Lormetazepam

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Lormetazepam
Systematic (IUPAC) name
9-chloro-6-(2-chlorophenyl)-4-hydroxy-2-methyl-2,5-
diazabicyclo[5.4.0]undeca-5,8,10,12-tetraen-3-one
Identifiers
CAS number 848-75-9
ATC code N05CD06
PubChem 13314
DrugBank ?
Chemical data
Formula C16H12Cl2N2O2 
Mol. mass 335.2
Pharmacokinetic data
Bioavailability 80%
Metabolism Hepatic
Half life 10-12 hours
Excretion Renal
Therapeutic considerations
Pregnancy cat.

D
Legal status

Schedule IV(US)
Routes Oral

Lormetazepam is available as a generic or available under the following trade or brand names (Noctamid®, Ergocalm®, Loramet®, Dilamet®, Sedaben®, Stilaze®, Nocton®, Pronoctan®, Noctamide®, Loretam®, Minias®, Aldosomnil®) and is also sometimes known as methyllorazepam, is a drug which is a benzodiazepine derivative. It possesses anxiolytic, anticonvulsant, sedative and skeletal muscle relaxant properties.

Lormetazepam is not approved for sale in the United States or Canada, though it is licensed it the UK as 0.5 and 1mg tablets for short term treatment (2-4 weeks) of severe or disabling insomnia. It is the most expensive hypnotic benzodiazepine on the UK market - costing upwards of £15 (trade price) for a 28 day supply of the 1mg variant. Recently however, prices have stabilised towards the £3 region. It's bioavailability was found to be 80%.[1]

Contents

[edit] Mechanism of Action

Lormetazepam and other benzodiazepine drugs act as positive modulators at the GABAa-benzodiazepine receptor complex. Lormetazepam binds to the benzodiazepine receptor which in turn enhances the effect of the GABAa receptor producing its therapeutic effects as well as adverse effects. When lormetazepam binds to the benzodiazepine receptor sites in sufficient quantities it produces sedation which is used clinically as a therapeutic treatment for insomnia. Lormetazepam alters the brain electrical activity which has been studied via EEG readings.[2] Changes in EEG can therefore be used to measure the sedative sleep promoting properties of lormetazepam.

[edit] Side Effects

Side effects of lormetazepam are similar to other benzodiazepines and can for the most part be regarded as a class effect.[3] Some side effects can be enhanced when lormetazepam is combined with other drugs with similar effects eg alcohol and nonbenzodiazepine drugs, with subsequent increased drowsiness, amnesia or respiratory depression. Lormetazepam has been associated with adversely affecting immediate and delayed recall memory functions.[4]

Side Effects List

[edit] Tolerance, Dependence and Withdrawal

It should be noted that the risks of tolerance, dependence and withdrawal are very low when the drug is used for 2 - 4 weeks only and that lormetazepam is generally a safe and effective drug when used for no longer than 2-4 weeks. Some sleep disturbance in the form of rebound insomnia can however occur even after short term usage of 7 days.[5]Those with a history of addiction may be at increased risk of problems of tolerance and dependence especially those with a past history of dependency on sedative hypnotic drugs.

Tolerance

Lormetazepam as with other benzodiazepines is generally only recommended for short term use (2-4 weeks) due to tolerance and loss of efficacy. Tolerance to the and loss of the sedative effects of benzodiazepine hypnotics occurs within 14 days of regular use.[6]

Dependence

Dependence is the medical term for addiction. Dependence can either be psychological or physical. Psychological dependence can manifest itself as a reliance on a drug to cope with every day life or in the form of craving. Physical dependence occurs due to physiological adaptions occurring as the body attempts to overcome the drugs effects which is known as tolerance and the continuing need to take the drug to avoid or suppress withdrawal symptoms which can sometimes resemble the original condition being treated. When the dose or the drug is discontinued withdrawal symptoms typically occur. Lormetazepam as with all other benzodiazepines produces both physical and psychological dependence but the main problem of concern is physical dependence which appears after the dosage is reduced or the drug is stopped completely. The dependence induced by lormetazepam is related to changes in the sensitivity of the GABA-BZD receptor complex.[7]

Withdrawal Symptoms

Withdrawal Symptoms which can occur from stopping benzodiazepines such as lormetazepam can include:[8]

Abrupt or over rapid withdrawal from high doses can provoke:

Withdrawal symptoms typically subside after 4 - 8 weeks but in aproximately 10 - 15% of individuals symptoms can perist for many months[9] and in rare cases years.[10] Some "Withdrawal Symptoms" can emerge despite a constant dosage with the body needing extra dosage in order to feel normal. This is sometimes associated with dosage escalation.

Lormetazepam has a short to intermediate half life of aproximately 10-12 hours. Shorter acting benzodiazepine compounds are generally associated with a more intense and immediate withdrawal reaction compared to longer acting benzodiazepines. For this reason it is generally recommended to cross from lormetazepam to an equivalent dose of diazepam to gradually taper the dosage.[11]

[edit] References

  1. ^ Hümpel1, M; Stoppelli, I.; Milia, S.; and Rainer, E. (1982). "Pharmacokinetics and biotransformation of the new benzodiazepine, lormetazepam, in man". Eur. J. Clin. Pharmaco. 21 (5): 421-425. DOI:10.1007/BF00542330. 
  2. ^ Kurowski, M; Ott H, Herrmann WM. (1982). "Relationship between EEG dynamics and pharmacokinetics of the benzodiazepine lormetazepam.". Pharmacopsychiatria. 15 (3): 77-83. Retrieved on 16/03/07. 
  3. ^ British National Formulary Benzodiazepines Information
  4. ^ Dorow, R; Berenberg D, Duka T, Sauerbrey N. (1987). "Amnestic effects of lormetazepam and their reversal by the benzodiazepine antagonist Ro 15-1788.". Psychopharmacology (Berl). 93 (4): 507-514. 
  5. ^ Kales, A; Bixler EO, Soldatos CR, Mitsky DJ, Kales JD. (1982). "Dose-response studies of lormetazepam: efficacy, side effects, and rebound insomnia.". J Clin Pharmacol. 22 (11-12): 520-530. Retrieved on 16/03/07. 
  6. ^ Smith AE (1989) Benzodiazepines - Use & Abuse - A GUIDE FOR PRESCRIBERS
  7. ^ Gerra, G; Giucasto G, Zaimovic A, Fertonani G, Chittolini B, Avanzini P, Caccavari R, Delsignore R (1996). "Intravenous flumazenil following prolonged exposure to lormetazepam in humans: lack of precipitated withdrawal.". Int Clin Psychopharmacol. 11 (2): 81-88. Retrieved on 16/03/07. 
  8. ^ Ashton CH PROTRACTED WITHDRAWAL SYMPTOMS FROM BENZODIAZEPINES
  9. ^ Ashton CH BENZODIAZEPINES: HOW THEY WORK AND HOW TO WITHDRAW
  10. ^ Lader M A pilot study of the effects of flumazenil on symptoms persisting after benzodiazepine withdrawal
  11. ^ (Roche Products (UK) Ltd 1990) Benzodiazepines and Your Patients: A Management Programme

[edit] External links

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