Sleeping pills are. Sleeping drugs. cyclopyrrolone derivative

• Chemical group or drug class	INN
  	short action (1-5 h)	medium duration of action (5-8 hours)	long-acting (more than 8 hours)
  Barbiturates			Phenobarbital.
  Benzodiazepines	Triazolam, Midazolam.	Temazepam.	Flunitrazepam, estazolam, nitrazepam, diazepam.
  Cyclopyrrolones	Zopiclone.
  Imidazopyridines	Zolpidem.
  Glycerol derivatives			Meprobamate.
  Aldehydes		Chloral hydrate.
  Sedative antipsychotics			Chlorpromazine, Clozapine, Chlorprothixene, Promazine, Levomepromazine, Thioridazine.
  Sedative antidepressants		Pipofezine, Benzoclidine.	Amitriptyline, Fluacysin.
  Antihistamines			Diphenhydramine, Hydroxyzine, Doxylamine, Promethazine.
  Bromureids			Bromised.
  Thiazole derivatives	Clomethiazole.

Barbiturates have a rapid hypnotic effect even in severe cases of insomnia, but significantly disrupt the physiological structure of sleep, shortening the paradoxical phase.

The main mechanism of the hypnotic, anticonvulsant and sedative effects of barbiturates is an allosteric interaction with a site of the GABA receptor complex, which leads to an increase in the sensitivity of the GABA receptor to the mediator and an increase in the duration of the activated state of the chloride channels associated with this receptor complex. As a result, for example, inhibition of the stimulating effect of the reticular formation of the brain stem on its cortex occurs.

Benzodiazepine derivatives most widely used as sleeping pills. Unlike barbiturates, they disrupt the normal structure of sleep to a lesser extent, are much less dangerous in terms of addiction formation, and do not cause pronounced side effects.

Zopiclone and zolpidem- representatives of new classes of chemical compounds. Zolpidem selectively interacts with benzodiazepine co-receptors, which facilitates GABAergic transmission. Zopiclone binds directly to the GABA regulated chloride ionophore. An increase in the flow of chloride ions into the cell causes hyperpolarization of the membrane and, accordingly, a strong inhibition of the neuron. Unlike benzodiazepines, the new drugs bind only to central benzodiazepine receptors and have no affinity for peripheral ones.
Zopiclone, unlike benzodiazepines, does not affect the duration of the paradoxical phase of sleep, which is necessary for the restoration of mental functions, memory, learning ability, and somewhat lengthens the slow-wave phase, which is important for physical recovery.
innovations. Zolpidem to a lesser extent increases the duration of slow-wave sleep, but more often, especially with prolonged use, prolongs REM sleep.

Meprobamate, like barbiturates, inhibits the paradoxical phase of sleep, it develops dependence.

Clomethiazole and chloral hydrate have a very rapid hypnotic effect and practically do not disrupt the structure of sleep, but clomethiazole is classified as a drug with a pronounced ability to cause drug dependence.

Bromureids have rarely been used in recent years. They are rapidly absorbed, but have an extremely slow metabolism, which often causes the development of cumulation and "bromism" (skin inflammatory diseases, conjunctivitis, ataxia, purpura, agranulocytosis, thrombocytopenia, depression or delirium).

Some antihistamines are still often used as sleeping pills: diphenhydramine, hydroxyzine, doxylamine, promethazine. They cause oppression of the paradoxical phase of sleep, a strong "aftereffect" (headaches, drowsiness in the morning) and have anticholinergic properties. Most
an important advantage of antihistamines is the absence of dependence formation even with prolonged use

In "big" psychiatry in psychotic states, sedative antipsychotics or sedative antidepressants are used to correct sleep disorders, depending on the leading syndrome.

Zatsepilova Tamara Anatolievna
Associate Professor of the Department of Pharmacology, Faculty of Pharmacy, MMA named after THEM. Sechenov

Sleeping pills are used to facilitate falling asleep and ensure normal sleep duration.

Modern sleeping pills must meet the following requirements: to quickly induce sleep and maintain its optimal duration, not to disturb the natural ratio of the main phases of sleep; not cause respiratory depression, memory impairment, addiction, physical and mental dependence.

The classification of sleeping pills is based on their chemical structure.

CLASSIFICATION OF SLEEPING DRUGS

1) benzodiazepine derivatives

Midazolam(Dormicum), Nitrazepam(Radedorm, Eunoktin), flunitrazepam(Rohypnol), Temazepam, Triazolam(Halcyone), Estazolam

The drugs of this group bind to a macromolecular receptor complex, including receptors sensitive to GABA, benzodiazepines, barbiturates, as well as chlorine ionophores. As a result of the increased action of GABA, there is a more frequent opening of chlorine ionophores, the entry of chlorine ions into neurons, hyperpolarization of the latter, and the development of inhibitory processes.

In addition to the hypnotic effect, benzodiazepines have a sedative, anxiolytic (anti-anxiety), anticonvulsant and central muscle relaxant effect. Benzodiazepines are indicated for insomnia caused by anxiety, stressful situation and characterized by difficulty falling asleep, frequent nocturnal and (or) early morning awakenings.

2) derivatives of imidazopyridine and pyrrolopyrazine

Zolpidem(Ivadal) Zopiclone(Imovan, Relaxon, Somnol)

This relatively new group of hypnotics has a number of advantages: sleep against their background is more physiological, there is a rapid falling asleep, and a muscle relaxant effect is not very pronounced. Such effects can be explained by more selective binding of drugs to the macroreceptor complex.

3) pyridine derivatives

doxylamine(Donormil)

According to the chemical structure, it is close to blockers of H1-histamine receptors, it penetrates well through the blood-brain barrier. The hypnotic effect is due to the blockade of the central H1-histamine receptors. Anti-allergic properties are not very pronounced. The drug is available in the form of regular or effervescent tablets.

4) derivatives of barbituric acid

Phenobarbital(Luminal) Cyclobarbital

Compared with hypnotics of other groups, barbiturates change the structure of sleep (reduce the duration of the fast-wave phase), cause withdrawal syndrome, induce microsomal liver enzymes, and are more dangerous in terms of developing drug dependence and the risk of poisoning. Currently, sleeping pills from this group are rarely used. Phenobarbital is currently classified as an anticonvulsant and is mainly included in the composition of combined sedative drugs (Valocordin, Corvalol, Valoserdin).

Cyclobarbital is part of the combined hypnotic drug Reladorm.

Table. Comparative characteristics of hypnotics

The pharmacokinetic indicator T1 / 2 (half-life) largely determines the rate of onset and duration of sleep. Midazolam and Triazolam, Zopiclone and Zolpidem are short-acting drugs (T1 / 2 - up to 6 hours). They should be recommended to patients in whom the process of falling asleep is disturbed. Temazepam, estazolam, doxylamine - drugs of medium duration of action (T1 / 2 - up to 18 hours). They should be recommended to patients in whom the process of falling asleep is disturbed, and sleep is not long. Nitrazepam and Flunitrazepam are long-acting drugs (T1 / 2 - over 30 hours). They should be recommended to patients whose sleep is not long.

The pharmacist should warn the patient about the need to determine the cause of insomnia and that these drugs should not be taken for a long time, since they can cause a number of negative side effects. The action of hypnotics can be enhanced by antihistamines and other CNS depressants. The day after taking sleeping pills, you should avoid driving and activities that require increased attention and speed of reaction. During treatment, alcohol is not allowed.

Sleep is a state of the body, which is characterized by the cessation of motor activity, a decrease in the function of analyzers, a reduction in contact with the environment, and a more or less complete shutdown of consciousness. Sleep is an active process in which the function of hypnogenic (promoting sleep) structures of the brain (parts of the thalamus, hypothalamus, reticular formation) is increased, and the function of activating structures (ascending reticular formation) is reduced. Natural sleep consists of two phases - "slow" and "fast". "Slow" sleep (orthodox, synchronized) takes up to 15% the entire duration of sleep, it provides physical rest for a person. "REM" sleep (paradoxical, desynchronized, accompanied by rapid eye movement) is 20-25% of the total duration of sleep, in this phase important mental processes occur, for example, memory consolidation. Sleep phases alternate. Violation of the duration of each phase (when using drugs, mental disorders) has an extremely unfavorable effect on the state of the body. For example, when a person is deprived of "REM" sleep, he feels lethargic and overwhelmed throughout the day, and the next night the duration of this phase increases compensatory. For sleep disorders, sleeping pills are prescribed. So, in case of sleep disturbance, short-acting hypnotics are prescribed, and long-acting drugs are used to maintain the required duration of sleep. Hypnotic drugs cause side effects: most drugs disrupt natural sleep and cause post-somnic disorders (lethargy, lethargy), the development of addiction. Physical addiction can develop to bar-biturates.

Classification of sleeping pills by chemical structure

1. Benzodiazepine derivatives: nitrazepam, flunitrazepam.

2. Barbiturates: sodium barbital, phenobarbital, sodium etaminal.

3. Preparations of different groups: imovan, sodium oxybutyrate (see drugs for anesthesia), dimedrol (see antihistamines).

In addition, sleeping pills are distinguished by the strength of the hypnotic effect, the speed of the onset of sleep and its duration.

Benzodiazepine derivatives (benzodiazepine receptor agonists) The hypnotic effect of benzodiazepines is associated with the inhibitory effect of drugs on the limbic system and the activating reticular formation. The mechanism of action of benzodiazepines is determined by interaction with special benzodiazepine receptors. Benzodiazepine receptors are part of a macromolecular complex that includes receptors sensitive to γ-aminobutyric acid (GABA), benzodiazepines and barbiturates, as well as chlorine ionophores. Due to allosteric interaction with specific receptors, benzodiazepines increase the affinity of GABA to GABA receptors and enhance the inhibitory effect of GABA. There is a more frequent opening of chlorine ionophores, while the flow of chlorine into neurons increases, which leads to an increase in the inhibitory postsynaptic potential.

Nitrazepam has a pronounced hypnotic, anxiolytic, anticonvulsant and central muscle relaxant effect. The hypnotic effect of nitrazepam occurs in 30-60 minutes and lasts up to 8 hours. The drug moderately inhibits the phase of "rapid" sleep. It is well absorbed, has a long half-life, and is metabolized in the liver. The drug accumulates. With repeated use, addiction develops. Indications for appointment - sleep disorders, especially those associated with emotional stress, anxiety, anxiety.

Benzodiazepine derivatives - midazolam (dormicum), flunitrazepam (rohypnol), al-prazolam are also used as hypnotics.

Benzodiazepines differ from barbiturates in that they change the structure of sleep to a lesser extent, have a greater breadth of therapeutic action, and do not cause the activation of microsomal enzymes.

Barbituric acid derivatives

Barbiturates interact with the allosteric site of the GABAd-benzodiazepine-barbiturate receptor complex and increase the affinity of GABA for GABA A receptors. This mechanism leads to inhibition of the reticular formation. Phenobarbital is a derivative of barbituric acid that has a long-term hypnotic effect. When taking the drug, sleep occurs after 30-60 minutes. The duration of the hypnotic effect of phenobarbital is 8 hours. Sleep induced by barbiturates is less physiological than sleep induced by benzodiazepines. Barbiturates significantly shorten REM sleep, which, when the drug is discontinued, can lead to the development of the “recoil” syndrome (compensation occurs in the form of an increase in the proportion of REM sleep). Barbiturates have antiepileptic and anticonvulsant activity. Phenobarbital causes the induction of microsomal liver enzymes, which increases the rate of biotransformation of xenobiotics and phenobarbital itself. With repeated use of phenobarbital, its activity decreases, addiction develops. Symptoms of addiction appear after two weeks of constant use of the drug. Prolonged use of barbiturates can lead to the development of drug dependence. After barbiturate sleep, lethargy, weakness, and a decrease in attention often occur.

An overdose of barbiturates leads to depression of the respiratory center. Treatment of poisoning begins with gastric lavage, forced diuresis. In a coma, artificial lung ventilation is used. Antagonist of barbiturates - analeptic - bemegrid.

Other groups of sleeping pills

Imovan (zopiclone) is a member of a new class of psychotropic drugs called cyclopyrrolones, which are structurally different from benzodiazepines and barbiturates. The hypnotic effect of imovan is due to a high degree of affinity for binding sites on the GABA receptor complex in the CNS. Imovan quickly induces sleep and maintains it without reducing the share of "REM" sleep. The absence of drowsiness in the morning favorably distinguishes a-yut imovan from drugs of the benzodiazepine and barbiturate series. The half-life period is 3.5-6 hours. Repeated intake of imovan is not accompanied by accumulation of the drug or its metabolites. Imovan is indicated for the treatment of insomnia, including difficulty falling asleep, nocturnal and early awakenings, as well as secondary sleep disorders in mental disorders. Prolonged use of imovan, like other sleeping pills, is not recommended; the course of treatment should not exceed 4 weeks. The most common side effect is a bitter or metallic taste in the mouth. Less common are gastrointestinal disorders (nausea, vomiting) and mental disorders (irritability, confusion, depressed mood). On awakening, drowsiness and, less commonly, dizziness and incoordination may be noted.

ANTICONVULTS AND ANTIEPILEPTICS

Anticonvulsants are used to eliminate convulsions of any origin. The cause of seizures can be diseases of the central nervous system (meningitis, encephalitis, epilepsy), metabolic disorders (hypocalcemia), hyperthermia, intoxication. The mechanism of action of anticonvulsants is to suppress the increased activity of neurons involved in the formation of a convulsive reaction and to suppress the irradiation of excitation by disrupting synaptic transmission. The anticonvulsants are sodium hydroxybutyrate(see drugs for anesthesia), benzodiazepines. barbiturates, magnesium sulfate.

Antiepileptic drugs are used to prevent or reduce convulsions or their equivalents (loss of consciousness, autonomic disorders) observed during recurrent seizures of various forms of epilepsy. There is no single mechanism of antiepileptic action of drugs. Some (difenin, carbamazepine) block sodium channels, others (barbiturates, benzodiazepines) activate the GABA system and increase the flow of chlorine into the cell, others (trimethine) block calcium channels. There are several forms of epilepsy:

large seizures - generalized tonic-clonic convulsions with loss of consciousness, followed in a few minutes by general depression of the central nervous system; small seizures - a short-term loss of consciousness with myoclonic convulsions; psychomotor automatisms - unmotivated actions with switched off consciousness. In accordance with the clinical manifestations of epilepsy, antiepileptic drugs are classified:

1. Means used for major epileptic seizures: phenobarbital, di-fenin, hexamidine.

2. Drugs used in small epileptic seizures: ethosuccimide, sodium valproate, clonazepam.

3. Means used for psychomotor seizures: carbamazepine, difenin.

4. Means used in status epilepticus: sibazon, sodium phenobarbital.

Medications used in grand mal seizures Phenobarbital (see Sleeping pills) is used in subhypnotic doses to treat epilepsy. The effectiveness of the drug is determined by its inhibitory effect on the excitability of neurons of the epileptogenic focus, as well as on the propagation of nerve impulses. With prolonged use of phenobarbital, the formation and activity of microsomal liver enzymes increases. Phenobarbital is slowly and well absorbed in the small intestine, its bioavailability is 80%. The maximum concentration in the blood is created 6-12 hours after taking a single dose of the drug. The half-life is on average about 10 hours. When prescribing the drug, especially in the first time, drowsiness is noted.

Difenin blocks sodium channels, prolongs the time of their inactivation and thus prevents the generation and propagation of electrical discharges in the central nervous system and thus prevents the development of seizures. Difenin is very well absorbed in the gastrointestinal tract, its bioavailability reaches almost 100%. It binds to plasma proteins by 90%, even a slight decrease in albumin binding leads to a significant increase in the amount of free substance in the blood, an increase in its effects and the possibility of developing intoxication. A stable concentration in the blood is achieved after 1-2 weeks of taking the drug. The metabolism of difenin occurs due to its hydroxylation in the liver with the formation of glucuronides. Difenin is an active inducer of hepatocyte microsomal enzymes. It stimulates its own biotransformation, as well as the inactivation of other antiepileptic drugs, steroid hormones, thyroxine, vitamin D in the liver. Treatment of epilepsy is long and therefore great attention must be paid to the development of side effects. Long-term use of the drug causes the development of peripheral neuropathy, gingival hyperplasia, hirsutism, megaloblastic anemia.

Hexamidine is similar in chemical structure to phenobarbital, but less active. The drug is well absorbed. In the process of metabolism in the liver, 25% of hexamidine is converted into phenobarbital. The drug may cause drowsiness, dizziness.

Drugs used in small epileptic seizures

Ethosuximide - is rapidly and completely absorbed when taken orally, the maximum concentration in the blood is created after 1-4 hours. The drug does not bind to plasma proteins, it is biotransformed in the liver by hydroxylation and glucuronization. About 20% of the administered dose of ethosuxemide is excreted unchanged in the urine. Undesirable side effects: anxiety, abdominal pain, with prolonged use - the development of eosinophilia and other hematopoietic disorders, lupus erythematosus. sodium valproate- inhibitor of GABA-transaminase - reduces the inactivation of GABA, one of the main inhibitory neurotransmitters. The drug not only prevents the development of epileptic seizures, but also improves the mental status of the patient, his mood. The drug is well absorbed in the gastrointestinal tract, bioavailability is about 100%. Sodium valproate is approximately 90% bound to plasma proteins. Signs of intoxication with sodium valproate are lethargy, nystagmus, balance and coordination disorders. With prolonged use, liver damage, pancreatitis, and a decrease in platelet aggregation are possible.

Clonazepam belongs to the group of benzodiazepines, which are GABA potentiators that can increase the sensitivity of GABA receptors to GABA. The bioavailability of clonazepam is about 98%, it is biotransformed in the liver. Side effects: fatigue, dysphoria, incoordination, nystagmus.

Drugs used in psychomotor seizures

Carbamazepine (Finlepsin) is similar in structure to tricyclic antidepressants. The mechanism of action of the drug is associated with the blockade of sodium channels. Its anti-epileptic effect is accompanied by an improvement in the behavior and mood of patients. Carbamazepine, in addition to its antiepileptic action, has the ability to relieve pain in trigeminal neuralgia. When taken orally, it is absorbed slowly, bioavailability is 80%. Biotransformed with the appearance of an active metabolite in the liver - epoxide. Epoxide has antiepileptic activity, which is 1/3 of that of carbamazepine. Carbamazepine is an inducer of microsomal liver enzymes, and it also stimulates its own biotransformation. Its half-life during the first weeks of treatment decreases from about 35 to 15-20 hours. The first signs of intoxication: diplopia, balance and coordination disorders, as well as CNS depression, dysfunction of the gastrointestinal tract. With prolonged use of the drug, a rash on the skin, damage to the hematopoietic function of the bone marrow, impaired renal and liver function may occur.

ANTIPARKINSONIC DRUGS

Parkinsonism is a syndrome of damage to the extrapyramidal nervous system, characterized by a combination of tremor (trembling), extrapyramidal muscle rigidity (sharply increased muscle tone) and akinesia (stiffness of movements). There are Parkinson's disease, secondary parkinsonism (vascular, drug, etc.) and parkinsonism syndrome in degenerative and hereditary diseases of the central nervous system. Despite the different etiologies of these diseases, the pathogenesis of symptoms is similar and is associated with progressive degeneration of nigrostriatal neurons, resulting in a decrease in dopamine synthesis and the activity of dopaminergic systems, while the activity of cholinergic systems (which are also involved in the regulation of

tor functions) increases relatively or absolutely. Pharmacotherapy of parkinsonism is aimed at correcting this imbalance of neurotransmitters that ensure the activity of the extrapyramidal nervous system. For pharmacotherapy of parkinsonism apply:

1. Means that affect the dopaminergic structures of the brain: a). The precursor of dopamine - levodopa, levodopa with a DOPA inhibitor

decarboxylases - - carbidopa (nakom);

b). Dopaminomimetics - direct (bromocriptine) and indirect (midantan)

2. Substances that depress the cholinergic structures of the brain (central anticholinergics) - cyclodol.

Drugs affecting the dopaminergic structures of the brain Levodopa

Since dopamine (and other catecholamines) does not pass through the blood-brain barrier (BBB), the metabolic precursor of dopamine, levodopa, is used for replacement therapy, which passes through the BBB and in dopaminergic neurons under the action of cerebral DOPA decarboxylase (DDC) is converted into dopamine. Levodopa reduces muscle rigidity and hypokinesia with little effect on tremor Treatment begins at a subthreshold dose and gradually over time 1,5-2 months, increase the dose until the effect occurs. With a rapid increase in the individual dose, the risk of early onset of side effects from the gastrointestinal tract and the cardiovascular system increases. This is due to the fact that in the gastrointestinal tract and bloodstream there is a "premature" decarboxylation of levodopa with the formation of not only dopamine, but also norepinephrine and adrenaline. This in 50 - 60% of cases leads to the appearance of nausea, vomiting, intestinal dyskinesia, cardiac arrhythmias, angina pectoris and fluctuations in blood pressure. Up to 80% of ingested levodopa undergoes "premature" decarboxylation, and only 1/5 of the dose taken reaches the brain and is metabolized by cerebral DDC with the formation of dopamine. Therefore, it is advisable to use levodopa in combination with peripheral DDC inhibitors - carbidopa or benserazide. Peripheral DDC inhibitors inhibit premature decarboxylation of levodopa in the gastrointestinal tract and bloodstream. When taking levodopa preparations with a DDC inhibitor, the frequency of cardiovascular and gastroenterological complications decreases to 4-6%. At the same time, inhibition of "premature" decarboxylation increases the flow of the accepted dose of levodopa through the BBB into the brain by 5 times. Therefore, when replacing "pure" levodopa with drugs with a DDC inhibitor, a 5-fold lower dose of levodopa is prescribed.

Bromkriptine is a derivative of the ergot alkaloid ergocryptine. It is a specific agonist of O 2 dopamine receptors. The drug has a distinct anti-Parkinsonian activity. In connection with the effect on the dopamine receptors of the hypothalamus, bromocriptine has an inhibitory effect on the secretion of hormones of the anterior pituitary gland, especially prolactin and somatotropin. The disadvantages are lower efficiency compared to levodopa and a high frequency of side effects (nausea, vomiting, anorexia, diarrhea, orthostatic hypotension, peripheral vasospasm, mental disorders).

Amantadine (midantan) is effective in almost half of patients, especially in combination with anticholinergics. Amantadine blocks glutamate receptors, enhances the release of dopamine into the synaptic cleft. Its positive quality is the effect on tremor. Side effects in the treatment of amantadine are anxiety, dizziness. Midantan glucuronide - gludantan is inferior in pharmacotherapeutic activity to amantadine hydrochloride, but rarely gives side effects.

Selegiline (deprenyl, umex) is a selective inhibitor of monoamine oxidase type B (MAO-B), which is involved in the degradation of dopamine. Thus, selegiline potentiates the effect of levodopa. Selegiline increases the life expectancy of patients receiving levodopa. This drug has an antioxidant effect on dopaminergic cells, and possibly has a neuroprotective effect, slowing down the progression of the disease.

Catechol-O-methyl-transferase (COMT) inhibitors

COMT naturally metabolizes L-DOPA to 3-0-methyldopa and dopamine to 3-0-methypdopamine. These compounds are not involved in the implementation of the function of dopamine neurons. COMT inhibitors interfere with the metabolism of dopamine and its precursor. Tolcapone is a COMT inhibitor passing through the BBB, i.e. acting both in the periphery and in the brain. The addition of tolcapone to levodopa increases and prolongs the steady-state plasma level of levodopa by 65%.

Anticholinergics (See anticholinergics)

Cholinolytic agents in parkinsonism stop the relative or absolute increase in the activity of cholinergic systems. All of them are antagonists of cholinergic receptors and are clinically approximately equivalent. Improvement occurs in 3/4 of patients, and rigidity is especially reduced. Cholinolytic agents are contraindicated in glaucoma and prostate adenoma. Side effects: dry mouth, blurred vision. The most commonly used anticholinergic for parkinsonism is cyclodol.

Rp: Nitrazepami 0.005

D.t.d. No. 10 in tab.

S. no 1 tablet at night

Rp: Phenobarbitali 0.05

D.t.d. No. 10 in tab.

S. no 1 tablet at night

Rp: Diphenini 0.117

D.t.d. No. 10 in tab.

Rp: Clonazepami 0.001

D.t.d. No. 20 in tab.

S. no 1 tablet 3 times a day

Rp: Carbamasepini 0.2

D.t.d. No. 10 in tab.

S. no 1 tablet 3 times a day

Rep: Sol. Sibazoni 0.5% - 2 ml

D.t.d. N 10 ampull.

S. no 2 ml intramuscularly

Rp: Levodopi 0.25

D.t.d. No. 100 in tab.

S. no 1 tablet 4 times a day

Rep: Tab. "Nakom"

D.t.d. No. 50 in tab.

S. no 1 tablet 3 times a day

Rp: Cyclodoli 0.002

D.t.d. No. 40 in tab.

S. no 1 tablet 3 times a day

Rp: Midantani 0.1

D.t.d. No. 10 in tab.

S. no 1 tablet 3 times a day

Hypnotics facilitate falling asleep, increase the depth and duration of sleep, and are used to treat insomnia (insomnia).
Sleep disorders are widespread in the modern world: 90% of people have suffered from insomnia at least once, 38-45% of the population are unhappy with their sleep, 1/3 of the population suffers from episodic or persistent sleep disorders that require treatment. Insomnia is one of the serious medical problems in the elderly. With psychogenic neurotic and psychotic disorders, the frequency of insomnia reaches 80%.
Wakefulness is turned on and maintained by the ascending reticular formation of the midbrain, which has a nonspecific activating effect on the cerebral cortex. In the brain stem during wakefulness, the activity of cholinergic and adrenergic synapses predominates. The electroencephalogram (EEG) of wakefulness is desynchronized - high-frequency and low-amplitude. Neurons generate action potentials asynchronously, in an individual continuous, frequent mode.
The duration of sleep in newborns is 12-16 hours per day, in adults - 6-8 hours, in the elderly - 4-6 hours. Sleep is regulated by the hypnogenic system of the brain stem. Its inclusion is associated with biological rhythms. The neurons of the dorsal and lateral hypothalamus secrete the mediator orexin A (hypocretin), which controls the wake-sleep cycle, eating behavior, the activity of the cardiovascular and endocrine systems.
According to polysomnography (electroencephalography, electrooculography, electromyography), slow and fast phases are distinguished in the structure of sleep, combined in cycles of 1.5–2 hours. During night sleep, 4–5 cycles are replaced. In the evening cycles, REM sleep is very low, in the morning cycles its share increases. In total, non-REM sleep takes 75 - 80%, REM sleep - 20

• 25% sleep duration.

1. - superficial sleep, or drowsiness (a-, p- and 0-rhythms on the EEG);
2. - sleep with sleep spindles (sleep spindles and 0-rhythm);
3. - IV - deep sleep with 5 waves.

REM sleep increases the synthesis of RNA and protein in the brain.
Slow-wave sleep deficiency is accompanied by chronic fatigue, anxiety, irritability, decreased mental performance, and motor imbalance. Insufficient duration of REM sleep leads to difficulties in solving interpersonal and professional problems, arousal, hallucinations. Performing complex tasks that require active attention may not be impaired, but simple tasks are more difficult.
With deprivation of one of the phases of sleep in the recovery period, its hyperproduction occurs compensatory. REM sleep and deep stages (III-IV) of non-REM sleep are the most vulnerable.
Sleeping pills are prescribed only for chronic insomnia (sleep disturbance for 3

• 4 weeks). There are three generations of sleeping pills:

1. generation - derivatives of barbituric acid (barbiturates);

Table 30

Table 31. The effect of hypnotics on the duration and structure of sleep

Note. | - increase, 4 - decrease, - no change.

1. generation - derivatives of benzodiazepine, ethanolamine, aliphatic compounds;
2. generation - derivatives of cyclopyrrolone and imidazopyridine. Information about sleeping pills

the development of anticonvulsant and central muscle relaxant effects.
Benzodiazepine derivatives make it easier to fall asleep, reduce the number of nocturnal awakenings and motor activity during sleep, and lengthen sleep. In the structure of sleep caused by benzodiazepines with an average duration of effect (TEMAZEPAM) and long-acting (NITRAZEPAM, FLUNITRAZEPAM), phase II of non-REM sleep prevails, although stages III-IV and REM sleep are reduced less than with the appointment of barbiturates. The post-somnic effect is manifested by drowsiness, lethargy, muscle weakness, slowing down of mental and motor reactions, impaired coordination of movements and the ability to concentrate, anterograde amnesia (loss of memory for current events), loss of sexual desire, arterial hypotension, increased bronchial secretion. The aftereffect is especially pronounced in elderly patients suffering from cognitive deficits. They, along with movement disorders and decreased attention, experience disorientation in space and time, a state of confusion, an inadequate reaction to external events, and imbalance.
The short-acting agent OXAZEPAM does not disturb the physiological structure of sleep. Awakening after taking oxazepam is not accompanied by aftereffect symptoms. TRIAZOLAM causes dysarthria, serious disorders of coordination of movements, disorders of abstract thinking, memory, attention, lengthens the reaction time of choice. These side effects limit the use of triazolam in medical practice.
A paradoxical reaction to taking benzodiazepines is possible in the form of euphoria, lack of rest, hypomania, hallucinations. With the rapid discontinuation of sleeping pills, a recoil syndrome occurs with complaints of "recurrent" insomnia, nightmares, bad mood, irritability, dizziness, tremors and lack of appetite. Some people continue to take sleeping pills, not so much to improve sleep, but to eliminate the unpleasant manifestations of the withdrawal syndrome.
The hypnotic effect of long-acting drugs persists for 3-4 weeks. systematic intake, short-acting drugs - within 3 - 14 days. None of the studies conducted have confirmed the presence of a hypnotic effect of benzodiazepines after 12 weeks. regular use.
Derivatives of benzodiazepine in hypnotic doses usually do not disturb breathing, cause only mild arterial hypotension and tachycardia. In patients with lung diseases, there is a danger of hypoventilation and hypoxemia, as the tone of the respiratory muscles and the sensitivity of the respiratory center to carbon dioxide decrease.
Compounds of the benzodiazepine series as central muscle relaxants can worsen the course of respiratory disorders during sleep. This syndrome occurs in 37% of people, more often in overweight men over 40 years of age. With apnea (Greek a - denial, ppoe - breathing), the respiratory flow stops or becomes below 20% of the original, with hypopnea - below 50%. The number of episodes is at least 10 per hour, their duration is 10 - 40 s.
There is an occlusion of the upper respiratory tract due to an imbalance in the movements of the muscles - dilators of the tongue, soft palate and pharynx. The flow of air into the respiratory tract stops, which is accompanied by snoring. At the end of the episode, hypoxia causes a "half-awakening" that returns muscle tone to the waking state and resumes breathing. Respiratory disorders during sleep are accompanied by anxiety, depression, daytime drowsiness, morning headache, nocturnal enuresis, arterial and pulmonary hypertension, arrhythmia, angina pectoris, cerebrovascular accident, sexual problems.
Hypnotics of the benzodiazepine group are well absorbed when taken orally, their connection with blood proteins is 70 - 99%. The concentration in the cerebrospinal fluid is the same as in the blood. In the molecules of nitrazepam and flunitrazepam, the nitro group is first reduced to the amino group, then the amino group is acetylated. Triazolam is oxidized by cytochrome P-450. a-Oxytriazolam and unchanged oxazepam and temazepam add glucuronic acid (see diagram in lecture 29).
Benzodiazepine derivatives are contraindicated in drug addiction, respiratory failure, myasthenia gravis. They are prescribed with caution in cholestatic hepatitis, renal failure, organic brain damage, obstructive pulmonary disease, depression, predisposition to drug dependence.

Derivatives of cyclopyrrolone and imidazopyridine
The cyclopyrrolone derivative ZOPICLON and the imidazopyridine derivative ZOLPIDEM, as ligands of allosteric benzodiazestic binding sites in the GABA-receptor complex, enhance GABAergic inhibition in the limbic system. Zopiclone acts on the γ1 and γ2 benzodiazepine receptors, while zolpidem acts only on γ1.
The drugs have a selective hypnotic effect, do not violate the physiological structure of sleep and biorhythmological type, do not form active metabolites. In patients taking zopiclone or zolpidem, there is no feeling of "artificiality" of sleep, after waking up there is a feeling of cheerfulness and freshness, increased efficiency, speed of mental reactions, vigilance. The hypnotic effect of these drugs persists for a week after discontinuation, the recoil syndrome does not occur (only on the first night sleep may worsen). In high doses, zopiclone exhibits anti-anxiety and anticonvulsant properties.
Zopiclone and zolpidem have an oral bioavailability of 70% and are rapidly absorbed from the intestine. Communication with proteins of zopiclone is 45%, zolpidem - 92%. The drugs penetrate well through the histohematogenous barriers, including the blood-brain and placental. Zopiclone, with the participation of the 3A4 isoenzyme of cytochrome P-450 of the liver, is converted into N-oxide with weak pharmacological activity and into two inactive metabolites. Metabolites are excreted in the urine (80%) and bile (16%). Zolpidem is oxidized by the same isoenzyme into three inactive substances that are excreted in the urine (1% unchanged) and bile. In people over 70 years of age and with liver diseases, elimination slows down, against the background of renal failure, it changes insignificantly.
Zopiclone and zolpidem only cause dizziness, drowsiness, depression, irritability, confusion, amnesia, and dependence in 1-2% of patients when taken in high doses. When taking zopiclone, 30% of patients complain of bitterness and dry mouth. The drugs are contraindicated in respiratory failure, obstructive sleep apnea, severe liver disease, pregnancy, children under 15 years of age. During breastfeeding, the use of zopiclone is prohibited (the concentration in breast milk is 50% of the concentration in the blood), it is permissible to use zolpidem with caution (the concentration is 0.02%).
Aliphatic derivatives
SODIUM OXYBUTYRATE (GHB) is converted to GABA. As a sleeping pill, it is taken orally. The duration of sleep is variable and ranges from 2 - 3 to 6 - 7 hours. The mechanism of action of sodium hydroxybutyrate is discussed in lecture 20.
The structure of sleep when prescribing sodium oxybutyrate differs little from the physiological one. Within the limits of normal fluctuations, lengthening of REM sleep and stage IV of non-REM sleep is possible. Aftereffect and recoil syndrome are absent.
The action of sodium hydroxybutyrate is dose-dependent: in small doses it has analgesic and sedative effects, in medium doses it has hypnotic and anticonvulsant effects, in large doses it has anesthetic effects.
Ethanolamine derivatives
DOXYLAMINE blocks histamine H-receptors and M-cholinergic receptors in the reticular formation. In terms of effectiveness for insomnia, it is comparable to benzodiazepine derivatives. The drug has a daily aftereffect, since its half-life is 11-12 hours. It is excreted unchanged (60%) and in the form of inactive metabolites with urine and bile. Side effects of doxylamine due to the blockade of peripheral M-cholinergic receptors include dry mouth, disturbance of accommodation, constipation, dysuria, fever. Doxylamine can cause delirium in the elderly. It is contraindicated in hypersensitivity, angle-closure glaucoma, urethroprostatic diseases, children under 15 years of age. Stop breastfeeding while taking doxylamine.
Barbiturates
In the group of barbiturates, the relative importance of ETAMINAL-SODIUM and PHENOBARBITAL was retained. Etaminal sodium has a hypnotic effect after 10-20 minutes, sleep lasts 5-6 hours.

Phenobarbital acts in 30-40 minutes for 6-8 hours.
Barbiturates are ligands for barbiturate receptors. In small doses, they allosterically enhance the action of GABA on GABA receptors. At the same time, the open state of chloride channels lengthens, the entry of chloride anions into neurons increases, and hyperpolarization and inhibition develop. In high doses, barbiturates directly increase the chlorine permeability of neuronal membranes. In addition, they inhibit the release of excitatory CNS mediators - acetylcholine and glutamic acid, block AMPA receptors (quisqualate receptors) of glutamic acid.
Barbiturates suppress the wakefulness system - the reticular formation of the midbrain, which contributes to the onset of sleep. They also inhibit the hypnogenic system of the hindbrain, which is responsible for REM sleep. As a result, the synchronizing effect on the cerebral cortex of the slow-wave sleep system - the thalamus, the anterior hypothalamus, and the raphe nuclei predominates.
Barbiturates make it easier to fall asleep, increase the total duration of sleep. The sleep pattern is dominated by phases II and III of non-REM sleep, superficial I and deep IV stages of non-REM sleep and REM sleep are reduced. A lack of REM sleep has undesirable consequences. Perhaps the development of neurosis and even psychosis. Cancellation of barbiturates is accompanied by hyperproduction of REM sleep with frequent awakenings, nightmares, a feeling of incessant mental activity. Instead of 4-5 episodes of REM sleep per night, there are 10-15 and even 25-30 episodes. When taking barbiturates for 5-7 days, the restoration of the physiological structure of sleep occurs only after 5-7 weeks. Patients develop psychological dependence.
Barbiturates have antihypoxic, anticonvulsant and antiemetic effects. Etaminal sodium is injected into a vein for non-inhalation anesthesia. Phenobarbital is prescribed for epilepsy.
Barbiturates are strong inducers of metabolic enzymes. In the liver, they double the biotransformation of steroid hormones, cholesterol, bile acids, vitamins D, K, folic acid, and drugs with metabolic clearance. Induction is accompanied by the development of rickets-like osteopathy, hemorrhage, macrocytic anemia, thrombocytopenia, metabolic incompatibility with combined pharmacotherapy. Barbiturates increase the activity of alcohol dehydrogenase and 8-aminolevulinic acid synthetase. The latter effect is dangerous exacerbation of porphyria.
Despite the inducing effect, phenobarbital undergoes material cumulation (the half-life is 100 hours) and has an aftereffect in the form of drowsiness, depression, weakness, impaired coordination of movements, headache, and vomiting. Awakening occurs in a state of mild euphoria, soon replaced by irritability and anger. The aftereffect of etaminal-sodium is less pronounced.
Barbiturates are contraindicated in severe diseases of the liver and kidneys, porphyria, myasthenia gravis, severe cerebral atherosclerosis, myocarditis, severe coronary heart disease, thyrotoxicosis, pheochromocytoma, prostate adenoma, angle-closure glaucoma, alcoholism, individual intolerance. With painful insomnia, they cause delirium, increasing the perception of pain.
PHARMACOTHERAPY OF INSOMNIA
The terms "insomnia" or "insomnia" mean disturbances in the quantity, quality or time of sleep, which are accompanied by a deterioration in daytime psychophysiological functioning - daytime sleepiness, anxiety, difficulty concentrating, memory loss, morning headache, arterial hypertension (mainly morning and diastolic ). The etiological factors of insomnia are varied - jet lag, stress, neurotic condition, depression, schizophrenia, alcohol abuse, endocrine-metabolic diseases, organic brain disorders, pain, pathological sleep syndromes (apnea, movement disorders such as myoclonus).
The following clinical variants of insomnia are known:

• presomnic (early) - difficulty falling asleep with a prolongation of the onset of sleep by more than 30 minutes (sometimes "fear of bed", "rituals of going to bed" are formed);
• intrasomnic (middle) - frequent nocturnal awakenings, after which the patient cannot fall asleep for a long time, with a feeling of superficial sleep;
• post-somnic (late) - painful early awakenings, when the patient, feeling sleepy, cannot fall asleep.

• for both disorders. Patients speak of insomnia if the subjective duration of sleep is less than 5 hours for three consecutive nights or its quality is impaired. In situations where the duration of sleep is normal, but its quality is changed, patients perceive their condition as
  insomnia. With presomnic insomnia, there are frequent transitions from stages I and II of slow-wave sleep to wakefulness. In patients with intrasomnic insomnia, non-REM sleep shifts to a superficial register with a decrease in deep stages III and IV. The predominance of a fast phase in the structure of sleep with nightmares, a feeling of weakness, and a lack of rest is especially difficult to tolerate.

• therapy begins with hygiene measures, psychotherapy, autorelaxation and the use of herbal sedatives;
• prefer short-acting hypnotics (oxazepam, zopiclone, zolpidem, doxylamine);
• with episodic insomnia, hypnotics are prescribed as needed;
• it is desirable to prescribe hypnotics in minimal doses in an intermittent mode - every other day, two days, on the third day, only on weekends;
• the duration of the course of therapy should not exceed 3-4 weeks, if long-term treatment is needed, “drug holidays” (breaks in prescription) are carried out, drugs are canceled for 1-2 months, reducing the dose by 25% for a quarter of the withdrawal period;
• older patients are advised to take half-dose hypnotics, especially carefully monitor the interaction of hypnotics with other drugs, take into account cognitive impairment, prolongation of the half-life, a greater risk of cumulation, recoil syndrome, drug dependence;
• in cases of sleep apnea, sleeping pills are not allowed;
• if the objectively recorded duration of sleep is at least 6 hours, with subjective dissatisfaction (distorted perception of sleep or sleep agnosia), psychotherapy is used instead of pharmacotherapy.

SLEEPING DRUGS POISONING
Acute poisoning
Benzodiazepine derivatives, having a wide range of therapeutic effects, rarely cause acute poisoning with a fatal outcome. When poisoning first occurs hallucinations, disorders
articulation, nystagmus, ataxia, muscle atony, followed by sleep, coma, respiratory depression, cardiac activity, collapse.
A specific antidote for hypnotics and tranquilizers of this group is the benzodiazepine receptor antagonist FLUMAZENIL (ANEXAT). At a dose of 1.5 mg, it occupies 50% of the receptors, 15 mg of flumazenil completely block the benzodiazepine allosteric center in the GABA-receptor complex. The half-life of flumazenil is short - 0.7 - 1.3 hours due to intensive biotransformation in the liver. The drug is injected into a vein slowly, trying to avoid the symptoms of "rapid awakening" (excitation, disorientation, convulsions, tachycardia, vomiting). In case of poisoning with long-acting benzodiazepines, it is administered repeatedly. Flumazenil in patients with epilepsy can cause an attack of convulsions, with dependence on benzodiazepine derivatives - an abstinence syndrome, with psychoses - their exacerbation.
Barbiturate poisoning is the most severe. It occurs with an accidental (drug automatism) or intentional (suicide attempt) overdose. 20 - 25% of people entering a specialized poison control center were taking barbiturates. The lethal dose is about 10 therapeutic doses: for short-acting barbiturates - 2

• 3 g, for long-acting barbiturates - 4 - 5 g.

• sleep, turning into a coma such as anesthesia, hypothermia, constriction of the pupils (with severe hypoxia, the pupils dilate), inhibition of reflexes - corneal, pupillary, pain, tactile, tendon (in case of poisoning with narcotic analgesics, tendon reflexes are preserved and even enhanced);
• depression of the respiratory center (sensitivity to carbon dioxide and acidosis decreases, but not to reflex hypoxic stimuli from the carotid glomeruli);
• bronchorrhea with a picture of pulmonary edema (increased secretory activity of the bronchial glands is not due to an increased parasympathetic effect on the bronchi and is not eliminated by atropine);
• violation of the dissociation of oxyhemoglobin, hypoxia, acidosis;
• weakening of cardiac activity due to blockade of sodium channels of cardiomyocytes and disruption of bioenergetics;
• collapse caused by inhibition of the vasomotor center, blockade of H-cholinergic receptors of sympathetic ganglia and myotropic antispasmodic effect on the vessels;
• anuria as a result of arterial hypotension.

reabsorption. Their elimination is accelerated by 8 - 10 r

Various sleep disorders in the modern world are quite common. It has been proven that insomnia is diagnosed in a larger percentage of the population in residents of large cities compared to residents of villages and towns. Sleeping pills are the main treatment for sleep disorders. What drugs are the strongest and can you buy them without a prescription?

The girl took pills to ease the onset of sleep

Classification of sleeping pills

Sleeping pills are called drugs that cause a state that, according to their characteristics, approach natural sleep and can speed up the process of falling asleep, increase the depth of sleep and its duration. The scientific name for a group of sleep medications is hypnotics. Small doses of these drugs have a relaxing and calming effect.

All hypnotics are divided into two large groups: drugs with narcotic and non-narcotic effects.

Non-narcotic hypnotics:

• Benzodiazepines - Nitrazepam, Dormicum, Flunitrazepam, Halcyon, Triazolam, Temazepam.
• Nonbenzodiazepines: Zolpidem (Ivadal), Zopiclone (Imovan).
• Histamine receptor blockers: Donormil.
• GABA derivatives: Phenibut.

Narcotic hypnotics:

• Barbiturates (derivatives of barbituric acid): Barbital, Phenobarbital, Estimal.

Benzodiazepines

This group of hypnotics includes substances that have hypnotic, anti-anxiety and antiepileptic effects. In sleep disorders, benzodiazepines accelerate the process of falling asleep and significantly lengthen the duration of rest. The action of drugs from this group affects the structure of sleep, shortening the phases of REM and REM sleep, so dreams with the use of benzodiazepines are an infrequent phenomenon.

The effectiveness of hypnotics from the benzodiazepine group increases due to the anxiolytic properties - relieving anxiety, tension, acute reaction to ongoing events, and therefore these drugs are the drugs of choice for the treatment of insomnia.

The list of drugs is quite extensive and includes trade names:

• Nitrazepam - "Eunoktin", "Radedorm", "Berlidorm".
• Midazolam - "Dormicum", "Flormidal".
• Triazolam - "Halcyone".
• Flunitrazepam - Rohypnol.

The average duration of treatment with benzodiazepines is 2 weeks. With a longer use - about 3-4 weeks, drug dependence develops. The abrupt cessation of taking these sleeping pills leads to the development of a withdrawal syndrome: the patient experiences anxiety, insomnia, he is tormented by nightmares, and there is a tremor of the limbs.

Psychoactive drugs with hypnotic, anxiolytic and anticonvulsant effects

An unpleasant effect of these sleeping pills is the “consequence syndrome” - after waking up, a person feels lethargy, weakness in the muscles, dizziness, drowsiness, impaired coordination of movements and a decrease in concentration. Similar symptoms are associated with the slow metabolism of benzodiazepines in the body - the drugs are absorbed into the blood from the stomach for a long time, and incomplete decay occurs in the liver with the excretion of active metabolites into the blood, which support the main effect of the tablets. In connection with this property, it is highly not recommended to use drugs for patients whose work requires concentration and concentration - drivers of vehicles, high-altitude workers.

Poisoning with benzodiazepines is quite rare due to their low toxicity.

Nonbenzodiazepines

The main drugs from this group were the so-called Z-drugs - Zopiclone, Zolpidem and Zaleplon. The gentle action of these tablets makes them safer than barbituric acid derivatives, and the reduced likelihood of developing physical dependence and addiction compared to benzodiazepines allows for longer treatment.

Like any other medicinal substances, non-benzodiazepine drugs have disadvantages - there is a possibility of developing amnesia, less often - hallucinations. Long-term use of Z-drugs may be accompanied by daytime sleepiness and anxiety. Zaleplon has a short half-life and is therefore safer for use in individuals whose activities require special attention.

Hypnotic drug of non-benzodiazepine structure

Treatment with nonbenzodiazepine drugs should not be stopped abruptly if therapy lasts more than 2 weeks, which is associated with an increased possibility of developing a withdrawal syndrome. The dose is reduced gradually, over several weeks, depending on the individual characteristics of the patient.

Histamine receptor blockers

A well-known property of drugs for the treatment of allergies is a hypnotic effect, on which the effect of the modern hypnotic drug Donormil is based. The mechanism of action of Donormil is based on its ability to influence certain parts of the brain responsible for the process of nervous excitation. The drug is dispensed from a pharmacy without a prescription, so it is more affordable. Among the side effects of Donormil should be highlighted severe dry mouth, constipation and urinary retention while taking sleeping pills. The drug is not addictive, and the possibility of poisoning is very low - not a single lethal outcome has been identified in case of an overdose.

Barbiturates

The main part of barbituric acid derivatives is excluded from the list of drugs for the treatment of insomnia due to the large number of side effects. In modern clinical practice, barbiturates are less and less prescribed to patients suffering from various sleep disorders. Sleep initiated by this group of drugs differs from normal physiological sleep - the cycle of phases is disturbed and its structure changes. Drug dependence develops immediately after repeated use, and long-term treatment provokes addiction. Sleep caused by narcotic sleeping pills is intermittent, the presence of nightmares is noted. After waking up, a person experiences severe drowsiness, fatigue, impaired coordination of movements.

A drug from the barbiturate group

Currently, only Phenobarbital and Cyclobarbital (Reladorm) are approved for use. Half the hypnotic dose of these drugs produces a relaxing effect, and exceeding the dosage by several times causes severe poisoning. Withdrawal syndrome develops immediately after the cessation of drug therapy and is expressed in severe insomnia, irritability, anxiety, bad mood and depression of performance.

GABA derivatives

Gamma-aminobutyric acid is an inhibitory mediator of the central nervous system and plays an important role in the formation of slow sleep. The main drug in this group is a remedy called Phenibut. This nootropic drug with a hypnotic effect helps to normalize the time to fall asleep and restores the normal cyclicity of sleep phases. Unlike drugs of the benzodiazepine series, Phenibut helps to prolong the phase of slow sleep, due to which the patient's well-being improves significantly after waking up. Sleeping pills have low toxicity, a short list of side effects and do not cause drug dependence.

Nootropic sleep aid

What is the best sleeping pill?

Only a doctor who knows all the individual characteristics of the patient's body and takes into account the type of sleep disturbance when prescribing a particular drug can answer this question. Only after a detailed history is taken, the doctor can issue a list of drugs for treatment with an exact indication of how many tablets should be taken.