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Nonbenzodiazepines (sometimes colloquially referred to as "Z-drugs") are a class of psychoactive substances similar in nature to benzodiazepines. The pharmacodynamics of nonbenzodiazepine drugs overlap almost exactly with those of benzodiazepine drugs, and therefore the drugs have similar benefits, side effects, and risks. Nonbenzodiazepines, however, have different or completely different chemical structures from benzodiazepines and are therefore not related to benzodiazepines at the molecular level.
Classes
Currently, the main chemical classes of nonbenzodiazepines are:
Imidazopyridines
Zolpidem (Ambien) Necopidem Saripidem
Pyrazolopyrimidines
Zaleplon (Sonata) Divaplon Fasiplon Indiplon Lorediplon Ocinaplon Panadiplon Taniplon
Cyclopyrrolones
Eszopiclone (Lunesta) Zopiclone (Imovane) Pagoclone Pazinaclone Suproclone Suriclone
β-carbolines
Abecarnil Gedocarnil ZK- 93423
CGS-9896 CGS-20625 CL-218 , 872 ELB-139 GBLD-345 L- 838, 417 NS- 2664 NS- 2710 Pipequaline RWJ - 51204 SB- 205 , 384 SL- 651 , 498 SX- 3228 TP- 003 TP- 13 TPA- 023 Y- 23684
Pharmacology
Nonbenzodiazepines are positive allosteric modulators of the GABA-A receptor. Like benzodiazepines, they exert their effects by binding to and activating the benzodiazepine site of the receptor complex.
Story
Nonbenzodiazepines have shown efficacy in the treatment of sleep disorders. There is limited evidence to suggest that tolerance to nonbenzodiazepines develops more slowly than to benzodiazepines. However, the data are limited, so no conclusions can be drawn. Regarding the long-term effects of nonbenzodiazepines, data are also limited. There are some differences between Z-drugs, for example, zaleplon does not cause tolerance and relapse effects.
pharmaceuticals
The first three nonbenzodiazepines on the market were the so-called "Z-drugs" Zopiclone, Zolpidem, and . All three drugs are sedatives and are used exclusively to treat mild insomnia. They are safer than older barbiturates, especially in overdose, and, compared with benzodiazepines, have less of a tendency to induce physical dependence and addiction. Z-drugs have gained wide popularity as a treatment for insomnia, especially in older patients. Long-term use of such drugs is not recommended, as the patient may develop tolerance and addiction. A survey of patients using non-benzodiazepine Z-drugs and benzodiazepine sedatives showed no difference in reports of side effects reported by 41% of users. Z-drug users were more likely to report attempts to stop taking sleeping pills than benzodiazepine users. The effectiveness of the drugs also did not differ.
Side effects
Z-drugs are not without drawbacks, and all three compounds produce side effects such as severe amnesia and, less commonly, hallucinations, especially when used in high doses. In rare cases, the use of such drugs can lead to a state of fugue, in which the patient can perform relatively complex activities, including cooking or driving a car, while unconscious and having no subsequent memory of the events that occurred after waking up. Although this effect is quite rare (and has also been observed with some previous generation sedatives such as temazepam and secobarbital), it can be potentially dangerous, so the search continues for new compounds with an improved side effect profile. Daytime discontinuation anxiety can also occur as a result of chronic nighttime use of nonbenzodiazepines such as zopiclone. Side effects of drugs in this class may vary due to differences in metabolism and pharmacology. For example, long-acting benzodiazepines can accumulate in the body, especially in the elderly or those with liver disease. Short-acting benzodiazepines are associated with a higher risk of more severe withdrawal symptoms. In the case of nonbenzodiazepines, zaleplon may be the safest in terms of sedation the day after administration, and, unlike and , zaleplon does not increase the risk of traffic accidents, even when used in the middle of the night, due to its ultra-short half-life.
Increased risk of depression
It has been claimed that insomnia can cause depression, suggesting that insomnia remedies may help treat depression. However, an analysis of clinical trial data submitted to the FDA for , and , showed that these sedative-hypnotics more than double the risk of developing depression compared with placebo. Hypnotics may thus be contraindicated in patients suffering from or at risk of depression. Sleeping pills lead to depression rather than relieve it. Studies have shown that long-term users of sedative-hypnotic drugs have a markedly increased risk of suicide, as well as an overall increase in the risk of mortality. On the other hand, cognitive behavioral therapy (CBT) for insomnia has been found to improve sleep quality and overall mental well-being.
Addiction and discontinuation
Nonbenzodiazepines should not be discontinued abruptly if the drugs are taken for more than a few weeks due to the risk of relapse and acute withdrawal reactions that may resemble those seen with benzodiazepine withdrawal. Treatment usually involves gradual dose reduction over weeks or several months, depending on the patient, dosage, and length of time of treatment. If this approach does not work, you can try switching to an equivalent dose of long-acting benzodiazepines (eg, chlordiazepoxide or ) followed by gradual dose reduction. In extreme cases, and in particular where there is severe addiction and/or abuse, inpatient detoxification may be required with .
Carcinogenicity
The Journal of Clinical Sleep Medicine published a systematic review of the medical literature on insomnia drugs and raised concerns about benzodiazepine receptor agonists, benzodiazepines and Z-drugs, which are used as sleep aids. The review found that almost all of the sleep disorder and drug trials were sponsored by the giants of the pharmaceutical industry. It found that the ratio of industry-favorable positive outcomes in industry-sponsored trials was 3.6 times higher than in non-industry-sponsored trials and that 24% of authors did not disclose the fact that pharmaceutical companies funded their published work. The paper pointed out that there are few studies of sleep aids independent of drug manufacturers. The author expressed concern about the lack of discussion of the side effects of benzodiazepine agonists, such as a significant increase in the risk of infection, cancer and increased mortality in trials of sleeping pills and an overemphasis on positive effects. No hypnotic manufacturer has attempted to refute the epidemiological data showing that the use of their product is correlated with increased mortality. The author stated that "in major trials of hypnotics, the possible adverse effects of hypnotics, such as daytime weakness, infections, cancer, and death, need to be examined in more detail and weighed against the resulting balance of benefits and risks." In clinical trials of these nonbenzodiazepine hypnotics, a significant increase in the risk of skin cancer and tumor development was found compared with placebo. Other types of cancer have also been observed, such as brain, lung, colon, breast, and bladder cancers. Nonbenzodiazepine users also experienced an increased risk of infections, possibly due to weakened immune function. It is assumed that the reason for the increased risk of developing cancer was either the suppression of immune function or the viral infections themselves. Initially, the FDA hesitated to approve certain nonbenzodiazepines due to concerns about an increased risk of cancer. The author reported that due to the fact that the FDA requires reporting of favorable and unfavorable results of clinical trials, the FDA New Drug Application data are more reliable than peer-reviewed literature data. In 2008, the FDA reanalyzed its data and confirmed an increased risk of cancer in randomized drug trials compared to placebo, but concluded that the risk of cancer was not related to the need for regulatory action.
Elderly patients
Nonbenzodiazepine hypnotics, similar to benzodiazepines, cause disturbances in body balance and standing stability in individuals who wake up during the night or the next morning; falls and hip fractures are frequently reported. Combined use with alcohol enhances these disorders. In relation to these violations, a partial, but incomplete, tolerance develops. In general, nonbenzodiazepines are not recommended for elderly patients due to an increased risk of falls and fractures. A detailed review of the medical literature regarding the control of insomnia, including in the elderly, found that there is sufficient evidence for the effectiveness and long-term benefits of non-pharmacological treatment of insomnia in adults of all age groups. Compared with benzodiazepines, nonbenzodiazepine hypnotics and sedatives show little benefit in efficacy or tolerability in the elderly. It has been found that newer drugs such as melatonin agonists may be more appropriate and effective treatments for chronic insomnia in the elderly. Long-term use of sedative-hypnotics for insomnia is not evidence-based and is not recommended due to possible side effects such as cognitive impairment (anterograde amnesia), daytime sedation, impaired motor coordination, and an increased risk of traffic accidents and falls. In addition, the efficacy and safety of long-term use of these agents is still to be determined. It was concluded that further research is needed to evaluate the long-term effects of treatment and the most appropriate treatment strategy for older adults with chronic insomnia.
controversy
A review of the literature on hypnotic drugs, including nonbenzodiazepine Z-drugs, concludes that the use of such drugs is associated with an unjustified risk to human health and there is no evidence of long-term effectiveness due to the development of tolerance. Risks include addiction, accidents, and other adverse outcomes. The gradual cessation of sleeping pills leads to better health without compromising sleep. It is advisable to administer hypnotics for only a few days at a low effective dose, and in the elderly avoid hypnotics if possible.
New connections
More recently, a number of non-sedating anxiolytics derived from the same structural families as Z-drugs such as pagoclone have been developed and approved for clinical use. Nonbenzodiazepine drugs are much more selective than older benzodiazepine anxiolytics, producing effective anxiety/panic relaxation with little or no sedation, anterograde amnesia, or anticonvulsant effects, and thus are potentially more effective than older antianxiety drugs. However, the anxiolytic nonbenzodiazepines are not widely used and many have failed after initial clinical trials, halting many projects including alpidem, indiplon and suriclone.
In the conditions of modern urban life and increased mental labor, a person often experiences unbearable stress. And stress, physical inactivity, the use of stimulants such as coffee, tobacco, alcohol contribute to sleep disturbance. Most often, for the symptomatic treatment of insomnia disorders (this is what insomnia is called), a mild sleeping pill, for example, of plant origin, is used.
A good sleeping pill should be effective and safe.
But medical science does not stand still, and drugs such as, for example, peony tincture, Corvalol and Fitosedan are being replaced by a new generation of sleep-improving drugs. In addition, they do not cause side effects inherent in the "classic" means. These drugs belong to the so-called Z - hypnotics. What is it and how to choose the most appropriate sedative or sleeping pill?
What are Z-hypnotic (sleeping) drugs?
As you know, "hypnotics", from the word "hypnosis" are called sleeping pills. According to modern standards, it is necessary to start the treatment of insomnia disorders (that is, insomnia and sleep disturbances) with non-drug methods: changing the mode of work and rest, walking, timely going to bed, treating diseases that can provoke insomnia, for example, thyrotoxicosis or neurasthenia.
In the event that these measures are not enough, then sedative preparations of plant origin are prescribed. They are available freely, without prescriptions, and almost all have a mild sedative and hypnotic effect. In this case, a weak effect is an advantage, since the degree of sleep disturbance is small. In addition, there is no addiction to them, and these drugs have a low price.
Perhaps the most effective effect is "Valocordin", due to the content of phenobarbital. It is the only barbiturate available without a prescription as part of Valocordin (Corvalol).
Valocordin has a sedative effect
In the event that sleep disorders become so pronounced that they interfere with work and lead a normal life, then the appointment of “real” sleeping pills is required, which cannot be purchased without appropriate prescriptions.
These drugs previously included barbiturates (Etaminal - sodium, Barbamil, Veronal), then they were replaced by benzodiazepine drugs, which were very actively used all over the world in the 70s - 80s of the twentieth century. In the USA, for example, there was even a “benzodiazepine epidemic”: it was believed that such drugs not only improve sleep and bring harmony with oneself and the outside world, but are also an excellent prevention of stress.
Time has shown that this is not so: benzodiazepine drugs, for example, nitrazepam (Radedorm) or Phenazepam, put a person into a deep sleep, but in the morning cause a feeling of weakness. They also relax muscles (muscle relaxation), which can be dangerous when driving. Also, these drugs cause a withdrawal syndrome: the patient "sits down" on such drugs.
Therefore, a persistent search continued for such means that satisfied a very “capricious” list of requirements. So, for example, it is known that a good sleeping pill of the new generation should be as close as possible to the ideal. It should immediately induce sleep, stop its action no later than an hour after waking up, maintain daytime vigor and performance, and not cause addiction and side effects. At the same time, the drug should not be used as a sedative, should not affect memory and thinking.
And finally, at the end of the twentieth century, such drugs appeared, they were called Z - hypnotics. They are able to very selectively affect the structures of inhibitory GABAergic (inhibitory) receptors. Scientifically, these drugs are called "non-benzodiazepine benzodiazepine receptor agonists." Representatives of this family began to enter the world pharmaceutical market in 1993.
The brightest representatives of the family
By tradition, all Z-drugs have an international non-proprietary name, which in Russian transcription begins with the letter "z". Consider the characteristic representatives of this class.
Zopiclone
Modern hypnotic drug of non-benzodiazepine structure
In the Russian Federation, it is better known under the trade name "Imovan". This is a light and convenient sleeping pill that can be taken without much fear for 2 to 3 weeks. Falling asleep usually occurs (however, as with other drugs of this family) within 1 to 2 hours after ingestion. Sleep is even and calm, morning awakening is quick, daytime well-being is good. A single daily dose is 7.5 mg. In the elderly, it is recommended to reduce the dosage by half. In this case, the time to fall asleep can be extended by 1-2 hours, but the drug will have less effect on the liver, since Imovan is contraindicated in severe violations of the liver and kidneys.
The cost of one package of "Imovan" (according to 2016 data) is, on average, 250 rubles for 20 tablets, for 3 weeks of admission.
Zolpidem
Another of the Z-hypnotics - Zolpidem
The second drug of this family is better known as Hypnogen or Ivadal. Take this tool (as well as other Z - hypnotics) should be taken within an hour immediately before going to bed, or even while already lying in bed. It has a good therapeutic breadth: the initial dose is 5 mg, the maximum is 10 mg.
It has a significant drawback - high cost. So, a similar number of tablets for 3 weeks of taking will already cost over 2,500 rubles, that is, ten times higher than that of Imovan.
Zaleplon
This preparation has beautiful musical trade names: "Andante" or "Sonata". This drug can be considered a really strong sleeping pill, but with its long-term use, a sharp withdrawal syndrome may develop, which will manifest itself in the form of persistent insomnia. Therefore, this drug should be taken in short courses and at a minimum dosage.
However, the indisputable "plus" is the fact that after taking it, it is completely eliminated from the body within 1-2 hours, so daytime sleepiness never occurs while taking zaleplon.
Its recommended dose coincides with the maximum - 10 mg. It is recommended to take it a couple of hours after eating, but no later than an hour before bedtime. The ideal option is to go to bed two hours after dinner and take this medicine at night.
The active ingredient in Andante is Zaleplon.
The cost of Zaleplon preparations is on average 460 rubles, but only for 7 tablets.
Therefore, in terms of a weekly course, we get:
- zopiclone 12.5 rubles;
- andante 460 rubles;
- ivadal 850 rub.
It should be recalled that these drugs are sold only by prescription. Perhaps this is an over-caution (after all, these drugs are relatively safe), but this is how it should be done in relation to all sleeping pills. After all, when barbiturates were sold without prescriptions, their overdose often caused death, and they were used to commit suicide attempts and various crimes.
All Z-hypnotics are released strictly by prescription.
In conclusion, we note that in case of severe sleep disorders, these drugs should become the basis of medical treatment, with zopiclone and zolpidem having an average time effect, and zaleplon - a drug with an ultra-short, "point" effect on insomnia.
The positive aspects of these drugs are the absence of respiratory disturbance during sleep and the minimal risk of developing sleep apnea, as well as vigorous awakening and good health during the day.
But still, the ideal option for treating insomnia disorders should be considered a modification of the patient's lifestyle, and joint efforts should be made by both the patient and the doctor to normalize sleep by physiological methods, leaving medications "in reserve".
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