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Zolpidem (Ambien)
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our most widely used hypnotic, is approved only for short-term management of insomnia. However, although approval is limited to short-term use, many patients have taken the drug long term with no apparent tolerance or increase in adverse effects. All zolpidem formulations have a rapid onset, and hence can help people who have difficulty falling asleep. In addition, the extended-release formulation—Ambien CR—can help people who have difficulty maintaining sleep.
Although structurally unrelated to the benzodiazepines, zolpidem binds to the benzodiazepine receptor site on the GABA receptor-chloride channel complex and shares some properties of the benzodiazepines. Like the benzodiazepines, zolpidem can reduce sleep latency and awakenings and can prolong sleep duration. The drug does not significantly reduce time in rapid-eye-movement (REM) sleep and causes little or no rebound insomnia when therapy is discontinued. In contrast to the benzodiazepines, zolpidem lacks anxiolytic, muscle relaxant, and anticonvulsant actions. Why? Because zolpidem doesn't bind with all benzodiazepine receptors. Rather, binding is limited to the benzodiazepine1 subtype of benzodiazepine receptors.
Zolpidem is rapidly absorbed following oral administration. Plasma levels peak in 2 hours. The drug is widely distributed, although levels in the brain remain low. Zolpidem is extensively metabolized to inactive compounds that are excreted in the bile, urine, and feces. The elimination half-life is 2.4 hours.
Zolpidem has a side effect profile like that of the benzodiazepines. Daytime drowsiness and dizziness are most common, and these occur in only 1% to 2% of patients. Like the benzodiazepines, zolpidem has been associated with sleep driving and other sleep-related complex behaviors. At therapeutic doses, zolpidem causes little or no respiratory depression. Safety in pregnancy has not been established. According to the FDA, zolpidem may pose a small risk of anaphylaxis and angioedema.
Short-term treatment is not associated with significant tolerance or physical dependence. Withdrawal symptoms are minimal or absent. Similarly, the abuse liability of zolpidem is low. Accordingly, the drug is classified under Schedule IV of the Controlled Substances Act.
Like other sedative-hypnotics, zolpidem can intensify the effects of other CNS depressants. Accordingly, patients should be warned against combining zolpidem with alcohol and all other drugs that depress CNS function.
first representative of a new class of hypnotics, the pyrazolopyrimidines. The drug is approved only for short-term management of insomnia, but prolonged use does not appear to cause tolerance. Like zolpidem, zaleplon binds to the benzodiazepine1 receptor site on the GABA receptor-chloride channel complex, and thereby enhances the depressant actions of endogenous GABA. In contrast to zolpidem, zaleplon has a very rapid onset and short duration of action, and hence is good for helping patients fall asleep, but not for maintaining sleep.
Zaleplon is rapidly and completely absorbed from the GI tract. However, because of extensive first-pass metabolism, bioavailability is only 30%. A large or high-fat meal can delay absorption substantially. Plasma levels peak about 1 hour after administration and then rapidly decline, returning to baseline in 4 to 5 hours. Zaleplon is metabolized by hepatic aldehyde oxidase prior to excretion in the urine. Its half-life is just 1 hour.
Because of its kinetic profile, zaleplon is well suited for people who have trouble falling asleep, but not for people who can't maintain sleep. The drug can also help people who need a sedative in the middle of the night: Because of its short duration, zaleplon can be taken at 3:00 AM without causing hangover when the alarm goes off at 7:00 AM.
Zaleplon is well tolerated. The most common side effects are headache, nausea, drowsiness, dizziness, myalgia, and abdominal pain. Like the benzodiazepines, zaleplon has been associated with rare cases of sleep driving and other complex sleep-related behaviors. Respiratory depression has not been observed. Physical dependence is minimal, the only sign being mild rebound insomnia the first night after drug withdrawal. Next-day sedation and hangover have not been reported. Like the benzodiazepines, zaleplon has a low potential for abuse, and hence is classified as a Schedule IV drug.
Cimetidine (a drug for peptic ulcer disease) inhibits hepatic aldehyde oxidase, and can thereby greatly increase levels of zaleplon. Accordingly, dosage of zaleplon must be reduced if these drugs are used concurrently.
Like zaleplon and zolpidem, eszopiclone binds selectively with the benzodiazepine1 receptor on the GABA receptor-chloride channel complex, and thereby enhances the depressant actions of endogenous GABA.
Eszopiclone is approved for treating insomnia, with no limitation on how long it can be used. This contrasts with zaleplon and zolpidem, which are approved for short-term use only. Does this mean that eszopiclone is safer than the other two drugs, or less likely to promote tolerance? Not necessarily. It only means that the manufacturer of eszopiclone conducted a prolonged (6-month) study, whereas the manufacturers of the other two drugs did not. In that prolonged study, eszopiclone reduced sleep latency and nighttime awakening, increased total sleep time and sleep quality, had no significant effect on sleep architecture, and showed no indication of tolerance.
Eszopiclone is generally well tolerated. The most common adverse effect is a bitter aftertaste, reported by 17% of patients dosed with 2 mg and 34% of those dosed with 3 mg. Other common effects are headache, somnolence, dizziness, and dry mouth. Rebound insomnia may occur on the first night after discontinuing the drug. Like the benzodiazepines and the other benzodiazepine-like drugs, eszopiclone has been associated with cases of sleep driving and other sleep-related complex behaviors. Rarely, eszopiclone may cause anaphylaxis or angioedema. Eszopiclone has a low potential for abuse and hence is classified as a Schedule IV drug.
Ramelteon [Rozerem] is a relatively new hypnotic with a unique mechanism of action: activation of receptors for melatonin. The drug is approved for treating chronic insomnia characterized by difficulty with sleep onset. Long-term use is permitted. Of the major drugs for insomnia, ramelteon is the only one not regulated as a controlled substance.
Therapeutic Use.
Ramelteon has a rapid onset (about 30 minutes) and short duration, and hence is good for inducing sleep but not for maintaining sleep. There are no significant residual effects on the day after dosing. Nor is there any rebound insomnia when treatment is stopped after 35 consecutive nights of use. When approving the drug, the FDA put no limit on how long it may be used.
Mechanism of Action.
Ramelteon activates receptors for melatonin—specifically the MT1 and MT2 subtypes, which are key mediators of the normal sleep-wakefulness cycle. Sleep promotion derives primarily from activating MT1 receptors
Ramelteon is very well tolerated. In clinical trials, the incidence of adverse effects was nearly identical to that of placebo. The most common side effects are somnolence (5% vs. 3% with placebo), dizziness (5% vs. 3%), and fatigue (4% vs. 2%). According to the FDA, ramelteon may share the ability of benzodiazepines to cause sleep driving and other sleep-related complex behaviors.
Ramelteon can increase levels of prolactin and reduce levels of testosterone. As a result, the drug has the potential to cause amenorrhea, galactorrhea, reduced libido, and fertility problems. If these occur, the prescriber should be consulted.