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Diazepam
Diazepam

Diazepam, first marketed as Valium, is a medicine of the benzodiazepine family that typically produces a calming effect.[5] It is commonly used to treat a range of conditions, including anxiety, alcohol withdrawal syndrome, benzodiazepine withdrawal syndrome, muscle spasms, seizures, trouble sleeping, and restless legs syndrome.[5] It may also be used to cause memory loss during certain medical procedures.[6][7] It can be taken by mouth, inserted into the rectum, injected into muscle, or injected into a vein.[7] When given into a vein, effects begin in one to five minutes and last up to an hour.[7] By mouth, effects may take 40 minutes to begin.[8]

Common side effects include sleepiness and trouble with coordination.[7] Serious side effects are rare.[5] They include suicide, decreased breathing, and an increased risk of seizures if used too frequently in those with epilepsy.[5][7][9] Occasionally excitement or agitation may occur.[10][11] Long term use can result in tolerance, dependence, and withdrawal symptoms on dose reduction.[5] Abrupt stopping after long-term use can be potentially dangerous.[5] After stopping, cognitive problems may persist for six months or longer.[10] It is not recommended during pregnancy or breastfeeding.[7] Its mechanism of action is by increasing the effect of the neurotransmitter gamma-aminobutyric acid (GABA).[10]

Diazepam was patented in 1959 by Hoffmann-La Roche.[5][12] It has been one of the most frequently prescribed medications in the world since its launch in 1963.[5] In the United States it was the highest selling medication between 1968 and 1982, selling more than two billion tablets in 1978 alone.[5] In 2016 it was the 112th most prescribed medication in the United States with more than 6 million prescriptions.[13] In 1985 the patent ended, and there are now more than 500 brands available on the market.[5] Diazepam is on the World Health Organization's List of Essential Medicines, the safest and most effective medicines needed in a health system.[14] The wholesale cost in the developing world is about US$0.01 per dose as of 2014.[15] In the United States, it is about US$0.40 per dose.[7]

Medical uses


Diazepam is mainly used to treat anxiety, insomnia, panic attacks and symptoms of acute alcohol withdrawal.

Diazepam has a number of uses including:

Dosages should be determined on an individual basis, depending on the condition being treated, severity of symptoms, patient body weight, and any other conditions the person may have.[24]

Intravenous diazepam or lorazepam are first-line treatments for status epilepticus.[10][26] However, intravenous lorazepam has advantages over intravenous diazepam, including a higher rate of terminating seizures and a more prolonged anticonvulsant effect. Diazepam gel was better than placebo gel in reducing the risk of non-cessation of seizures.[27] Diazepam is rarely used for the long-term treatment of epilepsy because tolerance to its anticonvulsant effects usually develops within six to 12 months of treatment, effectively rendering it useless for that purpose.[24][28]

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, or soman (or other organophosphate poisons), lindane, chloroquine, physostigmine, or pyrethroids.[24][29]

Diazepam is sometimes used intermittently for the prevention of febrile seizures that may occur in children under five years of age.[10] Recurrence rates are reduced, but side effects are common.[30] Long-term use of diazepam for the management of epilepsy is not recommended; however, a subgroup of 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.[10]

Because of its relatively long duration of action, and evidence of safety and efficacy, diazepam is preferred over other benzodiazepines for treatment of persons experiencing moderate to severe alcohol withdrawal.[31] An exception to this is when a medication is required intramuscular in which case either lorazepam or midazolam is recommended.[31]

Diazepam is used for the emergency treatment of eclampsia, when IV magnesium sulfate and blood-pressure control measures have failed.[32][33] Benzodiazepines do not have any pain-relieving properties themselves, and are generally recommended to avoid in individuals with pain.[34] However, benzodiazepines such as diazepam can be used for their muscle-relaxant properties to alleviate pain caused by muscle spasms and various dystonias, including blepharospasm.[35][36] Tolerance often develops to the muscle relaxant effects of benzodiazepines such as diazepam.[37] Baclofen[38] or tizanidine is sometimes used as an alternative to diazepam.

Diazepam is marketed in over 500 brands throughout the world.[39] It is supplied in oral, injectable, inhalation, and rectal forms.[24][40][41]

The United States military employs a specialized diazepam preparation known as Convulsive Antidote, Nerve Agent (CANA), which contains diazepam. 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 autoinjectors. 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.[42]

Contraindications


Use of diazepam should be avoided, when possible, in individuals with:[43]

  • Benzodiazepine abuse and misuse should be guarded against when prescribed to those with alcohol or drug dependencies or who have psychiatric disorders.[44]
  • Pediatric patients Less than 18 years of age, this treatment is usually not indicated, except for treatment of epilepsy, and pre- or postoperative treatment.
  • Elderly and very ill patients can possibly suffer apnea or cardiac arrest.
  • Intravenous or intramuscular injections in hypotensive people or those in shock should be administered carefully and vital signs should be monitored.[46]
  • Benzodiazepines such as diazepam are lipophilic and rapidly penetrate membranes, so rapidly cross over into the placenta with significant uptake of the drug. Use of benzodiazepines including diazepam in late pregnancy, especially high doses, can result in floppy infant syndrome.[48] 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.[49]

Adverse effects


Adverse effects of benzodiazepines such as diazepam include anterograde amnesia, 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 drug tolerance, benzodiazepine dependence, and benzodiazepine withdrawal syndrome.[10] 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 using benzodiazepines is not impaired. Tolerance to the cognitive-impairing effects of benzodiazepines does not tend to develop with long-term use, and the elderly are more sensitive to them.[50] 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.[10] Infusions or repeated intravenous injections of diazepam when managing seizures, for example, may lead to drug toxicity, including respiratory depression, sedation and hypotension. Drug tolerance may also develop to infusions of diazepam if it is given for longer than 24 hours.[10] Adverse effects such as sedation, benzodiazepine dependence, and abuse potential limit the use of benzodiazepines.[51] Sedatives and sleeping pills, including diazepam, have been associated with an increased risk of death.[52]

Diazepam has a range of side effects common to most benzodiazepines, including:

Less commonly, paradoxical side effects can occur, including nervousness, irritability, excitement, worsening of seizures, insomnia, muscle cramps, changes in libido, and in some cases, rage and violence. These adverse reactions are more likely to occur in children, the elderly, and individuals with a history of drug or alcohol abuse and or aggression.[10][55][56][57] Diazepam may increase, in some people, the propensity toward self-harming behaviours and, in extreme cases, may provoke suicidal tendencies or acts.[58] Very rarely dystonia can occur.[59]

Diazepam may impair the ability to drive vehicles or operate machinery.

During the course of therapy, tolerance to the sedative effects usually develops, but not to the anxiolytic and myorelaxant effects.[60]

Patients with severe attacks of apnea 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 alertness performance combined with increased feelings of sleepiness.[61]

Diazepam, as with other benzodiazepine drugs, can cause tolerance, physical dependence, substance use disorder, and benzodiazepine withdrawal syndrome. Withdrawal from diazepam or other benzodiazepines often leads to withdrawal symptoms similar to those seen during barbiturate 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.

Benzodiazepine treatment should be discontinued as soon as possible by a slow and gradual dose reduction regimen.[10][62] 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, but 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 expression, down-regulation of receptor sites, and desensitisation of receptor sites to the effect of GABA. About one-third of individuals who take benzodiazepines for longer than four weeks become dependent and experience withdrawal syndrome on cessation.[10]

Differences in rates of withdrawal (50–100%) vary depending on the patient sample.

Rebound anxiety, more severe than baseline anxiety, is also a common withdrawal symptom when discontinuing diazepam or other benzodiazepines.[64] 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.[65] The risk of pharmacological dependence on diazepam is significant, and patients experience symptoms of benzodiazepine withdrawal syndrome if it is taken for six weeks or longer.[66] In humans, tolerance to the anticonvulsant effects of diazepam occurs frequently.[67]

Improper or excessive use of diazepam can lead to dependence. At a particularly high risk for diazepam misuse, abuse or dependence are:

  • People with a history of alcohol or drug abuse or dependence[23][68] Diazepam increases craving for alcohol in problem alcohol consumers. Diazepam also increases the volume of alcohol consumed by problem drinkers.[69]
  • People with severe personality disorders, such as borderline personality disorder[70]

Patients from the aforementioned groups should be monitored very closely during therapy for signs of abuse and development of dependence.

People suspected of being dependent on benzodiazepine drugs should be very gradually tapered off the drug.

Diazepam is a good choice for tapering for those using high doses of other benzodiazepines since it has a long half-life thus withdrawal symptoms are tolerable.[71] The process is very slow (usually from 14 to 28 weeks) but is considered safe when done appropriately.[72]

Overdose


An individual who has consumed too much diazepam typically displays one or more of these symptoms in a period of approximately four hours immediately following a suspected overdose:[23][73]

  • Drowsiness
  • Mental confusion
  • Hypotension
  • Impaired motor functions Impaired reflexes Impaired coordination Impaired balance Dizziness
  • Coma

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 oral LD50 (lethal dose in 50% of the population) of diazepam is 720 mg/kg in mice and 1240 mg/kg in rats.[23] 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 desmethyldiazepam, oxazepam, and temazepam, according to samples taken in the hospital and as follow-up.[75]

Overdoses of diazepam with alcohol, opiates or other depressants may be fatal.[74][76]

Interactions


If diazepam is administered concomitantly with other drugs, attention should be paid to the possible pharmacological interactions.

Diazepam does not increase or decrease hepatic enzyme activity, and does not alter the metabolism of other compounds.

Agents with an effect on hepatic cytochrome P450 pathways or conjugation can alter the rate of diazepam metabolism.

Pharmacology


Diazepam is a long-acting "classical" benzodiazepine.

Diazepam inhibits acetylcholine release in mouse hippocampal synaptosomes.

Diazepam binds with high affinity to glial cells in animal cell cultures.[88] Diazepam at high doses has been found to decrease histamine turnover in mouse brain via diazepam's action at the benzodiazepine-GABA receptor complex.[89] Diazepam also decreases prolactin release in rats.[90]

Benzodiazepines are positive allosteric modulators of the GABA type A receptors (GABAA). The GABAA receptors are ligand-gated chloride-selective ion channels that are activated by GABA, the major inhibitory neurotransmitter in the brain. Binding of benzodiazepines to this receptor complex promotes binding of GABA, which in turn increases the total conduction of chloride ions across the neuronal cell membrane. This increased chloride ion influx hyperpolarizes the neuron's membrane potential. As a result, the difference between resting potential and threshold potential is increased and firing is less likely. As a result, the arousal of the cortical and limbic systems in the central nervous system is reduced.[3]

The GABAA receptor is a heteromer composed of five subunits, the most common ones being two αs, two βs, and one γ (α2β2γ). For each subunit, many subtypes exist (α1–6, β1–3, and γ1–3). GABAA receptors containing the α1 subunit mediate the sedative, the anterograde amnesic, and partly the anticonvulsive effects of diazepam. GABAA receptors containing α2 mediate the anxiolytic actions and to a large degree the myorelaxant effects. GABAA receptors containing α3 and α5 also contribute to benzodiazepines myorelaxant actions, whereas GABAA receptors comprising the α5 subunit were shown to modulate the temporal and spatial memory effects of benzodiazepines.[91] Diazepam is not the only drug to target these GABAA receptors. Drugs such as flumazenil also bind to GABAA to induce their effects.[92]

Diazepam appears to act on areas of the limbic system, thalamus, and hypothalamus, inducing anti-anxiolytic effects. Benzodiazepine drugs including diazepam increase the inhibitory processes in the cerebral cortex.[93]

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.

The muscle relaxant properties of diazepam are produced via inhibition of polysynaptic pathways in the spinal cord.[95]

Diazepam can be administered orally, intravenously (must be diluted, as it is painful and damaging to veins), intramuscularly (IM), or as a suppository.[24]

The onset of action is one to five minutes for IV administration and 15–30 minutes for IM administration.

Diazepam is highly lipid-soluble, and is widely distributed throughout the body after administration.

Diazepam is stored preferentially in some organs, including the heart.

Diazepam undergoes oxidative metabolism by demethylation (CYP 2C9, 2C19, 2B6, 3A4, and 3A5), hydroxylation (CYP 3A4 and 2C19) and glucuronidation in the liver as part of the cytochrome P450 enzyme system. It has several pharmacologically active metabolites. The main active metabolite of diazepam is desmethyldiazepam (also known as nordazepam or nordiazepam). Its other active metabolites include the minor active metabolites temazepam and oxazepam. These metabolites are conjugated with glucuronide, 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-life of about one to three days, and two to seven days for the active metabolite desmethyldiazepam.[10] Most of the drug is metabolised; very little diazepam is excreted unchanged.[24] 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.[97]

Physical and chemical properties


Diazepam is a 1,4-benzodiazepine.[3] Diazepam occurs as solid white or yellow crystals with a melting point of 131.5 to 134.5 °C.

Diazepam can absorb into plastics, so liquid preparations should not be kept in plastic bottles or syringes, etc. As such, it can leach into the plastic bags and tubing used for intravenous infusions.

Diazepam may be quantified 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.

History


Diazepam was the second benzodiazepine invented by Leo Sternbach of Hoffmann-La Roche at the company's Nutley, New Jersey, facility[101] following chlordiazepoxide (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 2.5 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.[102]

The benzodiazepines gained popularity among medical professionals as an improvement over barbiturates, which have a comparatively narrow therapeutic index, and are far more sedative 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 opioids).[74] 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.[103]

Marketed by Roche using an advertising campaign conceived by the William Douglas McAdams Agency under the leadership of Arthur Sackler,[104] diazepam was the top-selling pharmaceutical in the United States from 1969 to 1982, with peak annual sales in 1978 of 2.3 billion tablets.[102] Diazepam, along with oxazepam, nitrazepam and temazepam, represents 82% of the benzodiazepine market in Australia.[105] 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 paresis. It is also the first line of defense for a rare disorder called stiff-person syndrome.[22]

Society and culture


Diazepam is a drug of potential abuse and can cause drug dependence. Urgent action by national governments has been recommended to improve prescribing patterns of benzodiazepines such as diazepam.[106][107] A single dose of diazepam modulates the dopamine system in similar ways to how morphine and alcohol modulate the dopaminergic pathways.[108] Between 50 and 64% of rats will self-administer diazepam.[109] Diazepam has been shown to be able to substitute for the behavioural effects of barbiturates in a primate study.[110] Diazepam has been found as an adulterant in heroin.[111]

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.[112]

Sometimes, it is used by stimulant users to "come down" and sleep and to help control the urge to binge. These users often escalate dosage from 2 to 25 times the therapeutic dose of 5 to 10 mg.[113]

A large-scale study in the US, conducted by SAMHSA, using data from 2011, determined benzodiazepines were present in 28.7% of emergency department visits involving nonmedical use of pharmaceuticals. In this regard, benzodiazepines are second only to opiates, the study found in 39.2% of visits. About 29.3% of drug-related suicide attempts involve benzodiazepines, making them the most frequently represented class in drug-related suicide attempts. Males abuse benzodiazepines as commonly as females.[114]

Benzodiazepines, including diazepam, nitrazepam, and flunitrazepam, account for the largest volume of forged drug prescriptions in Sweden, a total of 52% of drug forgeries being for benzodiazepines.[115]

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 zolpidem and zopiclone.[98] In Northern Ireland, in cases where drugs were detected in samples from impaired drivers who were not impaired by alcohol, benzodiazepines were found in 87% of cases. Diazepam was the most commonly detected benzodiazepine.[116]

Diazepam is regulated in most countries as a prescription drug:

Diazepam is a Schedule IV controlled drug under the Convention on Psychotropic Substances.[117]

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.

Classified as a prescription drug, or in high dosage as a restricted drug (Betäubungsmittelgesetz, Anlage III*).[119]

Diazepam is Schedule 4 substance under the Poisons Standard (June 2018).[120] A schedule 4 drug is outlined in the Poisons Act 1964 as, "Substances, the use or supply of which should be by or on the order of persons permitted by State or Territory legislation to prescribe and should be available from a pharmacist on prescription." [120]

Diazepam is controlled as a Schedule IV substance under the Controlled Substances Act of 1970.

The states of California and Florida offer diazepam to condemned inmates as a pre-execution sedative as part of their lethal injection program, although the state of California has not executed a prisoner since 2006.[121][122] In August 2018, Nebraska used diazepam as part of the drug combination used to execute the first death row inmate executed in Nebraska in over 21 years.[123]

Veterinary uses


Diazepam is used as a short-term sedative and anxiolytic for cats and dogs,[124] sometimes used as an appetite stimulant.[124][125] It can also be used to stop seizures in dogs and cats.[126]

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