Anxiolytic and Hypnotic Drugs

PHRM 306

Overview
Anxiety is an unpleasant state of tension, apprehension, or uneasiness-a fear that seems to arise from a sometimes unknown source. Disorders involving anxiety are the most common mental disturbances.

Overview
The physical symptoms of severe anxiety are similar to those of fear (such as tachycardia, sweating, trembling, and palpitations) and involve sympathetic activation. Episodes of mild anxiety are common life experiences and do not warrant treatment.

Overview
However, the symptoms of severe, chronic, debilitating anxiety may be treated with antianxiety drugs (sometimes called anxiolytic or minor tranquilizers) and/or some form of behavioral or psychotherapy.

Overview
Because many of the antianxiety drugs also cause some sedation, the same drugs often function clinically as both anxiolytic and hypnotic (sleep-inducing) agents. In addition, some have anticonvulsant activity.

Benzodiazepines
Benzodiazepines are the most widely used anxiolytic drugs. They have largely replaced barbiturates and meprobamate in the treatment of anxiety, because the benzodiazepines are safer and more effective. Lethal dose of Benzodiazepines is over 1000 times greater than the therapeutic dose.

Types
Five types of Benzodiazepines 2-keto compounds: chlordiazepoxide, clorazepate, diazepam, flurazepam, halazepam, prazepam, and others. 3-hydroxy compounds: lorazepam, lormetazepam, oxazepam, temazepam

Types
7-nitro compounds: clonazepam, flunitrazepam, nimetazepam, nitrazepam Triazolo compounds: adinazolam, alprazolam, estazolam, triazolam Imidazo compounds: climazolam, loprazolam, midazolam

Benzodiazepines M/A
Binding of GABA to its receptor (GABAA) triggers an opening of a chloride channel, which leads to an increase in chloride conductance. Binding of a benzodiazepine to its receptor site will increase the affinity of GABA for the GABA-binding site (and vice versa) without actually changing the total number of sites.

Benzodiazepines M/A
Activation of the GABAA receptor increases chloride conductance through the ion channel, hyperpolarizing and thereby reducing the excitability of the postsynaptic neuron.

Figure Schematic diagram of benzodiazepine-GABA-chloride ion channel complex.

Actions
All benzodiazepines exhibit the following actions to a greater or lesser extent: Reduction of anxiety: At low doses, the benzodiazepines are anxiolytic. Sedative and hypnotic actions: All of the benzodiazepines used to treat anxiety have some sedative properties, and some can produce hypnosis (artificially produced sleep) at higher doses.

Actions
Anterograde amnesia: The temporary impairment of memory with use of the benzodiazepines is also mediated by the GABA receptors. This also impairs a person's ability to learn and form new memories.

Actions
Anticonvulsant: Several of the benzodiazepines have anticonvulsant activity. Muscle relaxant: At high doses, the benzodiazepines relax the spasticity of skeletal muscle

Dependence
Psychological and physical dependence on benzodiazepines can develop if high doses of the drugs are given over a prolonged period. Abrupt discontinuation of the benzodiazepines results in withdrawal symptoms, including confusion, anxiety, agitation, restlessness, insomnia, tension, and rarely, seizures.

Dependence
Long half-lives of benzodiazepines (flurazepam) : withdrawal symptoms may occur slowly. Benzodiazepines with a short elimination halflife (triazolam): induce more abrupt and severe withdrawal reactions than those seen with drugs that are slowly eliminated.

Adverse effects
Drowsiness and confusion: These effects are the two most common side effects of the benzodiazepines. Ataxia occurs at high doses and precludes activities that require fine motor coordination, such as driving an automobile.

Adverse effects
Precautions: Benzodiazepines should be used cautiously in treating patients with liver disease. They should be avoided in patients with acute narrow-angle glaucoma. Alcohol and other CNS depressants enhance the sedative-hypnotic effects of the benzodiazepines.

Barbiturates
The barbiturates were formerly the mainstay of treatment to sedate the patient or to induce and maintain sleep. Today, they have been largely replaced by the benzodiazepines, primarily because barbiturates induce tolerance, drugmetabolizing enzymes, physical dependence, and are associated with very severe withdrawal symptoms.

Barbiturates
Foremost is their ability to cause coma in toxic doses. Certain barbiturates, such as the very shortacting thiopental, are still used to induce anesthesia.

Mechanism of action
Barbiturates both enhance and mimic the action of GABA. By binding to their receptor, barbiturates decrease the rate of dissociation of GABA from its receptor and increase the duration of GABA-activated chloride ion channel openings.

Mechanism of action
At slightly higher but still clinically relevant concentrations, barbiturates directly activate chloride channels, even in the absence of GABA. Barbiturate enhancement of the action of GABA may be responsible for its sedativehypnotic effects, whereas the GABA-mimetic effect at slightly higher concentrations may be responsible for barbiturate anesthesia.

Actions
Anesthesia: Thiopental (IV), which acts within seconds and has a duration of action of about 30 minutes Seizures: Phenobarbital, which has a duration of action greater than a day Sedative and hypnotic (but not antianxiety) agents: Pentobarbital, secobarbital and amobarbital are short-acting barbiturates

Sedative-Hypnotic-Anxiolytic Drugs
A sedative drug decreases activity, moderates excitement, and calms the recipient. A hypnotic drug produces drowsiness and facilitates the onset and maintenance of a state of sleep that resembles natural sleep, and from which the patient can be easily aroused. An anxiolytic drug reduces anxiety.