Diazepam
Clinical data | |
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Pronunciation | /daɪˈæzɪpæm/ dy-AZ-ip-am |
Trade names | Valium, Vazepam, Valtoco, others[1] |
AHFS/Drugs.com | Monograph |
MedlinePlus | a682047 |
License data | |
Pregnancy category |
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Dependence liability | High[3] |
Addiction liability | Moderate[4][5] |
Routes of administration | oral, intramuscular, intravenous, rectal, nasal[6] |
Drug class | Benzodiazepine |
ATC code | |
Legal status | |
Legal status |
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Elimination half-life | (50 h); 20–100 h (32–200 h for main active metabolite desmethyldiazepam)[10][8][9] |
Excretion | Kidney |
Identifiers | |
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JSmol) | |
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Diazepam, first marketed as Valium, is a medicine of the
Common side effects include sleepiness and trouble with coordination.
Diazepam was patented in 1959 by
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 distinctive smell and has a low molecular weight (MW = 284,74 g/mol[13]). 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.[13] The LogP value indicates that diazepam has a tendency to dissolve more readily in lipid-based environments, such as chloroform, acetone, ethanol and ether, compared to water. While 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 has a better ability to permeate cells.[24] 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
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. Absorption appears to depend on several factors, such as temperature, concentration, flow rates, and tube length. Diazepam should not be administered if a precipitate has formed and does not dissolve.[27]
Medical uses
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).[28][29] In 2020, it was approved for use in the United States as a nasal spray to interrupt seizure activity in people with epilepsy.[6][30] 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.[17]
Diazepam has a number of uses, including:
- Treatment of anxiety,
- Treatment of neurovegetative symptoms associated with vertigo[32]
- Treatment of the symptoms of
- Short-term treatment of insomnia[28]
- Treatment of muscle spasms
- Treatment of tetanus, together with other measures of intensive treatment[34]
- Adjunctive treatment of spastic muscular paresis (paraplegia/tetraplegia) caused by cerebral or spinal cord conditions such as stroke, multiple sclerosis, or spinal cord injury (long-term treatment is coupled with other rehabilitative measures)[35]
- Palliative treatment of stiff person syndrome[36]
- Pre- or postoperative sedation, anxiolysis or amnesia (e.g., before endoscopic or surgical procedures)[35]
- Treatment of complications with stimulant overdoses and psychosis, such as cocaine or methamphetamine[26]
Used in treatment of organophosphate poisoning and reduces the risk of seizure induced brain and cardiac damage.
- Preventive treatment of hyperbaric oxygen therapy[37]
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.[26]
Seizures
Intravenous diazepam or lorazepam are first-line treatments for status epilepticus.[17][38] 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.[39] 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.[26][40]
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.[26][41]
Diazepam is sometimes used intermittently for the prevention of
Alcohol withdrawal
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.
Other
Diazepam is used for the emergency treatment of eclampsia, when IV magnesium sulfate and blood-pressure control measures have failed.[44][45] Benzodiazepines do not have any pain-relieving properties themselves, and are generally recommended to avoid in individuals with pain.[46] 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.[47][48] Tolerance often develops to the muscle relaxant effects of benzodiazepines such as diazepam.[49] Baclofen is sometimes used as an alternative to diazepam.[50]
Availability
Diazepam is marketed in over 500 brands throughout the world.[51] It is supplied in oral, injectable, inhalation, and rectal forms.[26][27][52]
The
Contraindications
Use of diazepam should be avoided, when possible, in individuals with:[54]
- Ataxia
- Severe hypoventilation
- Acute narrow-angle glaucoma
- Severe decrease elimination by a factor of two)
- Severe renal deficiencies (for example, patients on dialysis)
- Liver disorders
- Severe sleep apnea
- Severe depression, particularly when accompanied by suicidal tendencies
- Psychosis
- breast feeding[55]
- Caution required in elderly or debilitated patients
- Coma or shock
- Abrupt discontinuation of therapy
- Acute intoxication with narcotics, or other psychoactive substances (with the exception of hallucinogens or some stimulants, where it is occasionally used as a treatment for overdose)
- History of alcohol or drug dependence
- autoimmune disordercausing marked fatiguability
- Hypersensitivity or allergy to any drug in the benzodiazepine class
Caution
- Benzodiazepine abuse and misuse should be guarded against when prescribed to those with alcohol or drug dependencies or who have psychiatric disorders.[56]
- Pediatric patients
- Less than 18 years of age, this treatment is usually not indicated, except for treatment of epilepsy, and pre- or postoperative treatment. The smallest possible effective dose should be used for this group of patients.[57]
- Under 6 months of age, safety and effectiveness have not been established; diazepam should not be given to those in this age group.[36][57]
- Elderly and very ill patients can possibly experience apnea or cardiac arrest. Concomitant use of other central nervous system depressants increases this risk. The smallest possible effective dose should be used for this group of people.[57][58] The elderly metabolise benzodiazepines much more slowly than younger adults, and are also more sensitive to the effects of benzodiazepines, even at similar blood plasma levels. Doses of diazepam are recommended to be about half of those given to younger people, and treatment limited to a maximum of two weeks. Long-acting benzodiazepines such as diazepam are not recommended for the elderly.[17] Diazepam can also be dangerous in geriatric patients owing to a significant increased risk of falls.[59]
- Intravenous or intramuscular injections in hypotensive people or those in shock should be administered carefully and vital signs should be monitored.[58]
- Benzodiazepines such as diazepam are 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.[61]
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.[17] Like other benzodiazepines, diazepam impairs short-term memory and learning new information. Diazepam and other benzodiazepines can produce anterograde amnesia, but not retrograde amnesia. It 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.[62] 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.[17] 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.[17] Sedatives and sleeping pills, including diazepam, have been associated with an increased risk of death.[63]
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.[64]
Diazepam has a range of side effects common to most benzodiazepines, including:
- Suppression of slow wave sleep
- Impaired motor function
- Impaired coordination
- Impaired balance
- Dizziness
- Reflex tachycardia[65]
Less commonly,
Diazepam may impair the ability to drive vehicles or operate machinery. The impairment is worsened by consumption of alcohol, because both act as
During the course of therapy, tolerance to the sedative effects usually develops, but not to the anxiolytic and myorelaxant effects.[71]
Patients with severe attacks of
Diazepam in doses of 5 mg or more causes significant deterioration in alertness performance combined with increased feelings of sleepiness.[73]
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.[74]
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
Benzodiazepine treatment should be discontinued as soon as possible by a slow and gradual dose reduction regimen.
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%.[76]
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:
- People with a history of a substance use disorder or substance dependence.[36][81] Diazepam increases craving for alcohol in problem alcohol consumers. Diazepam also increases the volume of alcohol consumed by problem drinkers.[82]
- People with severe personality disorders, such as borderline personality disorder[83]
Patients from the aforementioned groups should be monitored very closely during therapy for signs of abuse and development of dependence. Therapy should be discontinued if any of these signs are noted, although if dependence has developed, therapy must still be discontinued gradually to avoid severe withdrawal symptoms. Long-term therapy in such instances is not recommended.[36][81]
People suspected of being dependent on benzodiazepine drugs should be very gradually tapered off the drug. Withdrawals can be life-threatening, particularly when excessive doses have been taken for extended periods of time. Equal prudence should be used whether dependence has occurred in therapeutic or recreational contexts.[84]
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.[85] The process is very slow (usually from 14 to 28 weeks) but is considered safe when done appropriately.[86]
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:[36][87]
- Drowsiness
- Mental confusion
- Hypotension
- Impaired motor function
- 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
The oral
Overdoses of diazepam with alcohol, opiates, or other depressants may be fatal.[88][90]
Interactions
If diazepam is administered concomitantly with other drugs, attention should be paid to the possible pharmacological interactions. Particular care should be taken with drugs that potentiate the effects of diazepam, such as barbiturates,
Diazepam does not increase or decrease hepatic enzyme activity, and does not alter the metabolism of other compounds. No evidence would suggest diazepam alters its own metabolism with chronic administration.[26]
Agents with an effect on hepatic
- Diazepam increases the central depressive effects of alcohol, other anticonvulsants such as phenobarbital, phenytoin, and carbamazepine. The euphoriant effects of opioids may be increased, leading to increased risk of psychological dependence.[17][57][91]
- synergistic enhancement of the hypotensive properties of benzodiazepines and alcohol.[92]
- Oral contraceptives significantly decrease the elimination of
- Rifampin, phenytoin, carbamazepine, and phenobarbital increase the metabolism of diazepam, thus decreasing drug levels and effects.[26] Dexamethasone and St John's wort also increase the metabolism of diazepam.[17]
- Diazepam increases the serum levels of phenobarbital.[94]
- Nefazodone can cause increased blood levels of benzodiazepines.[57]
- Cisapride may enhance the absorption, and therefore the sedative activity, of diazepam.[95]
- Small doses of theophylline may inhibit the action of diazepam.[96]
- Diazepam may block the action of levodopa (used in the treatment of Parkinson's disease).[91]
- Diazepam may alter digoxin serum concentrations.[26]
- Other drugs that may have interactions with diazepam include MAO inhibitors, and ranitidine.[57]
- Because it acts on the GABA receptor, the herb valerian may produce an adverse effect.[97]
- Foods that acidify the urine can lead to faster absorption and elimination of diazepam, reducing drug levels and activity.[91]
- Foods that alkalinize the urine can lead to slower absorption and elimination of diazepam, increasing drug levels and activity.[26]
- Reports conflict as to whether food in general has any effects on the absorption and activity of orally administered diazepam.[91]
Pharmacology
Diazepam is a long-acting "classical" benzodiazepine. Other classical benzodiazepines include
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.[101]
Diazepam binds with high affinity to
Mechanism of action
Benzodiazepines are
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.[105] Diazepam is not the only drug to target these GABAA receptors. Drugs such as flumazenil also bind to GABAA to induce their effects.[106]
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.[107]
The anticonvulsant properties of diazepam and other benzodiazepines may be in part or entirely due to binding to
The muscle relaxant properties of diazepam are produced via inhibition of
Pharmacokinetics
Diazepam can be administered orally, intravenously (must be diluted, as it is painful and damaging to veins), intramuscularly (IM), or as a suppository.[26]
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.
Diazepam is highly lipid-soluble, and is widely distributed throughout the body after administration. It easily crosses both the
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
Diazepam undergoes
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. [112]
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.[113][114][115]
Environmental
Diazepam is a common
History
Diazepam was the second benzodiazepine invented by
The benzodiazepines gained popularity among medical professionals as an improvement over
Marketed by Roche using an advertising campaign conceived by the William Douglas McAdams Agency under the leadership of
Society and culture
Recreational use
Diazepam is a medication with a high risk of misuse and can cause
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.[128]
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.[129]
A large-scale study in the US, conducted by
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 potential for misuse for benzodiazepines, zolpidem, and zopiclone.[113] 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.[131]
Legal status
Diazepam is regulated as a
International
Diazepam is a Schedule IV controlled drug under the Convention on Psychotropic Substances.[132]
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.[133]
Germany
Classified as a prescription drug, or in high dosage as a restricted drug (Betäubungsmittelgesetz, Anlage III).[134]
Australia
Diazepam is a Schedule 4 substance under the Poisons Standard (June 2018).[135] 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".[135]
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.[136][137] 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.[138]
Veterinary uses
Diazepam is used as a short-term sedative and anxiolytic for cats and dogs,[139] sometimes used as an appetite stimulant.[139][140] It can also be used to stop seizures in dogs and cats.[141]
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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 placement of an IV catheter.
Further reading
- Dean L (2016). "Diazepam Therapy and CYP2C19 Genotype". In Pratt VM, McLeod HL, Rubinstein WS, et al. (eds.). Medical Genetics Summaries. PMID 28520370. Bookshelf ID: NBK379740.
External links
- "Diazepam Nasal Spray". MedlinePlus.