Lorazepam is a high-potency short-to-intermediate-acting 3-hydroxy
benzodiazepineA benzodiazepine is a psychoactive drug whose core chemical structure is the fusion of a benzene ring and a diazepine ring...
drug that has all five intrinsic benzodiazepine effects:
anxiolyticAn anxiolytic is a drug used for the treatment of anxiety, and its related psychological and physical symptoms...
,
amnesicAnterograde amnesia is a loss of the ability to create new memories after the event that caused the amnesia, leading to a partial or complete inability to recall the recent past, while long-term memories from before the event remain intact. This is in contrast to retrograde amnesia, where memories...
,
sedativeA sedative or tranquilizer is a substance that induces sedation by reducing irritability or excitement....
/
hypnoticHypnotic drugs are a class of psychoactives whose primary function is to induce sleep and to be used in the treatment of insomnia and in surgical anesthesia...
,
anticonvulsantThe anticonvulsants are a diverse group of pharmaceuticals used in the treatment of epileptic seizures. Anticonvulsants are also increasingly being used in the treatment of bipolar disorder, since many seem to act as mood stabilizers, and in the treatment of neuropathic pain. The goal of an...
,
antiemeticAn antiemetic is a drug that is effective against vomiting and nausea. Antiemetics are typically used to treat motion sickness and the side effects of opioid analgesics, general anaesthetics, and chemotherapy directed against cancer....
and
muscle relaxantA muscle relaxant is a drug which affects skeletal muscle function and decreases the muscle tone. It may be used to alleviate symptoms such as muscle spasms, pain, and hyperreflexia. The term "muscle relaxant" is used to refer to two major therapeutic groups: neuromuscular blockers and spasmolytics...
. Lorazepam is used for the short-term treatment of anxiety, insomnia, acute seizures including
status epilepticusStatus epilepticus is a life-threatening condition in which the brain is in a state of persistent seizure. Definitions vary, but traditionally it is defined as one continuous unremitting seizure lasting longer than 5 minutes, or recurrent seizures without regaining consciousness between seizures...
and sedation of hospitalized patients, as well as sedation of aggressive patients.
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 GABA
A receptors in the
central nervous systemThe central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
. After its introduction in 1977, lorazepam's principal use was in treating
anxietyAnxiety is a psychological and physiological state characterized by somatic, emotional, cognitive, and behavioral components. The root meaning of the word anxiety is 'to vex or trouble'; in either presence or absence of psychological stress, anxiety can create feelings of fear, worry, uneasiness,...
. Among benzodiazepines, lorazepam has a relatively high
addictiveSubstance use disorders include substance abuse and substance dependence. In DSM-IV, the conditions are formally diagnosed as one or the other, but it has been proposed that DSM-5 combine the two into a single condition called "Substance-use disorder"....
potential. Lorazepam also has abuse potential; the main types of misuse are for recreational purposes or continued use against medical advice. The sedative-hypnotic and anterograde amnesia properties of lorazepam are sometimes used for criminal purposes.
Long-term effects of benzodiazepines include tolerance, dependence, a
benzodiazepine withdrawal syndromeBenzodiazepine withdrawal syndrome—often abbreviated to benzo withdrawal—is the cluster of symptoms which appear when a person who has taken benzodiazepines long term and has developed benzodiazepine dependence stops taking benzodiazepine drug or during dosage reductions...
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
anxietyAnxiety is a psychological and physiological state characterized by somatic, emotional, cognitive, and behavioral components. The root meaning of the word anxiety is 'to vex or trouble'; in either presence or absence of psychological stress, anxiety can create feelings of fear, worry, uneasiness,...
and
insomniaInsomnia is most often defined by an individual's report of sleeping difficulties. While the term is sometimes used in sleep literature to describe a disorder demonstrated by polysomnographic evidence of disturbed sleep, insomnia is often defined as a positive response to either of two questions:...
to seizures and
psychosisPsychosis means abnormal condition of the mind, and is a generic psychiatric term for a mental state often described as involving a "loss of contact with reality"...
. Due to tolerance and dependence, lorazepam is recommended for short-term use, 2–4 weeks only. Adverse effects including
anterograde amnesiaAnterograde amnesia is a loss of the ability to create new memories after the event that caused the amnesia, leading to a partial or complete inability to recall the recent past, while long-term memories from before the event remain intact. This is in contrast to retrograde amnesia, where memories...
, 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. Lorazepam impairs body balance and standing steadiness and is associated with falls and hip fractures in the elderly.
Medical uses
Lorazepam has relatively potent
anxiolyticAn anxiolytic is a drug used for the treatment of anxiety, and its related psychological and physical symptoms...
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. It is fast acting, and useful in treating fast onset panic anxiety.
Lorazepam has strong
sedativeA sedative or tranquilizer is a substance that induces sedation by reducing irritability or excitement....
/
hypnoticHypnotic drugs are a class of psychoactives whose primary function is to induce sleep and to be used in the treatment of insomnia and in surgical anesthesia...
effects, and the duration of clinical effects from a single dose makes it an appropriate choice for the short-term treatment of
insomniaInsomnia is most often defined by an individual's report of sleeping difficulties. While the term is sometimes used in sleep literature to describe a disorder demonstrated by polysomnographic evidence of disturbed sleep, insomnia is often defined as a positive response to either of two questions:...
, 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.
Lorazepam is sometimes used for individuals receiving
mechanical ventilationIn medicine, mechanical ventilation is a method to mechanically assist or replace spontaneous breathing. This may involve a machine called a ventilator or the breathing may be assisted by a physician, respiratory therapist or other suitable person compressing a bag or set of bellows...
. However, in critically ill patients,
propofolPropofol is a short-acting, intravenously administered hypnotic agent. Its uses include the induction and maintenance of general anesthesia, sedation for mechanically ventilated adults, and procedural sedation. Propofol is also commonly used in veterinary medicine...
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, with its anxiolytic and sedative effects, makes lorazepam useful as
premedicationPremedication refer to a drug treatment given to a patient before a medical procedure. These drugs are typically sedative or analgesic....
. 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. Lorazepam is sometimes used as an alternative to
midazolamMidazolam is a short-acting drug in the benzodiazepine class developed by Hoffmann-La Roche in the 1970s. The drug is used for treatment of acute seizures, moderate to severe insomnia, and for inducing sedation and amnesia before medical procedures. It possesses profoundly potent anxiolytic,...
in palliative sedation. In intensive care units lorazepam is sometimes used to produce anxiolysis,
hypnosisHypnosis is "a trance state characterized by extreme suggestibility, relaxation and heightened imagination."It is a mental state or imaginative role-enactment . It is usually induced by a procedure known as a hypnotic induction, which is commonly composed of a long series of preliminary...
, and
amnesiaAmnesia is a condition in which one's memory is lost. The causes of amnesia have traditionally been divided into categories. Memory appears to be stored in several parts of the limbic system of the brain, and any condition that interferes with the function of this system can cause amnesia...
.
Intravenous
diazepamDiazepam , first marketed as Valium by Hoffmann-La Roche is a benzodiazepine drug. Diazepam is also marketed in Australia as Antenex. It is commonly used for treating anxiety, insomnia, seizures including status epilepticus, muscle spasms , restless legs syndrome, alcohol withdrawal,...
or lorazepam are first-line treatments for convulsive
status epilepticusStatus epilepticus is a life-threatening condition in which the brain is in a state of persistent seizure. Definitions vary, but traditionally it is defined as one continuous unremitting seizure lasting longer than 5 minutes, or recurrent seizures without regaining consciousness between seizures...
. Lorazepam is more effective than diazepam in the treatment of status epilepticus. However, phenobarbitol has a superior success rate compared to lorazepam and other drugs, at least in the elderly.
The marked
anticonvulsantThe anticonvulsants are a diverse group of pharmaceuticals used in the treatment of epileptic seizures. Anticonvulsants are also increasingly being used in the treatment of bipolar disorder, since many seem to act as mood stabilizers, and in the treatment of neuropathic pain. The goal of an...
properties of lorazepam, and its pharmacokinetic profile, make intravenous lorazepam a reliable agent for terminating
acute seizuresStatus epilepticus is a life-threatening condition in which the brain is in a state of persistent seizure. Definitions vary, but traditionally it is defined as one continuous unremitting seizure lasting longer than 5 minutes, or recurrent seizures without regaining consciousness between 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 epilepsyEpilepsy is a common chronic neurological disorder characterized by seizures. These seizures are transient signs and/or symptoms of abnormal, excessive or hypersynchronous neuronal activity in the brain.About 50 million people worldwide have epilepsy, and nearly two out of every three new cases...
, 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-Protracted withdrawal:A protracted alcohol withdrawal syndrome occurs in many alcoholics where withdrawal symptoms continue beyond the acute withdrawal stage but usually at a subacute level of intensity and gradually decreasing with severity over time. This syndrome is also sometimes referred to...
. 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
haloperidolHaloperidol is a typical antipsychotic. It is in the butyrophenone class of antipsychotic medications and has pharmacological effects similar to the phenothiazines....
when there is the need for
rapid sedationSedation is the reduction of irritability or agitation by administration of sedative drugs, generally to facilitate a medical procedure or diagnostic procedure...
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
deliriumDelirium or acute confusional state is a common and severe neuropsychiatric syndrome with core features of acute onset and fluctuating course, attentional deficits and generalized severe disorganization of behavior...
is sometimes treated with lorazepam, but as it can cause paradoxical effects, it is preferably given together with
haloperidolHaloperidol is a typical antipsychotic. It is in the butyrophenone class of antipsychotic medications and has pharmacological effects similar to the phenothiazines....
. Lorazepam is absorbed relatively slowly if given intramuscularly, a common route in restraint situations.
CatatoniaCatatonia is a state of neurogenic motor immobility, and behavioral abnormality manifested by stupor. It was first described in 1874: Die Katatonie oder das Spannungsirresein ....
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 syndromeBenzodiazepine withdrawal syndrome—often abbreviated to benzo withdrawal—is the cluster of symptoms which appear when a person who has taken benzodiazepines long term and has developed benzodiazepine dependence stops taking benzodiazepine drug or during dosage reductions...
, should also respond to lorazepam treatment. As lorazepam can have paradoxical effects,
haloperidolHaloperidol is a typical antipsychotic. It is in the butyrophenone class of antipsychotic medications and has pharmacological effects similar to the phenothiazines....
is sometimes given concomitantly.
It is sometimes used in
chemotherapyChemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....
as an adjunct to
antiemeticAn antiemetic is a drug that is effective against vomiting and nausea. Antiemetics are typically used to treat motion sickness and the side effects of opioid analgesics, general anaesthetics, and chemotherapy directed against cancer....
s for treating anticipatory
nauseaNausea , is a sensation of unease and discomfort in the upper stomach with an involuntary urge to vomit. It often, but not always, precedes vomiting...
and
vomitingVomiting is the forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose...
, 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 syndromeCyclic vomiting syndrome or cyclical vomiting syndrome is a condition whose symptoms are recurring attacks of intense nausea, vomiting and sometimes abdominal pain and/or headaches or migraines...
.
Lorazepam is also used to treat acute symptoms of vertigo and dizziness for people with
Ménière's diseaseMénière's disease is a disorder of the inner ear that can affect hearing and balance to a varying degree. It is characterized by episodes of vertigo and tinnitus and progressive hearing loss, usually in one ear. It is named after the French physician Prosper Ménière, who, in an article published...
.
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
sublingualSublingual, literally 'under the tongue', from Latin, refers to the pharmacological route of administration by which drugs diffuse into the blood through tissues under the tongue...
tablet.
Lorazepam tablets and syrups are administered by mouth only. Lorazepam tablets of the Ativan brand also contain
lactoseLactose is a disaccharide sugar that is found most notably in milk and is formed from galactose and glucose. Lactose makes up around 2~8% of milk , although the amount varies among species and individuals. It is extracted from sweet or sour whey. The name comes from or , the Latin word for milk,...
,
microcrystalline celluloseCellulose is an organic compound with the formula , a polysaccharide consisting of a linear chain of several hundred to over ten thousand β linked D-glucose units....
, polacrilin,
magnesium stearateMagnesium stearate, also called octadecanoic acid, magnesium salt, is a white substance which is solid at room temperature. It has the chemical formula . It is a salt containing two equivalents of stearate and one magnesium cation...
, and colouring agents (indigo carmine—E132—in blue tablets and tartrazine—E102— in yellow tablets).
Lorazepam injectable solution is administered either by deep
intramuscular injectionIntramuscular injection is the injection of a substance directly into a muscle. In medicine, it is one of several alternative methods for the administration of medications . It is used for particular forms of medication that are administered in small amounts...
or by
intravenousIntravenous therapy or IV therapy is the infusion of liquid substances directly into a vein. The word intravenous simply means "within a vein". Therapies administered intravenously are often called specialty pharmaceuticals...
injection. The injectable solution comes in 1 mL
ampouleAn ampoule is a small sealed vial which is used to contain and preserve a sample, usually a solid or liquid. Ampoules are commonly made of glass, although plastic ampoules do exist....
s containing 2 mg or 4 mg lorazepam. The solvents used are
polyethylene glycol 400Polyethylene glycol is a polyether compound with many applications from industrial manufacturing to medicine. It has also been known as polyethylene oxide or polyoxyethylene , depending on its molecular weight, and under the tradename Carbowax.-Available forms:PEG, PEO, or POE refers to an...
and
propylene glycolPropylene glycol, also called 1,2-propanediol or propane-1,2-diol, is an organic compound with formula C3H8O2 or HO-CH2-CHOH-CH3...
. As a preservative, the injectable solution contains
benzyl alcoholBenzyl alcohol is an organic compound with the formula C6H5CH2OH. The benzyl group is often abbreviated "Bn", thus benzyl alcohol is denoted as BnOH. Benzyl alcohol is a colorless liquid with a mild pleasant aromatic odor. It is a useful solvent due to its polarity, low toxicity, and low vapor...
. 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. Adverse effects can include sedation and
hypotensionIn physiology and medicine, hypotension is abnormally low blood pressure, especially in the arteries of the systemic circulation. It is best understood as a physiologic state, rather than a disease. It is often associated with shock, though not necessarily indicative of it. Hypotension is the...
; the effects of lorazepam are increased in combination with other CNS depressant drugs. Other adverse effects include confusion,
ataxiaAtaxia is a neurological sign and symptom that consists of gross lack of coordination of muscle movements. Ataxia is a non-specific clinical manifestation implying dysfunction of the parts of the nervous system that coordinate movement, such as the cerebellum...
,
anterograde amnesiaAnterograde amnesia is a loss of the ability to create new memories after the event that caused the amnesia, leading to a partial or complete inability to recall the recent past, while long-term memories from before the event remain intact. This is in contrast to retrograde amnesia, where memories...
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 memoryExplicit memory is the conscious, intentional recollection of previous experiences and information. People use explicit memory throughout the day, such as remembering the time of an appointment or recollecting an event from years ago....
and
implicit memoryImplicit memory is a type of memory in which previous experiences aid in the performance of a task without conscious awareness of these previous experiences. Evidence for implicit memory arises in priming, a process whereby subjects show improved performance on tasks for which they have been...
. 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. 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. Cognitive impairment, behavioural disinhibition and respiratory depression as well as
hypotensionIn physiology and medicine, hypotension is abnormally low blood pressure, especially in the arteries of the systemic circulation. It is best understood as a physiologic state, rather than a disease. It is often associated with shock, though not necessarily indicative of it. Hypotension is the...
may also occur.
- Paradoxical effects: In some cases, there can be paradox
Similar to Circular reasoning, A paradox is a seemingly true statement or group of statements that lead to a contradiction or a situation which seems to defy logic or intuition...
ical 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. Paradoxical effects are more likely to occur with higher doses, in patients with pre-existing personality disorderPersonality disorders, formerly referred to as character disorders, are a class of personality types and behaviors. Personality disorders are noted on Axis II of the Diagnostic and Statistical Manual of Mental Disorders or DSM-IV-TR of the American Psychiatric Association.Personality disorders are...
s 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
Anterograde amnesia is a loss of the ability to create new memories after the event that caused the amnesia, leading to a partial or complete inability to recall the recent past, while long-term memories from before the event remain intact. This is in contrast to retrograde amnesia, where memories...
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
An Allergy is a hypersensitivity disorder of the immune system. Allergic reactions occur when a person's immune system reacts to normally harmless substances in the environment. A substance that causes a reaction is called an allergen. These reactions are acquired, predictable, and rapid...
or hypersensitivityHypersensitivity refers to undesirable reactions produced by the normal immune system, including allergies and autoimmunity. These reactions may be damaging, uncomfortable, or occasionally fatal. Hypersensitivity reactions require a pre-sensitized state of the host. The four-group classification...
– Past hypersensitivity or allergy to lorazepam, to any benzodiazepine, or to any of the ingredients in lorazepam tablets or injections
- Severe respiratory failure
The term respiratory failure, in medicine, is used to describe inadequate gas exchange by the respiratory system, with the result that arterial oxygen and/or carbon dioxide levels cannot be maintained within their normal ranges. A drop in blood oxygenation is known as hypoxemia; a rise in arterial...
– 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 asthmaStatus asthmaticus is an acute exacerbation of asthma that does not respond to standard treatments of bronchodilators and steroids. Symptoms include chest tightness, rapidly progressive dyspnea , dry cough, use of accessory muscles, labored breathing and extreme wheezing. It is a life-threatening...
. The anxiolytic effects may also be detrimental to a patient's willingness and ability to fight for breath. However, if mechanical ventilationIn medicine, mechanical ventilation is a method to mechanically assist or replace spontaneous breathing. This may involve a machine called a ventilator or the breathing may be assisted by a physician, respiratory therapist or other suitable person compressing a bag or set of bellows...
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
Ataxia is a neurological sign and symptom that consists of gross lack of coordination of muscle movements. Ataxia is a non-specific clinical manifestation implying dysfunction of the parts of the nervous system that coordinate movement, such as the cerebellum...
– 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
Glaucoma is an eye disorder in which the optic nerve suffers damage, permanently damaging vision in the affected eye and progressing to complete blindness if untreated. It is often, but not always, associated with increased pressure of the fluid in the eye...
– 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 glaucomaGlaucoma is an eye disorder in which the optic nerve suffers damage, permanently damaging vision in the affected eye and progressing to complete blindness if untreated. It is often, but not always, associated with increased pressure of the fluid in the eye...
.
- Sleep apnea
Sleep apnea is a sleep disorder characterized by abnormal pauses in breathing or instances of abnormally low breathing, during sleep. Each pause in breathing, called an apnea, can last from a few seconds to minutes, and may occur 5 to 30 times or more an hour. Similarly, each abnormally low...
– 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
Myasthenia gravis is an autoimmune neuromuscular disease leading to fluctuating muscle weakness and fatiguability...
– This condition is characterised by muscle weakness and a muscle relaxant such as lorazepam may exacerbate symptoms.
- Pregnancy
Pregnancy refers to the fertilization and development of one or more offspring, known as a fetus or embryo, in a woman's uterus. In a pregnancy, there can be multiple gestations, as in the case of twins or triplets...
and breast feeding – Lorazepam belongs to the Food and Drug AdministrationThe Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
(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 syndromeHypotonia is a state of low muscle tone , often involving reduced muscle strength. Hypotonia is not a specific medical disorder, but a potential manifestation of many different diseases and disorders that affect motor nerve control by the brain or muscle strength...
in the neonate, or respiratory depression necessitating ventilation. Regular lorazepam use during late pregnancy (the third trimester), carries a definite risk of benzodiazepine withdrawal syndromeBenzodiazepine withdrawal syndrome—often abbreviated to benzo withdrawal—is the cluster of symptoms which appear when a person who has taken benzodiazepines long term and has developed benzodiazepine dependence stops taking benzodiazepine drug or during dosage reductions...
in the neonate. Neonatal benzodiazepine withdrawal may include hypotoniaHypotonia is a state of low muscle tone , often involving reduced muscle strength. Hypotonia is not a specific medical disorder, but a potential manifestation of many different diseases and disorders that affect motor nerve control by the brain or muscle strength...
, reluctance to suck, apneic spells, cyanosisCyanosis is the appearance of a blue or purple coloration of the skin or mucous membranes due to the tissues near the skin surface being low on oxygen. The onset of cyanosis is 2.5 g/dL of deoxyhemoglobin. The bluish color is more readily apparent in those with high hemoglobin counts than it is...
, 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
Acute liver failure is the appearance of severe complications rapidly after the first signs of liver disease , and indicates that the liver has sustained severe damage . The complications are hepatic encephalopathy and impaired protein synthesis...
or kidney failure – Lorazepam may be safer than most benzodiazepines in patients with impaired liver functionAcute liver failure is the appearance of severe complications rapidly after the first signs of liver disease , and indicates that the liver has sustained severe damage . The complications are hepatic encephalopathy and impaired protein synthesis...
. Like oxazepamOxazepam , is a drug which is a short to intermediate acting 3-hydroxy benzodiazepine derivative...
, 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.
- Surgical premedication – Informed consent
Informed consent is a phrase often used in law to indicate that the consent a person gives meets certain minimum standards. As a literal matter, in the absence of fraud, it is redundant. An informed consent can be said to have been given based upon a clear appreciation and understanding of the...
that was given only after receiving lorazepam premedicationPremedication refer to a drug treatment given to a patient before a medical procedure. These drugs are typically sedative or analgesic....
could have its validity challenged later. Staff must use chaperoneIn clinical medicine, a chaperone is a person who serves as a witness for both a patient and a medical practitioner as a safeguard for both parties during a medical examination or procedure. The exact responsibilities vary according to the clinical situation....
s 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 (sedationSedation is the reduction of irritability or agitation by administration of sedative drugs, generally to facilitate a medical procedure or diagnostic procedure...
, ataxiaAtaxia is a neurological sign and symptom that consists of gross lack of coordination of muscle movements. Ataxia is a non-specific clinical manifestation implying dysfunction of the parts of the nervous system that coordinate movement, such as the cerebellum...
, hypotensionIn physiology and medicine, hypotension is abnormally low blood pressure, especially in the arteries of the systemic circulation. It is best understood as a physiologic state, rather than a disease. It is often associated with shock, though not necessarily indicative of it. Hypotension is the...
, and amnesiaAnterograde amnesia is a loss of the ability to create new memories after the event that caused the amnesia, leading to a partial or complete inability to recall the recent past, while long-term memories from before the event remain intact. This is in contrast to retrograde amnesia, where memories...
), 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
Substance abuse, also known as drug abuse, refers to a maladaptive pattern of use of a substance that is not considered dependent. The term "drug abuse" does not exclude dependency, but is otherwise used in a similar manner in nonmedical contexts...
– There is an increased risk of abuse of lorazepam.
- Comorbid psychiatric disorders – Increased risk of dependence and paradoxical adverse effects
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 dependenceBenzodiazepine dependence or benzodiazepine addiction is a condition during which a person is dependent on benzodiazepine drugs. Dependence can be either a psychological dependence, physical dependence, or a combination of the two...
. Potent benzodiazepines such as lorazepam,
alprazolamAlprazolam is a short-acting anxiolytic of the benzodiazepine class of psychoactive drugs. Alprazolam, like other benzodiazepines, binds to specific sites on the GABAA gamma-amino-butyric acid receptor...
, and
triazolamTriazolam is a benzodiazepine drug. It possesses pharmacological properties similar to that of other benzodiazepines, but it is generally only used as a sedative to treat severe insomnia...
have the highest risk of causing a dependence. 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. Due to the development of tolerance to the
anticonvulsantThe anticonvulsants are a diverse group of pharmaceuticals used in the treatment of epileptic seizures. Anticonvulsants are also increasingly being used in the treatment of bipolar disorder, since many seem to act as mood stabilizers, and in the treatment of neuropathic pain. The goal of an...
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 expressionGene expression is the process by which information from a gene is used in the synthesis of a functional gene product. These products are often proteins, but in non-protein coding genes such as ribosomal RNA , transfer RNA or small nuclear RNA genes, the product is a functional RNA...
.
The likelihood of dependence is relatively high with lorazepam compared to other
benzodiazepineA benzodiazepine is a psychoactive drug whose core chemical structure is the fusion of a benzene ring and a diazepine ring...
s. 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
diazepamDiazepam , first marketed as Valium by Hoffmann-La Roche is a benzodiazepine drug. Diazepam is also marketed in Australia as Antenex. It is commonly used for treating anxiety, insomnia, seizures including status epilepticus, muscle spasms , restless legs syndrome, alcohol withdrawal,...
, 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.
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
benzodiazepineA benzodiazepine is a psychoactive drug whose core chemical structure is the fusion of a benzene ring and a diazepine ring...
drugs, can cause
physical dependencePhysical dependence refers to a state resulting from chronic use of a drug that has produced tolerance and where negative physical symptoms of withdrawal result from abrupt discontinuation or dosage reduction...
,
addictionSubstance use disorders include substance abuse and substance dependence. In DSM-IV, the conditions are formally diagnosed as one or the other, but it has been proposed that DSM-5 combine the two into a single condition called "Substance-use disorder"....
, and what is known as the
benzodiazepine withdrawal syndromeBenzodiazepine withdrawal syndrome—often abbreviated to benzo withdrawal—is the cluster of symptoms which appear when a person who has taken benzodiazepines long term and has developed benzodiazepine dependence stops taking benzodiazepine drug or during dosage reductions...
. 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
psychosisPsychosis means abnormal condition of the mind, and is a generic psychiatric term for a mental state often described as involving a "loss of contact with reality"...
. 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.
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,
dysphoriaDysphoria is medically recognized as a mental and emotional condition in which a person experiences intense feelings of depression, discontent and indifference to the world around them.Mood disorders can induce dysphoria, often with a heightened risk of suicide, especially in...
, dizziness,
derealizationDerealization is an alteration in the perception or experience of the external world so that it seems unreal. Other symptoms include feeling as though one's environment is lacking in spontaneity, emotional coloring and depth. It is a dissociative symptom of many conditions, such as psychiatric and...
, depersonalization, numbness/tingling of extremities, hypersensitivity to light, sound, and smell, perceptual distortions, nausea, vomiting, diarrhea, appetite loss, hallucinations, delirium, seizures, tremor, stomach cramps,
myalgiaMyalgia means "muscle pain" and is a symptom of many diseases and disorders. The most common causes are the overuse or over-stretching of a muscle or group of muscles. Myalgia without a traumatic history is often due to viral infections...
, agitation, palpitations,
tachycardiaTachycardia comes from the Greek words tachys and kardia . Tachycardia typically refers to a heart rate that exceeds the normal range for a resting heart rate...
, panic attacks, short-term memory loss, and hyperthermia. It takes approximately 18–36 hours for the benzodiazepine to remove itself from the body. 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!That's Life! was a magazine-style television series on BBC1 between 26 May 1973 and 19 June 1994, presented by Esther Rantzen throughout the entire run, with various changes of co-presenters. The show was generally recorded about an hour prior to transmission, which was originally on Saturday...
", 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
disinhibitoryDisinhibition is a term in psychology used to describe a lack of restraint manifested in several ways, including disregard for social conventions, impulsivity, and poor risk assessment. Disinhibition affects motor, instinctual, emotional, cognitive and perceptual aspects with signs and symptoms...
and
amnesicAnterograde amnesia is a loss of the ability to create new memories after the event that caused the amnesia, leading to a partial or complete inability to recall the recent past, while long-term memories from before the event remain intact. This is in contrast to retrograde amnesia, where memories...
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. Lorazepam may also interact with
rifabutinRifabutin is a bactericidal antibiotic drug primarily used in the treatment of tuberculosis. The drug is a semi-synthetic derivative of rifamycin S. Its effect is based on blocking the DNA-dependent RNA-polymerase of the bacteria. It is effective against Gram-positive and some Gram-negative...
. Valproate, inhibits the metabolism of lorazepam, whereas
carbamazepineCarbamazepine is an anticonvulsant and mood-stabilizing drug used primarily in the treatment of epilepsy and bipolar disorder, as well as trigeminal neuralgia...
,
lamotrigineLamotrigine, marketed in the US and most of Europe as Lamictal by GlaxoSmithKline, is an anticonvulsant drug used in the treatment of epilepsy and bipolar disorder. It is also used as an adjunct in treating depression, though this is considered off-label usage...
,
phenobarbitalPhenobarbital or phenobarbitone is a barbiturate, first marketed as Luminal by Friedr. Bayer et comp. It is the most widely used anticonvulsant worldwide, and the oldest still commonly used. It also has sedative and hypnotic properties but, as with other barbiturates, has been superseded by the...
,
phenytoinPhenytoin sodium is a commonly used antiepileptic. Phenytoin acts to suppress the abnormal brain activity seen in seizure by reducing electrical conductance among brain cells by stabilizing the inactive state of voltage-gated sodium channels...
, 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.
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,
dysarthriaDysarthria is a motor speech disorder resulting from neurological injury of the motor component of the motor-speech system and is characterized by poor articulation of phonemes...
,
paradoxical reactionA paradoxical reaction or paradoxical effect is when medical treatment, usually a drug, has the opposite effect to that which would normally be expected.An example of a paradoxical reaction is when a pain relief medication causes an increase in pain...
s, drowsiness,
hypotoniaHypotonia is a state of low muscle tone , often involving reduced muscle strength. Hypotonia is not a specific medical disorder, but a potential manifestation of many different diseases and disorders that affect motor nerve control by the brain or muscle strength...
,
ataxiaAtaxia is a neurological sign and symptom that consists of gross lack of coordination of muscle movements. Ataxia is a non-specific clinical manifestation implying dysfunction of the parts of the nervous system that coordinate movement, such as the cerebellum...
,
hypotensionIn physiology and medicine, hypotension is abnormally low blood pressure, especially in the arteries of the systemic circulation. It is best understood as a physiologic state, rather than a disease. It is often associated with shock, though not necessarily indicative of it. Hypotension is the...
, hypnotic state,
comaIn medicine, a coma is a state of unconsciousness, lasting more than 6 hours in which a person cannot be awakened, fails to respond normally to painful stimuli, light or sound, lacks a normal sleep-wake cycle and does not initiate voluntary actions. A person in a state of coma is described as...
, cardiovascular depression, respiratory depression, and
deathDeath is the permanent termination of the biological functions that sustain a living organism. Phenomena which commonly bring about death include old age, predation, malnutrition, disease, and accidents or trauma resulting in terminal injury....
.
Early management of alert patients includes emetics,
gastric lavageGastric lavage, also commonly called stomach pumping or Gastric irrigation, is the process of cleaning out the contents of the stomach. It has been used for over 200 years as a means of eliminating poisons from the stomach. Such devices are normally used on a person who has ingested a poison or...
, 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
flumazenilFlumazenil is a benzodiazepine antagonist available for injection only, and the only benzodiazepine receptor antagonist on the market today.It was first introduced in 1987 by Hoffmann-La Roche under the trade name Anexate, but only approved by...
.
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. Opportunistic counseling has limited value here, as the patient is unlikely to recall this later, owing to drug-induced
anterograde amnesiaAnterograde amnesia is a loss of the ability to create new memories after the event that caused the amnesia, leading to a partial or complete inability to recall the recent past, while long-term memories from before the event remain intact. This is in contrast to retrograde amnesia, where memories...
.
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
anxiolyticAn anxiolytic is a drug used for the treatment of anxiety, and its related psychological and physical symptoms...
,
sedativeA sedative or tranquilizer is a substance that induces sedation by reducing irritability or excitement....
,
hypnoticHypnotic drugs are a class of psychoactives whose primary function is to induce sleep and to be used in the treatment of insomnia and in surgical anesthesia...
, amnesic,
anticonvulsantThe anticonvulsants are a diverse group of pharmaceuticals used in the treatment of epileptic seizures. Anticonvulsants are also increasingly being used in the treatment of bipolar disorder, since many seem to act as mood stabilizers, and in the treatment of neuropathic pain. The goal of an...
as well as
muscle relaxantA muscle relaxant is a drug which affects skeletal muscle function and decreases the muscle tone. It may be used to alleviate symptoms such as muscle spasms, pain, and hyperreflexia. The term "muscle relaxant" is used to refer to two major therapeutic groups: neuromuscular blockers and spasmolytics...
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
diazepamDiazepam , first marketed as Valium by Hoffmann-La Roche is a benzodiazepine drug. Diazepam is also marketed in Australia as Antenex. It is commonly used for treating anxiety, insomnia, seizures including status epilepticus, muscle spasms , restless legs syndrome, alcohol withdrawal,...
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. 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%) mean that lorazepam's volume of distribution is mainly the
vascularThe circulatory system is an organ system that passes nutrients , gases, hormones, blood cells, etc...
compartment, causing relatively prolonged peak effects. This contrasts with the highly lipid-soluble
diazepamDiazepam , first marketed as Valium by Hoffmann-La Roche is a benzodiazepine drug. Diazepam is also marketed in Australia as Antenex. It is commonly used for treating anxiety, insomnia, seizures including status epilepticus, muscle spasms , restless legs syndrome, alcohol withdrawal,...
, 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. 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 epilepticusStatus epilepticus is a life-threatening condition in which the brain is in a state of persistent seizure. Definitions vary, but traditionally it is defined as one continuous unremitting seizure lasting longer than 5 minutes, or recurrent seizures without regaining consciousness between seizures...
: Its high lipid solubility means it gets absorbed with equal speed whether given 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 epilepticusStatus epilepticus is a life-threatening condition in which the brain is in a state of persistent seizure. Definitions vary, but traditionally it is defined as one continuous unremitting seizure lasting longer than 5 minutes, or recurrent seizures without regaining consciousness between seizures...
.
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, half of which is lorazepam, half its inactive metabolite, lorazepam-glucuronide. A similar lorazepam dose given intravenously will result in an earlier and higher peak 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. 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, 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 receptorThe GABA receptors are a class of receptors that respond to the neurotransmitter gamma-aminobutyric acid , the chief inhibitory neurotransmitter in the vertebrate central nervous system...
s, which may also explain its marked amnesic effects. The main pharmacological effects of lorazepam are the enhancement of the effects of
GABAGabâ or gabaa, for the people in many parts of the Philippines), is the concept of a non-human and non-divine, imminent retribution. A sort of negative karma, it is generally seen as an evil effect on a person because of their wrongdoings or transgressions...
at the GABA
A receptor. Benzodiazepines, such as lorazepam enhance the effects of GABA at the GABA
A receptor via increasing the frequency of opening of the chloride ion channel on the GABA
A receptors; which results in the therapeutic actions of benzodiazepines. Benzodiazepines, however, do not on their own enhance the GABA
A receptors but require the
neurotransmitterNeurotransmitters are endogenous chemicals that transmit signals from a neuron to a target cell across a synapse. Neurotransmitters are packaged into synaptic vesicles clustered beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they bind to...
GABA to be present. Thus the effect of benzodiazepines is to enhance the effects of the neurotransmitter GABA.
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
chlordiazepoxideChlordiazepoxide, is a sedative/hypnotic drug and benzodiazepine. It is marketed under the trade names Angirex, Klopoxid, Librax , Libritabs, Librium, Mesural, Multum, Novapam, Risolid, Silibrin, Sonimen and Tropium.Chlordiazepoxide was the first benzodiazepine to be synthesised and...
and
oxazepamOxazepam , is a drug which is a short to intermediate acting 3-hydroxy benzodiazepine derivative...
.
- 2-amino-2′,5-dichlorobenzophenone is reacted with hydroxylamine
Hydroxylamine is an inorganic compound with the formula NH2OH. The pure material is a white, unstable crystalline, hygroscopic compound. However, hydroxylamine is almost always provided and used as an aqueous solution. It is used to prepare oximes, an important functional group. It is also an...
.
- The intermediate oxime
An oxime is a chemical compound belonging to the imines, with the general formula R1R2C=NOH, where R1 is an organic side chain and R2 may be hydrogen, forming an aldoxime, or another organic group, forming a ketoxime. O-substituted oximes form a closely related family of compounds...
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
Methylamine is the organic compound with a formula of CH3NH2. This colourless gas is a derivative of ammonia, but with one H atom replaced by a methyl group. It is the simplest primary amine. It is sold as a solution in methanol, ethanol, THF, and water, or as the anhydrous gas in pressurized...
, 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
Acetic anhydride, or ethanoic anhydride, is the chemical compound with the formula 2O. Commonly abbreviated Ac2O, it is the simplest isolatable acid anhydride and is a widely used reagent in organic synthesis...
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
Acetic anhydride, or ethanoic anhydride, is the chemical compound with the formula 2O. Commonly abbreviated Ac2O, it is the simplest isolatable acid anhydride and is a widely used reagent in organic synthesis...
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 the 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
diazepamDiazepam , first marketed as Valium by Hoffmann-La Roche is a benzodiazepine drug. Diazepam is also marketed in Australia as Antenex. It is commonly used for treating anxiety, insomnia, seizures including status epilepticus, muscle spasms , restless legs syndrome, alcohol withdrawal,...
,
clonazepamClonazepamis a benzodiazepine drug having anxiolytic, anticonvulsant, muscle relaxant, and hypnotic properties. It is marketed by Roche under the trade name Klonopin in the United States and Rivotril in Australia, Brazil, Canada and Europe...
,
oxazepamOxazepam , is a drug which is a short to intermediate acting 3-hydroxy benzodiazepine derivative...
,
nitrazepamNitrazepam is a type of benzodiazepine drug and is marketed in English-speaking countries under the following brand names: Alodorm, Arem, Insoma, Mogadon, Nitrados, Nitrazadon, Ormodon, Paxadorm, Remnos, and Somnite...
,
flurazepamFlurazepam is a drug which is a benzodiazepine derivative. It possesses anxiolytic, anticonvulsant, sedative and skeletal muscle relaxant properties. It produces a metabolite with a very long half-life , which may stay in the bloodstream for up to four days...
,
bromazepamBromazepam is a benzodiazepine derivative drug, patented by Roche in the 1963 and developed clinically in the 1970s...
and
clorazepateClorazepate , also known as clorazepate dipotassium, is a drug that is a benzodiazepine derivative. It possesses anxiolytic, anticonvulsant, sedative, hypnotic and skeletal muscle relaxant properties. Clorazepate is a prodrug for desmethyldiazepam, which is rapidly produced as an active metabolite...
. 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.
WyethWyeth, formerly one of the companies owned by American Home Products Corporation , was a pharmaceutical company. The company was based in Madison, New Jersey, USA...
's original
patentA patent is a form of intellectual property. It consists of a set of exclusive rights granted by a sovereign state to an inventor or their assignee for a limited period of time in exchange for the public disclosure of an invention....
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 brand names since then:
Almazine, Alzapam, Anxiedin, Anxira, Anzepam, Aplacasse, Aplacassee, Apo-Lorazepam, Aripax, Azurogen, Bonatranquan, Bonton, Control, Donix, Duralozam, Efasedan, Emotion, Emotival, Idalprem, Kalmalin, Larpose, Laubeel, Lopam, Lorabenz, Loram, Lorans, Lorapam, Lorat, Lorax, Lorazene, Lorazep, Lorazepam, Lorazin, Lorafen (PL), Lorazon, Lorenin, 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.The United States of America is a federal constitutional republic comprising fifty states and a federal district...
drug company
MylanMylan Inc. is a global generic and specialty pharmaceuticals company headquartered in Canonsburg, Pennsylvania. In 2007, Mylan acquired a controlling interest in India-based Matrix Laboratories Limited, a top producer of active pharmaceutical ingredients for generic drugs, and the generics...
agreed to pay $147 million to settle accusations by the
F.T.C.The Federal Trade Commission is an independent agency of the United States government, established in 1914 by the Federal Trade Commission Act...
that they had raised the price of generic lorazepam by 2600 percent and generic
clorazepateClorazepate , also known as clorazepate dipotassium, is a drug that is a benzodiazepine derivative. It possesses anxiolytic, anticonvulsant, sedative, hypnotic and skeletal muscle relaxant properties. Clorazepate is a prodrug for desmethyldiazepam, which is rapidly produced as an active metabolite...
by 3200 percent in 1998 after having obtained exclusive licensing agreements for certain ingredients.
Recreational use
Lorazepam is also used for other purposes, such as recreational use, wherein the drug is taken to achieve a high, or when the drug is continued long term against medical advice.
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 (which increases their potential for violence). The
anterograde amnesiaAnterograde amnesia is a loss of the ability to create new memories after the event that caused the amnesia, leading to a partial or complete inability to recall the recent past, while long-term memories from before the event remain intact. This is in contrast to retrograde amnesia, where memories...
and sedative-hypnotic effects of benzodiazepines such as lorazepam are sometimes used by predators on unwitting victims as
date rape drugA date rape drug is any drug that can be used to assist in the execution of a sexual assault, such as date rape. Drugs used to facilitate rape may have sedative, hypnotic, dissociative, and/or amnesiac effects, and can be added to a food or drink without the victim's knowledge.The act of adding...
s, or for the purpose of
robberyRobbery is the crime of taking or attempting to take something of value by force or threat of force or by putting the victim in fear. At common law, robbery is defined as taking the property of another, with the intent to permanently deprive the person of that property, by means of force or fear....
; however, alcohol is the most common drug involved in such 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 ActThe Controlled Substances Act was enacted into law by the Congress of the United States as Title II of the Comprehensive Drug Abuse Prevention and Control Act of 1970. The CSA is the federal U.S. drug policy under which the manufacture, importation, possession, use and distribution of certain...
in the U.S. and internationally under the United Nations
Convention on Psychotropic SubstancesThe Convention on Psychotropic Substances of 1971 is a United Nations treaty designed to control psychoactive drugs such as amphetamines, barbiturates, benzodiazepines, and psychedelics signed at Vienna on February 21, 1971...
. Lorazepam is a Schedule IV drug under the
Controlled Drugs and Substances ActThe Controlled Drugs and Substances Act is Canada's federal drug control statute. Passed in 1996 by the Chrétien government, it repeals the Narcotic Control Act and Parts III and IV of the Food and Drug Act and establishes eight Schedules of controlled substances and two Classes of precursors...
in Canada. In the United Kingdom, lorazepam is a Class C, Schedule 4 Controlled Drug under the Misuse of Drugs Regulations 2001.
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