Zolpidem (Ambien, Stilnox): Clinical Use, Mode Of Action, And Side Effects

Overview of Zolpidem

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Zolpidem is used for treating insomania or sleep disturbances caused by imbalance in certain brain hormones. Zolpidem is available by two forms immediate release and extended release. In immediate release, Zolpidem initiates sleep instantly and brand names of immediate release zolpidem are Ambien, Edluar, Intermezzo, Zolpimist etc. In case of extended release i.e. Ambien CR the first layer gets dissolved to make you fall asleep and the second layer gets dissolved slowly to help individual in staying asleep [1]. While Ambien, Zolpimist and Edluar are used in case of initiating sleep immediately, Intermezzo is used if patient get up in middle of night and find difficulty in sleeping again [2].

It acts by modulating benzodiazepine receptor’s alpha sub-unit which is located inside the GABA_A receptor chloride channel macromolecular complex. It must not be confused with benzodiazepines which get binds to all three alpha receptors present in the complex. Zolpidem is selective in its mode of action where it binds to only alpha-1 sub unit[3].

Sleep disorder medications fall into hypnotic or sedative class of drugs. In this class, there are two major type of drugs barbiturates and benzodiazepines. Although, Zolpidem fall into benzodiazepine class it binds more selectively than other benzodiazepines[4]. Seconal (Secobarbital) and Nembutal (Pentobarbital) are two examples of barbiturates. Barbiturates acts by producing a variety of effects which ranges from sleep inducers to anaesthesia. They falls under central nervous system depressants category . Although they have analgesic effects, they are not used in surgical process due to weak effects unless other barbiturates or analgesics are present. Barbiturates such as phenobarbital previously used as hypnotics, but with the advent of benzodiazepines they are replaced. Still certain barbiturates such as sodium thiopental are used as anti-convulsants or forcitel as analgesic in clustered migraine[5].

Mode of action is much different from benzodiazepines although they act as allosteric modulator. They act as agonist of GABA receptors. Unlike Zolpidem (Benzodiazepine) they gets bind to multiple sites in GABA’s transmembrane pocket which are homologus. The binding sites of barbiturates are distinct from benzodiazepines and GABA itself. Other GABAergenic binding, it also binds with Kainate type receptor and Blocks AMPA which are a type of inotropic glutamate receptors. Glutamate  are central nervous systems excitory neurotransmitters, thus barbiturates blocks AMPA and binds to GABA receptors to produce depressant effect on central nervous system. Zolpidem belongs to the class of Z drugs or non-benzodiazepines whose mechanism of action is almost similar except Z class drugs have very selective binding property as far as GABA is considered[6].

The side effects of Zolpidem are

Zolpidem is well tolerated among healthy young volunteers and doesn’t make significant changes in sleep patterns. However, nervous side effects can be seen or felt such as visual disturbances, dizziness, ataxia, etc. Other nervous system side effects which have been reported are – Headache, confusion, drugged feeling, anterograde amnesia, delirium, hallucinations, nightmares, nervousness, etc. has also been reported[7]. Rarely angioedema has been reported under hypersensitive side effects where tongue, larynx and glottis is affected. The side effects are seen after first or subsequent dosage of Zolpidem[8]. Anaphylaxis has also been reported in some cases evidenced by throat closing, nausea and dyspnea. Gastrointestinal side effects reported for Zolpidem are – Vomiting, nausea, dyspepsia, diarrhea and anorexia[9]. Transient sublingual erythema and transient sublingual parethesia of the tongue has also been reported in two different patients[9]. Among other side effects the tolerance effects of Zolpidem has been rarely reported. Withdrawl symptoms such as agitation, restlessness, depression, anxiety, insomania, etc. have been reported. Oral effects such as dry mouth and sleep driving have been reported in one case. The psychiatric effects which have been reported till yet are of combinatorial therapy. The other rare side effects of Zolpidem reported so far are – palpitations in cardiovascular side effects, urinary incontinence and urinary tract infection in genitourinary segment, hepatotoxicity has also been reported as a side effect in hepatic segment, similarly in musculoskeletal segment arthralgia and myalgia has also been reported[10].

Forms of Zolpidem and Their Uses

On a comparatory note seconal which is a barbiturate has more or less same side effects. The nervous system side effects reported for same are – somnolence, dizziness, headache, hyperkinesias, confusion, ataxia, etc. Similarly cardiovascular side effects include bradycardia, syncope and hypotension. Gastrointestinal side effects reported are nausea, vomiting and constipation. A hypersensitive reaction such as angioedema, exfoliative dermatitis and skin rashes has also been reported. Another major concern of using barbiturates is it increases malignancy frequency especially in liver and brain cancer in case of phenobarbital and other barbiturates. Physical and psychological side effects have also been reported during withdrawl of seconal. Psychiatric side effects have been reported with symptoms such as agitation, nervousness, nightmares, hallucinations, psychiatric disturbances, insomnia, anxiety, and abnormal thinking. Hypoventilation and apnea have been reported under respiratory side effects[11].

Children

The study of Zolpidem in prenatal children has not been studied yet. But severe respiratory distress have been reported in case of neonatal when Zolpidem was administered at end of pregnancy. The effect is more prominent when it was taken with other central nervous system depressants. Research suggests those children born to mothers who have been treated with Zolpidem during their pregnancy are at risk of withdrawl symptoms. Zolpidem is not recommended for pediatric use, as it effects on below 18 years is yet to be evaluated. Similarly, the Zolpidem tartarate tablets are not safe for children and under 18 years as no formal studies have been done in this section[12].

ELDERLY

Elderly patient may feel the sensitive effect of Zolpidem tartarate tablets. Elderly people with hepatic insufficiency may find difficulty in metabolizing the drug and its removal from the body as compared against normal individual. Thus, to avoid such complications the usual recommended dosage is 5 mg per day before bedtime for elderly patients. The major rationale is to prevent motor or cognitive impairment and unusual sensitivity shown towards Zolpidem tartarate tablets. The dosage for elderly patients is set at 5 mg per day based upon several pharmacokinetics studies. In elderly individuals, the C_max, T_1/2 and AUC are increased by 50%, 32% and 64% as compared to young individuals. This result is based upon single oral dose of 20 mg. Zolpidem tartarate tablets showed no deposition in elderly patient following a 10 mg nightly oral dose for 1 long week[12].

Hepatic Impairment

In case of hepatic impaired patients, the C_max and AUC have been reported two times and five times higher as compared against healthy individuals. The T_max remain same for both the groups. The mean half-life is four times higher i.e. 9.9 hours as compared against 2.2 hour in healthy individuals. This suggests the dosing must be done accordingly[12].

Renal Impairment

No dose adjustments is required in patients of renal failure or renal impairment as studies carried out in 11 renal failure patient suggests, no change in C_max, T_1/2 and AUC. All patients are given 10 mg Zolpidem orally for a period of 14 or 21 days. The patients are undergoing hemodialysis thrice a week. Zolpidem was found to be non-hemodylizable and no accumulation was also found. Therefore, it suggests no dose adjustments are required for Zolpidem[12].

Alternatives to Zolpidem and Their Modes of Action

Zolpidem is available in three dosage forms spray, tablet, tablet coated forms. The two pathway for administration are oral and sublingual. The different variants of dosage available for Zolpidem are – 10 mg, 5 mg, 12.5 mg (Controlled Release) and 6.25 mg (Controlled release). As per USP, 5 mg tablets are pink colored and 10 mg tablets are white colored. The storage temperature is 2o to 25 degree centigrade. The dosage form prescribed to different individuals depends upon health condition, age, and other associated conditions which might have potential effect on its effects. The stability and unstability issues are dependent upon various factors such as temperature, humidity, moisture and external factors. In general, the various dosage forms are stable as far as they are kept within temperature range[12].

Zolpidem is a Z class drug under benzodiazepines which has a similar mode of action against benzodiazepines. This is partly due to selective binding action of Zolpidem. Although from above discussion, it is evident Zolpidem is well tolerated by individuals of Insomnia as compared against barbiturates, research suggest barbiturates are highly dangerous in overdose as compared to benzodiazepines. Similarly, the side effects of Zolpidem are insignificant which are almost similar to other class of drugs, but the side effects of barbiturates induces different other complications. The psychiatric and psychological effects of barbiturates are more dangerous as compared to Zolpidem. Although the above mentioned factors may suggest Zolpidem as a better candidate against other drugs, the withdrawl issues might pose a setback to its first line recommendation. The dependence upon Z class of drugs is high and withdrawl is difficult which might force clinicians to look for non-benzodiazepines. The Z class of benzodiazepines is usually recommended for a shorter duration that is a week-long or 2-3 times a week to overcome situation induced insomnia. Therefore, Zolpidem is a better option against its rivalry drugs available for Insomnia[13].

References

1. Monti, J. M., Pandi-Perumal, S. R., & Langer, S. Z. Zolpidem: its use in the treatment of sleep disorders. Sleep disorders: diagnosis and therapeutics. Informa Healthcare, London, 295-323.

2. Greenblatt, D. J., & Roth, T. Zolpidem for insomnia. Expert opinion on pharmacotherapy, 2012. 13(6), 879-893.

3. Sanger, D. J. The pharmacology and mechanisms of action of new generation, non-benzodiazepine hypnotic agents. CNS drugs, 2004.18(1), 9-15.

4. Nishino, S., Mishima, K., Mignot, E., & Dement, W. Sedative-hypnotics. In The American Psychiatric Publishing Textbook of Psychopharmacology, 4th Edition. American Psychiatric Publishing, Inc. 2009

5. Oderda, G. Drug Class Review Sedative Hypnotic Oral Barbiturate Agents in the Treatment of Insomnia.2012

6. Löscher, W., & Rogawski, M. A. How theories evolved concerning the mechanism of action of barbiturates. Epilepsia, 2012.53(s8), 12-25.

7. Janjic, V., Radmanovic, B., Dejanovic, S. D., Ravanic, D., & Borovcanin, M. P. 8. b. 006 Side effects of zolpidem and temazepam in treating primary insomnia. European Neuropsychopharmacology, 2014.24, S737-S738.

8. Yang, L. P., & Deeks, E. D. Sublingual Zolpidem (Edluar™; Sublinox™). CNS drugs, 2012.26(11), 1003-1010.

9. Monti, J. M., & Pandi-Perumal, S. R. Role of zolpidem in the management of primary and comorbid insomnia. Advances in the Management of Primary and Secondary Insomnia, 93.2014

10. Taylor, D., Gehrman, P., Dautovich, N. D., Lichstein, K. L., & McCrae, C. S. Treating insomnia. In Handbook of Insomnia(pp. 37-56). Springer Healthcare Ltd. 2014

11. Schutte-Rodin, S., Broch, L., Buysse, D., Dorsey, C., & Sateia, M. Clinical guideline for the evaluation and management of chronic insomnia in adults. Journal of clinical sleep medicine: JCSM: official publication of the American Academy of Sleep Medicine, 2008.4(5), 487.

12. Holm, K. J., & Goa, K. L. Zolpidem. Drugs, 2010.59(4), 865-889.

13. Rösner, S., Soyka, M., Hajak, G., Wehrle, R., & Englbrecht, C. Zolpidem for insomnia. The Cochrane Library. 2013