Actual Assignment 2.Docx (1)

MEDSCI 204: Drug Assignment

Introduction

Zopiclone is a cyclopyrrolone derivative (1) which falls under a family of Non-benzodiazepine

hypnotic agents (2). Known by either one of its trade names Imovane or Zimovane (2),

zopiclone is found to have therapeutic actions on many psychophysical conditions but in

particular it is used to treat short-term insomnia (1). zopiclone was originally discovered and

introduced into the pharmaceutical market in the year 1986 by a French Pharmaceutical

Company “Rhone-Poulenc” which is now collectively a part of “Sanofi-Aventis” (2). The drug

is commonly administered orally (4) and studies have described improved absorption time

and greater hypnotic effect when patient had taken the zopiclone tablet in a standing

position rather than a supine position (4). Normal Prescription ranges per

administration/dosage is generally 7.5 mg (orally) (5) and is recommended that patients take

the drug 30-60 minutes prior to sleeping/bedtime (5). Dosage adjustments is a common

parameter to tailor for special population groups e.g. Elderlies and patients with Hepatic

insufficiency etc. (5). In the case of Dosage adjustments, patients are generally

recommended half of the standard dosage i.e. 3.75 mg (4) but this amount can be increased

up to a 7.5 mg if deemed necessary (3).

Despite being that of Non-benzodiazepine, zopiclone has exhibited similar pharmacological

characteristics as that of Benzodiazepine (4, 5). It has been shown that zopiclone achieves it

therapeutic actions through the agonist binding to 𝛾-aminobutyric acid (GABA) receptors and

thereby acts to enhance the inhibitory effects of the GABA neurotransmitter (6). With this

being said, Zopiclone agonist binding is not orthosteric to that of the benzodiazepine binding

sites but rather it associates to binding sites in close proximity to the Benzodiazepine-

receptor complex (5). As a consequence of enhancing the binding of GABA to the GABA-

chloride ionophore complex, zopiclone has produced pharmacological effects similar to that

of Benzodiazepine such as Anxiolytic, anticonvulsant and muscle relaxant properties (5).

Evidence on zopiclone dependency in the literatures have been described as being

“sporadic” (2). Nevertheless, available data has suggested the increased risk of dependency

and tolerance of zopiclone in conjunction with individual who have had a history of alcohol


Figure 1. Alignment of zopiclone with GABAA receptor pharmacophore (12)

and drug addiction. Furthermore, studies have also come to acknowledge potential in

zopiclone abuse in replacement for recreational drugs such as Heroin (2).

Composition/formulation and structure/nomenclature

In clinical practice, zopiclone is only available in its oral formulation; however there has been

reported cases of drug abuse whereby individuals have actively attempted to inject the drug

via intravenous methods (7), these situations however, are very scant compared to the

relative to the common method of zopiclone administration. The standard dosage

recommendation for zopiclone is 7.5 mg (tablet/oral form) prior to going to bed (8). In the

case of elderlies or individuals suffering from moderate-to-severe hepatic impairment it is

recommended that the starting dosage to be halved, though incremental changes can be

made along the process of treatment. (8)

Although zopiclone is a derivative of the cyclopyrrolone family i.e. unrelated to the

benzodiazepine family, it was suggested through studies that zopiclone acted as a full

agonist on the benzodiazepine GABAA receptors to induce corresponding hypnotic effects

(9). This observation lead to believe that there are certain degrees of chemical similarities of

zopiclone and other hypnotic

agents (of similar molecular

target) in comparison to the

class of benzodiazepine

drugs. Zopiclone has a

molecular weight of 388.82

and a chemical formula of

C17H17ClN6O3 (10). Studies

conducted regarding the

receptor site of the GABAA receptor in relation to its respective hypnotic agents have

revealed the presence of a pharmacophore. A pharmacophore describes the characteristic

features of a molecular complex which is vital for recognition and binding to that active site.

(11)

Figure 1. Demonstrates the aligning of the zopiclone molecule with the pharmacophore of

the benzodiazepine receptor site. The pyridine moiety of zopiclone is shown to interact with

region L1 of the receptor, the lone paired electron of carbonyl oxygen interacted with H1

(through hydrogen bonding) and finally the lone pair in amide carbonyl oxygen formed the

second hydrogen bond with H2 receptor of the protein complex (12). In order to achieve

therapeutic as well as physiological effects via GABA mediated receptors, the drug must fulfil


the various parameters relating to the pharmacophore. The drug must conform to the

Hydrogen accepting sites and lipophilic binding sites of the pharmacophore as well as

achieving similar volume profiles at respective binding sites as that of benzodiazepine.

Drugs which fall under these categories i.e. share similarities are drugs such as zopiclone,

zolpidem and other Z-class drugs. (12)

Absorption, distribution, metabolism and excretion

Extensive research has been conducted on the pharmacokinetic aspect of the drug

Zopiclone. Initial studies conducted by G. Callie, (1984) (13) suggested a rapid absorption

from the gastrointestinal tract that reaches a peak plasma concentration ranging from 54 to

86 𝜇g/L within the course of 0.5 to 4 hours following administration (13). Although Callie’s

data were established on the basis of data extrapolation from only a few plasma samples, it

suggested for unprecedented data on the pharmacokinetic properties of the drug. More

recent data acquired have come to suggest findings that corresponded to prior research

results; time peak of Zopiclone (tmax) was measured to occur within 1 to 2 hours following

administration and reaches a maximal peak plasma concentration of 131 𝜇g/L (under

administration of a standard 7.5 mg dosage, tablet form) (7). An absorption rate constant

was calculated to be at that of 1.3 h-1 and is associated with an absorption half-life of 0.52

hours. Oral bioavailability of the drug as compared to that of an index value (intravenous

injection) measures a substantially high value of 75-80% and is therefore implicative that

first-pass metabolism is diminished in Zopiclone absorption and distribution (7) (13). Factors

such as high-fat meal prior to drug intake does not affect AUC but it is causal of a reduction

in peak plasma concentration and delay in occurrence which is speculated to ultimately alter

the onset of the efficacy of the drug (14). Furthermore, it has also been concluded that

administration in a supine position results in a minor delay in drug absorption, but this delay

is insubstantial of holding any clinical significance. (14)

It is suggested that Zopiclone has a weak affinity to plasma protein. With only 52-59% of the

drug being bound to plasma proteins, this indicates that there is no apparent selective

interaction between the drug and red blood cells. With an apparent Volume distribution value

ranging between 92L and 140L (mean: 132 L) (7), as well as the observational data that

suggested that 50% of participants had come to experience the desired effect of the drug

within 30 minutes since administration (7)(13) , it may be conclusive that Zopiclone is rapidly

distributed within the circulation and allows for relatively fast onset of its hypnotic effects.

Furthermore, the rapid distribution of Zopiclone is manifested in saliva samples 15 minutes


into the time since administration such that salivary Zopiclone concentrations have exceeded

that in the plasma circulation; this finding could potentially suggest for the bitter taste upon

ingestion caused by salivary excretion of the drug (12). Using data from animal experiments,

it was suggested that highest levels of Zopiclone accumulation occurred at the level of

muscle, liver, fat tissue and kidney rather than in solid organs; this observation is also

confirmed through post-mortem examinations to which it was seen that there was an

insignificant quantity of Zopiclone distributed at the level of the solid organs but rather, a

much higher concentration in plasma. (13)

Zopiclone clearance is estimated to occur at rates between 13.9-18.5 L/h and this

accompanied with an elimination half-life (t1/2) of approximately 5 hours (range: 3.5-6.5

hours) (12). In contrast to a large majority of traditional benzodiazepine drugs, the

elimination half-life of Zopiclone and its metabolites are significantly lower; this reduces

potential for the prolonged after-effect that patients may experience due to residual drug in

the system which may adversely affect cognitive and psychomotor functions the next day.

The above pharmacokinetic parameters regarding half-life and clearance are those valid to a

healthy individual; it is observed that in elderlies (>65 years of age), there is an apparent

shift in parameters such as increase in AUC by 40% and a higher half-life of 9 hours

(compared to the mean value of 5 hours) and these can be ultimately attributed to changes

to the functional architecture of the liver and kidney with age (13).

Taken into account that the bioavailability of Zopiclone has achieved consistent values

between 75-80% from historic and current data, it can be assumed that the degree of first

pass metabolism is very much diminished. Body fluid samples have come to suggest that

only 7% of the initial dosage (parent drug) is excreted via the urine and the rest is mainly

metabolised prior to any elimination processes. The drug is primarily metabolised in the liver

via three biotransformation pathways: oxidation, decarboxylation and demethylation.

Approximately 50% of the initial dosage undergoes decarboxylation reactions and is

eliminated as carbon dioxide through the lungs (7)(12)(13). The two main urinary metabolites

of Zopiclone are the active Zopiclone-N-oxide (which contributes to ~12% of dose) and the

inactive/inert metabolite: N-desmethyl-zopiclone (which contributes to ~16% of dose). The

biotransformation of Zopiclone into these two urinary metabolites are mediated by the

cytochrome P450 isoenzymes: CYP34A, and to a lesser degree: CYP2C8 (7).As discussed

above, only an estimated 5-7% of the initial parent dose is excreted via the urine unchanged

and approximately 16% is presented in the faeces (biliary excretion). Excretion is also

evident via salivary secretion and it is this which contributes to the bitter, metallic after-taste

reported by patients upon ingestion; Zopiclone is also distributed into breast milk. The


approximated half-life of the two metabolite derivatives of Zopiclone: N-oxide derivative and

N-desmethyl derivate measure at 4.5 hours and 7.5 hours respectively; The N-oxide derivate

of Zopiclone although being an active metabolite, has a lesser extent in terms of

pharmacological activity compared to Zopiclone. (7)

Mechanism of action/ Therapeutic applications

Zopiclone is often regarded to as an alternative to the classic Benzodiazepine drug due to a

decreased elimination half-life of both itself and its constituting metabolites (12). Though

differing in chemical structure, Zopiclone shares similar pharmacological profiles as seen in

Benzodiazepine, achieving hypnotic, anxiolytic, myorelaxant, sedative and anticonvulsant

effects which is exploited to effectively target short-term (acute) insomnia (4)(7). In terms of

clinical relevance, Zopiclone is often regarded as being that superior to the traditional

benzodiazepines because of reduced concerns in tolerance and dependence profiles (7)(9);

it is often offered as an alternative to patients suffering from benzodiazepine withdrawal-

induced rebound insomnia (15)

Hypnotic agents are thought to induce their pharmacological properties through allosteric

modulation of the ionotropic GABAA receptor complexes, binding at the interface between

the γ and α subunits of the receptor (9). GABA being one of the most widespread inhibitory

neurotransmitters present in the CNS, has its actions mediated by 2 types of receptors: the

ionotropic GABAA receptor and the slower-acting metabotropic GABAC receptor (16). Studies

have suggested that the traditional hypnotic medications act through GABAA receptors, and

their presence in the system does not affect normal GABAC receptor functions. It is believed

that zopiclone acts to potentiate GABAA receptor functions, such that it mediates the influx of

Cl- ions into the neuronal membrane and thus hyperpolarizing and diminishes neuronal

firing. For some time, it was hypothesized that zopiclone shared the same binding domains

as that of the classic benzodiazepines (9). However with the addition of novel research

techniques such as photoaffinity labelling of hypnotic analogues as well as mutagenesis of

receptor amino acid residues it was suggested that it may be possible that zopiclone

interacts with slightly different amino acids and thereby producing a distinctive variant in

terms of receptor function following ligand binding (11). Characterization of the GABAA

pharmacophore revealed that there are some structural requirements such as lipophilic

regions and lone pair oxygen molecules which are needed to satisfy L and H regions

respectively; photolabelling has also revealed an important Histidine-101 side chain residue

believed to be crucial for the recognition of GABAA agonists (11)(9) . Despite some

similarities in interaction, it is suggested via a model of ligand binding (9) that

cyclopyrrolones interact at shallower depths of the receptor cleft compared to that of the


benzodiazepine agonists. This has caused researchers to suggest that it is these distinct

interactions of zopiclone that establishes it highly efficacious and superior therapeutic effect

compared to benzodiazepine.

1) Heterogeneity of GABAA receptor subtype

The differential expression of GABAA receptor phenotypes allows one to map out the

abundance of receptor subtypes in respect to both location and function. The most

widespread subtype in the CNS is the 𝛼1𝛽2𝛾2 receptor and it has been speculated

that it is this 𝛾2 subunit within the receptor complex that contributes a determining

role in neuronal inhibition of the central nervous system (7). Despite a non-specific

activation of all 𝛼 subtypes, zopiclone exhibits particularly high affinity binding profiles

to the 𝛼1 subtype (9). Together, it may be suggested that interaction due to high-

affinity binding profile of zopiclone allows for it to exhibit high therapeutic efficacy.

(9)(11)

2) GABA shift

GABA shift describes a process by which the presence of GABA at receptor sites

enhances mediation of compound pertaining to an intrinsic potentiation property (and

vice versa) (9). It was demonstrated that incubation of GABA at their binding sites

increased benzodiazepine affinity profiles. Ironically, it is also this theory of GABA

shift which helps to elucidate the loss of sensitivity towards benzodiazepine

suggesting that chronic administration of benzodiazepine is responsible for the loss

of GABA shift (9). In contrast to the above, zopiclone is believed to be the only full

agonist showing exception to GABA shifting; it does not undergo conversion into a

partial inverse agonist and therefore makes it less susceptible to the development of

tolerance and dependence. (9)

Upon examination of zopiclone’s clinical efficacy, it has been revealed from EEG recordings

that administration of zopiclone prior to going to sleep decreases the period of Non-REM

sleep while prolonging the time of stage 2 REM sleep (7). Comparative trials concerning

hypnotic efficacy has shown (in most cases) that zopiclone is either superior or equal to

most hypnotics in terms of treatment for insomnia. When compared to Diazepam, it was

revealed that only zopiclone administration significantly prolonged total sleep time (13.5% for

7.5 mg dosage and 26.6% for 15 mg dosage) (4). Zopiclone administration (7.5mg/day) for 4

weeks revealed a slightly more efficacious result compared to that of flunitrazepam

(1mg/day) for sleep quality and day-time wellbeing (4). These parameters have all come to

suggest that zopiclone is much more efficacious especially in treating short-term insomnia.


Currently, zopiclone is not used in combination with any other drug; there however are drug

interactions which may produce contraindications (see below). Although there have been

particular national restrictions governing availability, therapeutic monitoring is not required as

of this stage. (7)

Adverse effects/contraindication/drug interactions

Studies were conducted to investigate the residual effects of zopiclone compared to placebo

on the effects of driving performance following administration of the standard 7.5 mg oral

dose. It is believed that the mechanisms underlying residual daytime sedation is due to the

hypnotic effects elicited by both the drug itself as well the metabolite zopiclone-N-oxide

which, on its own is believed to have a weak hypnotic effect (14). Comparisons between

healthy individuals reported of having no problems relating to insomnia and individuals who

have had problems of chronic insomnia revealed that the effects of residual daytime

sedation was less pronounced (if even present) in the chronic hypnotic users compared to

that of the healthy infrequent users of zopiclone (17). In the cohort of chronic zopiclone

users, it is suggested that daytime awareness and alertness is heightened following intake in

the previous night before bedtime. In contrast, the opposite observation was reported in the

cohort of healthy, infrequent users, suggesting a significant impairment in driving

performance due to effects of residual daytime sedation. It is believed that the factor

contributing to these two opposing observations is the overestimation of the effects of

residual sedation on chronic hypnotic users as they have already developed a degree of

tolerance to the drug (zopiclone) (17). Interestingly, when zopiclone is removed from the lists

of medication given to people of the chronic users, effects of withdrawal had significantly

impacted on these performance parameters. In comparison however, it is revealed that

performance in the highway test for both cohorts was not seriously impaired and this can be

attributed to the notion that individuals are to compensate for any residual sleepiness and

aftereffects when performing simple and non-complex tasks. (17)

However, the most commonly reported adverse effect of zopiclone is the metallic after taste

which is associated to post-administration of the drug (7), reported by 10% of its recipients. It

is believed that this adverse effect is attributed to the fact that zopiclone is rapidly distributed

across the circulation and partial excretion has been revealed to occur at the level of the

salivary glands (7)(14). Because zopiclone acts as a full agonist on Benzodiazepine GABAA

receptors, mechanisms of dependence and withdrawal-induced rebound insomnia occurs via

similar mechanism as that of benzodiazepine; with this being said, zopiclone’s potential of


dependence and tolerance is greatly reduced compared to the traditional hypnotic agents

due to its short-acting purpose (9)(7). In the human body, dependence is largely the effects

of what is understood as being the “reward-system” in which the individual gives a reason to

a particular activity e.g. eating, drinking to a pleasurable after-sensation (18). Chronic use of

zopiclone against recommended dosage time frame will induce the down regulation of

GABAA receptors as well as up regulation receptors off antagonist effect to the

neurotransmitter. In the case whereby the patient removes zopiclone from their list of

medication(s), symptoms mirroring the drug’s original effect will occur; symptoms include:

nightmares, hypnogogic hallucinations, anxiety and muscle spasms etc. Furthermore,

shifting the mode of zopiclone and other hypnotics to that of an inverse agonist state will

heighten sensitivity of the brain towards excitatory drugs or stimuli, thereby causing

excitotoxicity in the CSN; this explains the occurrence of rebound insomnia in some patient

profiles. (19)

Patients suffering from hepatic insufficiency will have the processes by which zopiclone is

metabolised, compromised. As a result, it has been reported that those with hepatic

insufficiency have a prolonged t1/2 (by twice the normal length) (14), accompanied by a

decrease in the respective concentrations of its metabolites. Dosage adjustment is thereby

required in patient with severe liver diseases as well as in elderly patients who experience

moderate-to-severe hepatic diseases; beginning with a starting dosage of 3.75 mg. (7)(4)

Furthermore, it has been suggested that many individuals with a history in drug-abuse or

psychiatric disorders have a higher risk of developing dependence or recreational abuse. A

study conducted on 297 drug addicts had revealed that among the 88.5% of users that had

reported of taking the drug for sleep-enhancing effects, 56.7% had reported that they

actively take the drug to feel better whereas 22.9% revealed that they took the drug in order

to achieve the feeling of getting “high” (7).

In a case regarding a patient undergoing cross-treatment with both zopiclone and

nefazodone (anti-depressant), it was reported that the patient experienced symptoms such

as a morning drowsiness and the removal of zopiclone from her medication resulted in

decrease plasma levels of zopiclone (from 107 to 16.9 ng/mL). It is believed that nefazodone

as well other drugs such as cimetidine or erythromycin are potent inhibitors of Cytochrome

P450 enzymes (primary role in drug metabolism); inhibition of CYP450 will thereby prolong

the time which the active form of the drug persists in the body. Conversely, it is suggested

that potent inducers of CYP34A such as rifampicin and phenytoin etc. potentially interfere

with zopiclone efficacy. (7)


Funding and marketing issues

Since being introduced into the pharmaceutical market, zopiclone’s hypnotic effects have

been exploited for drug abuse purposes. There has been reported cases whereby

individuals undergo active incremental changes of dosage, reaching a summated daily

dosage of 105 mg which was taken as separated in 2-3 oral tablet forms (7). A study

branching off a Methadone program in Iceland had revealed that amongst the 38 patients

taking zopiclone, 16 had suggested that their misuse can be attributed to the degree of

tranquilization induced by the drug; out of these 16 patients, one had reported of attempting

to inject the drug. In addition to these reported cases of drug abuse, Zopiclone misuse has

also been associated with drug-facilitated crimes such as sexual assaults or robbery (7).

Recently, surveys have shown that there is an increase incidence whereby zopiclone is

purchased through false prescriptions or purchased on the street, as suggested by 56.7% of

zopiclone users. Other cases of the recreational use of zopiclone has been attributed to

factors such as induction of euphoria or even to disinhibit an anxiolytic effect. Ultimately,

these recurring incidences has established zopiclone as a substance for drug abuse. (7)

Out of the 59 countries that responded to the WHO survey on zopiclone, 34 countries

currently authorize the market distribution and availability of the drug to the public (7);

however one country has also revealed that the authorization status was shortly withdrawn

following its induction to the public (7). On a national scale, zopiclone is currently subsidized

by the country’s PHARMAC schedule. However with this being said, Apo-Zopiclone (7.5 mg,

film coated, 500 tablet, bottled) and Zopiclone actavis are the only brands of zopiclone that is

currently fully subsidized by the government at $11.90 per unit and $8.99 per unit

respectively (20). On the 4th of April, 2005, the United States had placed zopiclone and its

isomers in schedule IV as a part of the Controlled substances Act by the Drug enforcement

administration due arisen incidences of abuse (7). Along with the United States, Zopiclone is

also placed under control in France as it is a one of the top ten substances of falsified

prescription and illicit manufacturing (7). Other countries that have placed Zopiclone under

control are Mauritius and Turkey. However, in general, the act of limiting zopiclone’s market

availability on an international scale has caused many countries to respond in a very

sceptical way. In the 2005 WHO questionnaire regarding the substance, it was suggested by

countries such as China, Japan and Myanmar etc. that international governance of zopiclone

control will greatly affect the medical availability of the drug, especially in remote areas and

thereby changing the mode of circulation with the market. (7)


Part B – Would you take this Drug?

As a novel hypnotic agent induced into the market during the late 20th century (1986) (2),

zopiclone has received a diversity of responses, a majority being that of a supportive nature.

Personally, I value the quality of my sleep to a very high extent as I understand that the

quantity as well as quality of sleep will have a profound effect in terms of my various

performance parameters during in the next day. As a university student, I am often obligated

to various work and academic commitments during the week and it is this stress which has

overlaid a huge burden onto my sleep routine and quality. Studies have been conducted to

show the positive correlation between the amount of stress to the quality and quantity of

sleep for an individual; on top of this, sleep deprivation is also associated to a decline in

attentiveness and working memory functions as well as other symptoms such as physical

fatigue and emotional instability (21). With all these factors summated, I believe that it is

crucially important for me to undergo immediate treatment in the case of short-term, acute

insomnia as this will ensure that my ability to achieve maximal performance in both an

academic and work environment will not be hindered.

Zopiclone is a short-term acting hypnotic agent that has had its clinical efficacy proven to be

either equal if not superior to most of the traditional benzodiazepine hypnotic agents (9)(7).

In addition, it is also suggested through clinical trials and observational studies that the

potential for dependence and tolerance, though existent, is relatively much lower than that of

the traditional hypnotics. The main therapeutic target in zopiclone treatment is to improve

sleep duration as well as quality in individuals suffering from acute insomnia (4). Side-effects

relating to zopiclone are that of an anxiolytic, myorelaxant, and sedative property (4);

although these induced side-effects will not be the determining factors impacting my decision

of whether I would take this drug or not, its “tranquilizing and calming” (7) effect could

potentially be used to my advantage (In complement to its primary effect), providing that

drug usage is done in careful moderation and not recreationally. Conclusively, during the

transient periods of insomnia, I would consider taking the drug in order to prevent the

development of the range of manifesting effects caused by sleep deprivation.

As mentioned briefly above, there are still cases of reported incidences of tolerance and

other adverse effect (7)(2). However, the pharmacokinetics of zopiclone and its clinically

safety has been proven to be superior to the traditional hypnotics due to factors such as


decreased half-life and improved immediacy of its therapeutic efficacy. Surveys conducted

relating to the adverse effects of zopiclone are relatively much lower compared to its

comparative drugs and therefore it may be implied that usage of the drug is safe providing

moderate use stemming from a non-abuse intention. However, one factor that I may have to

take into consideration is zopiclone’s contraindications with alcohol (4). Alcohol is known as

a CNS depressant and consumption with zopiclone could potentially induce toxic and life-

threatening effects. As a result, if I was to use zopiclone as means of sleep medication, extra

caution must be taken such that I do not take it following a nights out or other activities

involving alcohol consumption.

Apo-Zopiclone is currently subsidized by the New Zealand government (7.5 mg, tablet, 500

tablets/bottle) at $11.90 per unit. Zopiclone activas is also subsidized containing the same

amount as that of Apo-Zopiclone but set at a price of $8.99 (21). This price is economically

affordable taking into account of my personal income; 500 tablets/bottle is however, in

excess considering the main therapeutic target is to treat short-term insomnia. With this

being said, expiry date which is generally 18 months, should be examined by infrequent

users, prior to consumption.

Clinical efficacy of zopiclone has been proven to be either equal or superior to that of the

classic benzodiazepine drugs; zopiclone is also often used as an alternative medication for

patients whom have developed tolerance or dependence to benzodiazepines (4)(7). Ethical

issues surrounding zopiclone is quite controversial but relatively minor in comparison to

issues relating other drugs. Restrictions in public distribution is thought to compromise

medical availability and therefore stemming other illicit forms of manufacturing and

purchasing (7). However, non-restricted availability will also conversely result in zopiclone

being used for abusive purposes (7). These ethical issues, however, do not apply to me

personally so will not impact on my decision of using the drug.


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21. Better Health Channel. Sleep deprivation - Better Health Channel [Internet]. 2015 [cited 23

September 2015]. Available from:

http://www.betterhealth.vic.gov.au/bhcv2/bhcarticles.nsf/pages/Sleep_deprivation?OpenDocume

nt

Actual Assignment 2.Docx (1)

Documents

zopiclone abuse

zopiclone dependency

tolerance of zopiclone

zopiclone tablet

alignment of zopiclone

zopiclone agonist binding

binding of gaba

benzodiazepine binding