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Zopiclone 2

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Group2 B309

on 1 March 2011

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Transcript of Zopiclone 2

ZOPICLONE IUPAC
6-(5-chloropyridin-2-yl)-7-oxo-5H,6H,7H-pyrrolo[3,4-b]pyrazin-5-yl 4-methylpiperazine-1-carboxylate

Brand names
Imovane (Canada)
Zimovane (U.K.)
Lunesta (U.S, (+)-enantiomer)
Amoban
Amovane
Imovance
Novo-zopiclone
Nu-Zopiclone
Ran-zopiclone
Rhovane
Sopivan
Ximovan Zopiclone Alternate Names Indications Pharmacokinetics Dosage Pharmacokinetics Unwanted Effects Alternate Treatments Fun Facts Zopiclone is a GABA-A (gamma amino butyric acid A) receptor agonist commonly implicated in the treatment of insomnia. Zopiclone is rapidly and well absorbed throughout the body, and it crosses the blood-brain barrier to affect the GABA-A receptors of the central nervous system (CNS). By its action at GABA-A receptors, zopiclone reduces the likelihood of an action potential and thereby induces muscle relaxation, reduces anxiety, and prevents convulsions. The most prominent and desired effect of zopiclone is sleep induction and maintenance. Frequent side effects of zopiclone include a decrease in daytime mental efficiency and a bitter or metallic taste.
The active enantiomer of zopiclone ((+) -zopiclone) is metabolized by three mechanisms: demethylation, oxidation, and oxidative decarboxylation. The metabolites produced are then primarily excreted in the urine. Although it shares a similar pharmaceutical profile with benzodiazepines, zopiclone is a cyclopyrrolone, a class of drugs which is more effective and less toxic than benzodiazepines. Abstract Zopiclone is indicated as a short term treatment for assistance in falling asleep or in maintaining a state of sleep. Contraindications Zopiclone is contraindicated majorly, in patients:
Suffering from impaired liver function
 - Zopiclone is metabolized by the CYP enzymes; therefore the
metabolism and resulting inactivation of Zopiclone depends
on liver function.
Using alcohol
 - Alcohol is also a CNS depressant: it will increase the effect of
zopiclone and appears to increase the risk of sleep-complex
behaviours.
Afflicted by chronic respiratory insufficiency [e.g. sleep apnea]
 - Zopiclone will increase the likelihood of a continued sleep
during an attack of respiratory insufficiency.
Diagnosed with myasthenia gravis
 - Zopiclone acts as a sedative, paralleling and enhancing the
effects of the myasthenia gravis disease.

Zopiclone is contraindicated to a lesser degree, in patients:
Younger than the age of 18 years or greater than the age of 65 years
 - The safety of Zopiclone when administered to youth has not
been established; geriatrics have a greater risk of dose-related
adverse effects [eg. drowsiness, dizziness, impaired
coordination].
Who are pregnant
 - Little data has been collected in regards to the effect of
Zopiclone on fetal development.
With known hypersensitivity to Zopiclone Dosage Unwanted Effects Major:
•Dysgeusia (distortion of taste to a bitter, metallic flavour; usually fleeting)
•Reduced mental efficiency
- Reduced concentration, attention and vigilance
- Confusion or anterograde amnesia (more common for seniors)
- Dizziness, headaches, blurred vision
•Behavioural changes (usually increased with chronic use or high dosage)
- Hallucinations
- Nightmares
- Anger, irritability
- Depersonalization
•Sleep changes:
- Disruption of REM sleep
- Complex sleep-related behaviours (For example, walking, talking,
or cooking while asleep or not fully awake
•Difficult or laboured breathing (shortness of breath, wheezing)
•Withdrawal symptoms

Minor:
•Chills
•Constipation or diarrhoea
•Decreased muscle tone, feeling of heavy arms and legs
•Decreased coordination and speech articulation
•Dry mouth or increase in the amount of saliva (more common for seniors)
•Indigestion, heartburn
•Increased sweating (more common for seniors)
•Change in appetite and weight
•Nausea, vomiting (more common for seniors)
•Tightness in chest
•Tingling, burning, or prickly sensation
•Trembling and shaking of limbs and digits (more common for seniors)
•Urticaria (hives), skin rash Alternative Treatments Behaviour Therapies
Learn good sleeping habits
Practice relaxation techniques (eg. muscle relaxation, breathing exercises)
Undertake cognitive behavioural therapy (to aid in reducing anxiety related to insomnia)
Restrict time in bed
Restrict sleep time
Lifestyle Changes
Avoid stimulants close to bedtime (eg. caffeine, tobacco)
Avoid some over-the-counter drugs such as allergy and cold medications
Drink an alcoholic drink prior to going to bed
Perform regular exercise early in the day (avoid exercise within 5-6 hours of going to bed)
Avoid drinking a lot or eating heavy meals prior to going to bed
Limit distractions at bedtime (eg. television, lights, computer, pets)
Establish and maintain a regular sleep schedule and bedtime routine
Avoid daytime naps
Gain light exposure during the day (may help to restore circadian rhythms)
Other
Acupuncture
Medicines Barbiturates
Pentobarbital (Nembutal)
Phenobarbital (Luminal)
Secobarbital (Seconal) Anti-depressants
Amitriptyline (Elavil)
Doxepin (Sinequan)
Trazodone (Desyrel) Benzodiazepines
Diazepam (Valium)
Flurazepam (Dalmane)
Oxazepam (Serax)
Temazepam (Restoril)
Triazolam (Halcion) Natural Medicines
Melatonin
L-tryptophan
Valerian teas/extracts
German chamomile
Hops
Kava
Lavender
Lemon balm
Passionflower
Skullcap
5-HTP
Coenzyme Q10 Anti-histamines
Diphenydramine (Bendryl)
Doxylamine (Unisom) Non-benzodiazepines
Zolpidem (Ambien)
Zaleplon (Sonata)
Ramalteon (Rozerem) Fun Facts References Zopiclone should always be taken just before bed. Its dosage in the following categories is as follows:

Adults:
Start: 5.0mg
Maximum: 7.5mg
Elderly:
Start: 3.75mg
Maximum: 7.5mg
Patients with hepatic or respiratory deficiency:
Start: 3.75mg
Maximum: 7.5mg
HOWEVER, it is highly recommended that patients with severe hepatic or respiratory deficiency do not take zopiclone
Patients with renal deficiency:
Start: 3.75mg
Maximum: 7.5mg
Pediatrics:
It is highly recommended that patients under the age of 18 do not take zopiclone.

Also, zopiclone should never be taken for more than 7-10 consecutive days due to its addictive nature and risk of tolerance.

Gradual dosage tapering is recommended in order to reduce withdrawl symptoms and to prevent seizures.

Overdoses leading to coma or death occur over a wide range of doses due to drug tolerance. Zopiclone acts on GABA-A (Gamma Amino Butyric Acid A) receptors found in brain tissue of the central nervous system. GABA is an abundant neurotransmitter in the central nervous system that binds to GABA receptors, producing an inhibitory effect on the neuron. There are two classes of GABA receptors: A and B. While GABA-A receptors differ from GABA-B receptors in location, structure, and mechanism, both share a common function. GABA-B receptors are G-protein coupled receptors and are found presynaptically, whereas GABA-A receptors are found post- and perisynaptically and have a ligand-gated ion channel structure.
The GABA-A receptor has a pentameric structure consisting of three different subunits (alpha, beta, and gamma) with a subunit ratio of 2:2:1, respectively. Each subunit can have 3-6 subtypes. The most common subtype is  alpha-1 beta-2 gamma-2 (Figure 3). The exact binding site of zopiclone has not been found but is known to be close to that of the benzodiazepine drug class: a cleft between the alpha and gamma subunits. It is possible that this site overlaps that of benzodiazepines, which is likely a factor contributing to the similar function that zopiclone and benzodiazepines share.
Zopiclone enhances the inhibitory effect that GABA produces when it binds to GABA-A. Zopiclone does not distinguish between alpha 1, alpha 2, or alpha 3 subunits but has a low affinity for alpha 4 and alpha 6 subunits. When zopiclone binds to the GABA-A receptor it increases channel opening, allowing an influx of chloride ions (Cl-) into the neuron. This provides a hyperpolarizing effect by reducing the charge on the inside of the neuron, making it more negative and therefore less likely to create an action potential. Zopiclone is a Canadian band whose music is a mixture of rock, funk, jazz, 80s new wave, and progressive. The band consists of four members from London, Ontario. One of the songs on their debut album is also named Zopiclone. http://www.zopicloneentertainment.com/sounds/08%20Track%208_Zopiclone.mp3 Mechanism of Action Belelli, D., Lambert, J.J. (2005). Neurosteroids: endogenous regulators of the GABAA
receptor. Nature Reviews Neuroscience, 6, 565-575. doi: 10.1038/nrn1703
Diav-Citrin, O., Okotore, B., Lucarelli, K., & Koren, G. (2000). Zopiclone use during pregnancy.
Canadian Family Physician, 46, 63-64. Retrieved from http://motherisk.org/prof/
updatesDetail.jsp?content_id=324
Doble, A., Canton, T., Malgouris, C., Stutzmann, J.M., Piot, O., Bardon, M.C., Blanchard, J.C.
(1995). The Mechanism of Action of Zopiclone. Eur psychiatry, Advance online
publication. doi: 10.1016/0924-9338(96)80093-9
Doghramj, K. (2009). Approach to the patient with a sleep or wakefulness disorder. Retrieved
from Merck Manuals Online Medical Library website: http://www.merckmanuals
.com /professional/print/sec16/ch215/ch215b.html
Drug Bank (2010). Zopiclone. Retrieved from http://www.drugbank.ca/drugs/DB01198
Drugs.com (2011). Zopiclone Tablets 3.75mg, 7.5mg. Retrieved from http://www.drugs.
com/uk/zopiclone-tablets-3-75mg-7-5mg-1478.html
Fernandez, C. et al. (1993) Pharmacokinetics of zopiclone and its enantiomers in caucasian
young healthy volunteers. Drug Metabolism and Disposition. 21(6) 1125-1128 Retrieved
from http://dmd.aspetjournals.org/content/21/6/1125.full.pdf+html
Health Canada (2009). Important safety information regarding the use of sleep aid drugs and
the risk of complex sleep-related behaviours. Retrieved from http://www.hc-
sc.gc.ca/ahc-asc/media/advisories-avis/_2009/2009_161-eng.php
Health Canada (2010). Zopiclone [Monograph]. Retrieved from Health Canada Drug Product
Database.
Hirst, A. & Sloan, R. (2009). Benzodiazepines and related drugs for insomnia in palliative
care. Cochrane Database of Systematic Reviews 2001, 4 (CD003346). doi:
10.1002/14651858 .CD003346.
Kleijn, J. (1989). Effects of zopiclone and temazepam on sleep, behavior, and mood during
the day. European Journal of Clinical Pharmacology, 10, 247-251. doi:
10.1007/BF00558155
Mann, K. et al. (1996). Acute, subchronic and discontinuation effects of zopiclone on sleep EEG
and nocturnal melatonin secretion. European Neuro-Psychopharmocology, 6, 1163-168
doi:10.1016/0924-977X(96)00014-4
Mayo Foundation for Medical Education and Research (2011). Treatments and drugs.
Retrieved from http://www.mayoclinic.com/health/insomnia/DS00187
/DSECTION=treatments-and-drugs
MediResource Inc. (2011). Are there any other precautions or warnings for Imovane?
Retrieved from http://chealth.canoe.ca/drug_info_details.asp
?channel_id=0&relation_id=0& brand_name_id=365&page_no=2#Warnings
MediResource Inc. (2011). What side effects are possible with Imovane? Retrieved from
http://chealth.canoe.ca/drug_info_details.asp?channel_id=0&relation_id=0
&brand_name_id=365&page_no=2#AdverseEffects
National Heart Lung and Blood Institute (2009). Insomnia. Retrieved from http://www
.nhlbi.nih.gov/health/dci/Diseases/inso/inso_all.html
Natural Medicines Comprehensive Database (2011). Retrieved from
http://naturaldatabase.therapeuticresearch.com/ce/CECourse.aspx?cs=&pm=5&s=nd
&pc=08-22&searchid=25270712#keywordanchor
Rang. H.P., Dale, M.M., Ritter, J.M., & Flower, R.J. (2007). Rang and Dale’s Pharmacology: 6th
Edition. Philadelphia, PA : Elsevier Limited.
Sanofi-aventis Canada Inc. (2009). Imovane (Zopiclone) [Monograph]. Retrieved from
http://www.sanofi-aventis.ca/products /en/imovane.pdf
UBC Therapeutics Initiative. (1995). To sleep or not to sleep, here are your questions. Retrieved
from http://www.interchg.ubc.ca/jauca/
UBC Therapeutics Initiative. (2004). Use of Benzodiazepines in BC: is it consistent with
recommendations? Retrieved from http://www.ti.ubc.ca
Voderholzer, U. et al. (2001) A double-blind study on the polysomnographic withdrawal effects
of zopiclone, zolpidem and triazolam in healthy subjects. Eur Arch Psychiatry Clin
Neurosci. 251, 117-123 doi: 10.1007/s004060170045 Introduction Chloe Mariani, DesErik Hall, Haley Dirksen, & Rebecca McOnie Group 2 - Biochemistry 309 Pharmacokinetics Absorption:
-Rapidly and well absorbed
-Bioavailability of more than 75%
Bioavailability increases to 94% in elderly patients
-Peak plasma concentrations reached in less than 2 hours
Higher for (+)-zopiclone
In patients with hepatic insufficiency peak plasma concentration is reached at 3.5 hours

Distribution:
-Crosses the blood-brain barrier
-Rapidly distributed from the vascular compartment
-Volume of distribution (Vd) is 91.8-104.6 L
Lower for (+)-zopiclone
-Plasma protein binding is low
Higher for (+)-zopiclone
-The hypnotic effect is apparent after 15 to 30 minutes

Metabolism:
-Metabolism of zopiclone is stereoselective
Half-life longer for (+)-zopiclone
-Three main routes of metabolism:
Demethylation
- Approximately 16% of dose is metabolized via demethylation
- Primary enzyme is CYP 3A4 and secondary enzyme is CYP 2C8
- N-desmethylzopiclone is formed and is inactive
- N-desmethylzopiclone average half-life is 7.4 hours
Oxidation
- Approximately 12% of dose is metabolized via oxidation
- Enzyme involved in oxidation is CYP 3A4
- N-oxidezopiclone is formed and is weakly active
- N-oxidezopiclone average half-life is 4.5 hours
Oxidative Decarboxylation
- 50% of dose is metabolized via oxidative decarboxylation
- Metabolite: CO2

Excretion:
-More than 90% of metabolized dose is excreted over 5 days
Urine: 75% (Includes most of the N-desmethyl and N-oxide derivatives)
Feces: 16%
Respiration (CO2)
-Breast milk (concentration is ~50% lower than that of the plasma level)
-4-5% of unchanged drug is excreted in the urine after 48 hours
-Elimination half life is longer in geriatrics and those suffering from hepatic insufficiency An influx of chloride ions into a GABA-A receptor after binding of zopiclone and GABA. A video representation of the mechanism of GABA binding to a GABA-A receptor causing an influx of chloride ions. Album cover of the band Zopiclone's debut album "Marble Sky". 7.5mg apo-zopiclone tablets. Insomnia affects 5 to 10 percent of the adult population worldwide, making treatment a high priority. The first class of drugs made to treat insomnia was the benzodiazepines, but these drugs have many side effects and can impact daytime functioning. Zopiclone was first developed in 1986 as an alternative to benzodiazepines because it is shorter acting, has a reduced rebound effect, and does not change the pattern of sleep as much as benzodiazepines. It was thought that these factors would decrease the dependence that people develop when taking hypnotic drugs. However, there is still risk of addiction and it is abused by people with and without insomnia. In Canada, zopiclone is sold as a racemic mixture of both of its enantiomers but only the (+)-enantiomer is pharmacologically active. In the United States, zopiclone is only sold as the active enantiomer under the name Lunesta. The chemical structure of zopiclone. Figure 1. Figure 2. Video 1. Figure 3. Figure 4. Zopiclone is contraindicated majorly in patients:
Suffering from impaired liver function
- Zopiclone is metabolized by the cytochrome P450 (CYP)
enzymes, therefore the metabolism and resulting
inactivation of zopiclone depend on liver function.
Using alcohol
- Alcohol is also a CNS depressant: it will increase the
effect of zopiclone and appears to increase the risk of
sleep-complex behaviours.
Afflicted by chronic respiratory insufficiency [eg. sleep apnea]
- Zopiclone will increase the likelihood of a continued
sleep during an attack of respiratory insufficiency.
Diagnosed with myasthenia gravis
- Zopiclone acts as a sedative, paralleling and enhancing
the effects of the myasthenia gravis disease.

Zopiclone is contraindicated to a lesser degree in patients:
Younger than the age of 18 years or greater than the age of 65 years
- The safety of zopiclone when administered to youth has
not been established; geriatrics have a greater risk of
dose-related adverse effects [eg. drowsiness, dizziness,
impaired coordination].
Who are pregnant
- Little data has been collected in regards to the effect of
zopiclone on fetal development.
With known hypersensitivity to zopiclone Chloe Mariani, Desmond Sailer, Erik Hall, Haley Dirksen, & Rebecca McOnie
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