Question:

Is it safe to take 2 mg of xanax and 40 mg of ambien?

Answer:

No. Do not take the two together. Not without consulting a doctor. This combination could lead to death.

More Info:


Zaleplon
InChI=1S/C17H15N5O/c1-3-21(12(2)23)15-6-4-5-13(9-15)16-7-8-19-17-14(10-18)11-20-22(16)17/h4-9,11H,3H2,1-2H3Yes 
Key:HUNXMJYCHXQEGX-UHFFFAOYSA-NYes  Zaleplon (marketed under the brand names Sonata, Starnoc and Andante) is a sedative-hypnotic, almost entirely used for the management/treatment of insomnia. It is a nonbenzodiazepine hypnotic from the pyrazolopyrimidine class. Sonata (US) is manufactured by King Pharmaceuticals of Bristol, TN. Gedeon Richter Plc. manufactures zaleplon under the brand name Andante. Starnoc has been discontinued in Canada. It is prescribed rarely in the United Kingdom; with zopiclone being the preferred Z-drug by the National Health Service (NHS), as zaleplon has been discontinued by the NHS. Zaleplon is effective in the management/treatment of insomnia, primarily characterized by difficulty falling asleep. Due to its ultra-short elimination half-life, zaleplon may not be effective in premature awakenings. It may result in an impaired ability to drive the next day, though it has proven promising when compared to other sedative-hypnotics and next day residual sedation. It may have advantages over benzodiazepines with less adverse effects. Zaleplon or any nonbenzodiazepine should never be combined with any alcoholic beverage as both substances modulate AGABA receptor sites, and in a synergistic manner increase the chances of fatal respiratory depression and asphyxiation from vomiting. Zaleplon is not recommended for chronic use in the elderly. The elderly are more sensitive to the adverse effects of zaleplon such as cognitive side effects. Zaleplon may increase the risk of injury among the elderly. It should not be used while in pregnancy or lactation, and in patients with a history of alcohol or drug abuse, psychotic illness or depression, clinicians should devote more attention. When compared with benzodiazepines, nonbenzodiazepines (including zaleplon) appear to offer few significant advantages in efficacy or tolerability among elderly individuals. Long-term use of sedative-hypnotics for insomnia has traditionally been discouraged for reasons that include concerns about such potential adverse drug effects as cognitive impairment, anterograde amnesia, daytime sedation, musculo-skeletal impairment, and subsequently an increased risk of harm to oneself (e.g. falling) and to others (e.g. automotive accidents). Though, quite obviously as the body and brain age, these aforementioned phenomena are expected events, as they occur daily regardless of ingestion of a sedative-hypnotic. Thus, statistically significant and empirical evidence are arguably still absent as dramatic precautions and conclusions are drawn irrespective of the debilitating realities that accompany insomnia and the fact that these medicines do indeed provide assistance to millions of elderly individuals. It is important to distinguish between the extrapolation of potential side effects relative to the vast number of examples, wherein the sedative-hypnotic has proven therapeutically beneficial and appropriate. In addition, some contend the efficacy and safety of long-term use of these agents remains to be enumerated, but there is nothing concrete to suggest that long term use poses any direct harm to a person. The side effects of zaleplon are similar to the side effects of benzodiazepines, although with less next-day sedation, and in two studies zaleplon use was found to not cause an increase in road traffic accidents, as compared to other hypnotics currently on the market. Zaleplon may prompt day-time or next-day residual sedation. Available data cannot provide a reliable estimate of the incidence of dependence during treatment at recommended doses of zaleplon (typically 5–20 mg before bed). Other sedative-hypnotics have been associated with various signs and symptoms of a withdrawal syndrome, following abrupt discontinuation, ranging from mild dysphoria and insomnia to more serious cases that include abdominal and muscle cramps, vomiting, sweating, tremors, and convulsions. Following, abrupt cessation, the seizure threshold is further lowered, wherein coma and death are possible outcomes if untreated. Some evidence suggests that zaleplon is not as chemically reenforcing and exhibits far less rebound effects when compared with other nonbenzodiazepines, or Z-drugs. Zaleplon, like zolpidem, zopiclone or eszopiclone are all specific agonists at the benzodiazepine sub-receptor site1 αAGABA. It also modulates the GABAA sub-sites, α2 and α3, to a lesser degree. It has no statistical significance as an anticonvulsant. However, as a pyrazolopyrimidine, zaleplon has served as a novel chemical platform, from which new anxiolytics, will hopefully arise. Much like zolpidem, as an imidazopyridine and also a full agonist at the GABAA α1 sub-receptor site, has been reviewed considerably with some novel contributions. See also: alpidem. Zaleplon selectively binds with high efficacy to the benzodiazepine site (ω1) on the α1-containing GABA-A receptors which help produce the primary therapeutic hypnotic properties. The ultra-short half-life gives zaleplon a unique advantage over other hypnotics because of its lack of next day residual effects on driving and other performance related skills. Unlike non-selective benzodiazepine drugs and zopiclone which distort the sleep pattern, zaleplon appears to induce sleep without disrupting the natural sleep architecture. A meta-analysis of randomised controlled clinical trials which compared benzodiazepines against zaleplon or other Z-drugs such as zolpidem, zopiclone and eszopiclone has found that there are few clear and consistent differences between zaleplon and the benzodiazepines in terms of sleep onset latency, total sleep duration, number of awakenings, quality of sleep, adverse events, tolerance, rebound insomnia and daytime alertness. Zaleplon has a pharmacological profile similar to benzodiazepines, that is characterized by an increase in slow wave deep sleep (SWDS) with rapid onset of hypnotic action. Zaleplon is a full agonist for the benzodiazepine receptor1α located on the receptorAGABA complex in the body, with lower affinity for the α2 and α3 sub-sites. It selectively enhances the action of GABA similar to, but more selectively than benzodiazepines. Zaleplon, although not a benzodiazepine, maintains a very similar chemical structure nonetheless; known for inducing hypnotic effects via α1 sub-receptor sites, anxiolytic and muscle relaxant effects via α2 and α3 sub-sites, with negligible anticonvulsant properties (via α5 sub-site), as zaleplon action is modulated at benzodiazepine receptor sites. The elimination half-life of zaleplon is about 1–1.5 hour. The absorption rate of zaleplon is rapid and the onset of therapeutic effects is typically breached within 5–15 minutes following ingestion. Zaleplon should be understood as an ultra short acting sedative-hypnotic drug for the treatment of insomnia. Zaleplon increases EEG power density in the delta frequency band and a decrease in the energy of the theta frequency band Pure zaleplon in its solid state is a white to off-white powder that has very low solubility in water as well as low solubility in ethanol and propylene glycol. It has a partition coefficient in octanol/water that is constant (log PC = 1.23) when the pH range is between 1 and 7. Zaleplon is primarily metabolised by aldehyde oxidase, and its half-life can be affected by substances which inhibit or induce aldehyde oxidase. Taken orally, zaleplon reaches full concentration in approximately one hour. It is extensively metabolised into 5-oxozaleplon and 5-oxodesethylzaleplon (the latter via desethylzaleplon), with less than 1% of it excreted intact in urine. Cimetidine, rifampicin and thioridazine cause interactions with zaleplon. Cimetidine alongside grapefruit, are known to increase blood plasma concentrations of benzodiazepines metabolized by the P450 CYP3A4 liver enzyme (e.g. alprazolam), as well as increasing the time by which the drug leaves the body, effectively extending the half-life and enhancing effects to potentially toxic levels. Thus, given the similarities between zaleplon and benzodiazepines, particularly in effect, and not just chemical structure, it is reasonable to take precautions (e.g. inquire at a pharmacy) before one consumes cimetidine (or grapefruit) while also taking zaleplon. Smoking tobacco/ingesting nicotine as well as caffeine likely reduces blood plasma concentrations of zaleplon, as sedative-hypnotic efficacy is diminished. This impact is shared by all GABAergics, whether nonbenzodiazepines, benzodiazepines, barbiturates, carbamates, quinazolines or alcohol. Zaleplon has the potential to be a drug of abuse, but more probable is that individuals prescribed zaleplon may use it to better fit their needs/desires (e.g. patient is allowed to individually titrate their dose nightly to help reduce early morning awakenings). Sometimes, this use involves a different delivery method (insufflating) to induce effects faster. Remaining cognizant of zaleplon's partial water solubility, the route of administration (RoA) that best delivers the entirety of any amount of zaleplon is via the mouth. Any other method, and zaleplon is simply being wasted, while likely damaging nasal passage-ways as well as the sinuses. Though, one should remain mindful that a vast majority of benzodiazepine and nonbenzodiazepine Z-drug users do not abuse their medicine. Thus, while it is possible to abuse zaleplon, it should not be presumed that the phenomenon is widespread or any notion that reformulation of the medicine, to prevent potential future abuse, is baseless. More concerning than zaleplon, is combining alcohol with zaleplon. This combination, is synergistic and volatile once it has entered the bloodstream. Fatal respiratory depression and asphyxiation from vomiting when combined with alcohol, are the primary reasons why zaleplon is a substance of concern. Given alcohol's widespread popularity worldwide, it cannot be presumed that zaleplon is a dangerous substance, rather it is only dangerous in certain combinations or doses. The mind and judgment altering effects of zaleplon are similar to those of many other benzodiazepines but the fast-acting nature and short half-life of the chemical mean that high dosages set on much more quickly and last for short periods of time (usually from 45 to 60 minutes). Insufflating the drug causes effects to happen even more quickly, and last for even shorter periods of time, with some loss of yield as zaleplon is not entirely water soluble. A common effect of zaleplon abuse is the occurrence of (typically short-lived) hallucinations, commonly involving perceptions of nonexistent creatures. Though, compared to other nonbenzodiazepines there are far less visual or audio hallucinations/disruptions, when compared with others in the class (e.g. zolpidem and the “Ambien Walrus”).][ Anterograde amnesia is a possibility, and can cause one to lose track of the amount of zaleplon already ingested, prompting one to ingest more than originally planned. However, continuous ingestion is extremely unlikely precisely because of zaleplon's quick onset of action.

Alprazolam
InChI=1S/C17H13ClN4/c1-11-20-21-16-10-19-17(12-5-3-2-4-6-12)14-9-13(18)7-8-15(14)22(11)16/h2-9H,10H2,1H3Yes 
Key:VREFGVBLTWBCJP-UHFFFAOYSA-NYes  Alprazolam (trade name Xanax, available among other generic names) is a short-acting anxiolytic of the benzodiazepine class of psychoactive drugs. Alprazolam, like other benzodiazepines, binds to specific sites on the AGABA gamma-amino-butyric acid receptor. Alprazolam is commonly used and FDA approved for the medical treatment of panic disorder, and anxiety disorders, such as generalized anxiety disorder (GAD) or social anxiety disorder (SAD). Alprazolam is available for oral administration in compressed tablet (CT) and extended-release capsule (XR) formulations. Alprazolam possesses anxiolytic, sedative, hypnotic, skeletal muscle relaxant, anticonvulsant, and amnestic properties. Alprazolam has a fast onset of action and symptomatic relief. Ninety percent of peak effects are achieved within the first hour (although onset may begin at 8–25 minutes of ingestion) of using either in preparation for panic disorder, and full peak effects are achieved in 1.5 and 1.6 hours respectively. Peak benefits achieved for generalized anxiety disorder (GAD) may take up to a week. Tolerance to the anxiolytic/antipanic effects is controversial with some authoritative sources reporting the development of tolerance, and others reporting no development of tolerance; tolerance will however, develop to the sedative-hypnotic effects within a couple of days. Withdrawal symptoms or rebound symptoms may occur after ceasing treatment abruptly following a few weeks or longer of steady dosing, and may necessitate a gradual dose reduction. Alprazolam is the most prescribed and the most misused benzodiazepine on the U.S. retail market. The potential for misuse among those taking it for medical reasons is controversial with some expert reviews stating that the risk is low and similar to that of other benzodiazepine drugs and others stating that there is a substantial risk of abuse and dependence in both patients and non-medical users of alprazolam and that the pharmacological properties of alprazolam, high affinity binding, high potency, having a short elimination half-life as well as a rapid onset of action increase the misuse potential of alprazolam. Compared to the large number of prescriptions, relatively few individuals increase their dose on their own initiative or engage in drug-seeking behavior. Alprazolam is classified as a schedule IV controlled substance by the U.S. Drug Enforcement Administration (DEA). Alprazolam is mostly used to treat anxiety disorders, panic disorders, and nausea due to chemotherapy. The FDA label advises that the physician should periodically reassess the usefulness of the drug. Alprazolam is effective in the relief of moderate to severe anxiety and panic attacks. It however is not a first line treatment, since the development of selective serotonin reuptake inhibitors, and alprazolam is no longer recommended for the treatment of panic disorder (in Australia) due to concerns regarding tolerance, dependence and abuse. Evidence supporting the effectiveness of alprazolam in treating panic disorder has been limited to 4 to 10 weeks. However, people with panic disorder have been treated on an open basis for up to 8 months without apparent loss of benefit. In the US alprazolam is FDA-approved for the treatment of panic disorder with or without agoraphobia. Alprazolam is recommended by the World Federation of Societies of Biological Psychiatry (WFSBP) for treatment-resistant cases of panic disorder where there is no history of tolerance or dependence, as of 2002. In the US alprazolam is FDA-approved for the management of anxiety disorders (a condition corresponding most closely to the APA Diagnostic and Statistical Manual DSM-IV-TR diagnosis of generalized anxiety disorder) or the short-term relief of symptoms of anxiety. Anxiety associated with depression is responsive to alprazolam. Demonstrations of the effectiveness by systematic clinical study are limited to 4 months duration for anxiety disorder. However, the research into antidepressant properties of alprazolam is of poor quality and only assessed the short-term effects of alprazolam against depression. In one study, some long term, high-dosage users of alprazolam developed reversible depression. In the UK, alprazolam is recommended for the short-term treatment (2–4 weeks) of severe acute anxiety. Alprazolam may be used in combination with other medications for chemotherapy-induced nausea and vomiting. Benzodiazepines cross the placenta, enter into the fetus and are also excreted with breast milk. The use of benzodiazepines during pregnancy or lactation has potential risks. The use of alprazolam in pregnancy is believed to be associated with congenital abnormalities. Diazepam and chlordiazepoxide have a better safety profile in pregnancy than alprazolam. Women who are pregnant or are planning on becoming pregnant should avoid starting alprazolam. Use in the last trimester may cause fetal drug dependence and withdrawal symptoms in the post-natal period as well as neonatal flaccidity and respiratory problems. However, in long-term users of benzodiazepines abrupt discontinuation due to concerns of teratogenesis has a high risk of causing extreme withdrawal symptoms and a severe rebound effect of the underlying mental health disorder. Spontaneous abortions may also result from abrupt withdrawal of psychotropic medications including benzodiazepines. Benzodiazepines, including alprazolam, are known to be excreted in human milk. Chronic administration of diazepam to nursing mothers has been reported to cause their infants to become lethargic and to lose weight. Benzodiazepines require special precaution if used in children and in alcohol- or drug-dependent individuals. Particular care should be taken in pregnant or elderly patients, patients with substance abuse history, particularly alcohol dependence and patients with comorbid psychiatric disorders. Use of alprazolam should be avoided or carefully monitored by medical professionals in individuals with the following conditions: myasthenia gravis, acute narrow-angle glaucoma, severe liver deficiencies (e.g., cirrhosis), severe sleep apnea, pre-existing respiratory depression, marked neuromuscular respiratory weakness including unstable myasthenia gravis, acute pulmonary insufficiency, chronic psychosis, hypersensitivity or allergy to alprazolam or other drugs in the benzodiazepine class, borderline personality disorder (may induce suicidality and dyscontrol). Like all central nervous system depressants, including alcohol, alprazolam in larger-than-normal doses can cause significant deterioration in alertness, combined with increased feelings of drowsiness, especially in those unaccustomed to the drug's effects. People driving or conducting activities that require vigilance should exercise caution in using alprazolam or any other depressant until they know how it affects them. Elderly individuals should be cautious in the use of alprazolam due to the possibility of increased susceptibility to side-effects, especially loss of coordination and drowsiness. Allergic reactions are unlikely to occur. The only common side effect is sleepiness when treatment is initiated. Possible side effects include: Although unusual, the following paradoxical reactions have been shown to occur: Alprazolam is primarily metabolised via CYP3A4. Combining CYP3A4 inhibitors such as cimetidine, erythromycin, fluoxetine, fluvoxamine, itraconazole, ketoconazole, nefazodone, propoxyphene, and ritonavir delay the hepatic clearance of alprazolam, which may result in excessive accumulation of alprazolam. This may result in exacerbation of its adverse effect profile. Imipramine and desipramine have been reported to be increased an average of 31% and 20%, respectively, by the concomitant administration of alprazolam tablets in doses up to 4 mg/day. Combined oral contraceptive pills reduce the clearance of alprazolam, which may lead to increased plasma levels of alprazolam and accumulation. Alcohol is one of the most important and common interactions. Alcohol and benzodiazepines such as alprazolam taken in combination have a synergistic effect on one another, which can cause severe sedation, behavioral changes, and intoxication. The more alcohol and alprazolam taken the worse the interaction. Combination of alprazolam with the herb kava can result in the development of a semi-comatose state. Hypericum conversely can lower the plasma levels of alprazolam and reduce its therapeutic effect. Overdoses of alprazolam can be mild to severe depending on how much of the drug is taken and any other drugs that have been taken. Alprazolam overdoses cause excess central nervous system (CNS) depression and may include one or more of the following symptoms: In a study of deaths in Palm Beach County where the drug alprazolam was detected, approximately 50% of cases were attributed to poly-drug use (the combined toxicity of two or more drugs). The majority of these cases included either cocaine or methadone. Alprazolam alone caused only 1% of the deaths. These results indicate alprazolam has a very low incidence of causing death when taken alone. Alprazolam, like other benzodiazepines, binds to specific sites on the GABAA gamma-amino-butyric acid receptor. When bound to these sites, which are referred to as benzodiazepine receptors, it modulates the effect of GABA A receptors and, thus, GABAergic neurons. Long-term use causes adaptive changes in the benzodiazepine receptors, making them less sensitive to stimulation and less powerful in their effects. Withdrawal and rebound symptoms commonly occur and necessitate a gradual reduction in dosage to minimize withdrawal effects when discontinuing. Not all withdrawal effects are evidence of true dependence or withdrawal. Recurrence of symptoms such as anxiety may simply indicate that the drug was having its expected anti-anxiety effect and that, in the absence of the drug, the symptom has returned to pretreatment levels. If the symptoms are more severe or frequent, the patient may be experiencing a rebound effect due to the removal of the drug. Either of these can occur without the patient's actually being drug-dependent. Alprazolam and other benzodiazepines may also cause the development of physical dependence, tolerance, and benzodiazepine withdrawal symptoms during rapid dose reduction or cessation of therapy after long-term treatment. There is a higher chance of withdrawal reactions if the drug is administered in a higher dosage than recommended, or if a patient stops taking the medication altogether without slowly allowing the body to adjust to a lower-dosage regimen. In 1992, Romach and colleagues reported that dose escalation is not a characteristic of long-term alprazolam users, and that the majority of long-term alprazolam users change their initial pattern of regular use to one of symptom control only when required. Some common symptoms of alprazolam discontinuation include malaise, weakness, insomnia, tachycardia, lightheadedness, and dizziness. Patients taking a dosing regimen larger than 4 mg per day have an increased potential for dependence. This medication may cause withdrawal symptoms upon abrupt withdrawal or rapid tapering, which in some cases have been known to cause seizures. The discontinuation of this medication may also cause a reaction called rebound anxiety. Delirium and seizures have been anecdotally reported in the medical literature from abrupt alprazolam discontinuation. In a 1983 study of patients who had taken long-acting benzodiazepines, e.g., clorazepate, for extended periods, the medications were stopped abruptly. Only 5% of patients who had been taking the drug for less than 8 months demonstrated withdrawal symptoms, but 43% of those who had been taking them for more than 8 months did. With alprazolam – a short-acting benzodiazepine – taken for 8 weeks, 35% of patients experienced significant rebound anxiety. To some degree, these older benzodiazepines are self-tapering. The benzodiazepines diazepam (Valium) and oxazepam (Serepax) have been found to produce fewer withdrawal reactions than alprazolam (Xanax), temazepam (Restoril/Normison), or lorazepam (Temesta/Ativan). Factors that determine the risk of psychological dependence or physical dependence and the severity of the benzodiazepine withdrawal symptoms experienced during dose reduction of alprazolam include: dosage used, length of use, frequency of dosing, personality characteristics of the individual, previous use of cross-dependent/cross-tolerant drugs (alcohol or other sedative-hypnotic drugs), current use of cross-dependent/-tolerant drugs, use of other short-acting, high-potency benzodiazepines, and method of discontinuation. Alprazolam may be quantitated in blood or plasma to confirm a diagnosis of poisoning in hospitalized patients, provide evidence in an impaired driving arrest or to assist in a medicolegal death investigation. Blood or plasma alprazolam concentrations are usually in a range of 10–100 μg/L in persons receiving the drug therapeutically, 100–300 μg/L in those arrested for impaired driving and 300–2000 μg/L in victims of acute overdosage. Most commercial immunoassays for the benzodiazepine class of drugs will cross-react with alprazolam, but confirmation and quantitation is usually performed using chromatographic techniques. Alprazolam is classed as a high-potency benzodiazepine and is a triazolobenzodiazepine, namely a benzodiazepine with a triazole ring attached to its structure. Benzodiazepines produce a variety of therapeutic and adverse effects by binding to the benzodiazepine receptor site on the AGABA receptor and modulating the function of the GABA receptor, the most prolific inhibitory receptor within the brain. The GABA chemical and receptor system mediates inhibitory or calming effects of alprazolam on the nervous system. The GABAA receptor is made up of 5 subunits out of a possible 19, and GABAA receptors made up of different combinations of subunits have different properties, different locations within the brain, and, importantly, different activities with regard to benzodiazepines. Benzodiazepines and in particular alprazolam causes a marked suppression of the hypothalamicpituitary-adrenal axis. The therapeutic properties of alprazolam are similar to other benzodiazepines and include anxiolytic, anticonvulsant, muscle relaxant, hypnotic and amnesic. Administration of alprazolam has been demonstrated to elicit an increase in striatal dopamine concentrations. Absorption Following oral administration, alprazolam is readily absorbed. Peak concentrations in the plasma occur in one to two hours following administration. Plasma levels are proportionate to the dose given; over the dose range of 0.5 to 3.0 mg, peak levels of 8.0 to 37 ng/mL were observed. Using a specific assay methodology, the mean plasma elimination half-life of alprazolam has been found to be about 11.2 hours (range: 6.3 to 26.9 hours) in healthy adults. Distribution In vitro, alprazolam is bound (80 percent) to human serum protein. Serum albumin accounts for the majority of the binding. Metabolism/Elimination Alprazolam is extensively metabolized in humans, primarily by cytochrome P450 3A4 (Cyp3A4), to two major metabolites in plasma: 4-hydroxyalprazolam and α- hydroxyalprazolam. A benzophenone derived from alprazolam is also found in humans. Half-lives are similar to that of alprazolam. The plasma concentrations of 4-hydroxyalprazolam and α-hydroxyalprazolam relative to unchanged alprazolam coincentration were always less than 4%. The reported relative potencies in benzodiazepines receptor binding experiments and in animals models of induced seizure inhibition are 0.2 and 0.66, respectively, for 4-hydroxyalprazolam and α-hydroxyalprazolam. Such low concentrations and lesser potencies of 4-hydroxyalprazolam and α-hydroxyalprazolam suggest that they are unlikely to contribute much to the pharmacological effects of alprazolam. The benzophenone metabolite is essentially inactive. Alprazolam and its metabolites are excreted primarily in the urine. Alprazolam is a chemical analog of triazolam that differs by the absence of a chlorine atom in the o-position of the 6-phenyl ring. The same scheme that was used to make triazolam can be used to make alprazolam, with the exception that it begins with 2-amino-5-chlorobenzophenone. However, a non-standard way of making alprazolam has been suggested, which comes from 2,6-dichloro-4-phenylquinoline, the reaction of which with hydrazine gives 6-chloro-2-hydrazino-4-phenylquinoline. Boiling this with triethyl orthoacetate in xylene leads to the heterocyclization into a triazole derivative. The resulting product undergoes oxidative cleavage using sodium periodate and ruthenium dioxide in an acetone–water system to give 2-[4-(3′-methyl-1,2,4-triazolo)]-5-chlorobenzophenone. Oxymethylation of the last using formaldehyde and subsequent substitution of the resulting hydroxyl group by phosphorus tribromide,gives 2-[4-(3′-methyl-5′-bromomethyl-1,2,4-triazolo)]-5-chlorobenzophenone. Substitution of the bromine atom with an amino group using ammonia and the spontaneous, intramolecular heterocyclization following that reaction gives alprazolam. Alprazolam was first released by Upjohn (now a part of Pfizer). It is covered under , which was filed on 29 October 1969, granted on 19 October 1976, and expired in September 1993. Alprazolam was released in 1981. The first approved indication was panic disorder. Alprazolam was originally perceived to have been a poor investment, as Upjohn management did not believe there to be a market for panic disorder-oriented anxiolytics. However, alprazolam soon proved itself in clinical phase, FDA-mandated trials. It became a blockbuster drug with two years of its original marketing in the US market. Today, it is clinically known for not only anxiolytic properties, but also a forgiving and statistically significant anti-depressant profile, given its triazolebenzodiazepine skeletal structure, it does maintain some affinity for serotonergic receptors. Today it is the most commonly prescribed benzodiazepine in the United States, and has been available as generic instant-release and extended-release tablets for years. Alprazolam may be also be indicated for the treatment of Generalized Anxiety Disorder, as well as for the treatment of anxiety conditions with co-morbid depression. Alprazolam is also often prescribed with instances of hypersomnia and co-morbid sleep deficits. There is a substantial risk of abuse and dependence in both patients and non-medical users of alprazolam; the pharmacological properties of alprazolam such as high affinity binding, high potency, being short-acting and having a rapid onset of action increase the abuse potential of alprazolam. The physical dependence and withdrawal syndrome of alprazolam also adds to the addictive nature of alprazolam. In the small subgroup of individuals who escalate their doses there is usually a history of alcohol or other substance use disorders. Despite this, most prescribed alprazolam users do not misuse their medication, and the long-term use of benzodiazepines does not generally correlate with the need for dose escalation. However, based on US findings from the Treatment Episode Data Set (TEDS), an annual compilation of patient characteristics in substance abuse treatment facilities in the United States, admissions due to "primary tranquilizer" (including, but not limited to, benzodiazepine-type) drug use increased 79% from 1992 to 2002, suggesting that misuse of benzodiazepines may be on the rise. The New York Times also reported in 2011 that "The Centers for Disease Control and Prevention last year reported an 89 percent increase in emergency room visits nationwide related to nonmedical benzodiazepine use between 2004 and 2008." Alprazolam is one of the most commonly prescribed and misused benzodiazepines in the United States. A large-scale nationwide U.S. government study conducted by SAMHSA found that, in the U.S., benzodiazepines are recreationally the most frequently used pharmaceuticals due to their widespread availability, accounting for 35% of all drug-related visits to hospital emergency and urgent care facilities. Men and women use benzodiazepines recreationally as commonly. The report found that alprazolam is the most common benzodiazepine for recreational use followed by clonazepam, lorazepam, and diazepam. The number of emergency room visits due to benzodiazepines increased by 36% between 2004 and 2006. Regarding the significant increases detected, it is worthwhile to consider that the number of pharmaceuticals dispensed for legitimate therapeutic uses may be increasing over time, and DAWN estimates are not adjusted to take such increases into account. Nor do DAWN estimates take into account the increases in the population or in ED use between 2004 and 2006. At a particularly high risk for misuse and dependence are people with a history of alcoholism or drug abuse and/or dependence and people with borderline personality disorder. Alprazolam, along with other benzodiazepines, is often used with other recreational drugs. These uses include aids to relieve the panic or distress of dysphoric ("bad trip") reactions to psychedelic drugs, such as LSD, and the drug-induced agitation and insomnia in the "comedown" stages of stimulant use, such as amphetamine, allowing sleep. Alprazolam may also be used in conjunction with other depressant drugs, such as alcohol, marijuana, heroin or other opiates, in an attempt to enhance the psychological effect of these drugs. The poly-drug use of powerful depressant drugs poses the highest level of health concerns due to a significant increase in the likelihood of experiencing an overdose which may result in fatal respiratory depression. A 1990 study claimed that diazepam has a higher misuse potential relative to other benzodiazepines, and that some data suggests that alprazolam and lorazepam resemble diazepam in this respect. Anecdotally injection of alprazolam has been reported, causing dangerous damage to blood vessels, closure of blood vessels (embolization) and decay of muscle tissue (rhabdomyolysis). Alprazolam is practically not soluble in water, when crushed in water it will not fully dissolve (40 µg/ml of O2H at pH 7). There have also been anecdotal reports of alprazolam being snorted. Due to the low weight of a dose, alprazolam in one case was found to be distributed on blotter paper in a manner similar to LSD. Alprazolam is available in English-speaking countries under the following brand names: In the United States, alprazolam is a prescription drug and is assigned to Schedule IV of the Controlled Substances Act by the Drug Enforcement Administration. Under the UK drug misuse classification system benzodiazepines are class C drugs (Schedule 4). In the UK, alprazolam is not available on the NHS and can only be obtained on a private prescription. Internationally, alprazolam is included under the United Nations Convention on Psychotropic Substances as Schedule IV. In Ireland, alprazolam is a Schedule 4 medicine. In Sweden, alprazolam is a prescription drug in List IV (Schedule 4) under the Narcotics Drugs Act (1968). In the Netherlands, alprazolam is a List 2 substance of the Opium Law and is available for prescription. M: PSO/PSI mepr dsrd (o, p, m, p, a, d, s), sysi/epon, spvo proc (eval/thrp), drug (N5A/5B/5C/6A/6B/6D)

Eszopiclone
InChI=1S/C17H17ClN6O3/c1-22-6-8-23(9-7-22)17(26)27-16-14-13(19-4-5-20-14)15(25)24(16)12-3-2-11(18)10-21-12/h2-5,10,16H,6-9H2,1H3/t16-/m0/s1Yes 
Key:GBBSUAFBMRNDJC-INIZCTEOSA-NYes  Eszopiclone, marketed by Sepracor under the brand-name Lunesta, is a nonbenzodiazepine hypnotic which is slightly effective for insomnia. Eszopiclone is the active dextrorotatory stereoisomer of zopiclone, and belongs to the class of drugs known as cyclopyrrolones. Eszopiclone (Lunesta) along with other "Z-drugs" including zolpidem (Ambien), zaleplon (Sonata) are the most commonly prescribed sedative hypnotics in the USA. Eszopiclone is not marketed in the European Union following a 2009 decision by the EMA denying it new active substance status, in which it ruled that eszopiclone was too similar to zopiclone to be considered a new patentable product. Eszopiclone is slightly effective in the treatment of insomnia where difficulty in falling asleep is the primary complaint. The benefit over placebo is of questionable clinical significance. Although the drug effect and the placebo response were rather small and of questionable clinical importance, the two together produce a reasonably large clinical response. It is not recommended for chronic use in the elderly. Sedative hypnotic drugs including eszopiclone are more commonly prescribed to the elderly than to younger patients despite benefits of medication being generally unimpressive. Care should be taken in choosing an appropriate hypnotic drug and if drug therapy is initiated it should be initiated at the lowest possible dose to minimise side effects.An extensive review of the medical literature regarding the management of insomnia and the elderly found that there is considerable evidence of the effectiveness and durability of non-drug treatments for insomnia in adults of all ages and that these interventions are underutilized. Compared with the benzodiazepines, the nonbenzodiazepinesedative-hypnotics, including eszopiclone appeared to offer few, if any, significant clinical advantages in efficacy or tolerability in elderly persons. It was found that newer agents with novel mechanisms of action and improved safety profiles, such as the melatonin agonists, hold promise for the management of chronic insomnia in elderly people. Long-term use of sedative-hypnotics for insomnia lacks an evidence base and has traditionally been discouraged for reasons that include concerns about such potential adverse drug effects as cognitive impairment (anterograde amnesia), daytime sedation, motor incoordination, and increased risk of motor vehicle accidents and falls. In addition, the effectiveness and safety of long-term use of these agents remain to be determined. It was concluded that more research is needed to evaluate the long-term effects of treatment and the most appropriate management strategy for elderly persons with chronic insomnia. Eszopiclone has fewer anticholinergic side effects than racemic zopiclone. The following side effects may occur from usage of eszopiclone (Lunesta): Common side effects can include: Less common side effects can include: neuropsychiatric adverse effects reported include; If a person does not sleep immediately after taking eszopiclone or if they get up shortly after taking the medication they may experience dizziness, lightheadedness, hallucinations (seeing things or hearing voices that are not there), as well as problems with coordination and memory. In the United States Eszopiclone is a schedule IV controlled substance under the Controlled Substances Act. Use of benzodiazepines and similar benzodiazepine-like drugs such as eszopiclone may lead to physical and psychological dependence. The risk of abuse and dependence increases with the dose and duration of usage and concomitant use of other psychoactive drugs. The risk is also greater in patients with a history of alcohol or drug abuse or history of psychiatric disorders. Tolerance may develop after repeated use of benzodiazepines and benzodiazepine-like drugs for a few weeks. Eszopiclone was studied for up to 6 months in a group of patients which showed no signs of tolerance or dependence in a study funded and carried out by Sepracor. A study of abuse potential of eszopiclone found that in persons with a known history of benzodiazepine abuse, eszopiclone at doses of 6 and 12 mg produced effects similar to those of diazepam 20 mg . The study found that at these doses which are two or more times greater than the maximum recommended doses, a dose-related increase in reports of amnesia and hallucinations was observed for both eszopiclone (lunesta) as well as for diazepam (Valium). Eszopiclone is dangerous in overdose. Signs of eszopiclone overdose reported included dulled mental status, ST-elevation coronary vasospasm, troponemia, ventricular fibrillation arrest and prolonged coma (lasting up to 48 hours). Texas poison control centers reported that during 2005-2006 there were 525 total eszopiclone overdoses recorded in the state of Texas, the majority of which were intentional suicide attempts. If consumed within the last hour, eszopiclone overdose can be treated with the administration of activated charcoal or via gastric lavage. In potentially fatal overdose cases where eszopiclone has been consumed more than one hour before treatment, overdose symptoms may be successfully reversed with the intravenous administration of flumazenil, although this is not recommended for mixed overdoses. Eszopiclone acts on benzodiazepine binding site situated on neuronsAGABA as an agonist. Eszopiclone is rapidly absorbed after oral administration, with serum levels peaking between 1 and 1.3 hours. The elimination half-life of eszopiclone is approximately 6 hours and it is extensively metabolized by oxidation and demethylation. Approximately 52% to 59% of a dose is weakly bound to plasma protein. Cytochrome P450 (CYP) isozymes CYP3A4 and CYP2E1 are involved in the biotransformation of eszopiclone; thus, drugs that induce or inhibit these CYP isozymes may affect the metabolism of eszopiclone. Less than 10% of the orally administered dose is excreted in the urine as racemic zopiclone. In terms of benzodiazepine receptor binding and relevant potency, 3 mg of eszopiclone is equivalent to 10 mg of diazepam. The Journal of Clinical Sleep Medicine published a paper which had carried out a systematic review of the medical literature concerning insomnia medications including eszopiclone. The review found that almost all trials of sleep disorders and drugs are sponsored by the pharmaceutical industry. It was found that the odds ratio for finding results favorable to industry in industry-sponsored trials was 3.6 times higher than non-industry-sponsored studies. The paper found that there is little research into hypnotics that is independent from the drug manufacturers. The author was concerned that there is no discussion in the medical literature of adverse effects of sedative hypnotics such as significantly increased levels of infection; increased rates of cancers; increased mortality in eszopiclone and other sedative hypnotic drugs; and an overemphasis on the positive effects. The author concluded by stating that "major hypnotic trials are needed to more carefully study potential adverse effects of hypnotics such as daytime impairment, infection, cancer, and death and the resultant balance of benefits and risks." In a 2009 article in the New England Journal of Medicine, "Lost in Transmission — FDA Drug Information That Never Reaches Clinicians", it was reported that the largest of three Lunesta trials found that compared to placebo Lunesta "was superior to placebo" while it only shortened initial time falling asleep by 15 minutes on average. "Clinicians who are interested in the drug’s efficacy cannot find efficacy information in the label: it states only that Lunesta is superior to placebo. The FDA’s medical review provides efficacy data, albeit not until page 306 of the 403-page document. In the longest, largest phase 3 trial, patients in the Lunesta group reported falling asleep an average of 15 minutes faster and sleeping an average of 37 minutes longer than those in the placebo group. However, on average, Lunesta patients still met criteria for insomnia and reported no clinically meaningful improvement in next-day alertness or functioning." On September 11, 2007, Sepracor signed a marketing deal with British pharmaceutical company GlaxoSmithKline for the rights to sell Eszopiclone (under the name Lunivia rather than Lunesta) in Europe. Sepracor was expected to receive approximately 155 million dollars if the deal went through. In 2008 Sepracor submitted an application to the EMA (the European Union's equivalent to the US FDA) for authorization to market the drug in the EU, and initially received a favourable response. However Sepracor withdrew its authorization application in 2009 after the EMA stated it would not be granting eszopiclone 'new active substance' status, as it was essentially pharmacologically and therapeutically too similar to zopiclone to be considered a new patentable product. Since zopiclone's patent has expired, this ruling would have allowed rival companies to also legally produce cheaper generic versions of eszopiclone for the European market. As of November 2012[update], Sepracor has not resubmitted its authorization application and Lunesta/Lunivia is not available in Europe. The deal with GSK fell through, and GSK instead launched a $3.3 billion deal to market Actelion's Almorexant sleeping tablet, which entered stage three medical trials before development was abandoned due to side effects.

Diazepam
InChI=1S/C16H13ClN2O/c1-19-14-8-7-12(17)9-13(14)16(18-10-15(19)20)11-5-3-2-4-6-11/h2-9H,10H2,1H3Yes 
Key:AAOVKJBEBIDNHE-UHFFFAOYSA-NYes  Diazepam , first marketed as Valium by Hoffmann-La Roche, is a benzodiazepine drug. It is commonly used to treat anxiety, panic attacks, insomnia, seizures (including status epilepticus), muscle spasms (such as in tetanus cases), restless legs syndrome, alcohol withdrawal, benzodiazepine withdrawal, opiate withdrawal syndrome and Ménière's disease. 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. It possesses anxiolytic, anticonvulsant, hypnotic, sedative, skeletal muscle relaxant, and amnestic properties. The pharmacological action of diazepam enhances the effect of the neurotransmitter GABA by binding to the benzodiazepine site on the receptorAGABA (via the constituent chlorine atom) leading to central nervous system depression. Adverse effects of diazepam include anterograde amnesia (especially at higher doses) and sedation, as well as paradoxical effects such as excitement, rage or worsening of seizures in epileptics. Benzodiazepines also can cause or worsen depression. Long-term effects of benzodiazepines such as diazepam include tolerance, benzodiazepine dependence and benzodiazepine withdrawal syndrome upon dose reduction. After cessation of benzodiazepines, cognitive deficits may persist for at least six months and it was suggested that longer than six months may be needed for recovery from some deficits. Diazepam also has physical dependence potential and can cause serious problems of physical dependence with long term use. Compared to other benzodiazepines, though, physical withdrawal from diazepam following long term use is usually far more mild due to its long elimination half-life. Nevertheless, urgent action by national governments to improve prescribing practices has been recommended. Diazepam is the drug of choice for treating benzodiazepine dependence, with its low potency, long duration of action and the availability of low-dose tablets making it ideal for gradual dose reduction and the circumvention of withdrawal symptoms. Advantages of diazepam are a rapid onset of action][ and high efficacy rates, which is important for managing acute seizures, anxiety attacks and panic attacks; benzodiazepines also have a relatively low toxicity in overdose. Diazepam is a core medicine in the World Health Organization's Essential Drugs List, which list minimum medical needs for a basic health care system. Diazepam, first synthesized by Leo Sternbach, is used to treat a wide range of conditions, and has been one of the most frequently prescribed medications in the world since its launch in 1963. Diazepam is mainly used to treat anxiety, insomnia, and symptoms of acute alcohol withdrawal. It is also used as a premedication for inducing sedation, anxiolysis or amnesia before certain medical procedures (e.g., endoscopy). Intravenous diazepam or lorazepam are first line treatments for status epilepticus; However, lorazepam has advantages over diazepam, including a higher rate of terminating seizures and a more prolonged anticonvulsant effect. Diazepam is rarely used for the long-term treatment of epilepsy because tolerance to its anticonvulsant effects usually develops within six to 12 months of treatment, effectively rendering it useless for that purpose. Diazepam is used for the emergency treatment of eclampsia, when IV magnesium sulfate and blood pressure control measures have failed. Benzodiazepines do not have any pain-relieving properties themselves, and are generally recommended to avoid in individuals with pain. However, benzodiazepines such as diazepam can be used for their muscle-relaxant properties to alleviate pain caused by muscle spasms and various dystonias, including blepharospasm. Tolerance often develops to the muscle relaxant effects of benzodiazepines such as diazepam. Baclofen or tizanidine is sometimes used as an alternative to diazepam. The anticonvulsant effects of diazepam can help in the treatment of seizures due to a drug overdose or chemical toxicity as a result of exposure to sarin, VX, soman (or other organophosphate poisons; See #CANA), lindane, chloroquine, physostigmine, or pyrethroids Diazepam is sometimes used intermittently for the prophylaxis of febrile seizures caused by high fever in children and neonates under five years of age. Long-term use of diazepam for the management of epilepsy is not recommended; however, a subgroup individuals with treatment resistant epilepsy benefit from long-term benzodiazepines and for such individuals clorazepate has been recommended due to its slower onset of tolerance to the anticonvulsant effects. Diazepam has a broad spectrum of indications (most of which are off-label), including: Dosages should be determined on an individual basis, depending upon the condition being treated, severity of symptoms, patient body weight, and any comorbid conditions the patient may have. Diazepam is marketed in over 500 brands throughout the world. It is supplied in oral, injectable, inhalation and rectal forms. The United States military employs a specialized diazepam preparation known as CANA (Convulsive Antidote, Nerve Agent), which contains a mixture of diazepam, atropine and pralidoxime. One CANA kit is typically issued to service members, along with three Mark I NAAK kits, when operating in circumstances where chemical weapons in the form of nerve agents are considered a potential hazard. Both of these kits deliver drugs using autoinjectors. They are intended for use in "buddy aid" or "self aid" administration of the drugs in the field prior to decontamination and delivery of the patient to definitive medical care. Use of diazepam should be avoided, when possible, in individuals with the following conditions: Adverse effects of benzodiazepines such as diazepam include anterograde amnesia and confusion (especially pronounced in higher doses) and sedation. The elderly are more prone to adverse effects of diazepam, such as confusion, amnesia, ataxia and hangover effects, as well as falls. Long-term use of benzodiazepines such as diazepam is associated with tolerance, benzodiazepine dependence and benzodiazepine withdrawal syndrome. Like other benzodiazepines, diazepam can impair short-term memory and learning of new information. While benzodiazepine drugs such as diazepam can cause anterograde amnesia, they do not cause retrograde amnesia; information learned before using benzodiazepines is not impaired. Tolerance to the cognitive-impairing effects of benzodiazepines does not tend to develop with long-term use, and the elderly are more sensitive to them. Additionally after cessation of benzodiazepines cognitive deficits may persist for at least six months; it is unclear whether these impairments take longer than six months to abate or if they are permanent. Benzodiazepines may also cause or worsen depression. Infusions or repeated intravenous injections of diazepam when managing seizures for example may lead to drug toxicity, including respiratory depression, sedation and hypotension. Tolerance may also develop to infusions of diazepam if it is given for longer than 24 hours. Adverse effects such as sedation, benzodiazepine dependence and abuse potential limit the use of benzodiazepines. Diazepam has a range of side effects common to most benzodiazepines, including: Less commonly, paradoxical side effects can occur, including nervousness, irritability, excitement, worsening of seizures, insomnia, muscle cramps, changes in libido and in some cases, rage and violence. These adverse reactions are more likely to occur in children, the elderly, and individuals with a history of drug or alcohol abuse and or aggression. Diazepam may increase, in some people, the propensity toward self-harming behaviours and, in extreme cases, may provoke suicidal tendencies or acts. Very rarely dystonia can occur. Diazepam may impair the ability to drive vehicles or operate machinery. The impairment is worsened by consumption of alcohol, because both act as central nervous system depressants. During the course of therapy, tolerance to the sedative effects usually develops, but not to the anxiolytic and myorelaxant effects. Patients with severe attacks of apnea during sleep may suffer respiratory depression (hypoventilation), leading to respiratory arrest and death. Diazepam in doses of 5 mg or more causes significant deterioration in alertness performance combined with increased feelings of sleepiness. Diazepam, as with other benzodiazepine drugs, can cause tolerance, physical dependence, addiction and what is known as the benzodiazepine withdrawal syndrome. Withdrawal from diazepam or other benzodiazepines often leads to withdrawal symptoms similar to those seen during barbiturate or alcohol withdrawal. The higher the dose and the longer the drug is taken, the greater the risk of experiencing unpleasant withdrawal symptoms. Withdrawal symptoms can occur from standard dosages and also after short-term use, and can range from insomnia and anxiety to more serious symptoms, including seizures and psychosis. Withdrawal symptoms can sometimes resemble pre-existing conditions and be misdiagnosed. Diazepam may produce less intense withdrawal symptoms due to its long elimination half-life. Benzodiazepine treatment should be discontinued as soon as possible via a slow and gradual dose reduction regimen. Tolerance develops to the therapeutic effects of benzodiazepines; for example tolerance occurs to the anticonvulsant effects and as a result benzodiazepines are not generally recommended for the long-term management of epilepsy. Dose increases may overcome the effects of tolerance, but tolerance may then develop to the higher dose and adverse effects may increase. The mechanism of tolerance to benzodiazepines includes uncoupling of receptor sites, alterations in gene expression, down-regulation of receptor sites, and desensitisation of receptor sites to the effect of GABA. Approximately one-third of individuals who take benzodiazepines for longer than four weeks become dependent and experience a withdrawal syndrome upon cessation. Differences in rates of withdrawal (50–100%) vary depending on the patient sample. For example, a random sample of long-term benzodiazepine users typically finds around 50% experience little or no withdrawal symptoms, with the other 50% experiencing notable withdrawal symptoms. Certain select patient groups show a higher rate of notable withdrawal symptoms, up to 100%. Rebound anxiety, more severe than baseline anxiety, is also a common withdrawal symptom when discontinuing diazepam or other benzodiazepines. Diazepam is therefore only recommended for short-term therapy at the lowest possible dose owing to risks of severe withdrawal problems from low doses even after gradual reduction. There is a significant risk of pharmacological dependence on diazepam and patients experiencing symptoms of benzodiazepine withdrawal syndrome if it is taken for six weeks or longer. In humans tolerance to the anticonvulsant effects of diazepam occurs frequently. Improper or excessive use of diazepam can lead to psychological dependence/drug addiction. At a particularly high risk for diazepam misuse, abuse or psychological dependence are: Patients from the aforementioned groups should be monitored very closely during therapy for signs of abuse and development of dependence. Therapy should be discontinued if any of these signs are noted, although if physical dependence has developed, therapy must still be discontinued gradually to avoid severe withdrawal symptoms. Long-term therapy in these people is not recommended. People suspected of being physiologically dependent on benzodiazepine drugs should be very gradually tapered off the drug. Although rare, withdrawals can be life-threatening, particularly when excessive doses have been taken for extended periods of time. Equal prudence should be used whether dependence has occurred in therapeutic or recreational contexts. An individual who has consumed too much diazepam typically displays one or more of the following symptoms in a period of approximately four hours immediately following a suspected overdose: 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. Although 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. The oral 50LD (lethal dose in 50% of the population) of diazepam is 720 mg/kg in mice and 1240 mg/kg in rats. D. J. Greenblatt and colleagues reported in 1978 on two patients who had taken 500 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, esmethyldiazepam, oxazepam, and temazepam; according to samples taken in the hospital and as follow-up. Overdoses of diazepam with alcohol, opiates and/or other depressants may be fatal. An Australian study has found people who take sleeping pills or antianxiety medications are more dangerous on the roads than drunk drivers. 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 enhance the effects of diazepam, such as barbiturates, phenothiazines, narcotics and antidepressants. 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. Agents that have 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. Diazepam is a long-acting "classical" benzodiazepine. Other classical benzodiazepines include chlordiazepoxide, clonazepam, lorazepam, oxazepam, nitrazepam, temazepam, 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 from some other anticonvulsive drugs with which it was compared. 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 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 binds to a specific subunit on the AGABA receptor at a site distinct from the binding site of the endogenous GABA molecule, known as an allosteric site. The GABAA receptor is an inhibitory channel which, when activated, decreases neuronal activity. Benzodiazepines do not supplement for the neurotransmitter GABA, rather benzodiazepines such as diazepam bind to a different location on the GABAA receptor, resulting in enhanced GABA effects. Benzodiazepines cause an increased opening of the chloride ion channel when GABA binds to its site on the GABAA receptor, leading to more chloride ions entering the neuron, which in turn leads to enhanced central nervous system depressant effects. Diazepam binds non-selectively to alpha1, alpha2, alpha3 and alpha5 subunit containing GABAA receptors. Because of the role of diazepam as a positive allosteric modulator of GABA, when it binds to benzodiazepine receptors, it causes inhibitory effects. This arises from the hyperpolarization of the postsynaptic membrane, owing to the control exerted over negative chloride ions by GABAA receptors. Diazepam appears to act on areas of the limbic system, thalamus, and hypothalamus, inducing anxiolytic effects. Its actions are due to the enhancement of GABA activity. Benzodiazepine drugs including diazepam increase the inhibitory processes in the cerebral cortex. The anticonvulsant properties of diazepam and other benzodiazepines may be in part or entirely due to binding to voltage-dependent sodium channels rather than benzodiazepine receptors. Sustained repetitive firing seems limited by benzodiazepines' effect of slowing recovery of sodium channels from inactivation. The muscle relaxant properties of diazepam are produced via inhibition of polysynaptic pathways in the spinal cord. Diazepam can be administered orally, intravenously (IV) (needs to be diluted, as it is painful and damaging to veins), intramuscularly (IM), or as a suppository. When administered orally, it is rapidly absorbed and has a fast onset of action. The onset of action is one to five minutes for IV administration and 15–30 minutes for IM administration. The duration of diazepam's peak pharmacological effects is 15 minutes to one hour for both routes of administration. The bioavailability after oral administration is 100%, and 90% after rectal administration. Peak plasma levels occur between 30 and 90 minutes after oral administration and between 30 and 60 minutes after intramuscular administration; after rectal administration, peak plasma levels occur after 10 to 45 minutes. Diazepam is highly protein bound, with 96 to 99% of the absorbed drug being protein bound. The distribution half-life of diazepam is two to 13 minutes. When diazepam is administered IM, absorption is slow, erratic and incomplete. Diazepam is highly lipid-soluble, and is widely distributed throughout the body after administration. It easily crosses both the blood–brain barrier and the placenta, and is excreted into breast milk. After absorption, diazepam is redistributed into muscle and adipose tissue. Continual daily doses of diazepam quickly build to a high concentration in the body (mainly in adipose tissue), far in excess of the actual dose for any given day. Diazepam is stored preferentially in some organs, including the heart. Absorption by any administered route and the risk of accumulation is significantly increased in the neonate, and withdrawal of diazepam during pregnancy and breast feeding is clinically justified. Diazepam undergoes oxidative metabolism by demethylation (CYP 2C9, 2C19, 2B6, 3A4, and 3A5), hydroxylation (CYP 3A4 and 2C19) and glucuronidation in the liver as part of the cytochrome P450 enzyme system. It has several pharmacologically active metabolites. The main active metabolite of diazepam is desmethyldiazepam (also known as nordazepam or nordiazepam). Its other active metabolites include the minor active metabolites temazepam and oxazepam. These metabolites are conjugated with glucuronide, and are excreted primarily in the urine. Because of these active metabolites, the serum values of diazepam alone are not useful in predicting the effects of the drug. Diazepam has a biphasic half-life of about one to three days, and two to seven days for the active metabolite desmethyldiazepam. Most of the drug is metabolised; very little diazepam is excreted unchanged. The elimination half-life of diazepam and also the active metabolite desmethyldiazepam increases significantly in the elderly, which may result in prolonged action, as well as accumulation of the drug during repeated administration. Diazepam may be quantitated in blood or plasma to confirm a diagnosis of poisoning in hospitalized patients, provide evidence in an impaired driving arrest or to assist in a medicolegal death investigation. Blood or plasma diazepam concentrations are usually in a range of 0.1-1.0 mg/L in persons receiving the drug therapeutically, 1–5 mg/L in those arrested for impaired driving and 2–20 mg/L in victims of acute overdosage. Most commercial immunoassays for the benzodiazepine class of drugs cross-react with diazepam, but confirmation and quantitation is usually performed using chromatographic techniques. Diazepam occurs as solid white or yellow crystals with 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 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). Diazepam has a shelf life of five years for oral tablets and three years for IV/IM solutions. 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, so is not stored in plastic bottles or syringes, etc. It can absorb into 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. From a chemical point of view, diazepam, 7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one, is the most simple of all of the examined derivatives of 1,4-benzodiazepin-2-ones. Various ways for the synthesis of diazepam from 2-amino-5-chlorobenzophenone have been proposed. The first two ways consist of the direct cyclocondensation of 2-amino-5-chlorobenzophenone or 2-methylamino-5-chlorobenzophenone with the ethyl ester of glycine hydrochloride. The amide nitrogen atom of the obtained 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one, is methylated by dimethylsulfate, which leads to the formation of diazepam. The second way differs from the first in that the methylation of nitrogen is accomplished before the cyclocondensation reaction. To do this, the initial 2-amino-5-chlorobenzophenone is first tosylated by p-toluenesulfonylchloride and the obtained tosylate transformed into the N-sodium salt, which is then alkylated by dimethylsulfate. The resulting 2-N-tosyl-N-methyl-5-chlorobenzophenone is hydrolyzed in an acidic medium, giving 2-methylamino-5-chlorobenzophenone, which undergoes cyclocondensation by reaction with ethyl ester of glycine hydrochloride, forming the desired diazepam. Diazepam synthesis2.png Diazepam was the second benzodiazepine invented by Dr. Leo Sternbach of Hoffmann-La Roche at the company's Nutley, New Jersey, facility 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. 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). 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. Diazepam was the top-selling pharmaceutical in the United States from 1969 to 1982, with peak sales in 1978 2.3 billion tablets. Diazepam, along with oxazepam, nitrazepam and temazepam, represents 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, for example, forms of paresis. It is also the first line of defense for a rare disorder called stiff-person syndrome. In recent years, the public perception of benzodiazepines has become increasingly negative. Diazepam is a drug of potential abuse and can cause serious problems of addiction and as a result is scheduled. Urgent action by national governments has been recommended to improve prescribing patterns of benzodiazepines such as diazepam. A single dose of diazepam modulates the dopamine system in similar ways to how morphine and alcohol modulate the dopaminergic pathways. Between 50 and 64% of rats will self administer diazepam. Benzodiazepines including diazepam in animal studies have been shown to increase reward-seeking behaviours by increasing impulsivity, which may suggest an increased risk of addictive behavioural patterns with usage of diazepam or other benzodiazepines. In addition, diazepam has been shown to be able to substitute for the behavioural effects of barbiturates in a primate study. Diazepam has been found as an adulterant in heroin. Diazepam drug misuse can occur either through recreational misuse where the drug is taken to achieve a high or when the drug is continued long term against medical advice. Sometimes, it is used by stimulant users to "come down" and sleep and to help control the urge to binge. A large-scale, nationwide study conducted by SAMHSA found benzodiazepines in the USA are the most frequently abused pharmaceutical, with 35% of drug-related visits to the emergency department involving benzodiazepines. They are more commonly abused than opiate pharmaceuticals, which accounted for 32% of visits to the emergency department. No other pharmaceutical is more commonly abused than benzodiazepines. Males abuse benzodiazepines as commonly as females. Of drugs used in attempted suicide, benzodiazepines are the most commonly used pharmaceutical drug, with 26% of attempted suicides involving benzodiazepines. The most commonly abused benzodiazepine is, however, alprazolam. Clonazepam is the second-most-abused benzodiazepine. Lorazepam is the third-most-abused benzodiazepine, and diazepam the fourth-most-abused benzodiazepine in the USA. Benzodiazepines, including diazepam, nitrazepam, and flunitrazepam, account for the largest volume of forged drug prescriptions in Sweden, a total of 52% of drug forgeries being for benzodiazepines. Diazepam was detected in 26% of cases of people suspected of driving under the influence of drugs in Sweden, and its active metabolite nordazepam was detected in 28% of cases. Other benzodiazepines and zolpidem and zopiclone also were found in high numbers. Many drivers had blood levels far exceeding the therapeutic dose range, suggesting a high degree of abuse potential for benzodiazepines and zolpidem and zopiclone. In Northern Ireland in cases where drugs were detected in samples from impaired drivers who were not impaired by alcohol, benzodiazepines were found in 87% of cases. Diazepam was the most commonly detected benzodiazepine. Diazepam is regulated in most countries as a prescription drug: The State of California offers diazepam to condemned inmates as a pre-execution sedative as part of their lethal injection program. Diazepam is used as a short-term sedative and anxiolytic for cats and dogs. It is also used for short-term treatment of seizures in dogs and short-term and long-term treatment of seizures in cats. It can also be used as an appetite stimulant. For emergency treatment of seizures, the typical dose is 0.5cmg/kg intravenously, or 1–2c;mg/kg of the injectable solution administered in the rectum. M: TOX gen / txn pto ant M: CNS anat (n/s/m/p/4/e/b/d/c/a/f/l/g)/phys/devp noco (m/d/e/h/v/s)/cong/tumr, sysi/epon, injr proc, drug (N1A/2AB/C/3/4/7A/B/C/D) M: PSO/PSI mepr dsrd (o, p, m, p, a, d, s), sysi/epon, spvo proc (eval/thrp), drug (N5A/5B/5C/6A/6B/6D)

Lorazepam
InChI=1S/C15H10Cl2N2O2/c16-8-5-6-12-10(7-8)13(19-15(21)14(20)18-12)9-3-1-2-4-11(9)17/h1-7,15,21H,(H,18,20)Yes 
Key:DIWRORZWFLOCLC-UHFFFAOYSA-NYes  Lorazepam (trademarked as Ativan) is a high-potency, intermediate-duration, 3-hydroxy benzodiazepine drug, often used as a sedative. Lorazepam has all six intrinsic benzodiazepine effects: anxiolysis, anterograde amnesia, sedation/hypnosis, anticonvulsion, antiemesis and muscle relaxation. Lorazepam is used for the short-term treatment of anxiety, insomnia, acute seizures including status epilepticus, and sedation of hospitalized patients, as well as sedation of aggressive patients. Lorazepam is also the most common benzodiazepine used to decrease the likelihood of agitation and seizures in patients who have overdosed on stimulant drugs. Lorazepam's effects are of intermediate duration which, similar to other benzodiazepines, exerts its therapeutic effects via its interaction at benzodiazepine binding sites, which are located on receptorsAGABA in the central nervous system. Although its half-life is shorter than that of other benzodiazepines, its affinity for its receptor translates to a relatively longer duration of action but still shorter than that of diazepam, following a single IV administration. After its introduction in 1977, lorazepam's principal use was in treating anxiety. Among benzodiazepines, lorazepam has a relatively high addictive potential. Lorazepam also has misuse potential; the main types of misuse are for recreational purposes or continued use against medical advice. Its sedative-hypnotic and anterograde amnesic properties are sometimes used for criminal purposes in a manner similar to GHB. Long-term effects of benzodiazepines include tolerance, dependence, a benzodiazepine withdrawal syndrome, and cognitive impairments which may not completely reverse after cessation of treatment; however, for most patients, cognitive impairment is not severe. Withdrawal symptoms can range from anxiety and insomnia to seizures and psychosis. Due to tolerance and dependence, lorazepam is recommended for short-term use, up to two to four weeks only. Adverse effects, including anterograde amnesia, depression and paradoxical effects such as excitement or worsening of seizures, may occur. Children and the elderly are more sensitive to the adverse effects of benzodiazepines. Lorazepam impairs body balance and standing steadiness and is associated with falls and hip fractures in the elderly. Lorazepam has relatively potent anxiolytic effects and its best-known indication is the short-term management of severe anxiety; the FDA advises against use of benzodiazepines such as lorazepam for longer than four weeks. It is fast acting, and useful in treating fast onset panic anxiety. Lorazepam has strong sedative/hypnotic effects, and the duration of clinical effects from a single dose makes it an appropriate choice for the short-term treatment of insomnia, in particular in the presence of severe anxiety. It has a fairly short duration of action. Withdrawal symptoms, including rebound insomnia and rebound anxiety, may occur after only seven days' administration of lorazepam. Lorazepam is sometimes used for individuals receiving mechanical ventilation. However, in critically ill patients, propofol has been found to be superior to lorazepam both in effectiveness and overall cost; as a result, the use of propofol for this indication is now encouraged, whereas the use of lorazepam is discouraged. Its relatively potent amnesic effect, with its anxiolytic and sedative effects, makes lorazepam useful as premedication. It is given before a general anaesthetic to reduce the amount of anaesthetic agent required, or before unpleasant awake procedures, such as in dentistry or endoscopies, to reduce anxiety, to increase compliance, and to induce amnesia for the procedure. Oral lorazepam is given 90 to 120 minutes before procedures, and intravenous lorazepam as late as 10 minutes before procedures. Lorazepam is sometimes used as an alternative to midazolam in palliative sedation. In intensive care units lorazepam is sometimes used to produce anxiolysis, hypnosis, and amnesia. Intravenous diazepam or lorazepam are first-line treatments for convulsive status epilepticus. Lorazepam is more effective than diazepam in the treatment of status epilepticus. However, phenobarbitol has a superior success rate compared to lorazepam and other drugs, at least in the elderly. Its marked anticonvulsant properties, and its pharmacokinetic profile, make intravenous lorazepam a reliable agent for terminating acute seizures, but it has relatively prolonged sedation after-effects. Oral lorazepam, and other benzodiazepines, have a role in long-term prophylactic treatment of resistant forms of petit mal epilepsy, but not as first-line therapies, mainly because of the development of tolerance to their effects. Lorazepam's anticonvulsant and CNS depressant properties are useful for the treatment and prevention of alcohol withdrawal syndrome. In this setting, impaired liver function is not a hazard with lorazepam, since lorazepam does not require oxidation, hepatic or otherwise, for its metabolism. Lorazepam is sometimes used as an alternative to haloperidol when there is the need for rapid sedation of violent or agitated individuals, but haloperidol plus promethazine is preferred due to better effectiveness and due to lorazepam's adverse effects on respiratory function. However, adverse effects such as behavioural disinhibition may make benzodiazepines inappropriate for some acutely psychotic patients. Acute delirium is sometimes treated with lorazepam, but as it can cause paradoxical effects, it is preferably given together with haloperidol. Lorazepam is absorbed relatively slowly if given intramuscularly, a common route in restraint situations. Catatonia with inability to speak is responsive and sometimes controlled with a single 2-mg oral, or slow intravenous dose of lorazepam. Symptoms may recur and treatment for some days may be necessary. Catatonia due to abrupt or too rapid withdrawal from benzodiazepines, as part of the benzodiazepine withdrawal syndrome, should also respond to lorazepam treatment. As lorazepam can have paradoxical effects, haloperidol is sometimes given concomitantly. It is sometimes used in chemotherapy as an adjunct to antiemetics for treating anticipatory nausea and vomiting, i.e. nausea and vomiting caused or worsened by psychological sensitization to the thought of being sick. It is also used as adjunct therapy for cyclic vomiting syndrome. Lorazepam is also used to treat acute symptoms of vertigo and dizziness for people with Ménière's disease][. Pure lorazepam is an almost white powder that is nearly insoluble in water and oil. In medicinal form, it is mainly available as tablets and a solution for injection, but, in some locations, it is also available as a skin patch, an oral solution, and a sublingual tablet. Lorazepam tablets and syrups are administered by mouth only. Lorazepam tablets of the Ativan brand also contain lactose, microcrystalline cellulose, polacrilin, magnesium stearate, and colouring agents (indigo carmine—E132—in blue tablets and tartrazine—E102— in yellow tablets). Lorazepam for injection formulated with polyethylene glycol 400 in propylene glycol with 2.0% benzyl alcohol as preservative. Lorazepam injectable solution is administered either by deep intramuscular injection or by intravenous injection. The injectable solution comes in 1 ml ampoules containing 2 or 4 mg of lorazepam. The solvents used are polyethylene glycol 400 and propylene glycol. As a preservative, the injectable solution contains benzyl alcohol. Toxicity from propylene glycol has been reported in the case of a patient receiving a continuous lorazepam infusion. Intravenous injections should be given slowly and patients closely monitored for side effects, such as respiratory depression, hypotension, or loss of airway control. Peak effects roughly coincide with peak serum levels, which occur 10 minutes after intravenous injection, up to 60 minutes after intramuscular injection, and 90 to 120 minutes after oral administration, but initial effects will be noted before this. A clinically relevant lorazepam dose will normally be effective for six to 12 hours, making it unsuitable for regular once-daily administration, so it is usually prescribed as two to four daily doses when taken regularly, but this may be extended to five or six, especially in the case of elderly patients who could not handle large doses at once. Any of the five intrinsic benzodiazepine effects possessed by lorazepam (sedative/hypnotic, muscle relaxant, anxiolytic, amnesic, and anticonvulsant) may be considered as adverse or side effects if unwanted. Adverse effects can include sedation and hypotension; the effects of lorazepam are increased in combination with other CNS depressant drugs. Other adverse effects include confusion, ataxia, anterograde amnesia and hangover effects. With long-term use of benzodiazepines, it is unclear whether cognitive impairments fully return to normal after cessation of therapy; cognitive deficits persist for at least six months after withdrawal, but longer than six months may be required for recovery of cognitive function. Lorazepam appears to have more profound adverse effects on memory than other benzodiazepines; it impairs both explicit and implicit memory. In the elderly, falls may occur as a result of benzodiazepines. Adverse effects are more common in the elderly, and they appear at lower doses than in younger patients. Benzodiazepines can cause or worsen depression. Paradoxical effects can also occur, such as worsening of seizures, or paradoxical excitement; paradoxical excitement is more likely to occur in the elderly, children, those with a history of alcohol abuse and in people with a history of aggression or anger problems. Lorazepam's effects are dose-dependent, meaning the higher the dose, the stronger the effects (and side effects) will be. Using the smallest dose needed to achieve desired effects lessens the risk of adverse effects. Sedation is the side effect for which most patients complain. In a group of around 3500 patients treated for anxiety, the most common side effects complained of from lorazepam were sedation (15.9%), dizziness (6.9%), weakness (4.2%), and unsteadiness (3.4%). Side effects such as sedation and unsteadiness increased with age. Cognitive impairment, behavioural disinhibition and respiratory depression as well as hypotension may also occur. High-dose or prolonged parentally administered lorazepam is sometimes associated with propylene glycol intoxication. Lorazepam should be avoided in people with: Dependence typified by a withdrawal syndrome occurs in about one-third of individuals who are treated for longer than four weeks with a benzodiazepine. Higher doses and longer periods of use increase the risk of developing a benzodiazepine dependence. Potent benzodiazepines, such as lorazepam, alprazolam, and triazolam, have the highest risk of causing a dependence. Tolerance to benzodiazepine effects develops with regular use. This is desirable with amnesic and sedative effects, but undesirable with anxiolytic, hypnotic, and anticonvulsant effects. Patients at first experience drastic relief from anxiety and sleeplessness, but symptoms gradually return, relatively soon in the case of insomnia, but more slowly in the case of anxiety symptoms. After four to six months of regular benzodiazepine use, evidence of continued efficacy declines. If regular treatment is continued for longer than this, dose increases may be necessary to maintain effects, but treatment-resistant symptoms may in fact be benzodiazepine withdrawal symptoms. Due to the development of tolerance to the anticonvulsant effects, benzodiazepines are generally not recommended for long-term use for the management of epilepsy. Increasing the dose may overcome tolerance, but tolerance may then develop to the higher dose and adverse effects may persist and worsen. The mechanism of tolerance to benzodiazepines is complex and involves receptorAGABA downregulation, alterations to subunit configuration of GABAA receptors, uncoupling and internalisation of the benzodiazepine binding site from the GABAA receptor complex as well as changes in gene expression. The likelihood of dependence is relatively high with lorazepam compared to other benzodiazepines. Lorazepam's relatively short serum half-life, its confinement mainly to the vascular space, and its inactive metabolite, results in interdose withdrawal phenomena and next-dose cravings. This may reinforce psychological dependence. Because of its high potency, the smallest lorazepam tablet strength of 0.5 mg is also a significant dose reduction (in the UK, the smallest tablet strength is 1.0 mg, which further accentuates this difficulty). To minimise the risk of physical/psychological dependence, lorazepam is best used only short-term, at the smallest effective dose. If any benzodiazepine has been used long-term, the recommendation is a gradual dose taper over a period of weeks, months or longer, according to dose and duration of use, degree of dependence and the individual. Coming off long-term lorazepam use may be more realistically achieved by a gradual switch to an equivalent dose of diazepam, a period of stabilization on this and only then initiating dose reductions. The advantage of switching to diazepam is dose reductions are felt less acutely, because of the longer half-lives (20–200 hours) of diazepam and its active metabolites. On abrupt or overly rapid discontinuation of lorazepam, anxiety and signs of physical withdrawal have been observed, similar to those seen on withdrawal from alcohol and barbiturates. Lorazepam, as with other benzodiazepine drugs, can cause physical dependence, addiction, and benzodiazepine withdrawal syndrome. The higher the dose and the longer the drug is taken, the greater the risk of experiencing unpleasant withdrawal symptoms. Withdrawal symptoms can, however, occur from standard dosages and also after short-term use. Benzodiazepine treatment should be discontinued as soon as possible via a slow and gradual dose reduction regimen. Rebound effects often resemble the condition being treated, but typically at a more intense level and may be difficult to diagnose. Withdrawal symptoms can range from mild anxiety and insomnia to more severe symptoms such as seizures and psychosis. The risk and severity of withdrawal is increased with long-term use, use of high doses, abrupt or over-rapid reduction, among other factors. Short-acting benzodiazepines such as lorazepam are more likely to cause a more severe withdrawal syndrome compared to longer-acting benzodiazepines. Withdrawal symptoms can occur after taking therapeutic doses of Ativan for as little as one week. Withdrawal symptoms include headaches, anxiety, tension, depression, insomnia, restlessness, confusion, irritability, sweating, dysphoria, dizziness, derealization, depersonalization, numbness/tingling of extremities, hypersensitivity to light, sound, and smell, perceptual distortions, nausea, vomiting, diarrhea, appetite loss, hallucinations, delirium, seizures, tremor, stomach cramps, myalgia, agitation, palpitations, tachycardia, panic attacks, short-term memory loss, and hyperthermia. It takes about 18–36 hours for the benzodiazepine to be removed from the body. The ease of addiction to lorazepam, (Ativan brand was particularly cited), and its withdrawal were brought to the attention of the British public during the early 1980s in Esther Rantzen's BBC TV series That's Life!, in a feature on the drug over a number of episodes. Lorazepam is not usually fatal in overdose, but may cause fatal respiratory depression if taken in overdose with alcohol. The combination also causes synergistic enhancement of the disinhibitory and amnesic effects of both drugs, with potentially embarrassing or criminal consequences. Some experts advise that patients should be warned against drinking alcohol while on lorazepam treatment, but such clear warnings are not universal. Synergistic adverse effects may also occur when lorazepam is administered with other drugs, such as opioids or other hypnotics. Lorazepam may also interact with rifabutin. Valproate inhibits the metabolism of lorazepam, whereas carbamazepine, lamotrigine, phenobarbital, phenytoin, and rifampin increase its rate of metabolism. Some antidepressants, antiepileptic drugs such as phenobarbital, phenytoin and carbamazepine, sedative antihistamines, opiates, antipsychotics and alcohol, when taken with lorazepam may result in enhanced sedative effects. In cases of a suspected lorazepam overdose, it is important to establish whether the patient is a regular user of lorazepam or other benzodiazepines, since regular use causes tolerance to develop. Also, one must ascertain whether other drugs were also ingested. Signs of overdose range through mental confusion, dysarthria, paradoxical reactions, drowsiness, hypotonia, ataxia, hypotension, hypnotic state, coma, cardiovascular depression, respiratory depression, and death. Early management of alert patients includes emetics, gastric lavage, and activated charcoal. Otherwise, management is by observation, including of vital signs, support and, only if necessary, considering the hazards of doing so, giving intravenous flumazenil. Patients are ideally nursed in a kind, nonfrustrating environment, since, when given or taken in high doses, benzodiazepines are more likely to cause paradoxical reactions. If shown sympathy, even quite crudely feigned, patients may respond solicitously, but they may respond with disproportionate aggression to frustrating cues. Opportunistic counseling has limited value here, as the patient is unlikely to recall this later, owing to drug-induced anterograde amnesia. Lorazepam may be quantitated in blood or plasma to confirm a diagnosis of poisoning in hospitalized patients, provide evidence in an impaired driving arrest or to assist in a medicolegal death investigation. Blood or plasma concentrations are usually in a range of 10-300 ug/l in persons either receiving the drug therapeutically or in those arrested for impaired driving. Approximately 300-1000 ug/l is found in victims of acute overdosage. Lorazepam has anxiolytic, sedative, hypnotic, amnesic, anticonvulsant, and muscle relaxant properties. It is a high-potency and an intermediate-acting benzodiazepine, and its uniqueness, advantages, and disadvantages are largely explained by its pharmacokinetic properties (poor water and lipid solubility, high protein binding and anoxidative metabolism to a pharmacologically inactive glucuronide form) and by its high relative potency (lorazepam 1–2 mg is equal in effect to diazepam 10 to 20 mg). The half-life of lorazepam is 10–20 hours. Lorazepam is highly protein bound and is extensively metabolised into pharmacologically inactive metabolites. Due to its poor lipid solubility, lorazepam is absorbed relatively slowly by mouth and is unsuitable for rectal administration. However, its poor lipid solubility and high degree of protein binding (85-90%) mean its volume of distribution is mainly the vascular compartment, causing relatively prolonged peak effects. This contrasts with the highly lipid-soluble diazepam, which, although rapidly absorbed orally or rectally, soon redistributes from the serum to other parts of the body, in particular body fat. This explains why one lorazepam dose, despite its shorter serum half-life, has more prolonged peak effects than an equivalent diazepam dose. Ativan (lorazepam) is rapidly conjugated at its 3-hydroxy group into lorazepam glucuronide which is then excreted in the urine. Lorazepam glu-curonide has no demonstrable CNS activity in animals. The plasma levels of lorazepam are proportional to the dose given. There is no evidence of accumulation of lorazepam on administration up to six months. On regular administration, diazepam will accumulate, since it has a longer half-life and active metabolites, these metabolites also have long half-lives. Clinical example: Diazepam has long been a drug of choice for status epilepticus; its high lipid solubility means it gets absorbed with equal speed whether given orally, or rectally (nonintravenous routes are convenient in outside hospital settings), but diazepam's high lipid solubility also means it does not remain in the vascular space, but soon redistributes into other body tissues. So, it may be necessary to repeat diazepam doses to maintain peak anticonvulsant effects, resulting in excess body accumulation. Lorazepam is a different case; its low lipid solubility makes it relatively slowly absorbed by any route other than intravenously, but once injected, it will not get significantly redistributed beyond the vascular space. Therefore, lorazepam's anticonvulsant effects are more durable, thus reducing the need for repeated doses. If a patient is known to usually stop convulsing after only one or two diazepam doses, it may be preferable because sedative after effects will be less than if a single dose of lorazepam is given (diazepam anticonvulsant/sedative effects wear off after 15–30 minutes, but lorazepam effects last 12–24 hours). The prolonged sedation from lorazepam may, however, be an acceptable trade-off for its reliable duration of effects, particularly if the patient needs to be transferred to another facility. Although lorazepam is not necessarily better than diazepam at initially terminating seizures, lorazepam is, nevertheless, replacing diazepam as the intravenous agent of choice in status epilepticus. Lorazepam serum levels are proportional to the dose administered. Giving 2 mg oral lorazepam will result in a peak total serum level of around 20 ng/ml around two hours later, half of which is lorazepam, half its inactive metabolite, lorazepam-glucuronide. A similar lorazepam dose given intravenously will result in an earlier and higher peak serum level, with a higher relative proportion of unmetabolised (active) lorazepam. On regular administration, maximum serum levels are attained after three days. Longer-term use, up to six months, does not result in further accumulation. On discontinuation, lorazepam serum levels become negligible after three days and undetectable after about a week. Lorazepam is metabolised in the liver by conjugation into inactive lorazepam-glucuronide. This metabolism does not involve hepatic oxidation, so is relatively unaffected by reduced liver function. Lorazepam-glucuronide is more water-soluble than its precursor, so gets more widely distributed in the body, leading to a longer half-life than lorazepam. Lorazepam-glucuronide is eventually excreted by the kidneys, and, because of its tissue accumulation, it remains detectable, particularly in the urine, for substantially longer than lorazepam. Relative to other benzodiazepines, lorazepam is thought to have high affinity for GABA receptors, which may also explain its marked amnesic effects. Its main pharmacological effects are the enhancement of the effects of GABA at the GABAA receptor. Benzodiazepines, such as lorazepam, enhance the effects of GABA at the GABAA receptor via increasing the frequency of opening of the chloride ion channel on the GABAA receptors; which results in the therapeutic actions of benzodiazepines. They, however, do not on their own enhance the GABAA receptors, but require the neurotransmitter GABA to be present. Thus, the effect of benzodiazepines is to enhance the effects of the neurotransmitter GABA. The magnitude and duration of lorazepam effects are dose-related, meaning larger doses have stronger and longer-lasting effects, because the brain has spare benzodiazepine drug receptor capacity, with single, clinical doses leading only to an occupancy of some 3% of the available receptors. The anticonvulsant properties of lorazepam and other benzodiazepines may be, in part or entirely, due to binding to voltage-dependent sodium channels rather than benzodiazepine receptors. Sustained repetitive firing seems to get limited, by the benzodiazepine effect of slowing recovery of sodium channels from inactivation in mouse spinal cord cell cultures. Lorazepam is synthesized according to a scheme containing some of the same elements for the synthesis of chlordiazepoxide and oxazepam. Lorazepam synthesis.png Historically, lorazepam is one of the "classical" benzodiazepines. Others include diazepam, clonazepam, oxazepam, nitrazepam, flurazepam, bromazepam and clorazepate. Lorazepam was first introduced by Wyeth Pharmaceuticals in 1977 under the brand names Ativan and Temesta. The drug was developed by President of Research, D.J. Richards. Wyeth's original patent on lorazepam is expired in the United States, but the drug continues to be commercially viable. As a measure of its ongoing success, it has been marketed under more than 70 brand names since then: Almazine, Alzapam, Anxiedin, Anxira, Anzepam, Aplacasse, Aplacassee, Apo-Lorazepam, Aripax, Azurogen, Bonatranquan, Bonton, Control, Donix, Duralozam, Efasedan, Emotion, Emotival, Idalprem, Kalmalin, Larpose, Laubeel, Lopam, Lorabenz, Loram, Lorans, Lorapam, Lorat, Lorax, Lorazene, Lorazep, Lorazepam, Lorazin, Lorafen (PL), Lorazon, Lorenin, Loresta, Loridem, Lorivan, Lorsedal, Lorzem, Lozepam, Merlit, Nervistop L, Nervistopl, NIC, Novhepar, Novolorazem, Orfidal, Piralone, Placidia, Placinoral, Punktyl, Quait, Renaquil, Rocosgen, Securit, Sedarkey, Sedatival, Sedizepan, Sidenar, Silence, Sinestron, Somnium, Stapam, Tavor, Titus, Tolid, Tranqil, Tranqipam, Trapax, Trapaxm, Trapex, Upan, Wintin, and Wypax. In 2000, the U.S. drug company Mylan agreed to pay $147 million to settle accusations by the FTC that they had raised the price of generic lorazepam by 2600% and generic clorazepate by 3200% in 1998 after having obtained exclusive licensing agreements for certain ingredients. Early lorazepam marketing, a 1977 direct-to-patient advertisement implying its positive effects: "Now it can be yours - The Ativan Experience." 1987 Ativan advertisement. "In a world where certainties are few...no wonder Ativan is prescribed by so many caring clinicians." Lorazepam is also used for other purposes, such as recreational use, wherein the drug is taken to achieve a high, or when the drug is continued long-term against medical advice. In addition to recreational use, benzodiazepines may be diverted and used to facilitate crime: Criminals may take them to deliberately seek disinhibition before committing crimes (which increases their potential for violence). The anterograde amnesia and sedative-hypnotic effects of benzodiazepines such as lorazepam are sometimes used by predators on unwitting victims as date rape drugs, or for the purpose of robbery; however, alcohol is the most common drug involved in such crimes. A large-scale, nationwide, U.S. government study of pharmaceutical-related emergency room (ER) visits by SAMHSA found sedative-hypnotics are the pharmaceuticals most frequently used outside of their prescribed medical purpose in the United States, with 35% of drug-related emergency room visits involving sedative-hypnotics. In this category, benzodiazepines are most commonly used. Males and females use benzodiazepines for nonmedical purposes equally. Of drugs used in attempted suicide, benzodiazepines are the most commonly used pharmaceutical drugs, with 26% of attempted suicides involving them. Lorazepam was the third-most-common benzodiazepine used outside of prescription in these ER visit statistics. Lorazepam is a Schedule IV drug under the Controlled Substances Act in the U.S. and internationally under the United Nations Convention on Psychotropic Substances. It is a Schedule IV drug under the Controlled Drugs and Substances Act in Canada. In the United Kingdom, it is a Class C, Schedule 4 Controlled Drug under the Misuse of Drugs Regulations 2001. M: CNS anat (n/s/m/p/4/e/b/d/c/a/f/l/g)/phys/devp noco (m/d/e/h/v/s)/cong/tumr, sysi/epon, injr proc, drug (N1A/2AB/C/3/4/7A/B/C/D) M: PSO/PSI mepr dsrd (o, p, m, p, a, d, s), sysi/epon, spvo proc (eval/thrp), drug (N5A/5B/5C/6A/6B/6D) M: DIG anat (t, g, p)/phys/devp/enzy noco/cong/tumr, sysi/epon proc, drug (A2A/2B/3/4/5/6/7/14/16), blte Note: See the receptor PAMsAGABA navbox for a full list of GABAA positive allosteric modulators.

Zolpidem
InChI=1S/C19H21N3O/c1-13-5-8-15(9-6-13)19-16(11-18(23)21(3)4)22-12-14(2)7-10-17(22)20-19/h5-10,12H,11H2,1-4H3Yes 
Key:ZAFYATHCZYHLPB-UHFFFAOYSA-NYes  Zolpidem (brand names Ambien, Ambien CR, Intermezzo, Stilnox, and Sublinox) is a prescription medication used for the treatment of insomnia and some brain disorders. It is a short-acting nonbenzodiazepine hypnotic of the imidazopyridine class that potentiates GABA, an inhibitory neurotransmitter, by binding to receptorsAGABA at the same location as benzodiazepines. It works quickly, usually within 15 minutes, and has a short half-life of two to three hours. Zolpidem has not adequately demonstrated effectiveness in maintaining sleep, unless delivered in a controlled-release (CR) form. However, it is effective in initiating sleep. Its hypnotic effects are similar to those of the benzodiazepine class of drugs, but it is molecularly distinct from the classical benzodiazepine molecule and is classified as an imidazopyridine. Flumazenil, a benzodiazepine receptor antagonist, which is used for benzodiazepine overdose, can also reverse zolpidem's sedative/hypnotic and memory-impairing effects. As a muscle relaxant and anticonvulsant, the drug's effects are not evident until dosages 10 and 20 times those required for sedation, respectively, are reached. For that reason, zolpidem has never been approved for either muscle relaxation or seizure prevention. Such drastically increased doses are also more inclined to induce one or more of the drug's adverse side effects, including hallucinations and amnesia. The United States patent for zolpidem was held by the French pharmaceutical corporation Sanofi-Aventis. On April 23, 2007, the U.S. Food and Drug Administration (FDA) approved 13 generic versions of zolpidem tartrate. Zolpidem is available from several generic manufacturers in the UK, as a generic from Sandoz in South Africa and TEVA in Israel, as well as from other manufacturers such as Ratiopharm (Germany). On 2012, a study published in the BMJ Open journal revealed that sleeping pills, including zolpidem, are associated with a higher risk of death and cancer diagnosis. Nevertheless, the study only showed a link, and did not prove the deaths were caused by the pills or by other symptoms related to insomnia. On January 10, 2013, the Food and Drug Administration announced it is requiring the manufacturer of Ambien and Zolpimist to cut the recommended dosage for women in half, after laboratory studies showed that the medicines can leave patients drowsy in the morning and at risk for car accidents.The FDA recommended that manufacturers extend the new dosage cuts to men as well, who process the drug at a faster rate. However, the reasons why men and women catabolize the drugs at different rates is still unknown. In May 2013, the FDA approved label changes specifying new dosage recommendations for Zolpidem products because of concerns regarding next-morning impairment. Clinicians prescribe zolpidem for short-term (usually about two to six weeks) treatment of insomnia. Zolpidem has not proven effective in maintaining sleep, but addresses sleep-initiation problems. The effect over placebo is of marginal clinical benefit. Side effects may include: Some users have reported unexplained sleepwalking][ while using zolpidem, as well as sleep driving, binge eating while asleep, and performing other daily tasks while sleeping. Research by Australia's National Prescribing Service found these events occur mostly after the first dose taken, or within a few days of starting therapy. Rare reports of sexual parasomnia episodes related to zolpidem intake have also been reported. Sleepwalkers can sometimes perform these tasks as normally as they might if they were awake. They can sometimes carry on complex conversations and respond appropriately to questions or statements, so much so that observers may believe them to be awake. This is in contrast to "typical" sleep talking, which can usually be identified easily and is characterised by incoherent speech that often has no relevance to the situation or that is so disorganised as to be completely unintelligible. Those under the influence of this medication may seem fully aware of their environments, though they are still asleep. This can bring about concerns for the safety of the sleepwalkers and others. These side effects may be related to the mechanism that also causes zolpidem to produce its hypnotic properties. It is unclear whether the drug is responsible for the behavior, but a class-action lawsuit was filed against Sanofi-Aventis in March 2006 on behalf of those who reported symptoms. Conversely, it is possible some users believed they were asleep during these events because they do not remember the events, due to the short-term memory loss and anterograde amnesia side effects. Residual 'hangover' effects, such as sleepiness and impaired psychomotor and cognitive function, may persist into the day following nighttime administration. Such effects may impair the ability of users to drive safely and increase risks of falls and hip fractures. The Sydney Morning Herald in Australia in 2007 reported a man who fell 30 meters to his death from a high-rise unit balcony may have been sleepwalking under the influence of Stilnox. The coverage prompted over 40 readers to contact the newspaper with their own accounts of Stilnox-related automatism, and as of March 2007[update], the drug was under review by the Adverse Drug Reactions Advisory Committee. In February 2008, the Australian Therapeutic Goods Administration attached a Black Box Warning to zolpidem, stating, that "Zolpidem may be associated with potentially dangerous complex sleep-related behaviours that may include sleep walking, sleep driving, and other bizarre behaviours. Zolpidem is not to be taken with alcohol. Caution is needed with other CNS depressant drugs. Limit use to four weeks maximum under close medical supervision." This report received widespread media coverage after the death of Australian student Mairead Costigan, who fell 20 m from the Sydney Harbour Bridge while under the influence of Stilnox. A review medical publication found long-term use of zolpidem is associated with drug tolerance, drug dependence, rebound insomnia and CNS-related adverse effects. It was recommended that zolpidem be used for short periods of time using the lowest effective dose. Zolpidem 10 mg is effective in treating insomnia when used intermittently no fewer than three and no more than five pills per week for a period of 12 weeks. The 15-mg zolpidem dosage provided no clinical advantage over the 10-mg zolpidem dosage. Nonpharmacological treatment options (e.g. cognitive behavioral therapy for insomnia), however, were found to have sustained improvements in sleep quality. Animal studies of the tolerance-inducing properties have shown that in rodents, zolpidem has less tolerance-producing potential than benzodiazepines, but in primates the tolerance-producing potential of zolpidem was the same as that of benzodiazepines. Tolerance to the effects of zolpidem can develop in some people in just a few weeks. Abrupt withdrawal may cause delirium, seizures, or other severe effects, especially if used for prolonged periods and at high dosages. When drug tolerance and physical dependence to zolpidem has developed, treatment usually entails a gradual dose reduction over a period of months to minimise withdrawal symptoms, which can resemble those seen during benzodiazepine withdrawal. Failing that, an alternative method may be necessary for some patients, such as a switch to a benzodiazepine equivalent dose of a longer-acting benzodiazepine drug, such as diazepam or chlordiazepoxide, followed by a gradual reduction in dosage of the long-acting benzodiazepine. Sometimes for difficult-to-treat patients, an inpatient flumazenil rapid detoxification program can be used to detoxify from a zolpidem drug dependence or addiction. Alcohol has cross tolerance with GABAA receptor positive modulators such as the benzodiazepines and the nonbenzodiazepine drugs. For this reason, alcoholics or recovering alcoholics may be at increased risk of physical dependency on zolpidem. Also, alcoholics and drug abusers may be at increased risk of abusing and or becoming psychologically dependent on zolpidem. It should be avoided in those with a history of alcoholism, drug misuse, physical dependency, or psychological dependency on sedative-hypnotic drugs. Zolpidem has rarely been associated with drug-seeking behavior, the risk of which is amplified in patients with a history of drug or alcohol abuse. An overdose of zolpidem may cause excessive sedation, pin-point pupils, or depressed respiratory function, which may progress to coma, and possibly death. Combined with alcohol, opiates, or other CNS depressants, it may be even more likely to lead to fatal overdoses. Zolpidem overdosage can be treated with the benzodiazepine receptor antagonist flumazenil, which displaces zolpidem from its binding site on the benzodiazepine receptor to rapidly reverse the effects of the zolpidem. Zolpidem may be quantitated in blood or plasma to confirm a diagnosis of poisoning in hospitalized patients, provide evidence in an impaired driving arrest, or to assist in a medicolegal death investigation. Blood or plasma zolpidem concentrations are usually in a range of 30–300 μg/l in persons receiving the drug therapeutically, 100–700 μg/l in those arrested for impaired driving, and 1000–7000 μg/l in victims of acute overdosage. Analytical techniques, in general, involve gas or liquid chromatography. Use of zolpidem may impair driving skills with a resultant increased risk of road traffic accidents. This adverse effect is not unique to zolpidem but also occurs with other hypnotic drugs. Caution should be exercised by motor vehicle drivers. Studies showed that eight hours after a 10 mg bedtime dose, 15% of women and 3% of men would have blood levels which producing impaired driving skills; for a 12.5 mg extended-release dose, the risk increased to 33% and 25%, respectively. Consequently, the FDA recommended the dose for women be reduced for women and that prescribers should consider lower doses for men. The elderly are more sensitive to the effects of hypnotics including zolpidem. Zolpidem causes an increased risk of falls and may induce adverse cognitive effects. An extensive review of the medical literature regarding the management of insomnia and the elderly found there is considerable evidence of the effectiveness and durability of nondrug treatments for insomnia in adults of all ages, and these interventions are underused. Compared with the benzodiazepines, the nonbenzodiazepine (including zolpidem) sedative-hypnotics appeared to offer few, if any, significant clinical advantages in efficacy or tolerability in elderly persons. Newer agents with novel mechanisms of action and improved safety profiles, such as the melatonin agonists, were found to hold promise for the management of chronic insomnia in elderly people. Long-term use of sedative-hypnotics for insomnia lacks an evidence base and has traditionally been discouraged for reasons that include concerns about such potential adverse drug effects as cognitive impairment (anterograde amnesia), daytime sedation, motor incoordination, and increased risk of motor vehicle accidents and falls. In addition, the effectiveness and safety of long-term use of these agents remain to be determined. More research is needed to evaluate the long-term effects of treatment and the most appropriate management strategy for elderly persons with chronic insomnia. Patients suffering from gastroesophageal reflux disease had reflux events measured to be significantly longer when taking zolpidem than on placebo. (The same trend was found for reflux events in patients without GERD). This is assumed to be due to suppression of arousal during the reflux event, which would normally result in a swallowing reflex to clear gastric acid from the esophagus. Patients with GERD who take zolpidem thus experience significantly higher esophageal exposure to gastric acid, which increases the likelihood of developing esophageal cancer. Zolpidem has been assigned to pregnancy category C by the FDA. Animal studies have revealed evidence of incomplete ossification and increased postimplantation fetal loss at doses greater than seven times the maximum recommended human dose or higher; however, teratogenicity was not observed at any dose level. There are no controlled data in human pregnancy. In one case report, zolpidem was found in cord blood at delivery. Zolpidem is only recommended for use during pregnancy when benefits outweigh risks. Zaleplon and Zolpidem both are agonists at the GABA A ɣ 1 subunit. Due to its selective binding, Zolpidem has very weak anxiolytic, myorelaxant, and anticonvulsant properties but very strong hypnotic properties. Zolpidem binds with high affinity and acts as a full agonist at the 1α-containing receptorsAGABA, about 10-fold lower affinity for those containing the 2α- and 3α- receptorAGABA subunits, and with no appreciable affinity for 5α subunit-containing receptors. ω1 type GABAA receptors are the α1-containing GABAA receptors and ω2 GABAA receptors are the α2-, 3α-, 4α-, α5-, and 6α-containing GABAA receptors. ω1 GABAA receptors are found primarily in the brain, whereas ω2 receptors are found primarily in the spine. Thus, zolpidem has a preferential binding for the GABAA-benzodiazepine receptor complex in the brain but a low affinity for the GABAA-benzodiazepine receptor complex in the spine. Like the vast majority of benzodiazepine-like molecules, zolpidem has no affinity for α4 and α6 subunit-containing receptors. Zolpidem positively modulates GABAA receptors, it is presumed by increasing the GABAA receptor complex's apparent affinity for GABA without affecting desensitization or peak current. Like zaleplon (Sonata), zolpidem may increase slow wave sleep but cause no effect on stage 2 sleep. A meta-analysis of the randomised, controlled, clinical trials that compared benzodiazepines against nonbenzodiazepines such as zolpidem has shown few consistent differences between zolpidem and benzodiazepines in terms of sleep onset latency, total sleep duration, number of awakenings, quality of sleep, adverse events, tolerance, rebound insomnia, and daytime alertness. Notable drug-drug interactions with the pharmacokinetics of zolpidem include chlorpromazine, fluconazole, imipramine, itraconazole, ketoconazole, rifampicin, and ritonavir. Interactions with carbamazepine and phenytoin can be expected based on their metabolic pathways, but have not yet been studied. There does not appear to be any interaction between zolpidem and cimetidine or ranitidine. Zolpidem has a potential for either medical misuse when the drug is continued long term without or against medical advice, or recreational use when the drug is taken to achieve a "high". The transition from medical use of zolpidem to high-dose addiction or drug dependence can occur when used without a doctor's recommendation to continue using it, when physiological drug tolerance leads to higher doses than the usual 5 mg or 10 mg, when consumed through inhalation or injection, or when taken for purposes other than as a sleep aid. Misuse is more prevalent in those who have been dependent on other drugs in the past, but tolerance and drug dependence can still sometimes occur in those without a history of drug dependence. Chronic users of high doses are more likely to develop physical dependence on the drug, which may cause severe withdrawal symptoms, including seizures, if abrupt withdrawal from zolpidem occurs. One case history reported a woman detoxifying from a high dose of zolpidem experiencing a generalized seizure, with clinical withdrawal and dependence effects reported to be similar to the benzodiazepine withdrawal syndrome. Nonmedical use of zolpidem is increasingly common in U.S.A, Canada, and the UK. Recreational users report that resisting the drug's hypnotic effects can in some cases elicit vivid visuals and a body high. Some users have reported decreased anxiety, mild euphoria, perceptual changes, visual distortions, and hallucinations. Other drugs, including the benzodiazepines and zopiclone, are also found in high numbers of suspected drugged drivers. Many drivers have blood levels far exceeding the therapeutic dose range suggesting a high degree of excessive-use potential for benzodiazepines, zolpidem and zopiclone. U.S. Congressman Patrick J. Kennedy says that he was using Zolpidem (Ambien) and Phenergan when caught driving erratically at 3AM. "I simply do not remember getting out of bed, being pulled over by the police, or being cited for three driving infractions," Kennedy said. Zolpidem, along with the other benzodiazepine-like Z-drugs is a Schedule IV controlled substance in the USA, according to the Controlled Substances Act, given its potential for abuse and dependence. According to the U.S. Drug Enforcement Administration, zolpidem (Ambien, Stilnox) is quickly overtaking illegal sedatives as the most common date-rape drug. Perpetrators of sexual assault have used zolpidem on unsuspecting victims. Zolpidem is one of the most common GABA-potentiating sleeping medications prescribed in the Netherlands, with a total of 582,660 prescriptions dispensed in 2008. The United States Air Force uses zolpidem as one of the hypnotics approved as "no-go pills" to help aviators and special duty personnel sleep in support of mission readiness (the other hypnotics used are temazepam and zaleplon during war time). "Ground tests" are required prior to authorization issued to use the medication in an operational situation. Zolpidem may provide short-lasting but effective improvement in symptoms of aphasia present in some survivors of stroke. The mechanism for improvement in these cases remains unexplained and is the focus of current research by several groups, to explain how a drug which acts as a hypnotic-sedative in people with normal brain function, can paradoxically increase speech ability in people recovering from severe brain injury. Use of zolpidem for this application remains experimental at this time, and is not officially approved by any pharmaceutical manufacturers of zolpidem or medical regulatory agencies worldwide. Zolpidem is being studied to determine if it causes improved responsiveness or regional cerebral perfusion in patients with persistent vegetative states.

Clonazepam
InChI=1S/C15H10ClN3O3/c16-12-4-2-1-3-10(12)15-11-7-9(19(21)22)5-6-13(11)18-14(20)8-17-15/h1-7H,8H2,(H,18,20)Yes 
Key:DGBIGWXXNGSACT-UHFFFAOYSA-NYes  Clonazepam is a benzodiazepine drug having anxiolytic, anticonvulsant, muscle relaxant, sedative, and hypnotic properties. It is marketed by Roche under the trade name Klonopin in the United States, Rivotril in Argentina, Australia, Brazil, Canada, Costa Rica, Ireland and Italy, and linotril in India, South Korea, Mexico and Europe. Other names such as Ravotril, Rivatril, Clonex, Paxam, Petril or Kriadex are known throughout the rest of the world.][ Clonazepam has an unusually long elimination half-life of 18–50 hours, making it generally considered to be among the long-acting benzodiazepines. Clonazepam is a chlorinated derivative of nitrazepam and therefore a chloro-nitrobenzodiazepine. Clonazepam has an intermediate onset of action, with a peak blood levels occurring one to four hours after oral administration. Long-term effects of benzodiazepines include tolerance, benzodiazepine dependence, and benzodiazepine withdrawal syndrome, which occurs in a third of people treated with clonazepam for longer than four weeks. Clonazepam is classified as a high potency benzodiazepine. Benzodiazepines such as clonazepam have a fast onset of action and high effectiveness rate and low toxicity in overdose but, as most medications, it may have drawbacks due to adverse reactions including paradoxical effects and drowsiness. The benzodiazepine clorazepate may be an alternative to clonazepam due to a slow onset of tolerance and availability in slow-release formulation to counter fluctuations in blood levels. The pharmacological property of clonazepam as with other benzodiazepines is the enhancement of the neurotransmitter GABA via modulation of the receptorAGABA. Clonazepam may be prescribed for epilepsy. Clonazepam is approved by the Food and Drug Administration for treatment of epilepsy and Panic Disorder. It is approved for treatment of typical and atypical absences, infantile myoclonic, myoclonic and akinetic seizures and also as a second-line agent. Clonazepam is classified as a high potency benzodiazepine and is sometimes used as a second-line treatment of epilepsy. Clonazepam, like other benzodiazepines, while being a first-line treatment for acute seizures, is not suitable for the long-term treatment of seizures due to the development of tolerance to the anticonvulsant effects. The benzodiazepine clorazepate may be preferred over clonazepam due to a slower onset of tolerance and availability in slow-release formulation to counter fluctuations in blood levels. Clonazepam is also used for the treatment of panic disorder. The pharmacological property of clonazepam as with other benzodiazepines is the enhancement of the neurotransmitter GABA via modulation of the receptorAGABA. A subgroup of people with treatment resistant epilepsy may benefit from long-term use of clonazepam; the benzodiazepine clorazepate may be an alternative due to its slow onset of tolerance. Clonazepam has been found effective in treating epilepsy in children, and the inhibition of seizure activity seemed to be achieved already at low plasma levels of clonazepam. Thus clonazepam is sometimes used for certain rare childhood epilepsies. However, it has been found to be ineffective in the control of infantile spasms. Clonazepam is less effective and potent as an anticonvulsant in bringing infantile seizures under control compared with nitrazepam in the treatment of West syndrome, which is an age-dependent epilepsy affecting the very young. Clonazepam is mainly prescribed for the acute management of epilepsies. Clonazepam has been found to be effective in the acute control of nonconvulsive status epilepticus. However, the benefits tended to be transient in many of the patients, and the addition of phenytoin for lasting control was required in these patients. Clonazepam has also been found effective in treating: The effectiveness of clonazepam in the short-term treatment of panic disorder has been demonstrated in controlled clinical trials. Some long-term trials have suggested a benefit of clonazepam for up to three years without the development of tolerance but these trials were not placebo controlled. Clonazepam is also effective in the management of acute mania. Clonazepam may aggravate or cause major depressive disorder (clinical depression) and/or increase anxiety in the long-run, similar to other benzodiazepines in general. Clonazepam may help reduce the severity of tinnitus symptoms. Clonazepam was approved in the United States as a generic drug in 1997 and is now manufactured and marketed by several companies. Clonazepam is available as tablets (0.25 mg, 0.5 mg, 1.0 mg, 2.0 mg) and orally disintegrating tablets (wafers) (0.5 mg), an oral solution (drops), and as a solution for injection or intravenous infusion.][ While benzodiazepines induce sleep, they tend to produce a poorer quality sleep than natural sleep. Benzodiazepines such as clonazepam suppress REM sleep. After regular use rebound insomnia can occur when discontinuing clonazepam. The long term effects of clonazepam can include depression, disinhibition, and sexual dysfunction. Long-term use of benzodiazepines is also associated with cognitive impairments that can persist for at least six months post-withdrawal, but it is unclear whether these impairments take more than six months to abate or if they are permanent. Benzodiazepines may cause or worsen depression. Benzodiazepines such as clonazepam can be very effective in controlling status epilepticus, but, when used for longer periods of time, some potentially serious side-effects may develop, such as interference with cognitive functions and behavior. Many individuals treated on a long-term basis develop a form of dependence known as "low-dose dependence," as was shown in one double-blind, placebo-controlled study of 34 therapeutic low-dose benzodiazepine users — physiological dependence was demonstrated by flumazenil-precipitated withdrawal. Use of alcohol or other CNS depressants while taking clonazepam greatly intensifies the effects (and side-effects) of the drug. Side-effects of the drug itself are generally benign, but sudden withdrawal after long-term use can cause severe, even fatal, symptoms. Like all benzodiazepines, clonazepam is a benzodiazepine receptor agonist. One third of individuals treated with benzodiazepines for longer than four weeks develop a dependence on the drug and experience a withdrawal syndrome upon dose reduction. High dosage and long term use increases the risk and severity of dependence and withdrawal symptoms. Withdrawal seizures and psychosis can occur in severe cases of withdrawal and anxiety and insomnia in less severe cases of withdrawal. Gradual reduction in dosage reduces the severity of the benzodiazepine withdrawal syndrome. Due to the risks of tolerance and withdrawal seizures clonazepam is generally not recommended for the long-term management of epilepsies. Increasing the dose can overcome the effects of tolerance but tolerance to the higher dose may occur and adverse effects may increase. The mechanism of tolerance includes receptor desensitisation, down regulation, receptor uncoupling and alterations in subunit composition and alterations in gene transcription coding. Tolerance to the anticonvulsant effects of clonazepam occurs in both animals and humans. In humans, tolerance to the anticonvulsant effects of clonazepam occurs frequently. Chronic use of benzodiazepines leads to the development of tolerance with a decrease of benzodiazepine binding sites. The degree of tolerance is more pronounced with clonazepam than with chlordiazepoxide. In general, short-term therapy is more effective than long-term therapy with clonazepam for the treatment of epilepsy. Many studies have found that tolerance develops to the anticonvulsant properties of clonazepam with chronic use, which limits its long term effectiveness as an anticonvulsant. Abrupt or over-rapid withdrawal from clonazepam may result in the development of the benzodiazepine withdrawal syndrome, causing psychosis characterised by dysphoric manifestations, irritability, aggressiveness, anxiety, and hallucinations. Sudden withdrawal may also induce the potentially life threatening condition status epilepticus. Antiepileptic drugs, benzodiazepines such as clonazepam in particular, should be reduced slowly and gradually when discontinuing the drug to reduce withdrawal effects. Carbamazepine has been trialed in the treatment of clonazepam withdrawal and has been found to be ineffective in preventing clonazepam withdrawal status epilepticus from occurring. The elderly metabolise benzodiazepines more slowly than younger individuals and are also more sensitive to the effects of benzodiazepines even at similar blood plasma levels. Doses for the elderly are recommended to be about half of that given to younger adults and given for no longer than 2 weeks. Long-acting benzodiazepines such as clonazepam are not generally recommended for the elderly due the risk of drug accumulation. Caution in the elderly: increased risk of impairments, falls and drug accumulation. Benzodiazepines also require special precaution if used in pregnant, alcohol- or drug-dependent individuals and individuals with comorbid psychiatric disorders. Clonazepam is generally not recommended for use in elderly people for insomnia due to its high potency relative to other benzodiazepines. Caution in children: Clonazepam is not recommended for use in those under 18. Use in very young children may be especially hazardous. Of anticonvulsant drugs behavioural disturbances occur most frequently with clonazepam and phenobarbital. Caution using high dosages of clonazepam. Doses higher than 0.5 – 1 mg per day are associated with significant sedation. Clonazepam may aggravate hepatic porphyria. Caution in chronic schizophrenia. A 1982 double blinded placebo controlled study found clonazepam increases violent behavior in individuals with chronic schizophrenia. Clonazepam decreases the levels of carbamazepine, and likewise clonazepam's level is reduced by carbamazepine. Azole antifungals such as ketoconazole may inhibit the metabolism of clonazepam. Clonazepam may affect levels of phenytoin (diphenylhydantoin) by decreasing, or increasing. In turn Phenytoin may lower clonazepam plasma levels, by increasing the speed of clonazepam clearance by approximately 50% and decreasing its half-life by 31%. Clonazepam increases the levels of primidone, and phenobarbital. Combined use of clonazepam with certain antidepressants, antiepileptics such as phenobarbital, phenytoin and carbamazepine, sedative antihistamines, opiates, antipsychotics and alcohol may result in enhanced sedative effects. Clonazepam, like other benzodiazepines, will impair one's ability to drive or operate machinery. The central nervous system depressing effects of the drug can be intensified by alcohol consumption and therefore alcohol should be avoided while taking this medication. Benzodiazepines have been shown to cause both psychological and physical dependence. Patients physically dependent on clonazepam should be slowly titrated off under the supervision of a qualified healthcare professional to reduce the intensity of withdrawal or rebound symptoms. There is some medical evidence of various malformations, e.g., cardiac or facial deformations, when used in early pregnancy, however the data is not conclusive. The data are also inconclusive on whether benzodiazepines such as clonazepam cause developmental deficits or decreases in IQ in the developing fetus when taken by the mother during pregnancy. Clonazepam when used late in pregnancy may result in the development of a severe benzodiazepine withdrawal syndrome in the neonate. Withdrawal symptoms from benzodiazepines in the neonate may include hypotonia, apnoeic spells, cyanosis and impaired metabolic responses to cold stress. The safety profile of clonazepam during pregnancy is less clear than for other benzodiazepines and if benzodiazepines are indicated during pregnancy chlordiazepoxide and diazepam may be a safer choice. The use of clonazepam during pregnancy should only be used if the clinical benefits are believed to outweigh the clinical risks to the fetus. Caution is also required if clonazepam is used during breast feeding. Possible adverse effects of use of benzodiazepines such as clonazepam during pregnancy include; abortion, malformation, intrauterine growth retardation, functional deficits, floppy infant syndrome, carcinogenesis and mutagenesis. Neonatal withdrawal syndrome associated with benzodiazepines include hypertonia, hyperreflexia, restlessness, irritability, abnormal sleep patterns, inconsolable crying, tremors or jerking of the extremities, bradycardia, cyanosis, suckling difficulties, apnea, risk of aspiration of feeds, diarrhea and vomiting, and growth retardation. This syndrome can develop between 3 days and 3 weeks after birth and can have a duration of up to several months. The pathway by which clonazepam is metabolised is usually impaired in new borns. If clonazepam is used during pregnancy or breast feeding it is recommended that serum levels of clonazepam are monitored and signs of central nervous system depression and apnea are also monitored for. In many cases non-pharmacological treatments such as relaxation therapy, psychotherapy and avoidance of caffeine can be an effective and safer alternative to use of benzodiazepines for anxiety in pregnant women. Clonazepam's primary mechanism of action is the modulation of GABA function in the brain, by the benzodiazepine receptor, located on receptorsAGABA, which, in turn, leads to enhanced GABAergic inhibition of neuronal firing. Benzodiazepines do not replace GABA but rather enhance the effect of GABA at the GABAA receptor by increasing the opening frequency of chloride ion channels which leads to increased inhibitory effects with resultant central nervous system depression. In addition clonazepam decreases the utilization of 5-HT (serotonin) by neurons and has been shown to bind tightly to central type benzodiazepine receptors. Because clonazepam is effective in low milligram doses (0.5 mg clonazepam = 10 mg diazepam), it is said to be among the class of "highly potent" benzodiazepines. The anticonvulsant properties of benzodiazepines are due to enhancement of synaptic GABA responses and inhibition of sustained high frequency repetitive firing. Benzodiazepines, including clonazepam, bind to mouse glial cell membranes with high affinity. Clonazepam decreases release of acetylcholine in cat brain and decreases prolactin release in rats. Benzodiazepines inhibit cold-induced thyroid stimulating hormone (also known as TSH or thyrotropin) release. Benzodiazepines acted via micromolar benzodiazepine binding sites as channel blockers2+Ca and significantly inhibit depolarization-sensitive calcium uptake in experimentation on rat brain cell components. This has been conjectured as a mechanism for high-dose effects on seizures in the study. Clonazepam exerts its action by binding to the benzodiazepine site of the GABA receptors, which causes an enhancement of the electric effect of GABA binding on neurons, resulting in an increased influx of chloride ions into the neurons. This results in an inhibition of synaptic transmission across the central nervous system. Benzodiazepines do not have any effect on the levels of GABA in the brain. Clonazepam has no effect on GABA levels and has no effect on gamma-aminobutyric acid transaminase. Clonazepam does however affect glutamate decarboxylase activity. It differs insofar from other anticonvulsant drugs it was compared to in a study. Benzodiazepine receptors are found in the central nervous system but are also found in a wide range of peripheral tissues such as longitudinal smooth muscle-myenteric plexus layer, lung, liver and kidney as well as mast cells, platelets, lymphocytes, heart and numerous neuronal and non-neuronal cell lines. Clonazepam is lipid soluble, and rapidly crosses the blood–brain barrier and penetrates the placenta. It is extensively metabolised into pharmacologically inactive metabolites. Clonazepam is metabolized extensively via nitroreduction by cytochrome P450 enzymes, particularly CYP2C19 and to a lesser extent CYP3A4. Erythromycin, clarithromycin, ritonavir, itraconazole, ketoconazole, nefazodone, and grapefruit juice are inhibitors of CYP3A4 and can affect the metabolism of benzodiazepines. It has an elimination half-life of 19–60 hours. Peak blood concentrations of 6.5–13.5 ng/mL were usually reached within 1–2 hours following a single 2 mg oral dose of micronized clonazepam in healthy adults. In some individuals, however, peak blood concentrations were reached at 4–8 hours. Clonazepam passes rapidly into the central nervous system, with levels in the brain corresponding with levels of unbound clonazepam in the blood serum. Clonazepam plasma levels are very unreliable amongst patients. Plasma levels of clonazepam can vary as much as tenfold between different patients. Clonazepam is largely bound to plasma proteins. Clonazepam passes through the blood–brain barrier easily, with blood and brain levels corresponding equally with each other. The metabolites of clonazepam include 7-aminoclonazepam, 7-acetaminoclonazepam and 3-hydroxy clonazepam. An individual who has consumed too much clonazepam may display one or more of the following symptoms: Coma can be cyclic, with the individual alternating from a comatose state to a hyperalert state of consciousness, as occurred in a 4-year-old boy who suffered an overdose of clonazepam. The combination of clonazepam and certain barbiturates e.g. amobarbital at prescribed doses has resulted in a synergistic potentiation of the effects of each drug leading to serious respiratory depression. Overdose symptoms may include extreme drowsiness, confusion, muscle weakness, and fainting. Clonazepam and 7-aminoclonazepam may be quantified in plasma, serum or whole blood in order to monitor compliance in those receiving the drug therapeutically, to confirm the diagnosis in potential poisoning victims or to assist in the forensic investigation in a case of fatal overdosage. Both the parent drug and 7-aminoclonazepam are unstable in biofluids, and therefore specimens should be preserved with sodium fluoride, stored at the lowest possible temperature and analyzed quickly to minimize losses. A 2006 US government study of nationwide emergency department (ED) visits conducted by SAMHSA found that sedative-hypnotics in the USA were the most frequently implicated pharmaceutical drug in ED visits. Benzodiazepines accounted for the majority of these. Clonazepam was the second most frequently implicated benzodiazepine in ED visits in the study. The study examined the number of times non-medical use of certain drugs were implicated in ED visits; the criteria for non-medical use in this study were purposefully broad, and include for example, drug abuse, accidental or intentional overdose, or adverse reactions resulting from legitimate use of the medication. Clonazepam, 5-(2-chlorphenyl)-1,3-dihydro-7-nitro-2H-1,4-benzodiazepine-2-one, is synthesized by following a standard scheme of making derivatives of 1,4-benzodiazepines, with the exception that the acceptor nitro group (in this example) on C7 of the benzodiazepine system is introduced at the last stage of synthesis. The synthesis of clonazepam begins with 2-chloro-2′-nitrobenzophenone, which is reduced to 2-chloro-2'-aminobenzophenone by hydrogen over Raney nickel. The amino derivative is amidated by 2-bromoacetyl bromide to give the bromacetamide and is further converted into aminoacetamide upon reaction with ammonia. Upon reaction of this with pyridine, it is cycled into 5-(2-chlorophenyl)-2,3-dihydro-1H-1,4-benzodiazepine-2-one. The nitration of the resulting product in mild conditions (potassium nitrate in sulfuric acid) results in clonazepam.</ref> M: CNS anat (n/s/m/p/4/e/b/d/c/a/f/l/g)/phys/devp noco (m/d/e/h/v/s)/cong/tumr, sysi/epon, injr proc, drug (N1A/2AB/C/3/4/7A/B/C/D)
ambien xanax Magnesium Physiology Anxiolytics Hypnotics Nonbenzodiazepines Zolpidem Alprazolam

Magnesium is an essential element in biological systems. Magnesium occurs typically as the Mg2+ ion. It is an essential mineral nutrient (i.e., element) for life and is present in every cell type in every organism. For example, ATP (adenosine triphosphate), the main source of energy in cells, must be bound to a magnesium ion in order to be biologically active. What is called ATP is often actually Mg-ATP. Similarly, magnesium plays a role in the stability of all polyphosphate compounds in the cells, including those associated with DNA- and RNA synthesis.

Over 300 enzymes require the presence of magnesium ions for their catalytic action, including all enzymes utilizing or synthesizing ATP, or those that use other nucleotides to synthesize DNA and RNA.

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Organic chemistry

Organic chemistry is a chemistry subdiscipline involving the scientific study of the structure, properties, and reactions of organic compounds and organic materials, i.e., matter in its various forms that contain carbon atoms. Study of structure includes using spectroscopy and other physical and chemical methods to determine the chemical composition and constitution of organic compounds and materials. Study of properties includes both physical properties and chemical properties, and uses similar methods as well as methods to evaluate chemical reactivity, with the aim to understand the behavior of the organic matter in its pure form (when possible), but also in solutions, mixtures, and fabricated forms. The study of organic reactions includes both their preparation—by synthesis or by other means—as well as their subsequent reactivities, both in the laboratory and via theoretical (in silico) study.

The range of chemicals studied in organic chemistry include hydrocarbons, compounds containing only carbon and hydrogen, as well as compositions based on carbon but containing other elements. Organic chemistry overlaps with many areas including medicinal chemistry, biochemistry, organometallic chemistry, and polymer chemistry, as well as many aspects of materials science.

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