GU Exam question series – Zolpidem

INTRODUCTION AND CHEMISTRY

- Non benzodiazepine sedative-hypnotic

- Act mainly on benzodiazepine-1 receptor, action can be blocked by flumazenil
- No effect on other benzodiazepine receptor subtypes at usual doses, but less selective at
higher doses
- Oral bioavailability : 70%
- Food slows down absorption (Hence not ideal for patients who eat just before bedtime and
want a quick onset of action)
- Elimination half life : 2-5 hours
- No active metabolites, and short elimination half life mean that drug is usually completely
eliminated during the night and there are no daytime hangover symptoms
- Peak plasma concentration : 2-3 hours

PHARMACOLOGICAL ACTIONS

- Pharmacology of zolpidem predicts greater usefulness for falling asleep than for
maintenance of sleep and early morning awakenings
- CR formulation may be more useful in maintenance of sleep
- Selectivity for bzd-1 receptor results in hypnotic and some anxiolytic action without muscle
relaxant or anticonvulsant effects
- Lack of action at bzd-3 receptors appears to result in a lower incidence of withdrawal and
rebound symptoms, although these may occur at especially higher doses and more chronic
treatment

THERAPEUTIC INDICATIONS

- Short term treatment of insomnia (associated with a time limited stress) (behavioural
approaches more effective if insomnia is chronic)
- SOS for midnight awakenings if there are more than 4 hours of bedtime to planned time of
awakening (intermezzo formulation)
- treatment of jet lag
- to facilitate shift changes

COMPARISON TO BENZODIAZEPINES

- Similar efficacy in improving sleep latency and total sleep time, reducing nighttime
awakenings (CR) (all these are target symptoms)
- No reduction of REM or delta sleep, or any other changes in sleep architecture
- Tolerance, withdrawal and rebound insomnia much rarer than benzodiazepines
- No daytime hangover symptoms and daytime impairments
- Low abuse potential (History of drug addiction may increase risk of dependence)

ADVERSE EFFECTS

- More common in doses > 20 mg

- Memory impairment about 1.5 hours after dosing
- Complex automatisms including driving and eating, during sleep, with amnesia for the
behaviour, reflecting peak plasma level of drug
- Secretion in breast milk may cause sedation in nursing infants
- Tolerance and withdrawal may develop with high doses or with chronic administration

DOSING

- Initial dose 5 mg, may be increased to 10

- For CR preparations, initial dose is 6.25 mg, may be increased to 12.5
- Men – 10 mg/day of IR or 12.5 mg/day CR HS or 3.5 intermezzo sublingual (Stahl)
- Women – 5 IR or 6.25 CR HS or 1.75 intermezzo sublingual (Stahl)
- Gender difference in dosing recommended by FDA because clearance was found to be
slower in women
- For individuals with lower body weight, 5 or 6.25 may suffice
- Immediate release usually indicated for short term use, CR preparation may be used long
term
- Start low in pts with hepatic impairment and in the elderly, monitor pts with hepatic
impairment closely, no dosage adjustment required in renal impairment
- Preferably not used in pregnancy/lactation and children – use not approved in any of these
groups
- Rebound insomnia generally not seen on stopping drug
- In pts who have been taking it long term, better to taper to avoid withdrawal/risk of
rebound insomnia

REFERENCES

1. CTP, 10th ed
2. Prescriber’s guide, 6th ed