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Lorazepam
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| Systematic (IUPAC) name | |
| 9-chloro-6-(2-chlorophenyl)-4-hydroxy- 2,5-diazabicyclo[5.4.0]undeca- 5,8,10,12-tetraen-3-one |
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| Identifiers | |
| CAS number | |
| ATC code | N05 |
| PubChem | |
| DrugBank | |
| ChemSpider | |
| Chemical data | |
| Formula | C15H10Cl2N2O2 |
| Mol. mass | 321.2 g/mol |
| Pharmacokinetic data | |
| Bioavailability | 85% of oral dose |
| Metabolism | Hepatic glucuronidation |
| Half life | 9-16 hours[1][2][3] |
| Excretion | Renal |
| Therapeutic considerations | |
| Pregnancy cat. |
D(US) |
| Legal status | |
| Routes | Oral, I.M., I.V. and transdermal |
Lorazepam (also known by its brand name Ativan or Temesta) is a benzodiazepine drug with short to medium duration of action. It has all five intrinsic benzodiazepine effects: anxiolytic, sedative/hypnotic, anticonvulsant and muscle relaxant, to different extents.[4] It is a powerful anxiolytic and since its introduction in 1971, lorazepam's principal use has been in treating the symptom of anxiety. It is a unique benzodiazepine insofar as it has also found use as an adjunct antiemetic in chemotherapy. Among benzodiazepines, lorazepam has a relatively high addictive potential.[5]
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Lorazepam has relatively potent anxiolytic effects and its best known indication is the short-term management of severe anxiety. It is less useful in panic disorder.[6]
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, particularly in the presence of severe anxiety. Withdrawal symptoms, including rebound insomnia and rebound anxiety, may occur after only 7 days' administration of lorazepam.[7]
Its relatively potent amnesic effect[4], 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 dentistry or endoscopies, to reduce anxiety, increase compliance and 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.[8][9][10]
The marked anticonvulsant properties of lorazepam, and its pharmacokinetic profile, makes intravenous lorazepam a reliable agent for terminating acute seizures, but it has relatively prolonged sedation aftereffects. 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 resistance to their effects.[11]
Lorazepam's anticonvulsant, or CNS depressant, properties are useful for the prevention and treatment 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.[12][13]
Where there is need for rapid sedation of violent or agitated patients,[14][15] including acute delirium, lorazepam may be used, but as it can cause paradoxical effects, it is preferably given together with haloperidol.[16] 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.[17] As lorazepam can have paradoxical effects, haloperidol is sometimes given concomitantly.[18][16]
Lorazepam is unique among benzodiazepines in having potent antiemetic properties. It is used as an adjunct antiemetic for treating the nausea and vomiting frequently associated with cancer chemotherapy, usually together with first-line antiemetics such as 5-HT3 antagonists.[19] It is also used as adjunct therapy for cyclic vomiting syndrome.
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. The tablets contain 0.5 mg, 1 mg, or 2 mg lorazepam, with some differences between countries. Lorazepam tablets of the Ativan brand also contain lactose, microcrystalline cellulose, polacrilin potassium, magnesium stearate and colouring agents (Blue tablets: indigo carmine, E132; Yellow tablets: tartrazine, E102).
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.[20] Toxicity from propylene glycol has been reported in the case of a patient receiving a continuous lorazepam infusion.[21] 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,[22] which occur ten minutes after intravenous injection, up to one hour after intramuscular injection and about 120 minutes after oral administration[23][22], but initial effects are 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; it is therefore usually prescribed as two to four daily doses when taken regularly.
Lorazepam is an intermediate acting benzodiazepine and its uniqueness,[24] 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).[25][26] The half life of lorazepam is 10-20 hours.[27]
Because of its poor lipid solubility lorazepam is absorbed relatively slowly by mouth and is unsuitable for rectal administration. However, its poor lipid solubility and its high degree of protein binding (85-90%[23]) means that lorazepam's volume of distribution is mainly the vascular compartment. This contrasts with the highly lipid soluble diazepam which, although speedily absorbed orally or rectally, soon redistributes from the serum to other parts of the body, particularly body fat. This explains why one lorazepam dose, despite lorazepam's shorter serum half-life, has longer duration of effect than one diazepam dose.[28] On regular administration diazepam will however accumulate more, having a longer half-life and active metabolites with even longer half-lives.
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,[23][22] half of which is lorazepam, half its inactive metabolite, lorazepam-glucuronide.[33] A similar dose given intravenously will result in an earlier and higher peak serum level, with a higher proportion of unmetabolised (active) lorazepam.[34] 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.[23] 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 excreted by the kidneys[23] and remains detectable - particularly in the urine - for substantially longer than lorazepam.
Relative to other benzodiazepines, lorazepam is thought to have high affinity for GABA receptors,[35] which may also explain its marked[4] amnesic effects. The main pharmacological effects of lorazepam are the enhancement of GABA at the GABAA receptor.[36] Benzodiazepine drugs including lorazepam increase the inhibitory processes in the cerebral cortex.[37]
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[38].
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.[39]
Lorazepam must be avoided in patients with the following conditions:
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.[43]
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 regime.[44]
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.[45]
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 your body.[46]
Prescribers of lorazepam must be alert to the possibility of abuse or diversion for illegitimate use when prescribing for unsupervised outpatients. This applies particularly to patients with past or present substance abuse disorders, as persons with addictive personalities are more likely to abuse medications such as lorazepam. 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[47] (which increases their potential for violence) or they may give them to unwitting victims as date rape drugs, notably with alcohol.
In Northern Ireland in cases where drivers had low or no alcohol readings but were thought to be impaired through drugs, benzodiazepines were found to be present in 87% of cases.[48]
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 most frequently abused pharmaceuticals, with 35% of drug-related emergency room visits involving sedative-hypnotics. In this category benzodiazepines are most commonly abused. Males abuse benzodiazepines as commonly as women. 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 commonly abused benzodiazepine in these ED visit statistics. [49]
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.[4] Lorazepam's effects are dose-dependent, meaning that 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.
Lorazepam has an advantage of being non-sedative relative to its potent anxiolytic effects, but sedation is still the most complained-of side effect. 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.[50]
Full lists of Lorazepam side effects:
For lists of lorazepam side-effects, refer to the manufacturers' data sheets. Note, some may list side-effects for the entire benzodiazepine class, not the specific side-effect profile for lorazepam.
In cases of a suspected lorazepam overdose, it is important to establish if the patient is a regular user of lorazepam or other benzodiazepines, since regular use causes tolerance to develop. Also, one must ascertain if 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.[62] Opportunistic counseling has limited value here, as the patient is unlikely to recall this later, owing to drug-induced anterograde amnesia.
Historically, lorazepam is one of the "classical" benzodiazepines. Other classical benzodiazepines include diazepam, clonazepam, oxazepam, nitrazepam, flurazepam, bromazepam and clorazepate.[63] 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.[64]
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.[65] Lorazepam is a Schedule IV drug under the Controlled Drugs and Substances Act in Canada. In the United Kingdom, lorazepam is a Class 4 Controlled Drug under the Misuse of Drugs Regulations 2001.
Lorazepam has been mentioned in several contemporary media in recent years, with various clinical aspects highlighted. It is seen in medical situations, such as the TV series House, MD as the drug of choice for the cessation of seizures. Usage for seizures is also depicted in the movie Saw III where "Jigsaw" is being operated on and begins to convulse: the character performing the surgery yells many times for Ativan, but discovers that none is available in the limited operating area. Blue October mentions Lorazepam in their song "HRSA", where it is being prescribed in a psychiatric ward for a similar use. The dependency problem is portrayed in William Gibson's 2007 book Spook Country, in which the character Milgrim is addicted to Ativan and the character Brown exploits Milgrim's addiction, in order to control him, through a steady supply of Ativan and Rize (a brand of the benzodiazepine clotiazepam). In Martin Scorsese's recent film, The Departed, Billy Costigan--an edgy, bitter, intelligent undercover cop for the Massachusetts State Police--suffers from frequent anxiety and claims to have panic attacks and is occasionally seen in the film taking lorazepam.
In 2005, Fall Out Boy member Pete Wentz attempted to overdose on lorazepam when trying to attempt suicide; he included references to the episode in the songs "I've Got a Dark Alley and a Bad Idea That Says You Should Shut Your Mouth (Summer Song)" and "7 Minutes in Heaven (Atavan Halen)",[66] on the album From Under the Cork Tree.