Diazepam

Last updated

Diazepam
Diazepam structure.svg
Diazepam-from-xtal-3D-balls.png
Clinical data
Pronunciation /daɪˈæzɪpæm/ dy-AZ-ip-am
Trade names Valium, others [1]
AHFS/Drugs.com Monograph
MedlinePlus a682047
License data
Pregnancy
category
Dependence
liability 		High [3]
Addiction
liability 		Moderate [4] [5]
Routes of
administration 		oral, intramuscular, intravenous, rectal, nasal, [6] buccal film
Drug class Benzodiazepine
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability 76% (64–97%) oral, 81% (62–98%) rectal [12]
Metabolism Liver – CYP2B6 (minor route) to desmethyldiazepam, CYP2C19 (major route) to inactive metabolites, CYP3A4 (major route) to temazepam
Metabolites
Elimination half-life (50 h); 20–100 h (32–200 h for main active metabolite desmethyldiazepam) [10] [7] [8]
Excretion Kidney
Identifiers
  • 7-chloro-1-methyl-5-phenyl-3H-1,4-benzodiazepin-2-one
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.006.476 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C16H13ClN2O
Molar mass 284.74 g·mol−1
3D model (JSmol)
  • c1ccccc1C2=NCC(=O)N(C)c3ccc(Cl)cc23
  • InChI=1S/C16H13ClN2O/c1-19-14-8-7-12(17)9-13(14)16(18-10-15(19)20)11-5-3-2-4-6-11/h2-9H,10H2,1H3 Yes check.svgY
  • Key:AAOVKJBEBIDNHE-UHFFFAOYSA-N Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Diazepam, sold under the brand name Valium among others, is a medicine of the benzodiazepine family that acts as an anxiolytic. [14] It is used to treat a range of conditions, including anxiety, seizures, alcohol withdrawal syndrome, muscle spasms, insomnia, and restless legs syndrome. [14] It may also be used to cause memory loss during certain medical procedures. [15] [16] It can be taken orally (by mouth), as a suppository inserted into the rectum, intramuscularly (injected into muscle), intravenously (injection into a vein) or used as a nasal spray. [6] [16] When injected intravenously, effects begin in one to five minutes and last up to an hour. [16] When taken by mouth, effects begin after 15 to 60 minutes. [17]

Contents

Common side effects include sleepiness and trouble with coordination. [10] [16] Serious side effects are rare. [14] They include increased risk of suicide, decreased breathing, and an increased risk of seizures if used too frequently in those with epilepsy. [14] [16] [18] Occasionally, excitement or agitation may occur. [19] [20] Long-term use can result in tolerance, dependence, and withdrawal symptoms on dose reduction. [14] Abrupt stopping after long-term use can be potentially dangerous. [14] After stopping, cognitive problems may persist for six months or longer. [19] It is not recommended during pregnancy or breastfeeding. [16] Its mechanism of action works by increasing the effect of the neurotransmitter gamma-aminobutyric acid (GABA). [19]

Diazepam was patented in 1959 by Hoffmann-La Roche. [14] [21] [22] It has been one of the most frequently prescribed medications in the world since its launch in 1963. [14] In the United States it was the best-selling medication between 1968 and 1982, selling more than 2 billion tablets in 1978 alone. [14] In 2022, it was the 169th most commonly prescribed medication in the United States, with more than 3 million prescriptions. [23] [24] In 1985, the patent ended, and there are more than 500 brands available on the market. [14] It is on the World Health Organization's List of Essential Medicines. [25]

Structure, physical and chemical properties

Diazepam does not possess any chiral centers in its structure, but it does have two conformers. The two conformers mentioned were the 'P'-conformer and 'M'-conformer. Diazepam is an equimolar mixture and it was shown through CD spectra in serum protein solutions, that the 'P'-conformer is preferred by α1-acid glycoprotein binding.

The drug diazepam occurs as a pale yellow-white crystalline powder without a distinctive smell and has a low molecular weight (MW = 284.74 g/mol [15] ). This classic aryl 1,4-benzodiazepine possesses three acceptors and no hydrogen bond donors. Diazepam is moderately lipophilic with LogP (Octanol-Water Partition Coefficient) value of 2,82 and hydrophilic with a TPSA (Topological Polar Surface Area) value of 32.7 Ų. [15] The LogP value indicates that diazepam tends to dissolve more readily in lipid-based environments, such as chloroform, acetone, ethanol and ether, compared to water. The TPSA value implies that a segment of the molecule exhibits a degree of polarity or hydrophilicity and represents the collective surface area of polar atoms, like oxygen or nitrogen, along with their connected hydrogen atoms. A TPSA value of 32,7 Ų signifies a moderate level of polarity within the compound. TPSA is especially useful in medical chemistry as it shows the ability of a molecule to permeate cells. Molecules with PSA value smaller than 60-70 Ų have a better ability to permeate cells. [26] The balance between its lipophilic and hydrophilic characteristics can impact various aspects of the molecule’s behavior, including its solubility, absorption, distribution, metabolism, and potential interactions within the biological system.

Diazepam is overall a stable molecule. The British Pharmacopoeia lists it 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 ethyl alcohol, 1 in 2 of chloroform, 1 in 39 ether, and practically insoluble in water. The pH of diazepam is neutral (i.e., pH = 7). Due to additives such as benzoic acid/benzoate in the injectable form.[ clarification needed ] [27] Diazepam has a shelf life of five years for oral tablets and three years for IV/IM solutions. [28] Diazepam is stored at room temperature (15–30 °C). The solution for parenteral injection is kept so that it is protected from light and kept from freezing. The oral forms are stored in air-tight containers and protected from light. [29]

Diazepam can be absorbed into plastics, so liquid preparations are not kept in plastic bottles or syringes, etc. As such, it can leach into the plastic bags and tubing used for intravenous infusions. Absorption appears to depend on several factors, such as temperature, concentration, flow rates, and tube length. Diazepam is not be administered if a precipitate has formed and does not dissolve. [29]

Medical uses

Diazepam tablets (10, 5, and 2 mg) Diazepam(Valium) DOJ.jpg
Diazepam tablets (10, 5, and 2 mg)

Diazepam is mainly used to treat anxiety, insomnia, panic attacks, 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). [30] [31] In 2020, it was approved for use in the United States as a nasal spray to interrupt seizure activity in people with epilepsy. [6] [32] Diazepam is the most commonly used benzodiazepine for "tapering" benzodiazepine dependence due to the drug's comparatively long half-life, allowing for more efficient dose reduction. Benzodiazepines have a relatively low toxicity in overdose. [19]

Diazepam has several uses, including:

Used in the treatment of organophosphate poisoning and reduces the risk of seizure-induced brain and cardiac damage.

Dosages are typically 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. [28]

Seizures

Intravenous diazepam or lorazepam are first-line treatments for status epilepticus. [19] [40] 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. [41] Diazepam is rarely used for the long-term treatment of epilepsy because tolerance to its anticonvulsant effects usually develops within six to twelve months of treatment, effectively rendering it useless for that purpose. [28] [42]

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. [28] [43]

Diazepam is sometimes used intermittently for the prevention of febrile seizures that may occur in children under five years of age. [19] Recurrence rates are reduced, but side effects are common and the decision to treat febrile seizures (which are benign in nature) with medication uses these factors as part of the evaluation. [44] Long-term use of diazepam for the management of epilepsy is not recommended;[ by whom? ] 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. [19]

Alcohol withdrawal

Because of its relatively long duration of action, and evidence of safety and efficacy, diazepam is preferred over other benzodiazepines for the treatment of persons experiencing moderate to severe alcohol withdrawal. [45] An exception to this is when a medication is required intramuscular in which case either lorazepam or midazolam is recommended. [45]

Other

Diazepam is used for the emergency treatment of eclampsia when IV magnesium sulfate and blood-pressure control measures have failed. [46] [47] Benzodiazepines do not have any pain-relieving properties themselves and are generally recommended to be avoided in individuals with pain. [48] 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. [49] [50] Tolerance often develops to the muscle relaxant effects of benzodiazepines such as diazepam. [51] Baclofen is sometimes used as an alternative to diazepam. [52]

Availability

Diazepam is marketed in over 500 brands throughout the world. [53] It is supplied in oral, injectable, inhalation, and rectal forms. [28] [29] [54]

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 before decontamination and delivery of the patient to definitive medical care. [55]

Contraindications

Use of diazepam is avoided, when possible, in individuals with: [56]

Abuse and special populations

Adverse effects

Benzodiazepines, such as diazepam, can cause anterograde amnesia, confusion, and sedation. The elderly are more prone to diazepam's confusion, amnesia, ataxia, hangover symptoms, and falls. Long-term use of benzodiazepines, such as diazepam, induces tolerance, dependency, and withdrawal syndrome. [19] Like other benzodiazepines, diazepam impairs short-term memory and learning new information. Diazepam and other benzodiazepines can produce anterograde amnesia, but not retrograde amnesia, which means information learned before using benzodiazepines is not impaired. Short-term benzodiazepine use does not lead to tolerance, and the elderly are more sensitive to them. [64] Additionally, after stopping benzodiazepines, cognitive problems may last at least six months; it is unclear if these problems last for longer than six months or are permanent. Benzodiazepines may also cause or worsen depression. [19] 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. [19] Sedatives and sleeping pills, including diazepam, have been associated with an increased risk of death. [65]

In September 2020, the U.S. Food and Drug Administration (FDA) required the boxed warning be updated for all benzodiazepine medicines to describe the risks of abuse, misuse, addiction, physical dependence, and withdrawal reactions consistently across all the medicines in the class. [66]

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

Less commonly, paradoxical reactions 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 a substance use disorder, such as an alcohol use disorder, or a history of aggressive behavior. [19] [68] [69] [70] In some people, diazepam may increase the propensity toward self-harming behavior and, in extreme cases, may provoke suicidal tendencies or acts. [71] Very rarely dystonia can occur. [72]

Diazepam may impair the ability to drive vehicles or operate machinery. The impairment is worsened by the consumption of alcohol because both act as central nervous system depressants. [38]

During therapy, tolerance to the sedative effects usually develops, but not to the anxiolytic and myorelaxant effects. [73]

Patients with severe attacks of apnea during sleep may experience respiratory depression (hypoventilation), leading to respiratory arrest and death. [74]

Diazepam in doses of 5 mg or more causes significant deterioration in alertness performance combined with increased feelings of sleepiness. [75]

Tolerance and withdrawal

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. [76]

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. [45]

Benzodiazepine treatment is recommended to be discontinued as soon as possible by a slow and gradual dose reduction regimen. [19] [77] 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. [19]

Differences in rates of withdrawal (50–100%) vary depending on the patient sample. For example, a random sample of long-term benzodiazepine users typically finds around 50% experience few or no withdrawal symptoms, with the other 50% experiencing notable withdrawal symptoms. Certain select patient groups show a higher rate of notable withdrawal symptoms, up to 100%. [78]

Rebound anxiety, more severe than baseline anxiety, is also a common withdrawal symptom when discontinuing diazepam or other benzodiazepines. [79] 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. [80] 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.[ clarify ] [81] In humans, tolerance to the anticonvulsant effects of diazepam occurs frequently. [82]

Dependence

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

Patients from the aforementioned groups are monitored very closely during therapy for signs of abuse and development of dependence. Therapy is recommended to be discontinued if any of these signs are noted. If dependence has developed, therapy is still discontinued gradually to avoid severe withdrawal symptoms. Long-term therapy in such instances is not recommended. [38] [83]

People suspected of being dependent on benzodiazepine drugs are very gradually tapered off the drug. Withdrawals can be life-threatening, particularly when excessive doses have been taken for extended periods. Therefore, equal prudence is used whether dependence has occurred in therapeutic or recreational contexts. [86]

Diazepam is seen as 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. [87] The process is very slow (usually from 14 to 28 weeks) but is considered safe when done appropriately. [88]

Overdose

An individual who has consumed too much diazepam typically displays one or more of these symptoms in approximately four hours immediately following a suspected overdose: [38] [89]

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 antidote for an overdose of diazepam (or any other benzodiazepine) is flumazenil (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 respiration and stabilization of cardiovascular functions may also be necessary. Though not routinely indicated, activated charcoal can be used for decontamination of the stomach following a diazepam overdose. Emesis is contraindicated. Dialysis is minimally effective. Hypotension may be treated with levarterenol or metaraminol. [38] [28] [89] [90]

The oral LD50 (lethal dose in 50% of the population) of diazepam is 720 mg/kg in mice and 1240 mg/kg in rats. [38] D. J. Greenblatt and colleagues reported in 1978 on two patients who had taken 500 mg and 2000 mg of diazepam, respectively, went into moderately-deep comas, and were discharged within 48 hours without having experienced any important complications, despite having high concentrations of diazepam and its metabolites desmethyldiazepam, oxazepam, and temazepam, according to samples taken in the hospital and as follow-up. [91]

Overdoses of diazepam with alcohol, opiates, or other depressants may be fatal. [90] [92]

Interactions

If diazepam is administered concomitantly with other drugs, it is recommended that attention be paid to the possible pharmacological interactions. Particular care is taken with drugs that potentiate the effects of diazepam, such as barbiturates, phenothiazines, opioids, and antidepressants. [38]

Diazepam does not increase or decrease hepatic enzyme activity and does not alter the metabolism of other compounds. No evidence has suggested that diazepam alters its metabolism with chronic administration. [28]

Agents with 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. [28]

Pharmacology

5 mg Valium Roche packaging Australia 5mgrocheaus.jpg
5 mg Valium Roche packaging Australia

Diazepam is a long-acting "classical" benzodiazepine. Other classical benzodiazepines include chlordiazepoxide, clonazepam, lorazepam, oxazepam, nitrazepam, temazepam, flurazepam, bromazepam, and clorazepate. [100] Diazepam has anticonvulsant properties. [101] Benzodiazepines act via micromolar benzodiazepine binding sites as calcium channel blockers and significantly inhibit depolarization-sensitive calcium uptake in rat nerve cell preparations. [102]

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. [103]

Diazepam binds with high affinity to glial cells in animal cell cultures. [104] Diazepam at high doses has been found to decrease histamine turnover in mouse brain via diazepam's action at the benzodiazepine-GABA receptor complex. [105] Diazepam also decreases prolactin release in rats. [106]

Mechanism of action

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. The binding of benzodiazepines to this receptor complex promotes the 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. [1]

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. [107] Diazepam is not the only drug to target these GABAA receptors. Drugs such as flumazenil also bind to GABAA to induce their effects. [108]

Diazepam appears to act on areas of the limbic system, thalamus, and hypothalamus, inducing anxiolytic effects. Benzodiazepine drugs including diazepam increase the inhibitory processes in the cerebral cortex. [109]

The anticonvulsant properties of diazepam and other benzodiazepines may be in part or entirely due to binding to voltage-dependent sodium channels rather than GABAA receptors. Sustained repetitive firing seems limited by benzodiazepines' effect of slowing recovery of sodium channels from inactivation. [110]

The muscle relaxant properties of diazepam are produced via inhibition of polysynaptic pathways in the spinal cord. [111]

Pharmacokinetics

Diazepam can be administered orally, intravenously (it is always diluted, as it is painful and damaging to veins), intramuscularly (IM), or as a suppository. [28]

The onset of action is one to five minutes for IV administration and 15–30 minutes for IM administration. The duration of diazepam's peak pharmacological effects is 15 minutes to one hour for both routes of administration. [67] The half-life of diazepam, in general, is 30–56 hours. [1] Peak plasma levels occur between 30 and 90 minutes after oral administration and between 30 and 60 minutes after intramuscular administration; after rectal administration, peak plasma levels occur after 10 to 45 minutes. Diazepam is highly plasma protein-bound, with 96–99% of the absorbed drug being protein-bound. The distribution half-life of diazepam is two to 13 minutes. [19]

Diazepam is highly lipid-soluble and is widely distributed throughout the body after administration. It easily crosses both the blood–brain barrier and the placenta, and is excreted into breast milk. After absorption, diazepam is redistributed into muscle and adipose tissue. Continual daily doses of diazepam quickly build to a high concentration in the body (mainly in adipose tissue), far above the actual dose for any given day. [19] [28]

Diazepam is stored preferentially in some organs, including the heart. Absorption by any administered route and the risk of accumulation is significantly increased in the neonate, and withdrawal of diazepam during pregnancy and breastfeeding is clinically justified. [112]

Diazepam undergoes oxidative metabolism by demethylation (CYP2C9, 2C19, 2B6, 3A4, and 3A5), hydroxylation (CYP3A4 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. [19] Most of the drug is metabolized; very little diazepam is excreted unchanged. [28] 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. [113]

Synthesis

The synthesis of Diazepam was first achieved through a reaction pathway developed by Leo Sternbach and his team at Hoffmann-La Roche in the late 1950s.

Sternbach's method commenced with 2-amino-5-chlorobenzophenone, which undergoes cyclocondensation with glycine ethyl ester hydrochloride to construct the benzodiazepine core. This core is subsequently alkylated at the nitrogen in the 1-position using dimethyl sulfate in the presence of sodium methoxide and methanol under reflux conditions. Although the direct transformation from 2-amino-5-chlorobenzophenone to Nordazepam is conceptually straightforward, an alternative approach involving the treatment of 2-amino-5-chlorobenzophenon with chloroacetyl chloride, succeeded by ammoniation and heating, culminates in Nordazepam with enhanced yield and facilitates easier purification processes. [114]

Synthesis of Diazepam.jpg

Detection in body fluids

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. Blood or plasma diazepam concentrations are usually in a range of 0.1–1.0 mg/L in persons receiving the drug therapeutically. Most commercial immunoassays for the benzodiazepine class of drugs cross-react with diazepam, but confirmation and quantitation are usually performed using chromatographic techniques. [115] [116] [117]

Environmental

Diazepam is a common environmental contamination finding near human settlements. [118]

History

Diazepam was the second benzodiazepine invented by Leo Sternbach of Hoffmann-La Roche at the company's Nutley, New Jersey, facility [119] 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. [120]

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). [90] 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. [121]

Marketed by Roche using an advertising campaign conceived by the William Douglas McAdams Agency under the leadership of Arthur Sackler, [122] 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. [120] Diazepam, along with oxazepam, nitrazepam and temazepam, represents 82% of the benzodiazepine market in Australia. [123] 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.[ citation needed ] It is also the first line of defense for a rare disorder called stiff-person syndrome. [37]

Society and culture

Recreational use

Diazepam is a medication with a high risk of misuse and can cause drug dependence. Urgent action by national governments has been recommended to improve prescribing patterns of benzodiazepines such as diazepam. [124] [125] A single dose of diazepam modulates the dopamine system in similar ways to how morphine and alcohol modulate the dopaminergic pathways. [126] Between 50 and 64% of rats will self-administer diazepam. [127] Diazepam can substitute for the behavioral effects of barbiturates in a primate study. [128] Diazepam has been found as an adulterant in heroin. [129]

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. [130]

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 mg to 10 mg. [131]

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 misuse benzodiazepines as commonly as females. [132]

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, 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 potential for misuse of benzodiazepines, zolpidem, and zopiclone. [115] 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. [133]

Diazepam is regulated as a prescription medication:

International

Diazepam is a Schedule IV controlled drug under the Convention on Psychotropic Substances. [134]

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 makes it illegal to possess the drug without a prescription, and for such purposes, it is classified as a Class C drug. [135]

Germany

Classified as a prescription drug, or in high dosage as a restricted drug (Betäubungsmittelgesetz, Anlage III). [136]

Australia

Diazepam is a Schedule 4 substance under the Poisons Standard (June 2018). [137] 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". [137]

United States

Diazepam is controlled as a Schedule IV substance. [10]

Judicial executions

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. [138] [139] In August 2018, Nebraska used diazepam as part of the drug combination used to execute Carey Dean Moore, the first death row inmate executed in Nebraska in over 21 years. [140]

Veterinary uses

Diazepam is used as a short-term sedative and anxiolytic for cats and dogs, [141] sometimes used as an appetite stimulant. [141] [142] It can also be used to stop seizures in dogs and cats. [143]

Related Research Articles

<span class="mw-page-title-main">Benzodiazepine</span> Class of depressant drugs

Benzodiazepines, colloquially known as "benzos", are a class of depressant drugs whose core chemical structure is the fusion of a benzene ring and a diazepine ring. They are prescribed to treat conditions such as anxiety disorders, insomnia, and seizures. The first benzodiazepine, chlordiazepoxide (Librium), was discovered accidentally by Leo Sternbach in 1955, and was made available in 1960 by Hoffmann–La Roche, which followed with the development of diazepam (Valium) three years later, in 1963. By 1977, benzodiazepines were the most prescribed medications globally; the introduction of selective serotonin reuptake inhibitors (SSRIs), among other factors, decreased rates of prescription, but they remain frequently used worldwide.

<span class="mw-page-title-main">Alprazolam</span> Benzodiazepine medication

Alprazolam, sold under the brand name Xanax among others, is a fast-acting, potent tranquilizer of moderate duration within the triazolobenzodiazepine group of chemicals called benzodiazepines. Alprazolam is most commonly prescribed in the management of anxiety disorders, especially panic disorder and generalized anxiety disorder (GAD). Other uses include the treatment of chemotherapy-induced nausea, together with other treatments. GAD improvement occurs generally within a week. Alprazolam is generally taken orally.

<span class="mw-page-title-main">Lorazepam</span> Benzodiazepine medication

Lorazepam, sold under the brand name Ativan among others, is a benzodiazepine medication. It is used to treat anxiety, trouble sleeping, severe agitation, active seizures including status epilepticus, alcohol withdrawal, and chemotherapy-induced nausea and vomiting. It is also used during surgery to interfere with memory formation and to sedate those who are being mechanically ventilated. It is also used, along with other treatments, for acute coronary syndrome due to cocaine use. It can be given orally, transdermally, intravenously (IV), or intramuscularly When given by injection, onset of effects is between one and thirty minutes and effects last for up to a day.

<span class="mw-page-title-main">Clonazepam</span> Benzodiazepine medication

Clonazepam, sold under the brand name Klonopin among others, is a benzodiazepine medication used to prevent and treat anxiety disorders, seizures, bipolar mania, agitation associated with psychosis, obsessive–compulsive disorder (OCD), and akathisia. It is a long-acting tranquilizer of the benzodiazepine class. It possesses anxiolytic, anticonvulsant, sedative, hypnotic, and skeletal muscle relaxant properties. It is typically taken orally but is also used intravenously. Effects begin within one hour and last between eight and twelve hours in adults.

<span class="mw-page-title-main">Flumazenil</span> GABA receptor antagonist drug and benzodiazepine antidote

Flumazenil is a selective GABAA receptor antagonist administered via injection, otic insertion, or intranasally. Therapeutically, it acts as both an antagonist and antidote to benzodiazepines, through competitive inhibition.

<span class="mw-page-title-main">Nitrazepam</span> Benzodiazepine sedative

Nitrazepam, sold under the brand name Mogadon among others, is a hypnotic drug of the benzodiazepine class used for short-term relief from severe, disabling anxiety and insomnia. It also has sedative (calming) properties, as well as amnestic, anticonvulsant, and skeletal muscle relaxant effects.

<span class="mw-page-title-main">Bromazepam</span> Benzodiazepine drug

Bromazepam, sold under many brand names, is a benzodiazepine. It is mainly an anti-anxiety agent with similar side effects to diazepam. In addition to being used to treat anxiety or panic states, bromazepam may be used as a premedicant prior to minor surgery. Bromazepam typically comes in doses of 3 mg and 6 mg tablets.

<span class="mw-page-title-main">Oxazepam</span> Benzodiazepine medication

Oxazepam is a short-to-intermediate-acting benzodiazepine. Oxazepam is used for the treatment of anxiety, insomnia, and to control symptoms of alcohol withdrawal syndrome.

<span class="mw-page-title-main">Clobazam</span> Benzodiazepine class medication

Clobazam, sold under the brand names Frisium, Onfi and others, is a benzodiazepine class medication that was patented in 1968. Clobazam was first synthesized in 1966 and first published in 1969. Clobazam was originally marketed as an anxioselective anxiolytic since 1970, and an anticonvulsant since 1984. The primary drug-development goal was to provide greater anxiolytic, anti-obsessive efficacy with fewer benzodiazepine-related side effects.

<span class="mw-page-title-main">Nordazepam</span> Benzodiazepine derivative medication

Nordazepam is a 1,4-benzodiazepine derivative. Like other benzodiazepine derivatives, it has amnesic, anticonvulsant, anxiolytic, muscle relaxant, and sedative properties. However, it is used primarily in the treatment of anxiety disorders. It is an active metabolite of diazepam, chlordiazepoxide, clorazepate, prazepam, pinazepam, and medazepam.

<span class="mw-page-title-main">Clorazepate</span> Benzodiazepine medication

Clorazepate, sold under the brand name Tranxene among others, is a benzodiazepine medication. It possesses anxiolytic, anticonvulsant, sedative, hypnotic, and skeletal muscle relaxant properties. Clorazepate is an unusually long-lasting benzodiazepine and serves as a prodrug for the equally long-lasting desmethyldiazepam, which is rapidly produced as an active metabolite. Desmethyldiazepam is responsible for most of the therapeutic effects of clorazepate.

<span class="mw-page-title-main">Loprazolam</span> Benzodiazepine

Loprazolam (triazulenone) marketed under many brand names is a benzodiazepine medication. It possesses anxiolytic, anticonvulsant, hypnotic, sedative and skeletal muscle relaxant properties. It is licensed and marketed for the short-term treatment of moderately-severe insomnia.

<span class="mw-page-title-main">Lormetazepam</span> Benzodiazepine medication

Lormetazepam, sold under the brand name Noctamid among others, is a drug which is a short to intermediate acting 3-hydroxy benzodiazepine derivative and temazepam analogue. It possesses hypnotic, anxiolytic, anticonvulsant, sedative, and skeletal muscle relaxant properties.

<span class="mw-page-title-main">Bretazenil</span> Chemical compound

Bretazenil (Ro16-6028) is an imidazopyrrolobenzodiazepine anxiolytic drug which is derived from the benzodiazepine family, and was invented in 1988. It is most closely related in structure to the GABA antagonist flumazenil, although its effects are somewhat different. It is classified as a high-potency benzodiazepine due to its high affinity binding to benzodiazepine binding sites where it acts as a partial agonist. Its profile as a partial agonist and preclinical trial data suggests that it may have a reduced adverse effect profile. In particular bretazenil has been proposed to cause a less strong development of tolerance and withdrawal syndrome. Bretazenil differs from traditional 1,4-benzodiazepines by being a partial agonist and because it binds to α1, α2, α3, α4, α5 and α6 subunit containing GABAA receptor benzodiazepine receptor complexes. 1,4-benzodiazepines bind only to α1, α2, α3 and α5GABAA benzodiazepine receptor complexes.

<span class="mw-page-title-main">Chlordiazepoxide</span> Benzodiazepine class sedative and hypnotic medication

Chlordiazepoxide, trade name Librium among others, is a sedative and hypnotic medication of the benzodiazepine class; it is used to treat anxiety, insomnia and symptoms of withdrawal from alcohol, benzodiazepines, and other drugs.

<span class="mw-page-title-main">Benzodiazepine withdrawal syndrome</span> Signs and symptoms due to benzodiazepine discontinuation in physically dependent persons

Benzodiazepine withdrawal syndrome is the cluster of signs and symptoms that may emerge when a person who has been taking benzodiazepines as prescribed develops a physical dependence on them and then reduces the dose or stops taking them without a safe taper schedule.

<span class="mw-page-title-main">Alcohol withdrawal syndrome</span> Medical condition

Alcohol withdrawal syndrome (AWS) is a set of symptoms that can occur following a reduction in alcohol use after a period of excessive use. Symptoms typically include anxiety, shakiness, sweating, vomiting, fast heart rate, and a mild fever. More severe symptoms may include seizures, and delirium tremens (DTs); which can be fatal in untreated patients. Symptoms start at around 6 hours after the last drink. Peak incidence of seizures occurs at 24-36 hours and peak incidence of delirium tremens is at 48-72 hours.

<span class="mw-page-title-main">Benzodiazepine dependence</span> Medical condition

Benzodiazepine dependence defines a situation in which one has developed one or more of either tolerance, withdrawal symptoms, drug seeking behaviors, such as continued use despite harmful effects, and maladaptive pattern of substance use, according to the DSM-IV. In the case of benzodiazepine dependence, the continued use seems to be typically associated with the avoidance of unpleasant withdrawal reaction rather than with the pleasurable effects of the drug. Benzodiazepine dependence develops with long-term use, even at low therapeutic doses, often without the described drug seeking behavior and tolerance.

<span class="mw-page-title-main">Barbiturate</span> Class of depressant drugs derived from barbituric acid

Barbiturates are a class of depressant drugs that are chemically derived from barbituric acid. They are effective when used medically as anxiolytics, hypnotics, and anticonvulsants, but have physical and psychological addiction potential as well as overdose potential among other possible adverse effects. They have been used recreationally for their anti-anxiety and sedative effects, and are thus controlled in most countries due to the risks associated with such use.

References

  1. 1 2 3 "National Highway Traffic Safety Administration Drugs and Human Performance Fact Sheet- Diazepam". Archived from the original on 27 March 2017. Retrieved 13 November 2017.
  2. 1 2 "Valium". NPS MedicineWise. 31 January 2020. Archived from the original on 29 July 2020. Retrieved 9 January 2023.
  3. ↑ Edmunds M, Mayhew M (2013). Pharmacology for the Primary Care Provider (4th ed.). Mosby. p. 545. ISBN   978-0-323-08790-2. Archived from the original on 14 January 2023. Retrieved 13 July 2020.
  4. ↑ Clinical Addiction Psychiatry. Cambridge University Press. 2010. p. 156. ISBN   978-1-139-49169-3. Archived from the original on 8 September 2017.
  5. ↑ Ries RK (2009). Principles of addiction medicine (4 ed.). Philadelphia: Wolters Kluwer/Lippincott Williams & Wilkins. p. 106. ISBN   978-0-7817-7477-2. Archived from the original on 8 September 2017.
  6. 1 2 3 "Valtoco – diazepam spray". DailyMed. 13 January 2020. Archived from the original on 1 August 2020. Retrieved 13 February 2020.
  7. 1 2 "Diazepam Tablets BP 10 mg – Summary of Product Characteristics (SmPC)". (emc). 16 September 2019. Archived from the original on 25 July 2020. Retrieved 25 July 2020.
  8. 1 2 "Diazepam Injection BP Summary of Product Characteristics (SmPC)". emc. 17 January 2022. Archived from the original on 25 January 2023. Retrieved 11 February 2024.
  9. ↑ "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA . Retrieved 22 October 2023.
  10. 1 2 3 4 "Valium – diazepam tablet". DailyMed. 8 November 2019. Archived from the original on 28 June 2019. Retrieved 30 December 2019.
  11. ↑ "Libervant- diazepam film". DailyMed. 27 April 2024. Retrieved 18 May 2024.
  12. ↑ Dhillon S, Oxley J, Richens A (March 1982). "Bioavailability of diazepam after intravenous, oral and rectal administration in adult epileptic patients". British Journal of Clinical Pharmacology. 13 (3): 427–32. doi:10.1111/j.1365-2125.1982.tb01397.x. PMC   1402110 . PMID   7059446.
  13. ↑ Goodkin HP (2010). "Diazepam". In Panayiotopoulos CP (ed.). Atlas of Epilepsies. London: Springer. pp. 1727–1731. doi:10.1007/978-1-84882-128-6_263. ISBN   978-1-84882-128-6.
  14. 1 2 3 4 5 6 7 8 9 10 Calcaterra NE, Barrow JC (April 2014). "Classics in chemical neuroscience: diazepam (valium)". ACS Chemical Neuroscience. 5 (4): 253–60. doi:10.1021/cn5000056. PMC   3990949 . PMID   24552479.
  15. 1 2 3 "Diazepam". PubChem. U.S. National Library of Medicine. Retrieved 2 February 2024.
  16. 1 2 3 4 5 6 "Diazepam". The American Society of Health-System Pharmacists. Archived from the original on 30 June 2015. Retrieved 5 June 2015.
  17. ↑ Dhaliwal JS, Saadabadi A (September 2022). "Diazepam". StatPearls [Internet]. StatPearls Publishing. PMID   30725707. Archived from the original on 8 March 2021. Retrieved 13 October 2019.
  18. ↑ Dodds TJ (March 2017). "Prescribed Benzodiazepines and Suicide Risk: A Review of the Literature". The Primary Care Companion for CNS Disorders. 19 (2). doi: 10.4088/PCC.16r02037 . PMID   28257172.
  19. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 Riss J, Cloyd J, Gates J, Collins S (August 2008). "Benzodiazepines in epilepsy: pharmacology and pharmacokinetics". Acta Neurologica Scandinavica. 118 (2): 69–86. doi: 10.1111/j.1600-0404.2008.01004.x . PMID   18384456. S2CID   24453988.
  20. ↑ Perkin RM (2008). Pediatric hospital medicine : textbook of inpatient management (2nd ed.). Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins. p. 862. ISBN   978-0-7817-7032-3.
  21. ↑ Fischer J, Ganellin CR (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 535. ISBN   978-3-527-60749-5. Archived from the original on 14 January 2023. Retrieved 5 June 2020.
  22. ↑ USpatent 3371085,Sternbach LH, Reeder E,"5-ARYL-3H-1,4-BENZODIAZEPIN-2(1H)-ONES",published 1968-02-27,issued 1968-02-27, assigned to Hoffmann La Roche AG
  23. ↑ "The Top 300 of 2022". ClinCalc. Archived from the original on 30 August 2024. Retrieved 30 August 2024.
  24. ↑ "Diazepam Drug Usage Statistics, United States, 2013 - 2022". ClinCalc. Retrieved 30 August 2024.
  25. ↑ World Health Organization (2023). The selection and use of essential medicines 2023: web annex A: World Health Organization model list of essential medicines: 23rd list (2023). Geneva: World Health Organization. hdl: 10665/371090 . WHO/MHP/HPS/EML/2023.02.
  26. ↑ Pajouhesh H, Lenz GR (October 2005). "Medicinal chemical properties of successful central nervous system drugs". NeuroRx. 2 (4): 541–553. doi:10.1602/neurorx.2.4.541. PMC   1201314 . PMID   16489364.
  27. ↑ Plumb's, 6th edition page 372
  28. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 Munne P (1998). Ruse M (ed.). "Diazepam". Inchem.org. Archived from the original on 27 February 2006. Retrieved 11 March 2006.
  29. 1 2 3 4 Mikota SK, Plumb DC (2005). "Diazepam". The Elephant Formulary. Elephant Care International. Archived from the original on 8 September 2005.
  30. 1 2 3 4 "Diazepam". Drug Bank. Archived from the original on 24 December 2006.
  31. ↑ Bråthen G, Ben-Menachem E, Brodtkorb E, Galvin R, Garcia-Monco JC, Halasz P, et al. (August 2005). "EFNS guideline on the diagnosis and management of alcohol-related seizures: report of an EFNS task force". European Journal of Neurology. 12 (8): 575–81. doi: 10.1111/j.1468-1331.2005.01247.x . PMID   16053464. S2CID   25904252.
  32. ↑ "FDA approves Valtoco". Drugs.com. 13 January 2020. Archived from the original on 18 February 2020. Retrieved 18 February 2020.
  33. ↑ "Valium Tablets". NPS MedicineWise. Archived from the original on 29 July 2020. Retrieved 29 August 2019.
  34. ↑ Cesarani A, Alpini D, Monti B, Raponi G (March 2004). "The treatment of acute vertigo". Neurological Sciences. 25 (Suppl 1): S26-30. doi:10.1007/s10072-004-0213-8. PMID   15045617. S2CID   25105327.
  35. ↑ Lader M, Tylee A, Donoghue J (2009). "Withdrawing benzodiazepines in primary care". CNS Drugs. 23 (1): 19–34. doi:10.2165/0023210-200923010-00002. PMID   19062773. S2CID   113206.
  36. ↑ Okoromah CN, Lesi FE (2004). Okoromah CA (ed.). "Diazepam for treating tetanus". The Cochrane Database of Systematic Reviews. 2010 (1): CD003954. doi:10.1002/14651858.CD003954.pub2. PMC   8759227 . PMID   14974046.
  37. 1 2 3 "Diazepam: indications". Rxlist.com. RxList Inc. January 24, 2005. Archived from the original on February 16, 2006. Retrieved March 11, 2006.
  38. 1 2 3 4 5 6 7 8 9 "Diazepam". Prescription Drug Information. Thomson Healthcare (Micromedex). March 2000. Archived from the original on 19 June 2006. Retrieved 11 March 2006.
  39. ↑ Kindwall EP, Whelan HT (1999). Hyperbaric Medicine Practice (2nd ed.). Best Publishing Company. ISBN   978-0-941332-78-1.
  40. ↑ Walker M (September 2005). "Status epilepticus: an evidence based guide". BMJ. 331 (7518): 673–7. doi:10.1136/bmj.331.7518.673. PMC   1226249 . PMID   16179702.
  41. ↑ Prasad M, Krishnan PR, Sequeira R, Al-Roomi K (September 2014). "Anticonvulsant therapy for status epilepticus". The Cochrane Database of Systematic Reviews. 2014 (9): CD003723. doi:10.1002/14651858.CD003723.pub3. PMC   7154380 . PMID   25207925.
  42. ↑ Isojärvi JI, Tokola RA (December 1998). "Benzodiazepines in the treatment of epilepsy in people with intellectual disability". Journal of Intellectual Disability Research. 42 (Suppl 1): 80–92. PMID   10030438.
  43. ↑ Bajgar J (2004). Organophosphates/nerve agent poisoning: mechanism of action, diagnosis, prophylaxis, and treatment. Advances in Clinical Chemistry. Vol. 38. pp. 151–216. doi:10.1016/S0065-2423(04)38006-6. ISBN   978-0-12-010338-6. PMID   15521192.
  44. ↑ Offringa M, Newton R, Nevitt SJ, Vraka K (June 2021). "Prophylactic drug management for febrile seizures in children". The Cochrane Database of Systematic Reviews. 2021 (6): CD003031. doi:10.1002/14651858.CD003031.pub4. PMC   8207248 . PMID   34131913.
  45. 1 2 3 Weintraub SJ (February 2017). "Diazepam in the Treatment of Moderate to Severe Alcohol Withdrawal". CNS Drugs. 31 (2): 87–95. doi:10.1007/s40263-016-0403-y. PMID   28101764. S2CID   42610220.
  46. ↑ Kaplan PW (November 2004). "Neurologic aspects of eclampsia". Neurologic Clinics. 22 (4): 841–61. doi: 10.1016/j.ncl.2004.07.005 . PMID   15474770.
  47. ↑ Duley L (February 2005). "Evidence and practice: the magnesium sulphate story". Best Practice & Research. Clinical Obstetrics & Gynaecology. 19 (1): 57–74. doi:10.1016/j.bpobgyn.2004.10.010. PMID   15749066.
  48. ↑ Zeilhofer HU, Witschi R, Hösl K (May 2009). "Subtype-selective GABAA receptor mimetics—novel antihyperalgesic agents?" (PDF). Journal of Molecular Medicine. 87 (5): 465–9. doi:10.1007/s00109-009-0454-3. hdl: 20.500.11850/20278 . PMID   19259638. S2CID   5614111. Archived (PDF) from the original on 29 July 2020. Retrieved 13 December 2019.
  49. ↑ Mezaki T, Hayashi A, Nakase H, Hasegawa K (September 2005). "[Therapy of dystonia in Japan]". Rinsho Shinkeigaku = Clinical Neurology (in Japanese). 45 (9): 634–42. PMID   16248394.
  50. ↑ Kachi T (December 2001). "[Medical treatment of dystonia]". Rinsho Shinkeigaku = Clinical Neurology (in Japanese). 41 (12): 1181–2. PMID   12235832.
  51. ↑ Ashton H (May 2005). "The diagnosis and management of benzodiazepine dependence" (PDF). Current Opinion in Psychiatry. 18 (3): 249–55. doi:10.1097/01.yco.0000165594.60434.84. PMID   16639148. S2CID   1709063. Archived (PDF) from the original on 8 August 2017. Retrieved 13 May 2010.
  52. ↑ Mañon-Espaillat R, Mandel S (January 1999). "Diagnostic Algorithms for Neuromuscular Diseases". Clinics in Podiatric Medicine and Surgery. 16 (1): 67–79. doi:10.1016/S0891-8422(23)00935-7. PMID   9929772. S2CID   12493035.
  53. ↑ "International AED Database". ILAE. Archived from the original on 9 May 2008. Retrieved 16 September 2009.
  54. ↑ "Delivery of diazepam through an inhalation route". US Patent 6,805,853. PharmCast.com. 19 October 2004. Archived from the original on 17 October 2015. Retrieved 12 December 2014.
  55. ↑ U.S. Army Medical Research Institute of Chemical Defense, Medical Management of Chemical Casualties Handbook, Third Edition (June 2000), Aberdeen Proving Ground, MD, pp. 118–126.
  56. ↑ Epocrates. "Diazepam Contraindications and Cautions". US: Epocrates Online. Archived from the original on 10 July 2011. Retrieved 16 December 2008.
  57. ↑ Aparecido da Silva Junior C, Marques DA, Patrone LG, Biancardi V, Bícego KC, Gargaglioni LH (December 2022). "Intra-uterine diazepam exposure decreases the number of catecholaminergic and serotoninergic neurons of neonate rats". Neuroscience Letters. 795: 137014. doi:10.1016/j.neulet.2022.137014. PMID   36521643. S2CID   254555032.
  58. ↑ Authier N, Balayssac D, Sautereau M, Zangarelli A, Courty P, Somogyi AA, et al. (November 2009). "Benzodiazepine dependence: focus on withdrawal syndrome". Annales Pharmaceutiques Françaises. 67 (6): 408–13. doi:10.1016/j.pharma.2009.07.001. PMID   19900604.
  59. 1 2 3 4 5 6 7 "Diazepam". PDRHealth.com. 2006. Archived from the original on 17 January 2006. Retrieved 10 March 2006.
  60. 1 2 "Diazepam: precautions". Rxlist.com. RxList Inc. January 24, 2005. Archived from the original on April 7, 2006. Retrieved March 10, 2006.
  61. ↑ Shats V, Kozacov S (June 1995). "[Falls in the geriatric department: responsibility of the caregiver and the hospital]". Harefuah (in Hebrew). 128 (11): 690–3, 743. PMID   7557666.
  62. ↑ Kanto JH (May 1982). "Use of benzodiazepines during pregnancy, labour and lactation, with particular reference to pharmacokinetic considerations". Drugs. 23 (5): 354–80. doi:10.2165/00003495-198223050-00002. PMID   6124415. S2CID   27014006.
  63. ↑ McElhatton PR (1994). "The effects of benzodiazepine use during pregnancy and lactation". Reproductive Toxicology. 8 (6): 461–75. Bibcode:1994RepTx...8..461M. doi:10.1016/0890-6238(94)90029-9. PMID   7881198.
  64. ↑ Yudofsky SC, Hales RE (1 December 2007). The American Psychiatric Publishing Textbook of Neuropsychiatry and Behavioral Neurosciences, Fifth Edition (American Psychiatric Press Textbook of Neuropsychiatry). US: American Psychiatric Publishing, Inc. pp. 583–584. ISBN   978-1-58562-239-9. Archived from the original on 7 May 2016.
  65. ↑ Kripke DF (February 2016). "Mortality Risk of Hypnotics: Strengths and Limits of Evidence" (PDF). Drug Safety. 39 (2): 93–107. doi: 10.1007/s40264-015-0362-0 . PMID   26563222. S2CID   7946506. Archived (PDF) from the original on 14 March 2020. Retrieved 2 September 2019.
  66. ↑ "FDA expands Boxed Warning to improve safe use of benzodiazepine drug". U.S. Food and Drug Administration (FDA). 23 September 2020. Archived from the original on 24 September 2020. Retrieved 23 September 2020.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  67. 1 2 Langsam Y. "Diazepam (Valium and Others)". Brooklyn College (Eilat.sci.Brooklyn.CUNY.edu). Archived from the original on 30 July 2007. Retrieved 23 March 2006.
  68. ↑ Marrosu F, Marrosu G, Rachel MG, Biggio G (1987). "Paradoxical reactions elicited by diazepam in children with classic autism". Functional Neurology. 2 (3): 355–61. PMID   2826308.
  69. ↑ "Diazepam: Side Effects". RxList.com. Archived from the original on October 22, 2006. Retrieved September 26, 2006.
  70. ↑ Michel L, Lang JP (2003). "[Benzodiazepines and forensic aspects]". L'Encéphale (in French). 29 (6): 479–85. PMID   15029082. Archived from the original on 27 November 2007.
  71. ↑ Berman ME, Jones GD, McCloskey MS (February 2005). "The effects of diazepam on human self-aggressive behavior". Psychopharmacology. 178 (1): 100–6. doi:10.1007/s00213-004-1966-8. PMID   15316710. S2CID   20629702.
  72. ↑ Pérez Trullen JM, Modrego Pardo PJ, Vázquez André M, López Lozano JJ (1992). "Bromazepam-induced dystonia". Biomedicine & Pharmacotherapy. 46 (8): 375–6. doi:10.1016/0753-3322(92)90306-R. PMID   1292648.
  73. ↑ Hriscu A, Gherase F, Năstasă V, Hriscu E (October–December 2002). "[An experimental study of tolerance to benzodiazepines]". Revista Medico-Chirurgicala a Societatii de Medici Si Naturalisti Din Iasi. 106 (4): 806–11. PMID   14974234.
  74. ↑ McNicholas WT, Hansson D, Schiza S, Grote L (September 2019). "Sleep in chronic respiratory disease: COPD and hypoventilation disorders". European Respiratory Review. 28 (153): 190064. doi: 10.1183/16000617.0064-2019 . PMC   9488904 . PMID   31554703. S2CID   203440265.
  75. ↑ Kozená L, Frantik E, Horváth M (May 1995). "Vigilance impairment after a single dose of benzodiazepines". Psychopharmacology. 119 (1): 39–45. doi:10.1007/BF02246052. PMID   7675948. S2CID   2618084.
  76. ↑ Best KM, Boullata JI, Curley MA (February 2015). "Risk factors associated with iatrogenic opioid and benzodiazepine withdrawal in critically ill pediatric patients: a systematic review and conceptual model". Pediatric Critical Care Medicine. 16 (2): 175–83. doi:10.1097/PCC.0000000000000306. PMC   5304939 . PMID   25560429.
  77. ↑ MacKinnon GL, Parker WA (1982). "Benzodiazepine withdrawal syndrome: a literature review and evaluation". The American Journal of Drug and Alcohol Abuse. 9 (1): 19–33. doi:10.3109/00952998209002608. PMID   6133446.
  78. ↑ Onyett SR (April 1989). "The benzodiazepine withdrawal syndrome and its management". The Journal of the Royal College of General Practitioners. 39 (321): 160–3. PMC   1711840 . PMID   2576073.
  79. ↑ Chouinard G, Labonte A, Fontaine R, Annable L (1983). "New concepts in benzodiazepine therapy: rebound anxiety and new indications for the more potent benzodiazepines". Progress in Neuro-Psychopharmacology & Biological Psychiatry. 7 (4–6): 669–73. doi:10.1016/0278-5846(83)90043-X. PMID   6141609. S2CID   32967696.
  80. ↑ Lader M (December 1987). "Long-term anxiolytic therapy: the issue of drug withdrawal". The Journal of Clinical Psychiatry. 48 (Suppl): 12–6. PMID   2891684.
  81. ↑ Murphy SM, Owen R, Tyrer P (April 1989). "Comparative assessment of efficacy and withdrawal symptoms after 6 and 12 weeks' treatment with diazepam or buspirone". The British Journal of Psychiatry. 154 (4): 529–34. doi:10.1192/bjp.154.4.529. PMID   2686797. S2CID   5024826.
  82. ↑ Loiseau P (1983). "[Benzodiazepines in the treatment of epilepsy]". L'Encéphale. 9 (4 Suppl 2): 287B–292B. PMID   6373234.
  83. 1 2 "Diazepam: abuse and dependence". Rxlist.com. RxList Inc. January 24, 2005. Archived from the original on February 16, 2006. Retrieved March 10, 2006.
  84. ↑ Poulos CX, Zack M (November 2004). "Low-dose diazepam primes motivation for alcohol and alcohol-related semantic networks in problem drinkers". Behavioural Pharmacology. 15 (7): 503–12. doi:10.1097/00008877-200411000-00006. PMID   15472572. S2CID   23040302.
  85. ↑ Vorma H, Naukkarinen HH, Sarna SJ, Kuoppasalmi KI (2005). "Predictors of benzodiazepine discontinuation in subjects manifesting complicated dependence". Substance Use & Misuse. 40 (4): 499–510. doi:10.1081/JA-200052433. PMID   15830732. S2CID   1366333.
  86. ↑ Parr JM, Kavanagh DJ, Cahill L, Mitchell G, McD Young R (January 2009). "Effectiveness of current treatment approaches for benzodiazepine discontinuation: a meta-analysis". Addiction. 104 (1): 13–24. doi:10.1111/j.1360-0443.2008.02364.x. PMID   18983627.
  87. ↑ Thirtala T, Kaur K, Karlapati SK, Lippmann S (July 2013). "Consider this slow-taper program for benzodiazepines". Current Psychiatry. Archived from the original on 29 July 2020. Retrieved 29 August 2019.
  88. ↑ "Tapering Benzodiazepines" (PDF). Archived (PDF) from the original on 13 July 2018. Retrieved 29 August 2019.
  89. 1 2 "Diazepam: overdose". Rxlist.com. RxList Inc. January 24, 2005. Archived from the original on February 16, 2006. Retrieved March 10, 2006.
  90. 1 2 3 Barondes SH (2003). Better Than Prozac . New York: Oxford University Press. pp.  47–59. ISBN   978-0-19-515130-5.
  91. ↑ Greenblatt DJ, Woo E, Allen MD, Orsulak PJ, Shader RI (October 1978). "Rapid recovery from massive diazepam overdose". JAMA. 240 (17): 1872–4. doi:10.1001/jama.1978.03290170054026. PMID   357765.
  92. ↑ Lai SH, Yao YJ, Lo DS (October 2006). "A survey of buprenorphine related deaths in Singapore". Forensic Science International. 162 (1–3): 80–6. doi:10.1016/j.forsciint.2006.03.037. PMID   16879940.
  93. 1 2 3 4 Holt GA (1998). Food and Drug Interactions: A Guide for Consumers. Chicago: Precept Press. pp. 90–91. ISBN   978-0-944496-59-6.
  94. ↑ Zácková P, Kvĕtina J, Nĕmec J, Nĕmcová J (December 1982). "Cardiovascular effects of diazepam and nitrazepam in combination with ethanol". Die Pharmazie. 37 (12): 853–6. PMID   7163374.
  95. ↑ Back DJ, Orme ML (June 1990). "Pharmacokinetic drug interactions with oral contraceptives". Clinical Pharmacokinetics. 18 (6): 472–84. doi:10.2165/00003088-199018060-00004. PMID   2191822. S2CID   32523973.
  96. ↑ Bendarzewska-Nawrocka B, Pietruszewska E, Stepień L, Bidziński J, Bacia T (January–February 1980). "[Relationship between blood serum luminal and diphenylhydantoin level and the results of treatment and other clinical data in drug-resistant epilepsy]". Neurologia I Neurochirurgia Polska. 14 (1): 39–45. PMID   7374896.
  97. ↑ Bateman DN (1986). "The action of cisapride on gastric emptying and the pharmacodynamics and pharmacokinetics of oral diazepam". European Journal of Clinical Pharmacology. 30 (2): 205–8. doi:10.1007/BF00614304. PMID   3709647. S2CID   41495586.
  98. ↑ Mattila MJ, Nuotto E (1983). "Caffeine and theophylline counteract diazepam effects in man". Medical Biology. 61 (6): 337–43. PMID   6374311.
  99. ↑ "Possible Interactions with: Valerian". University of Maryland Medical Center . 13 May 2013. Archived from the original on 21 January 2013. Retrieved 12 December 2014.
  100. ↑ Braestrup C, Squires RF (April 1978). "Pharmacological characterization of benzodiazepine receptors in the brain". European Journal of Pharmacology. 48 (3): 263–70. doi:10.1016/0014-2999(78)90085-7. PMID   639854.
  101. ↑ Chweh AY, Swinyard EA, Wolf HH, Kupferberg HJ (February 1985). "Effect of GABA agonists on the neurotoxicity and anticonvulsant activity of benzodiazepines". Life Sciences. 36 (8): 737–44. doi:10.1016/0024-3205(85)90193-6. PMID   2983169.
  102. ↑ Taft WC, DeLorenzo RJ (May 1984). "Micromolar-affinity benzodiazepine receptors regulate voltage-sensitive calcium channels in nerve terminal preparations" (PDF). Proceedings of the National Academy of Sciences of the United States of America (PDF). 81 (10): 3118–22. Bibcode:1984PNAS...81.3118T. doi: 10.1073/pnas.81.10.3118 . PMC   345232 . PMID   6328498. Archived (PDF) from the original on 25 June 2008.
  103. ↑ Miller JA, Richter JA (January 1985). "Effects of anticonvulsants in vivo on high affinity choline uptake in vitro in mouse hippocampal synaptosomes". British Journal of Pharmacology. 84 (1): 19–25. doi:10.1111/j.1476-5381.1985.tb17368.x. PMC   1987204 . PMID   3978310.
  104. ↑ Gallager DW, Mallorga P, Oertel W, Henneberry R, Tallman J (February 1981). "[3H]Diazepam binding in mammalian central nervous system: a pharmacological characterization". The Journal of Neuroscience. 1 (2): 218–25. doi:10.1523/JNEUROSCI.01-02-00218.1981. PMC   6564145 . PMID   6267221.
  105. ↑ Oishi R, Nishibori M, Itoh Y, Saeki K (May 1986). "Diazepam-induced decrease in histamine turnover in mouse brain". European Journal of Pharmacology. 124 (3): 337–42. doi:10.1016/0014-2999(86)90236-0. PMID   3089825.
  106. ↑ Grandison L (1982). "Suppression of prolactin secretion by benzodiazepines in vivo". Neuroendocrinology. 34 (5): 369–73. doi:10.1159/000123330. PMID   6979001.
  107. ↑ Tan KR, Rudolph U, Lüscher C (2011). "Hooked on benzodiazepines: GABAA receptor subtypes and addiction" (PDF). University of Geneva . Archived (PDF) from the original on 1 July 2015. Retrieved 12 December 2014.
  108. ↑ Whirl-Carrillo M, McDonagh EM, Hebert JM, Gong L, Sangkuhl K, Thorn CF, et al. (October 2012). "Pharmacogenomics knowledge for personalized medicine". Clinical Pharmacology and Therapeutics. 92 (4): 414–7. doi:10.1038/clpt.2012.96. PMC   3660037 . PMID   22992668.
  109. ↑ Zakusov VV, Ostrovskaya RU, Kozhechkin SN, Markovich VV, Molodavkin GM, Voronina TA (October 1977). "Further evidence for GABA-ergic mechanisms in the action of benzodiazepines". Archives Internationales de Pharmacodynamie et de Thérapie. 229 (2): 313–26. PMID   23084.
  110. ↑ McLean MJ, Macdonald RL (February 1988). "Benzodiazepines, but not beta-carbolines, limit high-frequency repetitive firing of action potentials of spinal cord neurons in cell culture". The Journal of Pharmacology and Experimental Therapeutics. 244 (2): 789–95. PMID   2450203.
  111. ↑ Date SK, Hemavathi KG, Gulati OD (November 1984). "Investigation of the muscle relaxant activity of nitrazepam". Archives Internationales de Pharmacodynamie et de Thérapie. 272 (1): 129–39. PMID   6517646.
  112. ↑ Olive G, Dreux C (January 1977). "[Pharmacologic bases of use of benzodiazepines in peréinatal medicine]". Archives Françaises de Pédiatrie. 34 (1): 74–89. PMID   851373.
  113. ↑ Vozeh S (November 1981). "[Pharmacokinetic of benzodiazepines in old age]". Schweizerische Medizinische Wochenschrift. 111 (47): 1789–93. PMID   6118950.
  114. ↑ Stempel A, Reeder E, Sternbach LH (December 1965). "Quinazolines and 1,4-benzodiazepines. XXVII. Mechanism of ring enlargement of quinazoline 3-oxides with alkali to 1,4-benzodiazepin-2-one 4-oxides". The Journal of Organic Chemistry. 30 (12): 4267–4271. doi:10.1021/jo01023a063. PMID   4158669. Archived from the original on 3 February 2024. Retrieved 2 February 2024.
  115. 1 2 Jones AW, Holmgren A, Kugelberg FC (April 2007). "Concentrations of scheduled prescription drugs in blood of impaired drivers: considerations for interpreting the results". Therapeutic Drug Monitoring. 29 (2): 248–60. doi:10.1097/FTD.0b013e31803d3c04. PMID   17417081. S2CID   25511804.
  116. ↑ Fraser AD, Bryan W (1991). "Evaluation of the Abbott ADx and TDx serum benzodiazepine immunoassays for analysis of alprazolam". Journal of Analytical Toxicology. 15 (2): 63–5. doi:10.1093/jat/15.2.63. PMID   1675703.
  117. ↑ Baselt R (2011). Disposition of Toxic Drugs and Chemicals in Man (9th ed.). Seal Beach, CA: Biomedical Publications. pp. 471–473. ISBN   978-0-9626523-8-7.
  118. ↑ Chia MA, Lorenzi AS, Ameh I, Dauda S, Cordeiro-Araújo MK, Agee JT, et al. (May 2021). "Susceptibility of phytoplankton to the increasing presence of active pharmaceutical ingredients (APIs) in the aquatic environment: A review". Aquatic Toxicology. 234: 105809. Bibcode:2021AqTox.23405809C. doi:10.1016/j.aquatox.2021.105809. PMID   33780670. S2CID   232419482.
  119. ↑ Pollack A (26 June 2012). "Roche to Shut Former U.S. Headquarters". New York Times. Archived from the original on 31 March 2013. Retrieved 10 January 2014.
  120. 1 2 Sample I (3 October 2005). "Leo Sternbach's Obituary". The Guardian (Guardian Unlimited). Archived from the original on 28 August 2021. Retrieved 10 March 2006.
  121. ↑ Marshall KP, Georgievskava Z, Georgievsky I (June 2009). "Social reactions to Valium and Prozac: a cultural lag perspective of drug diffusion and adoption". Research in Social & Administrative Pharmacy. 5 (2): 94–107. doi:10.1016/j.sapharm.2008.06.005. PMID   19524858.
  122. ↑ "How the American opiate epidemic was started by one pharmaceutical company". Theweek.com. 4 March 2015. Archived from the original on 10 January 2018. Retrieved 10 January 2018.
  123. ↑ Mant A, Whicker SD, McManus P, Birkett DJ, Edmonds D, Dumbrell D (December 1993). "Benzodiazepine utilisation in Australia: report from a new pharmacoepidemiological database". Australian Journal of Public Health. 17 (4): 345–9. doi: 10.1111/j.1753-6405.1993.tb00167.x . PMID   7911332.
  124. ↑ Atack JR (May 2005). "The benzodiazepine binding site of GABA(A) receptors as a target for the development of novel anxiolytics". Expert Opinion on Investigational Drugs. 14 (5): 601–18. doi:10.1517/13543784.14.5.601. PMID   15926867. S2CID   22793644.
  125. ↑ Dièye AM, Sylla M, Ndiaye A, Ndiaye M, Sy GY, Faye B (June 2006). "Benzodiazepines prescription in Dakar: a study about prescribing habits and knowledge in general practitioners, neurologists and psychiatrists". Fundamental & Clinical Pharmacology. 20 (3): 235–8. doi:10.1111/j.1472-8206.2006.00400.x. PMID   16671957. S2CID   20619323.
  126. ↑ "New Evidence on Addiction To Medicines Diazepam Has Effect on Nerve Cells in the Brain Reward System". Medical News Today. August 2008. Archived from the original on 12 September 2008. Retrieved 25 September 2008.
  127. ↑ Yoshimura K, Horiuchi M, Inoue Y, Yamamoto K (January 1984). "[Pharmacological studies on drug dependence. (III): Intravenous self-administration of some CNS-affecting drugs and a new sleep-inducer, 1H-1, 2, 4-triazolyl benzophenone derivative (450191-S), in rats]". Nihon Yakurigaku Zasshi. Folia Pharmacologica Japonica. 83 (1): 39–67. doi: 10.1254/fpj.83.39 . PMID   6538866.
  128. ↑ Woolverton WL, Nader MA (December 1995). "Effects of several benzodiazepines, alone and in combination with flumazenil, in rhesus monkeys trained to discriminate pentobarbital from saline". Psychopharmacology. 122 (3): 230–6. doi:10.1007/BF02246544. PMID   8748392. S2CID   24836734.
  129. ↑ "Report of the International Narcotics Control Board for 1996" (PDF). United Nations. International Narcotics Control Board. 1996. p. 27. Archived (PDF) from the original on 24 September 2015. Retrieved 12 December 2014. Phenobarbital was identified as the psychotropic substance most frequently used as an adulterant in seized heroin; it was followed by diazepam and flunitrazepam.
  130. ↑ Griffiths RR, Johnson MW (2005). "Relative abuse liability of hypnotic drugs: a conceptual framework and algorithm for differentiating among compounds". The Journal of Clinical Psychiatry. 66 (Suppl 9): 31–41. PMID   16336040.
  131. ↑ Overclocker. "Methamphetamine and Benzodiazepines: Methamphetamine & Benzodiazepines". Erowid Experience Vaults. Archived from the original on 18 December 2008. Retrieved 26 September 2006.
  132. ↑ "Drug Abuse Warning Network, 2011: National Estimates of Drug-Related Emergency Department Visits". U.S. Department of Health and Human Services, Substance Abuse and Mental Health Services Administration. 2011. Archived from the original on 31 May 2014. Retrieved 20 April 2014.
  133. ↑ Cosbey SH (December 1986). "Drugs and the impaired driver in Northern Ireland: an analytical survey". Forensic Science International. 32 (4): 245–58. doi:10.1016/0379-0738(86)90201-X. PMID   3804143.
  134. ↑ "List of controlled Drugs". Archived from the original on 30 December 2011.
  135. ↑ "Anlage III (zu § 1 Abs. 1) verkehrsfähige und verschreibungsfähige Betäubungsmittel". Betäubungsmittelgesetz. 2001. Archived from the original on 3 January 2010. Retrieved 5 January 2010.
  136. 1 2 Poisons Standard June 2018 "Poisons Standard June 2018". Archived from the original on 19 January 2016. Retrieved 6 January 2016.
  137. ↑ "San Quentin State Prison Operational Procedure 0–770, Execution By Lethal Injection (pp. 44 & 92" (PDF). Archived from the original (PDF) on 25 June 2008. Retrieved 10 January 2014.
  138. ↑ "Execution by lethal injection procedures" (PDF). Florida Department of Corrections. 9 September 2013. Archived (PDF) from the original on 8 November 2013. Retrieved 25 August 2014.
  139. ↑ "Nebraska executes Carey Dean Moore for murders of Omaha cab drivers Maynard Helgeland, Reuel Van Ness Jr". Lincoln Journal Star. 14 August 2018. Archived from the original on 15 August 2018. Retrieved 15 August 2018.
  140. 1 2 "Drugs Affecting Appetite (Monogastric)". The Merck Veterinary Manual. Archived from the original on 28 October 2012. Retrieved 4 January 2014.
  141. ↑ Rahminiwati M, Nishimura M (April 1999). "Effects of delta 9-tetrahydrocannabinol and diazepam on feeding behavior in mice". The Journal of Veterinary Medical Science. 61 (4): 351–5. doi: 10.1292/jvms.61.351 . PMID   10342284.
  142. ↑ Shell L (March 2012). "Anticonvulsants Used to Stop Ongoing Seizure Activity". Archived from the original on 10 January 2014. Retrieved 10 January 2014. Dogs and Cats:
    A variety of drugs can be used to stop seizures in dogs and cats.
    Benzodiazepines:
    Diazepam is the most common benzodiazepine used in dogs and cats to reduce motor activity and permit the placement of an IV catheter.

Further reading

This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.