Lorazepam

Lorazepam, sold under the brand name

Ativan among others, is a benzodiazepine
medication.[3] It is used to treat anxiety
disorders, trouble sleeping, active seizures
including status epilepticus, alcohol
withdrawal, and chemotherapy-induced
nausea and vomiting.[3] It is also used
during surgery to interfere with memory
formation and to sedate those who are
being mechanically ventilated.[3][7] While it
can be used for severe agitation,
midazolam is usually preferred.[3] It is also
used, along with other treatments, for
acute coronary syndrome due to cocaine
use.[3] It can be given by mouth or as an
injection into a muscle or vein.[3] When
given by injection onset of effects is
between one and thirty minutes and
effects last for up to a day.[3]
 Lorazepam

Clinical data
Trade names Ativan, Tavor, Temesta,
others[2]
Synonyms O-Chloroxazepam, L-
Lorazepam Acetate
AHFS/Drugs.com Monograph
MedlinePlus a682053
Pregnancy AU: C
category
US: D (Evidence of risk)
Dependence Low to moderate[1]
liability
Routes of By mouth, intramuscular,
administration
intravenous, under the
tongue, and transdermal
ATC code N05BA06 (WHO )

Legal status
Legal status AU: S4 (Prescription
only)
CA: Schedule IV
DE: Prescription only
(Anlage III for higher
doses)
UK: Controlled Drug
(Benz) POM
 US: Schedule IV

Pharmacokinetic data
Bioavailability 85% when taken by
mouth
Metabolism Liver glucuronidation
Onset of action 1–5 min (IV), 15–30 min
(IM)[3]
Elimination half-life 10–20 hours[4][5][6]
Duration of action 12–24 hours[3]
Excretion Kidney

Identifiers

IUPAC name
7-Chloro-5-(2-chlorophenyl)-3-hydroxy-1,3-dihydro-1,4-benzodiazepin-2-one

CAS Number 846-49-1  

PubChem CID 3958

DrugBank DB00186  

ChemSpider 3821  

UNII O26FZP769L
KEGG D00365  

ChEMBL ChEMBL580  

CompTox Dashboard DTXSID7023225

(EPA)
ECHA InfoCard 100.011.534

Chemical and physical data

Formula C15H10Cl2N2O2
Molar mass 321.2 g/mol g·mol−1
3D model (JSmol) Interactive image

SMILES
ClC1=CC=CC=C1C2=NC(C(NC3=C2C=C(C=C3)Cl)=O)O

InChI
InChI=1S/C15H10Cl2N2O2/c16-8-5-6-12-10(7-8)13(19-15(21)14(20)18-12)9-3-1-2-4-11(9)17/h1-7,15,21H,(H,18,20) 
Key:DIWRORZWFLOCLC-UHFFFAOYSA-N 
    (what is this?)  (verify)

Common side effects include weakness,

sleepiness, low blood pressure, and a
decreased effort to breathe.[3] When given
intravenously the person should be closely
monitored.[3] Among those who are
depressed there may be an increased risk
of suicide.[3][8] With long-term use, larger
doses may be required for the same
effect.[3] Physical dependence and
psychological dependence may also
occur.[3] If stopped suddenly after long-
term use, benzodiazepine withdrawal
syndrome may occur.[3] Older people more
often develop adverse effects.[9] In this
age group lorazepam is associated with
falls and hip fractures.[10] Due to these
concerns, lorazepam use is generally only
recommended for up to two to four
weeks.[11]

Lorazepam was initially patented in 1963

and went on sale in the United States in
1977.[12] It is on the World Health
Organization's List of Essential Medicines,
the most effective and safe medicines
needed in a health system.[13] It is
available as a generic medication.[3] The
wholesale cost in the developing world of
a typical dose by mouth is between
US$0.02 and US$0.16 as of 2014.[14] In the
United States as of 2015 a typical month's
supply is less than US$25.[15] In 2016 it
was the 57th most prescribed medication
in the United States with more than 14
million prescriptions.[16]

Medical uses
Anxiety

Lorazepam has anxiety-reducing effects

and its best-known indication is the short-
term management of severe anxiety. In the
US, the FDA advises against use of
benzodiazepines such as lorazepam for
longer than four weeks.[11][17] It is fast
acting, and useful in treating fast onset
panic anxiety.[18]

Lorazepam can effectively reduce

agitation and induce sleep, and the
duration of effects from a single dose
makes it an appropriate choice for the
short-term treatment of insomnia,
especially in the presence of severe
anxiety or night terrors. It has a fairly short
duration of action.[19]

Withdrawal symptoms, including rebound

insomnia and rebound anxiety, may occur
after seven days' use of lorazepam.[20]
Seizures

Intravenous diazepam or lorazepam are

first-line treatments for convulsive status
epilepticus.[21][21] Lorazepam is more
effective than diazepam and intravenous
phenytoin in the treatment of status
epilepticus and has a lower risk of
continuing seizure that might require
additional medication.[22] However,
phenobarbital has a superior success rate
compared to lorazepam and other drugs,
at least in the elderly.[23][24]

Lorazepam's anticonvulsant properties

and pharmacokinetic profile, make
intravenous use reliable for terminating
acute seizures, but induces prolonged
sedation. Oral benzodiazepines, including
lorazepam are occasionally used as long-
term prophylactic treatment of resistant
absence seizures; because of gradual
tolerance to their anti-seizure effects,
benzodiazepines such as lorazepam are
not considered first-line therapies.[25]

Lorazepam's anticonvulsant and CNS

depressant properties are useful for the
treatment and prevention of alcohol
withdrawal syndrome. In this setting,
impaired liver function is not a hazard with
lorazepam, since lorazepam does not
require oxidation, the liver or otherwise, for
its metabolism.[26][27]

Sedation

Lorazepam is sometimes used for

individuals receiving mechanical
ventilation. However, in critically ill people,
propofol has been found to be superior to
lorazepam both in effectiveness and
overall cost; as a result, the use of
propofol for this indication is now
encouraged, whereas the use of
lorazepam is discouraged.[28]
Its relative effectiveness in preventing new
memory formation,[29] along with its ability
to reduce agitation and anxiety, makes
lorazepam useful as premedication. It is
given before a general anesthetic to
reduce the amount of anesthetic required,
or before unpleasant awake procedures,
such as in dentistry or endoscopies, to
reduce anxiety, to increase compliance,
and to induce amnesia for the procedure.
Lorazepam by mouth is given 90 to 120
minutes before procedures, and
intravenous lorazepam as late as 10
minutes before procedures.[30][31][32]
Lorazepam is sometimes used as an
alternative to midazolam in palliative
sedation.[33] In intensive care units
lorazepam is sometimes used to produce
anxiolysis, hypnosis, and amnesia.[34]

Agitation

Lorazepam is sometimes used as an

alternative to haloperidol when there is the
need for rapid sedation of violent or
agitated individuals,[35][36] but haloperidol
plus promethazine is preferred due to
better effectiveness and due to
lorazepam's adverse effects on respiratory
function.[37] However, adverse effects such
as behavioral disinhibition may make
benzodiazepines inappropriate for some
people who are acutely psychotic .[38]
Acute delirium is sometimes treated with
lorazepam, but as it can cause paradoxical
effects, it is preferably given together with
haloperidol.[39] Lorazepam is absorbed
relatively slowly if given intramuscularly, a
common route in restraint situations.

Other

Catatonia with inability to speak is

responsive to lorazepam. Symptoms may
recur and treatment for some days may be
necessary. Catatonia due to abrupt or
overly rapid withdrawal from
benzodiazepines, as part of the
benzodiazepine withdrawal syndrome,
should also respond to lorazepam
treatment.[40] As lorazepam can have
paradoxical effects, haloperidol is
sometimes given at the same time.[39][41]

It is sometimes used in chemotherapy in

addition to medications used to treat
nausea and vomiting, i.e. nausea and
vomiting caused or worsened by
psychological sensitization to the thought
of being sick.[42] It is also used as adjunct
therapy for cyclic vomiting syndrome.

Adverse effects
Many beneficial effects of lorazepam (e.g.,
sedative, muscle relaxant, anti-anxiety, and
amnesic effects) may become adverse
effects when unwanted.[29] Adverse
effects can include sedation and low
blood pressure; the effects of lorazepam
are increased in combination with other
CNS depressant drugs.[21][35] Other
adverse effects include confusion, ataxia,
inhibiting the formation of new memories,
and hangover effects. With long-term
benzodiazepine use it is unclear whether
cognitive impairments fully return to
normal after stopping lorazepam use;
cognitive deficits persist for at least six
months after withdrawal, but longer than
six months may be required for recovery of
cognitive function. Lorazepam appears to
have more profound adverse effects on
memory than other benzodiazepines; it
impairs both explicit and implicit
memory.[43][44] In the elderly, falls may
occur as a result of benzodiazepines.
Adverse effects are more common in the
elderly, and they appear at lower doses
than in younger people. Benzodiazepines
can cause or worsen depression.
Paradoxical effects can also occur, such
as worsening of seizures, or paradoxical
excitement; paradoxical excitement is
more likely to occur in the elderly, children,
those with a history of alcohol abuse, and
in people with a history of aggression or
anger problems.[9] Lorazepam's effects are
dose-dependent, meaning the higher the
dose, the stronger the effects (and side
effects) will be. Using the smallest dose
needed to achieve desired effects lessens
the risk of adverse effects. Sedative drugs
and sleeping pills, including lorazepam,
have been associated with an increased
risk of death.[45]

Sedation is the side effect people taking

lorazepam most frequently report. In a
group of around 3,500 people treated for
anxiety, the most common side effects
complained of from lorazepam were
sedation (15.9%), dizziness (6.9%),
weakness (4.2%), and unsteadiness
(3.4%). Side effects such as sedation and
unsteadiness increased with age.[46]
Cognitive impairment, behavioural
disinhibition and respiratory depression as
well as hypotension may also occur.[34][38]

Paradoxical effects: In some cases,

paradoxical effects can occur with
benzodiazepines, such as increased
hostility, aggression, angry outbursts,
and psychomotor agitation. These
effects are seen more commonly with
lorazepam than with other
benzodiazepines.[47] Paradoxical effects
are more likely to occur with higher
doses, in people with pre-existing
personality disorders and those with a
psychiatric illness. Frustrating stimuli
may trigger such reactions, though the
drug may have been prescribed to help
the person cope with such stress and
frustration in the first place. As
paradoxical effects appear to be dose-
related, they usually subside on dose
reduction or on complete withdrawal of
lorazepam.[48][49][50][51][52][53]
Suicidality: Benzodiazepines are
associated with increased risk of
suicide, possibly due to disinhibition.[8]
Higher dosages appear to confer greater
risk.
Amnesic effects: Among
benzodiazepines, lorazepam has
relatively strong amnesic effects,[29][54]
but people soon develop tolerance to
this with regular use. To avoid amnesia
(or excess sedation) being a problem,
the initial total daily lorazepam dose
should not exceed 2 mg. This also
applies to use for night sedation. Five
participants in a sleep study were
prescribed lorazepam 4 mg at night, and
the next evening, three subjects
unexpectedly volunteered memory gaps
for parts of that day, an effect that
 subsided completely after two to three
days' use.[55] Amnesic effects cannot be
estimated from the degree of sedation
present, since the two effects are
unrelated.

High-dose or prolonged parenterally

administered lorazepam is sometimes
associated with propylene glycol
poisoning.[34][56]

Contraindications

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Lorazepam should be avoided in people
with:

Allergy or hypersensitivity – Past

hypersensitivity or allergy to lorazepam,
to any benzodiazepine, or to any of the
ingredients in lorazepam tablets or
injections
Severe respiratory failure –
Benzodiazepines, including lorazepam,
may depress central nervous system
respiratory drive and are contraindicated
in severe respiratory failure. An example
would be the inappropriate use to relieve
anxiety associated with acute severe
asthma. The anxiolytic effects may also
be detrimental to a person's willingness
and ability to fight for breath. However, if
mechanical ventilation becomes
necessary, lorazepam may be used to
facilitate deep sedation.
Acute intoxication – Lorazepam may
interact synergistically with the effects
of alcohol, narcotics, or other
psychoactive substances. It should,
therefore, not be administered to a
drunk or intoxicated person.
Ataxia – This is a neurological clinical
sign, consisting of unsteady and clumsy
motion of the limbs and torso, due to the
failure of gross muscle movement
coordination, most evident on standing
and walking. It is the classic way in
which acute alcohol intoxication may
affect a person. Benzodiazepines
should not be administered to people
already-ataxic.
Acute narrow-angle glaucoma –
Lorazepam has pupil-dilating effects,
which may further interfere with the
drainage of aqueous humor from the
anterior chamber of the eye, thus
worsening narrow-angle glaucoma.
Sleep apnea – Sleep apnea may be
worsened by lorazepam's central
nervous system depressant effects. It
may further reduce the person's ability
to protect his or her airway during
sleep.[57]
Myasthenia gravis – This condition is
characterized by muscle weakness, so a
muscle relaxant such as lorazepam may
exacerbate symptoms.
Pregnancy and breastfeeding –
Lorazepam belongs to the Food and
Drug Administration (FDA) pregnancy
category D, which means it is likely to
cause harm to the developing baby if
taken during the first trimester of
pregnancy. The evidence is inconclusive
whether lorazepam if taken early in
pregnancy results in reduced
intelligence, neurodevelopmental
problems, physical malformations in
cardiac or facial structure, or other
malformations in some newborns.
Lorazepam given to pregnant women
antenatally may cause floppy infant
syndrome[58] in the neonate, or
respiratory depression necessitating
ventilation. Regular lorazepam use
during late pregnancy (the third
trimester), carries a definite risk of
benzodiazepine withdrawal syndrome in
the neonate. Neonatal benzodiazepine
withdrawal may include hypotonia,
reluctance to suck, apneic spells,
 cyanosis, and impaired metabolic
responses to cold stress. Symptoms of
floppy infant syndrome and the neonatal
benzodiazepine withdrawal syndrome
have been reported to persist from
hours to months after birth.[59]
Lorazepam may also inhibit fetal liver
bilirubin glucuronidation, leading to
neonatal jaundice. Lorazepam is present
in breast milk, so caution must be
exercised about breastfeeding.

Specific groups

Children and the elderly – The safety

and effectiveness of lorazepam is not
well determined in children under 18
years of age, but it is used to treat acute
seizures. Dose requirements have to be
individualized, especially in people who
are elderly and debilitated in whom the
risk of oversedation is greater. Long-
term therapy may lead to cognitive
deficits, especially in the elderly, which
may only be partially reversible. The
elderly metabolize benzodiazepines
more slowly than younger people and
are more sensitive to the adverse
effects of benzodiazepines compared to
younger individuals even at similar
plasma levels. Additionally, the elderly
tend to take more drugs which may
interact or enhance the effects of
benzodiazepines. Benzodiazepines,
including lorazepam, have been found to
increase the risk of falls and fractures in
the elderly. As a result, dosage
recommendations for the elderly are
about half of those used in younger
individuals and used for no longer than
two weeks.[9][60] Lorazepam may also be
slower to clear in the elderly, leading
potentially to accumulation and
enhanced effects.[61] Lorazepam, similar
to other benzodiazepines and
nonbenzodiazepines, causes
impairments in body balance and
standing steadiness in individuals who
wake up at night or the next morning.
Falls and hip fractures are frequently
reported. The combination with alcohol
increases these impairments. Partial,
but incomplete, tolerance develops to
these impairments.[10]
Liver or kidney failure – Lorazepam may
be safer than most benzodiazepines in
people with impaired liver function. Like
oxazepam, it does not require liver
oxidation, but only liver glucuronidation
into lorazepam-glucuronide. Therefore,
impaired liver function is unlikely to
result in lorazepam accumulation to an
extent causing adverse reactions.[26]
Similarly kidney disease has minimal
effects on lorazepam levels.[62]
Surgical premedication – Informed
consent given only after receiving
lorazepam premedication could have its
validity challenged later. Staff must use
chaperones to guard against allegations
of abuse during treatment. Such
allegations may arise because of
incomplete amnesia, disinhibition, and
impaired ability to process cues.
Because of its relative long duration of
residual effects (sedation, ataxia,
hypotension, and amnesia), lorazepam
premedication is best suited for hospital
inpatient use. People should not be
discharged from the hospital within 24
hours of receiving lorazepam
 premedication unless accompanied by a
caregiver. They should also not drive,
operate machinery, or use alcohol within
this period.
Drug and alcohol dependence – The risk
of abuse of lorazepam is increased in
dependent people.[60]
Comorbid psychiatric disorders also
increase the risk of dependence and
paradoxical adverse effects.[60]

Tolerance and dependence

Dependence typified by a withdrawal

syndrome occurs in about one-third of
individuals who are treated for longer than
four weeks with a benzodiazepine. Higher
doses and longer periods of use increase
the risk of developing a benzodiazepine
dependence. Potent benzodiazepines with
a relatively short half life, such as
lorazepam, alprazolam, and triazolam,
have the highest risk of causing a
dependence.[9] Tolerance to
benzodiazepine effects develops with
regular use. This is desirable with amnesic
and sedative effects but undesirable with
anxiolytic, hypnotic, and anticonvulsant
effects. People initially experience drastic
relief from anxiety and sleeplessness, but
symptoms gradually return, relatively soon
in the case of insomnia, but more slowly in
the case of anxiety symptoms. After four
to six months of regular benzodiazepine
use, evidence of continued efficacy
declines.

If regular treatment is continued for longer

than four to six months, dose increases
may be necessary to maintain effects, but
treatment-resistant symptoms may in fact
be benzodiazepine withdrawal
symptoms.[63] Due to the development of
tolerance to the anticonvulsant effects,
benzodiazepines are generally not
recommended for long-term use for the
management of epilepsy. Increasing the
dose may overcome tolerance, but
tolerance may then develop to the higher
dose and adverse effects may persist and
worsen. The mechanism of tolerance to
benzodiazepines is complex and involves
GABAA receptor downregulation,
alterations to subunit configuration of
GABAA receptors, uncoupling and
internalisation of the benzodiazepine
binding site from the GABAA receptor
complex as well as changes in gene
expression.[9]

The likelihood of dependence is relatively

high with lorazepam compared to other
benzodiazepines. Lorazepam's relatively
short serum half-life, its confinement
mainly to the vascular space, and its
inactive metabolite can result in interdose
withdrawal phenomena and next-dose
cravings, that may reinforce psychological
dependence. Because of its high potency,
the smallest lorazepam tablet strength of
0.5 mg is also a significant dose reduction
(in the UK, the smallest tablet strength is
1.0 mg, which further accentuates this
difficulty). To minimise the risk of
physical/psychological dependence,
lorazepam is best used only short-term, at
the smallest effective dose. If any
benzodiazepine has been used long-term,
the recommendation is a gradual dose
taper over a period of weeks, months or
longer, according to dose and duration of
use, the degree of dependence and the
individual.

Coming off long-term lorazepam use may

be more realistically achieved by a gradual
switch to an equivalent dose of diazepam
and a period of stabilization on this, and
only then initiating dose reductions. The
advantage of switching to diazepam is
that dose reductions are felt less acutely,
because of the longer half-lives (20–200
hours) of diazepam and its active
metabolites.[64]

Withdrawal
On abrupt or overly rapid discontinuation
of lorazepam, anxiety, and signs of
physical withdrawal have been observed,
similar to those seen on withdrawal from
alcohol and barbiturates. Lorazepam, as
with other benzodiazepine drugs, can
cause physical dependence, addiction, and
benzodiazepine withdrawal syndrome. The
higher the dose and the longer the drug is
taken, the greater the risk of experiencing
unpleasant withdrawal symptoms.
Withdrawal symptoms can, however, occur
from standard dosages and also after
short-term use. Benzodiazepine treatment
should be discontinued as soon as
possible via a slow and gradual dose
reduction regimen.[65] Rebound effects
often resemble the condition being
treated, but typically at a more intense
level and may be difficult to diagnose.
Withdrawal symptoms can range from
mild anxiety and insomnia to more severe
symptoms such as seizures and
psychosis. The risk and severity of
withdrawal are increased with long-term
use, use of high doses, abrupt or over-
rapid reduction, among other factors.
Short-acting benzodiazepines such as
lorazepam are more likely to cause a more
severe withdrawal syndrome compared to
longer-acting benzodiazepines.[9]
Withdrawal symptoms can occur after
taking therapeutic doses of Ativan for as
little as one week. Withdrawal symptoms
include headaches, anxiety, tension,
depression, insomnia, restlessness,
confusion, irritability, sweating, dysphoria,
dizziness, derealization, depersonalization,
numbness/tingling of extremities,
hypersensitivity to light, sound, and smell,
perceptual distortions, nausea, vomiting,
diarrhea, appetite loss, hallucinations,
delirium, seizures, tremor, stomach
cramps, myalgia, agitation, palpitations,
tachycardia, panic attacks, short-term
memory loss, and hyperthermia. It takes
about 18–36 hours for the benzodiazepine
to be removed from the body.[66] The ease
of addiction to lorazepam, (Ativan brand
was particularly cited), and its withdrawal
were brought to the attention of the British
public during the early 1980s in Esther
Rantzen's BBC TV series That's Life!, in a
feature on the drug over a number of
episodes.

Interactions

Lorazepam is not usually fatal in overdose,

but may cause fatal respiratory depression
if taken in overdose with alcohol. The
combination also causes synergistic
enhancement of the disinhibitory and
amnesic effects of both drugs, with
potentially embarrassing or criminal
consequences. Some experts advise that
people should be warned against drinking
alcohol while on lorazepam
treatment,[29][67] but such clear warnings
are not universal.[68] Synergistic adverse
effects may also occur when lorazepam is
administered with other drugs, such as
opioids or other hypnotics.[62] Lorazepam
may also interact with rifabutin.[69]
Valproate inhibits the metabolism of
lorazepam, whereas carbamazepine,
lamotrigine, phenobarbital, phenytoin, and
rifampin increase its rate of metabolism.
Some antidepressants, antiepileptic drugs
such as phenobarbital, phenytoin and
carbamazepine, sedative antihistamines,
opiates, antipsychotics and alcohol, when
taken with lorazepam may result in
enhanced sedative effects.[9]

Overdose

In cases of a suspected lorazepam

overdose, it is important to establish
whether the person is a regular user of
lorazepam or other benzodiazepines since
regular use causes tolerance to develop.
Also, one must ascertain whether other
substances were also ingested.
Signs of overdose range through mental
confusion, dysarthria, paradoxical
reactions, drowsiness, hypotonia, ataxia,
hypotension, hypnotic state, coma,
cardiovascular depression, respiratory
depression, and death.

Early management of people under alert

includes emetics, gastric lavage, and
activated charcoal. Otherwise,
management is by observation, including
of vital signs, support and, only if
necessary, considering the hazards of
doing so, giving intravenous flumazenil.
People are ideally nursed in a kind,
frustration-free environment, since, when
given or taken in high doses,
benzodiazepines are more likely to cause
paradoxical reactions. If shown sympathy,
even quite crudely feigned, people may
respond solicitously, but they may respond
with disproportionate aggression to
frustrating cues.[70] Opportunistic
counseling has limited value here, as the
person is unlikely to recall this later, owing
to drug-induced anterograde amnesia.

Detection in body fluids

Lorazepam may be quantitated in blood or
plasma to confirm poisoning in
hospitalized people, provide evidence of
an impaired driving arrest or to assist in a
medicolegal death investigation. Blood or
plasma concentrations are usually in a
range of 10–300 μg/l in persons either
receiving the drug therapeutically or in
those arrested for impaired driving.
Approximately 300–1000 μg/l is found in
people after acute overdosage.[71]
Lorazepam may not be detected by
commonly-used urine drug screenings for
benzodiazepines.[72][73]

Pharmacology
Lorazepam has anxiolytic, sedative,
hypnotic, amnesic, anticonvulsant, and
muscle relaxant properties.[74] It is a high-
potency and an intermediate-acting
benzodiazepine, and its uniqueness,[75][76]
advantages, and disadvantages are largely
explained by its pharmacokinetic
properties (poor water and lipid solubility,
high protein binding and anoxidative
metabolism to a pharmacologically
inactive glucuronide form) and by its high
relative potency (lorazepam 1 mg is equal
in effect to diazepam 10 mg).[77][78] The
biological half-life of lorazepam is 10–20
hours.[79]
Pharmacokinetics

Lorazepam is highly protein bound and is

extensively metabolized into
pharmacologically inactive metabolites.[9]
Due to its poor lipid solubility, lorazepam is
absorbed relatively slowly by mouth and is
unsuitable for rectal administration.
However, its poor lipid solubility and high
degree of protein binding (85–90%[80])
mean its volume of distribution is mainly
the vascular compartment, causing
relatively prolonged peak effects. This
contrasts with the highly lipid-soluble
diazepam, which, although rapidly
absorbed orally or rectally, soon
redistributes from the serum to other parts
of the body, in particular, body fat. This
explains why one lorazepam dose, despite
its shorter serum half-life, has more
prolonged peak effects than an equivalent
diazepam dose.[81] Lorazepam is rapidly
conjugated at its 3-hydroxy group into
lorazepam glucuronide which is then
excreted in the urine. Lorazepam
glucuronide has no demonstrable CNS
activity in animals. The plasma levels of
lorazepam are proportional to the dose
given. There is no evidence of
accumulation of lorazepam on
administration up to six months. On
regular administration, diazepam will
accumulate, since it has a longer half-life
and active metabolites, these metabolites
also have long half-lives.

Clinical example: Diazepam has long been

a drug of choice for status epilepticus; its
high lipid solubility means it gets absorbed
with equal speed whether given orally, or
rectally (nonintravenous routes are
convenient in outside hospital settings),
but diazepam's high lipid solubility also
means it does not remain in the vascular
space, but soon redistributes into other
body tissues. So, it may be necessary to
repeat diazepam doses to maintain peak
anticonvulsant effects, resulting in excess
body accumulation. Lorazepam is a
different case; its low lipid solubility
makes it relatively slowly absorbed by any
route other than intravenously, but once
injected, it will not get significantly
redistributed beyond the vascular space.
Therefore, lorazepam's anticonvulsant
effects are more durable, thus reducing
the need for repeated doses. If a person is
known to usually stop convulsing after
only one or two diazepam doses, it may be
preferable because sedative after effects
will be less than if a single dose of
lorazepam is given (diazepam
anticonvulsant/sedative effects wear off
after 15–30 minutes, but lorazepam
effects last 12–24 hours).[82] The
prolonged sedation from lorazepam may,
however, be an acceptable trade-off for its
reliable duration of effects, particularly if
the person needs to be transferred to
another facility. Although lorazepam is not
necessarily better than diazepam at
initially terminating seizures,[83] lorazepam
is, nevertheless, replacing diazepam as the
intravenous agent of choice in status
epilepticus.[84][85]

Lorazepam serum levels are proportional

to the dose administered. Giving 2 mg oral
lorazepam will result in a peak total serum
level of around 20 ng/ml around two hours
later,[80][86] half of which is lorazepam, half
its inactive metabolite, lorazepam-
glucuronide.[87] A similar lorazepam dose
given intravenously will result in an earlier
and higher peak serum level, with a higher
relative proportion of unmetabolised
(active) lorazepam.[88] On regular
administration, maximum serum levels are
attained after three days. Longer-term use,
up to six months, does not result in further
accumulation.[80] On discontinuation,
lorazepam serum levels become negligible
after three days and undetectable after
about a week. Lorazepam is metabolized
in the liver by conjugation into inactive
lorazepam-glucuronide. This metabolism
does not involve liver oxidation, so is
relatively unaffected by reduced liver
function. Lorazepam-glucuronide is more
water-soluble than its precursor, so gets
more widely distributed in the body,
leading to a longer half-life than
lorazepam. Lorazepam-glucuronide is
eventually excreted by the kidneys,[80] and,
because of its tissue accumulation, it
remains detectable, particularly in the
urine, for substantially longer than
lorazepam.

Pharmacodynamics
Relative to other benzodiazepines,
lorazepam is thought to have high affinity
for GABA receptors,[89] which may also
explain its marked amnesic effects.[29] Its
main pharmacological effects are the
enhancement of the effects of the
neurotransmitter GABA at the GABAA
receptor.[9] Benzodiazepines, such as
lorazepam, enhance the effects of GABA
at the GABAA receptor via increasing the
frequency of opening of the chloride ion
channel on the GABAA receptors; which
results in the therapeutic actions of
benzodiazepines. They, however, do not on
their own enhance the GABAA receptors,
but require the neurotransmitter GABA to
be present. Thus, the effect of
benzodiazepines is to enhance the effects
of the neurotransmitter GABA.[9][62]

The magnitude and duration of lorazepam

effects are dose-related, meaning larger
doses have stronger and longer-lasting
effects, because the brain has spare
benzodiazepine drug receptor capacity,
with single, clinical doses leading only to
an occupancy of some 3% of the available
receptors.[90]

The anticonvulsant properties of

lorazepam and other benzodiazepines
may be, in part or entirely, due to binding to
voltage-dependent sodium channels rather
than benzodiazepine receptors. Sustained
repetitive firing seems to get limited, by
the benzodiazepine effect of slowing
recovery of sodium channels from
inactivation in mouse spinal cord cell
cultures.[91]

Physical properties and

formulations
0.5 mg tablets of the Ativan brand of lorazepam

Pure lorazepam is an almost white powder

that is nearly insoluble in water and oil. In
medicinal form, it is mainly available as
tablets and a solution for injection, but, in
some locations, it is also available as a
skin patch, an oral solution, and a
sublingual tablet.

Lorazepam tablets and syrups are

administered by mouth only. Lorazepam
tablets of the Ativan brand also contain
lactose, microcrystalline cellulose,
polacrilin, magnesium stearate, and
coloring agents (indigo carmine in blue
tablets and tartrazine in yellow tablets).
Lorazepam for injection formulated with
polyethylene glycol 400 in propylene glycol
with 2.0% benzyl alcohol as preservative.

Lorazepam injectable solution is

administered either by deep intramuscular
injection or by intravenous injection. The
injectable solution comes in 1 ml
ampoules containing 2 or 4 mg of
lorazepam. The solvents used are
polyethylene glycol 400 and propylene
glycol. As a preservative, the injectable
solution contains benzyl alcohol.[92]
Toxicity from propylene glycol has been
reported in the case of a person receiving
a continuous lorazepam infusion.[93]
Intravenous injections should be given
slowly and they should be closely
monitored for side effects, such as
respiratory depression, hypotension, or
loss of airway control.

Peak effects roughly coincide with peak

serum levels,[86] which occur 10 minutes
after intravenous injection, up to 60
minutes after intramuscular injection, and
90 to 120 minutes after oral
administration,[80][86] but initial effects will
be noted before this. A clinically relevant
lorazepam dose will normally be effective
for six to 12 hours, making it unsuitable for
regular once-daily administration, so it is
usually prescribed as two to four daily
doses when taken regularly, but this may
be extended to five or six, especially in the
case of elderly people who could not
handle large doses at once.

Topical formulations of lorazepam, while

used as treatment for nausea especially in
people in hospice, ought not be used in
this form and for this purpose as they have
not been proven effective.[94]

History
1987 advertisement. "In a world where certainties are

few...no wonder Ativan is prescribed by so many caring

clinicians."

Historically, lorazepam is one of the

"classical" benzodiazepines. Others
include diazepam, clonazepam, oxazepam,
nitrazepam, flurazepam, bromazepam, and
clorazepate.[95] Lorazepam was first
introduced by Wyeth Pharmaceuticals in
1977 under the brand names Ativan and
Temesta.[96] The drug was developed by
President of Research, D.J. Richards.
Wyeth's original patent on lorazepam is
expired in the United States, but the drug
continues to be commercially viable.

Society and culture

Recreational use

Lorazepam is also used for other

purposes, such as recreational use,
wherein the drug is taken to achieve a
high, or when the drug is continued long-
term against medical advice.[97]
In addition to recreational use,
flunitrazepam, another member of the
benzodiazepine family, may be taken to
facilitate criminal activity.[51] The
anterograde amnesia and sedative-
hypnotic effects of benzodiazepines such
as lorazepam are sometimes used by
predators on unwitting victims as date
rape drugs, or for the purpose of robbery.

A large-scale, nationwide, U.S. government

study of pharmaceutical-related
emergency department (ED) visits by
SAMHSA found sedative-hypnotics are the
pharmaceuticals most frequently used
outside of their prescribed medical
purpose in the United States, with 35% of
drug-related emergency department visits
involving sedative-hypnotics. In this
category, benzodiazepines are most
commonly used. Males and females use
benzodiazepines for nonmedical purposes
equally. Of drugs used in attempted
suicide, benzodiazepines are the most
commonly used pharmaceutical drugs,
with 26% of attempted suicides involving
them. Lorazepam was the third-most-
common benzodiazepine used outside of
prescription in these ER visit statistics.[98]

Legal status
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.[99] It is a Schedule IV drug
under the Controlled Drugs and
Substances Act in Canada. In the United
Kingdom, it is a Class C, Schedule 4
Controlled Drug under the Misuse of Drugs
Regulations 2001.[100]

Pricing

In 2000, the U.S. drug company Mylan

agreed to pay $147 million to settle
accusations by the FTC that they had
raised the price of generic lorazepam by
2600% and generic clorazepate by 3200%
in 1998 after having obtained exclusive
licensing agreements for certain
ingredients.[101]

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External links
inchem.org – Lorazepam data sheet
benzo.org.uk – Ashton H.
Benzodiazepines: How They Work And
How to Withdraw. August 2002 (The
"Ashton Manual") .
U.S. National Library of Medicine: Drug
Information Portal – Lorazepam
Retrieved from
"https://en.wikipedia.org/w/index.php?
title=Lorazepam&oldid=913852799"

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