How do medications cause drowsiness?

Mechanisms of Medication-Induced Drowsiness

Medications cause drowsiness primarily through their effects on central nervous system neurotransmitter systems, particularly by enhancing inhibitory pathways or blocking excitatory pathways that regulate wakefulness and alertness. 1

Primary Mechanisms of Medication-Induced Drowsiness

1. CNS Depression

• GABA Enhancement: Many sedating medications work by enhancing the effects of gamma-aminobutyric acid (GABA), the main inhibitory neurotransmitter in the brain
  • Benzodiazepines and non-benzodiazepine hypnotics (Z-drugs) bind to GABA-A receptors, increasing chloride ion influx into neurons, resulting in neuronal inhibition 1
  • This inhibition slows brain activity, leading to sedation and drowsiness

2. Histamine Blockade

• H1 Receptor Antagonism: First-generation antihistamines readily cross the blood-brain barrier and block histamine H1 receptors in the central nervous system 1
  • Histamine is a key neurotransmitter for maintaining wakefulness
  • Blocking these receptors disrupts the normal wake-promoting function of histamine, causing sedation

3. Effects on Other Neurotransmitter Systems

• Anticholinergic Effects: Many medications (particularly first-generation antihistamines and tricyclic antidepressants) block muscarinic acetylcholine receptors 1

  • This disrupts the cholinergic system's role in arousal and attention
  • Results in drowsiness, confusion, and cognitive impairment

• Serotonin Modulation: Some medications affect serotonin pathways, which play a role in sleep-wake regulation

  • Certain antidepressants and antipsychotics can cause drowsiness through these mechanisms

• Opioid Receptor Activation: Opioids cause drowsiness through:

  • Direct activation of mu-opioid receptors in respiratory centers
  • Inhibition of arousal pathways in the brain stem
  • Depression of respiratory drive, leading to increased carbon dioxide levels that further depress consciousness 1

Medication Classes Most Associated with Drowsiness

1. Sedative-Hypnotics

• First-Generation Antihistamines (diphenhydramine, hydroxyzine):

  • Cause significant sedation through H1 receptor antagonism and anticholinergic effects
  • Performance impairment can exist without subjective awareness of drowsiness 1
  • Associated with impaired learning, school performance, and driving ability

• Benzodiazepines:

  • Enhance GABA-mediated inhibition
  • Can cause next-day impairment due to long half-lives of parent compounds and metabolites 1
  • Tolerance to sedative effects may develop with long-term use, but may not be complete 2

• Z-drugs (zolpidem, eszopiclone):

  • Work similarly to benzodiazepines but with more selective binding to GABA-A receptor subtypes
  • Can cause complex sleep behaviors and next-day impairment 3
  • Risk increases with higher doses or shortened sleep duration

2. Opioids

• Cause mixed obstructive and central sleep apnea through:
  • CNS respiratory depression
  • Relaxation of upper airway muscles
  • Blunted respiratory response to carbon dioxide and hypoxia 1
• Severity depends on dose, with 75-85% of patients on opioids experiencing at least mild sleep apnea 1

3. Antidepressants and Antipsychotics

• Sedating Antidepressants (mirtazapine, trazodone):

  • Block multiple receptors including histamine H1, causing significant drowsiness
  • Trazodone has high incidence of sedation, dizziness, and psychomotor impairment 4

• Antipsychotics:

  • First-generation and some second-generation antipsychotics cause sedation through histamine, dopamine, and serotonin receptor blockade
  • Quetiapine and olanzapine are particularly sedating 1

Variability in Sedative Effects

Individual Differences

• Age-Related Factors:

  • Elderly patients are more sensitive to sedative effects due to:
    • Altered pharmacokinetics (reduced drug clearance)
    • Changes in receptor sensitivity
    • Reduced blood-brain barrier integrity 1, 4
  • Elderly patients require lower doses of sedating medications 4

• Body Mass:

  • Patients with low body mass may experience greater sedation with standard doses 1
  • Drug distribution volume affects concentration at target sites

Differences Among Similar Medications

• Second-Generation Antihistamines:

  • Fexofenadine, loratadine, and desloratadine do not cause sedation at recommended doses
  • Cetirizine and intranasal azelastine may cause sedation at recommended doses 1
  • Loratadine and desloratadine can cause sedation at higher than recommended doses

• Hypnotics:

  • Triazolam has shorter duration but more pronounced memory impairment 5
  • Flurazepam has longer-lasting effects with significant daytime sedation during short-term use 6

Clinical Implications and Risk Mitigation

Safety Concerns

• Driving Impairment:

  • Drivers taking first-generation antihistamines are 1.5 times more likely to be responsible for fatal accidents 1
  • Morning-after effects can persist even without subjective awareness of drowsiness
  • Zolpidem can cause next-day impairment, especially if taken with less than 7-8 hours of sleep remaining 3

• Falls and Injuries:

  • Sedative-hypnotics increase fall risk, especially in elderly patients 1
  • Benzodiazepines and Z-drugs are associated with increased risk of fractures 1

Practical Recommendations

• Dosing Considerations:

  • Use the lowest effective dose, especially in elderly patients 4
  • Consider timing of administration relative to needed waking hours
  • Avoid AM/PM dosing regimens that combine second-generation antihistamines in the morning with first-generation antihistamines at night 1

• Drug Selection:

  • Choose medications with less sedative potential when possible (e.g., second-generation vs. first-generation antihistamines) 1
  • Consider alternatives to medications that cause weight gain, which can worsen sleep apnea 1

• Monitoring:

  • Assess for additive effects with multiple CNS depressants
  • Be aware that performance impairment can occur without subjective drowsiness 1
  • Monitor for complex sleep behaviors with hypnotics like zolpidem 3

Common Pitfalls and Caveats

• Tolerance Development: While tolerance to sedative effects may develop with continued use, it may not be complete, and performance may improve after discontinuation 2

• Rebound Effects: Abrupt discontinuation of sedating medications can lead to rebound insomnia or anxiety 6

• Additive Effects: Concomitant use of multiple CNS depressants (including alcohol) can dramatically increase sedation and impairment 1, 3

• Paradoxical Reactions: Some patients, particularly children and elderly, may experience paradoxical excitation rather than sedation with certain medications 1

• Masking of Sleep Disorders: Sedating medications may mask underlying sleep disorders such as obstructive sleep apnea that require specific treatment 1

Understanding these mechanisms can help clinicians select appropriate medications, anticipate side effects, and counsel patients effectively about managing medication-induced drowsiness.