'Diazepam' (), first marketed as 'Valium' by
Hoffmann-La Roche) is a
benzodiazepine derivative drug. It possesses
anxiolytic,
anticonvulsant,
sedative,
skeletal muscle relaxant and
amnestic properties. It is commonly used for treating
anxiety,
insomnia,
seizures, alcohol
withdrawal, and
muscle spasms. 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]
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.
[3] 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.
History
Diazepam was the second benzodiazepine to be invented by
Leo Sternbach of
Hoffmann-La Roche, and was approved for use in
1963. It is five times more potent than its predecessor,
chlordiazepoxide, which it quickly surpassed in terms of sales. After this initial success, other pharmaceutical companies began to introduce other benzodiazepine derivatives.
[4]
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).
[5]
Diazepam was the top-selling pharmaceutical in the
United States from 1969 to 1982, with peak sales in 1978 of 2.3 billion pills.
4 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, e.g., forms of
paresis. It is also the first line of defense for a rare disorder called
stiff-person syndrome.
[6]
Diazepam is also found in nature. Several plants, such as
potato and
wheat, contain trace amounts of naturally occurring diazepam and other benzodiazepines.
[7]
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. 7). Diazepam has a shelf-life of 5 years for oral tablets and 3 years for IV/IM solution.
[8]
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.
[9]
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 intervenous 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.
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
endogenous GABA molecule.
[10][11]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 GABA
A receptors.
10[12]
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[13]
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.
[14]
Pharmacokinetics
Diazepam can be administered orally,
intravenously,
intramuscularly, or as a
suppository.
[8]
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 the diazepam's main pharmacological effects is 15 minutes to 1 hour for both routes of administration.
[16]
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.
[9]
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.
89
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 are clinical justification to recommend the withdrawal of diazepam during pregnancy and breast feeding.
[18]
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.
9[19]
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.
9
Most of the drug is metabolised; very little diazepam is excreted unchanged.
8
In humans, the protein binding of diazepam is around 98.5%.
Indications
Diazepam is mainly used to treat anxiety, insomnia, and symptoms of acute
alcohol or
opiate withdrawal. It is also used as a
premedication for inducing sedation, anxiolysis or amnesia 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.
8[20]
Diazepam has a broad spectrum of indications (most of which are off-label), including:
★ Treatment of
anxiety,
panic attacks, and states of
agitation
★ Treatment of
status epilepticus, adjunctive treatment of other forms of epilepsy
★ Treatment of the symptoms of alcohol and opiate withdrawal
★ Short-term treatment of
insomnia
★ Treatment of
tetanus, together with other measures of intensive-treatment
[{{cite journal | first = C. N. | last = Okoromah | coauthors = F. E. Lesi | year = 2004 | title = Diazepam for treating tetanus | journal = Cochrane database of systematic reviews (Online) | issue = 1 | id = ]
★ Initial management of
mania, together with firstline drugs like
lithium,
valproate or other
antipsychotics
★ Adjunctive treatment (with
antidepressants) of
depression with symptoms of anxiety
★ Adjunctive treatment (with
antipsychotics), in patients who develop early
extrapyramidal side-effects
★ Adjunctive treatment of painful muscle conditions
6
★ 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)
6
★ Palliative treatment of
stiff person syndrome12
★ Pre-/postoperative sedation, anxiolysis and/or amnesia (e.g. before
endoscopic or surgical procedures)
6
★ Treatment of overdosage with
hallucinogens or CNS
stimulants8
★ Adjunctive treatment of drug-induced seizures, resulting from exposure to
sarin,
VX,
soman (or other
organophosphate poisons; See
CANA),
lindane,
chloroquine,
physostigmine, or
pyrethroids
8
★ Emergency treatment of
eclampsia, along with
IV magnesium sulfate
★
Prophylactic treatment of
oxygen toxicity during
hyperbaric oxygen therapy.
[21]
★ Used in the treatment for irritable bowel syndrome.
[22]
★ 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.
[23]
★ 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.
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.
8
Typical dosages for healthy adults range from 2mg per dose to 30mg per dose, 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.
12
Availability
Diazepam is supplied in the following forms:
★ For oral administration:
★
★ Tablets - 2mg, 5mg, 10mg
12. Generic versions available.
★
★ Capsules, time-release - 15mg (marketed by Roche as 'Valrelease'®)
9
★
★ Liquid solution - 1mg/ml in 500ml containers and unit-dose (5mg & 10mg); 5mg/ml in 30 ml dropper bottle (marketed by Roxane as 'Diazepam Intensol'®)
9
★ For parenteral administration:
★
★ Solution for IV/IM injection - 5mg/ml. 2ml ampoules and syringes; 1ml, 2ml, 10ml 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.
[24]9
★ For rectal administration:
★
★ Solution
8
★
★ Suppositories - 5mg and 10mg
[25]8
★ 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
[26]
Side effects
Diazepam has a range of side effects which are common to most benzodiazepines. Most common side effects include:
★
Somnolence
★ Suppression of REM sleep or dreaming
★ Addiction
★ Impaired motor function
★
★ Impaired coordination
★
★ Impaired balance
★
★
Dizziness
★
Depression
★
Anterograde amnesia (especially pronounced in higher doses)
★
Reflex tachycardia16
Rare paradoxical side effects can include: nervousness, irritability, insomnia, muscle cramps, and in extreme cases, rage, and violence.
[ Diazepam: Side Effects ] If these side effects are present, diazepam treatment should be immediately terminated.
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.
[27] 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.
[28] 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.
[29] 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.
[30]
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.
12
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.
Diazepam in doses of 5 mg or more causes significant deterioration in
vigilance performance combined with increased feelings of sleepiness.
[31]
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.
12
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.
8
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.
8
★ 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.
[32][33]
★
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.
89
★ Oral contraceptives ("the pill") significantly decrease the elimination of desmethyldiazepam, a major metabolite of diazepam.
33[34]
★
Rifampin,
phenytoin,
carbamazepine and
phenobarbital increase the metabolism of diazepam, thus decreasing drug levels and effects.
8
★
Nefazodone can cause increased blood levels of benzodiazepines.
33
★
Cisapride may enhance the absorption, and therefore the sedative activity, of diazepam.
[35]
★ Small doses of
theophylline may inhibit the action of diazepam.
★ Diazepam may block the action of
levodopa (used in the treatment of
Parkinson's Disease).
32
★ Diazepam may alter
digoxin serum concentrations.
8
★ Other drugs that may have interactions with diazepam include:
Antipsychotics (e.g.
chlorpromazine),
MAO inhibitors,
ranitidine.
33
★ Smoking
tobacco can enhance the elimination of diazepam and decrease its action.
32
★ Foods that acidify the urine can lead to faster absorption and elimination of diazepam, reducing drug levels and activity.
32
★ Foods that alkalinize the urine can lead to slower absorption and elimination of diazepam, increasing drug levels and activity.
8
★ There are conflicting reports as to whether food in general has any effects on the absorption and activity of orally administered diazepam.
32
Contraindications
Use of diazepam should be avoided, when possible, in individuals with the following conditions:
★
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)
★ Severe
sleep apnea
★ Severe
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 gravis
★ Hypersensitivity 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.
33
★
★ Under 6 months of age - Safety and effectiveness have not been established; diazepam should not be given to individuals in this age group.
1233
★ 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.
1233[36]
Diazepam may also be dangerous in geriatric patients due to a significant increased risk of falls.
[37]
★ I.V. or I.M. injections in hypotensive individuals or those in shock should be administered carefully and vital signs should be monitored.
36
Patients at a high risk for abuse and dependence
Diazepam can lead to
physiological tolerance, and psychological and/or physical dependence. At a particularly high risk for diazepam misuse, abuse, and dependence are:
★ Patients with a history of alcohol or drug abuse or dependence
12[38]
★ Emotionally unstable patients
★ Patients with severe personality disorders, such as
Borderline Personality Disorder★ Patients with chronic pain or other physical disorders
Patients 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.
1238 The
American Society of Addiction Medicine has policy indicating that patients with addictive disease should not be prescribed benzodiazepines such as diazepam.
Overdose
An individual who has consumed too much diazepam will display one or more of the following symptoms
12[39]:
★
Somnolence/difficulty staying awake
★ 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.
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 2000 and 500 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 use
Diazepam is often found as an
adulterant in heroin.
[ CHAPTER II. OPERATION OF THE INTERNATIONAL DRUG CONTROL SYSTEM International Narcotics Control Board ] 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
[ Methamphetamine and Benzodiazepines: Methamphetamine & Benzodiazepines Overclocker ]
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.
[41]
It is sometimes referred to by street names, including 'blues', 'mother's little helper', '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 status
Internationally, diazepam is a Schedule IV drug under the
Convention on Psychotropic Substances.
[42]
In the UK, it is classified as a
Class C drug.
Further reading
★ Fachinformationen (German) for Valium, provided by Roche Pharmaceuticals
★ Bandelow, Borwin et al. ''Handbuch der Arzneimitteltherapie, Bd.1, Psychopharmaka'', 2nd edition. Enke, 2004. ISBN 3-13-113041-5.
★ Benkert, Otto et al. ''Kompendium der Psychiatrischen Pharmakotherapie'', 5th edition. Springer, 2003. ISBN 3-540-21893-9.
References
1. Diazepam
2. Diazepam
3. WHO Model List of Essential Medicines
4. Leo Sternbach's Obituary
5. Better Than Prozac, , Samuel H., Barondes, Oxford University Press, 2003, ISBN 0-19-515130-5
6. Diazepam: indications
7.
8. Diazepam Pere Munne/M. Ruse, Ed.
9. Diazepam Mikota, Susan K. and Plumb, Donald C.
10. Molecules and Mental Illness, , Samuel H., Barondes, New York: Scientific American Library, 1999, ISBN 0-7167-6033-9
11.
12. Diazepam Thomson Healthcare (Micromedex)
13. Molecules and Mental Illness, , Samuel H., Barondes, Scientific American Library, 1999, ISBN 0-7167-6033-9
14. Benzodiazepines, but not beta carbolines, limit high frequency repetitive firing of action potentials of spinal cord neurons in cell culture., McLean MJ, , , J Pharmacol Exp Ther., 1988
15. Diazepam Pere Munne/M. Ruse, Ed.
16. DIAZEPAM (VALIUM AND OTHERS) Langsam, Yedidyah
17. Diazepam Mikota, Susan K. and Plumb, Donald C.
18. Pharmacologic bases of use of benzodiazepines in peréinatal medicine., Olive G, , , Arch Fr Pediatr., 1977
19. [Chemical and pharmacologic aspects of benzodiazepines], Oelschläger H., , , Schweiz Rundsch Med Prax., 1989
20. Benzodiazepines in the treatment of epilepsy in people with intellectual disability., , JI, Isojärvi, J Intellect Disabil Res., 1998
21. Hyperbaric Medicine Practice, Second Edition, , Kindwall, Eric P. (Ed.)/Whelan, Harry T. (Ed.), , Best Publishing Company, 1999, ISBN 0-941332-78-0
22. Neurological Encyclopedia. http://www.answers.com/diazepam
23. Epilepsy In Your Dog Or Cat
24. Diazepam: description
25. Enhanced Release of Diazepam From Hollow-Type Suppositorie, Kaewnopparat, N., Kaewnopparat, S., Rojanarat, W., Ingkatawornwong, S., , , International Journal of Pharmaceutical Compounding, 2004
26. Pharmaceutical Patents. http://www.pharmcast.com/Patents100/Yr2004/Oct2004/101904/6805853_Diazepam101904.htm
27. Stressful reactions and panic attacks induced by flumazenil in chronic benzodiazepine users., Bernik MA, , , Journal of psychopharmacology (Oxford, England)., 1998
28. A controlled study of flumazenil-precipitated withdrawal in chronic low-dose benzodiazepine users., Mintzer MZ, , , , 1999
29. Long-term anxiolytic therapy: the issue of drug withdrawal., Lader M., , , The Journal of clinical psychiatry., 1987
30. Comparative assessment of efficacy and withdrawal symptoms after 6 and 12 weeks' treatment with diazepam or buspirone., Murphy SM, Owen R, Tyrer P., , , The British journal of psychiatry : the journal of mental science., 1989
31. Vigilance impairment after a single dose of benzodiazepines., Kozená L, , , Psychopharmacology (Berl)., 1995
32. Food and Drug Interactions: A Guide for Consumers, , Gary A., Holt, Precept Press, 1998, ISBN 0-944496-59-8
33. Diazepam
34. Pharmacokinetic drug interactions with oral contraceptives., Back DJ, , , Clin Pharmacokinet., 1990
35. The action of cisapride on gastric emptying and the pharmacodynamics and pharmacokinetics of oral diazepam., Bateman, D.N., , , Eur J Clin Pharmacol., 1986
36. Diazepam: precautions
37. [Falls in the geriatric department: responsibility of the care-giver and the hospital], Shats V, , , Harefuah, 1995
38. Diazepam: abuse and dependence
39. Diazepam: overdose
40. A survey of buprenorphine related deaths in Singapore., , SH, Lai, Forensic Sci Int., 2006
41. Use of prescription forgeries in a drug abuse surveillance network., Bergman U, , , Eur J Clin Pharmacol., 1989
42. List of psychotropic substances under international control International Narcotics Control Board
External links
★
Roche Pharmaceuticals (US) - Valium Product Information
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