Global Perspectives
| Reviews |
| ZOLPIDEM - A REVIEW Compiled by - Dr Harish Shetty |
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Insomnia, the most common sleep disorder involves a disruption of normal sleep architecture. It is a subjective experience, which is the perception of sleep as inadequate or unsatisfying. Insomnia, whether transient (lasting for days), short term (lasting for weeks), or chronic, may be a serious problem affecting the quality of life, productivity as well as safety. Insomnia is generally treated with sedative therapy. Zolpidem is a new class of nonbenzodiazepine agent, which is a selective sleep restoring agent without any anxiolytic, anticonvulsant and myorelaxant activity. It has the ability to preserve the normal sleep architecture and has a favourable pharmacological, pharmacokinetic and tolerability profile. Langtry H.D. and Benfield P. in 19901, and also Holm K.J. and Goa K.L. in 20002, have reviewed extensively the pharmacodynamic and pharmacokinetic profile and therapeutic potential of zolpidem. This article briefly summarizes the reviews. Zolpidem – The Pharmacodynamic Profile Zolpidem, an imidazopyridine agent, is an agonist at the benzodiazepine receptor component of & gama; amino butyric acid (GABA)- receptor mediated chloride ionophore complex (GRSC)1,2. It is a chemically novel non-benzodiazepine sleep restoring agent which binds selectively to the benzodiazepine Omega1-receptor subtype in the brain, which correspond to GABAA receptors containing α1 sub-units. These receptors may be particularly important in mediating sleep effects1,2. With a rapid onset of action and short elimination half-life, zolpidem reduces the latency to and prolongs the duration of sleep in patients with insomnia2. Also, this drug does not appear to cause rebound insomnia or other withdrawal reactions after short term administration2. Sedative and sleep restoring effects1,2 Dose ranging studies suggests that zolpidem, administered at a dosage of 10 mg/ day, reduces the time of onset and prolongs the duration of sleep in healthy volunteers. Similar effects were found with zolpidem 10 mg in patients with insomnia1,2. Zolpidem at dosages from 5 mg/ day tended to reduce sleep latency, the number of wakenings and the total wake time while improving the efficiency of sleep. Zolpidem also has beneficial effects on sleep in volunteers at simulated altitude of 4000 meters, in heavy snorers, in hospitalized patients the night before surgery and in individuals who took the drug for the first 2 nights after eastward transatlantic travel. Effects on sleep patterns and stages: The sleep restoring activity of zolpidem and its effect on sleep architecture have been assessed in various clinical studies. These studies clearly indicate that zolpidem 10 mg is usually associated with no changes in sleep structure in healthy volunteers and in patients with insomnia including the elderly. Thus zolpidem does not alter patient’s sleep architecture and this is in contrast to benzodiazepines, which usually adversely affect the sleep structure by reducing slow wave sleep2. In one clinical study zolpidem was seen to increase slow wave sleep to a greater extent compared to zopiclone2. Zolpidem was also more effective than zopiclone at improving sleep microstructure (reducing the cyclic alteration pattern (CAP) rate of non REM sleep and the number of arousal events) in patients with situational or primary insomnia. The CAP rate significantly correlates with subjective appreciation of sleep quality2. Effects on psychomotor function: Clinical studies indicate that in patients with chronic insomnia, when zolpidem was administered at a dose of 10 mg/ day, the effects on psychomotor function were comparable to or less than those of flurazepam or flunitrazepam the morning after drug administration2. Effects on memory: Recent studies have confirmed that zolpidem generally does not produce next day memory impairment (6-10 hours after the dose) in patients with insomnia, in healthy volunteers, or in the elderly volunteers with delayed sleep onset1,2. In comparative studies zolpidem (10 mg) had effects on memory similar to or less than that of triazolam ( after a day time dose), similar to those of zopiclone (in healthy volunteers) and similar to or less than those of flunitrazepam (in healthy volunteers or patients with insomnia)2. Tolerance and dependence liability: Studies in humans have demonstrated zolpidem to be associated with a low abuse and dependence potential in humans. Tolerance (a decrease In drug efficacy and potency) was not reported in clinical trials of long-term treatment for up to 6 months1,2. Other effects: Zolpidem has no clinically significant effects on respiration in most volunteers, or in patients with Chronic Obstructive Pulmonary Disease2. Zolpidem – Pharmacokinetic Profile: Zolpidem is rapidly and well absorbed. It undergoes substantial first pass metabolism that results in an absolute bioavailability of approximately 70% after doses of 5-20 mg orally given as tablets or capsules and does not accumulate after multiple doses. A mean peak plasma concentration (Cmax) of 193 mg/L was reached 2.2 hours after administration of single 20 mg dose. The drug is highly protein bound. Zolpidem is extensively metabolized to 3 inactive metabolites by a range of P450 enzymes predominantly CYP3A4. The majority of the dose is excreted as metabolites in the bile, urine and faeces. Small amounts of zolpidem are excreted into the breast milk1,2. Patients with cirrhosis, the unbound fraction of the drug is increased and hence dosage reductions may be prudent In these patients with cirrhosis. Dosage reductions would appear to be prudent in patients with renal disease as there is slower elimination rate. Patients' ethnicity does not appear to affect the pharmacokinetics of the drug2. Zolpidem –Therapeutic Potential: The efficacy of zolpidem 10 mg/ day has been confirmed in around 4000 patients world over in general practice, hospitalized patients, in elderly patients and in patients with acute and chronic insomnia including those receiving concomitant treatment with selective serotonin re-uptake inhibitors (SSRIs). Some trials considered efficacy of zolpidem in patients with chronic insomnia1,2. Comparison with other hypnosedatives: At a dosage of 10 mg/ day, zolpidem was as effective as nitrazepam 5 mg/ day in psychiatric patients in two large 14 day trials. In other trials, which excluded psychiatric patients, significantly more zolpidem than nitrazepam patients rated their treatment as 'useful' or better based on their improvements in sleep and tolerability of the drug. Patients administered zolpidem 10 or 20 mg nightly had similar sleep responses to those of patients receiving flunitrazepam 1-2 mg, oxazepam 15 mg or triazolam 0.5 mg nightly. Zolpidem 20 mg resulted in faster sleep onset than oxazepam and similar sleep latency to triazolam. Zolpidem 10 or 20 mg/ day and flurazepam 30 mg/ day were both effective hypnotics. Flurazepam recipients reported significantly better sleep quality than patients receiving zolpidem, although the next day performance was better with zolpidem than flurazepam2. Use as a surgery premedicament: As an oral premedicant before surgery, zolpidem 10 or 20 mg was significantly superior to placebo in causing sedation. It reduced the anaesthetic dose but ended to prolong recovery relative to placebo. Zolpidem produced only minor interferance in psychomotor skills 3 hours post recovery. When compared with midazolam 15 mg or lorazepam 1 or 2.5 mg, zolpidem 10/ 20 mg produced a similar degree of sedation although midazolam 15 mg was a more powerful anxiolytic. Neither zolpidem dose prolonged recovery of responses to visual and auditory stimuli unlike lorazepam 2.5 mg2. Discontinuous or 'As needed' use: Zolpidem 10 mg/ day for 2-8 weeks (taken 'as needed' or for the first 5 days of each week) was found to be effective for the treatment of chronic insomnia. Zolpidem was associated with significant improvements in sleep quality, number of awakenings, refreshed feeling in the morning and sleep duration. Zolpidem is well tolerated in patients with insomnia including the elderly. The most common adverse events generally include nausea, dizziness and drowsiness. Post marketing studies of zolpidem that included a total of > 76000 patients have shown a low rate of adverse events with zolpidem. There was no evidence of rebound insomnia after sudden withdrawal of treatment with zolpidem 10 mg daily for up to 6 months1,2. Zolpidem resulted in double vision prior to anesthesia induction in a small number of patients and tended to reduce blood pressure in patients administered the drug as a preoperative sedative. Dosage and administration: Zolpidem is recommended to be administered immediately before bedtime for the treatment of insomnia. Initial dosage of zolpidem in patients <65 years experiencing acute insomnia is 10g, mg/ day. The maximum recommended dose is 10 mg/ day and each course of zolpidem should not exceed 4 weeks. For patients >65 years experiencing insomnia and in patients with hepatic impairment, an initial 5 mg dose may be increased to 10 mg maximum if needed. No dosage reduction is required in patients with renal impairment. The dosage should be reduced when given concomitantly with drugs having depressant effects on the CNS. Zolpidem is contraindicated in patients with severe hepatic impairment, obstructive sleep apnoea, acute pulmonary impairment or respiratory depression. The use of zolpidem during pregnancy and lactation is not recommended1,2. Conclusion: Zolpidem is effective and well tolerated in patients with insomnia including the elderly. Zolpidem has been found to be effective and well tolerated in clinical trials when administered in nightly doses of 10 or 20 mg for the treatment of insomnia. With its rapid onset and short duration of action, Zolpidem has been found to be similar or superior to flurazepam, flunitrazepam, oxazepam and triazolam in reducing sleep latency and nocturnal awakenings and in improving the duration and quality of sleep. Zolpidem appears to have minimal next day effects on cognition and psychomotor performance when administered at bedtime. In addition, there is little evidence of tolerance to the hypnotic effects of Zolpidem, or rebound insomnia or withdrawal symptoms after discontinuation of the drug when it is given as recommended (10 mg/ day for < 1 month). Reference:
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