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Zopiclone

Zopiclone. Is it safe ?. Case 1. M/79 Found unconscious in bed at 7am Last seen normal at 2am PH: HT, BPH, cataract Ex-heroin abuse; depression FU WPC, on zopiclone, mirtazapine, Adalat Retard. Case 1. P/E

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Zopiclone

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  1. Zopiclone Is it safe ?

  2. Case 1 • M/79 • Found unconscious in bed at 7am • Last seen normal at 2am • PH: HT, BPH, cataract Ex-heroin abuse; depression FU WPC, on zopiclone, mirtazapine, Adalat Retard

  3. Case 1 • P/E BP 137/91; pulse 84/min regular RR 10/min; decrease AE both sides; trachea central comatose, GCS 3/15, pupils operated no external wounds

  4. Case 1 • ECG : SR 84/min, no QRS widening • CXR : no pneumothorax, NAD • H’stix 18.6 • Astrup (arterial) (on 100% O2) : pH 6.95, pCO2 16, pO2 17; BE 5 Na 131, K 4.5, HCO3 27

  5. Case 1 • Progress : • Intubated in A&E (Scoline 100mg iv) • Medical ICU consulted • Admitted medical ward 1st and then transferred to ICU bed • Extubated next day and transfer back to medical ward • Transferred to Psy ward on day 4

  6. Case 1 • Further Hx in ward - moved to live with eldest son 2 months ago • Unaccustomed to living there • Low mood with suicidal thought for 1 mth • Missed wife who passed away 2 yrs ago • Began to collect sleeping pills (Zopiclone) from pharmacy, visited drug store 6 times buying 10 tabs each time • Took all 60 tabs of Zopiclone at home the night before admission and was found unconscious the next morning.

  7. Case 1 • Urine toxicology • Zopiclone metabolite • BDZ • Ranitidine • Propoxyphene metabolite • Mirtazapine and metabolite • lidocaine

  8. Case 2 • M/19 • Found unconscious by father at 7:30pm at home • 1 empty box of sleeping pills (Stilnox) and two half-filled cans of beer found • Last seen well playing TV games in the morning • Good past health • No suicidal idea recently

  9. Case 2 • P/E • BP 100/60, pulse 102/min, Temp 38.9oC • Pupils pinpoint, equal • GCS : 8/15 E1V2M5 • Chest clear, no heart murmur

  10. Case 2 • Ix in A&E: • CXR: clear • ECG: SR, no widening of QRS, 97/min • H’stix 5.2 • Astrup : pH 7.41, pCO2 5.4, pO2 23, HCO3 25.9, Na 133, K 4.2 - Triage 8: negative

  11. Case 2 • No response to Narcan (0.4mg x2) • SpO2 100% after oropharyngeal airway • Admitted medical ward • Blood : CK 12095 umol/l, AST 179, urea 2.4, Cr 73 • Urine myoglobin weakly positive • CT Brain : normal • Urine toxicology : BDZ, propranolol & metabolite, Zolpiderm & metabolite, Zopiclone metabolite • Blood for ethanol and paracetamol negative

  12. Case 2 • ICU consulted in medical ward ⇒ alkaline diuresis in medical ward, no need for ICU admission • Hydration and NaHCO3 given with good diuresis • Condition improved gradually • Further Hx : found suicide note at home, took multiple drugs including zopiclone • Psy consulted and home on Day 5

  13. Case 3 • F/26 • Good PH • Took ~ 100 tabs of Imovane 7.5mg at 21:30 hours • Felt unhappy due to love affairs • Sent in by ambulance at 22:23 hours (i.e one hour later) • fully conscious, BP 98/57, pulse 64/min • Looked depressed • Gastric lavage followed by activated charcoal given in A&E • Admitted medical ward and further history revealed multiple previous suicide attempts and social problems • Walked away at 03:00 hours next day • Urine for toxicology : Zopiclone & metabolite

  14. Case 4 • F/13 • Transferred in from SJH • Taken 2 white oval tablets (白瓜子) at 9am together with 2 other schoolmates at school • Found by teacher rolling on the floor, hyperactive and unsteady gait • C/O dizziness, nausea • PH good, no drug abuse history • P/E fully conscious, BP/P normal • ECG (done in SJH) normal • Admitted Pediatrics and home next day • Further Hx : smokes and drinks, repeated episodes of cutting wrists, mother dies early, lives with step mother • Urine for toxicology : Zopiclone metabolite

  15. Zopiclone - structure

  16. Zopiclone • Newer generation sedative mainly for treatment of insomnia • The first of the cyclopyrrolones with marked sedative properties in addition to anti-convulsant and anxiolytic properties. • Thought to act thro’ GABAA receptors, but at a site distinct from, but closely related to, the BDZ binding site. • Unlike BDZ, zopiclone binding is not modulated by GABA. • Alternative suggestion: zopiclone binds to the flumazenil binding site because zopiclone is able to displace flumazenil from its GABA binding site but unlike BDZ, this displacement is of a noncompetitive rather than a competitive nature. • Displays high-affinity binding only for central BDZ receptors and does not bind appreciably to those at peripheral sites. • Negligible binding to other types of neuroreceptors. • Has a broad spectrum of pharmacologic activity similar to BDZ with sedative-hypnotic, anticonvulsant, muscle relaxant, antiaggressive and anitconflict properties.

  17. Zopiclonemechanism of action

  18. Zopiclone • Rapidly absorbed after oral administration • Peak plasma conc within one hour • Oral bioavailability 80% with little (<20%) lost to first-pass metabolism • Distribution rapid and extensive • Plasma protein binding relatively low at ~45%, predominately to albumin • Metabolised mainly by hepatic oxidation, with <5% excreted unchanged in urine • Short plasma ½ life of 3.5 – 7 hrs, increasing slightly with age and doubled in liver disease • Effect enhanced and prolonged by alcohol without increasing the plasma conc. • Transient first degree AV heart block occurred after ingestion of 127.5 mg of zopiclone (with piperazine) • Taste alteration (bitter taste) in ~10% of recipients

  19. Zopiclone (c.f. BDZ) • Therapeutic efficacy : the hypnotic properties are either equal or superior to BDZ • Side effects : • Tolerance, dependence and rebound - no tolerance, little or no dependence, less rebound insomnia 2. Impairment in daytime functioning - little or no residual somnolence upon awakening in the morning 3. Effect on respiration - 7.5 mg produces no resp depression in healthy subjects and little change of ventilation in COPD patients - relatively safe in Obstructive Sleep Apnea patients 4. Effect on sleep architecture - no significant changes in REM sleep; a small increase of stage 2 sleep and of slow-wave sleep • Specific Indications of Zopiclone • Patients with diurnal or nocturnal resp impairments including snoring • Withdrawal from BDZ • Other e.g insomnia ass with shift-work

  20. Zopiclone • Potential for abuse, tolerance, dependence, addiction, or withdrawal • Report of physical dependence to zopiclone on a dose some 10 times the max recommended. • A withdrawal syndrome, including delirium, has been reported. (Harter et al 1999) • Death has been reported from zopiclone overdose : • Pounder and Davies 1994 : a young adult found dead no more than 6 hrs after ingesting ~420mg (56tab) zopiclone and under influence of alcohol; cause of death was aspiration of vomit • 72-yr-old woman with poor resp function died after ingesting 200 to 350mg (i.e. 26-46 tab) • 29-yr-old woman died after ingesting 150mg (i.e. 20tab) zopiclone with alcohol

  21. Zopiclone overdose S/S : - drowsiness, lethargy, ataxia, rarely coma - single case report of 1o HB Treatment • Supportive • Activated charcoal : unlikely to be of value in pure zopiclone overdose; may be given to patients with multiple drugs overdose • Antidote : flumazenil (should only be given in very selected cases) • Hemodialysis is of no use in removing zopiclone

  22. Zopiclone OverdoseQMH data • Period : 1-Mar-2004 to 28-Feb-2005 • No of Drug Overdose Cases : 267 • 209 admitted (78.3%) • 50 discharged from A&E (18.7%) • 8 DAMA from A&E (3%) • 49 involve zopiclone +/- other drugs / alcohol (18.35%) Male : Female = 18:31 = 1: 1.7 Age : 13-81 Median Age : 36 Average Age :39.5

  23. Zopiclone OverdoseQMH Experience History : • Zopiclone alone : 12/49 (24.5%) • Zopiclone and alcohol only : 10/49 (21.4%) • Zopiclone and other drugs : 21/49 (42.9%) • Found unconscious only with no Hx a/v : 6/49 (12.2%) (two of these took zopiclone only) Triage Cat.: • Cat. 1 : 8/49 (16.3%) • Cat. 2 : 24/49 (50%) • Cat. 3 : 17/49 (34.7%) No. of Zopiclone tablets taken : 2 – 100 - The one who took 100 tab was F/26, admitted medical ward and walked away the next day.

  24. Zopiclone OverdoseQMH Experience – Rx in A&E • ET intubation in A&E = 2/49 (4%) • Gastric Lavage in A&E = 1/49 (30.6%) • Activated charcoal in A&E = 15/49 (2%)

  25. Zopiclone OverdoseQMH data - Destination • Direct ICU Admission : 4 / 49 (8.2%) • Medical/Ped Admission : 34 / 49 (69.4%) (two cases transferred from medical to ICU later) • O Ward Admission : 7 / 49 (14.3%) (3 home; 3 admitted to Psy; 1 admitted to medical because of convulsion) • Direct Home / DAMA from A&E : 4 / 49 (8%) • Number of Cases admitted to Psy Ward thro’ A&E (O Ward) 3 thro’ medical 17 total 20/49 (40.8%)

  26. Zopiclone OverdoseQMH Experience - complications - Coma / drowsiness on presentation GCS <= 12 10/49 (20.4%) (3 of these took zopiclone only) • One case of CO2 retention (overdose with zopiclone only) • One case of rhadomyolysis • One case of convulsion

  27. Zopiclone OverdoseQMH Experience – stay in medical / ICU For ICU cases : • 6/49 admitted ICU (4 from A&E, 2 from medical) • Duration of stay in ICU : <= 1 day 4/6 (66.7%) <= 2 days 6/6 (100%) For those admitted to medical / pediatric ward +/- ICU cases: • 33/49 admitted medical ward directly • 1/49 admitted pediatric ward directly • 4/49 admitted medical ward thro’ ICU • 1/49 admitted medical ward thro’ O Ward • Total 39/49 admitted medical / pediatric ward +/- ICU • Duration of stay in medical / ped. Ward +/- ICU discharge on day 1 2/39 (5.1%) discharge on day 2 21/39 (53.8%) discharge on day 3 10/39 (25.6%) discharge on day 4 3/39 (7.7%) discharge on day 5 2/39 (5.1%) discharge on day 8 1/39 (2.6%) -Duration of stay in medical / ped ward +/- ICU <3 days 33/39 (84.6%)

  28. Zopiclone Overdose • Still safe • Not without complications • Gastric lavage is not indicated in general • Activated charcoal is of no use except in multiple drug overdose • Supportive measure is the main stay of treatment • Increasing trend to be abused by youngsters (Evidence is emerging that zopiclone is being a drug of misuse by “innovative addicts”.) • ? Need for tighter control

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