Lorazepam

Structural formula
Simplified structural formula - 1: 1 mixture of two enantiomers
General
Non-proprietary name	Lorazepam
other names	( RS ) -7-chloro-5- (2-chlorophenyl) -3-hydroxy-2,3-dihydro-1 H -1,4-benzodiazepin-2-one ( IUPAC ) (±) -7-Chloro-5- (2-chlorophenyl) -3-hydroxy-2,3-dihydro-1 H -1,4-benzodiazepin-2-one rac -7-chloro-5- (2-chlorophenyl) -3-hydroxy-2,3-dihydro-1 H -1,4-benzodiazepin-2-one Lorazepamum ( Latin )
Molecular formula	C 15 H 10 Cl 2 N 2 O 2
External identifiers / databases
CAS number 846-49-1 EC number 212-687-6 ECHA InfoCard 100.011.534 PubChem 3958 ChemSpider 3821 DrugBank DB00186 Wikidata Q408265
Drug information
ATC code	N05 BA06
Drug class	Anxiolytic Benzodiazepine Anticonvulsant
properties
Molar mass	321.16 g · mol -1
Physical state	Solid
Melting point	166-168 ° C
pK s value	13
solubility	Water: 80 mg l −1
safety instructions
Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed GHS labeling of hazardous substances Caution H and P phrases H: 361 P: 281
Toxicological data	4500 mg kg −1 ( LD 50 ,  rat ,  oral ) 1810 mg kg −1 ( LD 50 ,  mouse ,  ip )
As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Lorazepam is a drug from the group of benzodiazepines . Like all benzodiazepines, it has an anxiolytic (anxiolytic), anticonvulsant (suppresses epileptic potential), sedative (calming), hypnotic (sleep-promoting) and muscle-relaxing (antispasmodic, muscle-relaxing) effect; in this order from strong to weak. Lorazepam has a medium half - life .

It is mainly used as a sedative for anxiety and panic disorders, as the longer duration of action (for example a whole day) is desirable. It is used in intensive care and emergency medicine to break through a long-lasting, life-threatening epileptic seizure ( status epilepticus ) and for the prophylaxis of epileptic seizures. Another area of ​​application is the short-term treatment of sleep disorders if they are related to severe restlessness.

history

Lorazepam was patented by Wyeth in 1963 . Today the active ingredient is marketed by the Pfizer company under the brand name Tavor ( Temesta in Switzerland and Austria ) . In addition, there are many generics on the market that offer the active ingredient Lorazepam cheaper.

Lorazepam was the second most prescribed psychotropic drug in Germany in 2007 . This has changed significantly since 2013. The background and trigger were probably specialist articles in which studies were presented that came to the conclusion that the use of benzodiazepines could carry an increased risk of dementia . These reports ensured that benzodiazepines, which previously had a rather negative image due to their potential for dependence, continued to fall into disrepute. In 2013, the benzodiazepine lorazepam was only 15th on the list of the most prescribed psychotropic drugs. The first five places, for example, were taken by active ingredients from the group of antidepressants . This clearly shows the new trend: more antidepressants and neuroleptics are being prescribed. The prescriptions of benzodiazepines, however, continue to decline, although it is still unclear whether benzodiazepines really increase the risk of developing dementia.

Pharmacological properties

Lorazepam is rapidly and almost completely absorbed by the body after both oral and intravenous or intramuscular administration. The average absorption half-lives are between 10.8 and 40.4 minutes after oral administration and 12.1 and 40 minutes after intramuscular administration. After intravenous injection, the effect occurs after one to two minutes. From the immediately soluble oral dosage form (see below), lorazepam is predominantly not absorbed through the oral mucosa, but gastrointestinally with the saliva. A possible faster onset of action has not been proven.

The duration of action depends on the dosage and the stomach contents and is usually 5 to 9 hours. The half-life of lorazepam in patients with normal liver function is between 11 and 18 hours.

Clinical information

application areas

Lorazepam is given to:

• Treatment of restlessness (especially panic attacks )
• Short-term treatment of sleep disorders , especially if these are associated with severe states of restlessness (psychological or physical cause)
• Treating symptoms associated with alcohol withdrawal and opioid withdrawal
• Long-term treatment of otherwise resistant forms of epilepsy and general acute treatment
• intensive therapy of status epilepticus
• intensive therapy of catatonic states alone / or with neuroleptics
• Treatment of acute delirium , sometimes together with neuroleptics
• Supportive therapy for malaise / vomiting , often in conjunction with cancer chemotherapy , usually together with first-line antiemetics such as 5-HT ₃ antagonists
• supportive therapy against nausea with regular vomiting and as a premedication,
• Relief of uncomfortable procedures such as endoscopy and oral surgery
• Increasing the effectiveness of the main anesthetic drug
• Achievement of anterograde amnesia for the duration of the procedure
• supportive treatment for neuropathic pain or other severe pain conditions
• Treatment of the rare stiff-man syndrome (in combination with an immunosuppressant )

Contraindications

Lorazepam should not be taken in case of hypersensitivity to the active ingredient or to other benzodiazepines , myasthenia gravis , acute poisoning with alcohol, sleeping pills, pain relievers and psychotropic drugs , shock, coma, collapse states, and in children under twelve years of age. Particular caution is required in the case of severe respiratory insufficiency, sleep apnea syndrome, severe liver or kidney failure as well as drug, alcohol and drug addiction, especially with substances that affect the GABA receptor (alcohol, benzodiazepines, barbiturates ). For people under 18 years of age, the active ingredient is only approved if there is an urgent need, and the dose is generally reduced.

Lorazepam can make an existing depression worse. In those over 65 years of age, paradoxical behavior can arise that is ambiguous about the desired effect. These include aggressiveness, anger, and confusion.

Dosis, kind and Time of the Use

The mean daily dose is 0.5 mg to 3 mg.

Inability to speak catatonia responds to lorazepam orally or injected slowly intravenously . The catatonia may recur and treatment for a few days may be necessary. Occasionally a neuroleptic is administered at the same time.

The control of a status epilepticus requires slow intravenous injections, taking into account the possible occurrence of shortness of breath ( hypoventilation ) and low blood pressure ( hypotension ).

In any case, the dosage must be individual, especially in elderly and debilitated patients who are at greater risk of over-sedating the patient. The safety and effectiveness of lorazepam in people under the age of 18 has not been well researched, but it is used to treat consecutive seizures. At higher doses (preferably intravenously), the patient is often unable to remember unsightly events ( anterograde amnesia ) such as therapeutic interventions (endoscopy, etc.). This effect is desirable. In palliative medicine , v. a. For use in hospice services , lorazepam can be administered for anxiolysis (anxiety relief ), shielding sedation and relaxation.

Use during pregnancy and breastfeeding

There is clear evidence of benzodiazepine-related risks to the human fetus, which limits use in pregnancy to an absolute necessity. Given near the time of birth, lorazepam can induce withdrawal symptoms in infants.

unwanted effects

Like all benzodiazepines, lorazepam can be psychologically and / or physically addictive. Severe withdrawal symptoms, similar in occurrence to those of alcohol, barbiturates and other benzodiazepines, have been observed after abrupt discontinuation after prolonged use. Therefore, a gradual withdrawal ( tapering ) over a period of weeks or months, depending on the time in which it was taken and the dosage, is absolutely necessary.

Long-term therapy can lead to cognitive deficits which, however, are reversible after careful withdrawal. Possible cognitive impairments include confusion, depression, double vision, hallucinations, dizziness, movement disorders, uncoordinated movements, muscle cramps, restlessness, tremors, and fatigue.

In some cases, benzodiazepines can produce paradoxical effects, such as increased drive and aggression. Some health professionals think that these effects may be triggered by disinhibition and are therefore more common in patients who may be below average disinhibition due to pre-existing personality disorders . Paradoxical effects are observed particularly frequently during an application in mania and schizophrenia . After stopping it suddenly or tapering off too quickly, the same effects (anxiety, panic attacks, sometimes severe epileptic seizures - but much more pronounced) occur, sometimes even more pronounced, as before the start of the intake, sometimes even more so, which again leads to situations requiring treatment.

Lorazepam can have unpredictable residual effects such as tiredness, reduced ability to react, dizziness and low blood pressure, which can lead to significant restrictions in everyday life within twelve hours. Therefore, active participation in traffic, the use of machines and work without a secure footing should only be carried out with the consultation of a doctor.

abuse

→ Main article : Harmful use of benzodiazepines

Like other benzodiazepines, lorazepam is highly addictive and is also used in combination with other drugs in the context of polytoxicomania in order to strengthen or weaken their effect or as a self-medication for the side effects of drug abuse. The mixed consumption with alcohol and opioids can lead to life-threatening hypoventilation and even respiratory arrest due to massive sedation .

Prescribability and legal status

Lorazepam is regulated by narcotics law in Germany. Only preparations that contain up to 2.5 mg lorazepam per divided form without another substance from Annexes I to III of the BtMG only require a simple recipe, but no narcotic drug prescription .

Chemistry and stereoisomerism

( R ) shape (left) and ( S ) shape (right)

Lorazepam synthesis

The synthesis is described in the literature.

Lorazepam is a chiral drug with a stereocenter and is used medicinally as a racemate , i.e. as a 1: 1 mixture of the mirror image ( R ) and ( S ) form. As a rule, enantiomers have different pharmacokinetic and pharmacological properties; However, this is not relevant for lorazepam, since racemization occurs very quickly in aqueous solution , so the use of a pure enantiomer is not possible.

Trade names and dosage forms

Tavor / Tavor Expidet (D), Tolid (D), Ativan (USA, GB), Lorazepam dura (D), Merlit (A), Temesta (CH, AT, L, B), Temesta Expidet (CH) and various others Generics.

For patients who cannot swallow adequately and for applications in emergency medicine, there are orodispersible tablets or platelets (“expidet”) that dissolve in the mouth immediately after ingestion. The immediate solubility prevents retention in the mouth even in non-cooperative patients . However, the effect does not set in any faster, since lorazepam is hardly absorbed through the oral mucosa, but gastrointestinally.

Web links

• Poisons Information Monograph (PIM) for Lorazepam

Individual evidence

1. ↑ ^{a b c d e f} data sheet (±) -Lorazepam from Sigma-Aldrich , accessed on April 8, 2011 ( PDF ).
2. ↑ ^{a b} Entry on Lorazepam in the DrugBank of the University of Alberta .
3. ↑ Causality unclear: increased dementia rate with benzodiazepines. In: Doctors newspaper . October 24, 2012, accessed August 13, 2015 . 
4. ↑ Benzodiazepines: Alzheimer's helpers. doccheck.com, October 7, 2014, accessed on August 13, 2015.
5. ↑ Technical information Tavor® pro injectione 2 mg . As of February 2019. Pfizer Pharma PFE GmbH.
6. ↑ Guidelines of the German Society for Neurology, Status epilepticus in adulthood, definition of Status epilepticus (as of October 1, 2008).
7. ↑ Ernst Mutschler, Gerd Geisslinger, Heyo K. Kroemer , Sabine Menzel, Peter Ruth: Mutschler drug effects. Pharmacology - Clinical Pharmacology - Toxicology. 10th edition. Wissenschaftliche Verlagsgesellschaft, Stuttgart 2012, ISBN 3-8047-2898-7 . P. 174.
8. ^ ^{A b} Thomas Markham Brown, Alan Stoudemire: Psychiatric Side Effects of Prescription and Over-the-counter Medications. ISBN 0880488689 p. 138.
9. ^ ^{A b} Jeffrey K. Aronson: Meyler's Side Effects of Psychiatric Drugs. ISBN 978-0-080-93287-3 , p. 415.
10. ↑ ^{a b} Mary Anne Hochadel, Jerry Avorn: The AARP Guide to Pills. ISBN 1402744463 p. 572.
11. ↑ Appendix III (marketable narcotics ) to the BtMG.
12. ^ Axel Kleemann , Jürgen Engel, Bernd Kutscher, Dietmar Reichert: Pharmaceutical Substances . 4th edition. 2 volumes. Thieme-Verlag, Stuttgart 2000, ISBN 978-1-58890-031-9 ; online since 2003 with biannual additions and updates.
13. ↑ European Pharmacopoeia 3rd edition. 1997, official German edition, Deutscher Apotheker Verlag Stuttgart, Govi-Verla-Pharmazeutoscher Verlag Eschborn, ISBN 3-7692-2186-9 , p. 1206.
14. ↑ Miklós Simonyi, Joseph Gal, Bernhard Testa: Sings: The Code of Clarification . In: Miklós Simonyi (Ed.): Problems and Wonders if Chiral Molecules . Akadémiai Kiadó, Budapest 1990, ISBN 963-05-5881-5 , pp. 127-136.

This article is about a health issue. It is not used for self-diagnosis and does not replace a diagnosis by a doctor. Please note the information on health issues !