Introduction to Lorazepam

Lorazepam (Ativan, Temesta) is a quickly absorbed, short acting, and potent benzodiazepine. Lorazepam has a short half-life of 10 hours in part because none of its metabolites are pharmacologically active. But IV delivered lorazepam has efficacy between 82 and 100%; it enters cerebral tissue very quickly and is pharmacologically active there for up to 72 hours, much longer than diazepam. This makes it a good treatment for acute seizures and status epilipticus (seizures lasting more than five minutes, a serious medical emergency).[1] Because of its anticonvulsant and anxiolytic effects lorazepam is also used to treat symptoms of withdrawal from alcohol.[2] Lorazepam’s quick action makes it a good choice for psychiatric crises involving agitation, panic, aggression or violence,[3] and it is prescribed for intermittent severe anxiety such as experienced in relation to flying. Lorazepam is also administered preoperatively for its anxiolytic, sedating and amnestic effects, especially in patients with anxiety about surgery.[4] As all benzodiazepines do, lorazepam works on the GABA_A receptor. Lorazepam has a high risk of abuse, dependence, and addiction given its potency and short half-life. [REF]

Using Lorazepam

Ways of Administration

Lorazepam for anxiety, panic and insomnia is usually taken orally in doses of 0.5 to 2mg. For emergent situations the preferred route of administration is IV, but the rectal administration and IM injection is also used. Injectable lorazepam is administered either by deep intramuscular injection or intravenously.[5] Lorazepam has a mild, not bitter, taste[6] and thus the oral tablets can be administered buccally or sublingually, or chewed before swallowing, increasing the drug's absorption rate (though probably not by much.) In addition to these routes of administration, crushed lorazepam tablets are also insufflated (snorted) by recreational users.

Effects of Lorazepam

The normal therapeutic effects of lorazepam include anxiolysis (anxiety reduction), amnesia (memory loss), disinhibition, muscle relaxation, sedation, and sleepiness. Lorazepam reduces tension and anxiety, calms one's state of mind, and encourages sleep. Since lorazepam use causes tolerance rapidly (within 4 weeks at some doses) and because psychological and physical addiction can occur within a matter of 1-3 months (depending on dosage), courses of treatment are limited to two weeks if possible. (REF)

Combinations with Lorazepam

Combining Lorazepam with other central nervous system depressants is dangerous because of the likely additive effects increasing respiratory depression to potentially fatal levels. These depressants include alcohol, other benzodiazepines, barbiturates, antipsychotics, sedative antihistamines, anticonvulsants, delirant and dissociative drugs, muscle relaxants, opioids/opiates, sedative/hypnotics, anxiolytics, narcotic analgesics, and anesthetics. MAO inhibitors, and other antidepressants.[7]
Injectable lorazepam combined with scopolamine has been shown to increase sedation and produce both hallucinations and irrational behavior.[8]
Combining lorazepam with clozapine can produce increased sedation, excessive salivation, low blood pressure, loss of muscle coordination, delirium, and respiratory arrest. (REF)
The combination of lorazepam with valproate results in increased lorazepam blood levels and reduced lorazepam clearance. Combining lorazepam with probenecid may result in a more rapid onset or prolonged effect of lorazepam due to increased half-life and decreased clearance. Lorazepam dosage must be reduced by approximately 50% when combined with either of these medications. These effects are theorized to be due to inhibition of glucuronidation, the process responsible for metabolizing lorazepam to its pharmacologically inactive metabolites. (REF)
Theophylline and aminophylline may also reduce the sedative effects lorazepam.(REF)

Different Uses for Lorazepam

Lorazepam is used recreationally for its anti-anxiety, relaxing, hypnotic and sedating effects. Therapeutically it is used to treat and prevent both acute seizures and alcohol withdrawal syndrome,[9] as a treatment for catatonia, for rapid sedation in individuals who are agitated or violent,[10] for insomnia, panic attacks, and anxiety. (REF) Lorazepam is also used as an antiemetic premedication, usually alongside ondansetron and diphenhydramine, for nausea-inducing anticancer drugs.

Pharmacology of Lorazepam

Lorazepam has an oral bioavailablity of >90%. The time for lorazepam to achieve peak plasma concentrations is 15 min - 2.5 hours, with an average of 1 - 1.5 hours. Taking lorazepam orally with food that has a moderate level of fat will delay absorption and reduce the amount absorbed. [REF] Lorazepam has a short half-life– less than 10 hours but is highly potent because of its high in vivo affinity for its GABA_A receptor. Lorazepam is a classical benzodiazepine (along with chlordiazepoxide, lorazepam and temazepam) because its attributes are multi-faceted and it produces all effects that epilepsy: pharmacology and pharmacokinetics.[11]
Lorazepam works by activating the GABA_A receptor at the benzodiazepine (BZP) site. GABA levels in the brain are not increased by lorazepam, it potentiates naturally occurring GABA by binding to a benzodiazepine receptor site located on the post synaptic receptor plate in a GABAergic nerve terminal. Lorazepam’s presence there increases the CI conductance and thus increases GABA transmission, leading to the major inhibition of other neurotransmitters. This is how lorazepam creates sedation and its other effects. Glucuronidation by UGT, (uridine diphosphate glucuronosyltransferase.) is the primary pathway by which lorazepam is metabolized into its metabolites, all of which are pharmacologically inactive. Its excretion is primarily renal.[12]
LD₅₀ (mg/kg) :
Mice : 3178 orally
Rat : >5000 orally

Chemistry of Lorazepam

Column 1	Column 2
Systematic(IUPAC) name:	(RS)-9-chloro-6-(2-chlorophenyl)-4-hydroxy-2,5-diazabicyclo[5.4.0]undeca-5,8,10,12-tetraen-3-one
Synonyms:	7-Chloro-5-(2-chlorophenyl)-1,3-dihydro-3-hydroxy-2H-1,4-benzodiazepin-2-one, Wy-4036, Ativan, Emotival, Lorax, Lorsilan, Pro Dorm, Psicopax, Punktyl, Quait, Sedatival, Sedazin, Somagerol, Tavor, Temesta, Wypax
Molecular Formula:	C15H10Cl2N2O2
Molar mass:	321.16 g/mol [1]
CAS Registry Number:	846-49-1
Melting Point:	166-168 ℃
Boiling Point:	no data
Flash Point:	no data
Solubility:	0.08 mg/mL (water), 3 mg/mL (chloroform), 14 mg/mL (alcohol), 16 mg/mL (propylene glycol), 30 mg/mL (ethyl acetate). Soluble to 100 mM in DMSO and to 40 mM in ethanol
Additionnal data:	pK1 1.3, pK2 11.5
Notes:	none

[13]

The Dangers of Lorazepam

Physical Health Risks

Impaired Attention and alertness

People taking lorazepam who may drive, operate heavy machinery, or engage in other potentially dangerous physical activities should take great care. One is advised to take time first to learn how they react to lorazepam before engaging in any of these, since lorazepam, like all benzodiazepines, impairs attention and alertness.[14]

Lorazepam and Breastfeeding

Lorazepam is pregnancy category D (in the U.S.) as there is evidence for harm when taken during a pregnancy. It crosses the placental barrier and may cause fetal deformities when taken during the first trimester. Use during pregnancy has resulted in infants born with respiratory depression and hypothermia. Regular use in the third trimester can result in neonatal withdrawal syndrome.[15]
The benefit to lactating mothers of taking lorazepam must be weighed against risks this poses to neonates from lorazepam in breast milk which has been shown to cause sedation, inability to suckle, and irritability.[16][17]

Drug Interactions with UGT inducers

Possible increase of lorazepam dose should be considered when taking UGT (uridine diphosphate glucuronosyltransferase) inducers such as phenobarbital, phenytoin, and rifampin. Since these induce increased activity of the main enzyme responsible for metabolizing lorazepam into its inactive metabolites, their use decreases lorazepam blood levels and therefore its effects, possibly precipitating withdrawal symptoms in lorazepam dependent or addicted individuals. [18]

Reported Deaths

A study of sedative and anxiolytic involvement in poisoning deaths in New Zealand in 2001 found lorazepam to have been involved in 2 deaths, but to be among the safest of sedatives with a rate of 1.9 deaths per million defined daily doses dispensed (compared to alprazolam's 16, temazepam's 2.1, clonazepam's 16.1, diazepam’s of 5.2 and zopiclone's of 0.59.[19]

Mental Health Risks

Hallucinations, Suicidal Ideation and Paradoxical Reactions

Lorazepam can in rare cases cause hallucinations, confusion, depression, suicidal and/or thoughts of self-harm.[20] These are also potentially very serious, the medication should be stopped and immediate medical assistance sought. Paradoxical reactions also occur in which a person becomes hyperactive, agitated and hostile.[21]

Rebound Insomnia and Anxiety

Rebound insomnia and rebound anxiety can be caused when lorazepam is stopped too abruptly, especially if the use has been long term and/or at higher than normal therapeutic doses. effects have been shown to happen with as short a course of lorazepam as 7 days.[22]

Cognitive and Memory Deficiences

Lorazepam, like all benzodiazepines, there is health risk of causing forgetfulness, rebound amnesia, and difficulty with some cognitive tasks and concentration. Lorazepam has been shown to impair both explicit and implicit memory, unlike other benzodiazepines.[23][24]

Side Effects

Like many medications, lorazepam can cause an allergic reaction, but this is uncommon. Symptoms of an allergic reaction may include swelling of lips, throat, tongue and face, trouble breathing and hives. If this occurs medical help must be sought immediately since allergic reactions progress very quickly and they can be fatal, though death as an outcome is fairly rare.

Addiction

Physical Addiction

Given intravenously, lorazepam can be even more dependence and addiction causing than when taken orally, especially if intravenous use occurs over a protracted period of time. Stopping lorazepam without tapering may cause withdrawal. Lorazepam withdrawal symptoms can include headache, sweating, rebound insomnia and anxiety, dizziness, numbness/tingling of extremities, hypersensitivity to: sounds, light, noise, tactile sensations, and perceptual changes, involuntary movements, nausea, vomiting, diarrhea, loss of appetite, hallucinations/delirium, convulsions/seizures, tremor, abdominal cramps, myalgia, palpitations, tachycardia, hyperreflexia, and hyperthermia. Seizures may be more common for individuals with pre-existing seizure disorders or on drugs or medications that lower seizure threshold.[25]

Mental Addiction

Lorazepam, especially used long-term (more than two to four weeks), can cause dependence and mental addiction. Abruptly stopping lorazepam in these circumstances may cause anxiety, tension, depression, insomnia, restlessness, agitation, confusion, irritability, dysphoria, derealization, panic attacks, vertigo, depersonalization, and short-term memory loss.

Legal Status of Lorazepam

Lorazepam is a controlled substance 21 CFR 1308.14

United Nations

USA

Lorazepam is a Schedule 4 controlled substance throughout the U.S.

Australia

In Australia Lorazepam is a Schedule 4 prescription-only substance. In New South Wales, Australia, as with other Benzodiazepines, it is a Schedule 4 Appendix D substance which means that no repeats may be authorized unless with prior approval of the NSW Ministry of Health.

References

1. ^Elisabeth Rey, Jean-Marc Tréluyer and Gérard Pons. Benzodiazepines for Acute Seizures. Clinical Pharmacokinetics 36(6).1999
2. ^A prospective, randomized, trial of phenobarbital versus benzodiazepines for acute alcohol withdrawal. American Journal of Emergency Medicine. 29(4):382-5. 2011.
3. ^Emmerson B, Moudgil V, Woodbridge A, Burrows D, Kingswell B, Kubler P, McMahon K. A new clinical protocol for the pharmacological management of acute behavioral disturbance. Australasian Psychiatry. 2011 Oct;19(5):406-9. doi: 10.3109/10398562.2011.579972.
4. ^Lorazepam Injection Solution, Human Prescription Label. Revised: December 2008. Hospira, Inc., Lake Forest, IL 60045 USA
5. ^Lorazepam Injection Solution, Human Prescription Label. Revised: December 2008. Hospira, Inc., Lake Forest, IL 60045 USA
6. ^Author's personal experience
7. ^Lorazepam Injection Solution, Human Prescription Label. Revised: December 2008. Hospira, Inc., Lake Forest, IL 60045 USA
8. ^Lorazepam Injection Solution, Human Prescription Label. Revised: December 2008. Hospira, Inc., Lake Forest, IL 60045 USA
9. ^A prospective, randomized, trial of phenobarbital versus benzodiazepines for acute alcohol withdrawal. American Journal of Emergency Medicine. 29(4):382-5. 2011.
10. ^Emmerson B, Moudgil V, Woodbridge A, Burrows D, Kingswell B, Kubler P, McMahon K. A new clinical protocol for the pharmacological management of acute behavioural disturbance. Australasian Psychiatry. 2011 Oct;19(5):406-9. doi: 10.3109/10398562.2011.579972.
11. ^Riss J, Cloyd J, Gates J, Collins S. Benzodiazepines in epilepsy: pharmacology and pharmacokinetics. Acta Neurol Scand 2008: 118: 69–86.
12. ^Riss J, Cloyd J, Gates J, Collins S. Benzodiazepines in epilepsy: pharmacology and pharmacokinetics. Acta Neurol Scand 2008: 118: 69–86.
13. ^Merck Index, fifteenth edition (2013)
14. ^Clarkson JE, Gordon AM, Logan BK. Lorazepam and driving impairment. Journal of analytical toxicology. 2004, Sep; 28(6):475-80.
15. ^
    A G Whitelaw, A J Cummings, and I R McFadyen Effect of maternal lorazepam on the neonate.
    Br Med J (Clin Res Ed). 1981 Apr 4; 282(6270): 1106–1108.
16. ^Kelly LE, Poon S, Madadi P, Koren G. Neonatal benzodiazepines exposure during breastfeeding. Journal of Pediatrics. 2012;161:448-51.
17. ^Lorazepam Injection Solution, Human Prescription Label. Revised: December 2008. Hospira, Inc., Lake Forest, IL 60045 USA
18. ^Riss J, Cloyd J, Gates J, Collins S. Benzodiazepines in epilepsy: pharmacology and pharmacokinetics. Acta Neurol Scand 2008: 118: 69–86.
19. ^David M. Reith, John Fountain, Rebecca McDowell, and Murray Tilyard (2003) Comparison of the Fatal Toxicity Index of Zopiclone with Benzodiazepines.Journal of Toxicology: Clinical Toxicology 41(7): 975–980.
20. ^Lorazepam Tablets, Human Prescription Label. Revised: 10/2011. Sandoz Inc. Princeton NJ.
21. ^Lorazepam Tablets, Human Prescription Label. Revised: 10/2011. Sandoz Inc. Princeton NJ.
22. ^Lorazepam Tablets, Human Prescription Label. Revised: 10/2011. Sandoz Inc. Princeton NJ.
23. ^K. I. Bishop - H. V. Curran. Psychopharmacological analysis of implicit and explicit memory: a study with Iorazepam and the benzodiazepine antagonist flumazenil. Clinical Pharmacokinetics. 1999 Jun; 36 (6): 409-424
24. ^Loring DW, Marino SE, Drane DL, Parfitt D, Finney GR, Meador KJ. Lorazepam effects on Word Memory Test performance: a randomized, double-blind, placebo-controlled, crossover trial. Clinical Neuropsychology 2011 Jul;25(5):799-811.
25. ^Lorazepam Tablets, Human Prescription Label. Revised: 10/2011. Sandoz Inc. Princeton NJ.