Diazepam

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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 CID 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
20–100 hours (36-200 hours for main active
Half-life
metabolite desmethyldiazepam)
Excretion Renal
Therapeutic considerations
Pregnancy cat. C(AU) D(US)
Prescription Only (S4) (AU) Schedule IV (CA)
Legal status CD (UK) Schedule IV (US) Schedule IV
(International)
Routes Oral, IM, IV, suppository
(what is this?) (verify)

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 including status epilepticus, muscle spasms, 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 GABAA receptor
leading to central nervous system depression.[4] Diazepam has also been used as a
recreational drug.

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.[4] Diazepam also has abuse potential and can cause serious
problems of addiction. Urgent action by National Governments to improve prescribing
practices has been recommended.[5][6]

Advantages of diazepam are a rapid onset of action and high efficacy rates which is
important for managing acute seizures; 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.[7] 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.[8]

Contents
[hide]

• 1 History
• 2 Indications
o 2.1 Veterinary uses
o 2.2 Before judicial executions
o 2.3 Dosage
o 2.4 Availability
• 3 Contraindications
o 3.1 Special caution needed
o 3.2 Pregnancy
• 4 Side-effects
o 4.1 Tolerance and physical dependence
o 4.2 Overdose
• 5 Physical properties
• 6 Pharmacology
o 6.1 Mechanism of action
o 6.2 Pharmacokinetics
• 7 Interactions
• 8 Drug misuse and addiction
o 8.1 Patients at a high risk for abuse or addiction
• 9 Legal status
• 10 Toxicity
• 11 See also
• 12 References

• 13 External links

[edit] 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.[9]

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).[10]
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.[11]

Diazepam was the top-selling pharmaceutical in the United States from 1969 to 1982,
with peak sales in 1978 of 2.3 billion tablets.[9] Diazepam, along with oxazepam,
nitrazepam and temazepam, represents 82% of the benzodiazepine market in Australia.[12]
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.[13] In recent years, the
public perception of benzodiazepines has become increasingly negative.[6]

[edit] Indications
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).[14][15]

Intravenous diazepam or lorazepam are first line treatments for status epilepticus;[4][16]
However, lorazepam has advantages over diazepam including a higher rate of terminating
seizures and a more prolonged anticonvulsant effect.[17] 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.[18][19] Diazepam is used for the emergency treatment of eclampsia,
when IV magnesium sulfate and blood pressure control measures have failed.[20][21]
Benzodiazepines do not have any pain relieving properties of themselves and are
generally recommended to be avoided in individuals with pain.[22] 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[23][24] Tolerance often develops to the muscle relaxant effects of
benzodiazepines such as diazepam.[25] Baclofen[26] 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.[27]

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[18][28] Diazepam is sometimes used intermitently for the prophylaxis of febrile
seizures which occur as a result of a high fever in children and neonates under 5 years of
age.[29][4] 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[14]

• Treatment of neurovegetative symptoms associated with vertigo[30]
• Treatment of the symptoms of alcohol, opiate and benzodiazepine withdrawal[14]
[31]

• Short-term treatment of insomnia[14]

• Treatment of tetanus, together with other measures of intensive-treatment[32]
• 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)[13]
• Palliative treatment of stiff person syndrome[33]
• Pre-/postoperative sedation, anxiolysis and/or amnesia (e.g., before endoscopic or
surgical procedures)[13]
• Treatment of complications with hallucinogens, such as LSD or overdose of CNS
stimulants, such as cocaine, or methamphetamine.[18]
• Prophylactic treatment of oxygen toxicity during hyperbaric oxygen therapy[34]

Before judicial executions

• The State of California offers diazepam to condemned inmates as a pre-execution

sedative as part of their Lethal Injection program.[38]

[edit] 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.[18]

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.[33]
[edit] Availability

Diazepam is marketed in over 500 brands throughout the world.[39] It is supplied in the
following forms:

• For oral administration:

o Tablets – 1 mg, 2 mg, 5 mg, 10 mg.[33] Generic versions available.
o Capsules, time-release – 15 mg (marketed by Roche as Valrelease)[40]
o 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)[40]

• For parenteral administration:

o 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.[40][41]
 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:

o Tablets 5 mg
o Injection 5 mg/ml for intravenous, intramuscular or subcutaneous usage

• For parenteral administration:

 o 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.[40][41]

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:

o Solution[18]
o Suppositories – 5 mg and 10 mg[18][42]
o 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[43]

• 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.[44]

[edit] Contraindications
Use of diazepam should be avoided, when possible, in individuals with the following
conditions:[45]

• Ataxia
• Severe hypoventilation
• Acute narrow-angle glaucoma
• Severe hepatic deficiencies (hepatitis and liver cirrhosis decrease elimination by a
factor of 2)
• Severe renal deficiencies (e.g. 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, 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

[edit] Special caution needed

• Benzodiazepines require special precaution if used in the alcohol- or drug-

dependent individuals and individuals with comorbid psychiatric disorders.[46]

• Pediatric patients
o 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]
o Under 6 months of age – Safety and effectiveness have not been
established; diazepam should not be given to individuals in this age group.
[33][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.[33][47][48] 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.[49]

• I.V. or I.M. injections in hypotensive individuals or those in shock should be

administered carefully and vital signs should be monitored.[48]

• 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.[50]

[edit] 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.[51]

[edit] Side-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; additionally after cessation of benzodiazepines cognitive deficits may persist
for at least 6 months and may not fully return to normal. 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.[52]

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
o Impaired coordination
o Impaired balance
o Dizziness and nausea
• Depression[53]

• Reflex tachycardia[54]

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][55][56][57] Diazepam may increase, in some
people, the propensity toward self-harming behaviours and, in extreme cases, may
provoke suicidal tendencies or acts.[58] If these side-effects are present, diazepam
treatment should be immediately terminated.

Very rarely dystonia.[59] Benzodiazepines such as diazepam impair learning and memory
via their action on benzodiazepine receptors, which causes a dysfunction in the
cholinergic neuronal system.[60]
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.[33]

During the course of therapy, tolerance to the sedative effects usually develops, but not to
the anxiolytic and myorelaxant effects.[61]

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.[62]

[edit] 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 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][63]
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%.[64] Rebound anxiety, more severe than
baseline anxiety, is also a common withdrawal symptom when discontinuing diazepam or
other benzodiazepines.[65] 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.[66] 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.[67] In humans tolerance to the
anticonvulsant effects of diazepam occurs frequently.[68]

[edit] Overdose
Main article: Benzodiazepine 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.:[33][69]

• Drowsiness
• Mental confusion
• Hypotension
• Impaired motor functions
o Impaired reflexes
o Impaired coordination
o Impaired balance
o 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.[10][18][33][69]

The oral LD50 (lethal dose in 50% of the population) of diazepam is 720 mg/kg in mice
and 1240 mg/kg in rats.[33] 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.[70]

Overdoses of diazepam with alcohol, opiates and/or other depressants may be fatal.[10][71]

[edit] 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.[18] 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.
[40]

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.[40]

[edit] Pharmacology

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

Diazepam is a "classical" benzodiazepine. Other classical benzodiazepines include

chlordiazepoxide, clonazepam, lorazepam, oxazepam, nitrazepam, temazepam,
flurazepam[citation needed], bromazepam[citation needed], and clorazepate[citation needed].[72] Diazepam has
anticonvulsant properties.[73] 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.[74] Benzodiazepines act via micromolar benzodiazepine binding sites as
Ca2+ channel blockers and significantly inhibit depolarization-sensitive Calcium uptake
in rat nerve cell preparations.[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]

[edit] Mechanism of action

See also: Benzodiazepine
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. The GABAA
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 GABAA 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
GABAA 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 GABAA receptors.[6]

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.[33][80]

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][80]
Benzodiazepine drugs including diazepam increase the inhibitory processes in the
cerebral cortex.[81]

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.[82]

The muscle relaxant properties of diazepam are produced via inhibition of polysynaptic
pathways in the spinal cord.[83]

[edit] 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.[18]
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.[54] The bioavailability after oral
admministration 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 (this is painful, and not

advised), absorption is slow, erratic and incomplete.[14]

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][18]

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.[84]

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.[18]

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.[85]

[edit] 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.[33]

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.[18]

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.[18]

• 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][86][47]
• 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.[18][40] Oxcarbazepine, ticlopidine
as well as topiramate also inhibit the elimination of diazepam.[4]
• Alcohol (ethanol) in combination with diazepam may cause a synergistic
enhancement of the hypotensive properties of benzodiazepines and alcohol.[87]
• Oral contraceptives ("the pill") significantly decrease the elimination of
desmethyldiazepam, a major metabolite of diazepam.[47][88]
• Rifampin, phenytoin, carbamazepine and phenobarbital increase the metabolism
of diazepam, thus decreasing drug levels and effects.[18] Dexamethasone and St
John's wort also increase the metabolism of diazepam.[4]
• Diazepam increases the serum levels of phenobarbital.[89]
• Nefazodone can cause increased blood levels of benzodiazepines.[47]
• Cisapride may enhance the absorption, and therefore the sedative activity, of
diazepam.[90]
• Small doses of theophylline may inhibit the action of diazepam.[91]
• Diazepam may block the action of levodopa (used in the treatment of Parkinson's
Disease).[86]
• Diazepam may alter digoxin serum concentrations.[18]
• Other drugs that may have interactions with diazepam include: Antipsychotics
(e.g. chlorpromazine), MAO inhibitors, ranitidine.[47]
• Caffeine may antagonise the effects of diazepam and vice versa.[92]
• Smoking tobacco can enhance the elimination of diazepam and decrease its
action.[86]
• Because it acts on the GABA receptor the herb Valerian may produce an adverse
effect.[93]
 • Foods that acidify the urine can lead to faster absorption and elimination of
diazepam, reducing drug levels and activity.[86]
• Foods that alkalinize the urine can lead to slower absorption and elimination of
diazepam, increasing drug levels and activity.[18]
• There are conflicting reports as to whether food in general has any effects on the
absorption and activity of orally administered diazepam.[86]

[edit] Drug misuse and addiction

See also: Benzodiazepine drug misuse

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][6] A single dose of
diazepam modulates the dopamine system in similar ways to how morphine and alcohol
modulate the dopaminergic pathways.[94] Between 50 and 64% of rats will self administer
diazepam.[95] 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.[96] In addition diazepam has been shown to be able to substitute for the
behavioural effects of barbiturates in a primate study.[97] Diazepam has been found as an
adulterant in heroin.[98]

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.
[99]

Sometimes diazepam is used by stimulant users to 'come down' and sleep and to help
control the urge to binge.[100]

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.[101]

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.[102]
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.[103] 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.[104]

[edit] Patients at a high risk for abuse or addiction

Diazepam can lead to drug abuse and psychological dependence/drug addiction.[105] At a

particularly high risk for diazepam misuse, abuse or psychological dependence are:

• Patients with a history of alcohol or drug abuse or dependence[33][106] Diazepam

increases craving for alcohol in problem alcohol consumers. Diazepam also
increases the volume of alcohol consumed by problem drinkers.[107]
• Patients with severe personality disorders, such as Borderline Personality
Disorder[108]

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.[33][106]

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.