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 agitation related to alcohol withdrawal. Initially, once alcohol consumption has ceased, a high dose is administered and then every week or month (depending on the severity of the physical addiction) the dose is tapered downwards in a very gradual manner. (e.g 2mgs at a time)

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 diazepam is indeed a powerful sedative. In addition to treating anxiety disorders, providing short-term relief of anxiety symptoms and managing acute agitation from alcohol withdrawal, diazepam is used preoperatively and during endoscopic procedures to sedate, produce anteriograde amnesia and treat anxiety. Diazepam is also used as an adjunct for pain relief in some acute musculoskeletal conditions and to help control muscle spasms from inflammation, trauma, tetanus, and those caused by disorders such as paraplegia and cerebral palsy. [1]

Ways of Administration

Diazepam is administered orally in tablet and liquid form, rectally as a gel, and injected intramuscularly and IV. Diazepam is commonly prescribed in tablet form which comes in three strengths - 2mg , 5mg, and 10mg.
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.
Diazepam rectal gel contains 5 mg/mL diazepam, propylene glycol, ethyl alcohol (10%), hydroxypropyl methylcellulose, sodium benzoate, benzyl alcohol (1.5%), benzoic acid and water. Diazepam rectal gel is clear to slightly yellow and has a pH between 6.5 -7.2.

Effects of Diazepam

Diazepam relieves tension, calms one's 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, diazepam is used to treat alcohol withdrawal and 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. This does not mean oral usage cannot be habit-forming as well, any long-term use or abuse - prescribed or not, Valium is suggested only to be used for a short time. It is not advisable to take this medication for longer than 12 weeks (3 months) without a doctor's advice.

Since diazepam use rapidly causes tolerance (within 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.[2]

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]

Pharmacology of Diazepam

Diazepam has an oral bioavailability 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 metabolized by the liver via the Cytochrome P450 enzyme system. The main active metabolite is desmethyldiazepam. Minor active metabolites include temazepam and oxazepam. 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. [3]

Diazepam does not increase GABA levels in the brain but potentiates the actions of GABA 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. [4] 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 GABA_a 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. [5]

Chemistry of Diazepam

Column 1	Column 2
Systematic(IUPAC) name:	7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one
Synonyms:	7-chloro-1,3-dihydro-1-methyl-5-phenyl-1,4-benzodiazepin-2(3H)-one, 7-chloro-1-methyl-5-phenyl-3H-1,4-benzodiazepin-2(1H)-one, methyl diazepinone, diacepin, LA-III, Ro-5-2807, Wy-3467, NSC-77518, Apaurin, Bialzepam, Calmpose, Ceregulart, Dialar, Diastat, Diazemuls, Eurosan, Faustan, Gewalcalm, Lamra, Noan, Novazam, Paceum, Paxate, Relanium, Seduxen, Servizepam, Stesolid, Unisedil, Valiquid, Valium, Vival, Methyldiazepinone, Mandrozep
Molecular Formula:	C16H13ClN2O
Molar mass:	284.74 g/mol [2]
CAS Registry Number:	439-14-5
Melting Point:	131.5-134.5 ℃
Boiling Point:	no data
Flash Point:	no data
Solubility:	Practically insoluble in water; freely soluble in chloroform; soluble in benzene, DMF, acetone, alcohol (50 mg/L)
Additionnal data:	pKa 3.4
Notes:	Aspect : colorless to light yellow crystalline compound; prisms from ethanol

[1]

MSDS Downloadable .pdf
View attachment 30862

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). [6]

Physical Health Risks

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.[7]

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 labor 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.[8]

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. [9]

Overdose

One of the most serious dangers of diazepam 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.[10] [11]

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 antidepressants, or alcohol, severe toxicity or even death may occur.[12][13] 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.[14]

Reported Deaths

Benzodiazepines very rarely cause deaths when not taken with other drugs, medications or substances that either cause or potentiate CNS depression.[15] A study comparing fatalities due to benzodiazepines and zopiclone (a nonbenzodiazepine 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.[16]

Mental Health Risks

Anterograde Amnesia

Anterograde amnesia (the inability to convert short term memories into long term memories) has been reported with benzodiazepines taken in therapeutic doses. This is a rare side-effect of diazepam, but is dose-related and elderly subjects may be at particular risk. Cases of transient global amnesia have also been reported with benzodiazepine use.

Abnormal Thinking, Suicidal Ideation and Psychotic Behaviour

Diazepam use has a (very small) risk of abnormal thinking, thoughts of suicide and psychotic behavior. These may be characterized by decreased inhibition, for example in aggression or extroversion that seem excessive, as occurs with alcohol use. A history of violence or unusual reactions to sedatives seems associated with a greater risk of these rare effects and other bizarre behavior, hallucinations, and depersonalization. Such behaviors have been reported more with high doses and chronic use of benzodiazepines but also happen during acute, maintenance or withdrawal phases of benzodiazepine treatment. These are potentially very serious, diazepam should be stopped and immediate medical assistance sought.[17][18]

Rebound Insomnia and Anxiety

Rebound insomnia and rebound anxiety can be caused when diazepam is stopped too abruptly, especially if the use has been long term and/or at higher than normal therapeutic doses. Diazepam use should be tapered gradually as symptoms such as depression, nervousness, rebound insomnia, and irritability have been reported when diazepam is suddenly stopped in patients receiving even normal therapeutic doses for short periods of time.[19]

Side Effects

The most commonly reported side effects of diazepam are drowsiness, fatigue, and ataxia. Less frequently reported adverse reactions include: confusion, depression, dysarthria, headache, hypoactivity, slurred speech, syncope, tremor, vertigo, constipation, nausea, incontinence, changes in libido, urinary retention, bradycardia, cardiovascular collapse, hypotension, blurred vision, nystagmus, skin rash, hiccups, changes in salivation, neutropenia, and jaundice. [20]

Addiction

Physical Addiction

Chronic use (even at therapeutic doses) of diazepam may lead to the development of physical dependence and discontinuation of diazepam can lead to withdrawal and rebound effects (the return of symptoms diazepam was used to treat, sometimes in amplified form). Withdrawal symptoms often follow discontinuation of diazepam, especially if the diazepam isn't tapered but stopped suddenly. Withdrawal symptoms can include tremor, abdominal and muscle cramps, vomiting, sweating, headache, muscle pain, extreme anxiety, tension, restlessness, confusion, irritability, insomnia, and dysphoria. More serious symptoms of withdrawal can occur in those who abruptly stop high doses of diazepam which have been taken for long periods of time. These withdrawal symptoms can include derealization, depersonalization, hyperacusis, numbness and tingling of the extremities, hypersensitivity to sensations like light, noise and physical contact, as well as hallucinations and epileptic seizures. [21]

Mental Addiction

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.

Forms of Diazepam

Diazepam comes in tablet, liquid suppository, and injection forms.
The most common administration is via tablets.

Legal Status of Diazepam

United Nations

USA

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

EU

U.K.

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

Ireland

Netherlands

Other Countries

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.[22]

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 its own.

More Diazepam Sections

References

1. ^Valium (Diazepam) monograph, Roche, revised 2008.
2. ^Valium (Diazepam) monograph, Roche, revised 2008.
3. ^Mandrioli R, Mercolini L, Raggi MA. Benzodiazepine Metabolism: An Analytical Perspective (2008) Curr Drug Metab. 2008 Oct;9(8):827-44.
4. ^Valium (Diazepam) monograph, Roche, revised 2008.
5. ^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
6. ^Valium (Diazepam) monograph, Roche, revised 2008.
7. ^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.
8. ^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
9. ^Valium (Diazepam) monograph, Roche, revised 2008.
10. ^Bateman, D. Nicholas. Benzodiazepines (2012) Medicine, 2012, Vol.40(3), pp.111-111.
11. ^Valium (Diazepam) monograph, Roche, revised 2008.
12. ^Bateman, D. Nicholas. Benzodiazepines (2012) Medicine, 2012, Vol.40(3), pp.111-111.
13. ^http://edinburghnews.scotsman.com/ne...tal.6816091.jp
14. ^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.
15. ^Bateman, D. Nicholas. Benzodiazepines (2012) Medicine, 2012, Vol.40(3), pp.111-111.
16. ^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
17. ^Valium (Diazepam) monograph, Roche, revised 2008.
18. ^Hooker, EA., & Danzi, DF. (1988). Acute dystonic reaction due to diazepam. J Emerg Med, 6: 491-493.
19. ^Valium (Diazepam) monograph, Roche, revised 2008.
20. ^Valium (Diazepam) monograph, Roche, revised 2008.
21. ^Valium (Diazepam) monograph, Roche, revised 2008.
22. ^http://edinburghnews.scotsman.com/news/Diazepam-deaths-shock-for-Capital.6816091.jp

[1]Merck Index, fifteenth edition (2013)
[2]Calculated from Atomic Weights of the Elements, 2007
[3] Synthesis of Essential Drugs, 1st edition, Ruben Vardanyan & Victor Hruby, Elsevier