1. Anxiolytic, Sedative and Hypnotic Drugs
Course Coordinator
Jamaluddin Shaikh, Ph.D.
School of Pharmacy, University of Nizwa
Lecture-23 & 24
December 03, 2011

2. Few Terminologies Anxiety: Anxiolytic: Drugs which relieve anxiety
An unpleasant state of tension or uneasiness
Associated with medical conditions e.g., cardiovascular and GI diseases 
Anxiolytic: Drugs which relieve anxiety
Sedative / tranquilizer:
Drugs which decrease activity, and moderate excitement
Hypnotic:
Produces drowsiness and facilitates the onset and maintenance of a state of sleep that resembles natural sleep
Hypnotics induce sleep and anxiolytics reduce anxiety. There is considerable overlap between them

3. Anxiolytic and Hypnotic Drugs
Classification of anxiolytic and hypnotic drugs:
Benzodiazepines
Benzodiazepine antagonist
Other anxiolytic drugs
Barbiturates
Other hypnotic agents

4. Anxiolytic and Hypnotic Drugs
Classification of anxiolytic and hypnotic drugs:
Benzodiazepines
Benzodiazepine antagonist
Other anxiolytic drugs
Barbiturates
Other hypnotic agents

5. Benzodiazepines Name of few benzodiazepines (BZs): Alprazolam
Clonazepam
Diazepam
Flurazepam
Lorazepam
Triazolam

6. Benzodiazepines: Mechanism of Action
BZs act by binding the γ-aminobutyric acid (GABAA) receptor-chloride channel complex and facilitate the opening of the channel in the presence of GABA

7. GABA Receptor

8. Benzodiazepines: Mechanism of Action
Chloride channel

9. Benzodiazepines: Action
Reduction of anxiety:
At low doses, the BZs are anxiolytic
Reduce anxiety by selectively enhancing GABAergic transmission
Sedative and hypnotic actions:
Have sedative properties, and can produce hypnosis
Anticonvulsant:
BZs have anticonvulsant activity and used to treat epilepsy
Muscle relaxant:
At high doses, BZs relax the spasticity of skeletal muscle

10. Benzodiazepines: Therapeutic Use
Anxiety disorders
Muscular disorders
Seizures
Sleep disorders

11. Benzodiazepines: Pharmacokinetics
Absorption and distribution:
Lipophilic, rapidly and completely absorbed after oral dose
Duration of actions:
Divided into short-, intermediate-, and long-acting groups
Fate:
Metabolized by the hepatic enzyme
Drugs' effects are terminated by excretion and redistribution
Cross the placental barrier and may depress the CNS of the newborn if given before birth

12. Benzodiazepines: Adverse Effects
Drowsiness and confusion:
Most common side effects
Cognitive impairment can occur
Triazolam, one of the most potent oral BZs often shows early morning insomnia, and daytime anxiety
Precautions:
Used cautiously in treating patients with liver disease
Avoided in patients with acute narrow-angle glaucoma
Alcohol and other CNS depressants enhance the sedative-hypnotic effects of the BZs.

13. Anxiolytic and Hypnotic Drugs
Classification of anxiolytic and hypnotic drugs:
Benzodiazepines
Benzodiazepine antagonist
Other anxiolytic drugs
Barbiturates
Other hypnotic agents

14. Benzodiazepine Antagonist: Flumazenil
Antagonist of GABA-receptor that can rapidly reverse the effects of BZs
Available for intravenous administration only
Onset is rapid but duration is short, with a half-life of about 1 hour
Dizziness, nausea, vomiting, and agitation are the most common side effects

15. Anxiolytic and Hypnotic Drugs
Classification of anxiolytic and hypnotic drugs:
Benzodiazepines
Benzodiazepine antagonist
Other anxiolytic drugs
Barbiturates
Other hypnotic agents

16. Other Anxiolytic Drugs
Buspirone
Hydroxyzine
Antidepressants

17. Buspirone Efficacy comparable to that of the BZs
Actions mediated by serotonin receptors
Causes hypothermia and can increase prolactin and growth hormone
Undergoes metabolism by CYP3A4
Adverse effects: headaches, dizziness, and nervousness
Disadvantage of a slow onset of action

18. Hydroxyzine An antihistamine with antiemetic activity
Useful for patients with anxiety who have a history of drug abuse
Used for sedation prior to dental procedures or surgery
Drowsiness is a possible adverse effect

19. Antidepressants
Antidepressants have proven efficacy in managing the long-term symptoms of chronic anxiety disorders
The SSRIs, TCAs, and MAOIs all have potential usefulness in treating anxiety

20. Anxiolytic and Hypnotic Drugs
Classification of anxiolytic and hypnotic drugs:
Benzodiazepines
Benzodiazepine antagonist
OtheOther anxiolytic drugs
Barbiturates
Other hypnotic agents

21. Barbiturates Name of few barbiturates: Pentobarbital Phenobarbital
Thiopental

22. Barbiturates: Mechanism of Action
The sedative-hypnotic action of the barbiturates is due to their interaction with GABAA receptors, which enhances GABAergic transmission
Binding site is distinct from that of the BZs
Barbiturates potentiate GABA action on chloride entry into the neuron by prolonging the duration of the chloride channel openings

23. GABA Receptor

24. Barbiturates: Mechanism of Action

25. Barbiturates: Actions
Classified according to their duration of action:
Thiopental
Acts within seconds, duration of action is about 30 minutes
Used in the intravenous induction of anesthesia
Pentobarbital
Short-acting barbiturates
Effective as sedative and hypnotic agents
Phenobarbital
Duration of action greater than a day
Useful in the treatment of seizures

26. Barbiturates: Therapeutic Uses
Anesthesia:
The ultra short-acting barbiturates, such as thiopental, are used intravenously to induce anesthesia.
Anticonvulsant:
Phenobarbital is used in long-term management of tonic-clonic seizures
Phenobarbital has specific anticonvulsant activity
Anxiety:
Used as mild sedatives to relieve anxiety, nervous tension, and insomnia

27. Barbiturates: Pharmacokinetics
Absorbed orally and distributed throughout the body
Redistribute in the body from the brain to the skeletal muscle, and finally, to adipose tissue
Readily cross the placenta and can depress the fetus
Metabolized in the liver, and excreted in the urine

28. Barbiturates: Adverse Effects
CNS:
Cause drowsiness and impaired concentration
Drug hangover:
Produce a feeling of tiredness well after the patient wakes
Physical dependence:
Abrupt withdrawal from barbiturates may cause tremors, anxiety, weakness, restlessness, nausea and vomiting
Poisoning:
Barbiturate poisoning has been a leading cause of death resulting from drug overdoses

29. Anxiolytic and Hypnotic Drugs
Classification of anxiolytic and hypnotic drugs:
Benzodiazepines
Benzodiazepine antagonist
OtheOther anxiolytic drugs
Barbiturates
Other hypnotic agents

30. Other Hypnotic Agents
Zolpidem
Antihistamines
Ethanol

31. Zolpidem A hypnotic agent
Does not have BZ structure, but it acts on BZ1 receptor
Rapidly absorbed from the gastrointestinal tract
Rapid onset of action and short half-life (2 to 3 hrs)
Undergoes hepatic oxidation by the cytochrome P450
Adverse effects include nightmares, agitation, headache, dizziness, and daytime drowsiness

32. Antihistamines
Antihistamines with sedating properties, such as diphenhydramine and doxylamine, are effective in treating mild types of insomnia
They have numerous undesirable side effects that make them less useful than the BZs

33. Ethanol
Ethanol has anxiolytic and sedative effects, but its toxic potential outweighs its benefits
CNS depressant, producing sedation and, ultimately, hypnosis with increasing dosage
Readily absorbed orally
Metabolized primarily in the liver
Elimination is mostly through the kidney
Ethanol synergizes with many other sedative agents and can produce severe CNS depression