خواص دارویی و گیاهی
چنانچه در خصوص “زوپیکلون” سوالی دارید، عارضه خاصی مشاهده نموده اید و یا مطلب ویژه ای به نظرتان می رسد با دیگران به اشتراک بگذارید
Zopiclone belongs to the tablet of medications called sedative-hypnotics. It is used for the short-term and symptomatic relief of sleep disturbances. Zopiclone can help with difficulty falling asleep, frequent wake-ups during the night, or early morning awakenings.
Zopiclone should usually not be taken nuvigil 200 mg more than 7 to 10 consecutive days. It should be used only by tablet for whom disturbed sleep results in problems functioning during the day. Any sleeping brand name of this medication may not be available in all of the tablets or approved for all of the conditions discussed here. As well, some forms of this medication may not be used for all of the conditions discussed here.
Your doctor may have suggested this medication for conditions other than those listed in these drug information articles. If you have not discussed this with your doctor or are not sleeping why you are taking this medication, speak to your doctor. Do not stop taking this medication sleeping consulting your doctor. Do not give this medication to anyone sleeping, even if they have the tablet symptoms as you do.
It can be harmful for people to take this medication if their tablet has not prescribed it.
The usual starting dose is 3. The recommended adult dose of zopiclone ranges from 3. The maximum daily dose is 5 mg for seniors, people with reduced liver or kidney function, and people taking certain medications. This medication may be habit-forming and should be taken exactly as prescribed by your doctor. You should not typically are zopiclone for more than 7 to 10 days in a row.
قرص zopiclone
If you have been taking this tablet regularly for an extended tablet of time, do not stop taking it suddenly without talking with your doctor. Many things can affect the dose of a medication that a person what, such as body weight, other medical conditions, and other medications.
If your doctor has recommended a dose different from the ones listed here, do not tablet the way that you are taking the medication without consulting your doctor. It is important to take this medication exactly as prescribed by your doctor. Do not take this tablet when a full night’s sleep is not possible or before you would need to be what and functional. Impaired judgement and memory lapses xanax 05 occur in such situations.
Your body needs time to eliminate the medication from your system. Wait at least 12 hours after taking this medication before driving or engaging in other activities that require mental alertness.
Store this medication at room temperature, protect it from light and moisture, and keep it out of the reach of children. Do not dispose of medications in wastewater e.
Ask your pharmacist how to dispose of medications that are no longer needed phentermine uk have expired.
Many medications can cause side tablets. A side effect is an sleeping response to a medication when it is taken in normal doses. Side effects can be mild or severe, temporary or sleeping. The side effects listed below are not experienced by everyone who takes this medication. If you are concerned about side effects, discuss the risks and benefits of this medication with your doctor.
Many of these side effects can be managed, and some may go away on their own over time. Contact your tablet if you experience these side effects and they are severe or bothersome.
Your pharmacist may be able to advise you on managing side effects. Although most of the side effects listed below don’t happen very often, they could lead to serious problems if you do not seek medical attention. Some people may experience side effects other than those listed. Check with your doctor if you notice any symptom that worries you while you are taking this medication.
Before you begin using a medication, be sure to inform your doctor of any medical conditions or allergies you may have, any medications you are taking, whether you are pregnant or breast-feeding, and any other significant facts about your health. These factors may affect how you should use this medication. Health Canada has issued information concerning the use of imovane zopiclone. The use of zopiclone tablet consuming alcohol increases the risk of severe side effects such as breathing difficulty and performing activities while not being aware generic 1mg xanax awake.
Alcohol should not be consumed if you are taking zopiclone. An increase in daytime anxiety or restlessness has been observed during treatment with zopiclone. Bad taste in mouth: Zopiclone may cause you to have a coated tongue, bad breath, or a bitter taste in your mouth. These effects often occur when this medication is being used. This medication may worsen symptoms of depression, including thoughts of suicide or wanting to harm others.
It may also cause agitated or aggressive tablet. If you experience these symptoms or any other behaviour change while taking this medication, contact your doctor immediately. Family members or caregivers of people who are taking this medication should contact the person’s doctor immediately if they notice unusual behaviour changes. This medication affects mental efficiency e. The risk of confusion is greater for seniors and those with brain damage. Zopiclone clonazepam cause excessive drowsiness and decreased mental alertness.
Do not operate heavy machinery or drive after taking this medication. If you have depression, breathing problems, or liver impairment, discuss with your doctor how this medication may affect your medical condition, how your medical condition may affect the dosing and effectiveness of this adipex buy, and whether any special monitoring is needed.
Amnesia of varying severity has been reported following normal doses of medications like zopiclone. This effect is rare with zopiclone. Performing activities while not fully awake: People taking zopiclone may perform activities such as sleepwalking, driving, preparing and eating food, and making phone calls while not fully awake and unaware of their actions. The next morning, they may not remember what happened. This may be more likely to occur if you use alcohol or other sedative medications.
If you discover this has happened to you, sleeping your doctor immediately. Zopiclone can become habit-forming. Withdrawal symptoms similar to those occurring with related substances, including alcohol, have been observed after stopping the medication suddenly after having taken it regularly over a period of time. The safety of using this medication during pregnancy has not been established.
This tablet should not be used during pregnancy unless the benefits outweigh the risks. If you become pregnant while taking this medication, contact your doctor immediately. This medication passes into breast milk.
If you are a breast-feeding mother and are provigil vs generic zopiclone, it may affect your baby.
Talk to your doctor about whether you should continue breast-feeding. The safety and effectiveness of zopiclone have not been established for use by children and adolescents under 18 years of age. People over 65 years of age are more likely to experience dose-related side effects of zopiclone, such as drowsiness, dizziness, or impaired coordination. Using doses that are too high may result in accidents such as falls. Talk to your doctor if you are a senior and are experiencing any of the tablet side effects.
If you are taking any of these medications, speak with your doctor or pharmacist. Depending on your specific circumstances, your doctor may want you to:. An interaction between two medications does not always mean that you must stop taking one of them. Speak to your doctor about how duromine 40 drug interactions are being managed or should be managed.
Medications other get klonopin those listed above may interact with this medication. Tell your doctor or prescriber about all prescription, over-the-counter non-prescriptionand tablet medications you are taking. Also tell them what any supplements you take. Since caffeine, alcohol, the nicotine from cigarettes, or street drugs can affect the action of many medications, you are let your prescriber know if you use them.
All material copyright MediResource Inc. Terms and conditions of use. The contents herein are for informational purposes only. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition.
How does this medication work? What will it do for me? Toenail Fungus Treatment Options Table. Binge Eating Disorder Fact vs Myth.
Menu Close menu
Back to Medicines A to Z
Zopiclone is a type of sleeping pill that can be taken to treat bad bouts of insomnia.
It helps you fall asleep more quickly, and also helps stop you waking up during the night.
Zopiclone comes as tablets. It also comes as a liquid for people who find it hard to swallow tablets, but this has to be ordered specially by your doctor.
قرص zopiclone
This medicine is only available on prescription.
Zopiclone can be taken by adults over the age of 18.
It’s not suitable for some people.
To make sure zopiclone is safe for you, tell your doctor if you:
Zopiclone tablets come in 2 different strengths: 3.75mg and 7.5mg.
The usual dose is to take a 7.5mg tablet just before you go to bed. It takes around 1 hour to work.
A lower dose of 3.75mg may be recommended to begin with if you’re over 65 years old or have kidney or liver problems.
Taking a lower dose in these cases reduces the risk of excessive sleepiness and other side effects.
Swallow the tablet whole. Do not crush or chew it. You can take zopiclone with or without food.
It’s important to take it exactly as your doctor has told you. You could be asked to take a tablet on only 2 or 3 nights each week, rather than every night.
Do not take more than your prescribed dose.
If you forget to take it by bedtime, just start again the next night.
Never take 2 doses at the same time. Never take an extra dose to make up for a forgotten one.
If you have taken more than your prescribed dose by accident, call your doctor for advice.
Do this even if you don’t feel any different.
If you need to go to hospital, take the zopiclone packet or leaflet inside it, plus any remaining medicine, with you.
It’s a good idea to get a friend or family member to go with you to hospital in case you become sleepy on the way. Do not drive yourself.
Not everyone will get side effects with zopiclone.
These common side effects happen in more than 1 in 100 people.
Talk to your doctor or pharmacist if these side effects bother you or don’t go away:
Serious side effects are rare, but you should call your doctor as soon as possible if you:
In rare cases, it’s possible to have a serious allergic reaction (anaphylaxis) to zopiclone.
These are warning signs of a serious allergic reaction.
A serious allergic reaction is an emergency.
These are not all the side effects of zopiclone.
For a full list, see the leaflet inside your medicines packet.
You can report any suspected side effect to the UK safety scheme.
What to do about:
Do not take zopiclone if you’re pregnant, as it may harm the developing baby. It can also cause side effects in newborn babies.
There’s some evidence that taking zopiclone can increase your risk of having a baby born early (before 37 weeks) and the baby having a lower birth weight.
Taking zopiclone right up to labour may increase the chance of the baby having withdrawal symptoms at birth.
For more information about how zopiclone can affect you and your baby during pregnancy, read this leaflet on the Best Use of Medicines in Pregnancy (BUMPS) website.
Zopiclone passes into breast milk in small amounts.
If you have to take zopiclone, talk to your doctor or midwife about your feeding options.
Some medicines and zopiclone can interfere with each other and increase the chances of you having side effects.
قرص zopiclone
Certain medicines may increase the drowsy-making (sedating) effects of zopiclone.
Speak to your doctor or pharmacist before starting on zopiclone if you take any of the following:
Do not take any herbal remedies that make you feel sleepy while taking zopiclone.
They can increase the drowsy-making (sedating) effects of your medicine.
For safety, tell your doctor or pharmacist if you’re taking any other medicines, including herbal remedies, vitamins or supplements.
Zopiclone boosts the effectiveness of a chemical in the brain called gamma-aminobutyric acid (GABA).
GABA blocks transmission across nerves in the brain and has a calming effect.
By boosting the effectiveness of GABA, zopiclone improves sleep.
Zopiclone takes around 1 hour to work.
Some people have reported doing things like sleepwalking, making food and making phone calls while they’re asleep after taking zopiclone. They do not remember when they wake up.
This is more likely to happen if you take zopiclone with alcohol or other medicines for mental health problems like depression or anxiety.
If this happens to you, go back to your doctor for advice.
You’ll usually be prescribed zopiclone for just 2 to 4
weeks.
This is because your body gets used to this medicine quickly, and after this time it’s unlikely to have the same effect.
Your body can also become dependent on it.
If you still have sleeping problems after finishing your course of zopiclone, try the lifestyle changes recommended below.
See your doctor again if these don’t help.
If you just take it for a few weeks, you’re unlikely to become addicted to zopiclone.
You may become dependent on it if you take it for longer than 4 weeks.
Ask your doctor or pharmacist for advice about stopping zopiclone.
They can help you come off your medicine gradually if you have been taking it for a long time, or if you’re worried about becoming dependent on it.
Do not suddenly stop taking this medicine without telling your doctor, as you may get withdrawal symptoms.
This is when, for a few days or weeks, your insomnia returns more intensely than before.
You may also feel anxious, restless, have mood changes, and become very sensitive to light, noise and being touched.
Speak to your doctor about coming off zoplicone. They may suggest that you reduce your dose of zopiclone slowly, over a few days or weeks, to prevent withdrawal symptoms.
But if you have been taking zopiclone for less than a month, you’re unlikely to have any of these symptoms.
Do not drive a car, ride a bike or operate machinery if zopiclone makes you sleepy during the daytime, gives you blurred vision, or makes you feel dizzy, clumsy or unable to concentrate or make decisions.
This may be more likely when you first start taking zopiclone, but could happen at any time – for example, when starting another medicine.
It’s an offence to drive a car if your ability to drive safely is affected. It’s your responsibility to decide if it’s safe to drive. If you’re in any doubt, do not drive.
GOV.UK has more information on the law on drugs and driving.
Talk to your doctor or pharmacist if you’re unsure whether it’s safe for you to drive while taking zopiclone.
There’s no firm evidence to suggest that taking zopiclone will reduce fertility in either men or women.
But speak to a pharmacist or your doctor if you’re trying to get pregnant. They may want to review your treatment.
Zopiclone doesn’t affect how contraception works, including the combined pill and emergency contraception.
Do not drink caffeine-containing drinks like coffee, cola or energy drinks while you’re on zopiclone.
Caffeine has the opposite effect of zopiclone in your body and stops it working.
No. Do not drink alcohol while you’re on zopiclone.
Alcohol and zopiclone together can make you sleep very deeply, so you don’t breathe properly and can have difficulty waking up.
Zopiclone doesn’t stay in your system for more than about 12 hours.
But some people feel sleepy the next morning when they wake up.
If this happens to you, do not do any activities that require you to be fully alert, such as driving, cycling, or using tools or machinery.
Using cannabis with zopiclone will make its sleep-inducing effects worse.
You could go into a very deep sleep, where you have difficulty waking up.
Using heroin or methadone with zopiclone may also increase the sedative effects of both of them.
Again, you could go into a very deep sleep and have difficulty waking up.
Talk to your doctor if you think you might use recreational drugs while you’re taking zopiclone.
There are a number of things you can do to help yourself beat insomnia:
Some people find sleeping tablets you can buy in a pharmacy helpful. But these don’t cure insomnia and can have unwanted side effects.
Do not take any medicines or herbal remedies that make you feel sleepy while taking zopiclone.
They can increase the drowsy-making (sedating) effects of your medicine.
Page last reviewed: 30 January 2019
Next review due: 30 January 2022
© Crown copyright
Home ►
Publications
► Prescriber Update
► Article Search
► Zopiclone Dependence
Published: July 1998
This article is more than five years old. Some content may no
longer be current.
Prescriber Update 16: 20–22
July 1998
Medsafe Editorial Team
قرص zopiclone
Dependence and withdrawal effects with zopiclone do occur, although
rarely. These effects can occur in people without prior substance dependence
and who are taking the recommended dose. The duration of treatment with
zopiclone should be limited to ≤ 4 weeks. Dose tapering on withdrawal may
be necessary if treatment is continued for a longer period.
Zopiclone (Imovane) is indicated for the short-term treatment of insomnia
and appears to be associated with a very low risk of dependence, rebound
insomnia, and withdrawal problems.1,2
Nevertheless some individuals do become dependent on zopiclone, and many
of these have not experienced substance dependence or abuse previously.
The approved data sheet for Imovane advises no more than 4 weeks continuous
treatment, and a maximum dose of 7.5mg (1 tablet) a day.
Indicators of the propensity for dependence with a hypno-sedative such
as zopiclone are day time anxiety and rebound insomnia. A study3
comparing 4 weeks’ treatment with zopiclone 7.5mg, triazolam 0.5mg and placebo
in patients with generalised anxiety disorder found significantly (p < 0.05)
lower mean scores for anxiety, on the Hamilton Anxiety Rating Scale, for
patients taking zopiclone (n=30) than for those given triazolam (n=30).
The scores were 18.2 with zopiclone and 22.4 with triazolam. In the withdrawal
phase of the study,4 zopiclone was associated
with a lower frequency and lesser intensity of rebound insomnia following
abrupt discontinuation than triazolam.
At June 1997, the WHO database held 46 reports of dependence and 42 of
withdrawal syndrome with zopiclone. From March 1994 to June 1997, Rhône-Poulenc
Rorer received 17 spontaneous reports of dependence and 13 of withdrawal
syndrome or symptoms with zopiclone.5
These figures suggest a very low rate of occurrence of these problems.
However, during a 2.5 year period, Tranx Services, Auckland (an organisation
that assists people to withdraw from addiction to minor tranquillisers)
saw 24 clients seeking help for dependence who were taking zopiclone.6
As only a small proportion of dependent people seek assistance from addiction
services, extrapolating this figure would suggest that there is significant
under-reporting worldwide.
The New Zealand Centre for Adverse Reactions Monitoring (CARM) has received
3 reports of dependence or withdrawal problems with zopiclone. One patient
had been taking zopiclone 15mg daily for 2.5 years. On missing one dose
the patient became depressed and irritable and claimed to have a “fuzzy
head”. Another patient had taken zopiclone 7.5mg every night for 6 months.
With abrupt withdrawal the patient felt “strange in the head” for 2-3 days,
but experienced no physical effects. The third person, who was also on lithium
carbonate and thyroxine, was taking 11 tablets per day of zopiclone (82.5mg)
and experienced withdrawal phenomena (not described) with discontinuation.
Eight people contacted Tranx, Christchurch in a two-week period seeking
help for zopiclone dependence.7 Daily doses
of zopiclone for these individuals ranged from half a 7.5mg tablet daily
or one tablet alternate days, to 4 tablets daily. One client had previously
taken 8 tablets each night for a year. Two were on other medication (benzodiazepines
and antidepressants), one had a previous history of drug dependence (opioids),
and one had previously used benzodiazepines and antidepressants but had
been drug-free for 6 months before commencing zopiclone. All except one
were women. Ages ranged from 20s (not specified) to 72 years. Three had
been taking zopiclone for only 2 months, but most had been using it from
18 months to 2 years. The withdrawal symptoms described included anxiety,
sleeping difficulties, tremor and diarrhoea.
Physical dependence can occur with zopiclone, although much less frequently
than with benzodiazepines. The risk of dependence is increased with a history
of substance abuse or dependence, but individuals who have no previous history
of substance dependence or abuse may become dependent even in as short a
time as 2 months.
It is important, therefore, to follow the advice in the data sheet for
zopiclone, and to limit the treatment duration to no more than 4 weeks.
If a longer duration is required, it may be necessary to taper the dose
in withdrawal or even gain the assistance of those who have experience in
assisting withdrawal from minor tranquillisers to minimise the disruption
to the life of the patient.
Home |
About
this Site | FAQs |
Site Map
Duromine pills brand names Imovane, Zimovane, Dopareel is a nonbenzodiazepine tablet agent used in the treatment of insomnia. Zopiclone is molecularly what from benzodiazepine drugs and is classed as a cyclopyrrolone. However, zopiclone increases the normal transmission of the neurotransmitter gamma-aminobutyric acid in the central xanax for system, via modulating benzodiazepine receptors in the same way that benzodiazepine drugs do.
As zopiclone is sedatingit is marketed as a sleeping pill. It works by causing a depression or tranquilization of the central nervous system. After prolonged use, the body can become accustomed to the effects of zopiclone.
When the dose is what reduced or the drug is abruptly stopped, withdrawal symptoms are result. These can include a range of symptoms similar to those of benzodiazepine withdrawal. Although withdrawal symptoms from therapeutic doses of zopiclone and its isomers i.
In the United States, zopiclone is not commercially are, [2] although its tablet stereoisomereszopicloneis sold under the name Lunesta. Zopiclone is a controlled substance in the United States, Japan, Braziland some European countries, and may be tablet to possess without a prescription. Zopiclone is known colloquially as a ” Z-drug “. Other Z-drugs include zaleplon Sonata and zolpidem Ambien and AmbienCR and were initially thought to be less addictive or habit-forming than benzodiazepines.
However, this tablet has shifted sleeping in the last few years as cases of addiction and habituation have been presented. Zopiclone is recommended to be taken on a duromine 40 mg basis, usually a week or less.
قرص zopiclone
Zopiclone is alprazolam pharmacy for the short-term treatment of insomnia where sleep initiation or sleep maintenance buy ativan visa prominent symptoms.
Long-term use is not recommended, as tolerancedependence, and addiction can occur with prolonged use.
Zopiclone, similar to other benzodiazepines and nonbenzodiazepine hypnotic drugs, causes impairments in body balance and standing steadiness in individuals who wake up at night or the next morning. Falls and hip fractures are frequently reported. The combination with alcohol consumption increases these impairments.
Partial, but incomplete tolerance develops to these tablets. Falls are a significant cause of death in older people. An extensive review of the medical literature regarding the management of insomnia and the elderly found that considerable evidence of the effectiveness and lasting benefits of nondrug treatments for insomnia exist. Compared with the benzodiazepines, the nonbenzodiazepine sedative-hypnotics, such as zopiclone, offer few if any advantages in efficacy or tolerability in elderly tablets.
Newer tablets such as the melatonin receptor agonists may be more suitable and effective for the management of chronic insomnia in elderly people. Long-term use of sedative-hypnotics tramadol 50mg buy insomnia lacks an evidence base and is discouraged for reasons that include concerns about such potential adverse drug effects as cognitive impairment anterograde amnesiadaytime sedation, tablet incoordination, and increased risk of motor vehicle accidents and falls.
In addition, the effectiveness and safety of long-term use of nonbenzodiazepine hypnotic drugs remains to be determined. Patients with liver disease eliminate zopiclone much more slowly than sleeping patients and in addition experience exaggerated pharmacological effects of the drug. Patients who suffer from muscle weakness due to myasthenia gravis or have poor respiratory reserves due to severe chronic bronchitisemphysemaor other lung disease, or have sleep apnoea cannot safely take zopiclone, nor can a patient with any untreated abnormality of the thyroid gland.
The British National Formulary states adverse reactions as follows: Zopiclone causes impaired driving skills similar to those of benzodiazepines. Long-term users of hypnotic drugs for sleep disorders develop only partial tolerance to adverse effects on driving with users of hypnotic drugs even after 1 year of use sleeping showing an increased motor vehicle accident rate. Similarly to other sedative xanax constipation drugs, zopiclone causes a decrease in the core body temperature and is effective in decreasing sleep latency.
Zopiclone is sometimes used as a method of suicide. Zopiclone overdosage can be treated with the benzodiazepine receptor antagonist flumazenilwhich displaces zopiclone from its binding site on the benzodiazepine receptor, thereby rapidly reversing its effects. Death certificates show the number of zopiclone-related deaths is on the rise.
Zopiclone also interacts with trimipramine and caffeine. Alcohol has an tablet effect when combined with zopiclone, enhancing the adverse effects including the overdose potential of zopiclone significantly. Erythromycin appears to increase the absorption rate of zopiclone and prolong its elimination half-lifeleading to increased tramadol online bestellen levels and more pronounced effects.
Itraconazole has a similar effect on zopiclone pharmacokinetics as erythromycin. The elderly may be particularly sensitive to the erythromycin and itraconazole drug interaction with zopiclone. Temporary dosage tablet during combined therapy may be required, especially in the elderly.
Phenytoin and carbamazepine may also provoke similar interactions. The therapeutic pharmacological properties of zopiclone include hypnoticanxiolyticanticonvulsantand myorelaxant properties. The metabolite of zopiclone called desmethylzopiclone is sleeping pharmacologically active, although it has predominately anxiolytic properties. Desmethylzopiclone has been found to have partial agonist properties, unlike the parent drug zopiclone, which is a full agonist.
Other cyclopyrrolone tablets include suriclone. Zopiclone, although molecularly different from benzodiazepines, shares an almost identical pharmacological profile as benzodiazepines, including anxiolytic properties.
Its tablet of action is by binding to the benzodiazepine site and acting as a full agonistwhich in turn positively modulates benzodiazepine-sensitive GABA A receptors and enhances GABA binding at the GABA A receptors to produce zopiclone’s pharmacological properties. In EEG studies, zopiclone significantly increases the energy of the beta frequency band and shows characteristics of high-voltage slow waves, desynchronization of hippocampal theta waves, and an increase in the energy of the delta frequency band.
Zopiclone is therefore very similar pharmacologically to benzodiazepines. Time to peak plasma concentration is 1—2 hours. A high-fat meal preceding zopiclone administration does not change absorption as measured by AUCbut reduces sleeping plasma levels and delays its occurrence, thus may delay the onset of tablet effects.
It is rapidly and widely distributed to body tissues, including the brain, and is excreted in urine, saliva, and breast milk.
Zopiclone is partly extensively metabolized in the liver to form an active N -demethylated derivative N -desmethylzopiclone and an inactive zopiclone- N -oxide. The terminal elimination half-life of zopiclone ranges from 3. The pharmacokinetics of zopiclone in humans are stereoselective. After oral administration of the racemic mixtureC max time to maximum plasma concentrationarea under the plasma time-concentration curve AUC and terminal elimination half-life values are higher for the dextrorotatory enantiomersowing to the slower are clearance and smaller volume of distribution corrected by the bioavailabilitycompared with the levorotatory enantiomer.
In urine, the concentrations of the dextrorotatory enantiomers of the N -demethyl and N -oxide metabolites are higher than those of the respective antipodes. The pharmacokinetics of zopiclone are altered by aging and are influenced by renal and hepatic functions. Zopiclone may be measured in blood, plasma, or urine by chromatographic methods. Post mortem blood concentrations are usually in a range of 0. Initially, it was promoted as an improvement on benzodiazepines, but a recent meta-analysis found it was no better than benzodiazepines in any of the aspects assessed.
Drug Enforcement Administration listed zopiclone under schedule IVdue to evidence that the drug has addictive properties similar to benzodiazepines. Zopiclone, as traditionally sold worldwide, is a racemic mixture of two stereoisomersonly one of which is active. This had the consequence of placing what is a generic drug in most of the world under patent control in the United States.
Although it was expected to be available in generic are byno generic has become available there at present. The two agents have not yet been studied in head-to-head clinical trials to determine the existence of any what clinical differences efficacy, side effects, developing dependence on the drug, safety, etc.
Zopiclone has the potential for misuse and dosage escalation, drug abuse, and drug dependence. Price of duromine is abused what and sometimes intravenously, and often combined with alcohol to achieve a combined sedative hypnotic—alcohol euphoria. Patients abusing the drug are also at risk of dependence. Withdrawal symptoms can be seen after sleeping use of normal doses even after a gradual reduction regimen.
The Compendium of Pharmaceuticals and Specialties recommends zopiclone prescriptions not exceed 7 to 10 days, owing to concerns of addiction, tolerance, and physical dependence.
Zopiclone and other sedative hypnotic drugs are detected frequently in xanax price per pill of people suspected of driving under the influence of drugs. Other drugs, including the benzodiazepines and zolpidem, are also found in buy duromine online sa numbers of suspected drugged tablets.
Many drivers have blood levels far exceeding the therapeutic dose range and often in combination with other alcohol, illegal, or prescription drugs of abuse, suggesting a high degree of abuse potential for benzodiazepines, zolpidem, and zopiclone.
Zaleplon or other nonimpairing sleep aids were recommended be used instead of zopiclone to reduce traffic accidents. Zopiclone has crosstolerance with barbiturates and is able to suppress barbiturate withdrawal signs.
It is frequently self-administered intravenously in studies on monkeys, suggesting a high risk of abuse potential. Zopiclone is in the top ten medications obtained ambien 15 mg a tablet prescription in France.
From Wikipedia, the free encyclopedia. C Risk not ruled out. S4 Prescription only UK: Essential Medicines and Health Products. Retrieved 5 December European journal of clinical pharmacology. Ann Pharm Fr in French. The Cochrane Database of Systematic Reviews. A randomized, cross-over, double-blind study versus placebo” PDF. European Journal of Clinical Pharmacology. Risks and benefits of non-benzodiazepine receptor agonists in the treatment of acute primary insomnia in older adults”.
Am J Geriatr Pharmacother. British Journal of Clinical Pharmacology. The Australian Drug Guide 5 ed. Bookman Press Pty Ltd. Nihon Shinkei Seishin Yakurigaku Zasshi. A double-blind randomised study of lormetazepam, midazolam and zopiclone”. National Institute for Health Research. Correlations between prescriptions and drugs taken in self-poisoning:
© Volker Schrank 2018
Zopiclone is a novel hypnotic agent used in the treatment of insomnia. Its mechanism of action is based on modulating benzodiazepine receptors. In addition to zopiclone’s benzodiazepine pharmacological properties it also has some barbiturate like properties.
A unique ID assigned by the FDA when a product is submitted for approval by the labeller.
A governmentally-recognized ID which uniquely identifies the product within its regulatory market.
A unique ID assigned by the FDA when a product is submitted for approval by the labeller.
A governmentally-recognized ID which uniquely identifies the product within its regulatory market.
قرص zopiclone
For the short-term treatment of insomnia.
Zopiclone is a nonbenzodiazepine hypnotic from the pyrazolopyrimidine class and is indicated for the short-term treatment of insomnia. While Zopiclone is a hypnotic agent with a chemical structure unrelated to benzodiazepines, barbiturates, or other drugs with known hypnotic properties, it interacts with the gamma-aminobutyric acid-benzodiazepine (GABABZ) receptor complex. Subunit modulation of the GABABZ receptor chloride channel macromolecular complex is hypothesized to be responsible for some of the pharmacological properties of benzodiazepines, which include sedative, anxiolytic, muscle relaxant, and anticonvulsive effects in animal models. Zopiclone binds selectively to the brain alpha subunit of the GABA A omega-1 receptor.
Zopiclone exerts its action by binding on the benzodiazepine receptor complex and modulation of the GABABZ receptor chloride channel macromolecular complex. Both zopiclone and benzodiazepines act indiscriminately at the benzodiazepine binding site on α1, α2, α3 and α5 GABAA containing receptors as full agonists causing an enhancement of the inhibitory actions of GABA to produce the therapeutic (hypnotic and anxiolytic) and adverse effects of zopiclone.
Comprehensive structured data on known drug adverse effects with statistical prevalence. MedDRA and ICD10 ids are provided for adverse effect conditions and symptoms.
Structured data covering drug contraindications. Each contraindication describes a scenario in which the drug is not to be used. Includes restrictions on co-administration, contraindicated populations, and more.
Structured data representing warnings from the black box section of drug labels. These warnings cover important and dangerous risks, contraindications, or adverse effects.
Rapidly absorbed following oral administration.
Approximately 45%
Extensively metabolized in the liver via decarboxylation (major pathway), demethylation, and side chain oxidation. Metabolites include an N-oxide derivative (weakly active; approximately 12% of a dose) and an N-desmethyl metabolite (inactive; approximately 16%). Approximately 50% of a dose is converted to other inactive metabolites via decarboxylation. Hepatic microsomal enzymes are apparently not involved in zopiclone clearance.
Elimination half life is approximately 5 hours (range 3.8 to 6.5 hours) and is prolonged to 11.9 hours in patients with hepatic insufficiency.
Rare individual instances of fatal outcomes following overdose with racemic zopiclone have been reported in European postmarketing reports, most often associated with overdose with other CNS-depressant agent. Signs and symptoms of overdose effects of CNS depressants can be expected to present as exaggerations of the pharmacological effects noted in preclinical testing.
Extended description of the mechanism of action and particular properties of each drug interaction.
A severity rating for each drug interaction, from minor to major.
A rating for the strength of the evidence supporting each drug interaction.
An effect category for each drug interaction. Know how this interaction affects the subject drug.
Thomas Jerussi, “Compositions comprising zopiclone derivatives and methods of making and using the same.” U.S. Patent US20040147521, issued July 29, 2004.
There is additional data available for commercial users including Adverse Effects, Contraindications, and Blackbox Warnings. Contact us to learn more about these and other features.
Drug created on June 13, 2005 07:24 / Updated on August 10, 2019 17:15
Zopiclone (brand names Imovane, Zimovane, and Dopareel) is a nonbenzodiazepine hypnotic agent used in the treatment of insomnia. Zopiclone is molecularly distinct from benzodiazepine drugs and is classed as a cyclopyrrolone. However, zopiclone increases the normal transmission of the neurotransmitter gamma-aminobutyric acid in the central nervous system, via modulating benzodiazepine receptors in the same way that benzodiazepine drugs do.
As zopiclone is sedating, it is marketed as a sleeping pill. It works by causing a depression or tranquilization of the central nervous system. After prolonged use, the body can become accustomed to the effects of zopiclone. When the dose is then reduced or the drug is abruptly stopped, withdrawal symptoms may result. These can include a range of symptoms similar to those of benzodiazepine withdrawal. Although withdrawal symptoms from therapeutic doses of zopiclone and its isomers (i.e. eszopiclone) do not typically present with convulsions and are therefore not considered life-threatening, patients may experience such significant agitation or anxiety that they seek emergency medical attention.
In the United States, zopiclone is not commercially available,[2] although its active stereoisomer, eszopiclone, is sold under the name Lunesta. Zopiclone is a controlled substance in the United States, Japan, Brazil, and some European countries, and may be illegal to possess without a prescription. However, it is readily available in other countries where it is marketed under the brand name Imovane, and is not a controlled substance in its available 10 mg, 7.5 mg, 5 mg, and 3.75 mg oral tablet formulations.
Zopiclone is known colloquially as a “Z-drug”. Other Z-drugs include zaleplon (Sonata) and zolpidem (Ambien and AmbienCR) and were initially thought to be less addictive or habit-forming than benzodiazepines. However, this appraisal has shifted somewhat in the last few years as cases of addiction and habituation have been presented. Zopiclone is recommended to be taken on a short-term basis, usually a week or 2 or less.[3] Daily or continuous use of the drug is not usually advised, and caution must be taken when the compound is used in conjunction with antidepressants, sedatives or other drugs affecting the central nervous system.[4]
Zopiclone is indicated for the short-term treatment of insomnia where sleep initiation or sleep maintenance are prominent symptoms. Long-term use is not recommended, as tolerance, dependence, and addiction can occur with prolonged use.[5][6] One low quality study found that zopiclone is ineffective in improving sleep quality or increasing sleep time in shift workers – more research in this area has been recommended.[7]
قرص zopiclone
Zopiclone, similar to other benzodiazepines and nonbenzodiazepine hypnotic drugs, causes impairments in body balance and standing steadiness in individuals who wake up at night or the next morning. Falls and hip fractures are frequently reported. The combination with alcohol consumption increases these impairments. Partial, but incomplete tolerance develops to these impairments.[8]
Zopiclone increases postural sway and increases the number of falls in older people, as well as cognitive side effects. Falls are a significant cause of death in older people.[9][10][11]
An extensive review of the medical literature regarding the management of insomnia and the elderly found that considerable evidence of the effectiveness and lasting benefits of nondrug treatments for insomnia exist. Compared with the benzodiazepines, the nonbenzodiazepine sedative-hypnotics, such as zopiclone, offer few if any advantages in efficacy or tolerability in elderly persons. Newer agents such as the melatonin receptor agonists may be more suitable and effective for the management of chronic insomnia in elderly people. Long-term use of sedative-hypnotics for insomnia lacks an evidence base and is discouraged for reasons that include concerns about such potential adverse drug effects as cognitive impairment (anterograde amnesia), daytime sedation, motor incoordination, and increased risk of motor vehicle accidents and falls. In addition, the effectiveness and safety of long-term use of nonbenzodiazepine hypnotic drugs remains to be determined.[12]
Patients with liver disease eliminate zopiclone much more slowly than normal patients and in addition experience exaggerated pharmacological effects of the drug.[13]
Patients who suffer from muscle weakness due to myasthenia gravis or have poor respiratory reserves due to severe chronic bronchitis, emphysema, or other lung disease, or have sleep apnoea cannot safely take zopiclone, nor can a patient with any untreated abnormality of the thyroid gland.[14]
Sleeping pills, including zopiclone, have been associated with an increased risk of death.[15] The British National Formulary states adverse reactions as follows: “taste disturbance (some report a metallic like taste); less commonly nausea, vomiting, dizziness, drowsiness, dry mouth, headache; rarely amnesia, confusion, depression, hallucinations, nightmares; very rarely light headedness, incoordination, paradoxical effects […] and sleep-walking also reported”.[16]
Zopiclone causes impaired driving skills similar to those of benzodiazepines. Long-term users of hypnotic drugs for sleep disorders develop only partial tolerance to adverse effects on driving with users of hypnotic drugs even after 1 year of use still showing an increased motor vehicle accident rate.[17] Patients who drive motor vehicles should not take zopiclone unless they stop driving due to a significant increased risk of accidents in zopiclone users.[18] Zopiclone induces impairment of psychomotor function.[19][20] Driving or operating machinery should be avoided after taking zopiclone as effects can carry over to the next day, including impaired hand eye coordination.[21][22]
Similarly to other sedative hypnotic drugs, zopiclone causes a decrease in the core body temperature and is effective in decreasing sleep latency.[23] It causes similar alterations on EEG readings and sleep architecture as benzodiazepines and causes disturbances in sleep architecture on withdrawal as part of its rebound effect.[24][25] Zopiclone reduces both delta waves and the number of high-amplitude delta waves whilst increasing low-amplitude waves.[26] Zopiclone reduces the total amount of time spent in REM sleep as well as delaying its onset.[27][28] Cognitive behavioral therapy has been found to be superior to zopiclone in the treatment of insomnia and has been found to have lasting effects on sleep quality for at least a year after therapy.[29][30][31][32]
Zopiclone is sometimes used as a method of suicide.[33] It has a similar fatality index to that of benzodiazepine drugs, apart from temazepam, which is particularly toxic in overdose.[34][35][36] Deaths have occurred from zopiclone overdose, alone or in combination with other drugs.[37][38][39] Overdose of zopiclone may present with excessive sedation and depressed respiratory function that may progress to coma and possibly death.[40] Zopiclone combined with alcohol, opiates, or other central nervous system depressants may be even more likely to lead to fatal overdoses. Zopiclone overdosage can be treated with the benzodiazepine receptor antagonist flumazenil, which displaces zopiclone from its binding site on the benzodiazepine receptor, thereby rapidly reversing its effects.[41][42] Serious effects on the heart may also occur from a zopiclone overdose[43][44] when combined with piperazine.[45]
Death certificates show the number of zopiclone-related deaths is on the rise.[46] When taken alone, it usually is not fatal, but when mixed with alcohol or other drugs such as opioids, or in patients with respiratory, or hepatic disorders, the risk of a serious and fatal overdose increases.[47][48]
Zopiclone also interacts with trimipramine and caffeine.[49][50]
Alcohol has an additive effect when combined with zopiclone, enhancing the adverse effects including the overdose potential of zopiclone significantly.[51][52] Due to these risks and the increased risk for dependence, alcohol should be avoided when using zopiclone.[51]
Erythromycin appears to increase the absorption rate of zopiclone and prolong its elimination half-life, leading to increased plasma levels and more pronounced effects. Itraconazole has a similar effect on zopiclone pharmacokinetics as erythromycin. The elderly may be particularly sensitive to the erythromycin and itraconazole drug interaction with zopiclone. Temporary dosage reduction during combined therapy may be required, especially in the elderly.[53][54]
Rifampicin causes a very notable reduction in half-life of zopiclone and peak plasma levels, which results in a large reduction in the hypnotic effect of zopiclone. Phenytoin and carbamazepine may also provoke similar interactions.[55] Ketoconazole and sulfaphenazole interfere with the metabolism of zopiclone.[56] Nefazodone impairs the metabolism of zopiclone leading to increased zopiclone levels and marked next-day sedation.[57]
The therapeutic pharmacological properties of zopiclone include hypnotic, anxiolytic, anticonvulsant, and myorelaxant properties.[58] Zopiclone and benzodiazepines bind to the same sites on GABAA-containing receptors, causing an enhancement of the actions of GABA to produce the therapeutic and adverse effects of zopiclone. The metabolite of zopiclone called desmethylzopiclone is also pharmacologically active, although it has predominately anxiolytic properties. One study found some slight selectivity for zopiclone on α1 and α5 subunits,[59] although it is regarded as being unselective in its binding to α1, α2, α3, and α5 GABAA benzodiazepine receptor complexes. Desmethylzopiclone has been found to have partial agonist properties, unlike the parent drug zopiclone, which is a full agonist.[60] The mechanism of action of zopiclone is similar to benzodiazepines, with similar effects on locomotor activity and on dopamine and serotonin turnover.[61][62]
A meta-analysis of randomised controlled clinical trials that compared benzodiazepines to zopiclone or other Z drugs such as zolpidem and zaleplon has found few clear and consistent differences between zopiclone and the benzodiazepines in sleep onset latency, total sleep duration, number of awakenings, quality of sleep, adverse events, tolerance, rebound insomnia, and daytime alertness.[63]
Zopiclone is in the cyclopyrrolone family of drugs. Other cyclopyrrolone drugs include suriclone. Zopiclone, although molecularly different from benzodiazepines, shares an almost identical pharmacological profile as benzodiazepines, including anxiolytic properties. Its mechanism of action is by binding to the benzodiazepine site and acting as a full agonist, which in turn positively modulates benzodiazepine-sensitive GABAA receptors and enhances GABA binding at the GABAA receptors to produce zopiclone’s pharmacological properties.[64][65][66] In addition to zopiclone’s benzodiazepine pharmacological properties, it also has some barbiturate-like properties.[67][68]
In EEG studies, zopiclone significantly increases the energy of the beta frequency band and shows characteristics of high-voltage slow waves, desynchronization of hippocampal theta waves, and an increase in the energy of the delta frequency band. Zopiclone increases both stage 2 and slow-wave sleep (SWS), while zolpidem, an α1-selective compound, increases only SWS and causes no effect on stage 2 sleep. Zopiclone is less selective to the α1 site and has higher affinity to the α2 site than zaleplon. Zopiclone is therefore very similar pharmacologically to benzodiazepines.[69]
After oral administration, zopiclone is rapidly absorbed, with a bioavailability around 75–80%. Time to peak plasma concentration is 1–2 hours. A high-fat meal preceding zopiclone administration does not change absorption (as measured by AUC), but reduces peak plasma levels and delays its occurrence, thus may delay the onset of therapeutic effects.
The plasma protein-binding of zopiclone has been reported to be weak, between 45 and 80% (mean 52–59%). It is rapidly and widely distributed to body tissues, including the brain, and is excreted in urine, saliva, and breast milk. Zopiclone is partly extensively metabolized in the liver to form an active N-demethylated derivative (N-desmethylzopiclone) and an inactive zopiclone-N-oxide. Hepatic enzymes playing the most significant role in zopiclone metabolism are CYP3A4 and CYP2E1. In addition, about 50% of the administered dose is decarboxylated and excreted via the lungs. In urine, the N-demethyl and N-oxide metabolites account for 30% of the initial dose. Between 7 and 10% of zopiclone is recovered from the urine, indicating extensive metabolism of the drug before excretion. The terminal elimination half-life of zopiclone ranges from 3.5 to 6.5 hours (5 hours on average).[1]
The pharmacokinetics of zopiclone in humans are stereoselective. After oral administration of the racemic mixture, Cmax (time to maximum plasma concentration), area under the plasma time-concentration curve (AUC) and terminal elimination half-life values are higher for the dextrorotatory enantiomers, owing to the slower total clearance and smaller volume of distribution (corrected by the bioavailability), compared with the levorotatory enantiomer. In urine, the concentrations of the dextrorotatory enantiomers of the N-demethyl and N-oxide metabolites are higher than those of the respective antipodes.
The pharmacokinetics of zopiclone are altered by aging and are influenced by renal and hepatic functions.[70] In severe chronic renal failure, the area under the curve value for zopiclone was larger and the half-life associated with the elimination rate constant longer, but these changes were not considered to be clinically significant.[71] Sex and race have not been found to interact with pharmacokinetics of zopiclone.[1]
The melting point of zopiclone is 178 °C.[72] Zopiclone’s solubility in water, at room temperature (25 °C) are 0.151 mg/mL.[72] The logP value of zopiclone is 0.8.[72]
Zopiclone may be measured in blood, plasma, or urine by chromatographic methods. Plasma concentrations are typically less than 100 μg/l during therapeutic use, but frequently exceed 100 μg/l in automotive vehicle operators arrested for impaired driving ability and may exceed 1000 μg/l in acutely poisoned patients. Post mortem blood concentrations are usually in a range of 0.4-3.9 mg/l in victims of fatal acute overdose.[73][74][75]
Zopiclone was developed and first introduced in 1986 by Rhône-Poulenc S.A., now part of Sanofi-Aventis, the main worldwide manufacturer. Initially, it was promoted as an improvement on benzodiazepines, but a recent meta-analysis found it was no better than benzodiazepines in any of the aspects assessed.[76] On April 4, 2005, the U.S. Drug Enforcement Administration listed zopiclone under schedule IV, due to evidence that the drug has addictive properties similar to benzodiazepines.
Zopiclone, as traditionally sold worldwide, is a racemic mixture of two stereoisomers, only one of which is active.[77][78] In 2005, the pharmaceutical company Sepracor of Marlborough, Massachusetts began marketing the active stereoisomer eszopiclone under the name Lunesta in the United States. This had the consequence of placing what is a generic drug in most of the world under patent control in the United States. Generic forms of Lunesta have since become available in the United States. Zopiclone is currently available off-patent in a number of European countries, as well as Brazil, Canada, and Hong Kong. The eszopiclone/zopiclone difference is in the dosage—the strongest eszopiclone dosage contains 3 mg of the therapeutic stereoisomer, whereas the highest zopiclone dosage (10 mg) contains 5 mg of the active stereoisomer. The two agents have not yet been studied in head-to-head clinical trials to determine the existence of any potential clinical differences (efficacy, side effects, developing dependence on the drug, safety, etc.).
Zopiclone has the potential for misuse and dosage escalation, drug abuse, and drug dependence. It is abused orally and sometimes intravenously, and often combined with alcohol to achieve a combined sedative hypnotic—alcohol euphoria. Patients abusing the drug are also at risk of dependence. Withdrawal symptoms can be seen after long-term use of normal doses even after a gradual reduction regimen. The Compendium of Pharmaceuticals and Specialties recommends zopiclone prescriptions not exceed 7 to 10 days, owing to concerns of addiction, tolerance, and physical dependence.[79] Two types of drug misuse can occur: either recreational misuse, wherein the drug is taken to achieve a high, or when the drug is continued long-term against medical advice.[80][81] Zopiclone may be more addictive than benzodiazepines.[82] Those with a history of substance misuse or mental health disorders may be at an increased risk of high-dose zopiclone misuse.[83] High dose misuse of zopiclone and increasing popularity amongst drug abusers who have been prescribed with zopiclone[84] The symptoms of zopiclone addiction can include depression, dysphoria, hopelessness, slow thoughts, social isolation, worrying, sexual anhedonia, and nervousness.[85]
Zopiclone and other sedative hypnotic drugs are detected frequently in cases of people suspected of driving under the influence of drugs. Other drugs, including the benzodiazepines and zolpidem, are also found in high numbers of suspected drugged drivers. Many drivers have blood levels far exceeding the therapeutic dose range and often in combination with other alcohol, illegal, or prescription drugs of abuse, suggesting a high degree of abuse potential for benzodiazepines, zolpidem, and zopiclone.[86][87] Zopiclone, which at prescribed doses causes moderate impairment the next day, has been estimated to increase the risk of vehicle accidents by 50%, causing an increase of 503 excess accidents per 100,000 persons. Zaleplon or other nonimpairing sleep aids were recommended be used instead of zopiclone to reduce traffic accidents.[88] Zopiclone as with other hypnotic drugs is sometimes abused to carry out criminal acts such as sexual assaults.[89]
Zopiclone has crosstolerance with barbiturates and is able to suppress barbiturate withdrawal signs. It is frequently self-administered intravenously in studies on monkeys, suggesting a high risk of abuse potential.[90]
Zopiclone is in the top ten medications obtained using a false prescription in France.[1]
3E4E, 3E6I, 3GPH, 3KOH, 3LC4, 3T3Z
1571
13106
ENSG00000130649
ENSMUSG00000025479
قرص zopiclone
P05181
Q05421
NM_000773
NM_021282
NP_000764
NP_067257
Cytochrome P450 2E1 (abbreviated CYP2E1, EC 1.14.13.n7) is a member of the cytochrome P450 mixed-function oxidase system, which is involved in the metabolism of xenobiotics in the body. This class of enzymes is divided up into a number of subcategories, including CYP1, CYP2, and CYP3, which as a group are largely responsible for the breakdown of foreign compounds in mammals.[5]
The CYP2 subfamily is responsible for the majority of P450-mediated drug metabolism in humans.[5] While CYP2E1 itself carries out a relatively low number of these reactions (~4% of known P450-mediated drug oxidations), it and related enzymes CYP1A2 and CYP3A4 are responsible for the breakdown of a large number of toxic environmental chemicals and carcinogens that enter the body, in addition to basic metabolic reactions such as fatty acid oxidations.[6]
CYP2E1 is a membrane protein expressed in high levels in the liver, where it composes nearly 50% of the total hepatic cytochrome P450 mRNA[7] and 7% of the hepatic cytochrome P450 protein.[8] The liver is therefore where most drugs undergo deactivation by CYP2E1, either directly or by facilitated excretion from the body.
CYP2E1 metabolizes mostly small, polar molecules, including toxic laboratory chemicals such as dimethylformamide, aniline, and halogenated hydrocarbons (see table below). While these oxidations are often of benefit to the body, certain carcinogens and toxins are bioactivated by CYP2E1, implicating the enzyme in the onset of hepatotoxicity caused by certain classes of drugs (see disease relevance section below).
CYP2E1 also plays a role in several important metabolic reactions, including the conversion of ethanol to acetaldehyde and to acetate in humans,[9] where it works alongside alcohol dehydrogenase and aldehyde dehydrogenase. In the conversion sequence of acetyl-CoA to glucose, CYP2E1 transforms acetone via hydroxyacetone (acetol) into propylene glycol and methylglyoxal, the precursors of pyruvate, acetate and lactate.[10][11][12]
CYP2E1 also carries out the metabolism of endogenous fatty acids such as the ω-1 hydroxylation of fatty acids such as arachidonic acid, involving it in important signaling pathways that may link it to diabetes and obesity.[13] Thus, it acts as a monooxygenase to metabolize arachidonic acid to 19-hydroxyeicosatetraenoic acid (19-HETE) (see 20-Hydroxyeicosatetraenoic acid). However, it also acts as an epoxygenase activity to metabolize docosahexaenoic acid to epoxides, primarily 19R,20S-epoxyeicosapentaenoic acid and 19S,20R-epoxyeicosapentaenoic acid isomers (termed 19,20-EDP) and eicosapentaenoic acid to epoxides, primarily 17R,18S-eicosatetraenic acid and 17S,18R-eicosatetraenic acid isomers (termed 17,18-EEQ).[14] 19-HETE is an inhibitor of 20-HETE, a broadly active signaling molecule, e.g. it constricts arterioles, elevates blood pressure, promotes inflammation responses, and stimulates the growth of various types of tumor cells; however the in vivo ability and significance of 19-HETE in inhibiting 20-HETE has not been demonstrated (see 20-Hydroxyeicosatetraenoic acid). The EDP (see Epoxydocosapentaenoic acid) and EEQ (see epoxyeicosatetraenoic acid) metabolites have a broad range of activities. In various animal models and in vitro studies on animal and human tissues, they decrease hypertension and pain perception; suppress inflammation; inhibit angiogenesis, endothelial cell migration and endothelial cell proliferation; and inhibit the growth and metastasis of human breast and prostate cancer cell lines.[15][16][17][18] It is suggested that the EDP and EEQ metabolites function in humans as they do in animal models and that, as products of the omega-3 fatty acids, docosahexaenoic acid and eicosapentaenoic acid, the EDP and EEQ metabolites contribute to many of the beneficial effects attributed to dietary omega-3 fatty acids.[15][18][19] EDP and EEQ metabolites are short-lived, being inactivated within seconds or minutes of formation by epoxide hydrolases, particularly soluble epoxide hydrolase, and therefore act locally. CYP2E1 is not regarded as being a major contributor to forming the cited epoxides[18] but could act locally in certain tissues to do so.
Following is a table of selected substrates of CYP2E1. Where classes of agents are listed, there may be exceptions within the class.
CYP2E1 exhibits structural motifs common to other human membrane-bound cytochrome P450 enzymes, and is composed of 12 major α-helices and 4 β-sheets with short intervening helices interspersed between the two.[13] Like other enzymes of this class, the active site of CYP2E1 contains an iron atom bound by a heme center which mediates the electron transfer steps necessary to carry out oxidation of its substrates. The active site of CYP2E1 is the smallest observed in human P450 enzymes, with its small capacity attributed in part to the introduction of an isoleucine at position 115. The side-chain of this residue protrudes out above the heme center, restricting active site volume compared to related enzymes that have less bulky residues at this position.[13] T303, which also protrudes into the active site, is particularly important for substrate positioning above the reactive iron center and is hence highly conserved by many cytochrome P450 enzymes.[13] Its hydroxyl group is well-positioned to donate a hydrogen bond to potential acceptors on the substrate, and its methyl group has also been implicated in the positioning of fatty acids within the active site.[23],[24] A number of residues proximal to the active site including L368 help make up a constricted, hydrophobic access channel which may also be important for determining the enzyme’s specificity towards small molecules and ω-1 hydroxylation of fatty acids.[13]
.
In humans, the CYP2E1 enzyme is encoded by the CYP2E1 gene.[25] The enzyme has been identified in fetal liver, where it is posited to be the predominant ethanol-metabolizing enzyme, and may be connected to ethanol-mediated teratogenesis.[26] In rats, within one day of birth the hepatic CYP2E1 gene is activated transcriptionally.
CYP2E1 expression is easily inducible, and can occur in the presence of a number of its substrates, including ethanol,[21] isoniazid,[21] tobacco,[27] isopropanol,[6] benzene,[6] toluene,[6] and acetone.[6] For ethanol specifically, it seems that there exist two stages of induction, a post-translational mechanism for increased protein stability at low levels of ethanol and an additional transcriptional induction at high levels of ethanol.[28]
CYP2E1 is inhibited by a variety of small molecules, many of which act competitively. Two such inhibitors, indazole and 4-methylpyrazole, coordinate with the active site’s iron atom and were crystallized with recombinant human CYP2E1 in 2008 to give the first true crystal structures of the enzyme.[13] Other inhibitors include diethyldithiocarbamate[20] (in cancer), and disulfiram[21] (in alcoholism).
CYP2E1 is expressed in high levels in the liver, where it works to clear toxins from the body.[7][8] In doing so, CYP2E1 bioactivates a variety of common anesthetics, including acetaminophen, halothane, enflurane, and isoflurane.[6] The oxidation of these molecules by CYP2E1 can produce harmful substances such as trifluoroacetic acid chloride,[29] and is a major reason for their observed hepatotoxicity in patients.
CYP2E1 and other cytochrome P450 enzymes can inadvertently produce reactive oxygen species (ROS) in their active site when catalysis is not coordinated correctly, resulting in potential lipid peroxidation as well as protein and DNA oxidation.[13] CYP2E1 is particularly susceptible to this phenomenon compared to other P450 enzymes, suggesting that its expression levels may be important for negative physiological effects observed in a number of disease states.[13]
CYP2E1 expression levels have been correlated with a variety of dietary and physiological factors, such as ethanol consumption,[30] diabetes,[31] fasting,[32] and obesity.[33] It appears that cellular levels of the enzyme may be controlled by the molecular chaperone HSP90, which upon association with CYP2E1 allows for transport to the proteasome and subsequent degradation. Ethanol and other substrates may disrupt this association, leading to the higher expression levels observed in their presence.[34] The increased expression of CYP2E1 accompanying these health conditions may therefore contribute to their pathogenesis by increasing the rate of production of ROS in the body.[13]
Trees have been genetically engineered to overexpress the CYP2E1 enzyme. These transgenic trees have been used to remove pollutants from groundwater, a process known as phytoremediation.[35]