Lorazepam

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Lorazepam (marketed under the brand names Ativan®, Temesta®, Tavor®) is a drug which is a benzodiazepine derivative. Pharmacologically, it is classified as a sedative-hypnotic, anxiolytic and anticonvulsant.

Pharmacology and pharmacokinetics
Lorazepam is rapidly and nearly completely absorbed after any mode of application (oral, sublingual, i.m., i.v.). The onset of action is several minutes after i.v. injections, 30 to 45 minutes after oral/sublingual administration, and up to 1 hour after i.m. injections.

The duration of action depends on the dose, and is normally 6 to 12 hours. The half-life of lorazepam in patients with normal liver function is 11 to 18 hours. Therefore, 2 to 4 daily doses are often needed.

0.5mg (500µg) of lorazepam is equivalent to 5mg of diazepam. Other experts estimate a proportion of 1mg lorazepam to 5mg diazepam.

Indications
Lorazepam is indicated for:
 * Treatment of anxiety disorders
 * Short-term treatment of insomnia, particularly if associated with severe anxiety
 * Treatment of symptoms associated with alcohol withdrawal
 * As a premedication,
 * To facilitate unpleasant procedures, such as endoscopies and dental surgery.
 * To augment the action of the primary anaesthetic drug.
 * To produce varying degrees of anterograde amnesia for the duration of the procedure.
 * Long-term treatment of otherwise resistant forms of petit mal epilepsy
 * Acute therapy of status epilepticus
 * Acute therapy of catatonic states alone/or with haloperidol
 * As an initial adjunctive treatment for depressions, mania and psychosis
 * Treatment of acute delirium, preferably together with haloperidol
 * Supportive therapy of nausea/emesis frequently associated with cancer chemotherapy, usually together with firstline antiemetics like 5-HT3-antagonists

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

Dosage
Daily doses vary greatly from 0.5 mg bedtime for insomnia and 2.5 mg every 6 hours and more in the acute treatment of mania, before the firstline drugs (lithium, 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 i.v. injection. Catatonia may reoccur and treatment for some days may be necessary. Sometimes haloperidol is given concomitantly.

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

In any case, 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 i.v.-doses) the patient is frequently not able to recall unpleasant events (anterograde amnesia) such as therapeutic interventions (endoscopies etc.), which is a desirable effect. But in these cases the risk is given that a patient later makes unjustified allegations of sexual abuse during treatment due to poor recall.

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

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

The likelihood of abuse, dependence and withdrawal symptoms is substantially greater with lorazepam relative to other benzodiazepines because of its short half-life, higher potency and stronger binding to the GABA receptor complex. In this regard it behaves like alprazolam (short half-life and high potency) and clonazepam (long half-life and high potency).

Long term therapy may lead to cognitive deficits, however this is reversible upon discontinuation.

Generally, lorazepam is not suited for long-term treatment except when medically necessary. The stress of everyday life usually does not require treatment with an anxiolytic and is best treated with psychotherapy.

Lorazepam belongs to the FDA pregnancy category D which means that it is likely to cause harm to the unborn baby, although this is very rarely seen. Lorazepam given near the time of birth may cause floppy infant syndrome and withdrawal symptoms in the infant.

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 less than average inhibition.

Abuse
Those with preexisting substance abuse disorders or addictive personalities are likely to abuse medications such as lorazepam, and care should be taken when prescribing it on an outpatient basis. It is often used in an inpatient setting to assist with detox.


 * Illegal use: Special data is not available but as a highly potent benzodiazepine it might be used to modulate the effects of stimulant abuse or to help with a "bad trip" caused by LSD or other hallucinogens.  It can be expected that lorazepam has some street use to boost the euphoriant effects of opioids like heroin, perhaps heroin and other drugs could be "cut" with lorazepam without the knowledge of the user.  The risk if used together with an opioid is respiratory depression or arrest.


 * Date rape drug: Lorazepam has no particular taste and could in principle be misused as a 'date rape drug' since it has strong amnesic properties relatively to other benzodiazepines. But as lorazepam has poor water solubility flunitrazepam is the more commonly used drug for this purpose.  The action of lorazepam together with alcohol can be dangerous, both in terms of criminal behaviour and, in higher amounts, significant central nervous system depression manifesting as unconsciousness, respiratory depression, coma or - in rare instances - death.

Legal status
The patent on lorazepam held by Wyeth is expired in the United States. Generic versions of the drug are now available.

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.