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Diazepam
Systematic (IUPAC) name
7-chloro-1,3-dihydro-
1-methyl-5-phenyl-
1,4-benzodiazepin-2(3H)-one
Identifiers
CAS number 439-14-5
ATC code N05BA01 N05BA17
PubChem 3016
DrugBank APRD00642
ChemSpider 2908
Chemical data
Formula C16H13ClN2O 
Mol. mass 284.7 g/mol
SMILES eMolecules & PubChem
Pharmacokinetic data
Bioavailability 93%
Metabolism Hepatic - CYP2C19
Half life 20–100 hours
Excretion Renal
Therapeutic considerations
Pregnancy cat. C(AU) D(US)
Legal status Prescription Only (S4) (AU) Schedule IV (CA) CD (UK) Schedule IV (US) Schedule IV (International)
Routes Oral, IM, IV, suppository
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Diazepam (pronounced /daɪˈæzɨpæm/), first marketed as Valium (/ˈvæliəm/) by Hoffmann-La Roche, is a benzodiazepine derivative drug. It is commonly used for treating anxiety, insomnia, seizures, muscle spasms, restless legs syndrome, obsessive compulsive disorder[1], alcohol withdrawal, benzodiazepine withdrawal, and Ménière's disease. It may also be used before certain medical procedures (such as endoscopies) to reduce tension and anxiety, and in some surgical procedures to induce amnesia.[2][3] It possesses anxiolytic, anticonvulsant, hypnotic, sedative, skeletal muscle relaxant, and amnestic properties.[4]

Diazepam is a core medicine in the World Health Organization's "Essential Drugs List," which is a list of minimum medical needs for a basic health care system.[5] Diazepam is used to treat a wide range of conditions and has been one of the most frequently prescribed medications in the world for the past 40 years. It was first synthesized by Dr. Leo Sternbach.[6]

Contents

History

Diazepam was the second benzodiazepine to be invented by Sternbach of Hoffmann-La Roche, 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 two and a half 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.[7]

The benzodiazepines gained popularity among medical professionals as an improvement upon barbiturates, which have a comparatively narrow therapeutic index, and are far more sedating 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 other sedatives).[8]

Diazepam was the top-selling pharmaceutical in the United States from 1969 to 1982, with peak sales in 1978 of 2.3 billion tablets.[7] Diazepam, along with oxazepam, nitrazepam and temazepam, represents 82% of the benzodiazepine market in Australia.[9] While psychiatrists continue to prescribe diazepam for the short-term relief of anxiety, neurology has taken the lead in prescribing diazepam for the palliative treatment of certain types of epilepsy and spastic activity, for example, forms of paresis. It is also the first line of defense for a rare disorder called stiff-person syndrome.[10]

Indications

Diazepam is mainly used to treat anxiety, insomnia, and symptoms of acute alcohol or opiate withdrawal. It is also used as a premedication for inducing sedation, anxiolysis or amnesia before certain medical procedures (e.g., endoscopy).[11]

Intravenous diazepam or lorazepam are first line treatments for status epilepticus.[12] Diazepam is rarely used for the long-term treatment of epilepsy because tolerance to the anticonvulsant effects of diazepam usually develops within 6 to 12 months of treatment, effectively rendering it useless for this purpose.[13][14]

Diazepam has a broad spectrum of indications (most of which are off-label), including:

Veterinary uses

  • Diazepam is used as a short-term sedative and anxiolytic for cats and dogs. It is also used for short-term treatment of seizures in dogs and short-term and long-term treatment of seizures in cats. It can also be used as an appetite stimulant.[25][26] For emergent treatment of seizures, the typical dose is 0.5 mg/kg intravenously, or 1–2 mg/kg of the injectable solution administered in the rectum.[27]

Before judicial executions

Dosage

Dosages should be determined on an individual basis, depending upon the condition to be treated, the severity of symptoms, the body weight of the patient, and any comorbid conditions the patient may have.[13]

Typical dosages for healthy adults range from 2 mg per dose to 10 mg per dose taken 2 to 4 times per day, depending on such factors as body weight and condition being treated. For the elderly or people with liver disorders, initial dose is at the low end of the range, with the dose being increased as required.[18]

Availability

Diazepam(Valium) DOJ.jpg

Diazepam is marketed in over 500 brands throughout the world.[29] It is supplied in the following forms:

  • For oral administration:
    • Tablets – 2 mg, 5 mg, 10 mg.[18] Generic versions available.
    • Capsules, time-release – 15 mg (marketed by Roche as Valrelease)[30]
    • Liquid solution – 1 mg/ml in 500 ml containers and unit-dose (5 mg & 10 mg); 5 mg/ml in 30 ml dropper bottle (marketed by Roxane as Diazepam Intensol)[30]
  • For parenteral administration:
    • Solution for IV/IM injection – 5& mg/ml. 2 ml ampoules and syringes; 1 ml, 2 ml, 10 ml vials; 2 ml Tel-E-Ject; also contains 40% propylene glycol, 10% ethyl alcohol, 5% sodium benzoate and benzoic acid as buffers, and 1.5% benzyl alcohol as a preservative.[30][31]
      • Note: IM injection is largely less effective as the drug is injected into a tetanic muscle with compressed muscular veins. This does not allow the drug to reach the circulation rapidly. (See comment above, under Pharmacokinetics, re IM injection).

Seduxen (Diazepam, in Hungary, Russia, Poland, and other Eastern-European countries) is supplied in the following forms:

  • For oral administration:
    • Tablets 5 mg
    • Injection 5 mg/ml for intravenous, intramuscular or subcutaneous usage
  • For parenteral administration:
    • Solution for IV/IM injection – 5 mg/ml. 2 ml ampoules and syringes; 1 ml, 2 ml, 10 ml vials; 2 ml Tel-E-Ject; also contains 40% propylene glycol, 10% ethyl alcohol, 5% sodium benzoate and benzoic acid as buffers, and 1.5% benzyl alcohol as a preservative.[30][31]

Notice: IM injection is largely less effective as the drug is injected into a tetanic muscle with compressed muscular veins. This does not allow the drug to reach the circulation rapidly.

  • For rectal administration:
    • Solution[13]
    • Suppositories – 5 mg and 10 mg[13][32]
    • Rectal tubes
  • For inhalation administration: This method uses heating diazepam to form a vapor later producing an aerosol. This allows the drug to be passed through an inhalation route during an inhalation therapy. Provided in doses 2–20 mg either in a single inhalation or multiple small inhalations[33]
  • The United States military employs a specialized diazepam preparation known as CANA (Convulsive Antidote, Nerve Agent), which contains a mixture of diazepam, atropine and pralidoxime (2-PAM). One CANA kit is typically issued to service members, along with three Mark I NAAK kits, when operating in circumstances where chemical weapons in the form of nerve agents are considered a potential hazard. Both of these kits deliver drugs using auto-injectors. They are intended for use in "buddy aid" or "self aid" administration of the drugs in the field prior to decontamination and delivery of the patient to definitive medical care.[34]

Side-effects

Diazepam has a range of side-effects that are common to most benzodiazepines. Most common side-effects include:

Less common paradoxical side-effects can include nervousness, irritability, insomnia, muscle cramps, changes in libido (increased or decreased libido) and in some cases, rage, and violence.[38][39][40] Diazepam may increase, in some people, the propensity toward self-harming behaviours and, in extreme cases, may provoke suicidal tendencies or acts.[41] If these side-effects are present, diazepam treatment should be immediately terminated.

Very rarely dystonia.[42] Benzodiazepines such as diazepam impair learning and memory via their action on benzodiazepine receptors, which causes a dysfunction in the cholinergic neuronal system.[43]

Diazepam may impair the ability to drive vehicles or operate machinery. The impairment is worsened by consumption of alcohol, because both act as central nervous system depressants.[18]

During the course of therapy, tolerance to the sedative effects usually develops, but not to the anxiolytic and myorelaxant effects.[44]

Patients with severe attacks of apnea during sleep may suffer respiratory depression (hypoventilation) leading to respiratory arrest and death.

Diazepam in doses of 5 mg or more causes significant deterioration in alertness performance combined with increased feelings of sleepiness.[45]

Interactions

If diazepam is to be administered concomitantly with other drugs, attention should be paid to the possible pharmacological interactions. Particular care should be taken with drugs that enhance the effects of diazepam, such as barbiturates, phenothiazines, narcotics and antidepressants.[18]

Diazepam does not increase or decrease hepatic enzyme activity, and does not alter the metabolism of other compounds. There is no evidence that would suggest diazepam alters its own metabolism with chronic administration.[13]

Agents that have 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.[13]

Contraindications

Use of diazepam should be avoided, when possible, in individuals with the following conditions:[55]

Special caution needed

  • Pediatric patients
    • Less than 18 years of age – Treatment usually not indicated, except treatment of epilepsy, and pre-/postoperative treatment. The smallest possible effective dose should be used for this group of patients.[47]
    • Under 6 months of age – Safety and effectiveness have not been established; diazepam should not be given to individuals in this age group.[18][47]
  • Elderly and very ill patients – Possibility that apnea and/or cardiac arrest may occur. Concomitant use of other central nervous system depressants increases this risk. The smallest possible effective dose should be used for this group of patients.[18][47][57]

Diazepam may also be dangerous in geriatric patients owing to a significant increased risk of falls.[58]

  • I.V. or I.M. injections in hypotensive individuals or those in shock should be administered carefully and vital signs should be monitored.[57]
  • Benzodiazepines such as diazepam are lipophilic and rapidly penetrate membranes, and, therefore, rapidly cross over into the placenta with significant uptake of the drug. Use of benzodiazepines including diazepam in late pregnancy, especially high doses, may result in floppy infant syndrome.[59]

Pregnancy

Diazepam when taken late in pregnancy, during the third trimester, causes a definite risk of a severe benzodiazepine withdrawal syndrome in the neonate with symptoms including hypotonia, and reluctance to suck, to apnoeic spells, cyanosis, and impaired metabolic responses to cold stress. Floppy infant syndrome and sedation in the newborn may also occur. Symptoms of floppy infant syndrome and the neonatal benzodiazepine withdrawal syndrome have been reported to persist from hours to months after birth.[60]

Tolerance and physical dependence

Diazepam as with other benzodiazepine drugs can cause tolerance, physical dependence, addiction and what is known as the benzodiazepine withdrawal syndrome. Withdrawal from diazepam or other benzodiazepines often leads to withdrawal symptoms that are similar to those seen during barbiturate or alcohol withdrawal. The higher the dose and the longer the drug is taken for the greater the risk of experiencing unpleasant withdrawal symptoms. Withdrawal symptoms can occur from standard dosages and also after short-term use. Benzodiazepine treatment should be discontinued as soon as possible via a slow and gradual dose reduction regime.[61] It has been shown in a clinical study that between 50–100% of patients on low-dose long-term diazepam therapy are physically dependent on their medication, and experience withdrawal symptoms upon discontinuation from a dose taper.[62] The difference in rates of withdrawal (50–100%) varies depending on the patient sample being investigated. For example a random sample of long term benzodiazepine users typically finds that around 50% will experience little or no withdrawal symptoms and the other 50% experiencing notable withdrawal symptoms. Certain select patient groups will show a higher rate of notable withdrawal symptoms, up to 100%.[63] Rebound anxiety, more severe than baseline anxiety, is also a common withdrawal symptom when discontinuing diazepam or other benzodiazepines.[64] Diazepam is therefore only recommended for short-term therapy at the lowest possible dose owing to risks of severe withdrawal problems from low doses even after gradual reduction.[65] There is a significant risk of pharmacological dependence on diazepam and patients experiencing symptoms of benzodiazepine withdrawal syndrome if it is taken for 6 weeks or longer.[66] In humans tolerance to the anticonvulsant effects of diazepam occurs frequently.[67]

Overdose

An individual that has consumed too much diazepam will typically display one or more of the following symptoms in the period up around four hours immediately following a suspected overdose.:[18][68]

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

Although not usually fatal when taken alone, a diazepam overdose is considered a medical emergency and generally requires the immediate attention of medical personnel. The 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. Although 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.[8][13][18][68]

The oral LD50 (lethal dose in 50% of the population) of diazepam is 720 mg/kg in mice and 1240 mg/kg in rats.[18] D. J. Greenblatt and colleagues reported in 1978 on two patients who had taken 500 and 2000 mg of diazepam, respectively, went into moderately-deep comas, and were discharged within 48 hours without having experienced important complications, in spite of having high concentrations of diazepam and its metabolites—desmethyldiazepam, oxazepam, and temazepam—according to samples taken in the hospital and as follow-up.[69]

Overdoses of diazepam with alcohol, opiates and/or other depressants may be fatal.[8][70]

Physical properties

Diazepam occurs as solid white or yellow crystals and has a melting point of 131.5 to 134.5 °C. It is odorless, and has a slightly bitter taste. The British Pharmacopoeia lists diazepam 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 of ethyl alcohol, 1 in 2 of chloroform, 1 in 39 of ether, and practically insoluble in water. The pH of diazepam is neutral (i.e., pH = 7). Diazepam has a shelf-life of 5 years for oral tablets and 3 years for IV/IM solution.[13] Diazepam should be stored at room temperature (15–30°C). The solution for parenteral injection should be protected from light and kept from freezing. The oral forms should be stored in air-tight containers and protected from light.[30]

Diazepam can absorb into plastic, and, therefore, diazepam solution is not stored in plastic bottles or syringes, etc. It can absorb into plastic bags and tubing used for intravenous infusions. Absorption appears to be dependent on several factors such as temperature, concentration, flow rates, and tube length. Diazepam should not be administered if a precipitate has formed and will not dissolve.[30]

Pharmacology

Non-U.S.A. 10mg Valium.

Diazepam is a "classical" benzodiazepine. Other classical benzodiazepines include chlordiazepoxide, clonazepam, lorazepam, oxazepam, alprazolam, nitrazepam, flurazepam, bromazepam, and clorazepate.[71] Diazepam has anticonvulsant properties.[72] Diazepam has no effect on GABA levels and no effect on glutamate decarboxylase activity but has a slight effect on gamma-aminobutyric acid transaminase activity. It differs insofar from some other anticonvulsive drugs it was compared with.[73] Benzodiazepines act via micromolar benzodiazepine binding sites as Ca2+ channel blockers and significantly inhibit depolarization-sensitive Calcium uptake in rat nerve cell preparations.[74]

Diazepam affects the emotional-motivational component of the pain experience, but not the sensory discriminative component or the central control of pain.[75] 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.[76]

Diazepam binds with high affinity to glial cells in animal cell cultures.[77] Diazepam at high doses has been found to decrease histamine turnover in mouse brain via diazepam's action at the benzodiazepine-GABA receptor complex.[78] Diazepam also decreases prolactin release in rats.[79]

Mechanism of action

Diazepam is a benzodiazepine that binds to a specific subunit on the GABAA receptor at a site that is distinct from the binding site of the endogenous GABA molecule.[80][81] The GABAA receptor is an inhibitory channel which, when activated, decreases neuronal activity.

Because of the role of diazepam as a positive allosteric modulator of GABA, when it binds to benzodiazepine receptors it causes inhibitory effects. This arises from the hyperpolarization of the post-synaptic membrane, owing to the control exerted over negative chloride ions by GABAA receptors.[18][80]

Benzodiazepines including diazepam, however, do not have any effect on the levels of GABA in the brain.[82]

Diazepam appears to act on areas of the limbic system, thalamus, and hypothalamus, inducing anxiolytic effects. Its actions are due to the enhancement of GABA activity.[2][80] Benzodiazepine drugs including diazepam increase the inhibitory processes in the cerebral cortex.[83]

The anticonvulsant properties of diazepam and other benzodiazepines may be in part or entirely due to binding to voltage-dependent sodium channels rather than benzodiazepine receptors. Sustained repetitive firing seems to be limited by benzodiazepines' effect of slowing recovery of sodium channels from inactivation.[84]

The muscle relaxant properties of diazepam are produced via inhibition of polysynaptic pathways in the spinal cord.[85]

Pharmacokinetics

Generic pack of 5mg Diazepam.

Diazepam can be administered orally, intravenously, intramuscularly, or as a suppository.[13]

When diazepam is administered orally, it is rapidly absorbed and has a fast onset of action. The onset of action is 1–5 minutes for IV administration and 15–30 minutes for IM administration. The duration of diazepam's peak pharmacological effects is 15 minutes to 1 hour for both routes of administration.[37]

Peak plasma levels are achieved 30 minutes to 2 hours after oral administration. When diazepam is administered as an intramuscular injection, absorption is slow, erratic and incomplete.[11]

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 will quickly build up to a high concentration in the body (mainly in adipose tissue), which will be far in excess of the actual dose for any given day.[13][30]

There is preferential storage of diazepam in some organs including the heart. Absorption by any administered route and the risk of accumulation is significantly increased in the neonate and there is clinical justification to recommend the withdrawal of diazepam during pregnancy and breast feeding.[86]

Diazepam undergoes oxidative metabolism by CYP2C19 in the liver as part of the cytochrome P450 enzyme system. It has a biphasic half-life of 1–2 and 2–5 days, and has several pharmacologically active metabolites. The main active metabolite of diazepam is desmethyldiazepam (also known as nordazepam or nordiazepam). Diazepam's other active metabolites include 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.[11][30][87]

Diazepam has a half-life (t1/2α) of 20–50 hours, and desmethyldiazepam has a half-life of 30–200 hours and is considered to be a long-acting benzodiazepine.[30]

Most of the drug is metabolised; very little diazepam is excreted unchanged.[13]

In humans, the protein binding of diazepam is around 98.5%.[11]

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.[88]

Drug misuse and addiction

Diazepam is a drug of potential abuse and addiction. A single dose of diazepam modulates the dopamine system in similar ways to how morphine and alcohol modulate the dopaminergic pathways.[89] Between 50 and 64% of rats will self administer diazepam.[90] Benzodiazepines including diazepam in animal studies have been shown to increase reward seeking behaviours by increasing impulsivity, which may suggest an increased risk of addictive behavioural patterns with usage of diazepam or other benzodiazepines.[91] In addition diazepam has been shown to be able to substitute for the behavioural effects of barbiturates in a primate study.[92] Diazepam has been found as an adulterant in heroin.[93]

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.[94]

Sometimes diazepam is used by stimulant users to 'come down' and sleep and to help control the urge to binge.[95]

A large-scale nationwide USA government study conducted by SAMHSA found that benzodiazepines in the USA are the most frequently abused pharmaceutical with 35% of drug-related visits to the Emergency Department involved benzodiazepines. Benzodiazepines are more commonly abused than opiate pharmaceuticals, which accounted for 32% of visits to the emergency department. No other pharmaceutical is more commonly abused than benzodiazepines. Males abuse benzodiazepines as commonly as females. Of drugs used in attempted suicide benzodiazepines are the most commonly-used pharmaceutical drug, with 26% of attempted suicides involving benzodiazepines. The most commonly-abused benzodiazepine is, however, alprazolam. Clonazepam is the second-most-abused benzodiazepine. Lorazepam is the third-most-abused benzodiazepine, and diazepam the fourth-most-abused benzodiazepine in the USA.[96]

Benzodiazepines, including diazepam, nitrazepam, and flunitrazepam account for the largest volume of forged drug prescriptions in Sweden, a total of 52% of drug forgeries being for benzodiazepines.[97]

Diazepam was detected in 26% of cases of people suspected of driving under the influence of drugs in Sweden and its active metabolite nordazepam was detected in 28% of cases. Other benzodiazepines and zolpidem and zopiclone also were found in high numbers. Many drivers had blood levels far exceeding the therapeutic dose range suggesting a high degree of abuse potential for benzodiazepines and zolpidem and zopiclone.[98] In Northern Ireland in cases where drugs were detected in samples from impaired drivers who were not impaired by alcohol, benzodiazepines were found to be present in 87% of cases. Diazepam was the most commonly detected benzodiazepine.[99]

Patients at a high risk for abuse or addiction

Diazepam can lead to drug abuse and psychological dependence/drug addiction.[100] At a particularly high risk for diazepam misuse, abuse or psychological dependence are:

  • Patients with a history of alcohol or drug abuse or dependence[18][101] Diazepam increases craving for alcohol in problem alcohol consumers. Diazepam also increases the volume of alcohol consumed by problem drinkers.[102]
  • Patients with severe personality disorders, such as Borderline Personality Disorder[103]

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 physical dependence has developed therapy must still be discontinued gradually to avoid severe withdrawal symptoms. Long-term therapy in these patients is not recommended.[18][101]

Patients suspected of being physiologically addicted to benzodiazepine drugs should be very gradually tapered off the drug. Although rare, withdrawals can be life-threatening particularly when excessive doses have been taken for extended periods of time. Equal prudence should be used whether addiction has occurred in therapeutic or recreational contexts.

Legal status

Diazepam is regulated in most countries as a prescription drug:

Toxicity

Laboratory tests assessing the toxicity of diazepam, nitrazepam and chlordiazepoxide on mice spermatozoa found that diazepam produced toxicities in sperm including abnormalities involving both the shape and size of the sperm head. Nitrazepam, however, caused more profound abnormalities than diazepam.[106]

See also

References

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Simple English

[[File:|thumb|A pack of 5mg diazepam tablets]] Diazepam is a drug. It is a benzodiazepine which has a relatively long half-life. It is mostly used to treat anxiety, certain forms of epilepsy, and sleeping problems. Like with other benzodiazepines, there is a risk of addiction. For this reason the drug is used to treat acute cases. It should not be taken for longer than a few weeks. According to the World Health Organization diazepam is an essential drug.

Diazepam is marketed under a number of names; its original trade name was Valium. It is one of the drugs prescribed most often. It is used recreationally to cause a calming effect.









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