A heterocyclic compound or ring structure is a cyclic compound that has atoms of at least two different elements as members of its ring. Heterocyclic chemistry is the branch of organic chemistry dealing with the synthesis and applications of these heterocycles. Examples of heterocyclic compounds include all of the nucleic acids, the majority of drugs, most biomass, many natural and synthetic dyes. Although heterocyclic chemical compounds may be inorganic compounds or organic compounds, most contain at least one carbon. While atoms that are neither carbon nor hydrogen are referred to in organic chemistry as heteroatoms, this is in comparison to the all-carbon backbone, but this does not prevent a compound such as borazine from being labelled "heterocyclic". IUPAC recommends the Hantzsch-Widman nomenclature for naming heterocyclic compounds. Heterocyclic compounds can be usefully classified based on their electronic structure; the saturated heterocycles behave like the acyclic derivatives. Thus and tetrahydrofuran are conventional amines and ethers, with modified steric profiles.
Therefore, the study of heterocyclic chemistry focuses on unsaturated derivatives, the preponderance of work and applications involves unstrained 5- and 6-membered rings. Included are pyridine, thiophene and furan. Another large class of heterocycles are fused to benzene rings, which for pyridine, thiophene and furan are quinoline, benzothiophene and benzofuran, respectively. Fusion of two benzene rings gives rise to a third large family of compounds the acridine, dibenzothiophene and dibenzofuran; the unsaturated rings can be classified according to the participation of the heteroatom in the conjugated system, pi system. Heterocycles with three atoms in the ring are more reactive because of ring strain; those containing one heteroatom are, in general, stable. Those with two heteroatoms are more to occur as reactive intermediates. Common 3-membered heterocycles with one heteroatom are: Those with two heteroatoms include: Compounds with one heteroatom: Compounds with two heteroatoms: With heterocycles containing five atoms, the unsaturated compounds are more stable because of aromaticity.
The 5-membered ring compounds containing two heteroatoms, at least one of, nitrogen, are collectively called the azoles. Thiazoles and isothiazoles contain a nitrogen atom in the ring. Dithiolanes have two sulfur atoms. A large group of 5-membered ring compounds with three heteroatoms exists. One example is dithiazoles that contain a nitrogen atom. Six-membered rings with a single heteroatom: With two heteroatoms: With three heteroatoms: With four heteroatoms: With five heteroatoms: The hypothetical compound with six nitrogen heteroatoms would be hexazine. With 7-membered rings, the heteroatom must be able to provide an empty pi orbital for "normal" aromatic stabilization to be available. Compounds with one heteroatom include: Those with two heteroatoms include: Names in italics are retained by IUPAC and they do not follow the Hantzsch-Widman nomenclature Heterocyclic rings systems that are formally derived by fusion with other rings, either carbocyclic or heterocyclic, have a variety of common and systematic names.
For example, with the benzo-fused unsaturated nitrogen heterocycles, pyrrole provides indole or isoindole depending on the orientation. The pyridine analog is isoquinoline. For azepine, benzazepine is the preferred name; the compounds with two benzene rings fused to the central heterocycle are carbazole and dibenzoazepine. Thienothiophene are the fusion of two thiophene rings. Phosphaphenalenes are a tricyclic phosphorus-containing heterocyclic system derived from the carbocycle phenalene; the history of heterocyclic chemistry began in the 1800s, in step with the development of organic chemistry. Some noteworthy developments: 1818: Brugnatelli isolates alloxan from uric acid 1832: Dobereiner produces furfural by treating starch with sulfuric acid 1834: Runge obtains pyrrole by dry distillation of bones 1906: Friedlander synthesizes indigo dye, allowing synthetic chemistry to displace a large agricultural industry 1936: Treibs isolates chlorophyl derivatives from crude oil, explaining the biological origin of petroleum.
1951: Chargaff's rules are described, highlighting the role of heterocyclic compounds in the genetic code. Heterocyclic compounds are pervasive in many areas of technology. Many drugs are heterocyclic compounds. Hantzsch-Widman nomenclature, IUPAC Heterocyclic amines in cooked meat, US CDC List of known and probable carcinogens, American Cancer Society List of known carcinogens by the State of California, Proposition 65
Neurotransmitters are endogenous chemicals that enable neurotransmission. It is a type of chemical messenger which transmits signals across a chemical synapse, such as a neuromuscular junction, from one neuron to another "target" neuron, muscle cell, or gland cell. Neurotransmitters are released from synaptic vesicles in synapses into the synaptic cleft, where they are received by neurotransmitter receptors on the target cells. Many neurotransmitters are synthesized from simple and plentiful precursors such as amino acids, which are available from the diet and only require a small number of biosynthetic steps for conversion. Neurotransmitters play a major role in shaping everyday life and functions, their exact numbers are unknown, but more than 200 chemical messengers have been uniquely identified. Neurotransmitters are stored in synaptic vesicles, clustered close to the cell membrane at the axon terminal of the presynaptic neuron. Neurotransmitters are released into and diffuse across the synaptic cleft, where they bind to specific receptors on the membrane of the postsynaptic neuron.
Most neurotransmitters are about the size of a single amino acid. A released neurotransmitter is available in the synaptic cleft for a short time before it is metabolized by enzymes, pulled back into the presynaptic neuron through reuptake, or bound to a postsynaptic receptor. Short-term exposure of the receptor to a neurotransmitter is sufficient for causing a postsynaptic response by way of synaptic transmission. In response to a threshold action potential or graded electrical potential, a neurotransmitter is released at the presynaptic terminal. Low level "baseline" release occurs without electrical stimulation; the released neurotransmitter may move across the synapse to be detected by and bind with receptors in the postsynaptic neuron. Binding of neurotransmitters may influence the postsynaptic neuron in either an inhibitory or excitatory way; this neuron may be connected to many more neurons, if the total of excitatory influences are greater than those of inhibitory influences, the neuron will "fire".
It will create a new action potential at its axon hillock to release neurotransmitters and pass on the information to yet another neighboring neuron. Until the early 20th century, scientists assumed that the majority of synaptic communication in the brain was electrical. However, through the careful histological examinations by Ramón y Cajal, a 20 to 40 nm gap between neurons, known today as the synaptic cleft, was discovered; the presence of such a gap suggested communication via chemical messengers traversing the synaptic cleft, in 1921 German pharmacologist Otto Loewi confirmed that neurons can communicate by releasing chemicals. Through a series of experiments involving the vagus nerves of frogs, Loewi was able to manually slow the heart rate of frogs by controlling the amount of saline solution present around the vagus nerve. Upon completion of this experiment, Loewi asserted that sympathetic regulation of cardiac function can be mediated through changes in chemical concentrations. Furthermore, Otto Loewi is credited with discovering acetylcholine —the first known neurotransmitter.
Some neurons do, communicate via electrical synapses through the use of gap junctions, which allow specific ions to pass directly from one cell to another. There are four main criteria for identifying neurotransmitters: The chemical must be synthesized in the neuron or otherwise be present in it; when the neuron is active, the chemical must produce a response in some target. The same response must be obtained. A mechanism must exist for removing the chemical from its site of activation. However, given advances in pharmacology and chemical neuroanatomy, the term "neurotransmitter" can be applied to chemicals that: Carry messages between neurons via influence on the postsynaptic membrane. Have little or no effect on membrane voltage, but have a common carrying function such as changing the structure of the synapse. Communicate by sending reverse-direction messages that affect the release or reuptake of transmitters; the anatomical localization of neurotransmitters is determined using immunocytochemical techniques, which identify the location of either the transmitter substances themselves, or of the enzymes that are involved in their synthesis.
Immunocytochemical techniques have revealed that many transmitters the neuropeptides, are co-localized, that is, one neuron may release more than one transmitter from its synaptic terminal. Various techniques and experiments such as staining and collecting can be used to identify neurotransmitters throughout the central nervous system. There are many different ways. Dividing them into amino acids and monoamines is sufficient for some classification purposes. Major neurotransmitters: Amino acids: glutamate, aspartate, D-serine, γ-aminobutyric acid, glycine Gasotransmitters: nitric oxide, carbon monoxide, hydrogen sulfide Monoamines: dopamine, epinephrine, serotonin Trace amines: phenethylamine, N-methylphenethylamine, tyramine, 3-iodothyronamine, tryptamine, etc. Peptides: oxytocin, substance P, cocaine and amphetamine regulated transcript, opioid peptides Purines: adenosine triphosphate, adenosine Catecholamines: dopamine, epinephrine Others: acetylcholine, etc. In addition, over 50 neuroactive pepti
Zopiclone is a nonbenzodiazepine hypnotic agent used in the treatment of insomnia. Zopiclone is classed as a cyclopyrrolone. However, zopiclone increases the normal transmission of the neurotransmitter gamma-aminobutyric acid in the central nervous system, via modulating benzodiazepine receptors in the same way that benzodiazepine drugs do; as zopiclone is sedating, it is marketed as a sleeping pill. It works by causing a tranquilization of the central nervous system. After prolonged use, the body can become accustomed to the effects of zopiclone; when the dose is reduced or the drug is abruptly stopped, withdrawal symptoms may result. These can include a range of symptoms similar to those of benzodiazepine withdrawal. Although withdrawal symptoms from therapeutic doses of zopiclone and its isomers do not present with convulsions and are therefore not considered life-threatening, patients may experience such significant agitation or anxiety that they seek emergency medical attention. In the United States, zopiclone is not commercially available, although its active stereoisomer, eszopiclone, is sold under the name Lunesta.
Zopiclone is a controlled substance in the United States, Japan and some European countries, may be illegal to possess without a prescription. However, it is available in other countries where it is marketed under the brand name Imovane, is not a controlled substance in its available 10 mg, 7.5 mg, 5 mg, 3.75 mg oral tablet formulations. Zopiclone is known colloquially as a "Z-drug". Other Z-drugs include zaleplon and zolpidem and were thought to be less addictive or habit-forming than benzodiazepines. However, this appraisal has shifted somewhat in the last few years as cases of addiction and habituation have been presented. Zopiclone is recommended to be taken on a short-term basis a week or less. Daily or continuous use of the drug is not advised, caution must be taken when the compound is used in conjunction with antidepressants, sedatives or other drugs affecting the central nervous system. Zopiclone is indicated for the short-term treatment of insomnia where sleep initiation or sleep maintenance are prominent symptoms.
Long-term use is not recommended, as tolerance and addiction can occur with prolonged use. One low quality study found that zopiclone is ineffective in improving sleep quality or increasing sleep time in shift workers - more research in this area has been recommended. Zopiclone, 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 reported; the combination with alcohol consumption increases these impairments. Partial, but incomplete tolerance develops to these impairments. Zopiclone increases postural sway and increases the number of falls in older people, as well as cognitive side effects. Falls are a significant cause of death in older people. An extensive review of the medical literature regarding the management of insomnia and the elderly found that considerable evidence of the effectiveness and lasting benefits of nondrug treatments for insomnia exist.
Compared with the benzodiazepines, the nonbenzodiazepine sedative-hypnotics, such as zopiclone, offer few if any advantages in efficacy or tolerability in elderly persons. Newer agents such as the melatonin receptor agonists may be more suitable and effective for the management of chronic insomnia in elderly people. Long-term use of sedative-hypnotics for insomnia lacks an evidence base and is discouraged for reasons that include concerns about such potential adverse drug effects as cognitive impairment, daytime sedation, motor incoordination, increased risk of motor vehicle accidents and falls. In addition, the effectiveness and safety of long-term use of nonbenzodiazepine hypnotic drugs remains to be determined. Patients with liver disease eliminate zopiclone much more than normal patients and in addition experience exaggerated pharmacological effects of the drug. Patients who suffer from muscle weakness due to myasthenia gravis or have poor respiratory reserves due to severe chronic bronchitis, emphysema, or other lung disease, or have sleep apnoea cannot safely take zopiclone, nor can a patient with any untreated abnormality of the thyroid gland.
Sleeping pills, including zopiclone, have been associated with an increased risk of death. The British National Formulary states adverse reactions as follows: "taste disturbance. Zopiclone causes impaired driving skills similar to those of benzodiazepines. Long-term users of hypnotic drugs for sleep disorders develop only partial tolerance to adverse effects on driving with users of hypnotic drugs after 1 year of use still showing an increased motor vehicle accident rate. Patients who drive motor vehicles should not take zopiclone unless they stop driving due to a significant increased risk of accidents in zopiclone users. Zopiclone induces impairment of psychomotor function. Driving or operating machinery should be avoided after taking zopiclone as effects can carry over to the next day, including impaired hand eye coordination. To other sedative hypnotic drugs, zopiclone causes a decrease in the core body temperature and is effective in decreasing sleep latency, it causes similar alterations on EEG readings and sleep architecture as benzo
Benzodiazepines, sometimes called "benzos", are a class of psychoactive drugs whose core chemical structure is the fusion of a benzene ring and a diazepine ring. The first such drug, was discovered accidentally by Leo Sternbach in 1955, made available in 1960 by Hoffmann–La Roche, since 1963, has marketed the benzodiazepine diazepam. In 1977 benzodiazepines were globally the most prescribed medications, they are in the family of drugs known as minor tranquilizers. Benzodiazepines enhance the effect of the neurotransmitter gamma-aminobutyric acid at the GABAA receptor, resulting in sedative, anxiolytic and muscle relaxant properties. High doses of many shorter-acting benzodiazepines may cause anterograde amnesia and dissociation; these properties make benzodiazepines useful in treating anxiety, agitation, muscle spasms, alcohol withdrawal and as a premedication for medical or dental procedures. Benzodiazepines are categorized as either intermediary, or long-acting. Short- and intermediate-acting benzodiazepines are preferred for the treatment of insomnia.
Benzodiazepines are viewed as safe and effective for short-term use, although cognitive impairment and paradoxical effects such as aggression or behavioral disinhibition occur. A minority of people can have paradoxical reactions such as worsened panic. Benzodiazepines are associated with increased risk of suicide. Long-term use is controversial because of concerns about decreasing effectiveness, physical dependence, an increased risk of dementia. Stopping benzodiazepines leads to improved physical and mental health; the elderly are at an increased risk of both short- and long-term adverse effects, as a result, all benzodiazepines are listed in the Beers List of inappropriate medications for older adults. There is controversy concerning the safety of benzodiazepines in pregnancy. While they are not major teratogens, uncertainty remains as to whether they cause cleft palate in a small number of babies and whether neurobehavioural effects occur as a result of prenatal exposure. Benzodiazepines can cause dangerous deep unconsciousness.
However, they are less toxic than their predecessors, the barbiturates, death results when a benzodiazepine is the only drug taken. When combined with other central nervous system depressants such as alcoholic drinks and opioids, the potential for toxicity and fatal overdose increases. Benzodiazepines are misused and taken in combination with other drugs of abuse. Benzodiazepines possess psycholeptic, hypnotic, anticonvulsant, muscle relaxant, amnesic actions, which are useful in a variety of indications such as alcohol dependence, anxiety disorders, panic and insomnia. Most are administered orally. In general, benzodiazepines are well-tolerated and are safe and effective drugs in the short term for a wide range of conditions. Tolerance can develop to their effects and there is a risk of dependence, upon discontinuation a withdrawal syndrome may occur; these factors, combined with other possible secondary effects after prolonged use such as psychomotor, cognitive, or memory impairments, limit their long-term applicability.
The effects of long-term use or misuse include the tendency to cause or worsen cognitive deficits and anxiety. The College of Physicians and Surgeons of British Columbia recommends discontinuing the usage of benzodiazepines in those on opioids and those who have used them long term. Benzodiazepines can have serious adverse health outcomes, these findings support clinical and regulatory efforts to reduce usage in combination with non-benzodiazepine receptor agonists; because of their effectiveness and rapid onset of anxiolytic action, benzodiazepines are used for the treatment of anxiety associated with panic disorder. However, there is disagreement among expert bodies regarding the long-term use of benzodiazepines for panic disorder; the views range from those that hold that benzodiazepines are not effective long-term and that they should be reserved for treatment-resistant cases to those that hold that they are as effective in the long term as selective serotonin reuptake inhibitors. The American Psychiatric Association guidelines note that, in general, benzodiazepines are well tolerated, their use for the initial treatment for panic disorder is supported by numerous controlled trials.
APA states that there is insufficient evidence to recommend any of the established panic disorder treatments over another. The choice of treatment between benzodiazepines, SSRIs, serotonin–norepinephrine reuptake inhibitors, tricyclic antidepressants, psychotherapy should be based on the patient's history and other individual characteristics. Selective serotonin reuptake inhibitors are to be the best choice of pharmacotherapy for many patients with panic disorder, but benzodiazepines are often used, some studies suggest that these medications are still used with greater frequency than the SSRIs. One advantage of benzodiazepines is that they alleviate the anxiety symptoms much faster than antidepressants, therefore may be preferred in patients for whom rapid symptom control is critical. However, this advantage is offset by the possibility of developing benzodiazepine dependence. APA does not recommend benzodiazepines for persons with depressive
Hypnotic or soporific drugs known as sleeping pills, are a class of psychoactive drugs whose primary function is to induce sleep and to be used in the treatment of insomnia, or for surgical anesthesia. This group is related to sedatives. Whereas the term sedative describes drugs that serve to calm or relieve anxiety, the term hypnotic describes drugs whose main purpose is to initiate, sustain, or lengthen sleep; because these two functions overlap, because drugs in this class produce dose-dependent effects they are referred to collectively as sedative-hypnotic drugs. Hypnotic drugs are prescribed for insomnia and other sleep disorders, with over 95% of insomnia patients being prescribed hypnotics in some countries. Many hypnotic drugs are habit-forming and, due to a large number of factors known to disturb the human sleep pattern, a physician may instead recommend changes in the environment before and during sleep, better sleep hygiene, the avoidance of caffeine or other stimulating substances, or behavioral interventions such as cognitive behavioral therapy for insomnia before prescribing medication for sleep.
When prescribed, hypnotic medication should be used for the shortest period of time necessary. Among individuals with sleep disorders, 13.7% are taking or prescribed nonbenzodiazepines, while 10.8% are taking benzodiazepines, as of 2010. Early classes of drugs, such as barbiturates, have fallen out of use in most practices but are still prescribed for some patients. In children, prescribing hypnotics is not yet acceptable unless used to treat night terrors or somnambulism. Elderly people are more sensitive to potential side effects of daytime fatigue and cognitive impairments, a meta-analysis found that the risks outweigh any marginal benefits of hypnotics in the elderly. A review of the literature regarding benzodiazepine hypnotics and Z-drugs concluded that these drugs can have adverse effects, such as dependence and accidents, that optimal treatment uses the lowest effective dose for the shortest therapeutic time period, with gradual discontinuation in order to improve health without worsening of sleep.
Falling outside the above-mentioned categories, the neuro-hormone melatonin has a hypnotic function. Hypnotica was a class of somniferous drugs and substances tested in medicine of the 1890s and including: Urethan, Methylal, paraldehyde, Hypnon and Ohloralamid or Chloralimid. Research about using medications to treat insomnia evolved throughout the last half of the 20th century. Treatment for insomnia in psychiatry dates back to 1869 when chloral hydrate was first used as a soporific. Barbiturates emerged as the first class of drugs that emerged in the early 1900s, after which chemical substitution allowed derivative compounds. Although the best drug family at the time they were dangerous in overdose and tended to cause physical and psychological dependence. During the 1970s, quinazolinones and benzodiazepines were introduced as safer alternatives to replace barbiturates. Benzodiazepines are not without their drawbacks. Questions have been raised as to. Nonbenzodiazepines are the most recent development.
Although it's clear that they are less toxic than their predecessors, comparative efficacy over benzodiazepines have not been established. Without longitudinal studies, it is hard to determine. Other sleep remedies that may be considered "sedative-hypnotics" exist. Examples of these include mirtazapine, clonidine and the over-the-counter sleep aid diphenhydramine. Off-label sleep remedies are useful when first-line treatment is unsuccessful or deemed unsafe. Barbiturates are drugs that act as central nervous system depressants, can therefore produce a wide spectrum of effects, from mild sedation to total anesthesia, they are effective as anxiolytics and anticonvulsalgesic effects. They have dependence liability, both psychological. Barbiturates have now been replaced by benzodiazepines in routine medical practice – for example, in the treatment of anxiety and insomnia – because benzodiazepines are less dangerous in overdose. However, barbiturates are still used in general anesthesia, for epilepsy, assisted suicide.
Barbiturates are derivatives of barbituric acid. The principal mechanism of action of barbiturates is believed to be positive allosteric modulation of GABAA receptors. Examples include amobarbital, phenobarbital and sodium thiopental. Quinazolinones are a class of drugs which function as hypnotic/sedatives that contain a 4-quinazolinone core, their use has been proposed in the treatment of cancer. Examples of quinazolinones include cloroqualone, etaqualone, mebroqualone and methaqualone. Benzodiaz