Diazepam

Diazepam ( /daɪˈæzɨpæm/), first marketed as Valium ( /ˈvæliəm/) by Hoffmann-La Roche is a benzodiazepine drug. Diazepam is also marketed in Australia as Antenex. It is commonly used for treating anxiety, insomnia, seizures including status epilepticus, muscle spasms (such as in cases of tetanus), restless legs syndrome, alcohol withdrawal, benzodiazepine withdrawal and Ménière's disease. It may also be used before certain medical procedures (such as endoscopies) to reduce tension and anxiety, and in some surgical procedures to induce amnesia. It possesses anxiolytic, anticonvulsant, hypnotic, sedative, skeletal muscle relaxant, and amnestic properties. The pharmacological action of diazepam enhances the effect of the neurotransmitter GABA by binding to the benzodiazepine site on the GABAA receptor leading to central nervous system depression.

Adverse effects of diazepam include anterograde amnesia (especially at higher doses) and sedation 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 dependence as well as a benzodiazepine withdrawal syndrome 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 abuse potential and can cause serious problems of addiction. 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 Organization'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 Sternbach.

Diazepam is mainly used to treat anxiety, insomnia, and symptoms of acute alcohol withdrawal. It is also used as a premedication for inducing sedation, anxiolysis or amnesia before certain medical procedures (e.g., endoscopy).

Intravenous diazepam or lorazepam are first line treatments for status epilepticus; However, lorazepam 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 epilepsy 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 eclampsia, when IV magnesium sulfate 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 blepharospasm Tolerance often develops to the muscle relaxant effects of benzodiazepines such as diazepam. Baclofen or tizanidine 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 sarin, VX, soman (or other organophosphate poisons; See #CANA), lindane, chloroquine, physostigmine, or pyrethroids 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 clorazepate 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:

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 comorbid conditions the patient may have.

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, atropine and pralidoxime (2-PAM). One CANA kit is typically issued to service members, along with three Mark I NAAK 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 decontamination and delivery of the patient to definitive medical care.

Use of diazepam should be avoided, when possible, in individuals with the following conditions:

Diazepam when taken late in pregnancy, during the third trimester, causes a definite risk of a severe benzodiazepine withdrawal syndrome in the neonate with symptoms including hypotonia, and reluctance to suck, to apnoeic spells, cyanosis, 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 of benzodiazepines such as diazepam include anterograde amnesia and confusion (especially pronounced in higher doses) and sedation. The elderly are more prone to adverse effects of diazepam such as confusion, amnesia, ataxia and hangover effects as well as falls. Long-term use of benzodiazepines such as diazepam is associated with tolerance, benzodiazepine dependence as well as a benzodiazepine withdrawal syndrome. 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 amnesia; 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 hypotension. Tolerance may also develop to infusions of diazepam if it is given for longer than 24 hours. Adverse effects such as sedation, benzodiazepine dependence 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:

Less commonly paradoxical side-effects can occur and include nervousness, irritability, excitement, worsening of seizures, insomnia, muscle cramps, changes in libido (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 dystonia 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.