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

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

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

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

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

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

GABA Receptor

Benzodiazepines: Mechanism of Action Chloride channel

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

Benzodiazepines: Therapeutic Use Anxiety disorders Muscular disorders Seizures Sleep disorders

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

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.

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

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

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

Other Anxiolytic Drugs Buspirone Hydroxyzine Antidepressants

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

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

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

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

Barbiturates Name of few barbiturates: Pentobarbital Phenobarbital Thiopental

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

GABA Receptor

Barbiturates: Mechanism of Action

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

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

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

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

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

Other Hypnotic Agents Zolpidem Antihistamines Ethanol

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

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

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