Zolpidem

Generic Name

Zolpidem

Brand Names

Ambien

Stilnox

Zolsana

Zolpidem Tartrate Tablets

Zolnox

Hypnogen

Sanval

Myslee

Zoldem

Drug Class

Non-benzodiazepine hypnotic

Belongs to the imidazopyridine chemical class

Pharmacologically a GABA-A receptor agonist with hypnotic action

Mechanism of Action

Zolpidem binds selectively to the benzodiazepine-1 (BZ1) subtype of the GABA-A receptor complex

This binding enhances the action of gamma-aminobutyric acid GABA

Increases chloride ion influx into neurons

Causes hyperpolarization of the postsynaptic membrane

Results in inhibition of neuronal firing and CNS depression

Produces sedative and hypnotic effects with minimal anxiolytic and anticonvulsant action

It induces sleep by reducing sleep latency and increasing total sleep time

Minimal effects on deep sleep and REM phases when used short term

Indications

Short-term treatment of insomnia

Indicated for patients with difficulty initiating sleep sleep-onset insomnia

Also used for nocturnal awakenings and early morning awakenings depending on formulation

Extended-release forms are used for sleep maintenance

Dosage and Administration

Immediate-release tablets 5 mg or 10 mg taken orally immediately before bedtime

Usual adult dose is 10 mg

In elderly debilitated or hepatic impaired patients the starting dose is 5 mg

Extended-release tablets 6.25 mg or 12.5 mg

Sublingual tablets available for middle-of-the-night awakenings

Spray formulations may be used where rapid onset is required

Should be taken on an empty stomach to enhance absorption

Should not be administered unless patient can stay in bed for 7 to 8 hours

Pharmacokinetics

Rapidly absorbed with peak plasma concentration within 05 to 3 hours

Bioavailability is 70 percent

Highly protein bound approximately 92 percent

Metabolized extensively in liver by CYP3A4 and other minor CYP enzymes

Inactive metabolites are excreted via the kidneys

Half-life is short around 2 to 3 hours

Extended-release and higher doses may prolong half-life

Elderly and those with hepatic impairment may experience slower clearance

Contraindications

Known hypersensitivity to zolpidem or components of the formulation

History of complex sleep behaviors like sleep-driving or sleepwalking with prior hypnotics

Severe hepatic impairment

Myasthenia gravis

Respiratory depression

Obstructive sleep apnea

Use during pregnancy and lactation not recommended unless benefits outweigh risks

Concomitant use with alcohol or other CNS depressants contraindicated

Warnings and Precautions

Complex sleep behaviors can occur including sleepwalking sleep-driving eating during sleep without awareness

These behaviors may occur even at recommended doses

Patients with history of psychiatric disorders or substance use disorder are at greater risk

Next-day impairment in mental alertness and coordination may occur especially with higher doses

Risk of falls particularly in elderly

Should not be combined with alcohol opioids or other sedatives due to enhanced CNS depression

Rebound insomnia may occur after abrupt discontinuation

Tolerance and psychological dependence can develop with prolonged use

Withdrawal symptoms can include anxiety tremor rebound insomnia and rarely seizures

Not intended for long-term use beyond 2 to 4 weeks

Adverse Effects

Common side effects

Daytime drowsiness

Dizziness

Headache

Fatigue

Diarrhea

Dry mouth

Nausea

Less common effects

Muscle weakness

Ataxia

Depression

Anterograde amnesia

Aggressive behavior

Hallucinations

Confusion

Rare serious effects

Respiratory depression

Allergic reactions including angioedema

Complex sleep behaviors with potential for injury

Suicidal ideation or self-harm especially in patients with depression

Withdrawal and Dependence

Chronic use may lead to physical and psychological dependence

Discontinuation should be gradual in long-term users

Abrupt withdrawal may cause rebound insomnia and anxiety

Risk of misuse is lower than benzodiazepines but still present

Overdose

Symptoms include somnolence

Ataxia

Confusion

Respiratory depression in severe cases

Coma may occur especially with alcohol or other CNS depressants

Management is supportive

Flumazenil may reverse effects but should be used cautiously due to seizure risk

Gastric lavage and activated charcoal may be considered if within a short window after ingestion

Drug Interactions

Pharmacodynamic interactions

Alcohol enhances CNS depressant effects

Concurrent use with opioids benzodiazepines antipsychotics antidepressants or antihistamines increases sedation

Use with muscle relaxants can lead to additive CNS depression

Pharmacokinetic interactions

CYP3A4 inhibitors such as ketoconazole erythromycin ritonavir increase zolpidem plasma levels and effects

CYP3A4 inducers such as rifampicin carbamazepine reduce zolpidem effectiveness

Co-administration with SSRIs may increase CNS adverse reactions including hallucinations and confusion

Use in Special Populations

Pregnancy category C not recommended unless benefits outweigh potential fetal risks

Crosses the placenta and may cause neonatal withdrawal or respiratory depression

Detected in breast milk and breastfeeding is not recommended

Elderly patients should be started at 5 mg dose due to prolonged clearance

In hepatic impairment the starting dose should be 5 mg and closely monitored

Use in children and adolescents is not recommended due to safety concerns

Comparative Pharmacology

Compared to zopiclone zolpidem has a shorter half-life

Less residual sedation the next morning

Zolpidem is more selective for the BZ1 subtype of GABA-A receptor

Zolpidem causes less disruption to sleep architecture

Compared to eszopiclone zolpidem has shorter duration of action

Eszopiclone is approved for chronic insomnia whereas zolpidem is for short-term use

Compared to benzodiazepines zolpidem has lower potential for dependence

Minimal muscle relaxant and anticonvulsant activity

Lower risk of psychomotor impairment but still present especially with higher doses

Formulations Available

Immediate-release tablets 5 mg and 10 mg

Extended-release tablets 625 mg and 125 mg

Sublingual tablets 175 mg 35 mg and 5 mg for middle-of-the-night awakening

Oral spray delivering 5 mg per actuation

Available as generic and branded formulations

Regulatory and Legal Status

Controlled substance

Schedule IV under the US Controlled Substances Act

Prescription-only

Similar regulatory status in EU and UK as a Class C controlled drug

Recommended for short-term use not exceeding 4 weeks

Monitoring Parameters

Monitor total sleep time and sleep quality

Evaluate for residual drowsiness or impairment the following day

Watch for signs of misuse or dependence

Monitor liver function in long-term use

Assess for unusual behavior including sleep activities performed unconsciously