Pharmacology

According to López-Muñoz et al., (2011) early barbiturates were used as anticonvulsants, sedatives, and hypnotics. The first therapeutically active barbiturates (barbital, malonal, and gardenal) were introduced into clinical practice in 1904, a time when anxiety was not acknowledged as a physiological disorder. It was not until 1955 that anxiety was recognized as a diagnosis, at which time meprobamate was introduced to ameliorate anxiety. Benzodiazepines were not marketed until 1960, when Librium was introduced into the drug market (Balon & Tone, 2009). Zorumski and Isenberg (2007) described how benzodiazepines and barbiturates bind to GABA receptors, and the different functions both drugs produce. Barbiturates directly release chloride channel openings, while benzodiazepines increase the affinity of GABA, the flow of chloride ions, and the duration of chloride channel openings. Barbiturates bind to the GABAa receptor at the beta subunit, which are binding sites distinct from GABA itself and different from the benzodiazepine binding-site as well. By having an individual binding site separate from the benzodiazepines, it allows for an increase in accessibility of receptors for GABA, while also providing chloride influxes from highly present GABAs. Barbiturates also enhance GABA responses by increasing the duration that chloride channels remain open. After the drug’s initiation, the time of the channel opening is about four to five times longer than without it (Zorumski & Isenberg).

Benzodiazepines and barbiturates are treatments for insomnia, anxiety, muscle spasms, and seizures. Even therapeutic dosage levels can produce physical dependence and increased tolerance. Pomerantz (2006) described how the introduction of barbiturates as a sleep aid influenced their study, eventually leading to the exploration of its possible use as a remedy for spastic activity associated with seizures and schizophrenia. Routine medical and dental procedures are also benefitted by barbiturates in sedation techniques (Pomerantz, 2006). Most recently, benzodiazepines have been used in anesthesia to reduce anxieties regarding procedural sedation (Balone, 2009). The National Institute of Mental Health states anxiety is the most common mental health problem in the United States. Nineteen million people are affected by the disorder and many are not treated medically nor undergo therapy (Balone, 2009). It is found that most abusers of benzodiazepines also abuse other substances. The future development of benzodiazepines aims to reduce its physical dependence, in order to eliminate withdrawal symptoms and facilitate its use for long-term treatment (Pomerantz, 2006).

History

Adolph von Baeyer, a German organic chemist, discovered malonylurea in 1864 from a reaction of urea with malonic acide, which eventually became known as barbituric acid (Lopez-Munoz et al., 2005). Von Baeyer’s discovery initially held no therapeutic significance, however, it influenced the production of similar drugs, such as diethyl-barbituric acid. In 1881, Conrad and Guthzeit produced diethyl-barbituric acid by treating the argentic salt of barbituric acid with ethliodid (Lopez-Munoz, 2005). In 1904, chemists Fischer and Freiherr von Mering created a barbiturate by replacing two ethyl groups for two hydrogens adjoined to carbon (Lopez-Munoz, 2005).

Following the introduction of barbiturates into clinical practice, Bayer pharmaceutical company put Luminal on the market in 1912. Luminal became the most widely used barbiturate, however, it did not eliminate the unwanted side effects of drowsiness or dependence associated with the drug. According to Tone (2005), the barbiturate Somnifen served as a generic anesthetic in 1921 when the French anesthetist Daniel Bardet developed it. Realizing the unwanted side effects of the drug, such as waking up sluggishly with migraine headaches, Bardet modified Somnifen. The newly altered barbiturate Pemocton, also known as sodium sec-butyl, was the first to be used consistently in anesthesia (Tone, 2005).

Anxiety was not always defined as a disorder. In the early 19th century, doctors could not detect signs of a physiological disease. Da Costa, a military doctor in the Civil War, studied traumatized soldiers and concluded that their peculiar behavior following egregious war incidents was due to irritation of the heart and frequent overexcitement (Lader, 1991). Labeling this condition as “irritable heart syndrome,” symptoms included respiratory difficulties, palpitations, shortness of breath, and digestive malfunctions. To treat the illness, Da Costa used digitalis, belladonna, opium, strychnine, and acetate derived from lead (Lader, 1991). As developments of future barbiturates were going on in Europe, Boston physician George Miller Beard built upon Da Costa’s “irritable heart syndrome” and described the disorder as a weakness of the