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Diazepam chemical structure
Diazepam

9-chloro-2-methyl-6-phenyl-
2,5-diazabicyclo[5.4.0]undeca-5,8,10,12-tetraen-3-one

IUPAC name
CAS number
439-14-5
ATC code

N05BA01

PubChem
3016
DrugBank
APRD00642
Chemical formula C16H13ClN2O
Molecular weight 284.7
Bioavailability 94%
Metabolism Hepatic
Elimination half-life 36-100 hours
Excretion Renal
Pregnancy category D (USA)
C (Aus)
Legal status Schedule IV (US)
Routes of administration Oral, I.M., I.V., suppository, parenteral

Diazepam (marketed under brand names Valium®, Seduxen® and, in Europe, Apozepam® and Diapam®) is a drug which is a benzodiazepine derivative. It possesses anxiolytic, anticonvulsant, sedative and skeletal muscle relaxant properties.

History

Diazepam was the second benzodiazepine to be invented by Leo Sternbach around 1960. It is five times more potent than its predecessor, chlordiazepoxide (Librium®), which it quickly overtook when first marketed in 1963. The benzodiazepines gained popularity among medical professionals as an improvement upon barbiturates, which have a comparatively narrow therapeutic index. At first, diazepam was considered something of a "wonder-drug": it was America's top-selling pharmaceutical from 1969 to 1982, with peak sales in 1978 of 2.3 billion pills ($US600 million in sales).

However, it is now known that benzodiazepines carry a risk of dependency. In the autumn of 1973, a report aired on the television show 60 Minutes attesting to the drug's addictiveness. This can occur in as little as four weeks. Following a controversial and often polemic discussion, benzodiazepine prescriptions declined by nearly half in the 1980's and 1990's.

Psychiatrists and neurologists have recently discovered new off-label uses for this 'old' drug, such as adjunctive treatment of extrapyramidal disorders or spastic paresis. This is most likely due to the inhibitory effects of the benzodiazepines (see Pharmacology section below).

Pharmacology

In animal models, diazepam appears to act on areas of the limbic system, thalamus and hypothalamus, inducing anxiolytic effects. It is thought to bind to GABAA receptors, (a sub-type of GABA receptors). Due to the role of diazepam as a GABAminergic agonist, when it binds to GABA receptors it causes inhibitory effects. This arises from the hyperpolarization of the postsynaptic membrane, due to the control exerted over negative chloride ions by GABAA receptors.

Diazepam is redistributed into tissues and fat deposits, where there are similar types of benzodiazepine receptors. In humans, tolerance to the sedative effects may develop within 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.

Pharmacokinetics

Diazepam can be administered orally, intravenously, intramuscularly, or as a suppository. When taken orally, diazepam is rapidly absorbed and shows a fast onset of action. Absorption is much slower and more erratic when diazepam is given as an intramuscular injection. Diazepam is highly lipid-soluble and therefore crosses the blood-brain barrier easily.

Diazepam is metabolised in the liver and has a biphasic half-life. The half-life (t1/2α) is 20-100 hours, and the main active metabolite, desmethyldiazepam, has a half-life of 36-200 hours. Diazepam's other active metabolites include, among others, temazepam and oxazepam. Diazepam and its metabolites are excreted into the urine.

Continual daily doses of diazepam will quickly build up to a high concentration in the body (mainly in fatty tissues), which will be far in excess of the actual dose for that day.

Indications

Diazepam is used to treat anxiety and tension, and is the most effective benzodiazepine for treating muscle spasms. It is also used as a sedative premedication for various medical procedures, and to treat alcohol and opiate withdrawal symptoms.

Occasionally, diazepam is used by military and paramilitary snipers to relax muscles and slow breathing for increased firing accuracy. Diazepam is one of the "standard benzodiazepines" most often used in clinics and for outpatients. It is listed in the World Health Organization List of "Essential Drugs".

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

  • Short-term treatment of insomnia
  • Treatment of anxiety, panic attacks, and states of agitation
  • Treatment of status epilepticus, adjunctive treatment for other forms of epilepsy
  • Treatment of tetanus, together with other measures of intensive-treatment
  • Initial management of mania, together with firstline drugs like Lithium, Valproate or neuroleptics
  • Treatment of the symptoms of alcohol and opiate withdrawal (under close clinical supervision)
  • Adjunctive treatment (with antidepressants) of depression, in patients developing suicidal thoughts, in order to decrease the risk of suicide until remission of depression is evident.
  • Adjunctive treatment (with neuroleptics), in patients who develop early extrapyramidal side-effects
  • Adjunctive treatment of overdosage with hallucinogens or CNS stimulants
  • Adjunctive treatment of painful muscle conditions
  • Palliative treatment of stiff person syndrome
  • 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 done together with other rehabilitative measures)
  • Pre-/postoperative sedation
  • Experimental treatment of children with anxiety due to separation from their parents (long-term hospitilizations, treatment in rehabiliative institutions far away from home etc.) and their normal social connections (also known under German term 'Trennungsangst')

In the treatment of status epilepticus and tetanus the use of diazepam can be life-saving.

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.

Dosage

Strictly individual, depending upon the condition to be treated, severity of symptoms, and weight of the patient. The elderly and those with preexisting liver disease experience an intensified and prolonged action of the drug; in elderly the elimination of Diazepam and its major metabolites is decreased by a factor of 2 to 4. Therefore, the single doses should be reduced and/or the dosing intervals spaced. General recommenations are:

  • Insomnia: 2 to 10mg oral, at bedtime (rarely exceeding 20mg)
  • Anxiety states and panic attacks: Single doses of 5 to 10mg oral, rectal or slow intravenous. In severe cases, a regular treatment of 5 to 10mg, up to 4 times daily, may be required.
  • Pre- and postoperative sedation: 5 to 10mg oral, rectal or slow intravenous, depending on other drugs used concomittantly. Postoperatively, 5 to 10mg can be given once or repeatedly.
  • Status epilepticus: 10 to 20mg intravenous initially, additional doses of 10mg may be given every 10 to 20 minutes, as long as seizures persist. In long-term treatment 5 to 15 mg orally per day together with primary therapy will normally suffice.
  • Tetanus: Continuous, large intravenous doses of up to 210mg daily are usually necessary
  • Painful muscle conditions: Depending on the individual, 4 to 40mg daily, oral or rectal.
  • Spastic paresis: Usually starting with 3 times daily 2mg, increasing to up to 3 times 20mg in slow increments, taking care to avoid ataxia.
  • Initial mangement of mania: 30 to 40mg daily oral or rectal, rarely more.
  • Overdosage with hallucinogens or central stimulants: normally a single intravenous dose of 10 to 20mg is sufficient.
  • Alcohol/opioid withdrawal: Depending on the individual, high initial doses (40 to 60mg daily oral), decreasing over time. Therapy should be terminated after 10 to 14 days to avoid development of addiction in this high-risk group of patients.
  • Adjunctive therapy in 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.
  • Adjunctive treatment of extrapyramidal side-effects: Depends on the individual. Most effective doses are not known so far. Do not administer for more than 4 weeks.

Doses for in-patients are usually higher than for out-patients.

Diazepam is supplied in the following forms:

  • Tablets - 2mg, 5mg, 10mg
  • I.V. or I.M. injection - 10mg
  • Suppositories - 5mg and 10mg
  • Controlled Release Capsules (Valrelease®) - 15mg
  • Liquid concentrate (Valiquid®), generics available

Side effects

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

Paradoxical side effects such as nervousness, irritability, insomnia, muscle cramps, and in extreme cases, even rage and violence, may be seen (these require immediate withdrawal of the drug). Diazepam can lead to physiological tolerance, and psychological and/or physical addiction.

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.

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.

Patients with 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.

Interactions

  • 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 (Tagamet®), omeprazole, ketoconazole, and fluoxetine prolong the action of diazepam by inhibiting its elimination. Disulfiram may act in the same way. Dose reductions during long-term therapy may be necessary.
  • Hormonal contraceptives ('the pill') significantly decrease the elimination of a major metabolite of diazepam (desmethyldiazepam).
  • Cisapride may enhance the absorption of diazepam and therefore increase the sedative activities of diazepam.
  • Smoking tobacco can enhance the elimination of diazepam and decrease its action.
  • Small doses of theophylline (asthma medication) inhibit the action of Diazepam
  • Diazepam may block the action of levodopa used in the treatment of Parkinson's Disease.
  • Diazepam may infrequently block the metabolism of phenytoin and therefore increase its actions and side-effects.
  • Foods that acidify the urine can lead to faster renal elimination, reducing the drug levels and activity.
  • There are conflicting reports as to whether food in general has any effects on the absorption and activity of diazepam

Contraindications

Use of diazepam should be avoided in individuals with the following conditions:

Special Caution Needed

  • Children and adolescents (less than 18 years of age) - Treatment usually not indicated, except treatment of epilepsy, and pre-/postoperative treatment; extended clinical data for this age group is currently lacking.
  • I.V. or I.M. injections in hypotensive individuals or those in shock should be administered carefully and vital signs should be monitored.

Patients at a High Risk for Abuse and Dependence

At a particularly high risk for misuse, abuse, and dependence are:

  • Patients with a history of alcohol or drug abuse or dependence
  • 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 group 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.

Routine examinations, including EKG, EEG or other laboratory tests, are useful for individuals under long-term treatment, although they are not strictly required.

Withdrawal procedure after long-term treatment

After continued therapy in excess of a few weeks, diazepam should never be stopped abruptly. It should instead be withdrawn gradually, over a period of weeks (or even months). The first 50% of the usual daily dose may be withdrawn quite rapidly, the next 25% fairly slowly and the last 25% very slowly, to avoid unpleasant and sometimes serious withdrawal effects. Sometimes a temporary halt after withdrawal of the first 50% is necessary.

Overdose

An individual who has consumed too much diazepam will display one or more of the following symptoms:

  • Somnolence (difficulty staying awake)
  • Mental confusion
  • Hypotension
  • Impaired motor functions
    • Impaired reflexes
    • Impaired coordination
    • Impaired balance
    • Dizziness
  • Coma

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®). 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.

The oral LD50 (i.e. lethal dose) of diazepam in humans, if taken alone, is estimated to be 500mg or more. 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. Overdoses of diazepam with alcohol and/or other depressants may be fatal.

Recreational use

Diazepam is often used as an adulterant in heroin. This is because diazepam amplifies greatly the euphoriant effects of heroin. Often users are not aware that they are also taking diazepam and that dependence on diazepam may have developed with chronic use leading to far greater withdrawal problems than with heroin alone.

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.

Generally, its recreational use is not as frequent as with alprazolam or flunitrazepam.

Legal Status

Internationally, diazepam is a Schedule IV drug under the Convention on Psychotropic Substances[1].

Trivia

  • The Rolling Stones paid tribute to Valium, the "little yellow pill", in their song, "Mother's Little Helper".
  • Also mentioned in the Lou Reed classic "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 bash)
  • Several plants, such as potato herbs (Solanum tuberosum), contain small amounts of naturally occurring diazepam and temazepam.
  • 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.
  • In the video game Metal Gear Solid you can use Diazepam to steady your aim while using a sniper rifle. It is also used by the enemy sniper (Sniper Wolf).

External Links

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.
  • Barondes, Samuel H. Better Than Prozac. New York: Oxford University Press, 2003. ISBN 0195151305.
  • Barondes, Samuel H. Molecules and Mental Illness. New York: Scientific American Library, 1999. ISBN 0716760339.
  • Benkert, Otto et al. Kompendium der Psychiatrischen Pharmakotherapie, 5th edition. Springer, 2003. ISBN 3540218939.
  • Holt, Gary A. Food and Drug Interactions: A Guide for Consumers. Chicago: Precept Press, 1998. ISBN 0944496598.



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