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. Diazepam is structurally related to quinazolines and is a hapten.
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.
Diazepam can absorb into plastic, and therefore diazepam solution is not stored in plastic bottles or syringes. 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.
Pharmacology
The
pharmacological actions of benzodiazepines at the GABAa receptor are similar to those of
neurosteroids.
Neuroactive steroids are positive
allosteric modulators of the GABAa receptor, enhancing
GABA function. Many benzodiazepines (diazepam,
medazepam,
estazolam,
flunitrazepam and
nitrazepam) potently inhibit the
enzymes involved in the
metabolism of neurosteroids. Long-term administration of benzodiazepines may influence the concentrations of
endogenous neurosteroids, and thereby would modulate the emotional state. Factors which affect benzodiazepines ability to alter neurosteroid levels depend on the molecular make up of the individual benzodiazepine molecule.
Presence of a substituent at N1 position of the diazepine ring and/or the chloro or nitro group at position 7 of the
benzene ring contribute to potent inhibition of the isoenzymes, and in turn a
bromo group at position 7 (for bromazepam) and additional substituents (3-hydroxy group for
oxazepam and tetrahydroxazole ring for
cloxazolam and
oxazolam) decrease the
inhibitory potency of benzodiazepines on neurosteroids.
Diazepam is a potent inducer of
melanogenesis in
melanoma cells via modulating cell differentiation. Diazepam at high doses has been found to decrease histamine turnover via diazepam's action at the benzodiazepine-GABA receptor complex. Diazepam also decreases prolactin release. Diazepam has an inhibitory effect on plasma
cholinesterase of 60--90 per cent.
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.
[19][20]The
GABAA receptor is an inhibitory channel which, when activated, decreases neurologic activity.
Due to 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, due to the control exerted over negative
chloride ions by GABAA receptors.
Benzodiazepines including diazepam however, do not have any affect on the levels of GABA in the brain.
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. Benzodiazepine drugs including diazepam increase the inhibitory processes in the cerebral cortex.
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.
The muscle relaxant properties of diazepam are produced via inhibition of
polysynaptic pathways in the spinal cord.
Pharmacokinetics
Diazepam can be administered orally,
intravenously,
intramuscularly, or as a
suppository.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.
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.
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.
There is preferential storage of diazepam in some organs including the heart. Absortion 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.
Diazepam is metabolised via oxidative pathways in the
liver via 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.
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.Most of the drug is metabolised; very little diazepam is excreted unchanged.
In humans, the protein binding of diazepam is around 98.5%.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.
IndicationsDiazepam 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 prior to certain medical procedures (e.g.
endoscopy).
Diazepam is rarely used for the long-term treatment of epilepsy. This is due to the fact that tolerance to the anticonvulsant effects of diazepam usually develops within 6 to 12 months of treatment, effectively rendering it useless for this purpose and also due to side effects - in particular sedation.
Diazepam has a broad spectrum of indications (most of which are off-label), including:
Treatment of
anxiety,
panic attacks, and states of
agitationTreatment of
status epilepticus, adjunctive treatment of other forms of epilepsy
Treatment of the symptoms of alcohol and opiate withdrawal
Short-term treatment of
insomniaTreatment of
tetanus, together with other measures of intensive-treatment
Initial management of
mania, together with firstline drugs like
lithium,
valproate or other
antipsychotics[
citation needed]
Adjunctive treatment of painful muscle conditions
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)
Palliative treatment of
stiff person syndromeUsed to alleviate the symptoms of
Lesch-Nyhan SyndromePre-/postoperative sedation, anxiolysis and/or amnesia (e.g. before
endoscopic or surgical procedures)
Treatment of overdosage with
hallucinogens or CNS
stimulantsAdjunctive treatment of drug-induced seizures, resulting from exposure to
sarin,
VX,
soman (or other
organophosphate poisons; See
CANA),
lindane,
chloroquine,
physostigmine, or
pyrethroidsEmergency treatment of
eclampsia, along with
IV magnesium sulfateProphylactic treatment of
oxygen toxicity during
hyperbaric oxygen therapy.
Used in the treatment for irritable bowel syndrome.
Used to treat pain resulting from muscle spasms caused by various spastic dystonias, including blepharospasm, spasmodic dysphonia and Meige's Syndrome.
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. For emergent treatment of seizures, the typical dose is 0.5 mg/kg intravenously or 1-2 mg/kg per rectum of the injectable solution.
Diazepam is also used as a muscle relaxant for horses, to be given intravenously, the usual dose is 0.02 - 0.1 mg/kg in conjunction with or just after induction of general anesthesia.
Judicial ExecutionsThe State of
California offers Diazepam to
condemned inmates as a pre-execution sedative.
DosageDosages 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.
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.
Trade namesValium® tablets in USA and many other countries;
Valium® capsules in
Italy,
Spain;
Novodipam® in
Canada;
Relanium® in
Poland;
Seduxen® in
Hungary,
Russia;
Diazepam-Desitin® rectal solution in Hungary, and other European countries;
Diazepam-Intensol®;
Valrelease®
Diapam® in
FinlandStesolid®
Sweden,
IcelandAnxicalm®
Ireland
AvailabilityDiazepam is supplied in the following forms:
For oral administration:
Tablets - 2 mg, 5 mg, 10 mg. Generic versions available.
Capsules, time-release - 15mg (marketed by Roche as Valrelease®)
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®)
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.
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.
Seduxen (Diazepam, in Hungary, Russia, Poland, and other Eastern-European countries) is supplied in the following forms:
For oral administration:
Tablets 5mg
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.
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
Suppositories - 5mg and 10mg
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 2mg-20mg either in a single inhalation or multiple small inhalations
Side effectsRare paradoxical side effects can include: nervousness, irritability, insomnia, muscle cramps, and in extreme cases, rage, and violence. If these side effects are present, diazepam treatment should be immediately terminated.
Benzodiazepines such as diazepam impair learning and memory via their action on benzodiazepine receptors which causes a dysfunction in the cholinergic neuronal system.
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.
During the course of therapy, tolerance to the sedative effects usually develops, but not to the anxiolytic and myorelaxant effects.
Patients with severe attacks of
apnea during sleep may suffer
respiratory depression (hypoventilation) leading to respiratory arrest and death.
Organic changes such as leukopenia and liver-damage of the cholostatic type with or without
jaundice (
icterus) have been observed in a few cases.[
citation needed]
Diazepam in doses of 5 mg or more causes significant deterioration in
vigilance performance combined with increased feelings of sleepiness.
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.
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.
Agents which 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.
Diazepam increases the central depressive effects of alcohol, other
hypnotics/sedatives (e.g. barbiturates), narcotics, and other
muscle relaxants. The euphoriant effects of opioids may be increased, leading to increased risk of psychological dependence.
Cimetidine,
omeprazole,
ketoconazole,
itraconazole,
disulfiram,
fluvoxamine,
isoniazid,
erythromycin,
probenecid,
propranolol,
imipramine,
ciprofloxacin,
fluoxetine and
valproic acid prolong the action of diazepam by inhibiting its elimination.
Alcohol (
ethanol) in combination with diazepam may cause a synergistic enhancement of the
hypotensive properties of benzodiazepines and alcohol.
Oral contraceptives ("the pill") significantly decrease the elimination of desmethyldiazepam, a major metabolite of diazepam.
Diazepam increases the serum levels of
phenobarbital.
Nefazodone can cause increased blood levels of benzodiazepines.
Cisapride may enhance the absorption, and therefore the sedative activity, of diazepam.
Small doses of
theophylline may inhibit the action of diazepam.
Smoking
tobacco can enhance the elimination of diazepam and decrease its action.
Because it acts on the GABA receptor the herb
Valerian may produce an adverse effect.
Foods that acidify the urine can lead to faster absorption and elimination of diazepam, reducing drug levels and activity.
Foods that alkalinize the urine can lead to slower absorption and elimination of diazepam, increasing drug levels and activity.
There are conflicting reports as to whether food in general has any effects on the absorption and activity of orally administered diazepam.
Contraindications
Use of diazepam should be avoided, when possible, in individuals with the following conditions:
AtaxiaSevere
hypoventilationAcute narrow-angle
glaucomaSevere
hepatic deficiencies (
hepatitis and liver
cirrhosis decrease elimination by a factor of 2)
Severe
renal deficiencies (e.g. patients on
dialysis)
Severe
sleep apneaSevere
depression, particularly when accompanied by suicidal tendencies
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)
Myasthenia gravisHypersensitivity or allergy to any drug in the
benzodiazepine class
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.
Under 6 months of age - Safety and effectiveness have not been established; diazepam should not be given to individuals in this age group.
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.
Diazepam may also be dangerous in geriatric patients due to a significant increased risk of falls.
I.V. or I.M. injections in hypotensive individuals or those in shock should be administered carefully and vital signs should be monitored.
Benzodiazepines such as diazepam are lipophilic and rapidly penetrate membranes and therefore rapidly crosses 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.
Dependence
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.
It has been shown in a clinical study that 100% of patients on low dose diazepam therapy long term are
physically dependent on their medication. Increased ratings of dizziness, blurred vision, heart pounding, feelings of unreality, pins and needles, nausea, sweatiness, noises louder than usual, jitteriness, things moving, sensitivity to touch and panic attacks may be experienced as withdrawal symptoms in low therapeutic dose long term users of diazepam when discontinuing their diazepam medication.
Rebound anxiety, more severe than baseline anxiety, is also a common withdrawal symptom when discontinuing diazepam or other benzodiazepines. Diazepam is therefore only recommended for short term therapy at the lowest possible dose due to risks of severe withdrawal problems from low doses even after gradual reduction.
There is a significant risk of pharmacological dependence on diazepam and patients experiencing the
benzodiazepine withdrawal syndrome if it is taken for 6 weeks or longer.
In humans tolerance to the anticonvulsant effects of diazepam occurs frequently.
[
edit] Patients at a high risk for abuse, dependence, tolerance, or addiction
Diazepam can lead to
physiological tolerance, and psychological and/or physical dependence.
At a particularly high risk for diazepam misuse, abuse, or dependence are:
Patients with a history of alcohol or drug abuse or dependence
Patients with severe personality disorders, such as
Borderline Personality DisorderPatients with an
Anxiety DisorderPatients from the aforementioned groups should be monitored very closely during therapy for signs of abuse and development of dependence. Discontinue therapy if any of these signs are noted. Long-term therapy in these patients is not recommended.
There is inconclusive evidence that diazepam if taken early in pregnancy may result in reduced IQ, neurodevelopmental problems, physical malformations in cardiac or facial structure as well as other malformations in some newborns, however the data is inconclusive.
Diazepam when taken during late in pregnancy, 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.
Overdose
An individual who has consumed too much diazepam will display one or more of the following symptoms:
Drowsiness
Mental confusion
HypotensionImpaired 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.
The oral
LD50 (lethal dose in 50% of the population) of diazepam is 720mg/kg in mice and 1240mg/kg in rats. 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.
Overdoses of diazepam with alcohol, opiates and/or other depressants may be fatal.
Recreational and illicit use
Diazepam is a drug of potential dependence and addiction. Between 50 and 64% of rats will self administer diazepam. 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. Diazepam is often found as an
adulterant in
heroin. This may be because diazepam greatly amplifies the effects of
opioids.
Sometimes diazepam is used by stimulant users to 'come down' and sleep and to help control the urge to binge.
Benzodiazepines, including diazepam,
temazepam,
nitrazepam and
flunitrazepam account for the largest volume of forged drug prescriptions in Sweden, a total of 52% of drug forgeries being for benzodiazepines.
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.
[78] 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.
It is sometimes referred to by street names, including 'blues', 'mother's little helper', 'diazies', 'drunk pills', 'vals', 'V', and occasionally 'ludes', mistaken for
Quaaludes. As well as less specific street terms, 'candy' (
pills), 'benzos' (
benzodiazepines), or downers (
depressants).
Legal statusLaboratory 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.
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