Diazepam

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[[Image:{{{image|Diazepam.png}}}|{{{width|220}}}px|Diazepam chemical structure]] Diazepam
7-chloro-1-methyl- 5-phenyl-1,3-dihydro-2H- 1,4-benzodiazepin-2-one IUPAC name
CAS number 439-14-5	}}}
PubChem {{{PubChem}}}	DrugBank {{{DrugBank}}}
Chemical formula	{{{chemical_formula}}}
Molecular weight	{{{molecular_weight}}}
Bioavailability	{{{bioavailability}}}
Metabolism	{{{metabolism}}}
Elimination half-life	{{{elimination_half-life}}}
Excretion	{{{excretion}}}
Pregnancy category	{{{pregnancy_category}}}
Legal status	{{{legal_status}}}
Routes of administration	{{{routes_of_administration}}}

| PubChem = 3016 | DrugBank = APRD00642 | chemical_formula = C{{#if:{{{1|}}}|_{{{1}}}|}}₁₆H{{#if:{{{1|}}}|_{{{1}}}}}₁₃Cl{{#if:{{{1|}}}|_{{{1}}}|}}N{{#if:{{{1|}}}|_{{{1}}}|}}₂O{{#if:{{{1|}}}|_{{{1}}}|}} | molecular_weight = 284.7 | molar_refractivity = 80.91 ± 0.5 cm³ | bioavailability = 93% | metabolism = Hepatic | elimination_half-life = 36-100 hours | excretion = Renal | pregnancy_category = D (USA)
C (Aus) | legal_status = Schedule IV (International) | routes_of_administration = Oral, IM, IV, suppository }}

Diazepam (marketed under brand names Valium®, Seduxen® and Apozepam®)<ref name="DrugBank">{{cite web | author= Wishart, David | year= 2006 | url= http://redpoll.pharmacy.ualberta.ca/drugbank/cgi-bin/getCard.cgi?CARD=APRD00642.txt | title= Diazepam | work= DrugBank | publisher= | accessdate= 2006-03-10 }}</ref> is a drug which is a benzodiazepine derivative. It possesses anxiolytic, anticonvulsant, sedative, skeletal muscle relaxant and amnestic properties. This makes it a useful drug for treating anxiety, insomnia, muscle spasms and some forms of epilepsy. It is also used before certain medical procedures (such as endoscopies) to reduce tension and anxiety, and in some surgical procedures to induce amnesia.<ref name="PubChem">{{cite web | author= | year= 2006 | url= http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=3016 | title= Diazepam | work= PubChem | publisher= National Institute of Health: National Library of Medicine | accessdate= 2006-03-11 }}</ref><ref name="NLM">{{cite web | author= | year= 2006 | url= http://www.nlm.nih.gov/cgi/mesh/2006/MB_cgi?mode=&term=Diazepam | title= Diazepam | work= Medical Subject Headings (MeSH) | publisher= National Library of Medicine | accessdate= 2006-03-10 }}</ref>

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.<ref name="essentialWHO">{{cite web

| year = March 2005
| url = http://whqlibdoc.who.int/hq/2005/a87017_eng.pdf
| title = WHO Model List of Essential Medicines
| format = PDF
| publisher = World Health Organization
| accessdate = 2006-03-12

}}</ref> Diazepam is used to treat a wide range of conditions and is one of the most frequently prescribed benzodiazepines.

Contents 1 History 2 Physical properties 3 Pharmacology 4 Pharmacokinetics 5 Indications 5.1 Veterinary uses 6 Dosage 6.1 Adult dosage recommendations 6.2 Pediatric dosage recommendations 6.3 Availability 7 Side effects 8 Interactions 9 Contraindications 9.1 Special caution needed 9.2 Patients at a high risk for abuse and dependence 10 Withdrawal 11 Overdose 12 Recreational use 13 Legal Status 14 Trivia 15 External links 16 References 17 Footnotes

History

Diazepam was the second benzodiazepine to be invented by Leo Sternbach, 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.<ref name="Obituary">{{cite news | author= Sample, Ian | title= Leo Sternbach's Obituary | date= Monday October 3, 2005 | publisher= The Guardian (Guardian Unlimited) | url= http://www.guardian.co.uk/medicine/story/0,,1583671,00.html | accessdate= 2006-03-10 }}</ref>

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).<ref name="Barondes1">{{cite book | first= Samuel H. | last= Barondes | year= 2003 | month= | title= Better Than Prozac | pages= 47-59 | publisher= New York: Oxford University Press | id= ISBN 0195151305 }}</ref>

Diazepam was the top-selling pharmaceutical in the United States from 1969 to 1982, with peak sales in 1978 of 2.3 billion pills.<ref name="Obituary" />

Over the years, physicians, psychiatrists and neurologists have discovered many new off-label uses for diazepam, such as treatment of spastic paresis and palliative treatment of stiff-person syndrome.<ref name="RXL.Indications">{{cite web | year= January 24, 2005 | url= http://www.rxlist.com/cgi/generic/diazepam_ids.htm | title= Diazepam: indications | work= Rxlist.com | publisher= RxList Inc. | accessdate= 2006-03-11 }}</ref>

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.<ref name="Inchem">{{cite web | author= Pere Munne/M. Ruse, Ed. | year= 1990/1998 Ed. | url= http://www.inchem.org/documents/pims/pharm/pim181.htm | title= Diazepam | work= Inchem.org | publisher= Inchem.org | accessdate= 2006-03-11 }}</ref>

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.<ref name="ElephantCare">{{cite web | author= Mikota, Susan K. and Plumb, Donald C. | year= 2005 | url= http://www.elephantcare.org/Drugs/diazepam.htm | title= Diazepam | work= The Elephant Formulary | publisher= Elephant Care International | accessdate= }}</ref>

Diazepam may absorb into plastic, and therefore diazepam solution should not be stored in plastic bottles or syringes. It may also 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.<ref name="ElephantCare" />

Pharmacology

In animal models, 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.<ref name="PubChem" /><ref name="Barondes2">{{cite book | first= Samuel H. | last= Barondes | year= 1999 | month= MONTH | title= Molecules and Mental Illness | pages= 190-194 | publisher= New York: Scientific American Library | id= ISBN 0716760339 }}</ref>

Diazepam binds to specific benzodiazepine sites on subunits of GABA_A receptors, which are distinctly different than those which endogenous GABA molecules bind to.<ref name="Barondes2" /><ref name="Pharma">{{cite journal | author= Sieghart, W. | title= Pharmacology of benzodiazepine receptors: an update | journal= Journal of Psychiatry and Neuroscience | year= 1994 | month = January | pages= 24-29 | volume= 19 | issue= 1 | id=Template:PMID | url= http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1188559 | accessdate= 2006-03-10 }}</ref>

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 postsynaptic membrane, due to the control exerted over negative chloride ions by GABA_A receptors.<ref name="Barondes2" /><ref name="Drugs.com">{{cite web | author= Thomson Healthcare (Micromedex) | year= March 2000 | url= http://www.drugs.com/pdr/diazepam.html | title= Diazepam | work= Prescription Drug Information | publisher= Drugs.com | accessdate= 2006-03-11 }}</ref>

In humans, tolerance to the sedative effects may develop within several weeks, but tolerance to the anxiolytic effects usually does not develop. Lorazepam, clonazepam and alprazolam show stronger anxiolytic effects compared to diazepam, but carry a higher risk of misuse, abuse, tolerance and dependence.Template:Fact

Pharmacokinetics

Diazepam can be administered orally, intravenously, intramuscularly, or as a suppository.<ref name="Inchem" />

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.<ref name="Cuny.edu">{{cite web | author= Langsam, Yedidyah | year= | url= http://eilat.sci.brooklyn.cuny.edu/newnyc/DRUGS/Diazepam.htm | title= DIAZEPAM (VALIUM AND OTHERS) | work= | publisher= Brooklyn College (Eilat.sci.Brooklyn.CUNY.edu) | accessdate= 2006-03-23 }}</ref>

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.<ref name="DrugBank" /><ref name="ElephantCare" />

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.<ref name="Inchem" /><ref name="ElephantCare" />

Diazepam is metabolised 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.<ref name="DrugBank" /><ref name="ElephantCare" />

Diazepam has a half-life (t1/2α) of 20-50 hours, and desmethyldiazepam has a half-life of 30-200 hours.<ref name="ElephantCare" />

Most of the drug is metabolised; very little diazepam is excreted unchanged.<ref name="Inchem" />

In humans, the protein binding of diazepam is around 98.5%.<ref name="DrugBank" />

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).<ref name="DrugBank" />

Diazepam is rarely used as a primary drug 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.<ref name="Inchem" />

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

• Treatment of anxiety, panic attacks, and states of agitation<ref name="DrugBank" />

• Treatment of status epilepticus, adjunctive treatment of other forms of epilepsy<ref name="DrugBank" />

• Treatment of the symptoms of alcohol and opiate withdrawal<ref name="DrugBank" />

• Short-term treatment of insomnia<ref name="DrugBank" />

• Treatment of tetanus, together with other measures of intensive-treatment<ref name=tetanus>Template:Cite journal}}</ref>

• Initial management of mania, together with firstline drugs like lithium, valproate or other antipsychoticsTemplate:Fact

• Adjunctive treatment (with antidepressants) of depression with symptoms of anxietyTemplate:Fact

• Adjunctive treatment (with antipsychotics), in patients who develop early extrapyramidal side-effectsTemplate:Fact

• Adjunctive treatment of painful muscle conditions<ref name="RXL.Indications" />

• 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)<ref name="RXL.Indications" />

• Palliative treatment of stiff person syndrome<ref name="Drugs.com" />

• Pre-/postoperative sedation, anxiolysis and/or amnesia (e.g. before endoscopic or surgical procedures)<ref name="RXL.Indications" />

• Treatment of overdosage with hallucinogens or CNS stimulants<ref name="Inchem" />

• Adjunctive treatment of drug-induced seizures, resulting from exposure to sarin, VX, soman (or other organophosphate poisons), lindane, chloroquine, physostigmine, or pyrethroids<ref name="Inchem" />

• Prophylactic treatment of oxygen toxicity during hyperbaric oxygen therapy.<ref name="Hyperbaric">{{cite book

| first= Kindwall, Eric P. (Ed.)/Whelan, Harry T. (Ed.) | last= | year= 1999 | month= | title= Hyperbaric Medicine Practice, Second Edition | pages= | publisher= Best Publishing Company | id= ISBN 0941332780 }}</ref>

Veterinary uses

Diazepam is very useful as short term sedative and anxiolytic for cats and dogs. It can also be used for preoperative sedation of cats and dogs and as an anticonvulsive suitable for short-term and long-term treatment, if sedation is tolerated. To terminate status epilepticus in cats, as much as 5mg is administered rectally or intervenously, repeating as needed.Template:Fact

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.<ref name="Inchem" />

Elderly patients and those with liver disorders experience decreased metabolism of diazepam; therefore the dosage for these patients should be reduced. General guidelines for this group of patients: initial doses of 2mg to 2.5mg, 1 or 2 times daily; increase gradually as required/tolerated.<ref name="Drugs.com" />

Adult dosage recommendations

• Insomnia - Up to 30mg orally, as a single dose, at bedtime.<ref name="Inchem" />

• Anxiety/panic attacks - Dosage differs depending upon severity of symptoms. For panic attacks, diazepam is taken "as needed".
  • Oral - 2mg to 10mg oral, 2 to 4 times daily.<ref name="Drugs.com" />
  • IV/IM - 2mg to 10mg. Repeat in 3 to 4 hours, if necessary.<ref name="RXL.Indications" />

• Pre-/postoperative sedation - If other premedications are used, they must be administered separately.<ref name="RXL.Indications" />
  • Oral - Up to 20mg as a single dose.<ref name="Inchem" />
  • IV/IM - 2mg to 10mg, repeated at intervals of at least 5 to 10 minutes, until adequate sedation and/or anxiolysis is achieved.<ref name="Inchem" />

• Status epilepticus
  • Oral - 2mg to 10mg, 2 to 4 times daily.<ref name="Drugs.com" />
  • IV/IM - 5mg to 10mg. May be repeated every 5 to 10 minutes until termination of seizures. Maximum dose of 40mg to 60mg can be used; if this dose is ineffective, other anticonvulsant drug therapy should be instituted.<ref name="Inchem" />
  • Rectal solution - 10mg as a single dose. May be repeated after 5 minutes, if necessary. The oral solution can also be administered rectally.<ref name="Inchem" />

• Painful muscle conditions or muscle spasms
  • Oral - Up to 15mg daily, in divided doses. In severe spasticity associated with cerebral palsy, doses may be increased gradually up to 60mg daily.<ref name="Inchem" />
  • IV/IM - 5mg to 10mg initially, then 5mg to 10mg in 3 to 4 hours, if necessary.<ref name="RXL.Indications" />

• Tetanus - 100 to 300µg/kg intravenously, repeated every 1 to 4 hours.<ref name="Inchem" />

• Spastic paresis - Usually starting with 3 times daily 2mg, increasing to up to 3 times 20mg in slow increments, taking care to avoid ataxia.Template:Fact

• Alcohol/opioid withdrawal - For symptomatic relief of agitation, tremor, delirium tremens and hallucinosis.
  • Oral - 10mg, 3 or 4 times during the first 24 hours. Reduce to 5mg, 3 or 4 times a day, or as needed.<ref name="Drugs.com" />
  • IV/IM - 10mg initially, 5mg to 10mg in 3 to 4 hours, if necessary.<ref name="RXL.Indications" />

• Initial treatment of mania - 30 to 40mg daily oral or rectal, rarely more.Template:Fact

• Overdosage with hallucinogens/CNS stimulants - Normally a single intravenous dose of 10 to 20mg is sufficient.Template:Fact

• Adjunctive treatment of depression - Usually 10 to 30mg daily oral, the greater part of the dose given at bedtime. The doses should be decreased and the medication stopped as soon as the clinical situation allows.Template:Fact

• Adjunctive treatment of extrapyramidal side-effects - Depends on the individual. Effective dose(s) unknown. Do not administer for more than 4 weeks.Template:Fact

• Cardioversion - To relieve anxiety/tension and to reduce recall of procedure. 5mg to 15mg IV, 5 to 10 minutes prior to the procedure.<ref name="RXL.Indications" />

• Prophylactic treatment of oxygen toxicity during hyperbaric therapy - 5mg to 10mg.<ref name="Hyperbaric" />

Pediatric dosage recommendations

• Patients over 6 months of age:
  • Initiate therapy with the lowest effective dose.<ref name="Drugs.com" />
  • Oral: Initial dose of 40 to 200µg/kg of bodyweight. Can be repeated as tolerated, up to 4 times daily.<ref name="Inchem" />
  • Rectal suppository: 40 to 200µg/kg of bodyweight, which can be repeated as tolerated up to 4 times daily.<ref name="Inchem" />
    • Sedation or muscle relaxation<ref name="Inchem" />
      • IV/IM - 200µg/kg of bodyweight.
    • Status epilepticus<ref name="Inchem" />
      • IV/IM - 200 to 300µg/kg of bodyweight. May be repeated after 5 to 10 minutes, if required.
      • Rectal solution - 5mg (for patients 1 to 3 years of age); repeat after 5 to 10 minutes, if necessary.
    • Tetanus<ref name="RXL.Indications" />
      • Patients 30 days to 5 years of age - 1mg to 2mg IV/IM, slowly; repeat every 3 to 4 hours, as necessary.
      • Patients 5 years of age or older - 5mg to 10mg IV/IM, slowly; repeat every 3 to 4 hours, as necessary.
    • Convulsive disorders<ref name="RXL.Indications" />
      • Patients 30 days to 5 years of age - 0.2mg to 0.5mg IV/IM, slowly, every 2 to 5 minutes. Maximum dose of 5mg.
      • Patients 5 years of age or older - 1mg IV/IM, slowly, every 2 to 5 minutes. Maximum of dose of 10mg. Repeat in 2 to 4 hours, if necessary.
  • Patients under 6 months of age:
    • Diazepam should not be given to children under 6 months of age.<ref name="Drugs.com" />

Availability

Diazepam is supplied in the following forms:

• For oral administration:
  • Tablets - 2mg, 5mg, 10mg<ref name="Drugs.com" />. Generic versions available.
  • Capsules, time-release - 15mg (marketed by Roche as Valrelease®)<ref name="ElephantCare" />
  • 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®)<ref name="ElephantCare" />

• 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.<ref name="RXL.Description">{{cite web

| year= January 24, 2005 | url= http://www.rxlist.com/cgi/generic/diazepam.htm | title= Diazepam: description | work= Rxlist.com | publisher= RxList Inc. | accessdate= 2006-03-10 }}</ref><ref name="ElephantCare" />

• For rectal administration:
  • Solution<ref name="Inchem" />
  • Suppositories - 5mg and 10mg<ref name="Suppositories">{{cite journal

| author= Kaewnopparat, N., Kaewnopparat, S., Rojanarat, W., Ingkatawornwong, S. | title= Enhanced Release of Diazepam From Hollow-Type Suppositories | journal= International Journal of Pharmaceutical Compounding | year= 2004 | month= July/August | pages= | volume= | issue= | id= | url= http://www.findarticles.com/p/articles/mi_qa4101/is_200407/ai_n9459054 | accessdate= 2006-03-10 }}</ref><ref name="Inchem" />

Side effects

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

• Somnolence
• Impaired motor function
  • Impaired coordination
  • Impaired balance
  • Dizziness
• Depression
• Anterograde amnesia (especially pronounced in higher doses)
• Reflex tachycardia<ref name="Cuny.edu" />

Rare paradoxical side effects can include: nervousness, irritability, insomnia, muscle cramps, and in extreme cases, rage and violence.Template:Fact If these side effects are present, diazepam treatment should be immediately terminated.

Up to 30% of individuals treated on a long-term basis develop a form of dependence known as "low-dose-dependence". These patients do not develop a tolerance, and do not need increasingly large doses to experience the euphoric side effects of the drug.Template:Fact

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.<ref name="Drugs.com" />

During the course of therapy, tolerance to the sedative effects usually develops.Template:Fact

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.Template:Fact

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.<ref name="Drugs.com" />

Diazepam does not increase or decrease hepatic enzyme activity, and does not alter the metabolism of other compounds. There is no evidence which would suggest that diazepam alters its own metabolism with chronic administration.<ref name="Inchem" />

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.<ref name="Inchem" />

• 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.<ref name="Holt">{{cite book

| first= Gary A. | last= Holt | year= 1998 | month= | title= Food and Drug Interactions: A Guide for Consumers | pages= 90-91 | publisher= Chicago: Precept Press | id= ISBN 0944496598 }}</ref><ref name="PDRhealth">{{cite web | author= | year= 2006 | url= http://www.pdrhealth.com/drug_info/rxdrugprofiles/drugs/val1473.shtml | title= Diazepam | work= PDRHealth.com | publisher= PDRHealth.com | accessdate= 2006-03-10 }}</ref>

• Cimetidine, omeprazole, ketoconazole, itraconazole, disulfiram, fluvoxamine, isoniazid, erythromycin, probenicid, propranolol, imipramine, ciprofloxacin, fluoxetine and valproic acid prolong the action of diazepam by inhibiting its elimination.<ref name="Inchem" /><ref name="ElephantCare" />

• Oral contraceptives ("the pill") significantly decrease the elimination of desmethyldiazepam, a major metabolite of diazepam.<ref name="PDRhealth" />

• Rifampin, phenytoin, carbamazepine and phenobarbital increase the metabolism of diazepam, thus decreasing drug levels and effects.<ref name="Inchem" />

• Nefazodone can cause increased blood levels of benzodiazepines.<ref name="PDRhealth" />

• Cisapride may enhance the absorption, and therefore the sedative activity, of diazepam.<ref name="Cisapride">{{cite journal

| author= Bateman, D.N. | title= The action of cisapride on gastric emptying and the pharmacodynamics and pharmacokinetics of oral diazepam. | journal= Eur J Clin Pharmacol. | year= 1986 | pages= 205-8 | volume= 30 | issue= 2 | id=PMID 3709647 }}</ref>

• Small doses of theophylline may inhibit the action of diazepam.Template:Fact

• Diazepam may block the action of levodopa (used in the treatment of Parkinson's Disease).<ref name="Holt" />

• Diazepam may alter digoxin serum concentrations.<ref name="Inchem" />

• Other drugs that may have interactions with diazepam include: Antipsychotics (e.g. chlorpromazine), MAO inhibitors, ranitidine.<ref name="PDRhealth" />

• Smoking tobacco can enhance the elimination of diazepam and decrease its action.<ref name="Holt" />
• Foods that acidify the urine can lead to faster absorption and elimination or diazepam, reducing drug levels and activity.<ref name="Holt" />
• Foods that alkalinize the urine can lead to slower absorption and elimination or diazepam, increasing drug levels and activity.<ref name="Inchem" />
• There are conflicting reports as to whether food in general has any effects on the absorption and activity of orally administered diazepam.<ref name="Holt" />

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
• 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.<ref name="PDRhealth" />
  • Under 6 months of age - Safety and effectiveness have not been established; diazepam should not be given to individuals in this age group.<ref name="Drugs.com" /><ref name="PDRhealth" />

• 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..<ref name="Drugs.com" /><ref name="PDRhealth" /><ref name="RXL.Caution">{{cite web

| year= January 24, 2005 | url= http://www.rxlist.com/cgi/generic/diazepam_wcp.htm | title= Diazepam: precautions | work= Rxlist.com | publisher= RxList Inc. | accessdate= 2006-03-10 }}</ref>

• I.V. or I.M. injections in hypotensive individuals or those in shock should be administered carefully and vital signs should be monitored.<ref name="RXL.Caution" />

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<ref name="Drugs.com" /><ref name="RXL.Abuse">{{cite web

| year= January 24, 2005 | url= http://www.rxlist.com/cgi/generic/diazepam_ad.htm#DA | title= Diazepam: abuse and dependence | work= Rxlist.com | publisher= RxList Inc. | accessdate= 2006-03-10 }}</ref>

• Emotionally unstable patientsTemplate:Fact
• Patients with severe personality disorders, such as Borderline Personality DisorderTemplate:Fact
• Patients with chronic pain or other physical disordersTemplate:Fact

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.<ref name="Drugs.com" /><ref name="RXL.Abuse" />

Withdrawal

Administration of therapeutic doses of diazepam for 6 weeks or longer can result in physical dependence, characterized by a withdrawal syndrome when the drug is discontinued. With larger doses, physical dependence develops more rapidly.<ref name="Inchem" />

After continued therapy in excess of a few weeks, diazepam should never be stopped abruptly. The dose should instead be lowered gradually, over a period of 2 to 4 weeks, in order to minimize withdrawal symptoms.<ref name="Inchem" /><ref name="RXL.Abuse" />

Withdrawal symptoms are initially minimal, and increase in severity over the first 5 to 9 days after ingestion of the drug is stopped. Diazepam's long half-life and active metabolites delay the onset of such symptoms.<ref name="Inchem" />

The withdrawal symptoms for diazepam are similar to those of other CNS depressants (e.g. alcohol, barbiturates), and can include<ref name="Inchem" />:

• Anxiety
• Dysphoria
• Irritability
• Insomnia
• Confusion
• Tremors
• Muscle spasms
• Abdominal and muscle cramps
• Anorexia (i.e. lack of appetite)
• Nausea/vomiting
• Hyperthermia/sweating
• Hypotension

In severe cases of diazepam withdrawal, symptoms can include:

• Convulsions (i.e. seizures)
• Death

The more severe side effects usually only develop for patients who were treated with excessive doses for extended periods of time. Usually only the milder symptoms develop in patients terminating therapeutic-level treatment after several months.<ref name="Drugs.com" />

Overdose

An individual who has consumed too much diazepam will display one or more of the following symptoms<ref name="Drugs.com" /><ref name="RXL.Overdose">{{cite web | year= January 24, 2005 | url= http://www.rxlist.com/cgi/generic/diazepam_od.htm | title= Diazepam: overdose | work= Rxlist.com | publisher= RxList Inc. | accessdate= 2006-03-10 }}</ref>:

• 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.<ref name="Inchem" /><ref name="Barondes1" /><ref name="Drugs.com" /><ref name="RXL.Overdose" />

The oral LD₅₀ (lethal dose in 50% of the population) of diazepam is 720mg/kg in mice and 1240mg/kg in rats.<ref name="Drugs.com" /> The oral LD₅₀ in humans, if taken alone, is estimated to be 500mg or more.Template:Fact A case where a patient took 300mg resulted only in prolonged sleep and consecutive drowsiness for the next days without serious impairment of cardiac or respiratory functions.Template:Fact

Overdoses of diazepam with alcohol and/or other depressants may be fatal.<ref name="Barondes1" />

Recreational use

Generally, diazepam is not used as a recreational drug as frequently as alprazolam or flunitrazepam.

Diazepam is often found as an adulterant in heroin.Template:Fact This may be because diazepam greatly amplifies the effects of opiods.

Sometimes diazepam is used by stimulant abusers to 'come down' and sleep and also by LSD users (or those using other hallucinogens) to help ease their trip without unpleasant after-effects.Template:Fact

Legal Status

Internationally, diazepam is a Schedule IV drug under the Convention on Psychotropic Substances.<ref name="Legal">{{cite web | author=International Narcotics Control Board | year=2003 | url= http://www.incb.org/pdf/e/list/green.pdf | title= List of psychotropic substances under international control | work= Green list | accessdate= 2006-03-11 }}</ref>

Trivia

• Mentioned in the Rolling Stones song "Mother's Little Helper" (the "little yellow pill", "You can tranquilize your mind").<ref name="Obituary" /><ref name="Barondes1" />
• Mentioned in the Lou Reed song "Walk on The Wild Side" (Jackie is just speeding away / Thought she was James Dean for a day / Then I guess she had to crash / Valium would have helped that batch).Template:Fact
• Mentioned in the Verve Pipe song "The Freshman" (His girl took a week's worth of Valium and slept).Template:Fact
• Mentioned in Jacqueline Susann's 1966 novel Valley of the Dolls, whose female characters used diazepam (which they called "dolls").<ref name="Obituary" />
• Several plants, such as potato and wheat, contain trace amounts of naturally occurring diazepam and other benzodiazepines.<ref name="Natural_sources">Template:Cite journal | accessdate= 2006-04-12}}</ref>
• In April 1975, a young New Jersey woman named Karen Ann Quinlan allegedly took a small dose of Valium along with alcohol, became unconscious and stopped breathing. She became comatose and was declared to be in a persistent vegetative state. Her right to die case ended up in the US Supreme Court. The life support system was not unplugged, however, and she was weaned from her respirator by doctors in 1976. She never woke up and died 9 years later.Template:Fact
• Diazepam has had many high-profile users, including Andy Warhol and Elvis Presley.<ref name="Obituary" />

External links

• Roche Pharmaceuticals (US) - Valium Product Information

References

• Fachinformationen (German) for Valium, provided by Roche Pharmaceuticals
• Bandelow, Borwin et al. Handbuch der Arzneimitteltherapie, Bd.1, Psychopharmaka, 2nd edition. Enke, 2004. ISBN 3131130415.
• Benkert, Otto et al. Kompendium der Psychiatrischen Pharmakotherapie, 5th edition. Springer, 2003. ISBN 3540218939.

Footnotes

Template:Benzodiazepines Template:Anticonvulsantsde:Diazepam es:Diazepam he:דיאזפם nl:Diazepam ja:ジアゼパム no:Diazepam pl:Diazepam pt:Diazepam ru:Сибазон fi:Diatsepaami sv:Diazepam

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