lorazepam

Lorazepam
Systematic ( IUPAC) name
9-chloro-6-(2-chlorophenyl)-4-hydroxy- 2,5-diazabicyclo[5.4.0]undeca- 5,8,10,12-tetraen-3-one
Identifiers
CAS number	846-49-1
ATC code	N05 BA06
PubChem	3958
DrugBank	APRD00116
Chemical data
Formula	C15 H10 Cl2 N2 O2
Mol. mass	321.2 g/mol
Pharmacokinetic data
Bioavailability	85%
Metabolism	Hepatic
Half life	10-20 hours
Excretion	Renal
Therapeutic considerations
Pregnancy cat.	D ( US )
Legal status	Schedule IV ( US )
Routes	Oral, I.M., I.V. and transdermal

Lorazepam, first marketed under the brand names Ativan and Temesta, is a benzodiazepine type drug. Lorazepam possesses, to different extents, the five principal benzodiazepine drug molecule properties: sedative/hypnotic, muscle relaxant, anxiolytic, amnesic and anticonvulsant. ^[1] It has also found use as an adjunct antiemetic.

Pharmacology and pharmacokinetics

Lorazepam is a potent, short- to medium-duration action benzodiazepine. Its uniqueness, ^[2] drawbacks and advantages are largely explained by its pharmacokinetic properties.

The British National Formulary and others equate the effect of lorazepam 1 mg to the effect of diazepam 10 mg. ^{[3] [4]}

Lorazepam may be administered orally, sublingually, intramuscularly, or intravenously. Peak effects roughly coincide with peak serum levels, ^[5] which occur 10 minutes after intravenous injection and up to 1 hour after intramuscular injection. Oral absorption is relatively slow with around 120 minutes to peak serum level, ^{[6] [5]} but the initial onset of effects will happen earlier as it is a potent drug.

Compared to other benzodiazepines, Lorazepam is thought to bind relatively strongly to GABA receptors[reference needed] which may explain its relatively strong amnesic effect. ^[1]

The magnitude and duration of lorazepam effects are proportional to doses administered. Clincially relevant doses will normally have effect for 6 to 12 hours, but larger doses cause stronger and longer lasting effects. Other than for night sedation, lorazepam is unsuitable for once-daily administration and usually prescribed as 2 to 4 daily doses.

In clinically relevant amounts lorazepam serum levels are proportional to the lorazepam doses given. Giving 2 mg oral lorazepam will result in a peak total serum lorazepam level of around 20 nanograms/ml around 2 hours later, ^{[6] [5]} half of which is lorazepam and half its inactive metabolite lorazepam-glucuronide. ^[7] A similar dose given intravenously will result in an earlier and higher peak serum level, with a higher proportion of unmetabolised active lorazepam. ^[8]

On regular lorazepam use, maximum serum levels are attained after three days and longer term use does not result in further accumulation. ^[6] On discontinuation, lorazepam serum levels become negligible after 3 days and undetectable after about a week. It is metabolised in the liver by conjugation into inactive lorazepam-glucuronide, which is excreted by the kidneys. ^[6] Lorazepam-glucuronide has a longer half-life than lorazepam and it gets more widely distributed in the body since it is more lipid-soluble. Lorazepam-Glucuronide therefore remains detectable in blood and urine for substantially longer than lorazepam.

Lorazepam is 85-90% protein bound ^[6] and has relatively low lipid solubility, so its volume of distribution is mainly the vascular compartment. This contrasts with the highly lipid soluble diazepam which, after reaching its peak serum level, soon redistributes in the body. A lorazepam dose therefore has longer duration of peak effects than a diazepam dose. However, on regular use diazepam will accumulate more because of its long half-life and because of its active metabolite with even longer half-life.

Clinical Example: Diazepam, intravenously or rectally, has long been a treatment agent of choice for status epilepticus. Diazepam's high lipid solubility explains why it it is absorbed with equal speed whether given intravenously or rectally, the rectal route being an advantage in many settings. However, diazepam's high lipid solubility also means that it will not remain in the vascular compartment but soon redistributes into body tissues. In treatment-resistant cases it may therefore be necessary to give repeated doses of diazepam, resulting in excess body accumulation. Lorazepam is an opposite case: its low lipid solubility makes it unsuitable for rectal administration, but once given intravenously it does not become significantly redistributed outside the vascular compartment. Lorazepam's anti-seizure effects therefore last longer than those of diazepam. On the other hand, if a patient is known to usually stop seizuring after one or two doses of diazepam, this may be preferable, since a single dose of diazepam will cause less prolonged sedation after-effects than would a single dose of lorazepam(diazepam anticonvulsant/sedative effects wear off after 15-30 minutes, but lorazepam effects last 12-24 hours< http://www.medscape.com/viewarticle/430209_3>). The more prolonged sedative effects of lorazepam may however be acceptable, given that its anti-seizure effects will also be of longer duration. Although lorazepam is not necessarily superior to diazepam in initially terminating seizures, ^[9] it is replacing diazepam as an agent of choice in status epilepticus, that is, where the intravenous route is available. ^{[10] [11]}.

Indications

Lorazepam is used in...

• Anxiety. Treatment of severe anxiety disorders, though less useful in panic disorder. ^[12].

• Insomnia. Short-term treatment of insomnia, particularly if associated with severe anxiety.

• Premedication. Either orally (2 hrs before) or intravenously (10 minutes before) a general anaesthetic, to reduce the amount of anaesthetic agent required and before unpleasant awake medical procedures such as dentistry or endoscopies to reduce anxiety, increase compliance and produce varying degrees of anterograde amnesia for the duration of the procedure. ^{[13] [14] [15]} Health staff must take precautions (chaperoning and avoiding ambiguous language and gestures) against patients later making unjustified allegations of sexual abuse during treatment, due to impaired memory and to drug-induced misinterpretations.

• Seizures. Acute intravenous treatment of status epilepticus and long-term oral treatment of otherwise resistant forms of petit mal epilepsy. The control of status epilepticus requires slow intravenous injections of 2 to 4 (or even 8) mg, while patients are closely monitored for side-effects of respiratory depression or hypotension.

• Drug and alcohol withdrawal. Prevention and treatment of alcohol withdrawal symptoms, particularly in patients with impaired liver function. ^{[16] [17]}

• Violence, agitation and mania. Rapid tranquilisation of violent or agitated patients, ^{[18] [19]} including acute delirium. As lorazepam can have paradoxical effects, it is preferably given together with haloperidol, ^[20]. Note, lorazepam is absorbed relatively slowly when given intramuscularly, a common route of administration in this setting.

• Catatonia. Acute therapy of catatonic states. Catatonia with inability to speak is responsive and sometimes controlled with a single 2 mg oral or slow intravenous dose of lorazepam. It may recur and treatment for some days may be necessary. As lorazepam can have paradoxical effects, haloperidol is sometimes given concomitantly ^{[21] [20]}.

• Nausea and vomiting. Adjunct antiemetic for treating nausea/ emesis frequently associated with cancer chemotherapy, usually together with first-line antiemetics such as 5-HT₃ antagonists. ^[22] It is also used as adjunct therapy for cyclic vomiting syndrome.

Formulations

Lorazepam is available in tablets, as a solution for intramuscular and intravenous injections. It is also available as a parenteral patch.

Daily doses vary greatly, from 0.5 mg at bedtime for insomnia to 2.5 mg every 6 hours or more in the acute treatment of mania, before drugs (such as lithium or valproic acid) take effect.

Safety considerations

Children and Elderly. Dose requirements have to be individualized, especially in the elderly and debilitated patients in whom the risk of oversedation is greater. Safety and effectiveness of lorazepam is not well determined in children under 18 years of age, but it is used to treat serial seizures.

Hepatic failure. Lorazepam may be safer than many other benzodiazepines in patients with impaired liver function because it does not require hepatic oxidation, but only hepatic glucuronidation into lorazepam-glucuronide. This means that, similar to oxazepam, it is less likely to accumulate to an extent where it causes adverse reactions. ^[16]

Renal failure. Lorazepam-glucuronide is excreted by the kidneys, which also excrete a small amount of unchanged lorazepam. In renal failure, marginal increases in lorazepam levels may therefore in theory occur. Impaired excretion of the inactive lorazepam-glucuronide is clinically unimportant.

Injections. After lorazepam injections, a patient should normally not be released from hospital settings without a care-giver (parent, spouse etc.) before 24 hours have elapsed, due to variable residual effects like sleepiness, vertigo, hypotension, etc. The patient should not drive a car or handle machines for 24 hours after an injection.

Paradoxical effects. In some cases there can be paradoxical effects with benzodiazepines, such as increased hostility and aggression. ^{[23] [24] [25] [26]} This is thought by some doctors to be due to disinhibition, and is therefore more likely to occur in those with preexisting personality disorders, who may have less than average inhibition.

Suicidality. Benzodiazepines in general may sometimes unmask suicidal ideation in depressed patients (indirectly, through disinhibition or fear reduction, rather than through any known direct effect). Though relatively non-toxic, the concern is that benzodiazepines may inadvertently become facilitators of suicidal behaviour. ^[27] Lorazepam should therefore not be prescribed alone in depression but only together with an appropriate antidepressant and at the minimal dose required.

Alcohol and alcoholics. Whereas lorazepam itself is not usually fatal in overdose, it can cause fatal respiratory depression if taken in overdose with alcohol. This is a dangerous combination which also causes mutual enhancement of the anterograde amnesia and disinhibition effects of both drugs, at times with forensic consequences. Patients should be warned against taking alcohol while on lorazepam treatment, ^{[1] [28]} but such advice is not universal. ^[29] Lorazepam is often used in an inpatient detox setting to relieve alcohol withdrawal effects. It should not be prescribed for this use on an outpatient basis, since it interacts strongly with alcohol and this particular patient group would be at higher risk of an interaction between lorazepam and larger amounts of alcohol. Another reason is that patients with preexisting substance abuse disorders or addictive personalities are also more likely to abuse medications such as lorazepam.

Amnesia. Among benzodiazepines, lorazepam has relatively strong amnesic effects, ^[1] but patients develop tolerance to this after a few days of regular use. Long term therapy may lead to cognitive deficits, especially in the elderly, who may already be more prone to forgetfulness, but this is reversible after a period of discontinuation.

Physical or psychological dependence. Lorazepam, like other benzodiazepines, can cause psychological and/or physical dependence. Anxiety symptoms and physical withdrawal symptoms similar in character to those of alcohol and barbiturates have been observed after abrupt discontinuation. The likelihood of dependence is thought to be substantially greater with lorazepam relative to other benzodiazepines because of its pharmacokinetic properties and its relative potency. Since lorazepam has a relatively short half-life confined mainly to the vascular compartment and no active metabolite, patients will have a clearer feel of the onset and waning of its effects, which may reinforce psychological dependence. Lorazepam's high potency makes even the smallest tablet strength of 0.5 mg a significant dose reduction(in the UK the smallest available tablet strength is 1.0 mg, further accentuating this difficulty). To minimise the risk of dependence, lorazepam is best used only short-term and at the minimum effective dose. If lorazepam has been used long-term, the recommendation is a gradual dose taper over a period of weeks or months, according to the dose and the duration of use. Coming off long-term lorazepam may be more realistically achieved by first gradually switching to an equivalent regular dose of diazepam, stabilising on this before considering dose reductions (dose reductions of regularly administered diazepam are felt less acutely, because of the longer half-lives of diazepam and of its active metabolite).

Pregnancy and breast feeding. Lorazepam belongs to the Food and Drug Administration (FDA) pregnancy category D which means that it is likely to cause harm to the unborn baby. Lorazepam given to a mother antenatally may cause floppy infant syndrome in the neonate, and neonatal withdrawal symptoms if the mother was on regular lorazepam.

Criminal abuse. In addition to purely recreational use, lorazepam and other benzodiazepines may be abused for crimes. Criminals may take them to deliberately seek disinhibition prior to committing a crime ^[26] (which may also make them more prone to commit violence) or they may administer them to victims as date rape drugs, especially together with alcohol.

Legal status

The original patent on lorazepam, held by Wyeth, is expired in the United States. Originally marketed under the brand name 'Ativan', generic versions of lorazepam are now available: Almazine, Anxiedin, Anxira, Anzepam, Aplacasse, Aplacassee, Apo-Lorazepam, Aripax, Azurogen, Bonatranquan, Bonton, Control, Duralozam, Efasedan, Emotion, Emotival, Kalmalin, Larpose, Laubeel, Lopam, Lorabenz, Loram, Lorans, Lorapam, Lorat, Lorax, Lorazene, Lorazep, Lorazepam, Lorazin, Lorazon, Lorenin, Loridem, Lorivan, Lorsedal, Lorzem, Lozepam, Merlit, Nervistop L, Nervistopl, NIC, Novhepar, Novolorazem, Orfidal, Punktyl, Renaquil, Rocosgen, Sedatival, Sedizepan, Sidenar, Silence, Sinestron, Somnium, Stapam, Tavor, Temesta, Titus, Tranqipam, Trapax, Trapex, Upan, Wintin and Wypax.

Lorazepam is a Schedule IV drug under the Controlled Substances Act in the U.S. and internationally under the United Nations Convention on Psychotropic Substances. ^[30]

In popular culture

• Fall Out Boy member Pete Wentz included references to his overdose on lorazepam in the songs "I've Got a Dark Alley and a Bad Idea That Says You Should Shut Your Mouth (Summer Song)" and "7 Minutes in Heaven (Atavan Halen)", ^[31] on the album From Under the Cork Tree.

• Blue October mentions the drug in their song "HRSA"

• Minus the Bear mentions the drug in thier song "Get Me Naked 2: Electric Boogaloo"

• In 2000, the U.S. drug company Mylan agreed to pay $147 million to settle accusations by the F.T.C. that they had raised the price of generic lorazepam by 2600 percent and generic clorazepate by 3200 percent in 1998 after having obtained exclusive licensing agreements for certain ingredients. ^[32]

• Ativan is the drug of choice for seizures on House, MD

• In the 2006 movie The Departed, Vera Farmiga's character Madolyn prescribes lorazepam to Leonardo DiCaprio's character Billy.

• In the movie " Saw III", when "Jigsaw" is being operated on he begins to convulse. The character performing the surgery yells many times for Ativan, but finds out that there is none available in the limited operating area.

References