Hypnotics

Hypnostics
Hypnotics are drugs that act as an CNS depressant. Drugs of first generation(barbiturate and non-barbiturate hypnotics) act primarily on teh ascending part of reticular formation, hypothalamus, thalamus and cerebral cortex. Hypnotics of second and third generation effect mainly on limbic system.

Hypnotics decrease vigility(vigilance). The effekt is graduated according to the dose size in order sedation-hypnosis-narkosis.

Sedation means calming the patient(motorically and mentally). Sedatives are considered to be those drugs that do not lead in themselves to teh induction of sleep. Those are for example plant extracts(Valerian officinalis – Tinctura valerianae, Maypop – Passiflora incarnata – NOPASSIT®, also bromisoval, guaifenezine – sedative, anxiolytic, myorelaxans). Some drugs included in this group in larger doses can still induce sleep(bromisoval, phenobarbital). They are considerate complementary drugs.

You will find more detailed information on the page Sedatives Hypnosis repressents a condition similar to physiological sleep. The ideal hypnotic should maintain the physiological sequence of REM and nonREM phases. However, most drugs shorten REM sleep, leading to a insufficient "sleep". After discontinuation of treatment a "rebound phenomenon" may occur, i.e

Mechanism of action

All hypnotics act on the GABA-benzodiazepine macromolecular complex, which is related to the activity of the chloride channel in a biomembrane of a neuron. GABA (gama-aminobutyric acid) is an inhibitory mediator that occupies its specific receptor, thereby leading to the opening of the channel and so the flow of chlorine ions intracellularly, so the intracellular potential decreases ever further. The consequence is hyperpolarization of the biomembrane and inhibition of function of the neuron. The occupation and influence of the benzodiazepine (BZ) receptor near the GABA receptor enhances the inhibitory influence of the mediator itself – GABA.

indication

 * sleep disorders
 * sleeplessnness(insomnia): inability to fall asleep, short sleep with early awakening, shallow sleep with frequent awakening

First generation
At pressent, they are no longer in this incation for their non-specific effect, easy inductoin of drug dependence, high toxicity(respiratory center depression) and numerous interactions with other drugs(induction of metabolism, especially barbiturates). This group inclucedes mainly brarbiturate hypnotics.

Second generation – benzodiazepine hypnotics
They are currently the drugs of choice in insomnia therapy. These hypnotics suppress REM sleep lightly or moderately strongly. Liver microsomal enzymes under their prolonged influence are not subject to induction. For these drugs, the range between toxic and therapeutic doses (i.e the pharmacotherapeutical window) is wide. With repeated administration, the risk of drug dependence is lower than with barbiturates. Withdrawal syndrome occurs under the image of insomnia, tremor, in more severe cases as epileptic seizure, hallucinations and delirium. The severity of withdrawal symptoms depends on the last doses of hypnotics (the higher the dose, the more dangerous the manifestations of withdrawal syndrome), on the value of biological half-life of the drug (the shorter the half-life, the greater the danger of provoking withdrawal syndrome).

Benzodiazepines have a specific antagonist at the BZ receptors – flumazenil. With its use, the effect of benzodiazepines (not barbiturates or alcohol) can be quickly abolished.

More detailed information can be found on the Benzodiazepine intoxication page Benzodiazepines are synergists of all CNS depressant drugs. They have adverse effects on memory and otjer cognitive function ( concentration of attention and judgement, learning ability), whick can manifest as amnesia, a disorder of continuity of consciousness, especially in the elderly. Benzodiazepines are not suitable for people, where increased attention and reactivity are required( drivinf, operating machinery). They also enhance the effects of alcohol and invertly alcohol inhibits the metabolism of long-acting benzodiazepines( e.g. inhibition is still evident 10 hours after the last dose of diazepam).

There is cross-tolerance between hypnotics and alcohol may be also included. This explains, why the effects of standard doses of hypnotics cannot be achieved with sufficient effect in individuals with a history of recent excessive use of these hypnotics or alcohol.

Drugs from both groups of anxiolytics pass rapidly through the placental barrier. They are metabolised slowly by the fetus. A teratogenic effect has not been proved but some authors describe a higher incidence of cleft lip and palate, lower birth weight and lenght of fetuses of mothers, which used these drugs in the first trimester of pregnancy. If given in the last trimester they may lead to toxic manifestations in the newborn( lethargy, hypotonia, hypothermia - so-called "floppy infant") or to a withdrawal syndrome( tremor, tachypnoea, convulsive manifestations, etc.). It is therefore recommended to discontinue anxiolytics as early as one month before delivery. Benzodiazepine anxiolytics pass into breast milk and may lead to excessive sedation of the infant. Therefore, mothers with a medium to long t1/2 should not breastfeed.

Benzodiazepines with strong hypnotic and weak anxiolytic effects
They also have a weak myorelaxant effect and their effect is therefore non-specific.

Short-acting (up to 6 hours after last dose)
*Midazolam- Used as a premedication before short-term surgical or internal procedures - gastroscopy, colonoskopy. ===== Medium long-acting(8-10 hours) ====== *Flunitrazepam

Long acting
*Nitrazepam, flurazepam - characterised by residual morning effects (drowsiness) and the possibility of cumulation.

Benzodiazepines with strong anxiolytic and weak hypnotic effect
*see Anxiolytics

The choice of medication is guided by teh type of insomnia

 * 1) for difficulty falling asleep, short-acting or medium long-acting hypnotics are used at usual doses, flunitrazepam at a low dose of up to 1 mg
 * 2) for recurrent noctural awakenings, higher doses of short-acting or usual doses of medium-acting hypnotics are used
 * 3) early awaking without teh need for morning vigilance is treated with long-acting hypnotics, if morning vigilance is needed medium-acting hypnotics may be used at usual dose

It is a seriuous error to prescribe hypnotics for longer periods(usually more than 2-3 weeks)

Overview of side effects of non-specific hypnotics

 * Residual somnolence and fatigue in the morning, especially due to drugs with a long biological half-life.
 * danger of acculumation.
 * Confusion(in the elderly).
 * Stimulant effect instead of inhibiotion, excitaion in children after barbiturates.
 * Diazepam is associated with depression and suicidal attempts.
 * Nightmares after Diazepam have also been described.
 * Amnesia for the duration of teh effect of the drug(i.e., anterograde amnesia, can be used for uncomfortable clinical examinations).
 * "Rebound insomnia" after discontinuations of the drug.
 * Potentation of CNS depressant effect in combination with other agents.