How do medications cause drowsiness?

Mechanisms of Medication-Induced Drowsiness

Medications cause drowsiness primarily through their effects on central nervous system neurotransmitter systems, with first-generation antihistamines, benzodiazepines, and opioids being the most common culprits due to their ability to cross the blood-brain barrier and affect alertness centers. 1

Primary Mechanisms of Medication-Induced Drowsiness

1. Histamine Receptor Antagonism

• First-generation antihistamines (e.g., diphenhydramine, hydroxyzine, clemastine) readily cross the blood-brain barrier and block H1 histamine receptors in the central nervous system
• Histamine is a key neurotransmitter for maintaining wakefulness and alertness
• Blocking these receptors disrupts the normal wake-promoting effects of histamine, leading to sedation 1
• Even when taken at bedtime, these medications can cause next-day drowsiness due to their long half-lives and persistence of metabolites 1

2. GABA Receptor Modulation

• Benzodiazepines and related drugs (e.g., zolpidem) enhance the inhibitory effects of gamma-aminobutyric acid (GABA)
• By binding to GABA-A receptors, these medications increase chloride ion influx into neurons, resulting in:
  • Hyperpolarization of cell membranes
  • Decreased neuronal excitability
  • CNS depression manifesting as drowsiness 1
• Different benzodiazepines have varying half-lives, affecting the duration of drowsiness 2

3. Opioid Receptor Activation

• Opioids (e.g., morphine, fentanyl) cause drowsiness through multiple mechanisms:
  • Direct activation of μ-opioid receptors in brain regions controlling arousal
  • Depression of respiratory centers in the ventrolateral medulla
  • Relaxation of upper airway muscles, potentially exacerbating sleep-disordered breathing 1
• Opioids can induce both obstructive and central sleep apnea, further contributing to daytime drowsiness 1

4. Serotonin Modulation

• Some antidepressants (particularly sedating ones) affect serotonin pathways that regulate sleep-wake cycles
• These medications may block serotonin reuptake or affect multiple neurotransmitter systems simultaneously 3

Medication Classes Most Commonly Associated with Drowsiness

Antihistamines

• First-generation antihistamines have significant sedative effects due to their ability to cross the blood-brain barrier 1
• Second-generation antihistamines vary in their sedative properties:
  • Fexofenadine, loratadine, and desloratadine typically do not cause sedation at recommended doses
  • Cetirizine and intranasal azelastine may cause sedation at standard doses 1

Hypnotics and Sedatives

• Benzodiazepines (e.g., temazepam, lorazepam) cause dose-dependent drowsiness and performance impairment 1, 2
• Z-drugs (e.g., zolpidem) can cause:
  • Complex sleep behaviors (sleep-walking, sleep-driving)
  • Next-day psychomotor impairment
  • Increased risk of falls, especially in elderly patients 4
• Residual effects are more pronounced when:
  • Less than 7-8 hours of sleep time remains
  • Higher than recommended doses are taken
  • Combined with other CNS depressants 4

Opioid Analgesics

• Opioids cause drowsiness through central respiratory depression and upper airway muscle relaxation 1
• Long-term opioid therapy can induce sleep-disordered breathing, increasing central apneas and decreasing obstructive apneas 1
• The sedative effects are dose-dependent and can be potentiated by other CNS depressants 1

Other Medications

• Muscle relaxants like baclofen can cause drowsiness through GABA-B receptor activation 1
• Antipsychotics have varying sedative properties:
  • Quetiapine and olanzapine are more sedating
  • Aripiprazole is less likely to cause drowsiness 1
• Antiepileptic drugs may cause sedation through various mechanisms including GABA enhancement 3

Special Considerations and Risk Factors

Elderly Patients

• Increased sensitivity to CNS depressant effects due to:
  • Age-related changes in pharmacokinetics
  • Decreased drug clearance
  • Changes in receptor sensitivity 1, 5
• Higher risk of adverse outcomes including falls and cognitive impairment 1
• Lower doses of sedating medications are recommended in this population 5

Drug Interactions

• Additive CNS depression occurs when combining multiple sedating medications 4
• Alcohol significantly potentiates the sedative effects of most drowsiness-inducing medications 4
• CYP3A4 inhibitors (e.g., ketoconazole) can increase blood levels of certain hypnotics, enhancing their sedative effects 4

Individual Variability

• Genetic differences in drug metabolism affect susceptibility to drowsiness
• Body weight influences drug distribution and effective concentration
• Patients with low body mass may experience more pronounced sedation at standard doses 1

Clinical Implications and Mitigation Strategies

• Select medications with lower sedative potential when possible (e.g., second-generation vs. first-generation antihistamines) 1
• Use the lowest effective dose, especially in elderly patients 5
• Advise patients about drowsiness risk and potential impairment of driving and other activities requiring alertness 4
• Consider timing of medication administration to minimize impact on daytime functioning 4
• Monitor for additive effects when multiple CNS depressants are used concurrently 4

Understanding these mechanisms allows for better medication selection, appropriate patient counseling, and implementation of strategies to minimize the impact of medication-induced drowsiness on daily functioning and quality of life.