Diazepam first marketed as Valium by Hoffmann-La Roche, is a benzodiazepine derivative drug. It possesses anxiolytic, anticonvulsant, sedative, skeletal muscle relaxant and amnestic properties. It is commonly used for treating anxiety, insomnia, seizures, alcohol withdrawal, and muscle spasms. It may also be used before certain medical procedures (such as endoscopies) to reduce tension and anxiety, and in some surgical procedures to induce amnesia.
Diazepam is a core medicine in the World Health Organization's "Essential Drugs List", which is a list of minimum medical needs for a basic health care system.[3] Diazepam is used to treat a wide range of conditions and has been one of the most frequently prescribed medications in the world for the past 40 years. It was first synthesized by Dr. Leo Sternbach.
History
Diazepam was the second benzodiazepine to be invented by Sternbach of Hoffmann-La Roche, and was approved for use in 1963. It is two and a half times more potent than its predecessor, chlordiazepoxide, which it quickly surpassed in terms of sales. After this initial success, other pharmaceutical companies began to introduce other benzodiazepine derivatives.
The benzodiazepines gained popularity among medical professionals as an improvement upon barbiturates, which have a comparatively narrow therapeutic index, and are far more sedating at therapeutic doses. The benzodiazepines are also far less dangerous; death rarely results from diazepam overdose, except in cases where it is consumed with large amounts of other depressants (such as alcohol or other sedatives).
Diazepam was the top-selling pharmaceutical in the United States from 1969 to 1982, with peak sales in 1978 of 2.3 billion tablets.Diazepam along with oxazepam, nitrazepam and temazepam represent 82% of the benzodiazepine market in Australia.While psychiatrists continue to prescribe diazepam for the short-term relief of anxiety, neurology has taken the lead in prescribing diazepam for the palliative treatment of certain types of epilepsy and spastic activity, e.g., forms of paresis. It is also the first line of defense for a rare disorder called stiff-person syndrome.
Physical properties
Diazepam occurs as solid white or yellow crystals and has a melting point of 131.5 to 134.5 °C. It is odorless, and has a slightly bitter taste. The British Pharmacopoeia lists diazepam as being very slightly soluble in water, soluble in alcohol and freely soluble in chloroform. The United States Pharmacopoeia lists diazepam as soluble 1 in 16 of ethyl alcohol, 1 in 2 of chloroform, 1 in 39 of ether, and practically insoluble in water. The pH of diazepam is neutral (i.e. pH = 7). Diazepam has a shelf-life of 5 years for oral tablets and 3 years for IV/IM solution.Diazepam should be stored at room temperature (15°-30°C). The solution for parenteral injection should be protected from light and kept from freezing. The oral forms should be stored in air-tight containers and protected from light.
Diazepam can absorb into plastic, and therefore diazepam solution is not stored in plastic bottles or syringes etc. It can absorb into plastic bags and tubing used for intravenous infusions. Absorption appears to be dependent on several factors such as temperature, concentration, flow rates and tube length. Diazepam should not be administered if a precipitate has formed and will not dissolve.
Pharmacology
Diazepam is a "classical" benzodiazepine. Other classical benzodiazepines include clonazepam, lorazepam, oxazepam, alprazolam, nitrazepam, flurazepam, bromazepam and clorazepate.Diazepam has anticonvulsant properties. Diazepam has no effect on GABA levels and no effect on glutamate decarboxylase activity but has a slight effect on gamma-aminobutyric acid transaminase activity. It differs insofar from some other anticonvulsive drugs, it was compared to.Benzodiazepines act via micromolar benzodiazepine binding sites as Ca2+ channel blockers and significantly inhibit depolarization-sensitive Calcium uptake in rat nerve cell preparations.
Diazepam inhibits acetylcholine release in mouse hippocampal synaptosomes. This has been found by measuring sodium-dependent high affinity choline uptake in mouse brain cells in vitro, after pretreatment of the mice with diazepam in vivo. This may play a role in explaining diazepam's anticonvulsant properties.
Diazepam binds with high affinity to glial cells in animal cell cultures.Diazepam binds to peripheral benzodiazepine receptors and inhibits the proliferation of rat thymoma cell cultures, mouse Swiss 3T3 cells cultures, B103 and B104 rat neuroblastoma cell cultures, and Friend mouse erythroleukemia cell cultures and inhibits the uptake of radiolabeled thymidine into rat thymoma cell cultures.Diazepam at high doses has been found to decrease histamine turnover in mouse brain via diazepam's action at the benzodiazepine-GABA receptor complex. Diazepam also decreases prolactin release in rats.
Diazepam is a core medicine in the World Health Organization's "Essential Drugs List", which is a list of minimum medical needs for a basic health care system.[3] Diazepam is used to treat a wide range of conditions and has been one of the most frequently prescribed medications in the world for the past 40 years. It was first synthesized by Dr. Leo Sternbach.
History
Diazepam was the second benzodiazepine to be invented by Sternbach of Hoffmann-La Roche, and was approved for use in 1963. It is two and a half times more potent than its predecessor, chlordiazepoxide, which it quickly surpassed in terms of sales. After this initial success, other pharmaceutical companies began to introduce other benzodiazepine derivatives.
The benzodiazepines gained popularity among medical professionals as an improvement upon barbiturates, which have a comparatively narrow therapeutic index, and are far more sedating at therapeutic doses. The benzodiazepines are also far less dangerous; death rarely results from diazepam overdose, except in cases where it is consumed with large amounts of other depressants (such as alcohol or other sedatives).
Diazepam was the top-selling pharmaceutical in the United States from 1969 to 1982, with peak sales in 1978 of 2.3 billion tablets.Diazepam along with oxazepam, nitrazepam and temazepam represent 82% of the benzodiazepine market in Australia.While psychiatrists continue to prescribe diazepam for the short-term relief of anxiety, neurology has taken the lead in prescribing diazepam for the palliative treatment of certain types of epilepsy and spastic activity, e.g., forms of paresis. It is also the first line of defense for a rare disorder called stiff-person syndrome.
Physical properties
Diazepam occurs as solid white or yellow crystals and has a melting point of 131.5 to 134.5 °C. It is odorless, and has a slightly bitter taste. The British Pharmacopoeia lists diazepam as being very slightly soluble in water, soluble in alcohol and freely soluble in chloroform. The United States Pharmacopoeia lists diazepam as soluble 1 in 16 of ethyl alcohol, 1 in 2 of chloroform, 1 in 39 of ether, and practically insoluble in water. The pH of diazepam is neutral (i.e. pH = 7). Diazepam has a shelf-life of 5 years for oral tablets and 3 years for IV/IM solution.Diazepam should be stored at room temperature (15°-30°C). The solution for parenteral injection should be protected from light and kept from freezing. The oral forms should be stored in air-tight containers and protected from light.
Diazepam can absorb into plastic, and therefore diazepam solution is not stored in plastic bottles or syringes etc. It can absorb into plastic bags and tubing used for intravenous infusions. Absorption appears to be dependent on several factors such as temperature, concentration, flow rates and tube length. Diazepam should not be administered if a precipitate has formed and will not dissolve.
Pharmacology
Diazepam is a "classical" benzodiazepine. Other classical benzodiazepines include clonazepam, lorazepam, oxazepam, alprazolam, nitrazepam, flurazepam, bromazepam and clorazepate.Diazepam has anticonvulsant properties. Diazepam has no effect on GABA levels and no effect on glutamate decarboxylase activity but has a slight effect on gamma-aminobutyric acid transaminase activity. It differs insofar from some other anticonvulsive drugs, it was compared to.Benzodiazepines act via micromolar benzodiazepine binding sites as Ca2+ channel blockers and significantly inhibit depolarization-sensitive Calcium uptake in rat nerve cell preparations.
Diazepam inhibits acetylcholine release in mouse hippocampal synaptosomes. This has been found by measuring sodium-dependent high affinity choline uptake in mouse brain cells in vitro, after pretreatment of the mice with diazepam in vivo. This may play a role in explaining diazepam's anticonvulsant properties.
Diazepam binds with high affinity to glial cells in animal cell cultures.Diazepam binds to peripheral benzodiazepine receptors and inhibits the proliferation of rat thymoma cell cultures, mouse Swiss 3T3 cells cultures, B103 and B104 rat neuroblastoma cell cultures, and Friend mouse erythroleukemia cell cultures and inhibits the uptake of radiolabeled thymidine into rat thymoma cell cultures.Diazepam at high doses has been found to decrease histamine turnover in mouse brain via diazepam's action at the benzodiazepine-GABA receptor complex. Diazepam also decreases prolactin release in rats.
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