The assignment: research a drug and describe the history, chemistry, indications, treatment effects, side effects. An emphasis on comparing the drug to other indicated drugs was also assigned.
Eliyahu N. Kassorla
Organic Chemistry I – Laboratory
Diazepam: A Literature Review of the Primitive Benzodiazepine
Diazepam is a benzodiazepine, a class of drugs that has anxiolytic, sedative, antispasmodic, and anticonvulsant properties. Benzodiazepines superseded the class of drugs called the barbiturates, as well as the carbamates, since their safety is greater and therapeutic range is wider. While there are side effects to the benzodiazepines, the risks are often weighed against their clinical efficacy in treatment and management of indicated disorders.
History and Discovery of Diazepam
The benzodiazepine era began in a laboratory at Hoffman-LaRoche in Nutley, NJ
(Lopez-Munoz, Alamo, & Garcia-Garcia, 2011, p.
The compound was first synthesized by a researcher named Leo Sternbach, who had
a research affinity for tricyclic compounds, including the heptoxdiazines her
worked on as a postdoctoral student (Lopez-Munoz, Alamo, &
Garcia-Garcia, 2011, p. 555). A new antipsychotic
agent had recently become commercialized, chlorpromazine, which also had a
tricyclic structure, led Sternbach to experiment on the effects of his old
compounds with lateral side chains attached (p. 555).
His development efforts led to the use of 4,5-benzo(hepto 1,2,6-oxdiazine) as
an investigational compound (p. 555).
The compound was screened, but showed no clinical effect (The discovery of chlordiazepoxide and the clinical
intoduction of benzodiazepines: Half a century of anxiolytic drugs, p. 556). After further
investigation, it was discovered that a different chemical compound had been
made, without the pharmacological properties desired; Sternbach synthesized new
analogs which it was though showed no biological activity (p. 556). After a year and a
half’s effort, two final compounds remained to be assayed, which were intended
to be thrown away; however, a colleague drew his attention to a “crystalized
base and its hydrochloride”, of which the “water-soluble salt” submitted for
assay (p. 556).
The new compounds had properties that were “superior to meprobamate [a
centrally acting muscle relaxant] in many trials in terms of anxiolytic effect
and as a central muscle relaxant, and also had some sedative properties similar
to chlorpromazine, and lacked any significant adverse effects (p. 556). As it turns out,
Sternbach “had used methylamine, a primary amine, by mistake, meaning that the
reaction had taken a different form (transposition reaction with ring
enlargement from the one observed after using secondary amines” (p. 556).
The compound produced, however, was not diazepam. Sternbach produced methaminodiazepoxide, renamed to chlordiazepoxide, and marketed as Librium
(Lopez-Munoz, Alamo, & Garcia-Garcia, 2011, p.
556.), (Sample, 2005). Librium is a larger
and more complex molecule than diazepam, and studies by Sternbach and others at
LaRoche found that simpler molecules had better bioactivity (Lopez-Munoz, Alamo, & Garcia-Garcia, 2011, p.
Simplifying the molecule to the fewest lateral chains yielded diazepam,
marketed as Valium (p. 557).
Structure of Diazepam
Diazepam is classified as a heterocyclic compound with two rings, the benzodiazepine and a benzene ring. The IUPAC name is 7-chloro-1-methyl-5-phenyl-3H-1,4-benzodiazepin-2-one
A benzodiazepine ring is a ring structure in which a benzene ring is fused with
a diazepine ring, which is structurally similar to benzene, but has a nitrogen
substituted for 1,4 on the diazepine ring, known as a 1,4-benzodiazipine (Sankar, 2012, p. 231). A
1,5-benzodiazipine exists, but so far, only one compound shows similar effects,
clobazam (Sankar, 2012, p. 231). Diazepam has an
oxygen double bonded to 3 of the diazepine ring at the R2 position, and
chlorine at the R2’ position along the benzene-side of the benzodiazepine-ring
at 7 (Diazepam, PubChem, 2005). Because diazepam is
the most basic of the benzodiazepine class of drugs, its structure is
prototypical of all classical and pharmacologically useful benzodiazepines,
only differing in side-chains at the R1, R2, and R2’ position. It is the
1,4-diazepine ring, along with the small size of the diazepam molecule, which
allows diazepam to cross the blood brain barrier.
Metabolism of Diazepam
After oral administration, greater than 90% is bioavailable, and blood plasma directly correlates with brain and cerebrospinal fluid concentrations
(Diazepam, PubChem, 2005). Diazepam is
metabolized into its main active metabolite desmethyldiazepam by
N-demethylation, as well as temazepam and oxazepam by hydroxylation (Valium (diazepam) tablet: [Roche Products Inc]), (Diazepam,
Diazepam’s active metabolites contributes to effect persistence for seven days,
which is clinically desirable and classifies diazepam as a long-acting
benzodiazepine (Sankar, 2012, p. 232). The metabolic
pathway that metabolizes diazepam is the cytochrome P450 family subunits 3A4
and 2C19 in order to reach desmethyldiazepam, which is again metabolized by 3A4
into temazepam; both are metabolized again to reach oxazepam (Valium (diazepam) tablet: [Roche Products Inc]), (Smith-Kielland, Skuterud, Olsen, & Morland,
2001, p. 237).
It can take 48 hours for first pass metabolism to demethylate diazepam to
desmethyldiazepam, and 100 hours to metabolize desmethyldiazepam into temazepam
and oxazepam through second pass metabolism (Valium (diazepam) tablet: [Roche Products Inc],
Diazepam and its metabolites are excreted through urine (Valium (diazepam) tablet: [Roche Products Inc]). Interactions with
34A inhibitors, such as fungicidals; bergamotten; and some antidepressants,
will decrease metabolism rate; those with hepatic insufficiency will also
experience a decreased metabolism and a longer effect (Valium (diazepam) tablet: [Roche Products Inc]).
In an investigation into metabolism between non-users and chronic users of diazepam, it was found that diazepam users more quickly and easily metabolize diazepam
(Smith-Kielland, Skuterud, Olsen, & Morland, 2001, p. 245). However, drug-users
has longer detection times, meaning that diazepam use was still detectable for
a longer time than drug users (p. 245).
Non-drug users had a much shorter detection period of detection, though a
slower conversion rate of diazepam into metabolites (pp. 243-244).
Comparison with Other Medications
The introduction of benzodiazepines co-occurred with a revolution in the field of psychology. The field of psychology had largely divided psychiatric disorders into “neuroses” and “psychoses”
(Lopez-Munoz, Alamo, & Garcia-Garcia, 2011, p. 554). Anxiety and
insomnia were considered “neuroses” (p. 554).
Treatment was limited to alcohol, toxic bromides, opiates, and barbiturates (p. 554). The introduction of
psychopharmaceuticals that were able to treat these disorders caused a shift in
psychological thinking, enabling psychologists to view psychiatric disorders as
organic brain disorders (p. 554).
Before benzodiazepines came into widespread use, barbiturates were the drugs of choice for treatment of anxiety, insomnia, and other assorted “neuroses”
(Lopez-Munoz, Alamo, & Garcia-Garcia, 2011, p. 555). However, they had
very narrow therapeutic ranges, above which could easily overdose. (p. 554). The main
barbiturates prescribed were phenobarbital and secobarbital. Other barbiturates
were in use, but these represent the two extremes – the least lipid
soluble (phenobarbital) to the most lipid soluble (secobarbital) (Secobarbital, PubChem, 2005).
Barbiturates are weak acids, and like benzodiazepines, the barbiturates are also heterocyclic compounds, being a diazine pyrimidone rather than a diazepine, with nitrogens affixex at 2,4, and oxygens double bonded at 1,3,5
(Secobarbital, PubChem). Barbiturates are
also small molecules, allowing them to easily cross the blood brain barrier (Secobarbital, PubChem). Barbiturates also
activate NMDA receptors, adding to sedative effects, and increasing toxic and
deadly overdose symptoms (Argyropoulos & Nutt, 1999, p. S410)
The carbamate series of medicines are best exemplified by the drug meprobamate, the prototypical exemplar of this drug class. Unlike barbiturates and benzodiazepines, meprobamate is a linear organic compound
Summary - CID 4064, 2005). Meprobamate has is bounded by amine
groups on each end of the linear chain; it is the amine group which exhibit the
biological activity (Meprobamate: Compound
Summary - CID 4064, 2005). Like barbiturates, meprobamate is
toxic in overdose, however it is less toxic than barbiturates (Lopez-Munoz, Alamo, & Garcia-Garcia, 2011, p. 555). Meprobamate is a
strong allosteric agonist of GABA-A, and overdose can mimic brain death and
coma (Meprobamate: Compound
Summary - CID 4064, 2005).
Mechanism of Action of Diazepam
Benzodiazepines, carbamates, and barbiturates all act on the neurotransmitter GABA, binding to a site near the GABAA receptor subtype
(Campo-Soria, Chang, & Weiss, 2006, p. 984). The binding site,
termed the Diazepam Binding Site (DZP) is distinct from the GABA binding site;
rather, benzodiazepines alter the receptor function, essentially amplifying the
inhibitory signal that GABA produces (Campo-Soria, Chang, & Weiss, 2006, pp. 984-985). By activating the
GABAA receptor, the chloride ion channel of the neuron opens, making
the neuron more negative (Sankar, 2012, p. 234). The more negative
the electrical gradient, the harder it is for the neuron to depolarize, making
neural activation less likely (Sankar, 2012, p. 234).
Classical benzodiazepines are considered full agonists of the GABAA receptor, in that they bind strongly to the many GABAA receptor subtypes
(Sankar, 2012, p. 239). The primary active
GABAA receptor subtypes include GABAAα1, GABAAα2, GABAAβ2, and GABAAγ3, and the most common
receptor configuration is GABA-Aα1β2γ3 (p. 239). The GABAAα1 receptor subtype is responsible
for sedation and retrograde amnesia from diazepam, GABAAα2 is responsible for the
anxiolytic effects of diazepam, while the GABAAα3 receptor subtype is responsible
for the anxiolytic effects of diazepam. Anticonvulsant effects are mediated by
α1, α2, and α3 receptor subtypes (p. 242).
The receptor subtypes are expressed in combinations of five types of any of the
sixteen subunits on the synaptic receptor surface, allowing many combinations
to be expressed, with two copies of the same α subtype, two copies of the same
type of β subtype, and a single γ receptor subtype (p. 230). When a
benzodiazepine binds to the subtype for which it is active, the physiological
effects are expressed, such as the anxiolytic effects expressed when the α1
subunit is bound to (p. 240).
When two GABA molecule bind to the GABA binding site, a “structural pertubation” is imparted that “is transferred to the other subunits [of GABAA] or subunit interfaces”
(Campo-Soria, Chang, & Weiss, 2006, p. 989). This binding keeps
the chloride channel open, amplifying the effect of GABA. It is this reduction
in neural activation that is responsible for the benzodiazepine’s ability to
prevent anxiety, by reducing activation in the brain regions responsible for
anxiety and fear, and seizures, by reducing the ability of the whole brain from
cortical spreading activation. Benzodiazepines cannot directly open the
chloride channel, which, unlike the barbiturates and carbamates, allows effects
to be reversed (Argyropoulos & Nutt, 1999, p. S410).
Desired Treatment Effects
The desired treatment effects of diazepam are a reduction of anxiety, a release of muscle tension and release of a muscle spasm, which tends to occur between one and one half hour after oral administration
(Diazepam, PubChem, 2005). A study in rats and
rabbits have indicated that the intranasal route of administration allows
diazepam to enter the brain across the blood-brain barrier through the
olfactory pathway, with effects occurring ten minutes after administration;
intravenous administration showed effects after only five minutes (Kaur &
Kwonho, 2008, pp. 27,31-32). The onset of
treatment effects were measured by analyzing saccade and eye movement
measurements (Kaur & Kwonho, 2008, p. 32).
Diazepam also acts as an antiepileptic, however, newer drugs specific to seizures are preferable because of side effects, discussed below. Further, tolerance to the effects of benzodiazepines, and “breakthrough seizures can occur after weeks or months” after beginning therapy
(Argyropoulos & Nutt, 1999, p. S409).
Tolerance to the treatment benzodiazepines can occur because of neural changes that adapt to the presence of the drug, causing neural compensation and gradual loss of efficacy. Tolerance to the effect of sedation develops more rapidly than diazepam’s anxiolytic and anticonvulsant effects
1985, p. 91).
Chronic administration followed by cessation leads to withdrawal symptoms if
diazepam is not tapered or reduced properly. Withdrawal from benzodiazepines,
including diazepam, can cause withdrawal symptoms, which need to be managed.
The withdrawal symptoms can occur after three weeks of use, followed by
cessation (Gerada & Ashworth, 1997, p. 297). Symptoms of
benzodiazepine withdrawal include “increased anxiety and perceptual
disturbances, especially heightened sensitivity to light and sound;
occasionally there are fits, hallucinations, and confusion” (p. 297). Current medical
practice is to translate the dose of alternative benzodiazepines into an
equivalent dose of diazepam (p. 297).
Diazepam has the benefit of being manufactured in dosages of ten, five, and two
milligrams, which allow the diazepam to be slowly tapered in a controlled
withdrawal (p. 299).
By reducing the dose by two milligrams every two weeks, shorter if withdrawing
from a small dose, a successful withdrawal can be attained with a minimum of
symptoms (p. 299).
Another indication for diazepam is in managing the effects of alcohol withdrawal in alcoholics
(Argyropoulos & Nutt, 1999, p. S409). Alcoholics in
withdrawal can have seizures, as well as “delirium tremens”, a severe shaking
and agitation (Argyropoulos & Nutt, 1999, p. S409).
Side Effects and Adverse Effects
Side effects of the benzodiazepines are typical of any anxiolytic and anticonvulsants, which is sedation
(Valium (diazepam) tablet: [Roche Products Inc],
Paradoxical effects occur rarely, but they include a worsening of anxiety, and
even possibly even a paradoxical seizure (Valium (diazepam) tablet: [Roche Products Inc],
Respiratory depression is also a potential side effect, since sedation is a
side effect (Valium (diazepam) tablet: [Roche Products Inc],
The effects tend to be dose-dependent, with side effects increasing as dose
increases (Diazepam, PubChem, 2005).
Diazepam displays teratogenic effects in mice in extremely high doses, “eight times the maximum recommended human dose”, and readily crosses both placental barriers of pregnant women and into the milk of nursing mothers
(Valium (diazepam) tablet: [Roche Products Inc], 2010).
Addiction in normal therapeutic doses is not normally pose a problem, however, administrations to patients with a history of drug abuse is cautioned
(Valium (diazepam) tablet: [Roche Products Inc],
A long-term effect of diazepam and other benzodiazepines is anterograde amnesia, including impairments of memory storage and retrieval
(Luscher, Baur, Goleldner, & Sigel, 2012, p. 1). Human studies in
memory of subjects reveal “diazepam produces its most prominent effect on
memory by diminishing acquisition of new information”, but leaves existing
memories intact (Petersen & Ghoneim, 1980, p. 88). A memory experiment
revealed that imagery recall was impaired, but recall with verbal cues was
largely unaffected (Petersen & Ghoneim, 1980, p. 88). Other
investigations have revealed that short-term memory is unaffected, but
long-term memory is impaired (Lister, 1985, p. 87). Individuals are
poor judges of their own abilities on benzodiazepines, as in a memory trial,
subjects on benzodiazepines rated their mental abilities as unchanged, while
results indicated impairment (Lister, 1985, p. 92).
Any compound capable of interrupting the metabolic breakdown of diazepam will increase the duration of effects, such as grapefruit juice, certain antifungals, and other CYP3A4 inhibitors
(Valium (diazepam) tablet: [Roche Products Inc],
Alcohol further amplifies this effect, as alcohol metabolism acts on GABA
pathways (Lopez-Munoz, Alamo, & Garcia-Garcia, 2011, p. 560).
Diazepam has been a drug that has been simultaneously been termed a boon and benefit to those with anxiety and seizure disorders, as well as a scourge to those who withdraw or become addicted. Diazepam has also allowed primitive psychologists to probe biological mechanisms underpinning many psychiatric disorders, causing a shift in paradigm from pseudoscientific reasoning into research into organic brain disorders and other neurological causes of disorders. Out of this revolution, the field of neuroscience and biopsychology. While all drugs must be weighed in terms of patient benefit versus patient risks, diazepam is clearly a “good” drug. Its versatility, available dosages, and efficacy make it an excellent first line choice in treating anxiety. Diazepam, though largely superseded by newer antiepileptic drugs, is still used in diagnostic cases. Diazepam is also the first line emergency-room sedative for agitated patients. Obviously, the risk of abuse and misuse requires a limit on the distribution of diazepam, and the other effects, such as sedation and the risk of harming a developing fetus, necessitate controls over who should be in possession of this drug, but its usefulness as a therapeutic tool is incredibly valuable.
Argyropoulos, S., & Nutt, D. (1999). The use of benzodiazepines in anxiety and other disorders. European Neuropsychopharmacology, 9 (Suppl. 6), S407-S412.
Campo-Soria, C., Chang, Y., & Weiss, D. (2006). Mechanism of action of benzodiazepines on GABA-A receptors. British Journal of Pharmacology(148), 984-990.
Gates, M. (1980). New synthesis of diazepam. Journal of Organic Chemistry, 1675-1681.
Gerada, C., & Ashworth, M. (1997, August 2). ABC of Mental Health: Addiction and dependence - I: Illicit drugs. British Medical Journal, 315, 297-300.
Ishikura, M., Mori, M., Ikeda, T., Terashima, M., & Ban, Y. (1981). New Synthesis of Diazepam and the Related 1,4-Benzodiazepines by means of Palladium-Catalyzed Carbonylation. Journal of Organic Chemistry, 2456-2461.
Kaur, P., & Kwonho, K. (2008). Pharmacokinetics and brain uptake of diazepam after intravenous and intranasal administration in rats and rabbits. International Journal of Pharmaceutics(364), 27-35. doi:10.1016/j.ijpharm.2008.07.030
Lister, R. (1985). The amnesic action of benzodiazepines in man. Neuroscience and Behavioral Reviews, 9(1 (Spring)), 87-94.
Lopez-Munoz, F., Alamo, C., & Garcia-Garcia, P. (2011). The discovery of chlordiazepoxide and the clinical intoduction of benzodiazepines: Half a century of anxiolytic drugs. Journal of Anxiety Disorders, 25(2011), 554-562. doi:10.1016/j.janxdis.2011.01.002
Luscher, B., Baur, R., Goleldner, M., & Sigel, E. (2012). Influence of GABA-A receptor α subunit isoforms on the benzodiazepine binding site. PLoSONE, 7(7), 1-8. doi:10.1371/journal.pone.0042101
National Center for Biotechnology Information. (2005, March 25). Diazepam: Compound Summary - CID 3016. Retrieved from PubChem Compound Database: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=3016&loc=es_rcs
National Center for Biotechnology Information. (2005, March 25). Meprobamate: Compound Summary - CID 4064. Retrieved from PubChem Compound Database: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=4064&loc=ec_rcs
National Center for Biotechnology Information. (2005, March 25). Penobarbital: Compound Sumamry - CID=4763. Retrieved from PubChem Compound Database: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=4763&loc=ec_rcs
National Center for Biotechnology Information. (2005, March 25). Secobarbital: Compound Summary - CID=5193. Retrieved from PubChem Compound Database: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=5193&loc=ec_rcs
National Library of Medicine. (2010, April). Valium (diazepam) tablet: [Roche Products Inc]. Retrieved from DailyMed: http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=554baee5-b171-4452-a50a-41a0946f956c
Petersen, R., & Ghoneim, M. (1980). Diazepam and human memory: Influence on aquisition, retrieval, and state dependent learning. Progress in neuro-psychopharmacology, 4(1), 81-89.
Sample, I. (2005, October 2). Leo Stenbach. The Guardian - Obituary, pp. 1-2. Retrieved November 17, 2012, from http://www.guardian.co.uk/society/2005/oct/03/health.guardianobituaries/print
Sankar, R. (2012). GABA-A receptor physiology and its relationship to the mechanism of action of the 1,5-Benzodiazepine clobazam. CNS Drugs, 26(3), 229-244.
Smith-Kielland, A., Skuterud, B., Olsen, K. M., & Morland, J. (2001). Urinary excretion of diazepam metabolites in healthy volunteers and drug users. Scandinavian Journal of Clinical and Laboratory Investigation(61), 237-246.
Sternbach, L., & Reeder, E. (1961). Quinazolines and 1,4-Benzodiazepines. IV. transformations of 7-Chloro-2-methylamino-5-phenyl-3H-1,4-benzodiazepine 4-Oxide. Journal of Organic Chemistry, 4936-4941.