Diazepam, sold under the brand name Valium among others, is a medication of the benzodiazepine family that acts as an anxiolytic. It is used to treat a range of conditions, including anxiety, seizures, alcohol withdrawal syndrome, muscle spasms, insomnia, and restless legs syndrome. It may also be used to cause memory loss during certain medical procedures.[17] 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.[4] When injected intravenously, effects begin in one to five minutes and last up to an hour.[18] When taken by mouth, effects begin after 15 to 60 minutes.[19]
Common side effects include sleepiness and trouble with coordination.[20][18] Serious side effects are rare. They include increased risk of suicide, decreased breathing, and a paradoxical increased risk of seizures if used too frequently in those with epilepsy.[18][21] Occasionally, excitement or agitation may occur.[22][23] Long-term use can result in tolerance, dependence, and withdrawal symptoms on dose reduction. Abrupt stopping after long-term use can be potentially dangerous. After stopping, cognitive problems may persist for six months or longer.[22] It is not recommended during pregnancy or breastfeeding.[18] Its mechanism of action works by increasing the effect of the neurotransmitter gamma-aminobutyric acid (GABA).[22]
Diazepam was patented in 1959 by Hoffmann-La Roche.[24][25] It has been one of the most frequently prescribed medications in the world since its launch in 1963. In the United States it was the best-selling medication between 1968 and 1982, selling more than 2billion tablets in 1978 alone. In 2023, it was the 183rd most commonly prescribed medication in the United States, with more than 2million prescriptions.[26][27] In 1985 the patent expired, and there are more than 500 brands available on the market.[28] It is on the World Health Organization's List of Essential Medicines.[29]
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).[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.[4][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.[22]
Diazepam has several uses, including:
Dosages are typically determined on an individual basis, depending on the condition being treated, the severity of symptoms, the patient's body weight, and any other conditions the person may have.
Contraindications
Use of diazepam is avoided, when possible, in individuals with:[55]
- Ataxia
- Severe hypoventilation
- Acute narrow-angle glaucoma
- Severe hepatic deficiencies (hepatitis and liver cirrhosis 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
- Pregnancy or breastfeeding[56]
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.[22] 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.[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.[22] 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.[22]
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:[32][86]
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 used only 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.[32][86]
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.[32]
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.
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.
- Diazepam increases the central depressive effects of alcohol, other hypnotics/sedatives (e.g., barbiturates), other muscle relaxants, certain antidepressants, sedative antihistamines, opioids, and antipsychotics, as well as anticonvulsants such as phenobarbital, phenytoin, and carbamazepine. The euphoriant effects of opioids may be increased, leading to an increased risk of psychological dependence.[22]
Pharmacology
Diazepam is a long-acting "classical" benzodiazepine. Other classical benzodiazepines include chlordiazepoxide, clonazepam, lorazepam, oxazepam, nitrazepam, temazepam, flurazepam, bromazepam, and clorazepate.[97] Diazepam has anticonvulsant properties.[98] Benzodiazepines act via micromolar benzodiazepine binding sites as calcium channel blockers and significantly inhibit depolarization-sensitive calcium uptake in rat nerve cell preparations.[99]
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.[100]
Chemistry
Diazepam does not possess any chiral centers in its structure, but it does have two conformers: 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[17]). 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.[17] 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 a PSA value smaller than 60–70 Ų have a better ability to permeate cells.[119] 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.
History
Diazepam was the second benzodiazepine invented by Leo Sternbach of Hoffmann-La Roche at the company's Nutley, New Jersey, facility[121] 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.[122]
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).[123] 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.[124]
Society and culture
Recreational use
Diazepam is a medication with a high risk of misuse and can cause drug dependence. Some pharmacologists recommend urgent action by national governments to improve prescribing patterns of benzodiazepines such as diazepam.[128][129] A single dose of diazepam modulates the dopamine system in similar ways to how morphine and alcohol modulate the dopaminergic pathways.[130] Between 50 and 64% of rats will self-administer diazepam.[131] Diazepam can substitute for the behavioral effects of barbiturates in a primate study.[132]
Veterinary uses
Diazepam is used as a short-term sedative and anxiolytic for cats and dogs,[145] sometimes used as an appetite stimulant.[145][146] It can also be used to stop seizures in dogs and cats.[147]
Further reading
External links
References
- Pharmacology for the Primary Care Provider Mosby, 2013, retrieved 13 July 2020^
- Clinical Addiction Psychiatry Cambridge University Press, 2010^
- Principles of addiction medicine Wolters Kluwer/Lippincott Williams & Wilkins, 2009^