Jump to content

Lorazepam

From Wikipedia, the free encyclopedia

This is an old revision of this page, as edited by Saturn 56 (talk | contribs) at 13:19, 29 June 2011. The present address (URL) is a permanent link to this revision, which may differ significantly from the current revision.

Lorazepam
Clinical data
Other namesO-Chloroxazepam, L-Lorazepam Acetate
Routes of
administration		Oral, I.M., I.V., sublingual, and transdermal
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability85% of oral dose
MetabolismHepatic glucuronidation
Elimination half-life9–16 hours[2][3][4]
ExcretionRenal
Identifiers
  • (RS)-9-chloro-6-(2-chlorophenyl)-4-hydroxy-
    2,5-diazabicyclo[5.4.0]undeca-
    5,8,10,12-tetraen-3-one
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.011.534 Edit this at Wikidata
Chemical and physical data
FormulaC15H10Cl2N2O2
Molar mass321.2 g/mol g·mol−1
3D model (JSmol)
  • Clc3ccccc3C/2=N/C(O)C(=O)Nc1c\2cc(Cl)cc1
  • 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) checkY
  • Key:DIWRORZWFLOCLC-UHFFFAOYSA-N checkY
  (verify)

Lorazepam (initially marketed under the brand names Ativan and Temesta) is a high-potency short-to-intermediate-acting 3-hydroxy benzodiazepine drug that has all five intrinsic benzodiazepine effects: anxiolytic, amnesic, sedative/hypnotic, anticonvulsant and muscle relaxant.[5][6] Lorazepam is used for the short-term treatment of anxiety, insomnia, acute seizures including status epilepticus and sedation of hospitalised patients, as well as sedation of aggressive patients.[6][7][8][9]

Lorazepam is considered to be a short-acting drug which, similar to other benzodiazepines, exerts its therapeutic as well as adverse effects via its interaction at benzodiazepine binding sites, which are located on GABAA receptors in the central nervous system. After its introduction in 1977, lorazepam's principal use was in treating anxiety. Among benzodiazepines, lorazepam has a relatively high addictive potential.[5][10] Lorazepam also has abuse potential; the main types of misuse are for recreational purposes or continued use against medical advice.[11] The sedative-hypnotic and anterograde amnesia properties of lorazepam are sometimes used for criminal purposes.[12][13]

Long-term effects of benzodiazepines include tolerance, dependence, a benzodiazepine withdrawal syndrome and cognitive 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 and psychosis. Due to tolerance and dependence, lorazepam is recommended for short-term use, 2–4 weeks only. Adverse effects including anterograde amnesia, depression and paradoxical effects such as excitement or worsening of seizures may occur. Children and the elderly are more sensitive to the adverse effects of benzodiazepines.[5][14][15] Lorazepam impairs body balance and standing steadiness and is associated with falls and hip fractures in the elderly.[16]

Medical uses

Lorazepam has relatively potent anxiolytic effects and its best-known indication is the short-term management of severe anxiety; the FDA advises against use of benzodiazepines such as lorazepam for longer than 2–4 weeks.[15][17] It is fast acting, and useful in treating fast onset panic anxiety.[18]

Lorazepam has strong sedative/hypnotic effects, and the duration of clinical effects from a single dose makes it an appropriate choice for the short-term treatment of insomnia, in particular in the presence of severe anxiety. It has a fairly short duration of action (Venable and Aschenbrenner 2009). Withdrawal symptoms, including rebound insomnia and rebound anxiety, may occur after only seven days' administration of lorazepam.[19]

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 of propofol for this indication is now encouraged, whereas the use of lorazepam for this indication is discouraged.[7]

Its relatively potent amnesic effect,[6] 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 lorazepam as late as 10 minutes before procedures.[20][21][22] Lorazepam is sometimes used as an alternative to midazolam in palliative sedation.[23] In intensive care units lorazepam is sometimes used to produce anxiolysis, hypnosis, and amnesia.[24]

Intravenous diazepam or lorazepam are first-line treatments for convulsive status epilepticus.[8][8] Lorazepam is more effective than diazepam in the treatment of status epilepticus.[25] However, phenobarbitol has a superior success rate compared to lorazepam and other drugs, at least in the elderly.[26][27]

The marked anticonvulsant properties of lorazepam, and its pharmacokinetic profile, make intravenous lorazepam a reliable agent for terminating acute seizures, but it has relatively prolonged sedation after-effects. Oral lorazepam, and other benzodiazepines, have a role in long-term prophylactic treatment of resistant forms of petit mal epilepsy, but not as first-line therapies, mainly because of the development of tolerance to their effects.[28]

Lorazepam's anticonvulsant and CNS depressant properties are useful for the treatment and prevention of alcohol withdrawal syndrome. In this setting, it is relevant that impaired liver function is not a hazard with lorazepam since lorazepam does not require oxidation, hepatic or otherwise, for its metabolism.[29][30]

Lorazepam is sometimes used as an alternative to haloperidol when there is the need for rapid sedation of violent or agitated individuals,[9][31] but haloperidol plus promethazine is preferred due to better effectiveness and due to lorazepam's adverse effects on respiratory function.[32] However, adverse effects such as behavioural disinhibition may make benzodiazepines inappropriate for some acutely psychotic patients.[33] Acute delirium is sometimes treated with lorazepam, but as it can cause paradoxical effects, it is preferably given together with haloperidol.[34] Lorazepam is absorbed 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 intravenous dose of lorazepam. Symptoms may recur and treatment for some days may be necessary. Catatonia due to abrupt or too rapid withdrawal from benzodiazepines, as part of the benzodiazepine withdrawal syndrome, should also respond to lorazepam treatment.[35] As lorazepam can have paradoxical effects, haloperidol is sometimes given concomitantly.[34][36]

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.[37] It is also used as adjunct therapy for cyclic vomiting syndrome.

Lorazepam is also used to treat acute symptoms of vertigo and dizziness for people with Ménière's disease[citation needed].

Formulation

0.5mg 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, lorazepam 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 colouring agents (indigo carmine—E132—in blue tablets and tartrazine—E102— in yellow tablets).

Lorazepam injectable solution is administered either by deep intramuscular injection or by intravenous injection. The injectable solution comes in 1 mL ampoules containing 2 mg or 4 mg lorazepam. The solvents used are polyethylene glycol 400 and propylene glycol. As a preservative, the injectable solution contains benzyl alcohol.[38] Toxicity from propylene glycol has been reported in the case of a patient receiving a continuous lorazepam infusion.[39] Intravenous injections should 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,[40] which occur 10 minutes after intravenous injection, up to 60 minutes after intramuscular injection, and 90 to 120 minutes after oral administration,[40][41] but initial effects will be noted before this. A clinically relevant lorazepam dose will normally be effective for 6 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.

Adverse effects

Any of the five intrinsic benzodiazepine effects possessed by lorazepam (sedative/hypnotic, muscle relaxant, anxiolytic, amnesic, and anticonvulsant) may be considered as "adverse effects," or "side effects," if unwanted.[6] Adverse effects can include sedation and hypotension; the effects of lorazepam are increased in combination with other CNS depressant drugs.[8][9] Other adverse effects include confusion, ataxia, anterograde amnesia and hangover effects. With long-term use of benzodiazepines it is unclear whether cognitive impairments fully return to normal after cessation of therapy; cognitive deficits persist for at least 6 months post-withdrawal, but it is possible that longer than 6 months is required for recovery of cognitive function. Lorazepam appears to have more profound adverse effects on memory than other benzodiazepines; lorazepam impairs both explicit memory and implicit memory. 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 patients. 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.[5] 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.

Sedation is the side effect that most patients complain of. In a group of around 3500 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.[42] Cognitive impairment, behavioural disinhibition and respiratory depression as well as hypotension may also occur.[24][33]

  • Paradoxical effects: In some cases, there can be paradoxical effects with benzodiazepines, such as increased hostility, aggression, angry outbursts, and psychomotor agitation. These effects are seen as more common with lorazepam than other benzodiazepines.[43] Paradoxical effects are more likely to occur with higher doses, in patients with pre-existing personality disorders and those with a psychiatric illness. It is worth noting that frustrating stimuli may trigger such reactions, even though the drug may have been prescribed to help the patient 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.[44][45][46][12][47][48]
  • Suicidality: Benzodiazepines may sometimes unmask suicidal ideation in depressed patients, possibly through disinhibition or fear reduction. The concern is that, though relatively nontoxic in themselves [verification needed], benzodiazepines may inadvertently become facilitators of suicidal behaviour.[49] Lorazepam should, therefore, not be prescribed in high doses or as the sole treatment in depression, but only with an appropriate antidepressant [specify].
  • Amnesic effects: Among benzodiazepines, lorazepam has relatively strong amnesic effects,[6][50] but patients 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 2–3 days' use.[51] 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 glycol intoxication.[24][52]

Contraindications

Lorazepam should be avoided in people with the following conditions:

  • 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 patient'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 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 already-ataxic patients.
  • Acute narrow-angle glaucoma – Lorazepam has pupil-dilating effects, which may further interfere with the drainage 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 may further reduce the patient's ability to protect his or her airway during sleep.
  • Myasthenia gravis – This condition is characterised by muscle weakness and a muscle relaxant such as lorazepam may exacerbate symptoms.
  • Pregnancy and breast feeding – Lorazepam belongs to the Food and Drug Administration (FDA) pregnancy category D, which means that it is likely to cause harm to the developing baby, if taken during the first trimester of pregnancy. There is inconclusive evidence that lorazepam, if taken early in pregnancy, may result in reduced IQ, 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[53] 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.[54] Lorazepam may also inhibit foetal liver bilirubin glucuronidation, leading to neonatal jaundice. Lorazepam is present in breast milk, so caution must be exercised about breast feeding.

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 the elderly and debilitated patients 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 metabolise 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.[5][55] Lorazepam may also be slower to clear in the elderly leading potentially to accumulation and enhanced effects.[56] 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.[16]
  • Liver or kidney failure – Lorazepam may be safer than most benzodiazepines in patients with impaired liver function. Like oxazepam, it does not require hepatic oxidation, but only hepatic glucuronidation into lorazepam-glucuronide. Therefore, impaired liver function is unlikely to result in lorazepam accumulation to an extent causing adverse reactions.[29] Similarly renal disease has minimal effects on lorazepam levels.[57]
  • Surgical premedication – Informed consent that was 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. Patients 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 – There is an increased risk of abuse of lorazepam.[55]
  • Comorbid psychiatric disorders – Increased risk of dependence and paradoxical adverse effects[55]

Tolerance and dependence

Dependence typified by a withdrawal syndrome occurs in approximately one third of individuals who are treated for longer than four weeks with a benzodiazepine. The higher doses and the longer periods benzodiazepines are taken increase the risk of developing a benzodiazepine dependence. Potent benzodiazepines such as lorazepam, alprazolam, and triazolam have the highest risk of causing a dependence.[5] Tolerance to benzodiazepine effects develops with regular use. This is desirable with amnesic and sedative effects, undesirable with anxiolytic, hypnotic, and anticonvulsant effects. Patients at first 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, there is little evidence of continued efficacy. If regular treatment is continued for longer than this, dose increases may be necessary to maintain effects, but treatment-resistant symptoms may in fact be benzodiazepine withdrawal symptoms.[58] 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.[5]

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 results in interdose withdrawal phenomena and next-dose cravings. This 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, degree of dependence and the individual. Coming off long-term lorazepam may be more realistically achieved by a gradual switch to an equivalent dose of diazepam, 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.[59]

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 what is known as the benzodiazepine withdrawal syndrome. The higher the dose and the longer the drug is taken for, 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.[60] 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 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 likely to cause a more severe withdrawal syndrome compared to longer-acting benzodiazepines.[5]

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 approximately 18–36 hours for the benzodiazepine to remove itself from the body.[61] The ease of addiction to Lorazepam, (the 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 patients should be warned against drinking alcohol while on lorazepam treatment,[6][62] but such clear warnings are not universal.[63] Synergistic adverse effects may also occur when lorazepam is administered with other drugs such as opioids or other hypnotics.[57] Lorazepam may also interact with rifabutin.[64] Valproate, inhibits the metabolism of lorazepam, whereas carbamazepine, lamotrigine, phenobarbital, phenytoin, rifampin increases the rate of metabolism of lorazepam. Some antidepressants, anti-epileptic drugs such as phenobarbital, phenytoin and carbamazepine, sedative antihistamines, opiates, antipsychotics and alcohol when taken with lorazepam may result in enhanced sedative effects.[5]

Overdose

See also: Benzodiazepine overdose

In cases of a suspected lorazepam overdose, it is important to establish whether the patient is a regular user of lorazepam or other benzodiazepines, since regular use causes tolerance to develop. Also, one must ascertain whether other 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, management is by observation, including of vital signs, support and, only if necessary, considering the hazards of doing so, giving intravenous flumazenil.

Patients are ideally nursed in a kind, non-frustrating 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.[65] Opportunistic counseling has limited value here, as the patient 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 a diagnosis of poisoning in hospitalized patients, provide evidence in an impaired driving arrest or to assist in a medicolegal death investigation. Blood or plasma lorazepam concentrations are usually in a range of 10-300 ug/L in persons either receiving the drug therapeutically or in those arrested for impaired driving, and 300-1000 ug/L in victims of acute overdosage.[66]

Pharmacology

Lorazepam has anxiolytic, sedative, hypnotic, amnesic, anticonvulsant as well as muscle relaxant properties.[67] Lorazepam is high-potency and an intermediate-acting benzodiazepine and its uniqueness,[68][69] advantages and disadvantages are largely explained by its pharmacokinetic properties (poor water and lipid solubility, high protein binding and non-oxidative metabolism to a pharmacologically inactive glucuronide form) and by its high relative potency (lorazepam 1 mg is equal in effect to diazepam 10 mg).[70][71] The half life of lorazepam is 10–20 hours.[72]

Pharmacokinetics

Lorazepam is highly protein bound and is extensively metabolised into pharmacologically inactive metabolites.[5] Due to its poor lipid solubility lorazepam is absorbed relatively slowly by mouth and is unsuitable for rectal administration. But its poor lipid solubility and high degree of protein binding (85-90%[41]) mean that lorazepam's 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 lorazepam's shorter serum half-life, has more prolonged peak effects than an equivalent diazepam dose.[73] On regular administration diazepam will, however, accumulate more, since it has a longer half-life and active metabolites with even longer 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 intravenously, orally, or rectally (non-intravenous routes are convenient in non-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 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 patient is known to usually stop convulsing after only one or two diazepam doses, diazepam 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).[74] The prolonged sedation from lorazepam may, however, be an acceptable trade-off for its reliable duration of effects, particularly if the patient needs to be transferred to another facility. Although lorazepam is not necessarily better than diazepam at initially terminating seizures,[75] lorazepam is, nevertheless, replacing diazepam as the intravenous agent of choice in status epilepticus.[76][77]

Lorazepam serum levels are proportional to the dose administered. Giving 2 mg oral lorazepam will result in a peak total serum lorazepam level of around 20 nanograms/ml around two hours later,[40][41] half of which is lorazepam, half its inactive metabolite, lorazepam-glucuronide.[78] 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.[79] On regular administration, maximum lorazepam serum levels are attained after three days. Longer-term use, up to six months, does not result in further accumulation.[41] On discontinuation, lorazepam serum levels become negligible after 3 days and undetectable after about a week. Lorazepam is metabolised in the liver by conjugation into inactive lorazepam-glucuronide. This metabolism does not involve hepatic oxidation and, therefore, is relatively unaffected by reduced liver function. Lorazepam-glucuronide is more water-soluble than its precursor and, therefore, gets more widely distributed in the body, leading to a longer half-life than lorazepam. Lorazepam-glucuronide is eventually excreted by the kidneys,[41] 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,[80] which may also explain its marked[6] amnesic effects. The main pharmacological effects of lorazepam are the enhancement of the effects of GABA at the GABAA receptor.[5] 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. Benzodiazepines, 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.[5][57]

The magnitude and duration of lorazepam effects are dose-related, meaning that larger doses have stronger and longer-lasting effects. This is 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.[81]

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.[82]

Chemistry

Lorazepam is synthesized according to a scheme containing some of the same elements for the synthesis of chlordiazepoxide 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. The 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 a 3-acetoxylated benzodiazepine, 7-chloro-1,3-dihydro-3-acetoxy-5-(2′-chlorphenyl)-2H-benzodiazepin-2-one.
  6. Hydrolysis of thee above product forms the desired product lorazepam.

  • S.C. Bell, U.S. patent 3,176,009 (1965).
  • American Home Products Corp., GB 1022642  (1962).
  • S.C. Bell, U.S. patent 3,296,249 (1967).
  • S.C. Bell, GB 1057492  (1967).
  • S.J. Childress, M.I. Gluckman, J. Pharm. Sci., 53, 577 (1964).
  • Attention: This template ({{cite doi}}) is deprecated. To cite the publication identified by doi:10.1021/jm00309a010, please use {{cite journal}} (if it was published in a bona fide academic journal, otherwise {{cite report}} with |doi=10.1021/jm00309a010 instead.

History

Historically, lorazepam is one of the "classical" benzodiazepines. Other classical benzodiazepines include diazepam, clonazepam, oxazepam, nitrazepam, flurazepam, bromazepam and clorazepate.[83] Lorazepam was first introduced by Wyeth Pharmaceuticals in 1971 under the brand names of Ativan and Temesta.[84] 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. As a measure of its ongoing success, it has been marketed under more than seventy generic brands 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, 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 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.[85]

Recreational use

See also: Nonmedical benzodiazepine drug use

Lorazepam is also used for other purposes. Recreational use, wherein the drug is taken to achieve a high, or when the drug is continued long term against medical advice.[11]

In addition to recreational use, benzodiazepines may be diverted and used to facilitate crime: Criminals may take them to deliberately seek disinhibition before committing crimes[12] (which increases their potential for violence). 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; however, alcohol is the most common drug involved in such crimes.[13]

A large-scale, nationwide, U.S. government study of pharmaceutical-related ED visits by SAMHSA found that sedative-hypnotics in the United States are the pharmaceuticals most frequently used outside of their prescribed medical purpose, with 35% of drug-related emergency room 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 drug, with 26% of attempted suicides involving benzodiazepines. Lorazepam was the third-most-common benzodiazepine used outside of prescription in these ED visit statistics.[86]

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.[87] Lorazepam is a Schedule IV drug under the Controlled Drugs and Substances Act in Canada. In the United Kingdom, lorazepam is a Class C, Schedule 4 Controlled Drug under the Misuse of Drugs Regulations 2001.[88]

References

  1. ^ "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA. Retrieved 22 Oct 2023.
  2. ^ Greenblatt DJ, Shader RI, Franke K, Maclaughlin DS, Harmatz JS, Allen MD, Werner A, Woo E (1991). "Pharmacokinetics and bioavailability of intravenous, intramuscular, and oral lorazepam in humans". J Pharm Sci. 68 (1): 57–63. doi:10.1002/jps.2600680119. PMID 31453.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  3. ^ Greenblatt DJ, von Moltke LL, Ehrenberg BL, Harmatz JS, Corbett KE, Wallace DW, Shader RI (2000). "Kinetics and dynamics of lorazepam during and after continuous intravenous infusion". Crit Care Med. 28 (8): 2750–2757. doi:10.1097/00003246-200008000-00011. PMID 10966246.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  4. ^ Papini O, da Cunha SP, da Silva Mathes Ado C, Bertucci C, Moisés EC, de Barros Duarte L, de Carvalho Cavalli R, Lanchote VL (2006). "Kinetic disposition of lorazepam with a focus on the glucuronidation capacity, transplacental transfer in parturients and racemization in biological samples" (PDF). J Pharm Biomed Anal. 40 (2): 397–403. doi:10.1016/j.jpba.2005.07.021. PMID 16143486.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  5. ^ a b c d e f g h i j k l Riss, J.; Cloyd, J.; Gates, J.; Collins, S. (2008). "Benzodiazepines in epilepsy: pharmacology and pharmacokinetics". Acta Neurol Scand. 118 (2): 69–86. doi:10.1111/j.1600-0404.2008.01004.x. PMID 18384456. {{cite journal}}: Unknown parameter |month= ignored (help)
  6. ^ a b c d e f g Hindmarch, Ian (January 30, 1997). "Benzodiazepines and their effects". benzo.org.uk. Retrieved 2007-05-13.
  7. ^ a b Cox, CE.; Reed, SD.; Govert, JA.; Rodgers, JE.; Campbell-Bright, S.; Kress, JP.; Carson, SS. (2008). "Economic evaluation of propofol and lorazepam for critically ill patients undergoing mechanical ventilation". Crit Care Med. 36 (3): 706–14. doi:10.1097/CCM.0B013E3181544248. PMC 2763279. PMID 18176312. {{cite journal}}: Unknown parameter |month= ignored (help)
  8. ^ a b c d Walker, M. (2005). "Status epilepticus: an evidence based guide". BMJ. 331 (7518): 673–7. doi:10.1136/bmj.331.7518.673. PMC 1226249. PMID 16179702. {{cite journal}}: Unknown parameter |month= ignored (help)
  9. ^ a b c Battaglia, J. (2005). "Pharmacological management of acute agitation". Drugs. 65 (9): 1207–22. doi:10.2165/00003495-200565090-00003. PMID 15916448. {{cite journal}}: Cite has empty unknown parameter: |month= (help)
  10. ^ Kemper N (December 5, 1980). "[Benzodiazepine dependence: addiction potential of the benzodiazepines is greater than previously assumed (author's transl)]". Deutsche medizinische Wochenschrift (1980). 105 (49): 1707–12. doi:10.1055/s-2008-1070941. PMID 7439058. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  11. ^ a b Griffiths RR, Johnson MW (2005). "Relative abuse liability of hypnotic drugs: a conceptual framework and algorithm for differentiating among compounds". J Clin Psychiatry. 66 Suppl 9: 31–41. PMID 16336040.
  12. ^ a b c Michel L, Lang JP (2003). "[Benzodiazepines and forensic aspects]". L'Encéphale (in French). 29 (6): 479–85. PMID 15029082.
  13. ^ a b Kintz, P. (2007). "Bioanalytical procedures for detection of chemical agents in hair in the case of drug-facilitated crimes" (PDF). Anal Bioanal Chem. 388 (7): 1467–74. doi:10.1007/s00216-007-1209-z. PMID 17340077. {{cite journal}}: Unknown parameter |month= ignored (help)
  14. ^ Stewart, SA. (2005). "The effects of benzodiazepines on cognition". J Clin Psychiatry. 66 Suppl 2: 9–13. PMID 15762814.
  15. ^ a b Food and Drug Administration (2007). "Ativan (lorazepam) Tablets Rx only" (PDF). USA: Food and Drug Administration. In general, benzodiazepines should be prescribed for short periods only (e.g. 2–4 weeks). Extension of the treatment period should not take place without reevaluation of the need for continued therapy. Continuous long-term use of product is not recommended. {{cite web}}: Unknown parameter |coauthors= ignored (|author= suggested) (help); Unknown parameter |month= ignored (help)
  16. ^ a b Mets, MA.; Volkerts, ER.; Olivier, B.; Verster, JC. (2010). "Effect of hypnotic drugs on body balance and standing steadiness". Sleep Med Rev. 14 (4): 259–67. doi:10.1016/j.smrv.2009.10.008. PMID 20171127. {{cite journal}}: Unknown parameter |month= ignored (help)
  17. ^ RONI CARYN RABIN, "Disparities: Study Finds Risk in Off-Label Prescribing"[1]
  18. ^ Lader M (1984). "Short-term versus long-term benzodiazepine therapy". Current Med Res Opin. 8 Suppl 4: 120–6. PMID 6144459.
  19. ^ Scharf MB (1982). "Lorazepam-efficacy, side effects, and rebound phenomena". Clin Pharmacol Ther. 31 (2): 175–9. doi:10.1038/clpt.1982.27. PMID 6120058. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help); Unknown parameter |month= ignored (help)
  20. ^ Maltais F, Laberge F, Laviolette M (1996). Template:PDFlink Chest 109 (5): 1195–8. PMID 8625666.
  21. ^ Heisterkamp DV, Cohen PJ (1975). "The effect of intravenous premedication with lorazepam (Ativan), pentobarbitone or diazepam on recall". Br J Anaesth. 47 (1): 79–81. doi:10.1093/bja/47.1.79. PMID 238548.
  22. ^ Tsui, BC.; Wagner, A.; Finucane, B. (2004). "Regional anaesthesia in the elderly: a clinical guide". Drugs Aging. 21 (14): 895–910. PMID 15554749.
  23. ^ Verhagen, EH.; Hesselmann, GM.; Besse, TC.; de Graeff, A. (2005). "[Palliative sedation]". Ned Tijdschr Geneeskd. 149 (9): 458–61. PMID 15771339. {{cite journal}}: Unknown parameter |month= ignored (help)
  24. ^ a b c Arcangeli, A.; Antonelli, M.; Mignani, V.; Sandroni, C. (2005). "Sedation in PACU: the role of benzodiazepines". Curr Drug Targets. 6 (7): 745–8. doi:10.2174/138945005774574416. PMID 16305452. {{cite journal}}: Unknown parameter |month= ignored (help)
  25. ^ Prasad, K.; Al-Roomi, K.; Krishnan, PR.; Sequeira, R.; Prasad, Kameshwar (2005). "Anticonvulsant therapy for status epilepticus". Cochrane Database Syst Rev (4): CD003723. doi:10.1002/14651858.CD003723.pub2. PMID 16235337. {{cite journal}}: Cite has empty unknown parameter: |month= (help)
  26. ^ Treiman, DM.; Walker, MC. (2006). "Treatment of seizure emergencies: convulsive and non-convulsive status epilepticus". Epilepsy Res. 68 Suppl 1: S77–82. doi:10.1016/j.eplepsyres.2005.07.020. PMID 16384688. {{cite journal}}: Unknown parameter |month= ignored (help)
  27. ^ Treiman, DM. (2007). "Treatment of convulsive status epilepticus". Int Rev Neurobiol. 81: 273–85. doi:10.1016/S0074-7742(06)81018-4. PMID 17433931.
  28. ^ Isojärvi, JI (1998). "Benzodiazepines in the treatment of epilepsy in people with intellectual disability". J Intellect Disabil Res. 42 (1): 80–92. PMID 10030438. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help); Unknown parameter |month= ignored (help)
  29. ^ a b Peppers MP (1996). "Benzodiazepines for alcohol withdrawal in the elderly and in patients with liver disease". Pharmacotherapy. 16 (1): 49–57. PMID 8700792.
  30. ^ Bråthen, G.; Ben-Menachem, E.; Brodtkorb, E.; Galvin, R.; Garcia-Monco, JC.; Halasz, P.; Hillbom, M.; Leone, MA.; Young, AB. (2005). "EFNS guideline on the diagnosis and management of alcohol-related seizures: report of an EFNS task force". Eur J Neurol. 12 (8): 575–81. doi:10.1111/j.1468-1331.2005.01247.x. PMID 16053464. {{cite journal}}: Unknown parameter |month= ignored (help)
  31. ^ Zoupanos, BN.; Bryois, C. (2005). "[Treatment of agitation in the emergency room]". Rev Med Suisse. 1 (27): 1810–3. PMID 16119296. {{cite journal}}: Unknown parameter |month= ignored (help)
  32. ^ Huf, G.; Alexander, J.; Allen, MH.; Raveendran, Nirmal S; Huf, Gisele (2005). "Haloperidol plus promethazine for psychosis induced aggression" (PDF). Cochrane Database Syst Rev (1): CD005146. doi:10.1002/14651858.CD005146. PMID 15654706.
  33. ^ a b Gillies, D.; Beck, A.; McCloud, A.; Rathbone, J.; Gillies, D. (2005). "Benzodiazepines alone or in combination with antipsychotic drugs for acute psychosis". Cochrane Database Syst Rev (4): CD003079. doi:10.1002/14651858.CD003079.pub2. PMID 16235313. {{cite journal}}: Cite has empty unknown parameter: |month= (help)
  34. ^ a b Bieniek SA, Ownby RL, Penalver A, Dominguez RA (1998). "A double-blind study of lorazepam versus the combination of haloperidol and lorazepam in managing agitation". Pharmacotherapy. 18 (1): 57–62. PMID 9469682.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  35. ^ Rosebush PI, Mazurek MF (1996). "Catatonia after benzodiazepine withdrawal". Journal of clinical psychopharmacology. 16 (4): 315–9. doi:10.1097/00004714-199608000-00007. PMID 8835707.
  36. ^ Van Dalfsen AN, Van Den Eede F, Van Den Bossche B, Sabbe BG (2006). "[Benzodiazepines in the treatment of catatonia]". Tijdschrift voor psychiatrie (in Dutch; Flemish). 48 (3): 235–9. PMID 16956088.{{cite journal}}: CS1 maint: multiple names: authors list (link) CS1 maint: unrecognized language (link)
  37. ^ Herrstedt J, Aapro MS, Roila F, Kataja VV (2005). Template:PDFlink Ann Oncol 16 Suppl 1: i77–9. PMID 15888767. doi:10.1093/annonc/mdi805
  38. ^ baxter.com - Lorazepam Injection Data Sheet
  39. ^ Yaucher NE, Fish JT, Smith HW, Wells JA (2003). "Propylene glycol-associated renal toxicity from lorazepam infusion". Pharmacotherapy. 23 (9): 1094–9. doi:10.1592/phco.23.10.1094.32762. PMID 14524641.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  40. ^ a b c Greenblatt DJ, Schillings RT, Kyriakopoulos AA, Shader RI, Sisenwine SF, Knowles JA, Ruelius HW (1976). "Clinical pharmacokinetics of lorazepam. I. Absorption and disposition of oral 14C-lorazepam". Clin Pharmacol Ther. 20 (3): 329–41. PMID 8232.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  41. ^ a b c d e "Lorzem Data Sheet". New Zealand Medicines and Medical Devices Safety Authority. June 4, 1999. Retrieved 2007-05-13.
  42. ^ "Ativan side effects". RxList. 2007. Retrieved 2007-08-10.
  43. ^ Sorel L (1981). "Comparative trial of intravenous lorazepam and clonazepam im status epilepticus". Clin Ther. 4 (4): 326–36. PMID 6120763. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  44. ^ Bond A, Lader M (1988). "Differential effects of oxazepam and lorazepam on aggressive responding". Psychopharmacology (Berl.). 95 (3): 369–73. doi:10.1007/BF00181949. PMID 3137624.
  45. ^ Pietras CJ, Lieving LM, Cherek DR, Lane SD, Tcheremissine OV, Nouvion S (2005). "Acute effects of lorazepam on laboratory measures of aggressive and escape responses of adult male parolees". Behav Pharmacol. 16 (4): 243–51. doi:10.1097/01.fbp.0000170910.53415.77. PMID 15961964.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  46. ^ Kalachnik JE, Hanzel TE, Sevenich R, Harder SR (2002). "Benzodiazepine behavioral side effects: review and implications for individuals with mental retardation". Am J Ment Retard. 107 (5): 376–410. doi:10.1352/0895-8017(2002)107<0376:BBSERA>2.0.CO;2. PMID 12186578.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  47. ^ Mancuso CE, Tanzi MG, Gabay M (2004). "Paradoxical reactions to benzodiazepines: literature review and treatment options". Pharmacotherapy. 24 (9): 1177–85. doi:10.1592/phco.24.13.1177.38089. PMID 15460178.{{cite journal}}: CS1 maint: multiple names: authors list (link) Free full text with registration
  48. ^ Goldney RD (1977). "Paradoxical reaction to a new minor tranquilizer". Med. J. Aust. 1 (5): 139–40. PMID 15198.
  49. ^ Edwards RA, Medlicott RW (1980). "Advantages and disadvantages of benzodiazepine prescription". N Z Med J. 92 (671): 357–9. PMID 6109269.
  50. ^ Izaute M, Bacon E (2005). "Specific effects of an amnesic drug: effect of lorazepam on study time allocation and on judgment of learning". Neuropsychopharmacology. 30 (1): 196–204. doi:10.1038/sj.npp.1300564. PMID 15483562. Free full text
  51. ^ Scharf MB, Kales A, Bixler EO, Jacoby JA, Schweitzer PK (1982). "Lorazepam-efficacy, side-effects, and rebound phenomena". Clin. Pharmacol. Ther. 31 (2): 175–9. doi:10.1038/clpt.1982.27. PMID 6120058.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  52. ^ Riker, RR.; Fraser, GL. (2005). "Adverse events associated with sedatives, analgesics, and other drugs that provide patient comfort in the intensive care unit". Pharmacotherapy. 25 (5 Pt 2): 8S–18S. doi:10.1592/phco.2005.25.5_Part_2.8S. PMID 15899744. {{cite journal}}: Unknown parameter |month= ignored (help)
  53. ^ Kanto JH. (1982). "Use of benzodiazepines during pregnancy, labour and lactation, with particular reference to pharmacokinetic considerations". Drugs. 23 (5): 354–80. doi:10.2165/00003495-198223050-00002. PMID 6124415. {{cite journal}}: Cite has empty unknown parameter: |coauthors= (help); Unknown parameter |month= ignored (help)
  54. ^ McElhatton PR. (1994). "The effects of benzodiazepine use during pregnancy and lactation". Reprod Toxicol. 8 (6): 461–75. doi:10.1016/0890-6238(94)90029-9. PMID 7881198. {{cite journal}}: Cite has empty unknown parameter: |coauthors= (help); Unknown parameter |month= ignored (help)
  55. ^ a b c Authier, N.; Balayssac, D.; Sautereau, M.; Zangarelli, A.; Courty, P.; Somogyi, AA.; Vennat, B.; Llorca, PM.; Eschalier, A. (2009). "Benzodiazepine dependence: focus on withdrawal syndrome". Ann Pharm Fr. 67 (6): 408–13. doi:10.1016/j.pharma.2009.07.001. PMID 19900604. {{cite journal}}: Unknown parameter |month= ignored (help)
  56. ^ Butler, JM.; Begg, EJ. (2008). "Free drug metabolic clearance in elderly people". Clin Pharmacokinet. 47 (5): 297–321. doi:10.2165/00003088-200847050-00002. PMID 18399712. {{cite journal}}: Cite has empty unknown parameter: |month= (help)
  57. ^ a b c Olkkola, KT.; Ahonen, J. (2008). "Midazolam and other benzodiazepines". Handb Exp Pharmacol. 182 (182): 335–60. doi:10.1007/978-3-540-74806-9_16. PMID 18175099.
  58. ^ Longo LP, Johnson B (2000). "Addiction: Part I. Benzodiazepines--side effects, abuse risk and alternatives". American Family Physician. 61 (7): 2121–8. PMID 10779253. Free full text
  59. ^ Heather Ashton, C (2001). "Reasons for a diazepam (Valium) taper". benzo.org.uk. Retrieved 2007-06-01. {{cite web}}: Unknown parameter |month= ignored (help)
  60. ^ MacKinnon GL (1982). "Benzodiazepine withdrawal syndrome: a literature review and evaluation". The American journal of drug and alcohol abuse. 9 (1): 19–33. doi:10.3109/00952998209002608. PMID 6133446. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  61. ^ FDA (2007). "Labeling Revision" (PDF). fda.gov. Retrieved 2007-10-03. {{cite web}}: Unknown parameter |month= ignored (help)
  62. ^ Genus Pharmaceuticals (January 21, 1998). "Lorazepam: Patient Information Leaflet, UK, 1998". benzo.org.uk. Retrieved 2007-05-14.
  63. ^ "Lorazepam". Patient UK. October 25, 2006. Retrieved 2007-05-14.
  64. ^ Baciewicz, AM.; Chrisman, CR.; Finch, CK.; Self, TH. (2008). "Update on rifampin and rifabutin drug interactions". Am J Med Sci. 335 (2): 126–36. doi:10.1097/MAJ.0b013e31814a586a. PMID 18277121. {{cite journal}}: Unknown parameter |month= ignored (help)
  65. ^ Coundil of Europe, Pompidou Group (Strassbourg, 2002) Contribution to the sensible use of benzodiazepines. ISBN 9789287147516.
  66. ^ R. Baselt, Disposition of Toxic Drugs and Chemicals in Man, 8th edition, Biomedical Publications, Foster City, CA, 2008, pp. 860–862.
  67. ^ Mandrioli, R.; Mercolini, L.; Raggi, MA. (2008). "Benzodiazepine metabolism: an analytical perspective". Curr Drug Metab. 9 (8): 827–44. doi:10.2174/138920008786049258. PMID 18855614. {{cite journal}}: Unknown parameter |month= ignored (help)
  68. ^ Pompéia S, Manzano GM, Tufik S, Bueno OF (2005). Template:PDFlink J Physiol 569 (2): 709. PMID 16322061. doi:10.1113/jphysiol.2005.569005. Letter.
  69. ^ Chouinard G (2004). "Issues in the clinical use of benzodiazepines: potency, withdrawal, and rebound". J Clin Psychiatry. 65 Suppl 5: 7–12. PMID 15078112.
  70. ^ British Medical Association and Royal Pharmaceutical Society of Great Britain (2007). British National Formulary (v53 ed.). London: BMJ and RPS Pub. ISBN 0-85369-731-0. {{cite book}}: Unknown parameter |month= ignored (help)
  71. ^ Nimmo, Ray (2007). "Benzodiazepine Equivalence Table". benzo.org.uk. Retrieved 2007-05-13. {{cite web}}: Unknown parameter |coauthors= ignored (|author= suggested) (help); Unknown parameter |month= ignored (help)
  72. ^ Professor heather Ashton (2007). "Benzodiazepine equivalency table". Retrieved September 23, 2007. {{cite web}}: Unknown parameter |month= ignored (help)
  73. ^ Funderburk FR, Griffiths RR, McLeod DR, Bigelow GE, Mackenzie A, Liebson IA, Nemeth-Coslett R (1988). "Relative abuse liability of lorazepam and diazepam: an evaluation in 'recreational' drug users". Drug and alcohol dependence. 22 (3): 215–22. doi:10.1016/0376-8716(88)90021-X. PMID 3234245.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  74. ^ Lackner TE (2002). "Strategies for optimizing antiepileptic drug therapy in elderly people". Pharmacotherapy. 22 (3): 329–64. doi:10.1592/phco.22.5.329.33192. PMID 11898891. Free full text with registration at Medscape
  75. ^ Choudhery V, Townend W (2006). "Best evidence topic reports. Lorazepam or diazepam in paediatric status epilepticus". Emergency Medicine Journal. 23 (6): 472–3. doi:10.1136/emj.2006.037606. PMC 2564351. PMID 16714516.
  76. ^ Henry JC, Holloway R (2006). Template:PDFlink Evid Based Med 11 (2): 54. PMID 17213084. doi:10.1136/ebm.11.2.54
  77. ^ Cock HR, Schapira AH (2002). "A comparison of lorazepam and diazepam as initial therapy in convulsive status epilepticus". QJM. 95 (4): 225–31. doi:10.1093/qjmed/95.4.225. PMID 11937649.
  78. ^ Papini O, Bertucci C, da Cunha SP, dos Santos NA, Lanchote VL (2006). "Quantitative assay of lorazepam and its metabolite glucuronide by reverse-phase liquid chromatography-tandem mass spectrometry in human plasma and urine samples". Journal of pharmaceutical and biomedical analysis. 40 (2): 389–96. doi:10.1016/j.jpba.2005.07.033. PMID 16243469.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  79. ^ Herman RJ, Van Pham JD, Szakacs CB (1989). "Disposition of lorazepam in human beings: enterohepatic recirculation and first-pass effect". Clin Pharmacol Ther. 46 (1): 18–25. doi:10.1038/clpt.1989.101. PMID 2743706.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  80. ^ Matthew E, Andreason P, Pettigrew K; et al. (1995). "Benzodiazepine receptors mediate regional blood flow changes in the living human brain". Proc. Natl. Acad. Sci. U.S.A. 92 (7): 2775–9. doi:10.1073/pnas.92.7.2775. PMC 42301. PMID 7708722. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link) PMC 42301
  81. ^ Sybirska E, Seibyl JP, Bremner JD; et al. (1993). "[123I]iomazenil SPECT imaging demonstrates significant benzodiazepine receptor reserve in human and nonhuman primate brain". Neuropharmacology. 32 (7): 671–80. doi:10.1016/0028-3908(93)90080-M. PMID 8395663. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  82. ^ McLean MJ (1988). "Benzodiazepines, but not beta carbolines, limit high frequency repetitive firing of action potentials of spinal cord neurons in cell culture". J Pharmacol Exp Ther. 244 (2): 789–95. PMID 2450203. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help); Unknown parameter |month= ignored (help)
  83. ^ Braestrup C (1 April 1978). "Pharmacological characterization of benzodiazepine receptors in the brain". Eur J Pharmacol. 48 (3): 263–70. doi:10.1016/0014-2999(78)90085-7. PMID 639854. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  84. ^ "Benzodiazepine Names". non-benzodiazepines.org.uk. Retrieved 2008-12-29.
  85. ^ Labaton, Stephen (July 13, 2000). "Generic-Drug Maker Agrees to Settlement In Price-Fixing Case". The New York Times. Retrieved 2007-05-14.
  86. ^ United States Government (2006). "Drug Abuse Warning Network, 2006: National Estimates of Drug-Related Emergency Department Visits". Substance Abuse and Mental Health Services Administration. Retrieved 9 February 2009. {{cite web}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  87. ^ International Narcotics Control Board (August 2003). Template:PDFlink, 23rd ed., Vienna: International Narcotics Control Board, p.7.
  88. ^ "List of Controlled Drugs" (PDF). UK Home Office. January 2006.

External links

Retrieved from "https://en.wikipedia.org/w/index.php?title=Lorazepam&oldid=436847750"