Diazepam first marketed as
Valium (icon) by
Hoffmann-La RocheF. Hoffmann-La Roche Ltd. is a Swiss global health-care company that operates worldwide under two divisions: Pharmaceuticals and Diagnostics. Its holding company, Roche Holding AG, has shares listed on the SIX Swiss Exchange....
is a
benzodiazepineA benzodiazepine is a psychoactive drug whose core chemical structure is the fusion of a benzene ring and a diazepine ring...
drugA drug, broadly speaking, is any substance that, when absorbed into the body of a living organism, alters normal bodily function. There is no single, precise definition, as there are different meanings in drug control law, government regulations, medicine, and colloquial usage.In pharmacology, a...
. Diazepam is also marketed in Australia as Antenex. It is commonly used for 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,...
,
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:...
,
seizureAn epileptic seizure, occasionally referred to as a fit, is defined as a transient symptom of "abnormal excessive or synchronous neuronal activity in the brain". The outward effect can be as dramatic as a wild thrashing movement or as mild as a brief loss of awareness...
s 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...
, muscle spasms (such as in cases of
tetanusTetanus is a medical condition characterized by a prolonged contraction of skeletal muscle fibers. The primary symptoms are caused by tetanospasmin, a neurotoxin produced by the Gram-positive, rod-shaped, obligate anaerobic bacterium Clostridium tetani...
),
restless legs syndromeRestless legs syndrome or Willis-Ekbom disease is a neurological disorder characterized by an irresistible urge to move one's body to stop uncomfortable or odd sensations. It most commonly affects the legs, but can affect the arms, torso, and even phantom limbs...
, alcohol withdrawal, benzodiazepine withdrawal and
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...
. It may also be used before certain medical procedures (such as
endoscopiesEndoscopy means looking inside and typically refers to looking inside the body for medical reasons using an endoscope , an instrument used to examine the interior of a hollow organ or cavity of the body. Unlike most other medical imaging devices, endoscopes are inserted directly into the organ...
) to reduce tension and anxiety, and in some surgical procedures to induce
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...
. It possesses
anxiolyticAn anxiolytic is a drug used for the treatment of anxiety, and its related psychological and physical symptoms...
,
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...
,
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...
,
sedativeA sedative or tranquilizer is a substance that induces sedation by reducing irritability or excitement....
, skeletal muscle relaxant, and amnestic properties. The pharmacological action of diazepam enhances the effect of the neurotransmitter
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...
by binding to the benzodiazepine site on the GABA
A receptor leading to
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...
depression.
Adverse effects of diazepam include
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...
(especially at higher doses) and
sedationSedation is the reduction of irritability or agitation by administration of sedative drugs, generally to facilitate a medical procedure or diagnostic procedure...
as well as paradoxical effects such as excitement, rage or worsening of seizures in epileptics. Benzodiazepines also can cause or worsen depression. Long-term effects of benzodiazepines such as diazepam include tolerance,
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...
as well as 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...
upon dose reduction; additionally after cessation of benzodiazepines cognitive deficits may persist for at least 6 months and may not fully return to normal, however it was suggested that longer than 6 months may be needed for recovery from some deficits. Diazepam also has physical dependence potential and can cause serious problems of physical dependence with long term use. However, compared to other benzodiazepines, physical withdrawal from diazepam following long term use is usually far more mild due to its long elimination half life. Nevertheless, urgent action by National Governments to improve prescribing practices has been recommended.
Advantages of diazepam are a rapid onset of action and high efficacy rates which is important for managing acute seizures; benzodiazepines also have a relatively low toxicity in overdose. Diazepam is a core medicine in the
World Health OrganizationThe World Health Organization is a specialized agency of the United Nations that acts as a coordinating authority on international public health. Established on 7 April 1948, with headquarters in Geneva, Switzerland, the agency inherited the mandate and resources of its predecessor, the Health...
's "Essential Drugs List", which is a list of minimum medical needs for a basic health care system. Diazepam is used to treat a wide range of conditions and has been one of the most frequently prescribed medications in the world for the past forty years. It was first synthesized by
Leo SternbachLeo Henryk Sternbach was a Polish-Jewish chemist who is credited with discovering benzodiazepines, main class of tranquilizers.-Biography:...
.
Medical uses
Diazepam is mainly used to treat
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,...
,
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:...
, and symptoms of acute alcohol withdrawal. It is also used as a
premedicationPremedication refer to a drug treatment given to a patient before a medical procedure. These drugs are typically sedative or analgesic....
for inducing
sedationSedation is the reduction of irritability or agitation by administration of sedative drugs, generally to facilitate a medical procedure or diagnostic procedure...
, anxiolysis or
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...
before certain medical procedures (e.g.,
endoscopyEndoscopy means looking inside and typically refers to looking inside the body for medical reasons using an endoscope , an instrument used to examine the interior of a hollow organ or cavity of the body. Unlike most other medical imaging devices, endoscopes are inserted directly into the organ...
).
Intravenous diazepam or
lorazepamLorazepam is a high-potency short-to-intermediate-acting 3-hydroxy benzodiazepine drug that has all five intrinsic benzodiazepine effects: anxiolytic, amnesic, sedative/hypnotic, anticonvulsant, antiemetic and muscle relaxant...
are first line treatments 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...
; However,
lorazepamLorazepam is a high-potency short-to-intermediate-acting 3-hydroxy benzodiazepine drug that has all five intrinsic benzodiazepine effects: anxiolytic, amnesic, sedative/hypnotic, anticonvulsant, antiemetic and muscle relaxant...
has advantages over diazepam including a higher rate of terminating seizures and a more prolonged anticonvulsant effect. Diazepam is rarely used for the long-term treatment of
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...
because tolerance to the anticonvulsant effects of diazepam usually develops within 6 to 12 months of treatment, effectively rendering it useless for that purpose. Diazepam is used for the emergency treatment of
eclampsiaEclampsia , an acute and life-threatening complication of pregnancy, is characterized by the appearance of tonic-clonic seizures, usually in a patient who had developed pre-eclampsia...
, when
IVIntravenous 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...
magnesium sulfateMagnesium sulfate is a chemical compound containing magnesium, sulfur and oxygen, with the formula MgSO4. It is often encountered as the heptahydrate epsomite , commonly called Epsom salt, from the town of Epsom in Surrey, England, where the salt was distilled from the springs that arise where the...
and blood pressure control measures have failed. Benzodiazepines do not have any pain relieving properties of themselves and are generally recommended to be avoided in individuals with pain. However, benzodiazepines such as diazepam can be used for their muscle relaxant properties to alleviate pain which is caused by muscle spasms, caused by various dystonias, including
blepharospasmA blepharospasm , is any abnormal contraction or twitch of the eyelid....
Tolerance often develops to the muscle relaxant effects of benzodiazepines such as diazepam.
BaclofenBaclofen is a derivative of gamma-aminobutyric acid . It is primarily used to treat spasticity and is under investigation for the treatment of alcoholism....
or
tizanidineTizanidine is a drug that is used as a muscle relaxant. It is a centrally acting α2 adrenergic agonist. It is used to treat the spasms, cramping, and tightness of muscles caused by medical problems such as multiple sclerosis, spastic diplegia, back pain, or certain other injuries to the spine or...
is sometimes used as an alternative to diazepam. Tizanidine has been found to be equally effective as other antispasmodic drugs and have superior tolerability than baclofen and diazepam.
The anticonvulsant effects of diazepam, can help in the treatment of seizures, due to a drug overdose or chemical toxicity as a result of exposure to
sarinSarin, or GB, is an organophosphorus compound with the formula [2CHO]CH3PF. It is a colorless, odorless liquid, which is used as a chemical weapon. It has been classified as a weapon of mass destruction in UN Resolution 687...
,
VXVX, IUPAC name O-ethyl S-[2-ethyl] methylphosphonothioate, is an extremely toxic substance whose only application is in chemical warfare as a nerve agent. As a chemical weapon, it is classified as a weapon of mass destruction by the United Nations in UN Resolution 687...
,
somanSoman, or GD , is an extremely toxic chemical substance. It is a nerve agent, interfering with normal functioning of the mammalian nervous system by inhibiting the cholinesterase enzyme. As a chemical weapon, it is classified as a weapon of mass destruction by the United Nations according to UN...
(or other
organophosphateAn organophosphate is the general name for esters of phosphoric acid. Phosphates are probably the most pervasive organophosphorus compounds. Many of the most important biochemicals are organophosphates, including DNA and RNA as well as many cofactors that are essential for life...
poisons; See #CANA),
lindaneLindane, also known as gamma-hexachlorocyclohexane, , gammaxene, Gammallin and erroneously known as benzene hexachloride , is an organochlorine chemical variant of hexachlorocyclohexane that has been used both as an agricultural insecticide and as a pharmaceutical treatment for lice and...
,
chloroquineChloroquine is a 4-aminoquinoline drug used in the treatment or prevention of malaria.-History:Chloroquine , N'--N,N-diethyl-pentane-1,4-diamine, was discovered in 1934 by Hans Andersag and co-workers at the Bayer laboratories who named it "Resochin". It was ignored for a decade because it was...
,
physostigminePhysostigmine is a parasympathomimetic alkaloid, specifically, a reversible cholinesterase inhibitor. It occurs naturally in the Calabar bean....
, or
pyrethroidA pyrethroid is an organic compound similar to the natural pyrethrins produced by the flowers of pyrethrums . Pyrethroids now constitute a major commercial household insecticides...
s Diazepam is sometimes used intermittently for the prophylaxis of febrile seizures which occur as a result of a high fever in children and neonates under 5 years of age. Long-term use of diazepam for the management of epilepsy is not recommended; however, a subgroup individuals with treatment resistant epilepsy benefit from long-term benzodiazepines and for such individuals
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...
has been recommended due to its slower onset of tolerance to the anticonvulsant effects.
Diazepam has a broad spectrum of indications (most of which are off-label), including:
- Treatment of anxiety
Anxiety 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,...
, panic attacks, and states of agitationPsychomotor agitation is a series of unintentional and purposeless motions that stem from mental tension and anxiety of an individual. This includes pacing around a room, wringing one's hands, pulling off clothing and putting it back on and other similar actions...
- Treatment of neurovegetative symptoms associated with vertigo
Vertigo is a type of dizziness, where there is a feeling of motion when one is stationary. The symptoms are due to a dysfunction of the vestibular system in the inner ear...
- Treatment of the symptoms of alcohol, opiate and benzodiazepine withdrawal
- Short-term treatment of insomnia
Insomnia 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:...
- Treatment of tetanus
Tetanus is a medical condition characterized by a prolonged contraction of skeletal muscle fibers. The primary symptoms are caused by tetanospasmin, a neurotoxin produced by the Gram-positive, rod-shaped, obligate anaerobic bacterium Clostridium tetani...
, together with other measures of intensive-treatment
- Adjunctive treatment of spastic muscular paresis
Paresis is a condition typified by partial loss of voluntary movement or by impaired movement. When used without qualifiers, it usually refers to the limbs, but it also can be used to describe the muscles of the eyes , the stomach , and also the vocal cords...
(para-/tetraplegia) caused by cerebral or spinal cordThe spinal cord is a long, thin, tubular bundle of nervous tissue and support cells that extends from the brain . The brain and spinal cord together make up the central nervous system...
conditions such as strokeA stroke, previously known medically as a cerebrovascular accident , is the rapidly developing loss of brain function due to disturbance in the blood supply to the brain. This can be due to ischemia caused by blockage , or a hemorrhage...
, multiple sclerosisMultiple sclerosis is an inflammatory disease in which the fatty myelin sheaths around the axons of the brain and spinal cord are damaged, leading to demyelination and scarring as well as a broad spectrum of signs and symptoms...
, spinal cord injury (long-term treatment is coupled with other rehabilitative measures)
- Palliative treatment of stiff person syndrome
Stiff person syndrome is a rare neurologic disorder of unknown etiology characterized by progressive rigidity and stiffness, primarily of the axial musculature, that is superimposed by spasms, resulting in postural deformities...
- Pre-/postoperative sedation, anxiolysis and/or amnesia (e.g., before endoscopic or surgical procedures)
- Treatment of complications with a hallucinogen crisis and stimulant
Stimulants are psychoactive drugs which induce temporary improvements in either mental or physical function or both. Examples of these kinds of effects may include enhanced alertness, wakefulness, and locomotion, among others...
overdoses and psychosis, such as LSDLysergic acid diethylamide, abbreviated LSD or LSD-25, also known as lysergide and colloquially as acid, is a semisynthetic psychedelic drug of the ergoline family, well known for its psychological effects which can include altered thinking processes, closed and open eye visuals, synaesthesia, an...
, cocaineCocaine is a crystalline tropane alkaloid that is obtained from the leaves of the coca plant. The name comes from "coca" in addition to the alkaloid suffix -ine, forming cocaine. It is a stimulant of the central nervous system, an appetite suppressant, and a topical anesthetic...
, or methamphetamine Methamphetamine is a psychostimulant of the phenethylamine and amphetamine class of psychoactive drugs...
.
- Prophylactic treatment of oxygen toxicity
Oxygen toxicity is a condition resulting from the harmful effects of breathing molecular oxygen at elevated partial pressures. It is also known as oxygen toxicity syndrome, oxygen intoxication, and oxygen poisoning...
during hyperbaric oxygen therapyHyperbaric medicine, also known as hyperbaric oxygen therapy , is the medical use of oxygen at a level higher than atmospheric pressure. The equipment required consists of a pressure chamber, which may be of rigid or flexible construction, and a means of delivering 100% oxygen...
Dosages should be determined on an individual basis, depending upon the condition to be treated, the severity of symptoms, the body weight of the patient, and any
comorbidIn medicine, comorbidity is either the presence of one or more disorders in addition to a primary disease or disorder, or the effect of such additional disorders or diseases.- In medicine :...
conditions the patient may have.
Availability
Diazepam is marketed in over 500 brands throughout the world. It is supplied in oral, injectable, inhalation and rectal forms.
The United States military employs a specialized diazepam preparation known as CANA (Convulsive Antidote, Nerve Agent), which contains a mixture of diazepam,
atropineAtropine is a naturally occurring tropane alkaloid extracted from deadly nightshade , Jimson weed , mandrake and other plants of the family Solanaceae. It is a secondary metabolite of these plants and serves as a drug with a wide variety of effects...
and
pralidoximePralidoxime or 2-PAM, usually as the chloride or methiodide salts, belongs to a family of compounds called oximes that bind to organophosphate-inactivated acetylcholinesterase. It is used to combat poisoning by organophosphates or acetylcholinesterase inhibitors , in conjunction with atropine and ...
(2-PAM). One CANA kit is typically issued to service members, along with three
Mark I NAAKThe Mark I NAAK, or MARK I Kit, is United States military nomenclature for the "Nerve Agent Antidote Kit". It is a dual-chamber autoinjector: Two anti-nerve agent drugs — atropine sulfate and pralidoxime chloride — each in injectable form, constitute the kit. The kits are only effective against the...
kits, when operating in circumstances where chemical weapons in the form of nerve agents are considered a potential hazard. Both of these kits deliver drugs using auto-injectors. They are intended for use in "buddy aid" or "self aid" administration of the drugs in the field prior to
decontaminationDecontamination is the process of cleansing the human body to remove contamination by hazardous materials including chemicals, radioactive substances, and infectious material...
and delivery of the patient to definitive medical care.
Contraindications
Use of diazepam should be avoided, when possible, in individuals with the following conditions:
- 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...
.
- Severe hypoventilation
In medicine, hypoventilation occurs when ventilation is inadequate to perform needed gas exchange...
.
- 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...
.
- Severe hepatic deficiencies (hepatitis
Hepatitis is a medical condition defined by the inflammation of the liver and characterized by the presence of inflammatory cells in the tissue of the organ. The name is from the Greek hepar , the root being hepat- , meaning liver, and suffix -itis, meaning "inflammation"...
and liver cirrhosisCirrhosis is a consequence of chronic liver disease characterized by replacement of liver tissue by fibrosis, scar tissue and regenerative nodules , leading to loss of liver function...
decrease elimination by a factor of 2).
- Severe renal deficiencies (for example, patients on dialysis
In medicine, dialysis is a process for removing waste and excess water from the blood, and is primarily used to provide an artificial replacement for lost kidney function in people with renal failure...
).
- Liver disorders.
- Severe respiratory disorders.
- Severe 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...
.
- Severe depression
Major depressive disorder is a mental disorder characterized by an all-encompassing low mood accompanied by low self-esteem, and by loss of interest or pleasure in normally enjoyable activities...
, particularly when accompanied by suicidal tendencies.
- Psychosis
Psychosis 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"...
.
- 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...
or breast feeding.
- Caution required in elderly or debilitated patients.
- Coma
In 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...
or shock.
- Abrupt discontinuation of therapy.
- Acute intoxication with alcohol
Ethanol, also called ethyl alcohol, pure alcohol, grain alcohol, or drinking alcohol, is a volatile, flammable, colorless liquid. It is a psychoactive drug and one of the oldest recreational drugs. Best known as the type of alcohol found in alcoholic beverages, it is also used in thermometers, as a...
, narcotics, or other psychoactive substances (with the exception of some hallucinogens, where it is occasionally used as a treatment for overdose).
- History of alcohol
Ethanol, also called ethyl alcohol, pure alcohol, grain alcohol, or drinking alcohol, is a volatile, flammable, colorless liquid. It is a psychoactive drug and one of the oldest recreational drugs. Best known as the type of alcohol found in alcoholic beverages, it is also used in thermometers, as a...
or drug dependence.
- Myasthenia gravis
Myasthenia gravis is an autoimmune neuromuscular disease leading to fluctuating muscle weakness and fatiguability...
, or MG, an autoimmune disorder causing marked fatiguability.
- Hypersensitivity
Hypersensitivity 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...
or allergyAn 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...
to any drug in the benzodiazepineA benzodiazepine is a psychoactive drug whose core chemical structure is the fusion of a benzene ring and a diazepine ring...
class.
Special caution needed
- Benzodiazepines require special precaution if used in the alcohol- or drug-dependent individuals and individuals with comorbid psychiatric disorders.
- Pediatric patients
- Less than 18 years of age – Treatment usually not indicated, except treatment of epilepsy, and pre-/postoperative treatment. The smallest possible effective dose should be used for this group of patients.
- Under 6 months of age – Safety and effectiveness have not been established; diazepam should not be given to individuals in this age group.
- Elderly and very ill patients – Possibility that apnea and/or cardiac arrest may occur. Concomitant use of other central nervous system depressants increases this risk. The smallest possible effective dose should be used for this group of patients. The elderly metabolise benzodiazepines much more slowly than younger adults and are also more sensitive to the effects of benzodiazepines even at similar blood plasma levels. Doses of diazepam are recommended to be about half of those given to younger individuals and treatment limited to a maximum of 2 weeks. Long-acting benzodiazepines such as diazepam are not recommended for the elderly. Diazepam may also be dangerous in geriatric patients owing to a significant increased risk of falls.
- I.V. or I.M. injections in hypotensive individuals or those in shock should be administered carefully and vital signs should be monitored.
- Benzodiazepines such as diazepam are lipophilic and rapidly penetrate membranes, and, therefore, rapidly cross over into the placenta with significant uptake of the drug. Use of benzodiazepines including diazepam in late pregnancy, especially high doses, may result in floppy infant syndrome.
Pregnancy
Diazepam when taken late in pregnancy, during the third trimester, causes a definite risk of a severe
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 with symptoms including
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...
, and reluctance to suck, to apnoeic 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. Floppy infant syndrome and sedation in the newborn may also occur. Symptoms of floppy infant syndrome and the neonatal benzodiazepine withdrawal syndrome have been reported to persist from hours to months after birth.
Adverse effects
Adverse effects of benzodiazepines such as diazepam include
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 confusion (especially pronounced in higher doses) and
sedationSedation is the reduction of irritability or agitation by administration of sedative drugs, generally to facilitate a medical procedure or diagnostic procedure...
. The elderly are more prone to adverse effects of diazepam such as confusion,
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...
,
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...
and hangover effects as well as falls. Long-term use of benzodiazepines such as diazepam is associated with tolerance,
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...
as well as 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...
. Like other benzodiazepines, diazepam can impair short-term memory and learning of new information. While benzodiazepine drugs such as diazepam can cause anterograde amnesia, they do not cause
retrograde amnesiaRetrograde amnesia is a loss of access to events that occurred, or information that was learned, before an injury or the onset of a disease....
; information learned before benzodiazepines is not impaired. Tolerance to the cognitive impairing effects of benzodiazepines does not tend to develop with long-term use. The elderly are more sensitive to the cognitive impairing effects of benzodiazepines. Additionally after cessation of benzodiazepines cognitive deficits may persist for at least six months; it is unclear whether these impairments take longer than six months to abate or if they are permanent. Benzodiazepines may also cause or worsen depression. Infusions or repeated intravenous injections of diazepam when managing seizures for example may lead to drug toxicity including respiratory depression, sedation 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...
. Tolerance may also develop to infusions of diazepam if it is given for longer than 24 hours. Adverse effects such as sedation,
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...
and abuse potential limit the use of benzodiazepines.
Diazepam has a range of side-effects that are common to most benzodiazepines. Most common side-effects include:
- Suppression of REM sleep
- Impaired motor function
- Impaired coordination
- Impaired balance
- Dizziness
Dizziness refers to an impairment in spatial perception and stability. The term is somewhat imprecise. It can be used to mean vertigo, presyncope, disequilibrium, or a non-specific feeling such as giddiness or foolishness....
and nausea
- Depression
Depression is a state of low mood and aversion to activity that can affect a person's thoughts, behaviour, feelings and physical well-being. Depressed people may feel sad, anxious, empty, hopeless, helpless, worthless, guilty, irritable, or restless...
- Reflex tachycardia
Tachycardia 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...
Less commonly paradoxical side-effects can occur and include nervousness, irritability, excitement, worsening of seizures, insomnia, muscle cramps, changes in
libidoLibido refers to a person's sex drive or desire for sexual activity. The desire for sex is an aspect of a person's sexuality, but varies enormously from one person to another, and it also varies depending on circumstances at a particular time. A person who has extremely frequent or a suddenly...
(increased or decreased libido) and in some cases, rage, and violence. These adverse reactions are more likely to occur in children, the elderly, individuals with a history of drug or alcohol abuse and people with a history of aggression. Diazepam may increase, in some people, the propensity toward self-harming behaviours and, in extreme cases, may provoke suicidal tendencies or acts. Very rarely
dystoniaDystonia is a neurological movement disorder, in which sustained muscle contractions cause twisting and repetitive movements or abnormal postures. The disorder may be hereditary or caused by other factors such as birth-related or other physical trauma, infection, poisoning or reaction to...
can occur.
Diazepam may impair the ability to drive vehicles or operate machinery. The impairment is worsened by consumption of alcohol, because both act as central nervous system depressants.
During the course of therapy, tolerance to the sedative effects usually develops, but not to the anxiolytic and myorelaxant effects.
Patients with severe attacks of
apneaApnea, apnoea, or apnœa is a term for suspension of external breathing. During apnea there is no movement of the muscles of respiration and the volume of the lungs initially remains unchanged...
during sleep may suffer respiratory depression (hypoventilation) leading to respiratory arrest and death.
Diazepam in doses of 5 mg or more causes significant deterioration in
alertnessAlertness is the state of paying close and continuous attention, being watchful and prompt to meet danger or emergency, or being quick to perceive and act. It is related to psychology as well as to physiology...
performance combined with increased feelings of sleepiness.
Tolerance and dependence
Diazepam 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 tolerance,
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...
. Withdrawal from diazepam or other benzodiazepines often leads to withdrawal symptoms that are similar to those seen during
barbiturateBarbiturates are drugs that act as central nervous system depressants, and can therefore produce a wide spectrum of effects, from mild sedation to total anesthesia. They are also effective as anxiolytics, as hypnotics, and as anticonvulsants...
or alcohol withdrawal. The higher the dose and the longer the drug is taken the greater the risk of experiencing unpleasant withdrawal symptoms. Withdrawal symptoms can occur from standard dosages and also after short-term use and can range from insomnia and anxiety to more serious symptoms including seizures and psychosis. Withdrawal symptoms can sometimes resemble pre-existing conditions and be misdiagnosed. Diazepam may produce less intense withdrawal symptoms due to its long elimination half-life. Benzodiazepine treatment should be discontinued as soon as possible via a slow and gradual dose reduction regime.
Tolerance develops to the therapeutic effects of benzodiazepines; for example tolerance occurs to the anticonvulsant effects and as a result benzodiazepines are not generally recommended for the long-term management of epilepsy. Dose increases may overcome the effects of tolerance, however, tolerance may then develop to the higher dose and adverse effects may increase. The mechanism of tolerance to benzodiazepines includes, uncoupling of receptor sites, alterations 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...
, down regulation of receptor sites and desensitisation of receptor sites to the effect of GABA. Approximately one third of individuals who take benzodiazepines for longer than 4 weeks become dependent and experience a withdrawal syndrome upon cessation. The difference in rates of withdrawal (50–100%) varies depending on the patient sample being investigated. For example, a random sample of long-term benzodiazepine users typically finds that around 50% will experience little or no withdrawal symptoms, with the other 50% experiencing notable withdrawal symptoms. Certain select patient groups will show a higher rate of notable withdrawal symptoms, up to 100%. Rebound anxiety, more severe than baseline anxiety, is also a common withdrawal symptom when discontinuing diazepam or other benzodiazepines. Diazepam is therefore only recommended for short-term therapy at the lowest possible dose owing to risks of severe withdrawal problems from low doses even after gradual reduction. There is a significant risk of pharmacological dependence on diazepam and patients experiencing symptoms 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...
if it is taken for 6 weeks or longer. In humans tolerance to the anticonvulsant effects of diazepam occurs frequently.
Dependence
Improper or excessive use of Diazepam can lead to
psychological dependenceIn the APA Dictionary of Psychology, psychological dependence is defined as "dependence on a psychoactive substance for the reinforcement it provides." Most times psychological dependence is classified under addiction...
/drug addiction. At a particularly high risk for diazepam misuse,
abuseSubstance 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...
or psychological dependence are:
- People with a history of alcohol or drug abuse or dependence Diazepam increases craving for alcohol in problem alcohol consumers. Diazepam also increases the volume of alcohol consumed by problem drinkers.
- People with severe personality disorders, such as Borderline Personality Disorder
Borderline personality disorder is a personality disorder described as a prolonged disturbance of personality function in a person , characterized by depth and variability of moods.The disorder typically involves unusual levels of instability in mood; black and white thinking, or splitting; the...
Patients from the aforementioned groups should be monitored very closely during therapy for signs of abuse and development of dependence. Therapy should be discontinued if any of these signs are noted, although if
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...
has developed therapy must still be discontinued gradually to avoid severe withdrawal symptoms. Long-term therapy in these people is not recommended.
People suspected of being physiologically dependent on benzodiazepine drugs should be very gradually tapered off the drug. Although rare, withdrawals can be life-threatening particularly when excessive doses have been taken for extended periods of time. Equal prudence should be used whether dependence has occurred in therapeutic or recreational contexts.
Diazepam in and of itself is not a recreational drug, but may be used to either enhance or "come down" from the effects of other recreational drugs. For example, diazepam increases the euphoriant effects of heroin (and other recreational opiates), yet decreases the undesirable side-effects of cocaine and/or methamphetamine come-down.
Overdose
An individual that has consumed too much diazepam will typically display one or more of the following symptoms in a period of approximately four hours immediately following a suspected overdose:
- Drowsiness
- Mental confusion
- Hypotension
In 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...
- Impaired motor functions
- Impaired reflexes
- Impaired coordination
- Impaired balance
- Dizziness
- Coma
In 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...
Although not usually fatal when taken alone, a diazepam overdose is considered a medical emergency and generally requires the immediate attention of medical personnel. The
antidoteAn antidote is a substance which can counteract a form of poisoning. The term ultimately derives from the Greek αντιδιδοναι antididonai, "given against"....
for an overdose of diazepam (or any other benzodiazepine) is
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...
(Anexate). This drug is only used in cases with severe respiratory depression or cardiovascular complications. Because flumazenil is a short-acting drug, and the effects of diazepam can last for days, several doses of flumazenil may be necessary.
Artificial respirationArtificial respiration is the act of assisting or stimulating respiration, a metabolic process referring to the overall exchange of gases in the body by pulmonary ventilation, external respiration, and internal respiration...
and stabilization of cardiovascular functions may also be necessary. Although not routinely indicated, activated charcoal can be used for decontamination of the stomach following a diazepam overdose. Emesis is contraindicated.
DialysisIn medicine, dialysis is a process for removing waste and excess water from the blood, and is primarily used to provide an artificial replacement for lost kidney function in people with renal failure...
is minimally effective. Hypotension may be treated with levarterenol or
metaraminolMetaraminol is a potent sympathomimetic amine used in the prevention and treatment of hypotension, particularly as a complication of anesthesia.It is an α1-adrenergic receptor agonist with some β effect....
.
The oral (lethal dose in 50% of the population) of diazepam is 720 mg/kg in mice and 1240 mg/kg in rats. D. J. Greenblatt and colleagues reported in 1978 on two patients who had taken 500 and 2000 mg of diazepam, respectively, went into moderately deep comas, and were discharged within 48 hours without having experienced any important complications, in spite of having high concentrations of diazepam and its metabolites, esmethyldiazepam, oxazepam, and temazepam; according to samples taken in the hospital and as follow-up.
Overdoses of diazepam with alcohol, opiates and/or other depressants may be fatal.
An Australian study has found people who take sleeping pills or anti-anxiety medications are more dangerous on the roads than drunk drivers.
Interactions
If diazepam is to be administered concomitantly with other drugs, attention should be paid to the possible pharmacological interactions. Particular care should be taken with drugs that enhance the effects of diazepam, such as barbiturates, phenothiazines, narcotics and antidepressants.
Diazepam does not increase or decrease hepatic enzyme activity, and does not alter the metabolism of other compounds. There is no evidence that would suggest diazepam alters its own metabolism with chronic administration.
Agents that have an effect on hepatic cytochrome P450 pathways or conjugation can alter the rate of diazepam metabolism. These interactions would be expected to be most significant with long-term diazepam therapy, and their clinical significance is variable.
- Diazepam increases the central depressive effects of alcohol, other hypnotic
Hypnotic 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...
s/sedatives (e.g., barbiturates), narcotics, other 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...
s, certain antidepressants, sedative antihistamines, opiates, and antipsychotics as well as anticonvulsants such as 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...
and carbamazepineCarbamazepine is an anticonvulsant and mood-stabilizing drug used primarily in the treatment of epilepsy and bipolar disorder, as well as trigeminal neuralgia...
. The euphoriant effects of opioids may be increased, leading to increased risk of psychological dependence.
- Cimetidine
Cimetidine INN is a histamine H2-receptor antagonist that inhibits the production of acid in the stomach. It is largely used in the treatment of heartburn and peptic ulcers. It is marketed by GlaxoSmithKline under the trade name Tagamet...
, omeprazoleOmeprazole is a proton pump inhibitor used in the treatment of dyspepsia, peptic ulcer disease , gastroesophageal reflux disease , laryngopharyngeal reflux and Zollinger–Ellison syndrome...
, oxcarbazepineOxcarbazepine is a anticholinergic anticonvulsant and mood stabilizing drug, used primarily in the treatment of epilepsy. It is also used to treat anxiety and mood disorders, and benign motor tics...
, ticlopidineTiclopidine is an antiplatelet drug in the thienopyridine family. Like clopidogrel, it is an adenosine diphosphate receptor inhibitor. It is used in patients in whom aspirin is not tolerated, or in whom dual antiplatelet therapy is desirable...
, topiramateTopiramate is an anticonvulsant drug. It was originally produced by Ortho-McNeil Neurologics and Noramco, Inc., both divisions of the Johnson & Johnson Corporation. This medication was discovered in 1979 by Bruce E. Maryanoff and Joseph F. Gardocki during their research work at McNeil...
, ketoconazoleKetoconazole is a synthetic antifungal drug used to prevent and treat fungal skin infections, especially in immunocompromised patients such as those with AIDS or those on chemotherapy. Ketoconazole is sold commercially as an anti-dandruff shampoo, topical cream, and oral tablet.Ketoconazole is...
, itraconazoleItraconazole , invented in 1984, is a triazole antifungal agent that is prescribed to patients with fungal infections. The drug may be given orally or intravenously.-Medical uses:...
, disulfiramDisulfiram is a drug discovered in the 1920s and used to support the treatment of chronic alcoholism by producing an acute sensitivity to alcohol. Trade names for disulfiram in different countries are Antabuse and Antabus manufactured by Odyssey Pharmaceuticals...
, fluvoxamineFluvoxamine is an antidepressant which functions as a selective serotonin reuptake inhibitor . Fluvoxamine was first approved by the U.S. Food and Drug Administration in 1993 for the treatment of obsessive compulsive disorder . Fluvoxamine CR is approved to treat social anxiety disorder...
, isoniazidIsoniazid , also known as isonicotinylhydrazine , is an organic compound that is the first-line antituberculosis medication in prevention and treatment. It was first discovered in 1912, and later in 1951 it was found to be effective against tuberculosis by inhibiting its mycolic acid...
, erythromycinErythromycin is a macrolide antibiotic that has an antimicrobial spectrum similar to or slightly wider than that of penicillin, and is often used for people who have an allergy to penicillins. For respiratory tract infections, it has better coverage of atypical organisms, including mycoplasma and...
, probenecidProbenecid is a uricosuric drug that increases uric acid excretion in the urine. It is primarily used in treating gout and hyperuricemia.Probenecid was developed as an alternative to caronamide...
, propranolol, imipramineImipramine , also known as melipramine, is an antidepressant medication, a tricyclic antidepressant of the dibenzazepine group...
, ciprofloxacinCiprofloxacin is a synthetic chemotherapeutic antibiotic of the fluoroquinolone drug class.It is a second-generation fluoroquinolone antibacterial. It kills bacteria by interfering with the enzymes that cause DNA to rewind after being copied, which stops synthesis of DNA and of...
, fluoxetineFluoxetine is an antidepressant of the selective serotonin reuptake inhibitor class. It is manufactured and marketed by Eli Lilly and Company...
and valproic acidValproic acid is a chemical compound that has found clinical use as an anticonvulsant and mood-stabilizing drug, primarily in the treatment of epilepsy, bipolar disorder, and, less commonly, major depression. It is also used to treat migraine headaches and schizophrenia...
prolong the action of diazepam by inhibiting its elimination.
- Alcohol (ethanol
Ethanol, also called ethyl alcohol, pure alcohol, grain alcohol, or drinking alcohol, is a volatile, flammable, colorless liquid. It is a psychoactive drug and one of the oldest recreational drugs. Best known as the type of alcohol found in alcoholic beverages, it is also used in thermometers, as a...
) in combination with diazepam may cause a synergistic enhancement of the hypotensive properties of benzodiazepines and alcohol.
- Oral contraceptives ("the pill") significantly decrease the elimination of desmethyldiazepam, a major metabolite of diazepam.
- Rifampin, phenytoin
Phenytoin 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...
, carbamazepineCarbamazepine is an anticonvulsant and mood-stabilizing drug used primarily in the treatment of epilepsy and bipolar disorder, as well as trigeminal neuralgia...
and 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...
increase the metabolism of diazepam, thus decreasing drug levels and effects. DexamethasoneDexamethasone is a potent synthetic member of the glucocorticoid class of steroid drugs. It acts as an anti-inflammatory and immunosuppressant...
and St John's wortSt John's wort is the plant species Hypericum perforatum, and is also known as Tipton's Weed, Chase-devil, or Klamath weed....
also increase the metabolism of diazepam.
- Diazepam increases the serum levels of phenobarbital
Phenobarbital 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...
.
- Nefazodone
Nefazodone is an antidepressant marketed by Bristol-Myers Squibb. Its sale was discontinued in 2003 in some countries due to the rare incidence of hepatotoxicity , which could lead to the need for a liver transplant, or even death. The incidence of severe liver damage is approximately 1 in every...
can cause increased blood levels of benzodiazepines.
- Cisapride
Cisapride is a gastroprokinetic agent, a drug which increases motility in the upper gastrointestinal tract. It acts directly as a serotonin 5-HT4 receptor agonist and indirectly as a parasympathomimetic. Stimulation of the serotonin receptors increases acetylcholine release in the enteric nervous...
may enhance the absorption, and therefore the sedative activity, of diazepam.
- Small doses of theophylline
Theophylline, also known as dimethylxanthine, is a methylxanthine drug used in therapy for respiratory diseases such as COPD and asthma under a variety of brand names. Because of its numerous side-effects, the drug is now rarely administered for clinical use. As a member of the xanthine family, it...
may inhibit the action of diazepam.
- Diazepam may block the action of levodopa
L-DOPA is a chemical that is made and used as part of the normal biology of some animals and plants. Some animals including humans make it via biosynthesis from the amino acid L-tyrosine. L-DOPA is the precursor to the neurotransmitters dopamine, norepinephrine , and epinephrine collectively...
(used in the treatment of Parkinson's DiseaseParkinson's disease is a degenerative disorder of the central nervous system...
).
- Diazepam may alter digoxin
Digoxin INN , also known as digitalis, is a purified cardiac glycoside and extracted from the foxglove plant, Digitalis lanata. Its corresponding aglycone is digoxigenin, and its acetyl derivative is acetyldigoxin...
serum concentrations.
- Other drugs that may have interactions with diazepam include: Antipsychotic
An antipsychotic is a tranquilizing psychiatric medication primarily used to manage psychosis , particularly in schizophrenia and bipolar disorder. A first generation of antipsychotics, known as typical antipsychotics, was discovered in the 1950s...
s (e.g. chlorpromazineChlorpromazine is a typical antipsychotic...
), MAO inhibitors, ranitidineRanitidine is a histamine H2-receptor antagonist that inhibits stomach acid production. It is commonly used in treatment of peptic ulcer disease and gastroesophageal reflux disease . Ranitidine is also used alongside fexofenadine and other antihistamines for the treatment of skin conditions...
.
- Caffeine
Caffeine is a bitter, white crystalline xanthine alkaloid that acts as a stimulant drug. Caffeine is found in varying quantities in the seeds, leaves, and fruit of some plants, where it acts as a natural pesticide that paralyzes and kills certain insects feeding on the plants...
may antagonise the effects of diazepam and vice versa.
- Smoking tobacco
Tobacco is an agricultural product processed from the leaves of plants in the genus Nicotiana. It can be consumed, used as a pesticide and, in the form of nicotine tartrate, used in some medicines...
can enhance the elimination of diazepam and decrease its action.
- Because it acts on the GABA receptor the herb Valerian
Valerian is a hardy perennial flowering plant, with heads of sweetly scented pink or white flowers which bloom in the summer months. Valerian flower extracts were used as a perfume in the sixteenth century....
may produce an adverse effect.
- Foods that acidify the urine can lead to faster absorption and elimination of diazepam, reducing drug levels and activity.
- Foods that alkalinize the urine can lead to slower absorption and elimination of diazepam, increasing drug levels and activity.
- There are conflicting reports as to whether food in general has any effects on the absorption and activity of orally administered diazepam.
Pharmacology
Diazepam is a long acting "classical" benzodiazepine. Other classical benzodiazepines include
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...
,
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...
,
lorazepamLorazepam is a high-potency short-to-intermediate-acting 3-hydroxy benzodiazepine drug that has all five intrinsic benzodiazepine effects: anxiolytic, amnesic, sedative/hypnotic, anticonvulsant, antiemetic and muscle relaxant...
,
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...
,
temazepamTemazepam is an intermediate-acting 3-hydroxy benzodiazepine. It is mostly prescribed for the short-term treatment of sleeplessness in patients who have difficulty maintaining sleep...
,
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...
. Diazepam has
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. Diazepam has no effect on GABA levels and no effect on glutamate decarboxylase activity but has a slight effect on gamma-aminobutyric acid transaminase activity. It differs insofar from some other anticonvulsive drugs it was compared with. Benzodiazepines act via micromolar benzodiazepine binding sites as Ca2+ channel blockers and significantly inhibit depolarization-sensitive Calcium uptake in rat nerve cell preparations.
Diazepam inhibits acetylcholine release in mouse hippocampal synaptosomes. This has been found by measuring sodium-dependent high affinity choline uptake in mouse brain cells in vitro, after pretreatment of the mice with diazepam in vivo. This may play a role in explaining diazepam's anticonvulsant properties.
Diazepam binds with high affinity to glial cells in animal cell cultures. Diazepam at high doses has been found to decrease histamine turnover in mouse brain via diazepam's action at the benzodiazepine-GABA receptor complex. Diazepam also decreases
prolactinProlactin also known as luteotropic hormone is a protein that in humans is encoded by the PRL gene.Prolactin is a peptide hormone discovered by Henry Friesen...
release in rats.
Mechanism of action
Diazepam is a benzodiazepine that binds to a specific subunit on the
GABAAThe GABAA receptor is an ionotropic receptor and ligand-gated ion channel. Its endogenous ligand is γ-aminobutyric acid , the major inhibitory neurotransmitter in the central nervous system. Upon activation, the GABAA receptor selectively conducts Cl- through its pore, resulting in...
receptor at a site that is distinct from the binding site of the
endogenousEndogenous substances are those that originate from within an organism, tissue, or cell. Endogenous retroviruses are caused by ancient infections of germ cells in humans, mammals and other vertebrates...
GABA molecule. The
GABAAThe GABAA receptor is an ionotropic receptor and ligand-gated ion channel. Its endogenous ligand is γ-aminobutyric acid , the major inhibitory neurotransmitter in the central nervous system. Upon activation, the GABAA receptor selectively conducts Cl- through its pore, resulting in...
receptor is an inhibitory channel which, when activated, decreases neuronal activity. Benzodiazepines do not supplement for the neurotransmitter GABA, rather benzodiazepines such as diazepam bind to a different location on the GABA
A receptor with the result that the effects of GABA are enhanced. Benzodiazepines cause an increased opening of the chloride ion channel when GABA binds to its site on the GABA
A receptor leading to more chloride ions entering the neuron which in turn leads to enhanced central nervous system depressant effects. Diazepam binds non-selectively to alpha1, alpha2, alpha3 and alpha5 subunit containing GABA
A receptors.
Because of the role of diazepam as a positive
allosteric modulatorIn biochemistry, allosteric regulation is the regulation of an enzyme or other protein by binding an effector molecule at the protein's allosteric site . Effectors that enhance the protein's activity are referred to as allosteric activators, whereas those that decrease the protein's activity are...
of GABA, when it binds to benzodiazepine receptors it causes inhibitory effects. This arises from the
hyperpolarizationHyperpolarization is a change in a cell's membrane potential that makes it more negative. It is the opposite of a depolarization.Hyperpolarization is often caused by efflux of K+ through K+ channels, or influx of Cl– through Cl– channels. On the other hand, influx of cations, e.g...
of the post-
synapticIn the nervous system, a synapse is a structure that permits a neuron to pass an electrical or chemical signal to another cell...
membrane, owing to the control exerted over negative
chlorideThe chloride ion is formed when the element chlorine, a halogen, picks up one electron to form an anion Cl−. The salts of hydrochloric acid HCl contain chloride ions and can also be called chlorides. The chloride ion, and its salts such as sodium chloride, are very soluble in water...
ionAn ion is an atom or molecule in which the total number of electrons is not equal to the total number of protons, giving it a net positive or negative electrical charge. The name was given by physicist Michael Faraday for the substances that allow a current to pass between electrodes in a...
s by GABA
A receptors.
Diazepam appears to act on areas of the
limbic systemThe limbic system is a set of brain structures including the hippocampus, amygdala, anterior thalamic nuclei, septum, limbic cortex and fornix, which seemingly support a variety of functions including emotion, behavior, long term memory, and olfaction. The term "limbic" comes from the Latin...
,
thalamusThe thalamus is a midline paired symmetrical structure within the brains of vertebrates, including humans. It is situated between the cerebral cortex and midbrain, both in terms of location and neurological connections...
, and
hypothalamusThe Hypothalamus is a portion of the brain that contains a number of small nuclei with a variety of functions...
, inducing anxiolytic effects. Its actions are due to the enhancement 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...
activity. Benzodiazepine drugs including diazepam increase the inhibitory processes in the cerebral cortex.
The anticonvulsant properties of diazepam 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 be limited by benzodiazepines' effect of slowing recovery of sodium channels from inactivation.
The muscle relaxant properties of Diazepam are produced via inhibition of polysynaptic pathways in the spinal cord.
Pharmacokinetics
Diazepam can be administered orally,
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...
ly (needs to be diluted, as it is painful and damaging to veins),
intramuscularIntramuscular 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...
ly (see below), or as a
suppositoryA suppository is a drug delivery system that is inserted into the rectum , vagina or urethra , where it dissolves.They are used to deliver both systemically-acting and locally-acting medications....
.
When Diazepam is administered orally, it is rapidly absorbed and has a fast onset of action. The onset of action is 1–5 minutes for IV administration and 15–30 minutes for IM administration. The duration of diazepam's peak pharmacological effects is 15 minutes to 1 hour for both routes of administration. The bioavailability after oral administration is 100 percent, and 90 percent after rectal administration. Peak plasma levels occur between 30 minutes and 90 minutes after oral administration and between 30 minutes and 60 minutes after intramuscular administration; after rectal administration peak plasma levels occur after 10 minutes to 45 minutes. Diazepam is highly protein bound with 96 to 99 percent of the absorbed drug being protein bound. The distribution half-life of diazepam is 2 minutes to 13 minutes.
When Diazepam is administered as an intramuscular injection, absorption is slow, erratic and incomplete.
Diazepam is highly lipid-soluble, and is widely distributed throughout the body after administration. It easily crosses both the
blood-brain barrierThe blood–brain barrier is a separation of circulating blood and the brain extracellular fluid in the central nervous system . It occurs along all capillaries and consists of tight junctions around the capillaries that do not exist in normal circulation. Endothelial cells restrict the diffusion...
and the
placentaThe placenta is an organ that connects the developing fetus to the uterine wall to allow nutrient uptake, waste elimination, and gas exchange via the mother's blood supply. "True" placentas are a defining characteristic of eutherian or "placental" mammals, but are also found in some snakes and...
, and is excreted into breast milk. After absorption, diazepam is redistributed into
muscleMuscle is a contractile tissue of animals and is derived from the mesodermal layer of embryonic germ cells. Muscle cells contain contractile filaments that move past each other and change the size of the cell. They are classified as skeletal, cardiac, or smooth muscles. Their function is to...
and adipose tissue. Continual daily doses of diazepam will quickly build up to a high concentration in the body (mainly in
adipose tissueIn histology, adipose tissue or body fat or fat depot or just fat is loose connective tissue composed of adipocytes. It is technically composed of roughly only 80% fat; fat in its solitary state exists in the liver and muscles. Adipose tissue is derived from lipoblasts...
), which will be far in excess of the actual dose for any given day.
There is preferential storage of Diazepam in some organs including the heart. Absorption by any administered route and the risk of accumulation is significantly increased in the neonate and there is clinical justification to recommend the withdrawal of diazepam during pregnancy and breast feeding.
Diazepam undergoes oxidative metabolism by Demethylation (CYP 2C9, 2C19, 2B6, 3A4, and 3A5), hydroxylation (CYP 3A4 and 2C19) as well as
glucuronidationGlucuronidation is the addition of glucuronic acid to a substrate. Glucuronidation is often involved in xenobiotic metabolism of substances such as drugs, pollutants, bilirubin, androgens, estrogens, mineralocorticoids, glucocorticoids, fatty acid derivatives, retinoids, and bile acids...
in the
liverThe liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
as part of the cytochrome P450 enzyme system. Diazepam has several pharmacologically active metabolites. The main active metabolite of diazepam is desmethyldiazepam (also known as
nordazepam or
nordiazepam). Diazepam's other active metabolites include the minor active metabolites
temazepamTemazepam is an intermediate-acting 3-hydroxy benzodiazepine. It is mostly prescribed for the short-term treatment of sleeplessness in patients who have difficulty maintaining sleep...
and
oxazepamOxazepam , is a drug which is a short to intermediate acting 3-hydroxy benzodiazepine derivative...
. These metabolites are conjugated with
glucuronideA glucuronide, also known as glucuronoside, is any substance produced by linking glucuronic acid to another substance via a glycosidic bond...
, and are excreted primarily in the urine. Because of these active metabolites, the serum values of diazepam alone are not useful in predicting the effects of the drug. Diazepam has a biphasic
half-lifeHalf-life, abbreviated t½, is the period of time it takes for the amount of a substance undergoing decay to decrease by half. The name was originally used to describe a characteristic of unstable atoms , but it may apply to any quantity which follows a set-rate decay.The original term, dating to...
of about 1–3 and 2–7 days for the active metabolite desmethyldiazepam.
Most of the drug is metabolised; very little diazepam is excreted unchanged.
The elimination half-life of diazepam and also the active metabolite desmethyldiazepam increases significantly in the elderly, which may result in prolonged action as well as accumulation of the drug during repeated administration.
Detection in body fluids
Diazepam 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 diazepam concentrations are usually in a range of 0.1-1.0 mg/L in persons receiving the drug therapeutically, 1–5 mg/L in those arrested for impaired driving and 2–20 mg/L in victims of acute overdosage. Most commercial immunoassays for the benzodiazepine class of drugs will cross-react with diazepam, but confirmation and quantitation is usually performed using chromatographic techniques.
Physical properties
Diazepam occurs as solid white or yellow crystals and has a melting point of 131.5 to 134.5 °C. It is odorless, and has a slightly bitter taste. The
British PharmacopoeiaThe British Pharmacopoeia is an annual published collection of quality standards for UK medicinal substances. It is used by individuals and organizations involved in pharmaceutical research, development, manufacture and testing....
lists diazepam as being very slightly soluble in water, soluble in alcohol and freely soluble in chloroform. The United States Pharmacopoeia lists diazepam as soluble 1 in 16 of ethyl alcohol, 1 in 2 of chloroform, 1 in 39 of
etherEthers are a class of organic compounds that contain an ether group — an oxygen atom connected to two alkyl or aryl groups — of general formula R–O–R'. A typical example is the solvent and anesthetic diethyl ether, commonly referred to simply as "ether"...
, and practically insoluble in water. The
pHIn chemistry, pH is a measure of the acidity or basicity of an aqueous solution. Pure water is said to be neutral, with a pH close to 7.0 at . Solutions with a pH less than 7 are said to be acidic and solutions with a pH greater than 7 are basic or alkaline...
of diazepam is neutral (i.e., pH = 7). Diazepam has a shelf-life of 5 years for oral tablets and 3 years for IV/IM solution.
Diazepam should be stored at room temperature (15–30°C). The solution for parenteral injection should be protected from light and kept from freezing. The oral forms should be stored in air-tight containers and protected from light.
Diazepam can absorb into plastic, and, therefore, diazepam solution is not stored in plastic bottles or syringes, etc. It can absorb into plastic bags and tubing used for intravenous infusions. Absorption appears to be dependent on several factors such as temperature, concentration, flow rates, and tube length. Diazepam should not be administered if a precipitate has formed and will not dissolve.
Chemistry
From a chemical point of view, diazepam, 7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one, is the most simple of all of the examined derivatives of 1,4-benzodiazepin-2-ones. Various ways for the synthesis of diazepam from 2-amino-5-chlorobenzophenone have been proposed. The first two ways consist of the direct cyclocondensation of 2-amino-5-chlorobenzophenone or 2-methylamino-5-chlorobenzophenone with the ethyl ester of glycine hydrochloride. The amide nitrogen atom of the obtained 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one, is methylated by dimethylsulfate, which leads to the formation of diazepam.
The second way differs from the first in that the methylation of nitrogen is accomplished
before the cyclocondensation reaction. In order to do this, the initial 2-amino-5-chlorobenzophenone is first tosylated by p-toluenesulfonylchloride and the obtained tosylate
transformed into the N-sodium salt, which is then alkylated by dimethylsulfate. The resulting 2-N-tosyl-N-methyl-5-chlorobenzophenone is hydrolyzed in an acidic medium, giving 2-methylamino-5-chlorobenzophenone, which undergoes cyclocondensation by reaction with ethyl ester of glycine hydrochloride, forming the desired diazepam.
History
Diazepam was the second benzodiazepine to be invented by Dr.
Leo SternbachLeo Henryk Sternbach was a Polish-Jewish chemist who is credited with discovering benzodiazepines, main class of tranquilizers.-Biography:...
of
Hoffmann-La RocheF. Hoffmann-La Roche Ltd. is a Swiss global health-care company that operates worldwide under two divisions: Pharmaceuticals and Diagnostics. Its holding company, Roche Holding AG, has shares listed on the SIX Swiss Exchange....
, following
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...
(Librium) which was approved for use in 1960. Released in 1963 as an improved version of Librium, diazepam became incredibly popular, helping Roche to become a pharmaceutical industry giant. It is two and a half times more potent than its predecessor, which it quickly surpassed in terms of sales. After this initial success, other pharmaceutical companies began to introduce other benzodiazepine derivatives.
The benzodiazepines gained popularity among medical professionals as an improvement upon
barbiturateBarbiturates are drugs that act as central nervous system depressants, and can therefore produce a wide spectrum of effects, from mild sedation to total anesthesia. They are also effective as anxiolytics, as hypnotics, and as anticonvulsants...
s, which have a comparatively narrow
therapeutic indexThe therapeutic index is a comparison of the amount of a therapeutic agent that causes the therapeutic effect to the amount that causes death or toxicity ....
, and are far more sedating at therapeutic doses. The benzodiazepines are also far less dangerous; death rarely results from diazepam overdose, except in cases where it is consumed with large amounts of other depressants (such as alcohol or other sedatives). Benzodiazepine drugs such as diazepam initially had widespread public support, but with time the view changed to one of growing criticism and calls for restrictions on their prescription.
Diazepam was the top-selling pharmaceutical in the
United StatesThe United States of America is a federal constitutional republic comprising fifty states and a federal district...
from 1969 to 1982, with peak sales in 1978 of 2.3 billion tablets. Diazepam, along with
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...
and
temazepamTemazepam is an intermediate-acting 3-hydroxy benzodiazepine. It is mostly prescribed for the short-term treatment of sleeplessness in patients who have difficulty maintaining sleep...
, represents 82% of the benzodiazepine market in Australia. While psychiatrists continue to prescribe diazepam for the short-term relief of anxiety, neurology has taken the lead in prescribing diazepam for the palliative treatment of certain types of epilepsy and spastic activity, for example, forms of
paresisParesis is a condition typified by partial loss of voluntary movement or by impaired movement. When used without qualifiers, it usually refers to the limbs, but it also can be used to describe the muscles of the eyes , the stomach , and also the vocal cords...
. It is also the first line of defense for a rare disorder called stiff-person syndrome. In recent years, the public perception of benzodiazepines has become increasingly negative.
Recreational use
Diazepam is a drug of potential abuse and can cause serious problems of addiction and as a result is scheduled. Urgent action by national governments has been recommended to improve prescribing patterns of benzodiazepines such as diazepam. A single dose of diazepam modulates the
dopamineDopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...
system in similar ways to how morphine and
alcoholEthanol, also called ethyl alcohol, pure alcohol, grain alcohol, or drinking alcohol, is a volatile, flammable, colorless liquid. It is a psychoactive drug and one of the oldest recreational drugs. Best known as the type of alcohol found in alcoholic beverages, it is also used in thermometers, as a...
modulate the dopaminergic pathways.
Between 50 and 64% of rats will self administer diazepam.
Benzodiazepines including diazepam in animal studies have been shown to increase reward seeking behaviours by increasing impulsivity, which may suggest an increased risk of addictive behavioural patterns with usage of diazepam or other benzodiazepines. In addition diazepam has been shown to be able to substitute for the behavioural effects of barbiturates in a
primateA primate is a mammal of the order Primates , which contains prosimians and simians. Primates arose from ancestors that lived in the trees of tropical forests; many primate characteristics represent adaptations to life in this challenging three-dimensional environment...
study.
Diazepam has been found as an
adulterantAn adulterant is a chemical substance which should not be contained within other substances for legal or other reasons. Adulterants may be intentionally added to more expensive substances to increase visible quantities and reduce manufacturing costs or for some other deceptive or malicious purpose...
in
heroin.
Diazepam drug misuse can occur either through recreational misuse where the drug is taken to achieve a high or when the drug is continued long term against medical advice.
Sometimes Diazepam is used by stimulant users to "come down" and sleep and to help control the urge to binge.
A large-scale nationwide USA government study conducted by SAMHSA found that benzodiazepines in the USA are the most frequently abused pharmaceutical with 35% of drug-related visits to the Emergency Department involved benzodiazepines. Benzodiazepines are more commonly abused than opiate pharmaceuticals, which accounted for 32% of visits to the emergency department. No other pharmaceutical is more commonly abused than benzodiazepines. Males abuse benzodiazepines as commonly as females. Of drugs used in attempted suicide benzodiazepines are the most commonly used pharmaceutical drug, with 26% of attempted suicides involving benzodiazepines. The most commonly abused benzodiazepine is, however,
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...
.
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...
is the second-most-abused benzodiazepine.
LorazepamLorazepam is a high-potency short-to-intermediate-acting 3-hydroxy benzodiazepine drug that has all five intrinsic benzodiazepine effects: anxiolytic, amnesic, sedative/hypnotic, anticonvulsant, antiemetic and muscle relaxant...
is the third-most-abused benzodiazepine, and diazepam the fourth-most-abused benzodiazepine in the USA.
Benzodiazepines, including Diazepam,
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...
, and
flunitrazepamFlunitrazepam is marketed as a potent hypnotic, sedative, anticonvulsant, anxiolytic, amnestic, and skeletal muscle relaxant drug most commonly known as Rohypnol...
account for the largest volume of forged drug prescriptions in Sweden, a total of 52% of drug forgeries being for benzodiazepines.
Diazepam was detected in 26% of cases of people suspected of driving under the influence of drugs in Sweden and its active metabolite nordazepam was detected in 28% of cases. Other benzodiazepines and zolpidem and zopiclone also were found in high numbers. Many drivers had blood levels far exceeding the therapeutic dose range suggesting a high degree of abuse potential for benzodiazepines and
zolpidemZolpidem is a prescription medication used for the short-term treatment of insomnia, as well as some brain disorders. It is a short-acting nonbenzodiazepine hypnotic of the imidazopyridine class that potentiates gamma-aminobutyric acid , an inhibitory neurotransmitter, by binding to GABAA...
and
zopicloneZopiclone is a non-benzodiazepine hypnotic agent used in the treatment of insomnia. In the United States, zopiclone is not commercially available, although its active stereoisomer, eszopiclone, is sold under the name Lunesta...
. In
Northern IrelandNorthern Ireland is one of the four countries of the United Kingdom. Situated in the north-east of the island of Ireland, it shares a border with the Republic of Ireland to the south and west...
in cases where drugs were detected in samples from impaired drivers who were not impaired by alcohol, benzodiazepines were found to be present in 87% of cases. Diazepam was the most commonly detected benzodiazepine.
Legal status
Diazepam is regulated in most countries as a
prescription drugA prescription medication is a licensed medicine that is regulated by legislation to require a medical prescription before it can be obtained. The term is used to distinguish it from over-the-counter drugs which can be obtained without a prescription...
:
- International: Diazepam is a Schedule IV controlled drug under the Convention on Psychotropic Substances
The 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...
.
- UK: classified as a controlled drug, listed under Schedule IV, Part I (CD Benz POM) of the Misuse of Drugs Regulations 2001, allowing possession with a valid prescription. The Misuse of Drugs Act 1971
The Misuse of Drugs Act 1971 is an Act of Parliament which represents UK action in line with treaty commitments under the Single Convention on Narcotic Drugs, the Convention on Psychotropic Substances, and the United Nations Convention Against Illicit Traffic in Narcotic Drugs and Psychotropic...
makes it illegal to possess the drug without a prescription, and for such purposes it is classified as a Class C drug.
- Germany: classified as a prescription drug, or in high dosage as a restricted drug (Betäubungsmittelgesetz, Anhang III).
Judicial executions
The State of
CaliforniaCalifornia is a state located on the West Coast of the United States. It is by far the most populous U.S. state, and the third-largest by land area...
offers diazepam to
condemnedCapital punishment, the death penalty, or execution is the sentence of death upon a person by the state as a punishment for an offence. Crimes that can result in a death penalty are known as capital crimes or capital offences. The term capital originates from the Latin capitalis, literally...
inmates as a pre-execution sedative as part of their
Lethal InjectionLethal Injection is the fourth studio album by California-based rapper Ice Cube. Similar to the rapper's previous albums, it was a commercial hit, debuting at #5 on the Billboard 200 with 215,000 copies sold in its first week...
program.
Veterinary uses
Diazepam is used as a short-term sedative and
anxiolyticAn anxiolytic is a drug used for the treatment of anxiety, and its related psychological and physical symptoms...
for cats and dogs. It is also used for short-term treatment of seizures in dogs and short-term and long-term treatment of seizures in cats. It can also be used as an appetite stimulant. For emergent treatment of seizures, the typical dose is 0.5cmg/kg intravenously, or 1–2c;mg/kg of the injectable solution administered in the rectum.
External links