Lorazepam 1

LorazepamNot to be confused with Loprazolam.

Lorazepam

Systematic (IUPAC) name

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

Clinical data

Trade names Ativan and others

AHFS/Drugs.com monograph [1]

MedlinePlus a682053 [2]

Pregnancy cat. C (AU) D (US)

Legal status Prescription Only (S4) (AU) Schedule IV (CA) CD (Benz) POM (UK) Schedule IV (US)

Dependence liability Moderate

Routes Oral, intramuscular, intravenous, sublingual, and transdermal

Pharmacokinetic data

Bioavailability 85% of oral dose

Metabolism Hepatic glucuronidation

Half-life 9–16 hours

Excretion Renal

Identifiers

CAS number 846-49-1 [3] 

ATC code N05BA06 [4]

PubChem CID 3958 [5]

DrugBank DB00186 [6]

ChemSpider 3821 [7] 

UNII O26FZP769L [8] 

Lorazepam 2

KEGG D00365 [9] 

ChEMBL CHEMBL580 [10] 

Synonyms O-Chloroxazepam, L-Lorazepam Acetate

Chemical data

Formula C15H10Cl2N2O2

Mol. mass 321.2 g/mol

 (what is this?)   (verify) [11]

Lorazepam (trademarked as Ativan or Orfidal) is a high-potency, intermediate-duration, 3-hydroxy benzodiazepinedrug, often used to treat anxiety disorders.[12] Lorazepam has all six intrinsic benzodiazepine effects: anxiolysis,anterograde amnesia, sedation/hypnosis, anti-seizure, antiemesis (anti-nausea/vomiting) and muscle relaxation.Lorazepam is used for the short-term treatment of anxiety, insomnia, acute seizures including status epilepticus, andsedation of hospitalized patients, as well as sedation of aggressive patients. Lorazepam is also the most commonbenzodiazepine used to decrease the likelihood of agitation and seizures in patients who have overdosed on stimulantdrugs.[13]

After its introduction in 1977, Lorazepam's principal use was in treating anxiety. Among benzodiazepines,Lorazepam has a relatively high physical addiction potential. Lorazepam also has misuse potential; the main types ofmisuse are for recreational purposes or continued use against medical advice. Its sedative-hypnotic and anterogradeamnesic properties are sometimes used for criminal purposes in a manner similar to GHB.Long-term effects of benzodiazepines include tolerance, dependence, a benzodiazepine withdrawal syndrome, andcognitive impairments which may not completely reverse after cessation of treatment; however, for most patients,cognitive impairment is not severe. Withdrawal symptoms can range from anxiety and insomnia to seizures andpsychosis. Due to tolerance and dependence, lorazepam is recommended for short-term use, up to two to four weeksonly. Adverse effects, including anterograde amnesia, depression and paradoxical effects such as excitement orworsening of seizures, may occur. Children and the elderly are more sensitive to the adverse effects ofbenzodiazepines. Lorazepam impairs body balance and standing steadiness and is associated with falls and hipfractures in the elderly.

Medical usesLorazepam has relatively potent anxiolytic effects and its best-known indication is the short-term management ofsevere anxiety; the FDA advises against use of benzodiazepines such as lorazepam for longer than four weeks. It isfast acting, and useful in treating fast onset panic anxiety.Lorazepam has strong sedative/hypnotic effects, and the duration of clinical effects from a single dose makes it anappropriate choice for the short-term treatment of insomnia, in particular in the presence of severe anxiety. It has afairly short duration of action.[14] Withdrawal symptoms, including rebound insomnia and rebound anxiety, mayoccur after only seven days' administration of lorazepam.Lorazepam is sometimes used for individuals receiving mechanical ventilation. However, in critically ill patients,propofol has been found to be superior to lorazepam both in effectiveness and overall cost; as a result, the use ofpropofol for this indication is now encouraged, whereas the use of lorazepam is discouraged.Its relatively potent amnesic effect, with its anxiolytic and sedative effects, makes lorazepam useful as premedication. It is given before a general anaesthetic to reduce the amount of anaesthetic agent 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. Oral lorazepam is given 90 to 120 minutes before procedures, and intravenous

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lorazepam as late as 10 minutes before procedures. Lorazepam is sometimes used as an alternative to midazolam inpalliative sedation. In intensive care units lorazepam is sometimes used to produce anxiolysis, hypnosis, andamnesia.Intravenous diazepam or lorazepam are first-line treatments for convulsive status epilepticus. Lorazepam is moreeffective than diazepam in the treatment of status epilepticus. However, phenobarbital has a superior success ratecompared to lorazepam and other drugs, at least in the elderly.Its marked anticonvulsant properties, and its pharmacokinetic profile, make intravenous lorazepam a reliable agentfor terminating acute seizures, but it has relatively prolonged sedation after-effects. Oral lorazepam, and otherbenzodiazepines, have a role in long-term prophylactic treatment of resistant forms of petit mal epilepsy, but not asfirst-line therapies, mainly because of the development of tolerance to their effects.Lorazepam's anticonvulsant and CNS depressant properties are useful for the treatment and prevention of alcoholwithdrawal syndrome. In this setting, impaired liver function is not a hazard with lorazepam, since lorazepam doesnot require oxidation, hepatic or otherwise, for its metabolism.Lorazepam is sometimes used as an alternative to haloperidol when there is the need for rapid sedation of violent oragitated individuals, but haloperidol plus promethazine is preferred due to better effectiveness and due tolorazepam's adverse effects on respiratory function. However, adverse effects such as behavioural disinhibition maymake benzodiazepines inappropriate for some acutely psychotic patients. Acute delirium is sometimes treated withlorazepam, but as it can cause paradoxical effects, it is preferably given together with haloperidol. Lorazepam isabsorbed relatively slowly if given intramuscularly, a common route in restraint situations.Catatonia with inability to speak is responsive and sometimes controlled with a single 2-mg oral, or slow intravenousdose of lorazepam. Symptoms may recur and treatment for some days may be necessary. Catatonia due to abrupt ortoo rapid withdrawal from benzodiazepines, as part of the benzodiazepine withdrawal syndrome, should also respondto lorazepam treatment. As lorazepam can have paradoxical effects, haloperidol is sometimes given concomitantly.It is sometimes used in chemotherapy as an adjunct to antiemetics for treating anticipatory nausea and vomiting, i.e.nausea and vomiting caused or worsened by psychological sensitization to the thought of being sick. It is also usedas adjunct therapy for cyclic vomiting syndrome.Lorazepam is also used to treat acute symptoms of vertigo and dizziness for people with Ménière'sdisease.Wikipedia:Citation needed

Formulation

0.5-mg tablets of the Ativan brand of lorazepam

Pure lorazepam is an almost white powder that is nearly insoluble inwater and oil. In medicinal form, it is mainly available as tablets and asolution for injection, but, in some locations, it is also available as askin 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, andcolouring agents (indigo carmine—E132—in blue tablets andtartrazine—E102— in yellow tablets). Lorazepam for injectionformulated with polyethylene glycol 400 in propylene glycol with2.0% benzyl alcohol as preservative.

Lorazepam injectable solution is administered either by deepintramuscular injection or by intravenous injection. The injectable

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solution comes in 1 ml ampoules containing 2 or 4 mg of lorazepam. The solvents used are polyethylene glycol 400and propylene glycol. As a preservative, the injectable solution contains benzyl alcohol.[15] Toxicity from propyleneglycol has been reported in the case of a patient receiving a continuous lorazepam infusion. Intravenous injectionsshould be given slowly and patients closely monitored for side effects, such as respiratory depression, hypotension,or loss of airway control.Peak effects roughly coincide with peak serum levels, which occur 10 minutes after intravenous injection, up to 60minutes after intramuscular injection, and 90 to 120 minutes after oral administration, but initial effects will be notedbefore this. A clinically relevant lorazepam dose will normally be effective for six to 12 hours, making it unsuitablefor regular once-daily administration, so it is usually prescribed as two to four daily doses when taken regularly, butthis may be extended to five or six, especially in the case of elderly patients who could not handle large doses atonce.Topical formulations of lorazepam, while used as treatment for nausea especially in patients in hospice, ought not beused in this form and for this purpose as they have not been proven effective.[16]

Adverse effectsAny of the five intrinsic benzodiazepine effects possessed by lorazepam (sedative/hypnotic, muscle relaxant,anxiolytic, amnesic, and anticonvulsant) may be considered as adverse or side effects if unwanted. Adverse effectscan include sedation and hypotension; the effects of lorazepam are increased in combination with other CNSdepressant drugs. Other adverse effects include confusion, ataxia, anterograde amnesia and hangover effects. Withlong-term use of benzodiazepines, it is unclear whether cognitive impairments fully return to normal after cessationof therapy; cognitive deficits persist for at least six months after withdrawal, but longer than six months may berequired for recovery of cognitive function. Lorazepam appears to have more profound adverse effects on memorythan other benzodiazepines; it impairs both explicit and implicit memory. In the elderly, falls may occur as a result ofbenzodiazepines. Adverse effects are more common in the elderly, and they appear at lower doses than in youngerpatients. Benzodiazepines can cause or worsen depression. Paradoxical effects can also occur, such as worsening ofseizures, or paradoxical excitement; paradoxical excitement is more likely to occur in the elderly, children, thosewith a history of alcohol abuse and in people with a history of aggression or anger problems. Lorazepam's effects aredose-dependent, meaning the higher the dose, the stronger the effects (and side effects) will be. Using the smallestdose needed to achieve desired effects lessens the risk of adverse effects.Sedation is the side effect for which most patients complain. In a group of around 3,500 patients 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. Cognitiveimpairment, behavioural disinhibition and respiratory depression as well as hypotension may also occur.• 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 as more common withlorazepam than other benzodiazepines. Paradoxical effects are more likely to occur with higher doses, in patientswith pre-existing personality disorders and those with a psychiatric illness. Frustrating stimuli may trigger suchreactions, though the drug may have been prescribed to help the patient cope with such stress and frustration inthe first place. As paradoxical effects appear to be dose-related, they usually subside on dose reduction or oncomplete withdrawal of lorazepam.

• Suicidality: Benzodiazepines may sometimes unmask suicidal ideation in depressed patients, possibly throughdisinhibition or fear reduction. The concern is that, though relatively nontoxic in themselvesWikipedia:Verifiability, benzodiazepines may inadvertently become facilitators of suicidalbehaviour.Wikipedia:Verifiability Lorazepam should, therefore, not be prescribed in high doses or as the soletreatment in depression, but only with an appropriate antidepressant Wikipedia:Citing sources.

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• Amnesic effects: Among benzodiazepines, lorazepam has relatively strong amnesic effects, but patients soondevelop tolerance to this with regular use. To avoid amnesia (or excess sedation) being a problem, the initial totaldaily lorazepam dose should not exceed 2 mg. This also applies to use for night sedation. Five participants in asleep study were prescribed lorazepam 4 mg at night, and the next evening, three subjects unexpectedlyvolunteered memory gaps for parts of that day, an effect that subsided completely after two to three days' use.Amnesic effects cannot be estimated from the degree of sedation present, since the two effects are unrelated.

High-dose or prolonged parentally administered lorazepam is sometimes associated with propylene glycolintoxication.

ContraindicationsLorazepam 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 useto relieve anxiety associated with acute severe asthma. The anxiolytic effects may also be detrimental to apatient'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 otherpsychoactive 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, dueto failure of gross muscle movement coordination, most evident on standing and walking. It is the classic way inwhich acute alcohol intoxication may affect a person. Benzodiazepines should not be administered toalready-ataxic patients.

• Acute narrow-angle glaucoma – Lorazepam has pupil-dilating effects, which may further interfere with thedrainage of aqueous humour 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 mayfurther reduce the patient's ability to protect his or her airway during sleep.

• Myasthenia gravis – This condition is characterised by muscle weakness, so a muscle relaxant such as lorazepammay exacerbate symptoms.

• Pregnancy and breast feeding – Lorazepam belongs to the Food and Drug Administration (FDA) pregnancycategory D, which means it is likely to cause harm to the developing baby, if taken during the first trimester ofpregnancy. Evidence is inconclusive whether lorazepam, if taken early in pregnancy, results in reducedintelligence, neurodevelopmental problems, physical malformations in cardiac or facial structure, or othermalformations in some newborns. Lorazepam given to pregnant women antenatally may cause floppy infantsyndrome in the neonate, or respiratory depression necessitating ventilation. Regular lorazepam use during latepregnancy (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, andimpaired metabolic responses to cold stress. Symptoms of floppy infant syndrome and the neonatalbenzodiazepine withdrawal syndrome have been reported to persist from hours to months after birth. Lorazepammay also inhibit foetal liver bilirubin glucuronidation, leading to neonatal jaundice. Lorazepam is present inbreast milk, so caution must be exercised about breast feeding.

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Special groups and situations• 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 theelderly and debilitated patients in whom the risk of oversedation is greater. Long-term therapy may lead tocognitive deficits, especially in the elderly, which may only be partially reversible. The elderly metabolisebenzodiazepines more slowly than younger people and are more sensitive to the adverse effects ofbenzodiazepines compared to younger individuals even at similar plasma levels. Additionally, the elderly tend totake more drugs which may interact or enhance the effects of benzodiazepines. Benzodiazepines, includinglorazepam, have been found to increase the risk of falls and fractures in the elderly. As a result, dosagerecommendations for the elderly are about half of those used in younger individuals and used for no longer thantwo weeks. Lorazepam may also be slower to clear in the elderly, leading potentially to accumulation andenhanced effects. Lorazepam, similar to other benzodiazepines and nonbenzodiazepines, causes impairments inbody balance and standing steadiness in individuals who wake up at night or the next morning. Falls and hipfractures are frequently reported. The combination with alcohol increases these impairments. Partial, butincomplete, tolerance develops to these impairments.

• Liver or kidney failure – Lorazepam may be safer than most benzodiazepines in patients with impaired liverfunction. Like oxazepam, it does not require hepatic oxidation, but only hepatic glucuronidation intolorazepam-glucuronide. Therefore, impaired liver function is unlikely to result in lorazepam accumulation to anextent causing adverse reactions. Similarly renal disease has minimal effects on lorazepam levels.

• Surgical premedication – Informed consent given only after receiving lorazepam premedication could have itsvalidity challenged later. Staff must use chaperones to guard against allegations of abuse during treatment. Suchallegations may arise because of incomplete amnesia, disinhibition, and impaired ability to process cues. Becauseof its relative long duration of residual effects (sedation, ataxia, hypotension, and amnesia), lorazepampremedication is best suited for hospital inpatient use. Patients should not be discharged from the hospital within24 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 patients.• Comorbid psychiatric disorders also increase the risk of dependence and paradoxical adverse effects.

Tolerance and dependenceDependence typified by a withdrawal syndrome occurs in about one-third of individuals who are treated for longerthan four weeks with a benzodiazepine. Higher doses and longer periods of use increase the risk of developing abenzodiazepine dependence. Potent benzodiazepines, such as lorazepam, alprazolam, and triazolam, have the highestrisk of causing a dependence. Tolerance to benzodiazepine effects develops with regular use. This is desirable withamnesic and sedative effects, but undesirable with anxiolytic, hypnotic, and anticonvulsant effects. Patients at firstexperience drastic relief from anxiety and sleeplessness, but symptoms gradually return, relatively soon in the caseof insomnia, but more slowly in the case of anxiety symptoms. After four to six months of regular benzodiazepineuse, evidence of continued efficacy declines. If regular treatment is continued for longer than this, dose increasesmay be necessary to maintain effects, but treatment-resistant symptoms may in fact be benzodiazepine withdrawalsymptoms. Due to the development of tolerance to the anticonvulsant effects, benzodiazepines are generally notrecommended for long-term use for the management of epilepsy. Increasing the dose may overcome tolerance, buttolerance may then develop to the higher dose and adverse effects may persist and worsen. The mechanism oftolerance to benzodiazepines is complex and involves GABAA receptor downregulation, alterations to subunitconfiguration of GABAA receptors, uncoupling and internalisation of the benzodiazepine binding site from theGABAA receptor complex as well as changes in gene expression.

Lorazepam 7

The likelihood of dependence is relatively high with lorazepam compared to other benzodiazepines. Lorazepam'srelatively short serum half-life, its confinement mainly to the vascular space, and its inactive metabolite, results ininterdose withdrawal phenomena and next-dose cravings. This may reinforce psychological dependence. Because ofits high potency, the smallest lorazepam tablet strength of 0.5 mg is also a significant dose reduction (in the UK, thesmallest tablet strength is 1.0 mg, which further accentuates this difficulty). To minimise the risk ofphysical/psychological dependence, lorazepam is best used only short-term, at the smallest effective dose. If anybenzodiazepine has been used long-term, the recommendation is a gradual dose taper over a period of weeks, monthsor longer, according to dose and duration of use, degree of dependence and the individual. Coming off long-termlorazepam use may be more realistically achieved by a gradual switch to an equivalent dose of diazepam, a period ofstabilization on this and only then initiating dose reductions. The advantage of switching to diazepam is dosereductions are felt less acutely, because of the longer half-lives (20–200 hours) of diazepam and its activemetabolites.

WithdrawalOn abrupt or overly rapid discontinuation of lorazepam, anxiety and signs of physical withdrawal have beenobserved, similar to those seen on withdrawal from alcohol and barbiturates. Lorazepam, as with otherbenzodiazepine drugs, can cause physical dependence, addiction, and benzodiazepine withdrawal syndrome. Thehigher the dose and the longer the drug is taken, the greater the risk of experiencing unpleasant withdrawalsymptoms. 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.Rebound effects often resemble the condition being treated, but typically at a more intense level and may be difficultto diagnose. Withdrawal symptoms can range from mild anxiety and insomnia to more severe symptoms such asseizures and psychosis. The risk and severity of withdrawal is 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 likelyto cause a more severe withdrawal syndrome compared to longer-acting benzodiazepines.Withdrawal symptoms can occur after taking therapeutic doses of Ativan for as little as one week. Withdrawalsymptoms 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, andhyperthermia. It takes about 18–36 hours for the benzodiazepine to be removed from the body. The ease of addictionto lorazepam, (Ativan brand was particularly cited), and its withdrawal were brought to the attention of the Britishpublic during the early 1980s in Esther Rantzen's BBC TV series That's Life!, in a feature on the drug over a numberof episodes.

InteractionsLorazepam is not usually fatal in overdose, but may cause fatal respiratory depression if taken in overdose withalcohol. 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 patients should be warned againstdrinking alcohol while on lorazepam treatment, but such clear warnings are not universal. Synergistic adverse effectsmay also occur when lorazepam is administered with other drugs, such as opioids or other hypnotics. Lorazepammay also interact with rifabutin. 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.

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OverdoseSee also: Benzodiazepine overdoseIn cases of a suspected lorazepam overdose, it is important to establish whether the patient is a regular user oflorazepam or other benzodiazepines, since regular use causes tolerance to develop. Also, one must ascertain whetherother drugs 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 alert patients includes emetics, gastric lavage, and activated charcoal. Otherwise, managementis by observation, including of vital signs, support and, only if necessary, considering the hazards of doing so, givingintravenous flumazenil.Patients are ideally nursed in a kind, nonfrustrating environment, since, when given or taken in high doses,benzodiazepines are more likely to cause paradoxical reactions. If shown sympathy, even quite crudely feigned,patients may respond solicitously, but they may respond with disproportionate aggression to frustrating cues.Opportunistic counseling has limited value here, as the patient is unlikely to recall this later, owing to drug-inducedanterograde amnesia.

Detection in body fluidsLorazepam may be quantitated in blood or plasma to confirm a diagnosis of poisoning in hospitalized patients,provide evidence in an impaired driving arrest or to assist in a medicolegal death investigation. Blood or plasmaconcentrations are usually in a range of 10-300 ug/l in persons either receiving the drug therapeutically or in thosearrested for impaired driving. Approximately 300-1000 ug/l is found in victims of acute overdosage.

PharmacologyLorazepam has anxiolytic, sedative, hypnotic, amnesic, anticonvulsant, and muscle relaxant properties. It is ahigh-potency and an intermediate-acting benzodiazepine, and its uniqueness, advantages, and disadvantages arelargely explained by its pharmacokinetic properties (poor water and lipid solubility, high protein binding andanoxidative metabolism to a pharmacologically inactive glucuronide form) and by its high relative potency(lorazepam 1–2 mg is equal in effect to diazepam 10 to 20 mg). The half-life of lorazepam is 10–20 hours.

PharmacokineticsLorazepam is highly protein bound and is extensively metabolised into pharmacologically inactive metabolites. Dueto its poor lipid solubility, lorazepam is absorbed relatively slowly by mouth and is unsuitable for rectaladministration. However, its poor lipid solubility and high degree of protein binding (85-90%) mean its volume ofdistribution is mainly the vascular compartment, causing relatively prolonged peak effects. This contrasts with thehighly lipid-soluble diazepam, which, although rapidly absorbed orally or rectally, soon redistributes from the serumto other parts of the body, in particular body fat. This explains why one lorazepam dose, despite its shorter serumhalf-life, has more prolonged peak effects than an equivalent diazepam dose. Ativan (lorazepam) is rapidlyconjugated at its 3-hydroxy group into lorazepam glucuronide which is then excreted in the urine. Lorazepamglu-curonide has no demonstrable CNS activity in animals. The plasma levels of lorazepam are proportional to thedose given. There is no evidence of accumulation of lorazepam on administration up to six months. On regularadministration, diazepam will accumulate, since it has a longer half-life and active metabolites, these metabolitesalso 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

Lorazepam 9

redistributes into other body tissues. So, it may be necessary to repeat diazepam doses to maintain peakanticonvulsant effects, resulting in excess body accumulation. Lorazepam is a different case; its low lipid solubilitymakes it relatively slowly absorbed by any route other than intravenously, but once injected, it will not getsignificantly redistributed beyond the vascular space. Therefore, lorazepam's anticonvulsant effects are more durable,thus reducing the need for repeated doses. If a patient is known to usually stop convulsing after only one or twodiazepam doses, it may be preferable because sedative after effects will be less than if a single dose of lorazepam isgiven (diazepam anticonvulsant/sedative effects wear off after 15–30 minutes, but lorazepam effects last 12–24hours). The prolonged sedation from lorazepam may, however, be an acceptable trade-off for its reliable duration ofeffects, particularly if the patient needs to be transferred to another facility. Although lorazepam is not necessarilybetter than diazepam at initially terminating seizures, lorazepam is, nevertheless, replacing diazepam as theintravenous agent of choice in status epilepticus.Lorazepam serum levels are proportional to the dose administered. Giving 2 mg oral lorazepam will result in a peaktotal serum level of around 20 ng/ml around two hours later, half of which is lorazepam, half its inactive metabolite,lorazepam-glucuronide. A similar lorazepam dose given intravenously will result in an earlier and higher peak serumlevel, with a higher relative proportion of unmetabolised (active) lorazepam. On regular administration, maximumserum levels are attained after three days. Longer-term use, up to six months, does not result in further accumulation.On discontinuation, lorazepam serum levels become negligible after three days and undetectable after about a week.Lorazepam is metabolised in the liver by conjugation into inactive lorazepam-glucuronide. This metabolism does notinvolve hepatic oxidation, so is relatively unaffected by reduced liver function. Lorazepam-glucuronide is morewater-soluble than its precursor, so gets more widely distributed in the body, leading to a longer half-life thanlorazepam. Lorazepam-glucuronide is eventually excreted by the kidneys, and, because of its tissue accumulation, itremains detectable, particularly in the urine, for substantially longer than lorazepam.

PharmacodynamicsRelative to other benzodiazepines, lorazepam is thought to have high affinity for GABA receptors, which may alsoexplain its marked amnesic effects. Its main pharmacological effects are the enhancement of the effects of GABA atthe GABAA receptor. Benzodiazepines, such as lorazepam, enhance the effects of GABA at the GABAA receptor viaincreasing the frequency of opening of the chloride ion channel on the GABAA receptors; which results in thetherapeutic actions of benzodiazepines. They, however, do not on their own enhance the GABAA receptors, butrequire the neurotransmitter GABA to be present. Thus, the effect of benzodiazepines is to enhance the effects of theneurotransmitter GABA.The magnitude and duration of lorazepam effects are dose-related, meaning larger doses have stronger andlonger-lasting effects, because the brain has spare benzodiazepine drug receptor capacity, with single, clinical dosesleading only to an occupancy of some 3% of the available receptors.The anticonvulsant properties of lorazepam and other benzodiazepines may be, in part or entirely, due to binding tovoltage-dependent sodium channels rather than benzodiazepine receptors. Sustained repetitive firing seems to getlimited, by the benzodiazepine effect of slowing recovery of sodium channels from inactivation in mouse spinal cordcell cultures.

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ChemistryLorazepam is synthesized according to a scheme containing some of the same elements for the synthesis ofchlordiazepoxide and oxazepam.1. 2-amino-2′,5-dichlorobenzophenone is reacted with hydroxylamine.2. The intermediate oxime is then reacted with chloracetyl chloride, and upon heterocyclization,

6-chloro-2-chlormethyl-4-(2′-chlorophenyl)quinazolin-3-oxide is formed.3. The above product is reacted with methylamine, as in the case of chlordiazepoxide, this leads to rearrangement

and a ring expansion, forming 7-chloro-2-methylamino-5-(2′-chlorphenyl)-3H-1,4-benzodiazepin-4-oxide.4. T he resulting benzodiazepin-4-oxide undergoes acetylation by acetic anhydride at the secondary nitrogen atom,

and is further hydrolyzed by hydrochloric acid into 7-chloro-5-(2′-chlorophenyl)-1,2-dihydro-3H-1,4-benzodiazepin-2-on-4-oxide.

5. Reaction of the above product with acetic anhydride leads to a Polonovski-type rearrangement reaction, giving a3-acetoxylated benzodiazepine, 7-chloro-1,3-dihydro-3-acetoxy-5-(2′-chlorphenyl)-2H-benzodiazepin-2-one.

6.6. Hydrolysis of the above product forms the desired product lorazepam.

Sources:[17][18][19][20][21]

HistoryHistorically, lorazepam is one of the "classical" benzodiazepines. Others include diazepam, clonazepam, oxazepam,nitrazepam, flurazepam, bromazepam and clorazepate. Lorazepam was first introduced by Wyeth Pharmaceuticals in1977 under the brand names Ativan and Temesta. 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 commerciallyviable. As a measure of its ongoing success, it has been marketed under more than 70 brand names since then:Almazine, Alzapam, Anxiedin, Anxira, Anzepam, Aplacasse, Aplacassee, Apo-Lorazepam, Aripax, Azurogen,Bonatranquan, Bonton, Control, Donix, Duralozam, Efasedan, Emotion, Emotival, Idalprem, Kalmalin, Larpose,Laubeel, Lopam, Lorabenz, Loram, Lorans, Lorapam, Lorat, Lorax, Lorazene, Lorazep, Lorazepam, Lorazin,Lorafen (PL), Lorazon, Lorenin, Loresta, Loridem, Lorivan, Lorsedal, Lorzem, Lozepam, Merlit, Nervistop L,Nervistopl, NIC, Novhepar, Novolorazem, Orfidal, Piralone, Placidia, Placinoral, Punktyl, Quait, Renaquil,Rocosgen, Securit, Sedarkey, Sedatival, Sedizepan, Sidenar, Silence, Sinestron, Somnium, Stapam, Tavor, Titus,Tolid, Tranqil, Tranqipam, Trapax, Trapaxm, Trapex, Upan, Wintin, and Wypax.In 2000, the U.S. drug company Mylan agreed to pay $147 million to settle accusations by the FTC that they hadraised the price of generic lorazepam by 2600% and generic clorazepate by 3200% in 1998 after having obtainedexclusive licensing agreements for certain ingredients.

Lorazepam 11

Recreational useSee also: Nonmedical benzodiazepine drug useLorazepam is also used for other purposes, such as recreational use, wherein the drug is taken to achieve a high, orwhen the drug is continued long-term against medical advice.In addition to recreational use, benzodiazepines may be diverted and used to facilitate crime: Criminals may takethem to deliberately seek disinhibition before committing crimes (which increases their potential for violence). Theanterograde amnesia and sedative-hypnotic effects of benzodiazepines such as lorazepam are sometimes used bypredators 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 room (ER) visits bySAMHSA found sedative-hypnotics are the pharmaceuticals most frequently used outside of their prescribed medicalpurpose in the United States, with 35% of drug-related emergency room visits involving sedative-hypnotics. In thiscategory, benzodiazepines are most commonly used. Males and females use benzodiazepines for nonmedicalpurposes equally. Of drugs used in attempted suicide, benzodiazepines are the most commonly used pharmaceuticaldrugs, with 26% of attempted suicides involving them. Lorazepam was the third-most-common benzodiazepine usedoutside of prescription in these ER visit statistics.

Legal statusLorazepam is a Schedule IV drug under the Controlled Substances Act in the U.S. and internationally under theUnited Nations Convention on Psychotropic Substances. It is a Schedule IV drug under the Controlled Drugs andSubstances Act in Canada. In the United Kingdom, it is a Class C, Schedule 4 Controlled Drug under the Misuse ofDrugs Regulations 2001.

References[1] http:/ / www. drugs. com/ monograph/ lorazepam. html[2] http:/ / www. nlm. nih. gov/ medlineplus/ druginfo/ meds/ a682053. html[3] http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2009/ MB_cgi?term=846-49-1& rn=1[4] http:/ / www. whocc. no/ atc_ddd_index/ ?code=N05BA06[5] http:/ / pubchem. ncbi. nlm. nih. gov/ summary/ summary. cgi?cid=3958[6] http:/ / www. drugbank. ca/ drugs/ DB00186[7] http:/ / www. chemspider. com/ Chemical-Structure. 3821. html[8] http:/ / fdasis. nlm. nih. gov/ srs/ srsdirect. jsp?regno=O26FZP769L[9] http:/ / www. kegg. jp/ entry/ D00365[10] https:/ / www. ebi. ac. uk/ chembldb/ index. php/ compound/ inspect/ CHEMBL580[11] http:/ / en. wikipedia. org/ w/ index. php?title=Special:ComparePages& rev1=419619495& page2=Lorazepam[12] USA-NIH Medline Plus information (https:/ / www. nlm. nih. gov/ medlineplus/ druginfo/ meds/ a682053. html#why)[13][13] Ellinwood, E.H., Jr. Emergency treatment of adverse reactions to CNS stimulants. A Treatment Manual for Acute Drug Abuse Emergencies.

DHEW Pub. No. (ADM) 76-230. Rockville, MD: Alcohol, Drug Abuse and Mental Health Administration, 1975.[14][14] (Venable and Aschenbrenner 2009)[15] baxter.com - Lorazepam Injection Data Sheet (http:/ / www. baxter. com/ products/ anesthesia/ anesthetic_pharmaceuticals/ downloads/

ativan. pdf)[16][16] , which cites[17][17] S.C. Bell, (1965)[18][18] American Home Products Corp., (1962)[19][19] S.C. Bell, (1967)[20][20] S.C. Bell, (1967)[21][21] S.J. Childress, M.I. Gluckman, J. Pharm. Sci., 53, 577 (1964)

Lorazepam 12

External links• inchem.org - Lorazepam data sheet (http:/ / www. inchem. org/ documents/ pims/ pharm/ pim223. htm)• rxlist.com - Lorazepam data sheet (http:/ / www. rxlist. com/ cgi/ generic/ loraz. htm)• drugs.com - Lorazepam data sheet (http:/ / www. drugs. com/ lorazepam. html)• baxter.com - Lorazepam Injection Data Sheet (http:/ / www. baxter. com/ products/ anesthesia/

anesthetic_pharmaceuticals/ downloads/ ativan. pdf)• NZ medsafe.govt.nz - Lorzem Data Sheet (http:/ / www. medsafe. govt. nz/ Profs/ Datasheet/ l/ Lorzemtab. htm)• benzo.org.uk - Genus/Wyeth 1998 UK Lorazepam Data Sheet (http:/ / www. benzo. org. uk/ lorazepam. htm)• benzo.org.uk - Ashton H. Benzodiazepines: How They Work And How to Withdraw. August 2002 (The "Ashton

Manual") (http:/ / benzo. org. uk/ manual/ index. htm).• ndaa.org - Drummer, OH. 'Benzodiazepines: Effects on Human Performance and Behavior'(Central Police

University Press, 2002) (http:/ / www. ndaa. org/ pdf/ ntlc_benzodiazepines. pdf).• U.S. National Library of Medicine: Drug Information Portal - Lorazepam (http:/ / druginfo. nlm. nih. gov/

drugportal/ dpdirect. jsp?name=Lorazepam)

Article Sources and Contributors 13

Article Sources and ContributorsLorazepam  Source: http://en.wikipedia.org/w/index.php?oldid=613398288  Contributors: 00AgentBond93, A S Houdini, AManWithNoPlan, Absentis, Acdx, AdelaMae, Adrian, Aleron235,AmiraChtourou, Amoeba Form, Andrew73, Andrewpmk, Andrewrost3241981, Andycjp, Arcadian, Arvindn, Aschwole, Aspensti, Astral, Astrbys, AxelBoldt, Bawles2, Bear475, BeastRHIT,Beetstra, Beezhive, Bellpepper, BenLib, Bender235, Bhadani, Blanchardb, BlueJaeger, Bluerasberry, Bobo192, Bodhijett, Boghog, Cacycle, Calton, Canihaveacookie, CardinalDan, Carealty,Carpetman2007, Casforty, Casliber, Checkingfax, ChemNerd, Chemgirl131, Chempedia, Chowbok, Chris the speller, ChrisGualtieri, Chrisminter, Cleduc, CliffC, Cobi, Colin, Coppertwig,CrazyChemGuy, Crumnut, Cryanb16690, Cubs197, Cyclonenim, DMahalko, DVdm, DangerousPanda, DavidLeighEllis, Dcs937, Deli nk, Dime5150, DocWatson42, Dowho, Driant,Drphilharmonic, Dtras, Dunstaple, EagleFan, Eatcacti, Echuck215, Edgar181, Editor2020, Eeekster, Eequor, Elb2000, Enviroboy, Epicgenius, Epolk, Esniad, Everything Else Is Taken, ExplodingBoy, Fawcett5, Fluoborate, FreplySpang, Fuhghettaboutit, FurrTrap, Fuse809, Fuzzform, Fvasconcellos, Galaxiaad, Garyzx, Geneb1955, Gigemag76, Girolamo Savonarola, Globemaster1776,Gogebic, Googie man, Half pint 707, HalfFullGlass, HazyM, Herbythyme, Historian932, HitroMilanese, Hoarderland, Hollyperidol, HowardJWilk, Ian Gottherd, Ifnord, Ihowell67, Indon,InternetMeme, Iridescent, J.delanoy, JForget, Japanese Searobin, Jdlambert, Jimfbleak, Jmh649, Jmrowland, Josie banana, JournalJunkie, Jpunzel, Julesd, Jü, Kazlow101, Kbir1, Keenan Pepper,Kelisi, Khoda Jan, Kinkyturnip, Klausness, Klemen Kocjancic, KnowledgeOfSelf, Korbnep, Kpjas, Kz9dsr0t387346, Lamro, Lexor, Likeane11, Limbo@MX, MadSurgeon, MaeseLeon,Mandarax, Markus451, Martin451, Matze6587, Maximumlobster, Medos2, MetalBrasil, Metalhead94, Mike Payne, MikeAllen, Moncrief, Mongreilf, Moskvax, Mr. Lefty, Mr. Stradivarius,MrADHD, Mschoel, Mykhal, NBINVDR1, Niceguyedc, NickCatal, Nirmos, Nmcou, NotAnIP83:149:66:11, Nsaum75, Nuggetboy, Oanabay04, Ohconfucius, Ohnoitsjamie, Op2mus,Panerai669, Pashihiko, Paskal T., Pentagron, Perspeculum, Petlif, Petrb, PhDP, Pharaoh of the Wizards, Philip Trueman, Pigkeeper, Pissant, Pluma, Ponyo, Preslethe, Psu256, Psychonaut,Puddinglovessausage, Qwasty, RCalabraro, RJaguar3, RainbowOfLight, Rbaselt, Reedy, Refault, Remember me, Remember the dot, Resurgent insurgent, Rich Farmbrough, Rimoll, Rjwilmsi,Rmky87, RobinHood70, Rock2e, Ronz, Rror, SGGH, Saturn 56, Sceptre, Schz, Scotleone, Seven of Nine, Snoopycool, Snowmanradio, Someguy1221, SqueakBox, Staciabb, Stevenfruitsmaak,Stilldoggy, Subom, Substatique, Sun Creator, Sunray, Svadhisthana, Swaggythechair, SwampFox556, THEN WHO WAS PHONE?, Tentinator, The Magnificent Clean-keeper, The Thing ThatShould Not Be, Thegoodson, Thornberrylc, Thumperward, Timeshift9, Timpo, Tins128, Titodutta, Tomasczt, TreasureXNY, Tribu akru, Tsiaojian lee, Tybalt01, UNOwenNYC, Unkept,Untilzero, Vaughan, Vivio Testarossa, WhatamIdoing, Wikid77, Wisdom89, Woodcore, Xcali, Xe7al, Ytcracker, Zachorious, Zenohockey, Ziva 84, 519 ,حسن علي البط anonymous edits

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