Benzodiazepines water-soluble

A water-soluble phosphine derivative of diazepam allows for more convenient parenteral tranquilizer therapy and avoids some complications due to blood pressure lowering caused by the propylene glycol medium otherwise required for administration. Fosazepam (82) is prepared from benzodiazepine by sodium hydride-mediated alkylation with chioromethyldimethyl phosphine... 

Midazolam is a water-soluble benzodiazepine that is often used in preference to diazepam, since recovery is faster than with diazepam. It is indicated for... 

Midazolam <1 Yes No No Minimal Minimal Water-soluble benzodiazepine... 

Midazolam (Versed), diazepam (Valium), and lo-razepam (Ativan) are benzodiazepine derivatives that are useful in anesthesia. Midazolam is the most popular of these agents for the induction of anesthesia. Its popularity is related to its aqueous solubility and to its short duration of action, which permits a prompt return of psychomotor competence. Unlike midazolam, lor-azepam and diazepam are not water soluble and must be formulated in propylene glycol the latter is irritating to the vasculature on parenteral administration. 

Nevertheless, the GABAergic properties of benzodiazepines remain their most important clinical application. Over the past 30 years, the most widely used benzodiazepine drug has been diazepam (1.6). It is an anxiolytic, sedative, and muscle relaxant the anxious, depressed person becomes more outgoing and relaxed. There have been many diazepam analogs. Oxazepam (4.177) and lorazepam (4.178) have similar effects. Temazepam (4.179), flunitrazepam (4.180), and flurazepam (4.181) are useful sedative-hypnotics. Clonazepam (4.182) is a clinically useful anticonvulsant. Brotizolam (4.183), a novel benzodiazepine analog, seems to be an effective sedative-hypnotic. Midazolam (4.184) is an imidazolo-benzodiazepine that is water soluble and thus easily injectable. It is a hypnotic sedative with marked amnestic (i.e., memory loss) properties and is used in dentistry, endoscopic procedures, and induction to anesthetics in the elderly and in... 

Diazepam, lorazepam, and midazolam are used for preanesthetic medication and as adjuvants during surgical procedures performed under local anesthesia. As a result of their sedative, anxiolytic, and amnestic properties, and their ability to control acute agitation, these compounds are considered to be the drugs of choice for premedication. (The basic pharmacology of benzodiazepines is discussed in Chapter 22.) Diazepam and lorazepam are not water-soluble, and their intravenous use necessitates nonaqueous vehicles, which cause pain and local irritation. Midazolam is water-soluble and is the benzodiazepine of choice for parenteral administration. It is important that the drug becomes lipid-soluble at physiologic pH and can readily cross the blood-brain barrier to produce its central effects. 

The water-soluble metabolites of benzodiazepines and other sedative-hypnotics are excreted mainly via the kidney. In most cases, changes in renal function do not have a marked effect on the elimination of parent drugs. Phenobarbital is excreted unchanged in the urine to a certain extent (20-30% in humans), and its elimination rate can be increased significantly by alkalinization of the urine. This is partly due to increased ionization at alkaline pH, since phenobarbital is a weak acid with a pKa of 7.4. Only trace amounts of the benzodiazepines appear in the urine unchanged. 

Yano, K., Takamatsu, N., Yamazaki, S., Sako, K., Nagura, S., Tomizawa, S., Shimaya, J. and Yamamoto, K. (1996). Crystal forms, improvements of dissolution and absorption of poorly water-soluble (R)-l-[2,3-dihydro-l-(2 -methylphenacyl)-2-OXO-5- phenyl-lH-l,4-benzodiazepin-3-yl]-3-(3-methylphenyl)urea (YM022). Yakugaku Zasshi—J. Pharm. Soc. Jpn., 116, 639-46. [245]... 

PEG 300 and PEG 400 are generally considered to be amongst the safest organic cosolvents. " " Loraze-pam, a benzodiazepine used for sedation and epilepsy, has a water solubility of only 0.08 mg/ml and is solubilized in Ativan to 2-4 mg/ml with propylene glycol and 18% PEG 400, and is administered either undiluted intramuscularly or by TV bolus after a two-fold dilution with saline, dextrose or lactated Ringer s. Methocarbamil, a skeletal muscle relaxant, has solubility in water of 25 mg/ml and is solubilized to 100 mg/ml in Robaxin using 50 /o PEG 300, which is... 

Although diazepam has a high bioavailability after oral administration (approaching 100%), it is administered in equine practice primarily by the i.v. route. Because of its low water solubility, diazepam is solubilized in propylene glycol for injection. The bioavailability of this formulation is poor after i.m. administration and diazepam is not recommended for i.m. use. When i.m. administration of a benzodiazepine is desired, the more water-soluble agent midazolam is recommended. In contrast to diazepam, midazolam has a poor oral bioavailability (42%) because of its high hepatic clearance and first-pass metabolism. Zolazepam, in combination with tiletamine, can also be administered i.m. 

Benzodiazepines, like most lipid-soluble drugs, undergo biotransformation to more water-soluble glucuronide compounds, which are eventually eliminated in the urine. The primary metabolites of diazepam (N-desmethyldiazepam) and midazolam (a-hydroxymidazolam) are pharmacologically active, with similar potency to their parent compounds. These active metabolites are probably of little clinical significance after i.v. administration, because of their rapid elimination and the significance of redistribution in the termination of the CNS effect. 

The position, by way of the hydroxy group, has been modified in an attempt to increase the water solubility of benzodiazepines, which are generally highly lipophilic compounds. For example, the amino ester derivative (32) of lorazepam had excellent water sol-... 

Bock, M. G., DiPardo, R. M., Mellin, E. C., Newton, R. C., Veber, D. F, Freedman, S. B. Second-generation benzodiazepine CCK-B antagonists. Development of subnanomolar analogs with selectivity and water solubility. J. Med. Chem. 1994, 37, 722-724. 

Midazolam, an imidazobenzodiazepine, have several properties that make it a benzodiazepine of interest with regard to seizure control and neuroprotection against nerve agents. It is water-soluble at acid pH, but highly lipid-soluble in... 

A Nudelman, R1 McCaully, SC Bell. Water-soluble derivatives of 3-oxy-substituted 1,4-benzodiazepines. 1 Pharm Sci 63(12) 1880, 1974. 

Benzodiazepines. Librium and VaHum were first iutroduced for their muscle relaxant activity, but became widely used for their antianxiety (minor tranquilizer) activity. The benzodiazepines bind to a drug receptor which modulates the binding of GABA to its receptor (100). Diazepam [439-14-5] (Valium), C gH 2ClN20, (3) is used as a premedicant to anesthesia to lessen preoperative anxiety and to prevent recall of the operative procedure. Midazolam [59467-70-8] (Versed) (4) a water soluble benzodiazepine having a shorter duration of action than diazepam (101),... 

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