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Sedative-Hypnotic Drugs

1. Benzodiazepines (BDZS)

a. Long-acting (> 24 hrs. half-life)

· Diazepam, Clonazepam, Clorazepate, Quazepam, Flurazepam & Clobazam

b. Intermediate-acting (12-24 hrs. half-life)

· Bromazepam, Lorazepam, Estazolam, Chlordiazepoxide & Temazepam

c. Short-acting (12 hrs. half-life)

· Alprazolam, Midazolam, Oxazepam & Triazolam

· Pharmacokinetics: BDZS are lipophilic, rapidly and completely absorbed. Distribution, throughout the body (brain, placenta and mother's milk).

· Mechanism of Action:

1) BDZS potentiate the action of GABA by binding to BDZS sites (BZ, or BZ) on GABA, receptors increasing their affinity for GABA.

2) This results in an increased opening of Cl channels and enhanced hyperpolarization sedative effect.

· Pharmacological Action:

All BDZS exhibit five therapeutic properties;

1) Anxiolytic (also known as minor tranquilizers)

2) Hypnotic

3) Amnesic Actions (memory loss)

4) Anticonvulsant

5) Muscle Relaxant.

· Therapeutic Uses:

1) Anxiety Disorders; selective serotonin reuptake inhibitors (SSRIS), are now considered to be drugs of first choice in anxiety disorders.

2) Sleep Disorders; Non-pharmacologic therapies are useful and safer for sleep disorders (should be used for a limited period), can cause a dose-dependent change in sleep patterns (Zolpidem, Zaleplon and Eszopiclone are less likely change sleep patterns).

3) Adjuncts to Anesthesia; Diazepam, Lorazepam & Midazolam are used IV in anesthesia, to facilitate amnesia.

4) Seizures; IV Clonazepam (stronger), Lorazepam (longer) and Diazepam (faster) are first-line choices.

5) Alcohol Withdrawal Syndrome; Chlordiazepoxide (most commonly), reduce the risk of withdrawal-related seizures.

6) Muscle Spasms; Diazepam is useful in the treatment of skeletal muscle spasms.

· Side Effects:

1) Next day drowsiness and confusion (most common side effects); Most common with long-acting as Diazepam & Flurazepam.

2) Next day sedation، ataxia and impair driving: Most common in elderly.

3) Hypotension & Respiratory Depression.

4) Rebound Insomnia، occur when I discontinued abruptly, most common after the use of short acting agents (most common with, Triazolam).

5) Tolerance, Dependence and Abuse; Triazolam (short acting agent) often shows a rapid development of tolerance and withdrawal symptoms.

·  BDZs reversal agent: Flumazenil rapidly reverses the effects of BDZS by competitive inhibition at the BDZS binding site on the GABAA receptor. IV administration only. Onset is rapid (within one to two min.), but the duration is short, with a half-life of about 1 hour

2. Barbiturates

    a. Long-acting

· Phenobarbital or Phenobarbitone

    b. Intermediate-short-acting

· Secobarbital, Amobarbital & Butalbital

     c. Ultra-short-acting:

· Thiopental

· Today they have been largely replaced by the benzodiazepines, because;

1) High therapeutic index.

2) More selective.

3) Mild physical dependence and tolerance.

4) Little cardiovascular and respiratory depression.

5) Not significantly enzyme inducer.

6) Available of specific antidote (Flumazenil)

· Pharmacokinetics:

Completely absorbed. Distribution; to all tissues and fluids (brain, placenta and mother's milk). Alkalization of urine increase elimination.

· Mechanism of Action:

Barbiturates enhances GABAergic transmission by binding to the site of barbiturates on the GABAA receptors due to prolonging the duration of the Cl channel openings thus sedative-hypnotic action.

· Barbiturates can block excitatory glutamate receptors.

· Pharmacological Action:-

1) CNS Depression

2) CVS Depression

3) Respiratory Depression

4) Liver Microsomal Enzyme Inducers.

· Therapeutic Uses:-

1) Anesthesia (Thiopental).

2) Sedative-hypnotic (rarely or not used), Butalbital is commonly used in combination with analgesics as a sedative to assist in the management of tension-headache or migraine headache.

3) Seizures; Phenobarbital has specific anticonvulsant activity

· Side Effects:-

1) Drowsiness, confusion and impaired concentration (most common).

2) CNS and CVS depressant effects.

3) Tolerance and dependence.

 

3. Non-Benzodiazepines (Z-drugs or newer hypnotics)

· Zolpidem, Zaleplon, Eszopiclone & Zopiclone

· Pharmacokinetics:

Zaleplon is short duration of action (3 hours)

Zolpidem and Zopiclone are intermediate acting (5 hours)

Eszopiclone is long acting (7 hours).

· Mechanism of Action:

are agonists at the GABAA α1 subunit by selectively binds to the BDZS binding site subtype BZ.

· Compared with BDZS:-

1) More selective as hypnotics agent.

2) Lower risk of tolerance and withdrawal.

3) No significantly alter the various sleep stages.

4) No anticonvulsant or muscle-relaxing properties.

5) No respiratory depressant effect.

· Side Effects:

Nightmares, agitation, anterograde amnesia, headache and daytime drowsiness

4. Serotonin Agonists

· Buspirone

· It is a selective 5-HT1A agonist, which is an antianxiety agent.

· It is primarily used to treat generalized anxiety disorder (GAD).

· Contraindication:

should not be used with patient taking MAOIS may cause serotonin syndrome.

 

5. Melatonin Agonists

· Ramelteon

· It is first in a new class of sleep agents that selective agonist at the MT1 and MT2 subtypes of melatonin receptors in the suprachiasmatic nucleus (SCN).

· Ramelteon used for long term for chronic insomnia, particularly in patients with difficulty in sleep initiation.

 

6. Others

· Chloral Hydrate is a non-barbiturate sedative-hypnotic.

· Suvorexant is a selective, dual orexin receptor antagonist (OX1 and OX2).

· OTC First generation antihistamines with sedating properties, such as Doxylamine and Diphenhydramine are effective.

· Doxepin is an older tricyclic antidepressant. It was recently approved at low doses for the management of insomnia

References

1. Medscape
2. PubMed
3. drugbank
4. pharmaguide
5. WebMD