Lorazepam

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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	N05BA06
PubChem	3958
DrugBank	APRD00116
Chemical data
Formula	C₁₅H₁₀Cl₂N₂
Mol. mass	321.2
Pharmacokinetic data
Bioavailability	85%
Metabolism	Hepatic
Half life	10-20 hours
Excretion	Renal
Therapeutic considerations
Pregnancy cat.	D (USA)
Legal status	Schedule IV(US)
Routes	Oral, I.M., I.V., parenteral

Lorazepam (first marketed under the brand names Ativan® and Temesta®) is a benzodiazepine type drug. As a benzodiazepine, lorazepam possesses all five principal benzodiazepine actions (sedative/hypnotic, muscle relaxant, anxiolytic, amnestic and anticonvulsant), but to different extents. Lorazepam also has found use as an adjunct anti-nausea drug. Lorazepam is a potent drug and its unique pharmacological properties underlie both its drawbacks and its advantages.

1 Pharmacology and pharmacokinetics
2 Indications
3 Form and Dosage
4 Safety Considerations
5 Abuse and Dependence
6 Legal status
7 References
8 External links

[edit] Pharmacology and pharmacokinetics

Lorazepam is a potent, short- to medium-duration action benzodiazepine. The British National Formulary equates the effects of 1 mg of lorazepam to the effects of 10mg diazepam. [1]

Lorazepam is rapidly and nearly completely absorbed after any mode of administration (oral, sublingual, intramuscular [i.m.], intravenous [i.v.]). Peak effects roughly coincide with peak serum levels, which occur several minutes after intravenous injections, 30 to 45 minutes after oral/sublingual administration, and up to 1 hour after intramuscular injections.

Lorazepam effects are proportional to serum levels and serum levels are proportional to the dose given. An oral dose of 2mg lorazepam will result in a total serum lorazepam level of around 20nanograms/ml, half of which is lorazepam and half its inactive metabolite, lorazepam glucuronide. Giving a similar amount of lorazepam intravenously will result in a higher peak serum lorazepam level, initially consisting mainly of unmetabolised, active lorazepam.

Lorazepam is metabolised in the liver, by conjugation, into lorazepam glucuronide which is excreted in the urine. Lorazepam glucuronide has a somewhat longer half-life than lorazepam and therefore remains detectable in blood and urine for longer than unchanged lorazepam.

Lorazepam may be safer than many other benzodiazepines in patients with impaired liver function because it does not require hepatic oxidation, which means that, similar to oxazepam, it is less likely to accumulate to an extent where it causes adverse reactions.^[2] On regular use, lorazepam builds up to maximum serum levels after only 3 days and longer term use does not result in further accumulation. Similarly, on discontinuation of regular use, lorazepam serum levels become negligible after 3 days and undetectable after a week.

The duration of clinical action depends on the dose administered. With normal sized doses, it is normally 6 to 12 hours, but a larger dose will cause more marked drug effects and longer duration of action. In patients with normal liver function the serum half-life of lorazepam is 11 to 18 hours, so it is unsuitable for once-daily administration and therefore usually given as 2 to 4 daily doses if administered regularly.

Because of lorazepam's relative low lipid solubility, its distribution in the body is mainly the vascular compartment. This contrasts with diazepam, which is highly lipid soluble and so more extensively distributed in the body. Also, lorazepam is thought to bind more strongly to GABA receptors. A single acute dose of lorazepam therefore has longer duration of peak effects than an equivalent single acute dose of diazepam, even though diazepam has both a longer half-life and an active metabolite with even longer half-life. Lorazepam is thus more predictable when used intravenously for status epilepticus, both in regard to its more prolonged anti-seizure effects and in less drug accumulation in the patient's body (causing prolonged sedation after effects), such as is seen when diazepam injections have needed to be repeated when their effects wore off. Lorazepam's inactive metabolite is another advantage over diazepam in this setting. Lorazepam is therefore replacing diazepam as an intravenous drug of choice in status epilepticus.

[edit] Indications

Lorazepam is indicated for:

Treatment of anxiety disorders (especially Panic Disorder)
Short-term treatment of insomnia, particularly if associated with severe anxiety
As a premedication before a general anaesthetic (to reduce the amount of a general anaesthetic drug needed) and before unpleasant awake medical procedures such as dentistry or endoscopies (by reducing anxiety, increasing compliance and producing varying degrees of anterograde amnesia for the procedure).
Acute therapy of status epilepticus
Long-term treatment of otherwise resistant forms of petit mal epilepsy
Prevention and treatment of alcohol withdrawal symptoms.
Treatment of acute delirium (preferably together with haloperidol as lorazepam can have paradoxical effects).
Acute therapy of catatonic states either alone, or preferably together with haloperidol as lorazepam can have paradoxical effects).
Adjunct therapy of nausea/emesis frequently associated with cancer chemotherapy, usually together with first-line antiemetics like 5-HT3-antagonists
Adjunct therapy for Cyclic vomiting syndrome

[edit] Form and Dosage

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 firstline drugs (such as lithium or valproic acid) control the situation.

Catatonia with inability to speak is very responsive and sometimes controlled with a single dose of 2 mg oral or slow intravenous injection. Catatonia may recur and treatment for some days may be necessary. Sometimes haloperidol is given concomitantly.

The control of status epilepticus requires slow intravenous injections of 2 to 4 (or even 8) mg. Patients should be closely monitored for respiratory depression and hypotensive effects

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. With higher doses (preferably given intravenously) the patient is frequently not able to recall unpleasant events (anterograde amnesia) such as endoscopies, which is a desirable and intended effect. In these cases there is a risk that a patient could later make an unjustified allegation of sexual abuse during treatment, due to both poor recall and drug-induced misinterpretations.

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

[edit] Safety Considerations

Lorazepam, like other benzodiazepines, can cause psychological and/or physical dependence. Withdrawal symptoms similar in character to those of alcohol and barbiturates have been observed after abrupt discontinuation. A gradual taper is therefore recommended over a period of weeks or even months, depending on the length of time it was used and the dosage taken.

In some cases there can be paradoxical effects with benzodiazepines, such as increased hostility and aggression. 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.

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. Lorazepam should therefore not be prescribed alone in depression but only together with an appropriate antidepressant and at the minimal dose required.

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 directly warned against taking alcohol while on lorazepam treatment.

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 in danger of an interaction between lorazepam and large amounts of alcohol.

Among benzodiazepines, lorazepam has relatively strong amnesic effects, 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.

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.

[edit] Abuse and Dependence

Those with preexisting substance abuse disorders or addictive personalities are more likely to abuse medications such as lorazepam, and care should be taken if prescribing it on an outpatient basis.

The likelihood of abuse, dependence and withdrawal symptoms is thought to be substantially greater with lorazepam relative to other benzodiazepines because of its particular properties: (a) Lorazepam binds relatively strongly to the GABA receptor complex. (b) Lorazepam has a short serum half-life and its effects wear off quicker due to it having no active metabolite, in contrast to diazepam. (c) Lorazepam is highly potent, making even 0.5mg a significant dose reduction. In the UK the smallest available tablet strength is 1mg, accentuating this problem.

Addiction is not a unique problem to lorazepam but for the reasons given above lorazepam is best used short-term to minimise this risk. Coming off lorazepam is more realistically achieved by, first, gradually changing over to an equivalent dose of diazepam and, secondly, stabilising the patient on diazepam before contemplating dose reductions. This stabilisation period is important since lorazepam levels (and effects) fluctuate more than those of diazepam: anxiety symptoms are more noticeable when lorazepam wears off and symptom relief more drastic when taking another dose, which may reinforce psychological dependence. Diazepam is here best administered once daily to tackle this aspect of dependence. The dose is reduced gradually over a period of months or years, depending on prior dose and duration of use.

[edit] Legal status

The original patent on lorazepam, held by Wyeth, is expired in the United States. It was originally marketed under the brand name Ativan, but generic versions of the drug are now available. Generic brand names include 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.

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.

Lorazepam is a Schedule IV drug under the Controlled Substances Act in the US and internationally under the United Nations Convention on Psychotropic Substances [3].