Diazepam: A Literature Review of the Primitive Benzodiazepine

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

Dr. Kuga

Diazepam: A Literature Review of the Primitive Benzodiazepine

Introduction

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 Benzodiazepines superseded the class of drugs called the barbiturates, as well as the carbamates, since their safety is greater and therapeutic range is wider.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. 555). 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. 557). 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 (Diazepam, PubChem, 2005). 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, PubChem). 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], 2010). 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). 

Barbiturates

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)

Carbamate

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 (Meprobamate: 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 GABA_A 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 GABA_A 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 GABA_A receptor, in that they bind strongly to the many GABA_A receptor subtypes (Sankar, 2012, p. 239). The primary active GABA_A receptor subtypes include GABA_Aα1, GABA_Aα2, GABA_Aβ2, and GABA_Aγ3, and the most common receptor configuration is GABA-A_α1β2γ3 (p. 239). The GABA_Aα1 receptor subtype is responsible for sedation and retrograde amnesia from diazepam, GABA_Aα2 is responsible for the anxiolytic effects of diazepam, while the GABA_Aα3 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 GABA_A] 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 (Lister, 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], 2010). Paradoxical effects occur rarely, but they include a worsening of anxiety, and even possibly even a paradoxical seizure (Valium (diazepam) tablet: [Roche Products Inc], 2010). Respiratory depression is also a potential side effect, since sedation is a side effect (Valium (diazepam) tablet: [Roche Products Inc], 2010). 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], 2010).

            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).

Drug-Drug Interactions

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], 2010).. Alcohol further amplifies this effect, as alcohol metabolism acts on GABA pathways (Lopez-Munoz, Alamo, & Garcia-Garcia, 2011, p. 560).

Conclusion

            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.

References

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