Sleep medications
Hypnotic sedative drugs - commonly referred to as " sleeping medicines " - are used to treat insomnia. In fact, these drugs are able to promote and facilitate the onset and maintenance of sleep.
Generally, the therapeutic effects of hypnotic sedatives are dose-dependent, ie they depend on the amount of drug administered.
At low doses, hypnotic sedatives induce sedation, at higher doses they cause hypnosis (ie sleep) and - further increasing the dose - they can be used in surgical anesthesia.
Often, hypnotic sedatives are associated with anxiolytic drugs. However, it is not correct to make such an association; in fact, many hypnotic sedatives also have anxiolytic activity, but not all anxiolytics induce sedation.
Hypnotic sedative drugs have been - and still are - extensively studied, since they are constantly looking for safer, more effective drugs with fewer side effects.
The ideal hypnotic drug should possess certain characteristics. These features are:
- Good therapeutic index;
- Rapidity of absorption;
- Rapid induction of sleep;
- Induction of a sleep qualitatively and quantitatively similar to the physiological one;
- Absence of residual effects upon awakening;
- Absence of active metabolites deriving from the metabolism of the drug and which could cause residual effects;
- Absence of rebound insomnia or rebound insomnia, that is, when treatment with the drug is interrupted, insomnia (rebound insomnia or rebound insomnia) should not occur. This effect occurs especially when the therapy is stopped abruptly, therefore it is always recommended to gradually stop the treatment;
- Absence of physical and psychic dependence;
- Absence of addiction;
- No interaction with ethanol. In fact, the sedative effects of many hypnotics are greatly increased by the simultaneous intake of alcohol. This association can cause - consequently - a worsening of the adverse effects induced by the drugs themselves;
- Absence of respiratory depression;
- Absence of memory effects.
In reality, the ideal hypnotic does not yet exist, although research has made many strides in this field.
In any case, to understand how the search for the ideal hypnotic has developed over time, it is useful to know sleep and the factors that influence it.
Stages of sleep
Initially, it was believed that sleep was just a passive process.
With the discovery of the electroencephalogram (ECG) in the late 1920s, it was possible to study brain electrical activity during sleep. Thus it was discovered that sleep was not at all a passive process, but that it was constituted by the alternation of a passive state and a state characterized by weak brain activity.
Following the numerous studies carried out, we arrived at the definition of three well-defined states:
- Waking state ;
- Slow wave sleep (sleep with non-rapid eye movements, also known as NREM or non-REM sleep);
- Paradoxical sleep (sleep with rapid eye movements, also known as REM sleep phase).
The NREM sleep phase is further divided into four stages:
- Stadiums 1 and 2, characterized by light sleep;
- Stages 3 and 4, characterized by a deeper sleep.
REM sleep, on the other hand, is the phase in which we memorize, order and learn.
In a normal adult, sleep begins with the NREM phase. This phase has an average duration of about 70-90 minutes. After this time, the REM phase begins, which has an approximate duration of 15-20 minutes. At the end of the REM phase, the first sleep cycle ends, which generally lasts from 90 to 120 minutes. After that, other cycles follow one another in which the REM phase gradually increases at the expense of the NREM and so on until waking up.
Any condition or factor that leads to alterations of this normal sleep cycle leads to REM or NREM sleep compensation phenomena on subsequent nights.
There are numerous factors that can influence sleep, which act in different regions of the brain, although - even today - the role of each of the brain regions involved in sleep is not completely clear.
Understanding how certain factors affect sleep is not only useful for understanding the mechanism of action of hypnotics, but also clarifies why there are drugs - which have nothing to do with hypnotics - with sedative activity. These include neuroleptics, antidepressants, antipsychotics and antihistamines.
Types of insomnia
Insomnia is a sleep disorder that affects both men and women. However, it has a higher incidence rate in women.
Insomnia can be defined as primary insomnia (when the cause is unknown) or secondary insomnia (when it is due to other causes, including stress, the use of drugs, psychiatric disorders or other diseases). The most common is secondary insomnia.
Insomnia can be further classified according to its duration:
- Transient insomnia, when it lasts less than three days;
- Short-term insomnia, the duration of which varies from three days to three weeks;
- Long-term insomnia, the duration of which exceeds three weeks.
Therefore, to perform a correct diagnosis of insomnia, an assessment of the "sleep period" and the number of nights in which the insomnia itself manifests itself is necessary.
Factors that influence sleep
Among the various endogenous factors that influence sleep we find neurotransmitters and neurohormonal modulators .
Below, the main exponents of these two categories of endogenous substances that regulate sleep and wakeful states are briefly illustrated.
Catecholamines
It has been hypothesized that catecholamines - in particular noradrenaline and dopamine - are involved in wakefulness and REM sleep.
In this regard, numerous studies have been conducted that have brought to light interesting mechanisms, although it is still not completely clear how catecholamines affect sleep. In any case, the results of these studies have established that:
- Some α 1 norepinephrine receptor agonists decrease REM sleep, while antagonists of this receptor increase it;
- Clonidine (a drug used in the treatment of hypertension), which is an α 2 receptor agonist for norepinephrine, is involved in sleep induction, but is able to inhibit stages 3 and 4 of NREM sleep;
- The waking state appears to be maintained through the activation of D2 receptors for dopamine, while a decrease in activity on these receptors favors the onset of sleep;
- D1 dopamine receptors are involved in the regulation of REM sleep, but do not affect its onset and maintenance.
Serotonin
In the beginning, serotonin (5-HT) was thought to promote sleep and prevent awakening. In fact, some studies have shown that this is not the case. In fact, the serotonin 5-HT1, 5-HT2 and 5-HT3 receptor agonists increase waking state and inhibit sleep. In contrast, 5-HT2 receptor antagonists promote an increase in NREM sleep and a decrease in REM sleep.
Furthermore, a theory has been proposed according to which 5-HT1A receptors and 5-HT2 receptors influence sleep as they promote the release of certain modulators by the hypothalamus.
Histamine
Histamine (H) also appears to be involved in wakefulness and REM sleep.
In particular, the histamine H1 receptor agonists and the H3 receptor antagonists increase the waking state. Conversely, H1 receptor antagonists and H3 receptor agonists decrease wakefulness.
H2 receptors also appear to be involved in sleep regulation.
Acetylcholine
The cholinergic system is implicated in the waking state and in the induction of REM sleep.
Studies conducted on animals have shown that cholinergic agonists and acetylcholinesterase inhibitors (an enzyme responsible for the metabolism of acetylcholine) are able to induce REM sleep, first passing through NREM sleep.
The administration of cholinergic antagonists, on the other hand, hinders the transition from NREM sleep to REM sleep.
Adenosine
Some studies have shown that adenosine is able to act as a neurotransmitter in the sleep-wake cycle of mammals. In fact, by stimulating the adenosine A1 receptors, a hypnotic effect is induced with an increase in both NREM and REM sleep.
Supporting this theory is the fact that methylxanthines (such as caffeine and theophylline) are able to block the receptors for adenosine at the central level, thus hindering the onset of sleep and increasing the waking state.
Γ-aminobutyric acid (GABA)
Γ-aminobutyric acid is the main inhibitory neurotransmitter of the brain. GABA performs its biological functions by binding to its specific receptors, GABA-A, GABA-B and GABA-C.
Almost all currently used hypnotic sedatives are GABA-A receptor agonists and - as such - they activate the receptor by promoting the cascade of inhibitory signals induced by GABA itself.
Growth hormone and prolactin
Growth hormone (GH) and prolactin (PRL) appear to be the hormones most involved in sleep regulation.
In normal adult individuals the GH level is kept low. However, in the NREM sleep phase there is an increased secretion of this hormone. There appears to be a correlation between the amount of GH secreted and the duration of NREM sleep.
This theory finds support in some studies conducted on elderly people in a healthy state. In fact, in these individuals, a reduction in GH secretion parallel to the decrease in NREM sleep was observed. This fact could also explain the decrease in sleep that is often observed in older people.
As for prolactin, however, it appears that the onset of sleep stimulates its secretion. Indeed, there appears to be a reciprocal relationship between the secretion of PRL and the onset of REM sleep or the onset of nocturnal awakening.
Melatonin
Melatonin affects the circadian rhythm and the sleep cycle. It is synthesized by the pineal gland (or epiphysis) and is secreted during sleep. The normal plasma concentration of melatonin during sleep is 100-200 pg / ml.
Three types of melatonin receptors are known, MT1, MT2 and MT3.
The MT1 receptor is involved in sleep induction, whereas the MT2 receptor appears to be involved in the regulation of circadian rhythm.
Classifications of hypnotic sedatives
There are various types of drugs that possess hypnotic activity. The main hypnotic sedative classes used for the treatment of insomnia are illustrated below.
Barbiturates
Barbiturates are the first type of hypnotic sedative drugs to be used.
Barbiturates exert a depressant action on the cerebral spinal level and depress neuronal activity, the activity of smooth muscles, skeletal muscles and cardiac muscle.
The effects induced by barbiturates are dose-dependent. In fact, depending on the type, quantity and route of administration chosen, barbiturates can be used as hypnotic sedative drugs, as anticonvulsants or as anesthetics.
Barbiturates exert their action by increasing the transmission of GABA. In particular, barbiturates bind to the picrotossin site present on the GABA-A receptor.
Picrotoxin is a phytotoxin extracted from the climbing plant Anamirta cocculus.
This toxin has convulsive properties and exerts an exciting action on the center of the breath and on the vasomotor center of the brain. One of the therapeutic uses of picrotoxin is precisely the treatment of acute barbiturate poisoning.
However, barbiturates are rarely used as hypnotic sedatives due to their narrow therapeutic index and because of the excessive depression they exert on the central nervous system. Furthermore, these drugs alter the transport of sugars and are powerful inducers of liver enzymes and this makes them the cause of possible drug interactions with other medicines. To conclude, barbiturates induce physical and psychic dependence, and tolerance.
For the reasons mentioned above, barbiturates are used more as anesthetics and antiepileptics (such as, for example, phenobarbital which is used as an anticonvulsant).
Benzodiazepines
Benzodiazepines are drugs with hypnotic, sedative, anxiolytic, anticonvulsant, muscle relaxant and anesthetic properties.
Benzodiazepines - such as barbiturates - also work by increasing GABAergic transmission. A specific benzodiazepine binding site (BZR) to which they bind is present on the GABA-A receptor. Once the bond is established, the receptor is activated and there is an increase in GABA-induced inhibitory signals.
Benzodiazepines increase total sleep and phases 3 and 4 of NREM sleep. However, they exert a slight suppression on the REM phase.
Benzodiazepines can be classified according to their plasma half-life:
- Short or very short half-life (2-6 hours), this category includes triazolam and midazolam;
- Intermediate half-life (6-24 hours), this category includes oxazepam, lorazepam, lormetazepam, alprazolam and temazepam;
- Long half-life (1-4 days), this category includes chlordiazepoxide, clorazepate, diazepam, flurazepam, nitrazepam, flunitrazepam, clonazepam, prazepam and bromazepam.
It should be remembered, however, that even benzodiazepines can induce physical dependence, psychic dependence and tolerance. However - compared to barbiturates - they have a less restricted therapeutic index.
Z drugs or Z drugs
These drugs are GABA-A receptor agonists and possess a non-benzodiazepine structure. Their mechanism of action, however, is similar to that of benzodiazepines, so they are sometimes referred to as benzodiazepine-like drugs.
The drugs belonging to this category have completely different chemical structures from one another; what unites them is the fact that their names all begin with the letter Z (hence the name Z drugs). These drugs are:
- Zolpidem, from the chemical point of view this drug is an imidazopyridine;
- Zaleplon, from the chemical point of view is a pyrazolopyrimidine;
- Zopiclone is a cyclopyrrolone from a chemical point of view. Initially zopiclone was marketed as a raceme, but - since the sedative activity is given only by the S enantiomer - in the United States only the pure enantiomer with the name Eszopiclone is marketed.
These drugs - although they have the same mechanism of action - have a different pharmacokinetic profile, a different bioavailability, a different volume of distribution and a different half-life time.
Compared to benzodiazepines, Z drugs seem to have a lower ability to induce dependence and a lower potential for abuse.
Melatonin MT1 receptor agonists
As mentioned above, the melatonin MT1 receptor is involved in sleep induction.
Following extensive research, modifications were made to the chemical structure of melatonin until ramelteon was obtained. This compound is a potent and selective agonist of the melatonin MT1 receptor and is able to reduce the time needed for falling asleep. However, ramelteon has a short plasma half-life, therefore, it is not as effective in maintaining sleep.
Compared to the GABA-A receptor agonists, however, ramelteon does not depress cognitive functions, memory or ability to concentrate at the doses usually used. Furthermore, it appears that it is not susceptible to abuse.
Melatonin
Although melatonin is an endogenous substance produced by the pineal gland, there are pharmaceutical preparations that contain it. It is mainly marketed as a substance able to combine sleep.
Chloral hydrate
This compound was introduced as a hypnotic sedative in the 1950s and 1960s, as it was able to induce sleep quickly and was quite effective even in its maintenance.
The mechanism of chloral is similar to that of barbiturates. Sleep appears one hour after ingesting the drug and can last 4-8 hours. However, chloral is no longer used in the treatment of insomnia due to its ability to induce dependence, its ability to depress cognitive activity and due to its potentially lethal toxicity.
Vegetable preparations against insomnia
Numerous vegetable preparations have been studied - and are still used - for the treatment of sleep disorders.
Among the various plants that have sedative properties, we mention the valerian, lavender, chamomile, lemon balm and passionflower.
Much attention was paid to the study of valerian. Some studies state that a dose of 450 mg of aqueous extract of valerian is the appropriate amount of preparation to induce sleep. Furthermore, if valerian is taken during the night, it appears that the cognitive and motor skills upon awakening are not affected.
At high doses of valerian, however, disturbances to the heart and depression of the central nervous system may arise.
