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Diazepam

Diazepam is a member of a group of medications that belong to a group known as benzodiazepines. As such it contains sedative, hypnotic, anxiolytic, amnesic, and anticonvulsant properties. It was designed as a "simpler" (and more potent) version of its predecessor chlordiazepoxide. It is commonly prescribed for anxiety disorders (GAD - generalized anxiety disorder, panic disorder) and also used frequently in the treatment of alcoholism. Its correct and medically supervised use facilitates a safe withdrawal from alcohol as it is a GABAergic drug; more specifically a GABAa full agonist.

Contents




[top]Introduction to Diazepam



Diazepam is known by the medical profession (although this term is seldom used when addressing a patient) as a minor tranquilizer. This belies the drugs true strength as it is indeed a powerful sedative. In small doses it will relieve anxiety. When taken in sufficient doses, like all benzodiazepines, it will induce sedation. It is often used to treat alcoholism. Initially, once alcohol consumption has ceased, a high dose is usually administered and then every week or month (depending on the severity of the physical addiction) the dose is titrated downwards in a very gradual manner. (e.g 2mgs at a time)


[top]Using Diazepam

Diazepam is known by the medical profession (although this term is seldom used when addressing a patient) as a minor tranquilizer. This belies the drugs true strength as it is indeed a powerful sedative. It small doses it will relieve anxiety.

[top]Ways of Administration

Diazepam comes in tablet, suppository gel and injectable form - it is commonly prescribed in tablet form which comes in three strengths - namely 2mg , 5mg and 10mg doses.
The 2mg tablets are "usually" in the UK - pure white.
The 5mg (details consistent with above) - come in yellow tablets.
The 10mg (details consistent with above) - come in blue tablets.

[top]Effects of Diazepam

Diazepam relieves tension, allays, calms ones state of mind, relaxes muscles, and encourages sleep. Diazepam has a range of uses. Besides being commonly used in the treatment of anxiety and anxiety related insomnia, they are given in the treatment of of alcohol withdrawal and epileptic treatments for epileptic seizures.

Given intravenously, diazepam can be even more habit forming than when taken orally, especially if intravenous administration occurs over a protracted period of time.

Since diazepam use will cause tolerance rapidly (with in 4 weeks at some doses) and because psychological and physical addiction can occur within a matter of 1-3 months (depending on dosage), course of treatment is limited to two weeks if possible.

[top]Combinations with Diazepam

Depending on the reason that diazepam is being prescribed or illicitly procured, there are a variety of combinations available.

Epilepsy patients are sometimes prescribed diazepam in conjunction with an anticonvulsant such as topiramate or pregabalin (although diazepam and pregabalin treatment on its own is not a complete or suitable treatment for epilepsy).[REF]


[top]Pharmacology of Diazepam

Diazepam has an oral bioavailablity of >90%. Average time to achieve peak plasma concentrations is 15 min - 2.5 hours, with an average of 1 - 1.5 hours. Taking diazepam orally with food that has a moderate level of fat will delay absorption and reduce the amount absorbed. [REF] Diazepam has a long half life - between 20 to 100 hours. In this respect it has the longest half life of all benzodiazepines, save very few like flurazepam (which is very rarely, if ever, prescribed). Diazepam is a classical benzodiazepine (along with chlordiazepoxide, lorazepam and temazepam) because its attributes are multi-faceted and it produces all results that benzodiazepines are capable of. [REF]

Diazepam does not actually increase GABA levels in the brain. Actually, it potentiates these levels by binding to a specific benzodiazepine receptor site, located on the post synaptic receptor plate in a GABAergic nerve terminal. This increases the CI conductance and thus causes the GABA transmission to be fortified, leading to the major inhibition of other neurotransmitters. This is how diazepam creates sedation in the patient/user. A recent study has suggested that the effects of diazepam observed at high versus low concentrations are caused by binding to at least two different benzodiazepine binding sites on GABAa receptors, the classical high-affinity binding site being responsible for effects such as amnesia, anxiolysis, and sedation, while a different nonclassical binding site is responsible for the hypnotic and immobilization effects of high doses of diazepam. [1]


[top]Chemistry of Diazepam

Systematic(IUPAC) name:7-chloro-1,3-dihydro-1-methyl-5-phenyl-1,4-benzodiazepin-2(3H)-one
Synonyms:Methyldiazepinone,Mandrozep
Molecular Formula:C16H13ClN2O
Molar mass:284.7 g/mol.
CAS Registry Number:439-14-5
Melting Point:131.5 to 134.5 ℃
Boiling Point:497.38 °C at 760 mmHg
Flash Point:254.607 °C
Solubility:Practically insoluble in water; freely soluble in chloroform; soluble in alcohol (50 mg/L)
MSDS Downloadable .pdf
diazepam-hospira.pdf


[top]The Dangers of Diazepam


As with all benzodiazepines, there are many dangers when using diazepam.
Diazepam is commonly abused for a variety of reasons as it is such a versatile and "useful" drug.
Benzodiazepines should be prescribed with special caution to children and the elderly (due to a marked increase in sedation). [REF]

[top]Physical Health Risks

[top]Compromised Alertness

People who are either driving or operating heavy machinery should take great care when taking Diazepam. One is advised to take time first to learn how they react to the drug before engaging in dangerous activities. Diazepam impairs ones attention and alertness.[2]

[top]Diazepam, Pregnancy, Labour and Lactation

Maternal diazepam use presents some risk to the fetus which must be weighed against therapeutic value for the mother. Diazepam in therapeutic doses during the second and third trimesters of pregnancy appears safe, but there is conflicting evidence regarding diazepam during the first trimester, with some studies indicating risk of birth defects. Administering diazepam during labour or very late in the third trimester risks floppy infant syndrome, infant withdrawal, mild sedation, reluctance to suck, and cyanosis. Given the possibility of diazepam and active metabolites becoming present in breast milk, maternal diazepam use during lactation can cause infant weight loss, sedation and lethargy; the lowest possible doses are thus recommended.[3]

[top]Drug Interactions with CYP-3A4 inhibitors and antidepressants

Caution should also be taken when taking Diazepam with CYP-3A4 inhibitors such as fluoxetine (Prozac) and with erythromycin and cimetidine (Tagamet). These will dramatically increase the sedative effects of the drug as diazepam uses CYP-3A4 to be metabolized. [REF]

[top]Overdose

One of the most serious dangers of all is overdose. In very serious overdoses with severe respiratory depression and or heart rhythm abnormalities an antidote, flumazenil (Anexate), can be administered; because of diazepam's extremely long half-life this needs to be re-administered several times.[4]

The severity of diazepam overdose is dependent on how many tablets/milligrams have been ingested. When diazepam is taken in a combined overdose together with opiates, tricyclic anti-depressants, or alcohol, severe toxicity or even death may occur.[5][6] There have been cases reported, however, in which overdoses as high as 750 mg of diazepam resulted in sedation followed by full recovery and discharge from hospital within 24 hours. The toxicity of a diazepam overdose thus appears to be more a function of having coingested other interacting drugs than the absolute amount of diazepam taken or blood levels of it or its active metabolites.[7]

[top]Reported Deaths

Benzodiazapines very rarely cause deaths when not taken with other drugs, medications or substances that either cause or potentiate CNS depression.[8] A study comparing fatalities due to benzodiazapines and zopiclone (a nonbenzodiazapine hypnosedative) found that 39 of the 200 poisoning fatalities in NZ for 2001 involved hypnosedatives; of these 10 involved diazepam, but in none of these was diazepam the sole agent of death. The study found only 5.2 deaths per million prescriptions for diazepam (compared to 38.1 for alprazolam/xanax).[9]

[top]Mental Health Risk 1

Sometimes people who take diazepam experience paradoxical reactions such as: twitches and tremor, aggression, hostile rage, or hyperactivity. If this happens then the prescribing doctor should be contacted immediately and the medication should be gradually reduced (under medical supervision). [REF]

[top]Mental Health Risk 2

Diazepam rarely induces suicidal ideation. If this happens one should stop taking this medicine and contact ones doctor immediately. [REF]


[top]Producing Diazepam

Many pathways exist for diazepam, those are represented below (adapted from ref [1]). These pathways are representative for the synthesis of many benzodiazepines, including flunitrazepam, bromazepam, clonazepam, nitrazepam, phenazepam.


[top]Forms of Diazepam

Diazepam comes in tablet, liquid suppository, and injection forms.

The most common administration is orally, via tablets.


[top]Legal Status of Diazepam

[top]United Nations

[top]USA

In U.S.A : CSA Schedule IV, Rx only

[top]EU

[top]U.K.

U.K.: Class C drug. Not controlled, but prescription only.

[top]Ireland

[top]Netherlands

[top]Other Countries



[top]History of Diazepam

Diazepam was the second benzodiazepine to be invented after chlordiazepoxide. It was released in 1963. The medicine became extremely popular at first. In time, criticism began to grow and their truly addictive nature was discovered.[10]

The benefits of diazepam were noticed and noted too however, such as their comparative safety when compared with barbiturates. These can kill in overdose due to their effect on the GABA nerve terminals. Since barbiturates cause CI conductance to be permanently increased in GABA terminals, even with the absence of GABA transmission and release itself, diazepam is far safer as it only works in conjunction with naturally produced GABA. It does not have any effect on GABA levels on it's own.


[top]More Diazepam Sections

[top]Popularity of Diazepam over time



[top]The Latest Diazepam Threads

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[top]References

  1. ^ Berthold Drexler, Stefan Zinser, Harald Hentschke, and Bernd Antkowiak. Diazepam Decreases Action Potential Firing of Neocortical Neurons via Two Distinct Mechanisms. Anesthesia and analgesia, 2010, Vol.111(6), pp.1394-9
  2. ^ Fiona Charlson, Louisa Degenhardt, Jennifer McLaren, Wayne Hall, and Michael Lynskey A systematic review of research examining benzodiazepine-related mortality. Pharmacoepidemiology and Drug Safety 2009; 18: 93–103.
  3. ^ Mohammad Masud Iqbal, Tanveer Sobhan, Thad Ryals. Effects of Commonly Used Benzodiazepines on the Fetus, the Neonate, and the Nursing Infant. Psychiatric Services. January 2002 Vol. 53 No. 1
  4. ^ Bateman, D. Nicholas. Benzodiazepines (2012) Medicine, 2012, Vol.40(3), pp.111-111.
  5. ^ Bateman, D. Nicholas. Benzodiazepines (2012) Medicine, 2012, Vol.40(3), pp.111-111.
  6. ^ http://edinburghnews.scotsman.com/ne...tal.6816091.jp
  7. ^ Marcia Divoll, David J. Greenblatt, Yves Lacasse, and Richard I. Shader. "Benzodiazepine overdosage: Plasma concentrations and clinical outcome". Journal of the American Medical Association 240 (17): 1872–4.
  8. ^ Bateman, D. Nicholas. Benzodiazepines (2012) Medicine, 2012, Vol.40(3), pp.111-111.
  9. ^ David M. Reith, John Fountain, Rebecca McDowell, and Murray Tilyard. Comparison of the Fatal Toxicity Index of Zopiclone with Benzodiazepines. Journal of Toxicology Clinical Toxicology. Vol. 41, No. 7, pp. 975–980, 2003
  10. ^ http://edinburghnews.scotsman.com/ne...tal.6816091.jp


Created by Nanashi, 08-08-2011 at 02:12
Last edited by John_bob, 16-03-2014 at 13:27
Last comment by John_bob on 16-03-2014 at 13:38
9 Comments, 48,573 Views

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