Zolpidem

Usage

• Zolpidem is prescribed for the short-term treatment of insomnia characterized by difficulties with sleep initiation. It may also be used for sleep maintenance.
• Pharmacological classification: Zolpidem is classified as a sedative-hypnotic and is a non-benzodiazepine hypnotic of the imidazopyridine class.
• Mechanism of Action: Zolpidem acts as an agonist at the benzodiazepine receptor’s omega-1 subtype. This interaction enhances the inhibitory effects of GABA, the primary inhibitory neurotransmitter in the central nervous system, leading to sedation and sleep.

Alternate Names

• Zolpidem doesn’t have many alternate names. It is sometimes referred to as Zolpidem Tartrate, which denotes the tartrate salt form of the drug.
• Brand names: Ambien, Ambien CR, Edluar, Intermezzo, Zolpimist.

How It Works

• Pharmacodynamics: Zolpidem enhances the effect of GABA by binding to the benzodiazepine-1 (BZ1) receptor on the GABAA receptor complex. This promotes chloride influx into neurons, leading to hyperpolarization and decreased neuronal excitability in the central nervous system, promoting sleep.
• Pharmacokinetics:
  • Absorption: Zolpidem is rapidly absorbed after oral administration. Food reduces the rate and extent of absorption. Sublingual formulations bypass first-pass metabolism, leading to faster onset of action.
  • Metabolism: Zolpidem is primarily metabolized in the liver by CYP3A4 enzymes.
  • Elimination: The metabolites are primarily excreted in the urine.
• Mode of Action: Zolpidem selectively binds to the BZ1 receptor subtype of the GABAA receptor complex, modulating the receptor’s response to GABA and enhancing its inhibitory effects.
• Elimination Pathways: Hepatic metabolism via CYP3A4 followed by renal excretion of metabolites.

Dosage

Standard Dosage

Adults:

• Immediate-release: Initial dose: 5 mg for women and 5 mg or 10 mg for men taken orally once daily immediately before bedtime. The dose can be increased to 10 mg if the 5 mg dose is ineffective. Do not exceed 10 mg per day. Administer only if at least 7-8 hours remain before the planned time of awakening.
• Extended-release: Initial dose: 6.25 mg for women and 6.25 mg or 12.5 mg for men taken orally once daily immediately before bedtime. The dose can be increased to 12.5 mg if the 6.25 mg dose is ineffective. Do not exceed 12.5 mg per day. Administer only if at least 7-8 hours remain before the planned time of awakening.
• Sublingual (for sleep onset): Initial dose: 5 mg for women and 5 mg or 10 mg for men. If the 5 mg dose is not effective, it may be increased to 10 mg. Do not exceed 10 mg per day, taken immediately before bedtime.
• Sublingual (for middle-of-the-night awakening): 1.75 mg for women and 3.5 mg for men, only once per night if at least 4 hours remain before the planned time of awakening.

Children:

Zolpidem is not recommended for use in children under 18 years of age.

Special Cases:

• Elderly Patients: Initial dose 5 mg for immediate-release or sublingual formulations and 6.25 mg for extended-release formulations.
• Patients with Renal Impairment: Dosage adjustment may not be necessary but close monitoring is recommended.
• Patients with Hepatic Dysfunction: Initial dose 5 mg for all formulations. Avoid use in severe hepatic impairment.
• Patients with Comorbid Conditions: Dose adjustments may be necessary based on the specific comorbidity and other medications the patient is taking. Consult relevant guidelines.

Clinical Use Cases

The use of zolpidem is primarily indicated for short-term management of insomnia, and its clinical use in the settings described below is generally not recommended, especially for extended durations. Other sedative-hypnotics or anesthetic agents are typically more appropriate for these specific scenarios.

• Intubation: Not typically indicated.
• Surgical Procedures: Not typically indicated for intraoperative sedation or anesthesia.
• Mechanical Ventilation: Not typically indicated.
• Intensive Care Unit (ICU) Use: Not recommended due to the risk of delirium.
• Emergency Situations: Not typically indicated.

Dosage Adjustments

Dose modifications are based on patient-specific factors, including renal or hepatic dysfunction and concomitant medications, especially CYP3A4 inhibitors or inducers.

Side Effects

Common Side Effects

Drowsiness, dizziness, headache, diarrhea, nausea, daytime fatigue.

Rare but Serious Side Effects

Angioedema, anaphylaxis, complex sleep behaviors (sleepwalking, sleep-eating, sleep-driving), hallucinations, worsening of depression, suicidal thoughts.

Long-Term Effects

Potential for dependence and tolerance with prolonged use. Rebound insomnia may occur upon discontinuation.

Adverse Drug Reactions (ADR)

Severe anaphylactic reactions require immediate medical attention. Complex sleep behaviors should be carefully monitored.

Contraindications

• Hypersensitivity to zolpidem.
• Severe hepatic insufficiency.
• Obstructive sleep apnea.
• Myasthenia gravis.
• Acute or severe respiratory depression.
• Previous history of complex sleep behaviors after taking zolpidem.

Drug Interactions

• CNS depressants (alcohol, opioids, benzodiazepines): Additive effects, increased risk of respiratory depression.
• CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, erythromycin): Increased zolpidem levels.
• CYP3A4 inducers (e.g., rifampin, St. John’s Wort): Decreased zolpidem levels.
• Other medications: Refer to comprehensive drug interaction resources for specific interactions.

Pregnancy and Breastfeeding

• Pregnancy Safety Category: C (Consult specialist).
• Fetal risks: May cause respiratory depression and sedation in neonates. There are limited reports of moderate to severe neonatal respiratory depression requiring artificial ventilation or intratracheal intubation when zolpidem was used late in pregnancy.
• Breastfeeding: Zolpidem is excreted in breast milk. Potential for neonatal sedation and respiratory depression. Consider the risks and benefits.
• Safer alternative options should be considered during pregnancy and breastfeeding.

Drug Profile Summary

• Mechanism of Action: BZ1 receptor agonist, enhances GABAergic neurotransmission.
• Side Effects: Drowsiness, dizziness, headache, complex sleep behaviors, anaphylaxis (rare).
• Contraindications: Hypersensitivity, severe hepatic insufficiency, obstructive sleep apnea, myasthenia gravis, acute/severe respiratory depression.
• Drug Interactions: CNS depressants, CYP3A4 inhibitors and inducers.
• Pregnancy & Breastfeeding: Use with caution. Potential for neonatal respiratory depression and sedation.
• Dosage: Adults: 5-10 mg immediate-release, 6.25-12.5 mg extended-release. Elderly/Hepatic Impairment: 5 mg. Pediatrics: Not recommended.
• Monitoring Parameters: Respiratory rate, mental status, next-day psychomotor function.

Popular Combinations

Zolpidem is not typically used in combination with other medications for the treatment of insomnia.

Precautions

• General Precautions: Evaluate for underlying sleep disorders and comorbid conditions. Screen for history of substance abuse.
• Specific Populations: See Dosage section.
• Lifestyle Considerations: Avoid alcohol and other CNS depressants. Advise against driving or operating machinery after taking zolpidem.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Zolpidem?

A: The standard adult dosage for immediate-release zolpidem is 5 mg for women and 5 mg or 10 mg for men, taken once daily immediately before bedtime. For the extended-release formulation, it’s 6.25 mg for women and 6.25 or 12.5 mg for men. Elderly patients should start with lower doses.

Q2: How long can a patient take Zolpidem?

A: Zolpidem is indicated for short-term use, generally not exceeding 4 weeks, including any tapering period. Long-term use should be avoided due to the risk of tolerance and dependence.

Q3: What are the common side effects of Zolpidem?

A: Common side effects include drowsiness, dizziness, headache, nausea, diarrhea, and daytime fatigue.

Q4: What are the serious side effects of Zolpidem that warrant attention?

A: Rare but serious side effects include complex sleep behaviors (e.g., sleepwalking, sleep-driving), angioedema, anaphylaxis, hallucinations, and worsening of depression or suicidal thoughts.

Q5: Can Zolpidem be used during pregnancy or breastfeeding?

A: Zolpidem is generally not recommended during pregnancy or breastfeeding due to the potential for fetal/neonatal harm, including respiratory depression and sedation. If considered essential, consult a specialist to weigh the risks and benefits carefully.

Q6: How does hepatic impairment affect Zolpidem dosage?

A: Patients with mild to moderate hepatic impairment should start with a lower dose (5 mg). Zolpidem should be avoided in patients with severe hepatic impairment.

Q7: Does Zolpidem interact with other medications?

A: Yes, Zolpidem interacts with other CNS depressants (alcohol, opioids, benzodiazepines), CYP3A4 inhibitors, and CYP3A4 inducers. It is essential to review a patient’s medication list for potential interactions.

Q8: What are the signs of Zolpidem overdose?

A: Signs of zolpidem overdose may include CNS depression ranging from drowsiness to coma, respiratory depression, and hypotension. Supportive care and symptomatic treatment are essential.

Q9: How should Zolpidem be discontinued?

A: Abrupt discontinuation can lead to rebound insomnia. Tapering the dose gradually is recommended, especially after prolonged use.