Giulia Massano, Giulia Rivetti, Luca Guaschino
Zolpidem is a non benzodiazepine hypnotic agent with weak anxiolytic activities, muscle relaxants and anticonvulsants. Chemically it is a imidazopiridine derivative, the structure of which differs both from that of benzodiazepines and of zopiclone.
Structure
C 19 H 21 N 3 O
EXCIPIENTS
Tablet core:
- lactose monohydrate
- microcrystalline cellulose
- sodium starch glycolate (type A)
- magnesium stearate
- hypromellose
Coating:
- hypromellose
- titanium dioxide (E171)
- macrogol 400
Sleep is divided into non-REM (non-Rapid Eyes Movement) and REM (Rapid Eyes Movement).
The non-REM sleep is characterized by alternating CAP periods (cyclic Alternative Pattern) to non-CAP periods. These periods have two phases: phase A (greater sensitivity to external sensorial stimulations that disturb sleep) and phase B (higher awakening threshold). The CAP rate is the objective parameter that measures the stability of sleep and it can be seen as the ratio "length of periods ZIP / sleep duration."
Zolpidem is effective in inducing and subsequently maintaining the physiological parameters of sleep.
Zolpidem acts on the stage of deep sleep, during which is greater the influence of the phase A of the CAP period. In treating chronic insomnia, the drug reduces the levels of CAP from pathological values around 60% at amounts equal to 26%.
Zolpidem causes a rapid induction of sleep (15-30 minutes of administration): Unlike the benzodiazepines, it does not change the phase of REM sleep and leaves unchanged or extends the duration of deep sleep. It reduces the latency to sleep, the number of night-time awakenings and time awake at night, extending the duration of total sleep.
COMPARISON WITH BENZODIAZEPINES
In studies comparing the short and long half-life benzodiazepines, zolpidem showed an comparable improvement regarding sleep latency, number of nocturnal awakenings, duration, sleep quality and clinical residual effects (sedation and deficits in behavior during the day).
For what concernes the pharmacokinetic profile, zolpidem should lead to lower residual daytime effects compared to benzodiazepines, especially those with short duration of action which result in lower incidence of side effects, less risk of rebound insomnia (symptoms returned but in a more severe way) and minor alteration of sleep stages.
The pharmacodynamic differences between zolpidem and benzodiazepines may be explained with the fact that the drug has specific affinity towards the receptor sites omega1 (benzodiazepines links equally with the three receptor sites, omega1, omega2, omega3).
Comparative pharmacokinetics and pharmacodynamics of short-acting hypnosedatives: zaleplon, zolpidem and zopiclone 2004
Clinically important drug interactions with zopiclone, zolpidem and zaleplon 2003
STRUCTURE OF GABA
GABA : It is a protein composed of 5 subunits, each subunit has also several subtypes.
The α subunit contains the binding site for benzodiazepines and the β subunit that for GABA. The site regulates benzodiazepine positively (agonist action) or negatively (inverse agonist action) the action of GABA on the receptor and requires the presence of the γ subunit to exert its effects.
The GABA receptor complex has 5 binding sites:
1 - Site of the GABA (β subunit)
2 - Site of benzodiazepines (α subunit) - omega 1, 2, 3
3 - Site of picrotoxin
4 - Site of Barbiturates
5 - Site of the chlorine (γ subunit)
The benzodiazepine receptor sites differs in three subpopulations: the subpopulation
- omega 1 at the level of the cerebellum, the subpopulation
- omega2 at the level of the spinal cord and the subpopulation
- omega3 at the level of peripheral tissues.
Zolpidem possesses high affinity for the receptor sites omega1, not so much for the receptor sites omega2 and very low affinity for the receptor sites omega3.
MECHANISM OF ACTION
The drug acts in a selective manner at the level of benzodiazepine receptors that are part of the macromolecular complex of the GABA receptor-ergico (GRSC); this complex is responsible for the activity of chloride channels and for the response to the activation by the inhibitory neurotransmitter GABA . The bond GABA receptor induces the opening of chloride channels, and the omega site, the benzodiazepine receptor site, modulates the affinity competitive GABA receptor.
The benzodiazepines strenghthen the activity of GABA by acting as positive modifiers and that is causing a conformational change of the protein complex GABAA, increasing the receptor affinity for the GABA.
The GABA determines a selective increase of the permeability of the cell membrane ion chlorine, causing post-synaptic inihibition (or pre-synaptic) via hyperpolarization of the cell membrane.
METABOLISM
After oral administration, zolpidem is rapidly and completely absorbed from the gastrointestinal tract, passes into the bloodstream and from there it is metabolized in the liver. The duration of action lasts about 6 hours.
Citocromiali isoenzymes involved in the reactions of biotransformation and they are CYP3A4 and, to a lesser extent, CYP1A2. The metabolism of the drug provides:
1) Reactions of oxidations of methyl groups present both on the aromatic ring and on the imidazopiridine ring;
2) imidazopiridine ring hydroxylation reactions.
From oxidation of the methyl group of the aromatic ring and the imidazopiridine ring, derive metabolites alcohol and carboxylic, including the metabolite I (oxidation of the aromatic ring) and the metabolite II (oxidation of the imidazopiridine ring). From the idro-oxidation of the imidazopiridine ring, derive hydroxylated metabolites, including the metabolite X.
Zolpidem is mostly expelled through urine, and in smaller parts with faeces.
There are – strong CYP3A4 inducing drugs (phenobarbital, phenytoin, carbamazepine, rifampicin) that may reduce the blood concentration of zolpidem by metabolic induction (reduced therapeutic effects). The co-administration of zolpidem and rifampicin (a medicine used to treat tuberculosis that inhibits RNA synthesis in Mycobacterium tuberculosis, link of f & n if there) resulted in a reduction of the pharmacodynamic effects of zolpidem;
- strong CYP3A4 inducing drugs where zolpidem is metabolized by CYP CYP3A4 and to a shorter extent, by CYP1A2, drugs with inhibitory activities of these two isoenzymes that may increase the blood concentration of zolpideminhibition (possible increase in toxic effects). In susceptible patients may increase the sedative effects of zolpidem.
Zolpidem is an imidazopyridine agonist with high affinity to the benzodiazepine site of GABA (A) receptors containing alpha 1 subunits. Recently, zolpidem has been reported to be useful in treating subgroups of parkinsonian patients.
Spinocerebellar ataxia (SCA) is an inherited disorder of brain function characterized by progressive incoordination of gait and often associated with poor coordination of hands, speech and eye movements. It is a slowly progressive disease that worsens gradually in a period of years.Zolpidem is a sedative nonbenzodiazepine imidazopyridine in the class and is chemically distincted from other sedatives. It is a short-acting hypnotic, with an effective selective agonist for γ-aminobutyric acid (GABA) type A receptors in the brain. It was initially considered by physicians as almost devoid of abuse and dependence potential. Curiously, apart from its hypnotic effects, zolpidem has been shown to improve catatonia, aphasia, Parkinson disease , and ataxia. However, reports of zolpidem abuse or dependence are increasing and more attention should be given in terms of zolpidem loosen the progression of SCA
Farmacocinetica-metabolismo
High-Dose Zolpidem Withdrawal Seizure in a Patient With Spinocerebellar Ataxia 2011
Zolpidem modulates GABA receptor function in subthalamic nucleus 2007
VIDEO
SIDE EFFECTS
Side effects that may result in medication are related to individual comparisons, which appear with greater frequency within the hour following intake unless you lay down or fall asleep immediately. The side effects can affect different organs with serious clinical manifestations. It can cause mental disorders: agitation, irritability, aggression, hallucinations, somnambulism ( ), Amnesia, delusions. For the most part in elderly subjects. Distrubi nervous system: drowsiness the following girono, confusion, headache, dizziness and fatigue. Eye: double vision (diplopia). Ear: movement disorders (ataxia) and sensation of dizziness with loss of balance (vertigo). Stomach and intestines: diarrhea, nausea, vomiting. Skin: skin reactions. Muscles: muscle weakness. It Should not be taken on alcohol because it may increase the effect of induction of sleep. The long-term use over time can lead to physical or psychological dependence. In fact Zolpidem acts by binding preferably to the receptor omega1 of GABA (A), but with a high intake the drug may lose its selectivity and also bind to receptors omega2 (those x benzodiazepines) leading to an anxiolytic effect. So at high doses it can have an effect to relieve anxiety and abrupt discontinuation that would produce symptoms of abstinenceas palpitations, anxiety and tremor. Following the phenomenon of addiction is not recommended for people who abuse drugs. Do not take during pregnancy or breast feeding, because it can cross the placenta and be present in breast milk.
INTERACTIONS WITH OTHER DRUGS
Agonist opioids, phenothiazines, barbiturates, alcohol, general anesthetics, MAO inhibitors, tricyclic antidepressants, hypnotics, anxiolytics / sedatives, narcotic analgesics, anticonvulsants, and antihistamines: given concurrently with zolpidem may increase sedation, respiratory depression and central effects induced by medication.
When administered concomitantly with narcotic analgesics it can cause increased euphoria, thereby increasing the risk of psychological dependence.
The association between zolpidem drug and CNS depressants should be monitored.
Alcohol: may cause increased sedation of the nervous system when taken in combination with zolpidem.
Chlorpromazine, imipramine: the simultaneous intake of zolpidem results in a reduction in peak plasma concentrations of these drugs.
Potent inducers of CYP3A4 drugs (phenobarbital, phenytoin, carbamazepine, rifampin, St. John's Wort) may reduce the blood concentration of zolpidem by metabolic induction (reduced therapeutic effects). The co-administration of zolpidem and rifampicin results in a reduction of the pharmacodynamic effects of the drug to induce sleep. Monitor the combined association.
Strong inducing CYP3A4 drugs such as zolpidem are metabolized by CYP CYP3A4 and to a shorter extent, by CYP1A2, drugs with inhibitory activities of these two isoenzymes could, theoretically, increase the blood concentration of zolpidem for metabolic inhibition ( possibility of increased toxicity). In a study of interaction between zolpidem and itraconazole, there was no pharmacokinetic interaction between the two drugs.
Flumazenil: antagonizes the pharmacological effects of zolpidem.
Pharmacokinetic interaction between zolpidem and ciprofloxacin in healthy volunteers 2011
Pharmacokinetic interaction between zolpidem and carbamazepine in healthy volunteers 2011
