Sedative-Hypnotic drugs

Sedatives

Drugs that reduce anxiety and induce calmness without causing sleep.

Hypnotics

Drugs that promote sleep onset and maintenance.

Overlap

Many drugs have both sedative and hypnotic effects depending on the dose.

Benzodiazepines

Diazepam, Alprazolam, Lorazepam

Barbiturates

Phenobarbital, Secobarbital

Non-Benzodiazepine Hypnotics

Zolpidem, Zaleplon, Eszopiclone

Melatonin Receptor Agonists

Ramelteon

Orexin Receptor Antagonists

Suvorexant

Antihistamines

Diphenhydramine, Doxylamine

Other classification of sedative-hypnotic drugs

Chloral Hydrate, Paraldehyde (rarely used today)

Benzodiazepines

Mechanism: Bind to all GABA-A receptor subtypes

Benzodiazepines

Indications: Anxiety, insomnia, seizures, muscle relaxation

Benzodiazepines

Half-life: Varies (short to long)

Benzodiazepines

Side Effects: Drowsiness, dependance, withdrawal

Benzodiazepines

Dependence Risk: High

Benzodiazepines

Clinical use: Broad but limited by risks

Non-Benzodiazepine Hypnotics

Mechanism: Bind selectively to a1-subunit

Non-Benzodiazepine Hypnotics

Indication: Insomnia (short-term)

Non-Benzodiazepine Hypnotics

Half-life: Short (1-3 hours)

Non-Benzodiazepine Hypnotics

Side Effects: Dizziness, complex sleep behavior

Non-Benzodiazepine Hypnotics

Dependence risk: Low

Non-Benzodiazepine Hypnotics

Clinical use: Safe for short-term insomnia

GABA-A Receptor Complex

The primary target for most sedative-hypnotics.

GABA (gamma-aminobutyric acid)

major inhibitory neurotransmitter in the CNS

CNS depression

Sedative-hypnotics enhance GABAergic neurotransmission, leading to

Benzodiazepines

Bind to a specific site on the GABA-A receptor (α-subunit)

Benzodiazepines

Increase the frequency of chloride channel opening → hyperpolarization → inhibition of neuronal firing

Barbiturates

Bind to a different site on the GABA-A receptor

Barbiturates

Prolong the duration of chloride channel opening → stronger CNS depression

Non-Benzodiazepine Hypnotics

Selective for the α1-subunit of the GABA-A receptor → primarily hypnotic effects

Melatonin Receptor Agonists

Act on MT1 and MT2 receptors in the suprachiasmatic nucleus → regulate circadian rhythm.

Orexin Receptor Antagonist

Block orexin receptors (OX1R and OX2R) → reduce wakefulness

5-10 mg

Diazepam dose

0.25-0.5mg

Alprazolam dosing

1-2 mg

Lorazepam dose

Benzodiazepines

Pharmacokinetics:

• Rapid absorption, metabolized in the liver

Benzodiazepines

Dosing varies based on indication (e.g., lower doses for anxiety, higher doses for insomnia)

Benzodiazepines

Clinical Uses:

• Anxiety disorders, insomnia, muscle relaxation, alcohol withdrawal, seizure control.

Benzodiazepines

Contraindications:

• Pregnancy (risk of fetal dependence and withdrawal).

• Severe respiratory disease (risk of respiratory depression).

• Acute narrow-angle glaucoma.

Benzodiazepines

Adverse Effects:

• Sedation, dizziness, cognitive impairment, dependence, withdrawal symptoms

(e.g., rebound anxiety, seizures)

Benzodiazepines

Special Considerations:

• Avoid abrupt discontinuation; taper dose to prevent withdrawal.

30-120mg

Phenobarbital dose

100 mg

Secobarbital dose

Barbiturates

Clinical Uses:

• Insomnia (rarely used today), seizure disorders, anesthesia induction.

Barbiturates

Pharmacokinetics:

• Long-acting (e.g., phenobarbital) vs. short-acting (e.g., secobarbital).

Barbiturates

Contraindications:

• Porphyria (can trigger acute attacks).

• Severe liver or respiratory disease.

Barbiturates

Adverse Effects:

• Respiratory depression, dependence, tolerance, overdose risk

(narrow therapeutic index).

Barbiturates

Special Considerations:

• High risk of fatal overdose in combination with alcohol or opioids.

1-3mg

Eszopiclone dose

5-10mg

Zaleplon dose

5-10mg

Zolpidem dose

Non-Benzodiazepine Hypnotics

Contraindications:

• Severe liver impairment, concurrent use with CNS depressants.

Non-Benzodiazepine Hypnotics

Clinical Uses:

• Short-term treatment of insomnia.

Non-Benzodiazepine Hypnotics

Pharmacokinetics:

• Rapid onset, short duration of action (ideal for sleep-onset

insomnia).

Non-Benzodiazepine Hypnotics

Special Considerations:

• Lower risk of dependence compared to benzodiazepines.

Non-Benzodiazepine Hypnotics

Adverse Effects:

• Dizziness, headache, complex sleep behaviors (e.g., sleepwalking,

sleep-driving).

8mg

Ramelteon dose

Melatonin Receptor Agonists

Pharmacokinetics:

• Rapidly absorbed, metabolized by CYP1A2.

Melatonin Receptor Agonists

Clinical Uses:

• Insomnia, particularly sleep-onset insomnia.

Melatonin Receptor Agonists

Contraindications:

• Severe liver impairment.

Melatonin Receptor Agonists

Special Considerations:

• No risk of dependence or withdrawal.

Melatonin Receptor Agonists

Adverse Effects:

• Dizziness, fatigue, hormonal effects (e.g., decreased

testosterone).

10–20 mg

Suvorexant dose

Orexin Receptor Antagonists

Clinical Uses:

• Insomnia, particularly maintenance insomnia.

Orexin Receptor Antagonists

Contraindications:

• Narcolepsy (can exacerbate symptoms).

Orexin Receptor Antagonists

Adverse Effects:

• Somnolence, headache, rare complex sleep behaviors

Orexin Receptor Antagonists

Special Considerations:

• Novel mechanism of action; useful for patients with

difficulty staying asleep.

Orexin Receptor Antagonists

Pharmacokinetics:

• Moderate onset, intermediate duration of action.

25mg

Doxylamine dose

25-50mg

Diphenhydramine dose

Antihistamines

Special Considerations:

• Limited use due to anticholinergic effects; not

recommended for long-term use.

Antihistamines

Pharmacokinetics:

• Rapid onset, intermediate duration of action.

Antihistamines

Clinical Uses:

• Mild sedation, over-the-counter sleep aids.

Antihistamines

Contraindications:

• Glaucoma, urinary retention, severe liver disease.

Antihistamines

Adverse Effects:

• Dry mouth, blurred vision, constipation, next-day

drowsiness.