diazepam

Diazepam

Systematic (IUPAC) name
7-chloro-1,3-dihydro- 1-methyl-5-phenyl- 1,4-benzodiazepin-2(3H)-one
Clinical data
Trade names	Diastat, Valium
AHFS/Drugs.com	monograph
MedlinePlus	a682047
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
Pharmacokinetic data
Bioavailability	(93-100%)
Metabolism	Hepatic - CYP2C19
Half-life	20–100 hours (36-200 hours for main active metabolite desmethyldiazepam)
Excretion	Renal
Identifiers
CAS number	439-14-5 Y
ATC code	N05BA01 N05BA17
PubChem	CID 3016
DrugBank	DB00829
ChemSpider	2908 Y
UNII	Q3JTX2Q7TU Y
KEGG	D00293 Y
ChEBI	CHEBI:49575 Y
ChEMBL	CHEMBL12 Y
Chemical data
Formula	C16H13ClN2O
Mol. mass	284.7 g/mol
SMILES	eMolecules & PubChem
InChI 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 Y Key:AAOVKJBEBIDNHE-UHFFFAOYSA-N Y
N(what is this?)  (verify)

Diazepam ( /daɪˈæzɨpæm/), first marketed as Valium ( /ˈvæliəm/) by Hoffmann-La Roche, is a benzodiazepine drug. Diazepam is also marketed in Australia as Antenex. It is commonly used for treating anxiety, insomnia, seizures including status epilepticus, muscle spasms (such as in cases of tetanus), restless legs syndrome, 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.^[1][2] It possesses anxiolytic, anticonvulsant, hypnotic, sedative, skeletal muscle relaxant, and amnestic properties.^[3] The pharmacological action of diazepam enhances the effect of the neurotransmitter GABA by binding to the benzodiazepine site on the GABA_A receptor (via the constituent chlorine atom) leading to central nervous system depression.^[4]

Adverse effects of diazepam include anterograde amnesia (especially at higher doses) and sedation as well as paradoxical effects such as excitement, rage or worsening of seizures in epileptics. Benzodiazepines also can cause or worsen depression. Long-term effects of benzodiazepines such as diazepam include tolerance, benzodiazepine dependence as well as a benzodiazepine withdrawal syndrome upon dose reduction; additionally after cessation of benzodiazepines cognitive deficits may persist for at least 6 months and may not fully return to normal, however it was suggested that longer than 6 months may be needed for recovery from some deficits.^[4] Diazepam also has physical dependence potential and can cause serious problems of physical dependence with long term use. However, compared to other benzodiazepines, physical withdrawal from diazepam following long term use is usually far more mild due to its long elimination half life. Nevertheless, urgent action by National Governments to improve prescribing practices has been recommended.^[5]

Advantages of diazepam are a rapid onset of action and high efficacy rates which is important for managing acute seizures, anxiety attacks and panic attacks; benzodiazepines also have a relatively low toxicity in overdose.^[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.^[6] Diazepam was first synthesized by Leo Sternbach^[7], is used to treat a wide range of conditions, and has been one of the most frequently prescribed medications in the world since its launch in 1963.

Medical uses

Diazepam pills, (2mg, 5mg, and 10mg)

Diazepam is mainly used to treat anxiety, insomnia, 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).^[8][9]

Intravenous diazepam or lorazepam are first line treatments for status epilepticus;^[4][10] However, lorazepam has advantages over diazepam including a higher rate of terminating seizures and a more prolonged anticonvulsant effect.^[11] 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 that purpose.^[12][13] Diazepam is used for the emergency treatment of eclampsia, when IV magnesium sulfate and blood pressure control measures have failed.^[14][15] Benzodiazepines do not have any pain relieving properties of themselves and are generally recommended to be avoided in individuals with pain.^[16] However, benzodiazepines such as diazepam can be used for their muscle relaxant properties to alleviate pain which is caused by muscle spasms, caused by various dystonias, including blepharospasm^[17][18] Tolerance often develops to the muscle relaxant effects of benzodiazepines such as diazepam.^[19] Baclofen^[20] or tizanidine is sometimes used as an alternative to diazepam. Tizanidine has been found to be equally effective as other antispasmodic drugs and have superior tolerability than baclofen and diazepam.^[21]

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, soman (or other organophosphate poisons; See #CANA), lindane, chloroquine, physostigmine, or pyrethroids^[12][22] Diazepam is sometimes used intermittently for the prophylaxis of febrile seizures which occur as a result of a high fever in children and neonates under 5 years of age.^[4][23] Long-term use of diazepam for the management of epilepsy is not recommended; however, a subgroup 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.^[4]

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

• Treatment of anxiety, panic attacks, and states of agitation^[8]
• Treatment of neurovegetative symptoms associated with vertigo^[24]
• Treatment of the symptoms of alcohol, opiate and benzodiazepine withdrawal^[8][25]
• Short-term treatment of insomnia^[8]
• Treatment of tetanus, together with other measures of intensive-treatment^[26]
• Adjunctive treatment of spastic muscular paresis (para-/tetraplegia) caused by cerebral or spinal cord conditions such as stroke, multiple sclerosis, spinal cord injury (long-term treatment is coupled with other rehabilitative measures)^[27]
• Palliative treatment of stiff person syndrome^[28]
• Pre-/postoperative sedation, anxiolysis and/or amnesia (e.g., before endoscopic or surgical procedures)^[27]
• Treatment of complications with a hallucinogen crisis and stimulant overdoses and psychosis, such as LSD, cocaine, or methamphetamine.^[12]
• Prophylactic treatment of oxygen toxicity during hyperbaric oxygen therapy^[29]

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.^[12]

Availability

Diazepam is marketed in over 500 brands throughout the world.^[30] It is supplied in oral, injectable, inhalation and rectal forms.^[12][31][32]

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.^[33]

Contraindications

Use of diazepam should be avoided, when possible, in individuals with the following conditions:^[34]

• Ataxia.
• Severe hypoventilation.
• Acute narrow-angle glaucoma.
• Severe hepatic deficiencies (hepatitis and liver cirrhosis decrease elimination by a factor of 2).
• Severe renal deficiencies (for example, patients on dialysis).
• Liver disorders.
• Severe respiratory disorders.
• Severe sleep apnea.
• Severe depression, particularly when accompanied by suicidal tendencies.
• Psychosis.
• Pregnancy or breast feeding.
• Caution required in elderly or debilitated patients.
• Coma or shock.
• Abrupt discontinuation of therapy.
• Acute intoxication with alcohol, narcotics, or other psychoactive substances (with the exception of some hallucinogens and/or stimulants, where it is occasionally used as a treatment for overdose).
• History of alcohol or drug dependence.
• Myasthenia gravis, or MG, an autoimmune disorder causing marked fatiguability.
• Hypersensitivity or allergy to any drug in the benzodiazepine class.

Special caution needed

• Benzodiazepines require special precaution if used in the alcohol- or drug-dependent individuals and individuals with comorbid psychiatric disorders.^[35]

• 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.^[36]
  • Under 6 months of age – Safety and effectiveness have not been established; diazepam should not be given to individuals in this age group.^[28][36]

• 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.^[28][36][37] 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 individuals and treatment limited to a maximum of 2 weeks. Long-acting benzodiazepines such as diazepam are not recommended for the elderly.^[4] Diazepam may also be dangerous in geriatric patients owing to a significant increased risk of falls.^[38]

• I.V. or I.M. injections in hypotensive individuals or those in shock should be administered carefully and vital signs should be monitored.^[37]

• 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.^[39]

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.^[40]

Adverse effects

Adverse effects of benzodiazepines such as diazepam include anterograde amnesia and confusion (especially pronounced in higher doses) and sedation. The elderly are more prone to adverse effects of diazepam such as confusion, amnesia, ataxia and hangover effects as well as falls. Long-term use of benzodiazepines such as diazepam is associated with tolerance, benzodiazepine dependence as well as a benzodiazepine withdrawal syndrome.^[4] Like other benzodiazepines, diazepam can impair short-term memory and learning of new information. While benzodiazepine drugs such as diazepam can cause anterograde amnesia, they do not cause retrograde amnesia; information learned before benzodiazepines is not impaired. Tolerance to the cognitive impairing effects of benzodiazepines does not tend to develop with long-term use. The elderly are more sensitive to the cognitive impairing effects of benzodiazepines.^[41] Additionally after cessation of benzodiazepines cognitive deficits may persist for at least six months; it is unclear whether these impairments take longer than six months to abate or if they are permanent. Benzodiazepines may also cause or worsen depression.^[4] Infusions or repeated intravenous injections of diazepam when managing seizures for example may lead to drug toxicity including respiratory depression, sedation as well as hypotension. Tolerance may also develop to infusions of diazepam if it is given for longer than 24 hours.^[4] Adverse effects such as sedation, benzodiazepine dependence and abuse potential limit the use of benzodiazepines.^[42]

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

• Suppression of REM sleep
• Impaired motor function
  • Impaired coordination
  • Impaired balance
  • Dizziness and nausea
• Depression^[43]
• Reflex tachycardia^[44]

Less commonly paradoxical side-effects can occur and include nervousness, irritability, excitement, worsening of seizures, insomnia, muscle cramps, changes in libido (increased or decreased libido) and in some cases, rage, and violence. These adverse reactions are more likely to occur in children, the elderly, individuals with a history of drug or alcohol abuse and people with a history of aggression.^{[4][45][46][47]} Diazepam may increase, in some people, the propensity toward self-harming behaviours and, in extreme cases, may provoke suicidal tendencies or acts.^[48] Very rarely dystonia can occur.^[49]

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.^[28]

During the course of therapy, tolerance to the sedative effects usually develops, but not to the anxiolytic and myorelaxant effects.^[50]

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.^[51]

Tolerance and 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 the greater the risk of experiencing unpleasant withdrawal symptoms.

Withdrawal symptoms can occur from standard dosages and also after short-term use and can range from insomnia and anxiety to more serious symptoms including seizures and psychosis. 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.

Benzodiazepine treatment should be discontinued as soon as possible via a slow and gradual dose reduction regime.^[4][52] 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, however, 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. Approximately one third of individuals who take benzodiazepines for longer than 4 weeks become dependent and experience a withdrawal syndrome upon cessation.^[4]

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, with the other 50% experiencing notable withdrawal symptoms. Certain select patient groups will show a higher rate of notable withdrawal symptoms, up to 100%.^[53]

Rebound anxiety, more severe than baseline anxiety, is also a common withdrawal symptom when discontinuing diazepam or other benzodiazepines.^[54] 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.^[55] 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.^[56] In humans tolerance to the anticonvulsant effects of diazepam occurs frequently.^[57]

Dependence

Improper or excessive use of Diazepam can lead to psychological dependence/drug addiction.^[58] At a particularly high risk for diazepam misuse, abuse or psychological dependence are:

• People with a history of alcohol or drug abuse or dependence^[28][59] Diazepam increases craving for alcohol in problem alcohol consumers. Diazepam also increases the volume of alcohol consumed by problem drinkers.^[60]
• People with severe personality disorders, such as Borderline Personality Disorder^[61]

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 people is not recommended.^[28][59]

People suspected of being physiologically dependent on 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 dependence has occurred in therapeutic or recreational contexts.

Diazepam in and of itself is not a recreational drug, but may be used to either enhance or "come down" from the effects of other recreational drugs. For example, diazepam increases the euphoriant effects of heroin (and other recreational opiates), yet decreases the undesirable side-effects of cocaine and/or methamphetamine come-down.

Overdose

An individual that has consumed too much diazepam will typically display one or more of the following symptoms in a period of approximately four hours immediately following a suspected overdose:^[28][62]

• 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.^{[12][28][62][63]}

The oral LD₅₀ (lethal dose in 50% of the population) of diazepam is 720 mg/kg in mice and 1240 mg/kg in rats.^[28] D. J. Greenblatt and colleagues reported in 1978 on two patients who had taken 500 and 2000 mg of diazepam, respectively, went into moderately deep comas, and were discharged within 48 hours without having experienced any important complications, in spite of having high concentrations of diazepam and its metabolites, esmethyldiazepam, oxazepam, and temazepam; according to samples taken in the hospital and as follow-up.^[64]

Overdoses of diazepam with alcohol, opiates and/or other depressants may be fatal.^[63][65]

An Australian study has found people who take sleeping pills or anti-anxiety medications are more dangerous on the roads than drunk drivers.^[66]

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.^[28]

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.^[12]

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.^[12]

• Diazepam increases the central depressive effects of alcohol, other hypnotics/sedatives (e.g., barbiturates), narcotics, other muscle relaxants, certain antidepressants, sedative antihistamines, opiates, and antipsychotics as well as anticonvulsants such as phenobarbital, phenytoin and carbamazepine. The euphoriant effects of opioids may be increased, leading to increased risk of psychological dependence.^[4][36][67]
• Cimetidine, omeprazole, oxcarbazepine, ticlopidine, topiramate, ketoconazole, itraconazole, disulfiram, fluvoxamine, isoniazid, erythromycin, probenecid, propranolol, imipramine, ciprofloxacin, fluoxetine and valproic acid prolong the action of diazepam by inhibiting its elimination.^[4][12][31]
• Alcohol (ethanol) in combination with diazepam may cause a synergistic enhancement of the hypotensive properties of benzodiazepines and alcohol.^[68]
• Oral contraceptives ("the pill") significantly decrease the elimination of desmethyldiazepam, a major metabolite of diazepam.^[36][69]
• Rifampin, phenytoin, carbamazepine and phenobarbital increase the metabolism of diazepam, thus decreasing drug levels and effects.^[12] Dexamethasone and St John's wort also increase the metabolism of diazepam.^[4]
• Diazepam increases the serum levels of phenobarbital.^[70]
• Nefazodone can cause increased blood levels of benzodiazepines.^[36]
• Cisapride may enhance the absorption, and therefore the sedative activity, of diazepam.^[71]
• Small doses of theophylline may inhibit the action of diazepam.^[72]
• Diazepam may block the action of levodopa (used in the treatment of Parkinson's Disease).^[67]
• Diazepam may alter digoxin serum concentrations.^[12]
• Other drugs that may have interactions with diazepam include: Antipsychotics (e.g. chlorpromazine), MAO inhibitors, ranitidine.^[36]
• Caffeine may antagonise the effects of diazepam and vice versa.^[73]
• Smoking tobacco can enhance the elimination of diazepam and decrease its action.^[67]
• Because it acts on the GABA receptor the herb Valerian may produce an adverse effect.^[74]
• Foods that acidify the urine can lead to faster absorption and elimination of diazepam, reducing drug levels and activity.^[67]
• Foods that alkalinize the urine can lead to slower absorption and elimination of diazepam, increasing drug levels and activity.^[12]
• There are conflicting reports as to whether food in general has any effects on the absorption and activity of orally administered diazepam.^[67]

Pharmacology

10mg Valium.

Diazepam is a long acting "classical" benzodiazepine. Other classical benzodiazepines include chlordiazepoxide, clonazepam, lorazepam, oxazepam, nitrazepam, temazepam, flurazepam, bromazepam, and clorazepate.^[75] Diazepam has anticonvulsant properties.^[76] 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.^[77] Benzodiazepines act via micromolar benzodiazepine binding sites as Ca2+ channel blockers and significantly inhibit depolarization-sensitive Calcium uptake in rat nerve cell preparations.^[78]

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.^[79]

Diazepam binds with high affinity to glial cells in animal cell cultures.^[80] Diazepam at high doses has been found to decrease histamine turnover in mouse brain via diazepam's action at the benzodiazepine-GABA receptor complex.^[81] Diazepam also decreases prolactin release in rats.^[82]

Mechanism of action

Diazepam is a benzodiazepine that binds to a specific subunit on the GABA_A receptor at a site that is distinct from the binding site of the endogenous GABA molecule. The GABA_A receptor is an inhibitory channel which, when activated, decreases neuronal activity. Benzodiazepines do not supplement for the neurotransmitter GABA, rather benzodiazepines such as diazepam bind to a different location on the GABA_A receptor with the result that the effects of GABA are enhanced. Benzodiazepines cause an increased opening of the chloride ion channel when GABA binds to its site on the GABA_A receptor leading to more chloride ions entering the neuron which in turn leads to enhanced central nervous system depressant effects.^[4] Diazepam binds non-selectively to alpha1, alpha2, alpha3 and alpha5 subunit containing GABA_A receptors.^[83]

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 GABA_A receptors.^[28][84]

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.^[1][84] Benzodiazepine drugs including diazepam increase the inhibitory processes in the cerebral cortex.^[85]

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.^[86]

The muscle relaxant properties of Diazepam are produced via inhibition of polysynaptic pathways in the spinal cord.^[87]

Pharmacokinetics

Generic pack of 5mg Diazepam.

Diazepam can be administered orally, intravenously (needs to be diluted, as it is painful and damaging to veins), intramuscularly (see below), or as a suppository.^[12]

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.^[44] The bioavailability after oral administration is 100 percent, and 90 percent after rectal administration. Peak plasma levels occur between 30 minutes and 90 minutes after oral administration and between 30 minutes and 60 minutes after intramuscular administration; after rectal administration peak plasma levels occur after 10 minutes to 45 minutes. Diazepam is highly protein bound with 96 to 99 percent of the absorbed drug being protein bound. The distribution half-life of diazepam is 2 minutes to 13 minutes.^[4]

When Diazepam is administered as an intramuscular injection, absorption is slow, erratic and incomplete.^[8]

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.^[4][12]

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.^[88]

Diazepam undergoes oxidative metabolism by Demethylation (CYP 2C9, 2C19, 2B6, 3A4, and 3A5), hydroxylation (CYP 3A4 and 2C19) as well as glucuronidation in the liver as part of the cytochrome P450 enzyme system. Diazepam 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 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 1–3 and 2–7 days for the active metabolite desmethyldiazepam.^[4]

Most of the drug is metabolised; very little diazepam is excreted unchanged.^[12]

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.^[89]

Detection in body fluids

Diazepam may be quantitated 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, 1–5 mg/L in those arrested for impaired driving and 2–20 mg/L in victims of acute overdosage. Most commercial immunoassays for the benzodiazepine class of drugs will cross-react with diazepam, but confirmation and quantitation is usually performed using chromatographic techniques.^[90][91][92]

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.^[12] 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.^[31]

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.^[31]

Chemistry

From a chemical point of view, diazepam, 7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one, is the most simple of all of the examined derivatives of 1,4-benzodiazepin-2-ones. Various ways for the synthesis of diazepam from 2-amino-5-chlorobenzophenone have been proposed. The first two ways consist of the direct cyclocondensation of 2-amino-5-chlorobenzophenone or 2-methylamino-5-chlorobenzophenone with the ethyl ester of glycine hydrochloride. The amide nitrogen atom of the obtained 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one, is methylated by dimethylsulfate, which leads to the formation of diazepam.

The second way differs from the first in that the methylation of nitrogen is accomplished before the cyclocondensation reaction. In order to do this, the initial 2-amino-5-chlorobenzophenone is first tosylated by p-toluenesulfonylchloride and the obtained tosylate transformed into the N-sodium salt, which is then alkylated by dimethylsulfate. The resulting 2-N-tosyl-N-methyl-5-chlorobenzophenone is hydrolyzed in an acidic medium, giving 2-methylamino-5-chlorobenzophenone, which undergoes cyclocondensation by reaction with ethyl ester of glycine hydrochloride, forming the desired diazepam.^{[93][94][95][96][97]}

History

Diazepam was the second benzodiazepine to be invented by Dr. Leo 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.^[98]

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).^[63] 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.^[99]

Diazepam was the top-selling pharmaceutical in the United States from 1969 to 1982, with peak sales in 1978 of 2.3 billion tablets.^[98] Diazepam, along with oxazepam, nitrazepam and temazepam, represents 82% of the benzodiazepine market in Australia.^[100] 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.^[27] In recent years, the public perception of benzodiazepines has become increasingly negative.^[83]

Society and culture

Recreational use

Diazepam is a drug of potential abuse and can cause serious problems of addiction and as a result is scheduled. Urgent action by national governments has been recommended to improve prescribing patterns of benzodiazepines such as diazepam.^[5][83] A single dose of diazepam modulates the dopamine system in similar ways to how morphine and alcohol modulate the dopaminergic pathways.^[101] Between 50 and 64% of rats will self administer diazepam.^[102] 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.^[103] In addition diazepam has been shown to be able to substitute for the behavioural effects of barbiturates in a primate study.^[104] Diazepam has been found as an adulterant in heroin.^[105]

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.^[106]

Sometimes Diazepam is used by stimulant users to "come down" and sleep and to help control the urge to binge.^[107]

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.^[108]

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.^[109]

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.^[110] 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.^[111]

Legal status

Diazepam is regulated in most countries as a prescription drug:

• International: Diazepam is a Schedule IV controlled drug under the Convention on Psychotropic Substances.^[112]
• 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. "List of Controlled Drugs". http://www.homeoffice.gov.uk/publications/alcohol-drugs/drugs/drug-licences/controlled-drugs-list?view=Binary. 
• Germany: classified as a prescription drug, or in high dosage as a restricted drug (Betäubungsmittelgesetz, Anhang III).^[113]

Judicial executions

The State of California offers diazepam to condemned inmates as a pre-execution sedative as part of their Lethal Injection program.^[114]

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.^[115][116] For emergent treatment of seizures, the typical dose is 0.5cmg/kg intravenously, or 1–2c;mg/kg of the injectable solution administered in the rectum.^[117]

References

External links

• Roche Pharmaceuticals (AUS) - Valium Product Information
• U.S. National Library of Medicine: Drug Information Portal - Diazepam
• Flash animation about how bromazepam works (mechanism of action)
• Albany Medical Center – "Medication of the month"