Loprazolam

Loprazolam
Clinical data
Trade names	Dormonoct, Havlane, Sonin, Somnovit, others
AHFS/Drugs.com	International Drug Names
Pregnancy; category	D;
Routes of; administration	Oral
ATC code	N05CD11 (WHO) ;
Legal status
Legal status	BR: Class B1 (Psychoactive drugs); CA: Schedule IV; DE: Prescription only (Anlage III for higher doses); US: Schedule IV;
Pharmacokinetic data
Metabolism	Hepatic
Elimination half-life	6–12 hours
Excretion	Renal
Identifiers
	IUPAC name (2Z)-6-(2-Chlorophenyl)-2-[(4-methyl-1-piperazinyl)methylene]-8-nitro-2,4-dihydro-1H-imidazo[1,2-a][1,4]benzodiazepin-1-one;
CAS Number	61197-73-7 ;
PubChem CID	3033860;
DrugBank	DB13643 ;
ChemSpider	2298440 ;
UNII	759N8462G8;
KEGG	D07326 ;
CompTox Dashboard (EPA)	DTXSID30894873 ;
ECHA InfoCard	100.293.781
Chemical and physical data
Formula	C23H21ClN6O3
Molar mass	464.91 g·mol−1
3D model (JSmol)	Interactive image;
	SMILES [O-][N+](=O)c1cc4c(cc1)N/2C(=O)C(\N=C\2C/N=C4/c3ccccc3Cl)=C\N5CCN(C)CC5;
	InChI InChI=1S/C23H21ClN6O3/c1-27-8-10-28(11-9-27)14-19-23(31)29-20-7-6-15(30(32)33)12-17(20)22(25-13-21(29)26-19)16-4-2-3-5-18(16)24/h2-7,12,14H,8-11,13H2,1H3/b19-14- ; Key:UTEFBSAVJNEPTR-RGEXLXHISA-N ;
	(what is this?) (verify)

Loprazolam (triazulenone) marketed under many brand names is a benzodiazepine medication. It possesses anxiolytic, anticonvulsant, hypnotic, sedative and skeletal muscle relaxant properties. It is licensed and marketed for the short-term treatment of moderately-severe insomnia.

It was patented in 1975 and came into medical use in 1983.^[2]

Medical uses

Insomnia can be described as a difficulty falling asleep, frequent awakening, early awakenings or a combination of each. Loprazolam is a short-acting benzodiazepine and is sometimes used in patients who have difficulty in maintaining sleep or have difficulty falling asleep. Hypnotics should only be used on a short-term basis or in those with chronic insomnia on an occasional basis.^[3]

Dose

The dose of loprazolam for insomnia is usually 1 mg but can be increased to 2 mg if necessary. In the elderly a lower dose is recommended due to more pronounced effects and a significant impairment of standing up to 11 hours after dosing of 1 mg of loprazolam. The half-life is much more prolonged in the elderly than in younger patients. A half-life of 19.8 hours has been reported in elderly patients.^[4] Patients and prescribing physicians should, however, bear in mind that higher doses of loprazolam may impair long-term memory functions.^[5]

Side effects

Side effects of loprazolam are generally the same as for other benzodiazepines such as diazepam.^[6] The most significant difference in side effects of loprazolam and diazepam is it is less prone to day time sedation as the half-life of loprazolam is considered to be intermediate whereas diazepam has a very long half-life. The side effects of loprazolam are the following:

drowsiness
paradoxical increase in aggression
lightheadedness
confusion
muscle weakness
ataxia (particularly in the elderly)
amnesia
headache
vertigo
hypotension
salivation changes
gastro-intestinal disturbances
visual disturbances
dysarthria
tremor
changes in libido
incontinence
urinary retention
blood disorders and jaundice
skin reactions
dependence and withdrawal reactions

Residual 'hangover' effects after nighttime administration of loprazolam such as sleepiness, impaired psychomotor and cognitive functions may persist into the next day which may increase risks of falls and hip fractures.^[7]

Tolerance, dependence and withdrawal

Loprazolam, like all other benzodiazepines, is recommended only for the short-term management of insomnia in the UK, owing to the risk of serious adverse effects such as tolerance, dependence and withdrawal, as well as adverse effects on mood and cognition. Benzodiazepines can become less effective over time, and patients can develop increasing physical and psychological adverse effects, e.g., agoraphobia, gastrointestinal complaints, and peripheral nerve abnormalities such as burning and tingling sensations.^[8]^[9]

Loprazolam has a low risk of physical dependence and withdrawal if it is used for less than 4 weeks or very occasionally. However, one placebo-controlled study comparing 3 weeks of treatment for insomnia with either loprazolam or triazolam showed rebound anxiety and insomnia occurring 3 days after discontinuing loprazolam therapy, whereas with triazolam the rebound anxiety and insomnia was seen the next day. The differences between the two are likely due to the differing elimination half-lives of the two drugs.^[10]^[11] These results would suggest that loprazolam and possibly other benzodiazepines should be prescribed for 1–2 weeks rather than 2–4 weeks to reduce the risk of physical dependence, withdrawal, and rebound phenomenon.

Withdrawal symptoms

Slow reduction of the dosage over a period of months at a rate that the individual can tolerate greatly minimizes the severity of the withdrawal symptoms. Individuals who are benzodiazepine dependent often cross to an equivalent dose of diazepam to taper gradually, as diazepam has a longer half-life and small dose reductions can be achieved more easily.^[12]^[13]

anxiety and panic attacks
sweating
nightmares
insomnia
headache
tremor
nausea and vomiting
feelings of unreality
abnormal sensation of movement
hypersensitivity to stimuli
hyperventilation
flushing
sweating
palpitations
dimensional distortions of rooms and television pictures
paranoid thoughts and feelings of persecution
depersonalization
fears of going mad
heightened perception of taste, smell, sound, and light; photophobia
agoraphobia
clinical depression
poor memory and concentration
aggression
excitability
Somatic Symptoms
numbness
altered sensations of the skin
pain
stiffness
weakness in the neck, head, jaw, and limbs
muscle fasciculation, ranging from twitches to jerks, affecting the legs or shoulders
ataxia
paraesthesia
influenza-like symptoms
blurred double vision
menorrhagia
loss of or dramatic gain in appetite
thirst with polyuria
urinary incontinence
dysphagia
abdominal pain
diarrhoea
constipation

Major complications can occur after abrupt or rapid withdrawal, especially from high doses, producing symptoms such as:

psychosis
confusion
visual and auditory hallucinations
delusions
epileptic seizures (which may be fatal)
suicidal thoughts or actions
abnormal, often severe, drug seeking behavior

It has been estimated that between 30% and 50% of long-term users of benzodiazepines will experience withdrawal symptoms.^[14] However, up to 90% of patients withdrawing from benzodiazepines experienced withdrawal symptoms in one study, but the rate of taper was very fast at 25% of dose per week.^[15] Withdrawal symptoms tend to last between 3 weeks to 3 months, although 10–15% of people may experience a protracted benzodiazepine withdrawal syndrome with symptoms persisting and gradually declining over a period of many months and occasionally several years.^[16]

Contraindications and special caution

Benzodiazepines require special precaution if used in the elderly, during pregnancy, in children, alcohol or drug-dependent individuals and individuals with comorbid psychiatric disorders.^[17] Loprazolam, similar to other benzodiazepines and nonbenzodiazepine hypnotic drugs causes impairments in body balance and standing steadiness in individuals who wake up at night or the next morning. Falls and hip fractures are frequently reported. The combination with alcohol increases these impairments. Partial, but incomplete tolerance develops to these impairments.^[18]

Mechanism of action

Loprazolam is a benzodiazepine, which acts via positively modulating the GABA_A receptor complex via a binding to the benzodiazepine receptor which is situated on alpha subunit containing GABA_A receptors. This action enhances the effect of the neurotransmitter GABA on the GABA_A receptor complex by increasing the opening frequency of the chloride ion channel. This action allows more chloride ions to enter the neuron which in turn produces such effects as; muscle relaxation, anxiolytic, hypnotic, amnesic and anticonvulsant action. These properties can be used for therapeutic benefit in clinical practice. These properties are also sometimes used for recreational purposes in the form of drug abuse of benzodiazepines where high doses are used to achieve intoxication and or sedation.^[19]^[20]

Pharmacokinetics

After oral administration of loprazolam, it takes about 3 hours and a half for serum concentration levels of loprazolam plus its active metabolite piperazine N-Oxide to peak (source https://www.medicines.org.uk/emc/product/4192/smpc, significantly longer than other benzodiazepine hypnotics. This delay brings into question the benefit of loprazolam for the treatment of insomnia when compared to other hypnotics (particularly when the major complaint is difficulty falling asleep instead of difficulty maintaining sleep for the entire night), although some studies show that loprazolam may induce sleep within half an hour, indicating rapid penetration into the brain. The peak plasma delay of loprazolam, therefore, may not be relevant to loprazolam's efficacy as a hypnotic. If taken after a meal it can take even longer for loprazolam plasma levels to peak and peak levels may be lower than normal. Loprazolam significantly alters electrical activity in the brain as measured by EEG, with these changes becoming more pronounced as the dose increases. Roughly half of each dose is metabolized in humans to produce an active metabolite, (a piperazine with lesser potency),^[21] the other half is excreted unchanged. The half-life of the active metabolite is about the same as the parent compound loprazolam.^[22]

References

^ 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.
^ Fischer J, Ganellin CR (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 539. ISBN 9783527607495.
^ Rickels K (1986). "The clinical use of hypnotics: indications for use and the need for a variety of hypnotics". Acta Psychiatrica Scandinavica. Supplementum. 332 (S332): 132–141. doi:10.1111/j.1600-0447.1986.tb08990.x. PMID 2883820. S2CID 46560074.
^ Swift CG, Swift MR, Ankier SI, Pidgen A, Robinson J (August 1985). "Single dose pharmacokinetics and pharmacodynamics of oral loprazolam in the elderly". British Journal of Clinical Pharmacology. 20 (2): 119–128. doi:10.1111/j.1365-2125.1985.tb05041.x. PMC 1400680. PMID 2864049.
^ Bareggi SR, Ferini-Strambi L, Pirola R, Franceschi M, Smirne S (1991). "Effects of loprazolam on cognitive functions". Psychopharmacology. 104 (3): 337–342. doi:10.1007/bf02246033. PMID 1681558. S2CID 20804897.
^ British National Formulary Benzodiazepines Information
^ Vermeeren A (2004). "Residual effects of hypnotics: epidemiology and clinical implications". CNS Drugs. 18 (5): 297–328. doi:10.2165/00023210-200418050-00003. PMID 15089115. S2CID 25592318.
^ Committee on Safety of Medicines (1988). "Benzodiazepines, Dependence and Withdrawal Symptoms". Medicines Control Agency UK Government. Retrieved 2007-03-21.
^ Ashton CH (1987). "Benzodiazepine Withdrawal: Outcome in 50 Patients". British Journal of Addiction. 82 (6). benzo: 665–671. doi:10.1111/j.1360-0443.1987.tb01529.x. PMID 2886145. Retrieved 2007-03-21.
^ Morgan K, Oswald I (March 1982). "Anxiety caused by a short-life hypnotic". British Medical Journal. 284 (6320): 942. doi:10.1136/bmj.284.6320.942. PMC 1496517. PMID 6121606.
^ Morgan K, Adam K, Oswald I (1984). "Effect of loprazolam and of triazolam on psychological functions". Psychopharmacology. 82 (4): 386–388. doi:10.1007/BF00427691. PMID 6145178. S2CID 26198409.
^ McConnell JG (2007). "The Clinicopharmacotherapeutics of Benzodiazepine and Z drug dose Tapering Using Diazepam". BCNC. Archived from the original on 2015-03-07. Retrieved 2007-06-09.
^ (Roche Products (UK) Ltd 1990) Benzodiazepines and Your Patients: A Management Programme
^ Ashton CH (1985). "Benzodiazepine Dependence and Withdrawal: An Update". benzo org uk. Retrieved 2007-03-21.
^ Schweizer E, Rickels K, Case WG, Greenblatt DJ (October 1990). "Long-term therapeutic use of benzodiazepines. II. Effects of gradual taper". Archives of General Psychiatry. 47 (10). Arch Gen Psychiatry: 908–915. doi:10.1001/archpsyc.1990.01810220024003. PMID 2222130.
^ Ashton CH (2002). "BENZODIAZEPINES: How They Work and How to Withdraw". benzo org uk. Retrieved 2007-03-21.
^ Authier N, Balayssac D, Sautereau M, Zangarelli A, Courty P, Somogyi AA, et al. (November 2009). "Benzodiazepine dependence: focus on withdrawal syndrome". Annales Pharmaceutiques Françaises. 67 (6): 408–413. doi:10.1016/j.pharma.2009.07.001. PMID 19900604.
^ Mets MA, Volkerts ER, Olivier B, Verster JC (August 2010). "Effect of hypnotic drugs on body balance and standing steadiness". Sleep Medicine Reviews. 14 (4): 259–267. doi:10.1016/j.smrv.2009.10.008. PMID 20171127.
^ Bateson AN (2002). "Basic pharmacologic mechanisms involved in benzodiazepine tolerance and withdrawal". Current Pharmaceutical Design. 8 (1). ingentaconnect: 5–21. doi:10.2174/1381612023396681. PMID 11812247.
^ Ashton CH (2002). "BENZODIAZEPINE ABUSE". Harwood Academic. Retrieved 2007-03-22.
^ Clark BG, Jue SG, Dawson GW, Ward A (June 1986). "Loprazolam. A preliminary review of its pharmacodynamic and pharmacokinetic properties and therapeutic efficacy in insomnia". Drugs. 31 (6): 500–516. doi:10.2165/00003495-198631060-00003. PMID 2874007.
^ Mamelak M, Bunting P, Galin H, Price V, Csima A, Young T, et al. (April 1988). "Serum and quantitative electroencephalographic pharmacokinetics of loprazolam in the elderly". Journal of Clinical Pharmacology. 28 (4): 376–383. doi:10.1002/j.1552-4604.1988.tb03162.x. PMID 3392236. S2CID 681684.