Diazepam detailed information

Jump to navigation Jump to search
Diazepam detailed information
Clinical data
Pregnancy
category
  • AU: C
  • US: D (Evidence of risk)
Routes of
administration		Oral, IM, IV, suppository
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability93%
MetabolismHepatic
Elimination half-life20–100 hours
ExcretionRenal
Identifiers
CAS Number
PubChem CID
DrugBank
E number{{#property:P628}}
ECHA InfoCard{{#property:P2566}}Lua error in Module:EditAtWikidata at line 36: attempt to index field 'wikibase' (a nil value).
Chemical and physical data
FormulaC16H13ClN2O
Molar mass284.7 g/mol

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Associate Editor-In-Chief: Cafer Zorkun, M.D., Ph.D. [2]


Overview

Diazepam (Template:IPAEng), 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. It was invented by Dr. Leo Sternbach.

History

Diazepam was the second benzodiazepine to be invented by Sternbach of Hoffmann-La Roche, and was approved for use in 1963. It is two and a half 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 tablets.[4] Diazepam along with oxazepam, nitrazepam and temazepam represent 82% of the benzodiazepine market in Australia.[6] 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.[7]

Diazepam is also found in nature. Several plants, such as potato and wheat, contain trace amounts of naturally occurring diazepam and other benzodiazepines.[8]

Physical properties

Diazepam occurs as solid white or yellow crystals and has a melting point of 131.5 to 134.5 °C. It is odorless, and has a slightly bitter taste. The British Pharmacopoeia lists diazepam as being very slightly soluble in water, soluble in alcohol and freely soluble in chloroform. The United States Pharmacopoeia lists diazepam as soluble 1 in 16 of ethyl alcohol, 1 in 2 of chloroform, 1 in 39 of ether, and practically insoluble in water. The pH of diazepam is neutral (i.e. pH = 7). Diazepam has a shelf-life of 5 years for oral tablets and 3 years for IV/IM solution.[9] 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.[10]

Diazepam can absorb into plastic, and therefore diazepam solution is not stored in plastic bottles or syringes etc. It can absorb into plastic bags and tubing used for intravenous infusions. Absorption appears to be dependent on several factors such as temperature, concentration, flow rates and tube length. Diazepam should not be administered if a precipitate has formed and will not dissolve.[10]

Pharmacology

Diazepam is a "classical" benzodiazepine, other classical benzodiazepines include; clonazepam, lorazepam, oxazepam, nitrazepam, flurazepam, bromazepam and clorazepate.[11] Diazepam has anticonvulsant properties.[12] Diazepam is structurally related to quinazolines.[13] Diazepam has no effect on GABA levels and no effect on glutamate decarboxylase activity but has a slight effect on gaba-aminobutyric acid transaminase activity.[14] Benzodiazepines have calcium antagonist activity which may explain reports of systemic and coronary vasodilation by benzodiazepine drugs such as diazepam.[15] Benzodiazepines act via micromolar benzodiazepine binding sites as Ca2+ channel blockers and significantly inhibit depolarization-sensitive Calcium uptake.[16]

Diazepam and other benzodiazepines may influence neurosteroid metabolism and progesterone levels which in turn may adversely influence the functions of the brain and reproductive system. 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.[17] Diazepam inhibits acetylcholine release and sodium-dependent high affinity choline uptake which may play a role in diazepam's anticonvulsant properties.[18]

Diazepam binds with high affinity to glial cells.[19] Diazepam binds to peripheral benzodiazepine receptors and inhibits the proliferation of thymoma cells, Swiss 3T3 cells, B103 and B104 neuroblastoma cells, and Friend erythroleukemia cells and inhibits the uptake of thymidine into cells and inhibits the uptake of serotonin by platelets.[20] Diazepam is a potent inducer of melanogenesis in melanoma cells via modulating cell differentiation.[21] Diazepam at high doses has been found to decrease histamine turnover via diazepam's action at the benzodiazepine-GABA receptor complex.[22] Diazepam also decreases prolactin release.[23] Diazepam has an inhibitory effect on plasma cholinesterase of 60–90 per cent.[24]

Mechanism of action

Template:Seealso 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.[25][26] The GABAA receptor is an inhibitory channel which, when activated, decreases neurologic activity.

Because of the role of diazepam as a positive allosteric modulator of GABA, when it binds to benzodiazepine receptors it causes inhibitory effects. This arises from the hyperpolarization of the post-synaptic membrane owing to the control exerted over negative chloride ions by GABAA receptors.[25][27]

Benzodiazepines including diazepam however, do not have any effect on the levels of GABA in the brain.[28]

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][25] Benzodiazepine drugs including diazepam increase the inhibitory processes in the cerebral cortex.[29]

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.[30]

The muscle relaxant properties of diazepam are produced via inhibition of polysynaptic pathways in the spinal cord.[31]

Pharmacokinetics

Diazepam can be administered orally, intravenously, intramuscularly, or as a suppository.[9]

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.[32]

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.[33][10]

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.[9][10]

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.[34]

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.[33][10][35] Diazepam is also metabolised to a benzophenone compound.[36]

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.[10]

Most of the drug is metabolised; very little diazepam is excreted unchanged.[9]

In humans, the protein binding of diazepam is around 98.5%.[33]

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.[37]

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 before certain medical procedures (e.g. endoscopy).[33]

Diazepam is rarely used for the long-term treatment of epilepsy because tolerance to the anticonvulsant effects of diazepam usually develops within 6 to 12 months of treatment, effectively rendering it useless for this purpose and also because of side-effects - in particular sedation.[9][38]

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

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.[42]
  • 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 executions

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.[9]

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.[27]

Trade names

Availability

File:Diazepam(Valium) DOJ.jpg

Diazepam is supplied in the following forms:

  • For oral administration:
    • Tablets - 2 mg, 5 mg, 10 mg.[27] Generic versions available.
    • Capsules, time-release - 15mg (marketed by Roche as Valrelease)[10]
    • 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)[10]
  • 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.[44][10]

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.[44][10]

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[9]
    • Suppositories - 5mg and 10mg[45][9]
    • 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[46]

Side effects

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

Rare paradoxical side effects can include: nervousness, irritability, insomnia, muscle cramps, and in extreme cases, rage, and violence.[48][49][50] 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.[51]

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.[27]

During the course of therapy, tolerance to the sedative effects usually develops, but not to the anxiolytic and myorelaxant effects.[52]

Patients with severe attacks of apnea during sleep may suffer respiratory depression (hypoventilation) leading to respiratory arrest and death.

Organic changes such as leukopenia[53] 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 alertness performance combined with increased feelings of sleepiness.[54]

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.[27]

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.[9]

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.[9]

Contraindications

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

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.[56]
    • Under 6 months of age - Safety and effectiveness have not been established; diazepam should not be given to individuals in this age group.[27][56]
  • 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.[27][56][63]

Diazepam may also be dangerous in geriatric patients owing to a significant increased risk of falls.[64]

  • I.V. or I.M. injections in hypotensive individuals or those in shock should be administered carefully and vital signs should be monitored.[63]
  • 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.[65]

Dependence

Diazepam as with other benzodiazepine drugs can cause physical dependence, addiction and what is known as the benzodiazepine withdrawal syndrome. Withdrawal from diazepam or other benzodiazepines often leads to withdrawal symptoms which are similar to those seen during alcohol and barbiturate withdrawal. 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.[66] 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.[67] 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.[68] Rebound anxiety, more severe than baseline anxiety, is also a common withdrawal symptom when discontinuing diazepam or other benzodiazepines.[69] Diazepam is therefore only recommended for shortterm therapy at the lowest possible dose owing to risks of severe withdrawal problems from low doses even after gradual reduction.[70] 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.[71]

In humans tolerance to the anticonvulsant effects of diazepam occurs frequently.[72]

Patients at a high risk for abuse, dependence, tolerance, or addiction

Diazepam can lead to physiological tolerance, and psychological and/or physical dependence.[73] At a particularly high risk for diazepam misuse, abuse, or dependence are:

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.[27][74] The American Society of Addiction Medicine has policy indicating that patients with addictive disease should not be prescribed benzodiazepines such as diazepam.

Patients suspected of being physiologically addicted to benzodiazepine drugs should be very gradually tapered off the drug. Although rare withdrawals can be life threatening particularly when excessive doses have been taken for extended periods of time. Equal prudence should be used whether addiction has occurred in therapeutic or recreational contexts.

A large scale nation wide USA government study conducted by SAMHSA found that benzodiazepines in the USA are the most frequently abused pharmaceutical with 35% of drug related visits to the Emergency Department involved benzodiazepines. Benzodiazepines are more commonly abused than opiate pharmaceuticals which accounted for 32% of visits to the emergency department. No other pharmaceutical is more commonly abused than benzodiazepines. Males abuse benzodiazepines as commonly as women. Of drugs used in attempted suicide benzodiazepines are the most commonly used pharmaceutical drug with 26% of attempted suicides involving benzodiazepines. The most commonly abused benzodiazepine is however, alprazolam. Clonazepam is the 2nd most abused benzodiazepine. Lorazepam is the third most commonly abused benzodiazepine and diazepam the 4th most commonly abused benzodiazepine in the USA. Alprazolam is also commonly abused in combination with alcohol.[76]

Pregnancy

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.[77]

Overdose

An individual who has consumed too much diazepam will display one or more of the following symptoms:[27][78]

  • Drowsiness
  • 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.[9][5][27][78]

The oral LD50 (lethal dose in 50% of the population) of diazepam is 720 mg/kg in mice and 1240 mg/kg in rats.[27] 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.[79]

Overdoses of diazepam with alcohol, opiates and/or other depressants may be fatal.[5][80]

Recreational and illicit use

Diazepam is a drug of potential dependence and addiction. Between 50 and 64% of rats will self administer diazepam.[81] 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.[82] Diazepam is often found as an adulterant in heroin.[83] 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.[84]

Benzodiazepines, including diazepam, nitrazepam and flunitrazepam account for the largest volume of forged drug prescriptions in Sweden, a total of 52% of drug forgeries being for benzodiazepines.[85]

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.[86] 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.[87]

Legal status

Internationally, diazepam is a Schedule IV drug under the Convention on Psychotropic Substances.[88] In the UK, it is classified as a Class C drug.

Toxicity

Laboratory 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.[89]

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. ↑ 1.0 1.1 "Diazepam". PubChem. National Institute of Health: National Library of Medicine. 2006. Retrieved 2006-03-11.
  2. ↑ "Diazepam". Medical Subject Headings (MeSH). National Library of Medicine. 2006. Retrieved 2006-03-10.
  3. ↑ "WHO Model List of Essential Medicines" (PDF). World Health Organization. March 2005. Retrieved 2006-03-12.
  4. ↑ 4.0 4.1 Sample, Ian (Monday October 3, 2005). "Leo Sternbach's Obituary". The Guardian (Guardian Unlimited). Retrieved 2006-03-10. Check date values in: |date= (help)
  5. ↑ 5.0 5.1 5.2 Barondes, Samuel H. (2003). Better Than Prozac. New York: Oxford University Press. pp. 47–59. ISBN 0-19-515130-5.
  6. ↑ Mant A (1993). "Benzodiazepine utilisation in Australia: report from a new pharmacoepidemiological database". Aust J Public Health. 17 (4): 345–9. PMID 7911332. Unknown parameter |coauthors= ignored (help); Unknown parameter |month= ignored (help)
  7. ↑ 7.0 7.1 7.2 7.3 "Diazepam: indications". Rxlist.com. RxList Inc. January 24, 2005. Retrieved 2006-03-11.
  8. ↑ Wildmann J, Vetter W, Ranalder UB, Schmidt K, Maurer R, Mohler H (1988). "Occurrence of pharmacologically active benzodiazepines in trace amounts in wheat and potato". Biochem Pharmacol. 37 (19): 3549–59. doi:10.1016/0006-2952(88)90384-X. PMID 3178869. |access-date= requires |url= (help)
  9. ↑ 9.00 9.01 9.02 9.03 9.04 9.05 9.06 9.07 9.08 9.09 9.10 9.11 9.12 9.13 9.14 9.15 9.16 Pere Munne/M. Ruse, Ed. (1990/1998 Ed.). "Diazepam". Inchem.org. Inchem.org. Retrieved 2006-03-11. Check date values in: |year= (help)
  10. ↑ 10.00 10.01 10.02 10.03 10.04 10.05 10.06 10.07 10.08 10.09 10.10 Mikota, Susan K. and Plumb, Donald C. (2005). "Diazepam". The Elephant Formulary. Elephant Care International.
  11. ↑ Braestrup C (1978). "Pharmacological characterization of benzodiazepine receptors in the brain". Eur J Pharmacol. 48 (3): 263–70. doi:10.1016/0014-2999(78)90085-7. PMID 639854. Unknown parameter |day= ignored (help); Unknown parameter |coauthors= ignored (help); Unknown parameter |month= ignored (help)
  12. ↑ Chweh AY (25). "Effect of GABA agonists on the neurotoxicity and anticonvulsant activity of benzodiazepines". Life Sci. 36 (8): 737–44. doi:10.1016/0024-3205(85)90193-6. PMID 2983169. Unknown parameter |coauthors= ignored (help); Unknown parameter |month= ignored (help); Check date values in: |date=, |year= / |date= mismatch (help)
  13. ↑ Earley JV (1979). "Quinazolines and 1,4-benzodiazepines. LXXXIX: Haptens useful in benzodiazepine immunoassay development". J Pharm Sci. 68 (7): 845–50. doi:10.1002/jps.2600680715. PMID 458601. Unknown parameter |coauthors= ignored (help); Unknown parameter |month= ignored (help)
  14. ↑ Battistin L (1984). "Effects of some anticonvulsant drugs on brain GABA level and GAD and GABA-T activities". Neurochem Res. 9 (2): 225–31. doi:10.1007/BF00964170. PMID 6429560. Unknown parameter |coauthors= ignored (help); Unknown parameter |month= ignored (help)
  15. ↑ Cantor EH (1984). "Interaction of calcium channel blockers with non-neuronal benzodiazepine binding sites". Proc Natl Acad Sci U S A (PDF). 81 (5): 1549–52. doi:10.1073/pnas.81.5.1549. PMID 6324202. Unknown parameter |coauthors= ignored (help); Unknown parameter |month= ignored (help)
  16. ↑ Taft WC (1984). "Micromolar-affinity benzodiazepine receptors regulate voltage-sensitive calcium channels in nerve terminal preparations" (PDF). Proc Natl Acad Sci U S A (PDF). 81 (10): 3118–22. doi:10.1073/pnas.81.10.3118. PMID 6328498. Unknown parameter |coauthors= ignored (help); Unknown parameter |month= ignored (help)
  17. ↑ Usami N (2002). "Substrate specificity of human 3(20)alpha-hydroxysteroid dehydrogenase for neurosteroids and its inhibition by benzodiazepines" (pdf). Biol Pharm Bull. 25 (4): 441–5. doi:10.1248/bpb.25.441. PMID 11995921. Unknown parameter |coauthors= ignored (help); Unknown parameter |month= ignored (help)
  18. ↑ Miller JA (1985). "Effects of anticonvulsants in vivo on high affinity choline uptake in vitro in mouse hippocampal synaptosomes" (PDF). Br J Pharmacol. 84 (1): 19–25. PMID 3978310. Unknown parameter |coauthors= ignored (help); Unknown parameter |month= ignored (help)
  19. ↑ Gallager DW (1981). "[3H]Diazepam binding in mammalian central nervous system: a pharmacological characterization". J Neurosci (PDF). 1 (2): 218–25. PMID 6267221. Unknown parameter |coauthors= ignored (help); Unknown parameter |month= ignored (help)
  20. ↑ Wang JK, Morgan JI, Spector S (1984). "Benzodiazepines that bind at peripheral sites inhibit cell proliferation" (PDF). Proc Natl Acad Sci U S A. 81 (3): 753–6. doi:10.1073/pnas.81.3.753. PMID 6322168. Unknown parameter |month= ignored (help)
  21. ↑ Matthew E (1981). "Benzodiazepines have high-affinity binding sites and induce melanogenesis in B16/C3 melanoma cells". Proc Natl Acad Sci U S A. 78 (6): 3935–9. doi:10.1073/pnas.78.6.3935. PMID 6267610. Unknown parameter |coauthors= ignored (help); Unknown parameter |month= ignored (help)
  22. ↑ Oishi R (27). "Diazepam-induced decrease in histamine turnover in mouse brain". Eur J Pharmacol. 124 (3): 337–42. doi:10.1016/0014-2999(86)90236-0. PMID 3089825. Unknown parameter |coauthors= ignored (help); Unknown parameter |month= ignored (help); Check date values in: |date=, |year= / |date= mismatch (help)
  23. ↑ Grandison L (1982). "Suppression of prolactin secretion by benzodiazepines in vivo". Neuroendocrinology. 34 (5): 369–73. doi:10.1159/000123330. PMID 6979001.
  24. ↑ Holmes JH (1978). "Effect of benzodiazepine derivatives on human blood cholinesterase in vitro". Res Commun Chem Pathol Pharmacol. 21 (2): 367–70. PMID 29327. Unknown parameter |coauthors= ignored (help); Unknown parameter |month= ignored (help)
  25. ↑ 25.0 25.1 25.2 Barondes, Samuel H. (1999). Molecules and Mental Illness. New York: Scientific American Library. pp. 190–194. ISBN 0-7167-6033-9. Unknown parameter |month= ignored (help)
  26. ↑ Sieghart, W. (1994). "Pharmacology of benzodiazepine receptors: an update". Journal of Psychiatry and Neuroscience. 19 (1): 24–29. PMID 8148363. Retrieved 2006-03-10. Unknown parameter |month= ignored (help)
  27. ↑ 27.00 27.01 27.02 27.03 27.04 27.05 27.06 27.07 27.08 27.09 27.10 27.11 27.12 Thomson Healthcare (Micromedex) (March 2000). "Diazepam". Prescription Drug Information. Drugs.com. Retrieved 2006-03-11.
  28. ↑ Varotto M (1981). "[Pharmacological influences on the brain level and transport of GABA. I) Effect of various antipileptic drugs on brain levels of GABA]". Boll Soc Ital Biol Sper. 57 (8): 904–8. PMID 7272065. Unknown parameter |coauthors= ignored (help); Unknown parameter |month= ignored (help)
  29. ↑ Zakusov VV (1977). "Further evidence for GABA-ergic mechanisms in the action of benzodiazepines". 229 (2): 313–26. PMID 23084. Text " Archives internationales de pharmacodynamie et de thérapie. " ignored (help); Unknown parameter |coauthors= ignored (help); Unknown parameter |month= ignored (help)
  30. ↑ McLean MJ (1988). "Benzodiazepines, but not beta carbolines, limit high frequency repetitive firing of action potentials of spinal cord neurons in cell culture". J Pharmacol Exp Ther. 244 (2): 789–95. PMID 2450203. Unknown parameter |coauthors= ignored (help); Unknown parameter |month= ignored (help)
  31. ↑ Date SK (1984). "Investigation of the muscle relaxant activity of nitrazepam". Arch Int Pharmacodyn Ther. 272 (1): 129–39. PMID 6517646. Unknown parameter |coauthors= ignored (help); Unknown parameter |month= ignored (help)
  32. ↑ 32.0 32.1 Langsam, Yedidyah. "DIAZEPAM (VALIUM AND OTHERS)". Brooklyn College (Eilat.sci.Brooklyn.CUNY.edu). Retrieved 2006-03-23.
  33. ↑ 33.0 33.1 33.2 33.3 33.4 33.5 33.6 33.7 "Drug Bank - Diazepam".
  34. ↑ Olive G (1977). "Pharmacologic bases of use of benzodiazepines in peréinatal medicine". Arch Fr Pediatr. 34(1): 74–89. PMID 851373. Unknown parameter |coauthors= ignored (help); Unknown parameter |month= ignored (help)
  35. ↑ Oelschläger H. (4). "[Chemical and pharmacologic aspects of benzodiazepines]". Schweiz Rundsch Med Prax. 78 (27–28): 766–72. PMID 2570451. Unknown parameter |month= ignored (help); Check date values in: |date=, |year= / |date= mismatch (help)
  36. ↑ Vu Duc T (1985). "[Validation of a method for detecting benzodiazepines in the urine by acid extraction of their benzophenones and thin layer chromatography]". Ann Biol Clin (Paris). 43 (3): 261–5. PMID 2862815. Unknown parameter |coauthor= ignored (help)
  37. ↑ Vozeh S. (21). "[Pharmacokinetic of benzodiazepines in old age]". Schweiz Med Wochenschr. 111 (47): 1789–93. PMID 6118950. Unknown parameter |month= ignored (help); Check date values in: |date=, |year= / |date= mismatch (help)
  38. ↑ Isojärvi, JI (1998). "Benzodiazepines in the treatment of epilepsy in people with intellectual disability". J Intellect Disabil Res. 42 (1): 80–92. PMID 10030438. Unknown parameter |coauthors= ignored (help); Unknown parameter |month= ignored (help)
  39. ↑ Okoromah, C. N. (2004). "Diazepam for treating tetanus". Cochrane database of systematic reviews (Online) (1). PMID 14974046. Unknown parameter |coauthors= ignored (help)
  40. ↑ Hyperbaric Medicine Practice, Second Edition. Best Publishing Company. 1999. ISBN 0-941332-78-0. Unknown parameter |coauthors= ignored (help); |first1= missing |last1= in Authors list (help)
  41. ↑ Neurological Encyclopedia. http://www.answers.com/diazepam
  42. ↑ Hines, Ron DVM PhD (January 14, 2006). "Epilepsy In Your Dog Or Cat". 2nd Chance Sanctuary Pet Health Center. Unknown parameter |accessyear= ignored (|access-date= suggested) (help); Unknown parameter |accessmonthday= ignored (help)
  43. ↑ San Quentin State Prison Operational Procedure 0-770, Execution By Lethal Injection (pp. 43 & 92). http://www.cdcr.ca.gov/News/docs/RevisedProtocol.pdf
  44. ↑ 44.0 44.1 "Diazepam: description". Rxlist.com. RxList Inc. January 24, 2005. Retrieved 2006-03-10.
  45. ↑ Kaewnopparat, N., Kaewnopparat, S., Rojanarat, W., Ingkatawornwong, S. (2004). "Enhanced Release of Diazepam From Hollow-Type Suppositorie". International Journal of Pharmaceutical Compounding. Retrieved 2006-03-10. Unknown parameter |month= ignored (help)
  46. ↑ Pharmaceutical Patents. http://www.pharmcast.com/Patents100/Yr2004/Oct2004/101904/6805853_Diazepam101904.htm
  47. ↑ Jones DM (1979). "Drugs and human memory: effects of low doses of nitrazepam and hyoscine on retention". Br J Clin Pharmacol. 7 (5): 479–83. PMID 475944. Unknown parameter |coauthors= ignored (help); Unknown parameter |month= ignored (help)
  48. ↑ Marrosu, F. (1987). "Paradoxical reactions elicited by diazepam in children with classic autism". Functional Neurology. 2 (3): 355–361. PMID 2826308. Unknown parameter |month= ignored (help); Unknown parameter |coauthors= ignored (help); |access-date= requires |url= (help)
  49. ↑ "Diazepam: Side Effects". RxList.com. Unknown parameter |accessyear= ignored (|access-date= suggested) (help); Unknown parameter |accessmonthday= ignored (help)
  50. ↑ Michel, L. (2003). "Benzodiazépines et passage à l'acte criminel / Benzodiazepines and forensic aspects". L'Encéphale. 29 (6): 479–85. PMID 15029082. Unknown parameter |coauthors= ignored (help); Unknown parameter |month= ignored (help)
  51. ↑ Nabeshima T (1990). "Effects of benzodiazepines on passive avoidance response and latent learning in mice: relationship to benzodiazepine receptors and the cholinergic neuronal system". J Pharmacol Exp Ther. 255 (2): 789–94. PMID 2173758. Unknown parameter |coauthors= ignored (help); Unknown parameter |month= ignored (help)
  52. ↑ Hriscu, A. (2002). "[An experimental study of tolerance to benzodiazepines]". Revista Medico-Chirurgicală̆ a Societă̆ţ̜ii de Medici ş̧i Naturaliş̧ti din Iaş̧i. 106 (4): 806–811. PMID 14974234. Unknown parameter |coauthors= ignored (help); Unknown parameter |month= ignored (help)
  53. ↑ Haerten, K. (September 19, 1975). "[Leukopenia following benzodiazepine derivatives]". Die Medizinische Welt. 26 (38): 1712–1714. PMID 1186464. Unknown parameter |coauthors= ignored (help); Check date values in: |date= (help)
  54. ↑ Kozená L (1995). "Vigilance impairment after a single dose of benzodiazepines". Psychopharmacology (Berl). 119 (1): 39–45. PMID 7675948. Unknown parameter |coauthors= ignored (help); Unknown parameter |month= ignored (help)
  55. ↑ 55.0 55.1 55.2 55.3 55.4 Holt, Gary A. (1998). Food and Drug Interactions: A Guide for Consumers. Chicago: Precept Press. pp. 90–91. ISBN 0-944496-59-8.
  56. ↑ 56.0 56.1 56.2 56.3 56.4 56.5 56.6 "Diazepam". PDRHealth.com. PDRHealth.com. 2006. Retrieved 2006-03-10.
  57. ↑ Zácková P (1982). "Cardiovascular effects of diazepam and nitrazepam in combination with ethanol". Pharmazie. 37 (12): 853–6. PMID 7163374. Unknown parameter |coauthors= ignored (help); Unknown parameter |month= ignored (help)
  58. ↑ Back DJ (1990). "Pharmacokinetic drug interactions with oral contraceptives". Clin Pharmacokinet. 18 (6): 472–84. PMID 2191822. Unknown parameter |coauthors= ignored (help); Unknown parameter |month= ignored (help)
  59. ↑ Bendarzewska-Nawrocka B (1980). "[Relationship between blood serum luminal and diphenylhydantoin level and the results of treatment and other clinical data in drug-resistant epilepsy]". Neurol Neurochir Pol. 14 (1): 39–45. PMID 7374896. Unknown parameter |coauthors= ignored (help); Unknown parameter |month= ignored (help)
  60. ↑ Bateman, D.N. (1986). "The action of cisapride on gastric emptying and the pharmacodynamics and pharmacokinetics of oral diazepam". Eur J Clin Pharmacol. 30 (2): 205–8. doi:10.1007/BF00614304. PMID 3709647.
  61. ↑ Mattila, M. J. (1983). "Caffeine and theophylline counteract diazepam effects in man". Medical Biology. 61 (6): 337–343. PMID 6374311. Unknown parameter |coauthors= ignored (help)
  62. ↑ Possible Interactions with: Valerian, University of Maryland Medical Center, http://www.umm.edu/altmed/articles/valerian-000934.htm
  63. ↑ 63.0 63.1 "Diazepam: precautions". Rxlist.com. RxList Inc. January 24, 2005. Retrieved 2006-03-10.
  64. ↑ Shats V (1). "[Falls in the geriatric department: responsibility of the care-giver and the hospital]". Harefuah. 128 (11): 690–3. PMID 7557666. Unknown parameter |coauthors= ignored (help); Unknown parameter |month= ignored (help); Check date values in: |date=, |year= / |date= mismatch (help)
  65. ↑ Kanto JH. (1982). "Use of benzodiazepines during pregnancy, labour and lactation, with particular reference to pharmacokinetic considerations". Drugs. 23 (5): 354–80. doi:10.2165/00003495-198223050-00002. PMID 6124415. Unknown parameter |month= ignored (help)
  66. ↑ MacKinnon GL (1982). "Benzodiazepine withdrawal syndrome: a literature review and evaluation". The American journal of drug and alcohol abuse. 9 (1): 19–33. doi:10.3109/00952998209002608. PMID 6133446. Unknown parameter |coauthors= ignored (help)
  67. ↑ Bernik MA (1998). "Stressful reactions and panic attacks induced by flumazenil in chronic benzodiazepine users". Journal of psychopharmacology (Oxford, England). 12 (2): 146–50. PMID 9694026. Unknown parameter |coauthors= ignored (help)
  68. ↑ Mintzer MZ (1999). "A controlled study of flumazenil-precipitated withdrawal in chronic low-dose benzodiazepine users". 147 (2): 200–9. PMID 10591888. Unknown parameter |coauthors= ignored (help); Unknown parameter |month= ignored (help)
  69. ↑ Chouinard G (1983). "New concepts in benzodiazepine therapy: rebound anxiety and new indications for the more potent benzodiazepines". Prog Neuropsychopharmacol Biol Psychiatry. 7 (4–6): 669–73. doi:10.1016/0278-5846(83)90043-X. PMID 6141609. Unknown parameter |coauthors= ignored (help)
  70. ↑ Lader M. (1987). "Long-term anxiolytic therapy: the issue of drug withdrawal". The Journal of clinical psychiatry. 48: 12–6. PMID 2891684. Unknown parameter |month= ignored (help)
  71. ↑ Murphy SM, Owen R, Tyrer P. (1989). "Comparative assessment of efficacy and withdrawal symptoms after 6 and 12 weeks' treatment with diazepam or buspirone". The British Journal of Psychiatry: the journal of mental science. 154: 529–34. PMID 2686797.
  72. ↑ Loiseau P (1983). "[Benzodiazepines in the treatment of epilepsy]". Encephale. 9 (4 Suppl 2): 287B–292B. PMID 6373234.
  73. ↑ 73.0 73.1 "Treating Anxiety -- Avoiding Dependence on Xanax, Klonopin, Valium, and Other Antianxiety Drugs". johnshopkinshealthalerts.com. Johnshopkinshealthalerts.com. 2005. Retrieved 2007-12-23.
  74. ↑ 74.0 74.1 "Diazepam: abuse and dependence". Rxlist.com. RxList Inc. January 24, 2005. Retrieved 2006-03-10.
  75. ↑ Vorma, Helena (2005). "Predictors of Benzodiazepine Discontinuation in Subjects Manifesting Complicated Dependence" (PDF). Substance Use & Misuse. 40 (4): 499–510. PMID 15830732. Retrieved 2006-09-25. Unknown parameter |coauthors= ignored (help)
  76. ↑ United States Government (2004). "Drug Abuse Warning Network, 2004: National Estimates of Drug-Related Emergency Department Visits". Substance Abuse and Mental Health Services Administration. Unknown parameter |accessdaymonth= ignored (help); Unknown parameter |accessyear= ignored (|access-date= suggested) (help); Unknown parameter |coauthors= ignored (help)
  77. ↑ McElhatton PR. (1994). "The effects of benzodiazepine use during pregnancy and lactation". Reprod Toxicol. 8 (6): 461–75. doi:10.1016/0890-6238(94)90029-9. PMID 7881198. Unknown parameter |month= ignored (help)
  78. ↑ 78.0 78.1 "Diazepam: overdose". Rxlist.com. RxList Inc. January 24, 2005. Retrieved 2006-03-10.
  79. ↑ Greenblatt, D. J. (October 20, 1978). "Rapid recovery from massive diazepam overdose". Journal of the American Medical Association. 240 (17): 1872–4. PMID 357765. Unknown parameter |coauthors= ignored (help); Check date values in: |date= (help)
  80. ↑ Lai, SH (2006). "A survey of buprenorphine related deaths in Singapore". Forensic Sci Int. 162(1–3): 80–6. PMID 16879940. Unknown parameter |coauthors= ignored (help); Unknown parameter |month= ignored (help)
  81. ↑ Yoshimura K (1984). "[Pharmacological studies on drug dependence. (III): Intravenous self-administration of some CNS-affecting drugs and a new sleep-inducer, 1H-1, 2, 4-triazolyl benzophenone derivative (450191-S), in rats]". Nippon Yakurigaku Zasshi. 83 (1): 39–67. PMID 6538866. Unknown parameter |coauthors= ignored (help); Unknown parameter |month= ignored (help)
  82. ↑ Thiébot MH (1985). "Benzodiazepines reduce the tolerance to reward delay in rats". Psychopharmacology (Berl). 86 (1–2): 147–52. doi:10.1007/BF00431700. PMID 2862657. Unknown parameter |coauthors= ignored (help)
  83. ↑ International Narcotics Control Board (1996). "CHAPTER II. OPERATION OF THE INTERNATIONAL DRUG CONTROL SYSTEM". REPORT OF THE INTERNATIONAL NARCOTICS CONTROL BOARD FOR 1996. Unknown parameter |accessyear= ignored (|access-date= suggested) (help); Unknown parameter |accessmonthday= ignored (help)
  84. ↑ Overclocker. "Methamphetamine and Benzodiazepines: Methamphetamine & Benzodiazepines". Erowid Experience Vaults. Unknown parameter |accessyear= ignored (|access-date= suggested) (help); Unknown parameter |accessmonthday= ignored (help)
  85. ↑ Bergman U (1989). "Use of prescription forgeries in a drug abuse surveillance network". Eur J Clin Pharmacol. 36 (6): 621–3. doi:10.1007/BF00637747. PMID 2776820. Unknown parameter |coauthors= ignored (help)
  86. ↑ Jones AW (2007). "Concentrations of scheduled prescription drugs in blood of impaired drivers: considerations for interpreting the results". Ther Drug Monit. 29 (2): 248–60. doi:10.1097/FTD.0b013e31803d3c04. PMID 17417081. Unknown parameter |coauthors= ignored (help); Unknown parameter |month= ignored (help)
  87. ↑ Cosbey SH. (1986). "Drugs and the impaired driver in Northern Ireland: an analytical survey". Forensic Sci Int. 32 (4): 245–58. doi:10.1016/0379-0738(86)90201-X. PMID 3804143. Unknown parameter |month= ignored (help)
  88. ↑ Kar RN (1983). "Induction of sperm head abnormalities in mice by three tranquilizers". Cytobios. 36 (141): 45–51. PMID 6132780. Unknown parameter |coauthors= ignored (help)

External links

Template:Benzodiazepines Template:Anticonvulsants Template:Anxiolytics

Template:Link FA bg:Диазепам cs:Diazepam da:Diazepam de:Diazepam gl:Diazepam it:Diazepam he:דיאזפאם hu:Diazepám ml:ഡയസെപാം nl:Diazepam no:Diazepam simple:Diazepam fi:Diatsepaami sv:Diazepam


Template:WikiDoc Sources

Retrieved from "https://www.wikidoc.org/index.php?title=Diazepam_detailed_information&oldid=672753"