the Nervous System

Besides the nervous system, GABA is also produced at relatively high levels in the insulin-producing β-cells of the pancreas. The β-cells secrete GABA along with insulin and the GABA binds to GABA receptors on the neighbouring islet α-cells and inhibits them from secreting glucagon (which would counteract insulin’s effects).

GABA can promote the replication and survival of β-cells and also promote the conversion of α-cells to β-cells, which may lead to new treatments for diabetes.

Alongside GABAergic mechanisms, GABA has also been detected in other peripheral tissues including intestines, stomach, Fallopian tubes, uterus, ovaries, testes, kidneys, urinary bladder, the lungs and liver, albeit at much lower levels than in neurons or β-cells.

Experiments on mice have shown that hypothyroidism induced by fluoride poisoning can be halted by administering GABA. The test also found that the thyroid recovered naturally without further assistance after the Fluoride had been expelled by the GABA.

Immune cells express receptors for GABA and administration of GABA can suppress inflammatory immune responses and promote “regulatory” immune responses, such that GABA administration has been shown to inhibit autoimmune diseases in several animal models.

In 2018, GABA has shown to regulate secretion of a greater number of cytokines. In plasma of T1D patients, levels of 26 cytokines are increased and of those, 16 are inhibited by GABA in the cell assays.

In 2007, an excitatory GABAergic system was described in the airway epithelium. The system is activated by exposure to allergens and may participate in the mechanisms of asthma. GABAergic systems have also been found in the testis and in the eye lens.

GABA occurs in plants.

Structure and Conformation

GABA is found mostly as a zwitterion (i.e. with the carboxyl group deprotonated and the amino group protonated). Its conformation depends on its environment. In the gas phase, a highly folded conformation is strongly favoured due to the electrostatic attraction between the two functional groups. The stabilisation is about 50 kcal/mol, according to quantum chemistry calculations. In the solid state, an extended conformation is found, with a trans conformation at the amino end and a gauche conformation at the carboxyl end. This is due to the packing interactions with the neighbouring molecules. In solution, five different conformations, some folded and some extended, are found as a result of solvation effects. The conformational flexibility of GABA is important for its biological function, as it has been found to bind to different receptors with different conformations. Many GABA analogues with pharmaceutical applications have more rigid structures in order to control the binding better.

Biosynthesis

GABA is primarily synthesized from glutamate via the enzyme glutamate decarboxylase (GAD) with pyridoxal phosphate (the active form of vitamin B6) as a cofactor. This process converts glutamate (the principal excitatory neurotransmitter) into GABA (the principal inhibitory neurotransmitter).

GABA can also be synthesized from putrescine by diamine oxidase and aldehyde dehydrogenase.

Traditionally it was thought that exogenous GABA did not penetrate the blood–brain barrier, however more current research indicates that it may be possible, or that exogenous GABA (i.e. in the form of nutritional supplements) could exert GABAergic effects on the enteric nervous system which in turn stimulate endogenous GABA production. The direct involvement of GABA in the glutamate-glutamine cycle makes the question of whether GABA can penetrate the blood-brain barrier somewhat misleading, because both glutamate and glutamine can freely cross the barrier and convert to GABA within the brain.

Metabolism

GABA transaminase enzymes catalyse the conversion of 4-aminobutanoic acid (GABA) and 2-oxoglutarate (α-ketoglutarate) into succinic semialdehyde and glutamate. Succinic semialdehyde is then oxidized into succinic acid by succinic semialdehyde dehydrogenase and as such enters the citric acid cycle as a usable source of energy.

Pharmacology

Drugs that act as allosteric modulators of GABA receptors (known as GABA analogues or GABAergic drugs), or increase the available amount of GABA, typically have relaxing, anti-anxiety, and anti-convulsive effects. Many of the substances below are known to cause anterograde amnesia and retrograde amnesia.

In general, GABA does not cross the blood-brain barrier, although certain areas of the brain that have no effective blood–brain barrier, such as the periventricular nucleus, can be reached by drugs such as systemically injected GABA. At least one study suggests that orally administered GABA increases the amount of human growth hormone (HGH). GABA directly injected to the brain has been reported to have both stimulatory and inhibitory effects on the production of growth hormone, depending on the physiology of the individual. Certain pro-drugs of GABA (e.g. picamilon) have been developed to permeate the blood-brain barrier, then separate into GABA and the carrier molecule once inside the brain. Prodrugs allow for a direct increase of GABA levels throughout all areas of the brain, in a manner following the distribution pattern of the pro-drug prior to metabolism.

GABA enhanced the catabolism of serotonin into N-acetylserotonin (the precursor of melatonin) in rats. It is thus suspected that GABA is involved in the synthesis of melatonin and thus might exert regulatory effects on sleep and reproductive functions.

Chemistry

Although in chemical terms, GABA is an amino acid (as it has both a primary amine and a carboxylic acid functional group), it is rarely referred to as such in the professional, scientific, or medical community. By convention the term “amino acid”, when used without a qualifier, refers specifically to an alpha amino acid. GABA is not an alpha amino acid, meaning the amino group is not attached to the alpha carbon. Nor is it incorporated into proteins as are many alpha-amino acids.

GABAergic Drugs

GABAA receptor ligands are shown in the following table.

Activity at GABAALigand
Orthosteric AgonistMuscimol, GABA, gaboxadol (THIP), isoguvacine, progabide, piperidine-4-sulfonic acid (partial agonist).
Positive allosteric modulatorsBarbiturates, benzodiazepines, neuroactive steroids, niacin/niacinamide, nonbenzodiazepines (i.e. z-drugs, e.g. zolpidem, eszopiclone), etomidate, etaqualone, alcohol (ethanol), theanine, methaqualone, propofol, stiripentol, and anaesthetics (including volatile anaesthetics), glutethimide.
Orthosteric (competitive) AntagonistBicuculline, gabazine, thujone, and flumazenil.
Uncompetitive antagonist (e.g. channel blocker)Picrotoxin, and cicutoxin.
Negative allosteric modulatorsNeuroactive steroids (Pregnenolone sulfate), furosemide, oenanthotoxin, and amentoflavone.

Additionally, carisoprodol is an enhancer of GABAA activity. Ro15-4513 is a reducer of GABAA activity

GABAergic pro-drugs include chloral hydrate, which is metabolised to trichloroethanol, which then acts via the GABAA receptor.

Skullcap and valerian are plants containing GABAergic substances[citation needed]. Furthermore, the plant kava contains GABAergic compounds, including kavain, dihydrokavain, methysticin, dihydromethysticin and yangonin.

Other GABAergic modulators include:

  • GABAB receptor ligands.
    • Agonists: baclofen, propofol, GHB, and phenibut.
    • Antagonists: phaclofen and saclofen.
  • GABA reuptake inhibitors: deramciclane, hyperforin, and tiagabine.
  • GABA transaminase inhibitors: gabaculine, phenelzine, valproate, vigabatrin, and lemon balm (Melissa officinalis).
  • GABA analogues: pregabalin, gabapentin, picamilon, and progabide.

In Plants

GABA is also found in plants. It is the most abundant amino acid in the apoplast of tomatoes. Evidence also suggests a role in cell signalling in plants.