Delorazepam

Last updated
Delorazepam
Delorazepam 200.svg
Delorazepam molecule ball.png
Clinical data
Trade names EN, Dadumir
Routes of
administration 		Oral
ATC code
  • none
Legal status
Legal status
Pharmacokinetic data
Bioavailability 87%
Metabolism Hepatic
Elimination half-life 60–140 hours
Excretion Renal
Identifiers
  • 7-Chloro-5-(2-chlorophenyl)-1,3-dihydro-1,4-benzodiazepin-2(2H)-one
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.018.884 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C15H10Cl2N2O
Molar mass 305.16 g·mol−1
3D model (JSmol)
  • ClC1=CC=CC=C1C2=NCC(NC3=C2C=C(C=C3)Cl)=O
  • InChI=1S/C15H10Cl2N2O/c16-9-5-6-13-11(7-9)15(18-8-14(20)19-13)10-3-1-2-4-12(10)17/h1-7H,8H2,(H,19,20) Yes check.svgY
  • Key:CHIFCDOIPRCHCF-UHFFFAOYSA-N Yes check.svgY
   (verify)

Delorazepam, also known by the synonyms chlordesmethyldiazepam and nordiclazepam, is a drug which is a benzodiazepine and a derivative of desmethyldiazepam. [2] It is marketed in Italy, where it is available under the trade name EN and Dadumir. [3] Delorazepam (chlordesmethyldiazepam) is also an active metabolite of the benzodiazepine drugs diclazepam and cloxazolam. [4] Adverse effects may include hangover type effects, drowsiness, behavioural impairments [5] [6] and short-term memory impairments. [7] Similar to other benzodiazepines delorazepam has anxiolytic, [8] skeletal muscle relaxant, [9] hypnotic [5] and anticonvulsant properties. [10]

Contents

Indications

Delorazepam is mainly used as an anxiolytic because of its long elimination half-life; showing superiority over the short-acting drug lorazepam. [11] In comparison with the antidepressant drugs, paroxetine and imipramine, delorazepam was found to be more effective in the short-term but after 4 weeks the antidepressants showed superior anti-anxiety effects. [12]

Delorazepam is also used as a premedication for dental phobia for its anxiolytic properties. [13] High doses of Delorazepam may be administered the night before a dental (or other medical) procedure in order to provide relief from anxiety-associated insomnia that night with the effects persisting long enough to sufficiently treat anxiety the next day.

Delorazepam has also demonstrated effectiveness in treating alcohol withdrawal. [14]

Availability

Delorazepam is available in tablet and liquid drop formulations. The liquid drop formulation is absorbed more quickly and has improved bioavailibility. [15]

Pharmacology

Delorazepam is well absorbed after administration, reaching peak plasma levels within 1 – 2 hours. It has a very long elimination half-life and can still be detected 72 hours after dosing. [16] Bioavailability is about 77 percent. Peak plasma levels occur at just over one hour after administration. Significant accumulation occurs of delorazepam due to its slow metabolism; [17] the elderly metabolise delorazepam and its active metabolite slower than younger individuals, resulting in a dose of delorazepam accumulating faster and peaking at a higher plasma concentration than an equal dose administered to a younger individual. The elderly also have a poorer response to the therapeutic effects and a higher rate of adverse effects. The elimination half-life of delorazepam is 80–115 hours. The active metabolite of delorazepam is lorazepam and represents about 15 - 24 percent of the parent drug (delorazepam). [15] [18] [19] The pharmacokinetics of delorazepam are not altered if it is taken with food, except for some slowing of absorption. [20] Delorazepams potency is approximately equal to that of lorazepam, being ten times more potent by weight than diazepam (1 mg delorazepam = 1 mg lorazepam = 5 mg diazepam), [21] typical doses range from 0.5 mg - 2 mg. Treatment is generally initiated at 1 mg for healthy adults and 0.5 mg in pediatric and geriatric patients and patients with mild renal impairment, treatment is contraindicated in patients with moderate or severe renal impairment.

Side effects and contraindications

Delorazepam hosts all the classic side-effects of GABAA positive allosteric modulators (like other benzodiazepines). These include sedation/somnolence, dizziness/ataxia, amnesia, reduced inhibition, increased talkativeness/sociability, euphoria, impaired judgement, hallucinations, and respiratory depression. Paradoxical reactions including increased anxiety, excitation, and aggression may occur and are more common in elderly, pediatric, and schizophrenic patients. In rare instances, delorazepam may cause suicidal ideation and actions.

Long term use of delorazepam (as well as all other benzodiazepines) has been found to increase long term cognitive deficits (persisting longer than sixth months) which some researchers claim to be permanent. Short term use may occasionally cause depression and the risk of depressive symptoms occurring increases considerably with longer terms of use, delorazepam is not intended to be used for more than 2–4 weeks unless it used only occasionally on an as-needed basis. When being used on an as-needed basis the need for delorazepam therapy should be re-evaluated each time a new prescription for delorazepam is issued, and alternative medications should be considered if patients begin to take delorazepam habitually (many days in a row).

The most serious effect of long term delorazepam use is dependence, with withdrawal symptoms which mimic delirium tremens presenting when delorazepam use is discontinued. Although the withdrawal effects from delorazepam are generally less severe than its shorter-acting counterparts, they can be life-threatening. Slow de-titration of delorazepam over a period of weeks or months is generally suggested to minimize the severity of withdrawal. Psychological effects of withdrawal such as rebound anxiety and insomnia have been known to persist for months after physical dependence has been successfully treated.

Delorazepam is contraindicated in those with severe schizophrenia or schizo-affective disorders, those with a known allergy or hypersensitivity to delorazepam or related benzodiazepines, and those with moderate to severe renal impairment (delorazepam is sometimes administered at a reduced dose to patients with mild renal impairment). Delorazepam is generally considered to be contraindicated in patients with severe acute or chronic illnesses but is occasionally used in the palliative care of terminal patients during their last days/weeks of life.

Patients with a history of substance and/or alcohol use are believed to have an increased risk of abusing delorazepam (as well as all other benzodiazepines), this must be considered when a physician prescribes delorazepam to such patients. Although all patients being treated with delorazepam should be routinely monitored for signs of use and diversion of medication, increased monitoring of patients with a history of substance and/or alcohol use is always warranted. Non-medical benzodiazepine use in patients who have them prescribed on an as-needed basis for chronic/refractory anxiety, insomnia, and intermittent muscle spasms has occurred and generally occurs very slowly, becoming evident only after months or years since the initiation of therapy. Monitoring of patients actively using delorazepam should never be discontinued even if the patients has been stable on the medication for many months or years.

Caution must be used when delorazepam is administered alongside other sedative medications (ex. opiates, barbiturates, z-drugs, and phenothiazines) due to an increased risk of sedation, ataxia, and (potentially fatal) respiratory depression. Although overdoses of benzodiazepines alone rarely result in death, the combination of benzodiazepines and other sedatives (particularly other gabaminergic drugs such as barbiturates and alcohol) is far more likely to result in death.

Special cautions

People with renal failure on haemodialysis have a slow elimination rate and a reduced volume of distribution of the drug. [22] Liver disease has a profound effect on the elimination rate of delorazepam, resulting in the half-life almost doubling to 395 hours, whereas healthy patients showed an elimination half-life of 204 hours on average. Caution is recommended when using delorazepam in patients with liver disease. [23]

See also

Related Research Articles

<span class="mw-page-title-main">Benzodiazepine</span> Class of depressant drugs

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<span class="mw-page-title-main">Diazepam</span> Benzodiazepine sedative

Diazepam, sold under the brand name Valium among others, is a medicine of the benzodiazepine family that acts as an anxiolytic. It is used to treat a range of conditions, including anxiety, seizures, alcohol withdrawal syndrome, muscle spasms, insomnia, and restless legs syndrome. It may also be used to cause memory loss during certain medical procedures. It can be taken orally, as a suppository inserted into the rectum, intramuscularly, intravenously or used as a nasal spray. When injected intravenously, effects begin in one to five minutes and last up to an hour. When taken by mouth, effects begin after 15 to 60 minutes.

<span class="mw-page-title-main">Alprazolam</span> Benzodiazepine medication

Alprazolam, sold under the brand name Xanax and others, is a fast-acting, potent tranquilizer of moderate duration within the triazolobenzodiazepine group of chemicals called benzodiazepines. Alprazolam is most commonly prescribed in the management of anxiety disorders, especially panic disorder and generalized anxiety disorder (GAD). Other uses include the treatment of chemotherapy-induced nausea, together with other treatments. GAD improvement occurs generally within a week. Alprazolam is generally taken orally.

<span class="mw-page-title-main">Lorazepam</span> Benzodiazepine medication

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<span class="mw-page-title-main">Zopiclone</span> Hypnotic medication

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<span class="mw-page-title-main">Bromazepam</span> Benzodiazepine drug

Bromazepam, sold under many brand names, is a benzodiazepine. It is mainly an anti-anxiety agent with similar side effects to diazepam. In addition to being used to treat anxiety or panic states, bromazepam may be used as a premedicant prior to minor surgery. Bromazepam typically comes in doses of 3 mg and 6 mg tablets.

<span class="mw-page-title-main">Oxazepam</span> Benzodiazepine medication

Oxazepam is a short-to-intermediate-acting benzodiazepine. Oxazepam is used for the treatment of anxiety and insomnia and in the control of symptoms of alcohol withdrawal syndrome.

<span class="mw-page-title-main">Nordazepam</span> Benzodiazepine derivative medication

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<span class="mw-page-title-main">Alpidem</span> Anxiolytic medication

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<span class="mw-page-title-main">Loprazolam</span> Benzodiazepine

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<span class="mw-page-title-main">Camazepam</span> Chemical compound

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<span class="mw-page-title-main">Clotiazepam</span> Chemical compound

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References

  1. ↑ Anvisa (2023-03-31). "RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial" [Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese). Diário Oficial da União (published 2023-04-04). Archived from the original on 2023-08-03. Retrieved 2023-08-16.
  2. ↑ Govoni S, Fresia P, Spano PF, Trabucchi M (November 1976). "Effect of desmethyldiazepam and chlordesmethyldiazepam on 3',5'-cyclic guanosine monophosphate levels in rat cerebellum". Psychopharmacology. 50 (3): 241–4. doi:10.1007/BF00426839. PMID   188062. S2CID   32711086.
  3. ↑ "Benzodiazepine Names". non-benzodiazepines.org.uk. Archived from the original on 2008-12-08. Retrieved 2008-12-29.
  4. ↑ Oliveira-Silva D, Oliveira CH, Mendes GD, Galvinas PA, Barrientos-Astigarraga RE, De Nucci G (December 2009). "Quantification of chlordesmethyldiazepam by liquid chromatography-tandem mass spectrometry: application to a cloxazolam bioequivalence study". Biomedical Chromatography. 23 (12): 1266–75. doi:10.1002/bmc.1249. PMID   19488979.
  5. 1 2 Zimmermann-Tansella C, Tansella M, Lader M (October 1976). "The effects of chlordesmethyldiazepam on behavioral performance and subjective judgment in normal subjects". Journal of Clinical Pharmacology. 16 (10 Pt 1): 481–88. PMID   977791.
  6. ↑ Cesco G, Giannico S, Fabbruci I, Scaggiante L, Montanaro N (1977). "Single-blind evaluation of hypnotic activity of chlordesmethyldiazepam in No-placebo-reactor medical patients". Arzneimittel-Forschung. 27 (1): 146–8. PMID   322671.
  7. ↑ Scarone S, Strambi LF, Cazzullo CL (1981). "Effects of two dosages of chlordesmethyldiazepam on mnestic-information processes in normal subjects". Clinical Therapeutics. 4 (3): 184–91. PMID   6796270.
  8. ↑ Andreoli V, Maffei F, Montanaro N, Morandini G (February 1977). "Double-blind cross-over clinical comparison of two 2'-chloro benzodiazepines: 7-chloro-5-(2-chlorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one (chlordesmethyldiazepam) versus 7-chloro-5-(o-chlorophenyl)-1,3-dihydro-3-hydroxy-2H-1,4-benzodiazepin-2-one (lorazepam) in neurotic anxiety". Arzneimittel-Forschung. 27 (2): 436–9. PMID   16622.
  9. ↑ Kostowski W, Płaźnik A, Puciłowski O, Trzaskowska E, Lipińska T (1981). "Some behavioral effects of chlorodesmethyldiazepam and lorazepam". Polish Journal of Pharmacology and Pharmacy. 33 (6): 597–602. PMID   6127668.
  10. ↑ Curatolo P, Cusmai R, Trasatti G, Sciarretta A (1985). "[Effects of intravenous administration of chlordesmethyldiazepam on paroxysmal intercritical activity in various electroclinical forms of infantile epilepsy]". Rivista di Neurologia. 55 (6): 377–86. PMID   3938567.
  11. ↑ Bertin I, Colombo G, Furlanut M, Benetello P (1989). "Double-blind placebo cross-over study of long-acting (chlordesmethyldiazepam) versus short-acting (lorazepam) benzodiazepines in generalized anxiety disorders". International Journal of Clinical Pharmacology Research. 9 (3): 203–8. PMID   2568350.
  12. ↑ Rocca P, Fonzo V, Scotta M, Zanalda E, Ravizza L (May 1997). "Paroxetine efficacy in the treatment of generalized anxiety disorder". Acta Psychiatrica Scandinavica. 95 (5): 444–50. doi: 10.1111/j.1600-0447.1997.tb09660.x . PMID   9197912. S2CID   28985221.
  13. ↑ Manani G, Baldinelli L, Cordioli G, Consolati E, Luisetto F, Galzigna L (1995). "Premedication with chlordemethyldiazepam and anxiolytic effect of diazepeam in implantology". Anesthesia Progress. 42 (3–4): 107–12. PMC   2148912 . PMID   8934975.
  14. ↑ Cazzato G, Gioseffi M, Torre P, Coppola N (Nov–Dec 1982). "[Prevention and therapy of delirium tremens with tiapride and chlordesmethyldiazepam]". Rivista di Neurologia. 52 (6): 331–42. PMID   6130594.
  15. 1 2 Bareggi SR, Truci G, Leva S, Zecca L, Pirola R, Smirne S (1988). "Pharmacokinetics and bioavailability of intravenous and oral chlordesmethyldiazepam in humans". European Journal of Clinical Pharmacology. 34 (1): 109–12. doi:10.1007/BF01061430. PMID   2896126. S2CID   1574555.
  16. ↑ Dal Bo L, Marcucci F, Mussini E, Perbellini D, Castellani A, Fresia P (1980). "Plasma levels of chlorodesmethyldiazepam in humans". Biopharmaceutics & Drug Disposition. 1 (3): 123–6. doi:10.1002/bdd.2510010306. PMID   6778522. S2CID   33627270.
  17. ↑ European Journal of Clinical Pharmacology 1988, Volume 34, Issue 1, pp 109-112 'Pharmacokinetics and bioavailability of intravenous and oral chlordesmethyldiazepam in humans' S.R.Bareggi, G.Truci, S.Leva, L.Zecca, R.Pirola, S.Smirne
  18. ↑ Bareggi SR, Nielsen NP, Leva S, Pirola R, Zecca L, Lorini M (1986). "Age-related multiple-dose pharmacokinetics and anxiolytic effects of delorazepam (chlordesmethyldiazepam)". International Journal of Clinical Pharmacology Research. 6 (4): 309–14. PMID   2875955.
  19. ↑ Bareggi SR, Pirola R, Leva S, Zecca L (1986). "Pharmacokinetics of chlordesmethyldiazepam after single-dose oral administration in humans". European Journal of Drug Metabolism and Pharmacokinetics. 11 (3): 171–4. doi:10.1007/BF03189844. PMID   3102240. S2CID   19525288.
  20. ↑ Bareggi SR, Pirola R, Truci G, Leva S, Smirne S (April 1988). "Effect of food on absorption of chlordemethyldiazepam". Arzneimittel-Forschung. 38 (4): 561–2. PMID   2900012.
  21. ↑ Alfredo Carlo Altamura, Donatella Moliterno, Silvia Paletta, Michele Maffini, Massimo Carlo Mauri & Silvio Bareggi (2013) Understanding the pharmacokinetics of anxiolytic drugs, Expert Opinion on Drug Metabolism & Toxicology, 9:4, 423-440, DOI: 10.1517/17425255.2013.759209
  22. ↑ Sennesael J, Verbeelen D, Vanhaelst L, Pirola R, Bareggi SR (1991). "Pharmacokinetics of intravenous and oral chlordesmethyldiazepam in patients on regular haemodialysis". European Journal of Clinical Pharmacology. 41 (1): 65–8. doi:10.1007/BF00280109. PMID   1782980. S2CID   31251671.
  23. ↑ Bareggi SR, Pirola R, Potvin P, Devis G (1995). "Effects of liver disease on the pharmacokinetics of intravenous and oral chlordesmethyldiazepam". European Journal of Clinical Pharmacology. 48 (3–4): 265–8. doi:10.1007/bf00198309. PMID   7589052. S2CID   19145264.
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