Diazepam
Diazepam, first marketed as Valium, is a medicine of the benzodiazepine family that acts as an anxiolytic.[13] It is commonly used to treat a range of conditions, including anxiety, seizures, alcohol withdrawal syndrome, muscle spasms, insomnia, and restless legs syndrome.[13] It may also be used to cause memory loss during certain medical procedures.[14][15] It can be taken orally (by mouth), as a suppository inserted into the rectum, intramuscularly (injected into muscle), intravenously (injection into a vein) or used as a nasal spray.[6][15] When injected intravenously, effects begin in one to five minutes and last up to an hour.[15] Orally, effects begin after 15 to 60 minutes.[16]
Clinical data
Valium, Vazepam, Valtoco, others[1]
- AU: C[2]
High[3]
- AU: S4 (Prescription only)[2]
- BR: Class B1 (Psychoactive drugs)
- CA: Schedule IV
- DE: Prescription only (Anlage III for higher doses)
- NZ: Class C
- UK: POM (Prescription only)[8][9]
- US: WARNING[7]Schedule IV[10]
- UN: Psychotropic Schedule IV
- In general: ℞ (Prescription only)
76% (64–97%) oral, 81% (62–98%) rectal[11]
C16H13ClN2O
284.74 g·mol−1
Common side effects include sleepiness and trouble with coordination.[10][15] Serious side effects are rare.[13] They include increased risk of suicide, decreased breathing, and an increased risk of seizures if used too frequently in those with epilepsy.[13][15][17] Occasionally, excitement or agitation may occur.[18][19] Long-term use can result in tolerance, dependence, and withdrawal symptoms on dose reduction.[13] Abrupt stopping after long-term use can be potentially dangerous.[13] After stopping, cognitive problems may persist for six months or longer.[18] It is not recommended during pregnancy or breastfeeding.[15] Its mechanism of action works by increasing the effect of the neurotransmitter gamma-aminobutyric acid (GABA).[18]
Diazepam was patented in 1959 by Hoffmann-La Roche.[13][20][21] It has been one of the most frequently prescribed medications in the world since its launch in 1963.[13] In the United States it was the best-selling medication between 1968 and 1982, selling more than 2 billion tablets in 1978 alone.[13] In 2021, it was the 149th most commonly prescribed medication in the United States, with more than 3 million prescriptions.[22][23] In 1985, the patent ended, and there are more than 500 brands available on the market.[13] It is on the World Health Organization's List of Essential Medicines.[24]
Structure, physical and chemical properties[edit]
Diazepam does not possess any chiral centers in its structure, but it does have two conformers. The two conformers mentioned were the 'P'-conformer and 'M'-conformer. Diazepam is an equimolar mixture and it was shown through CD spectra in serum protein solutions, that the 'P'-conformer is preferred by α1-acid glycoprotein binding.
The drug diazepam occurs as a pale yellow-white crystalline powder without distinctive smell and has a low molecular weight (MW = 284,74 g/mol[14]). This classic aryl 1,4-benzodiazepine possesses three acceptors and no hydrogen bond donors. Diazepam is moderately lipophilic with LogP (Octanol-Water Partition Coefficient) value of 2,82 and hydrophilic with a TPSA (Topological Polar Surface Area) value of 32.7 Ų.[14] The LogP value indicates that diazepam has a tendency to dissolve more readily in lipid-based environments, such as chloroform, acetone, ethanol and ether, compared to water. While the TPSA value implies that a segment of the molecule exhibits a degree of polarity or hydrophilicity and represents the collective surface area of polar atoms, like oxygen or nitrogen, along with their connected hydrogen atoms. A TPSA value of 32,7 Ų signifies a moderate level of polarity within the compound. TPSA is especially useful in medical chemistry as it shows the ability of a molecule to permeate cells. Molecules with PSA value smaller than 60-70 Ų has a better ability to permeate cells.[25] The balance between its lipophilic and hydrophilic characteristics can impact various aspects of the molecule’s behavior, including its solubility, absorption, distribution, metabolism, and potential interactions within the biological system.
Diazepam is overall a stable molecule. The British Pharmacopoeia lists it 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 ethyl alcohol, 1 in 2 of chloroform, 1 in 39 ether, and practically insoluble in water. The pH of diazepam is neutral (i.e., pH = 7). Due to additives such as benzoic acid/benzoate in the injectable form.[26] Diazepam has a shelf life of five years for oral tablets and three years for IV/IM solutions.[27]
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.[28]
Diazepam can absorb into plastics, so liquid preparations should not be kept in plastic bottles or syringes, etc. As such, it can leach into the plastic bags and tubing used for intravenous infusions. Absorption appears to depend on several factors, such as temperature, concentration, flow rates, and tube length. Diazepam should not be administered if a precipitate has formed and does not dissolve.[28]
An individual who has consumed too much diazepam typically displays one or more of these symptoms in a period of approximately four hours immediately following a suspected overdose:[37][88]
Although not usually fatal when taken alone, a diazepam overdose is considered a medical emergency and generally requires the immediate attention of medical personnel. The antidote for an overdose of diazepam (or any other benzodiazepine) is flumazenil (Anexate). This drug is only used in cases with severe respiratory depression or cardiovascular complications. Because flumazenil is a short-acting drug, and the effects of diazepam can last for days, several doses of flumazenil may be necessary. Artificial respiration and stabilization of cardiovascular functions may also be necessary. Though not routinely indicated, activated charcoal can be used for decontamination of the stomach following a diazepam overdose. Emesis is contraindicated. Dialysis is minimally effective. Hypotension may be treated with levarterenol or metaraminol.[37][27][88][89]
The oral LD50 (lethal dose in 50% of the population) of diazepam is 720 mg/kg in mice and 1240 mg/kg in rats.[37] D. J. Greenblatt and colleagues reported in 1978 on two patients who had taken 500 mg and 2000 mg of diazepam, respectively, went into moderately-deep comas, and were discharged within 48 hours without having experienced any important complications, in spite of having high concentrations of diazepam and its metabolites desmethyldiazepam, oxazepam, and temazepam, according to samples taken in the hospital and as follow-up.[90]
Overdoses of diazepam with alcohol, opiates, or other depressants may be fatal.[89][91]
If diazepam is administered concomitantly with other drugs, attention should be paid to the possible pharmacological interactions. Particular care should be taken with drugs that potentiate the effects of diazepam, such as barbiturates, phenothiazines, opioids, and antidepressants.[37]
Diazepam does not increase or decrease hepatic enzyme activity, and does not alter the metabolism of other compounds. No evidence would suggest diazepam alters its own metabolism with chronic administration.[27]
Agents with an effect on hepatic cytochrome P450 pathways or conjugation can alter the rate of diazepam metabolism. These interactions would be expected to be most significant with long-term diazepam therapy, and their clinical significance is variable.[27]
History[edit]
Diazepam was the second benzodiazepine invented by Leo Sternbach of Hoffmann-La Roche at the company's Nutley, New Jersey, facility[118] following chlordiazepoxide (Librium), which was approved for use in 1960. Released in 1963 as an improved version of Librium, diazepam became incredibly popular, helping Roche to become a pharmaceutical industry giant. It is 2.5 times more potent than its predecessor, which it quickly surpassed in terms of sales. After this initial success, other pharmaceutical companies began to introduce other benzodiazepine derivatives.[119]
The benzodiazepines gained popularity among medical professionals as an improvement over barbiturates, which have a comparatively narrow therapeutic index, and are far more sedative 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 opioids).[89] Benzodiazepine drugs such as diazepam initially had widespread public support, but with time the view changed to one of growing criticism and calls for restrictions on their prescription.[120]
Marketed by Roche using an advertising campaign conceived by the William Douglas McAdams Agency under the leadership of Arthur Sackler,[121] diazepam was the top-selling pharmaceutical in the United States from 1969 to 1982, with peak annual sales in 1978 of 2.3 billion tablets.[119] Diazepam, along with oxazepam, nitrazepam and temazepam, represents 82% of the benzodiazepine market in Australia.[122] 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, for example, forms of paresis. It is also the first line of defense for a rare disorder called stiff-person syndrome.[36]