Lorazepam

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. 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. Lorazepam also has abuse potential; the main types of misuse are for recreational purposes or continued use against medical advice. Lorazepam impairs body balance and standing steadiness and is associated with falls and hip fractures in the elderly. It is fast 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 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 7 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 of propofol for this indication is now encouraged, whereas the use of lorazepam for this indication is discouraged.

Its relatively potent amnesic effect, Lorazepam is sometimes used as an alternative to midazolam in palliative sedation. In intensive care units lorazepam is sometimes used to produce anxiolysis, hypnosis, and amnesia.

Intravenous diazepam or lorazepam are first-line treatments for convulsive status epilepticus. However, phenobarbitol has a superior success rate compared to lorazepam and other drugs, at least in the elderly.

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.

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.

Lorazepam is sometimes used as an alternative to haloperidol when there is the need for rapid sedation of violent or agitated individuals, but haloperidol plus promethazine is preferred due to better effectiveness and due to lorazepam's adverse effects on respiratory function. However, adverse effects such as behavioural disinhibition may make benzodiazepines inappropriate for some acutely psychotic patients. Acute delirium is sometimes treated with lorazepam, but as it can cause paradoxical effects, it is preferably given together with haloperidol. 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. 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 used as adjunct therapy for cyclic vomiting syndrome.

Also used to treat acute symptoms of vertigo and dizziness for people with Ménière's disease.

Formulation

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. Toxicity from propylene glycol has been reported in the case of a patient receiving a continuous lorazepam infusion. 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, which occur 10 minutes after intravenous injection, up to 60 minutes after intramuscular injection, and 90 to 120 minutes after oral administration, 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. Cognitive impairment, behavioural disinhibition and respiratory depression as well as hypotension may also occur. 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. 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 , benzodiazepines may inadvertently become facilitators of suicidal behaviour. Lorazepam should, therefore, not be prescribed in high doses or as the sole treatment in depression, but only with an appropriate antidepressant . Amnesic effects: Among benzodiazepines, lorazepam has relatively strong amnesic effects, 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. 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.

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 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. 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. Lorazepam may also be slower to clear in the elderly leading potentially to accumulation and enhanced effects. 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. 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. Similarly renal disease has minimal effects on lorazepam levels. 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 GABA_A receptor downregulation, alterations to subunit configuration of GABA_A receptors, uncoupling and internalisation of the benzodiazepine binding site from the GABA_A receptor complex as well as changes in gene expression.

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. 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. 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, but such clear warnings are not universal. Synergistic adverse effects may also occur when lorazepam is administered with other drugs such as opioids or other hypnotics. 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. 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.

Pharmacology

Lorazepam has anxiolytic, sedative, hypnotic, amnesic, anticonvulsant as well as muscle relaxant properties. Lorazepam is high-potency and an intermediate-acting benzodiazepine and its uniqueness, 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). The half life of lorazepam is 10–20 hours.

Pharmacokinetics

Lorazepam is highly protein bound and is extensively metabolised into pharmacologically inactive metabolites. 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). 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, lorazepam is, nevertheless, replacing diazepam as the intravenous agent of choice in status epilepticus.

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, 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. 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. which may also explain its marked

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.

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.

Chemistry

Lorazepam is synthesized according to a scheme containing some of the same elements for the synthesis of chlordiazepoxide and oxazepam. #2-amino-2′,5-dichlorobenzophenone is reacted with hydroxylamine. #The intermediate oxime is then reacted with chloracetyl chloride, and upon heterocyclization 6-chloro-2-chlormethyl-4-(2′-chlorophenyl)quinazolin-3-oxide is formed. #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. #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. #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. #Hydrolysis of thee above product forms the desired product lorazepam. S.C. Bell, (1965). American Home Products Corp., (1962). S.C. Bell, (1967). S.C. Bell, (1967).

S.J. Childress, M.I. Gluckman, J. Pharm. Sci., 53, 577 (1964).

History

Historically, lorazepam is one of the "classical" benzodiazepines. Other classical benzodiazepines include diazepam, clonazepam, oxazepam, nitrazepam, flurazepam, bromazepam and clorazepate. Lorazepam was first introduced by Wyeth Pharmaceuticals in 1971 under the brand names of 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 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.

Recreational 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.

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

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.

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. 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.

References

External links

inchem.org - Lorazepam data sheet

rxlist.com - Lorazepam data sheet

drugs.com - Lorazepam data sheet

baxter.com - Lorazepam Injection Data Sheet

NZ medsafe.govt.nz - Lorzem Data Sheet

benzo.org.uk - Genus/Wyeth 1998 UK Lorazepam Data Sheet

benzo.org.uk - Ashton H. Benzodiazepines: How They Work And How to Withdraw. August 2002 (The "Ashton Manual").

ndaa.org - Drummer, OH. 'Benzodiazepines: Effects on Human Performance and Behavior'(Central Police University Press, 2002).

U.S. National Library of Medicine: Drug Information Portal - Lorazepam

Category:Benzodiazepines Category:Antiemetics Category:Lactams Category:Organochlorides