Anxiolytics and Hypnotics

Anxiety : is an unpleasant state of tension, apprehension, or uneasiness (a fear that arises from either a known or an unknown source).
The physical symptoms of severe anxiety are similar to those of fear (such as tachycardia, sweating, trembling, and palpitations) and involve sympathetic activation.

Anxiolytic and hypnotic drugs
Benzodiazepines
Benzodiazepines are widely used anxiolytic drugs. They have largely replaced barbiturates in the treatment of anxiety and insomnia, because benzodiazepines are generally considered safer and more effective.
Benzodiazepines?are?active?orally?and?differ?mainly?in respect?of?their?duration?of?action. Short-acting agents (e.g.?Lorazepam?and?Temazepam,?half-lives?8–12?h)?are?metabolised?to?inactive?compounds?and?are?used?mainly?as?sleeping?pills.
Some?long-acting?agents?(e.g.Diazepam?and?Chlordiazepoxide) are?converted?to a? long-lasting?active?metabolite?(nordazepam).
Some used?intravenously, for?example?Diazepam in status epilepticus,?Midazolam?in?anaesthesia.

Mechanism of action
The targets for benzodiazepine actions are the ?-aminobutyric acid (GABAA) receptors. [Note: GABA is the major inhibitory neurotransmitter in the central nervous system (CNS).] The GABAA receptors are composed of a combination of five ?, ?, and ? subunits that span the postsynaptic membrane. Binding of a benzodiazepine to its receptor site increases the affinity of GABA for the GABA-binding site. Binding of GABA to its receptor triggers an opening of the central ion channel, allowing chloride through the pore. Benzodiazepines increase the frequency of channel openings produced by GABA

Pharmacological actions
1. Reduction of anxiety: At low doses, the benzodiazepines are anxiolytic. They are thought to reduce anxiety by selectively enhancing GABAergic transmission in neurons having the ?2 subunit in their GABAA receptors, thereby inhibiting neuronal circuits in the limbic system of the brain.
2. Sedative/hypnotic: All benzodiazepines have sedative and calming properties, and some can produce hypnosis (artificially produced sleep) at higher doses. The hypnotic effects are mediated by the ?1-GABAA receptors.
3. Anterograde amnesia: Temporary impairment of memory with use of the benzodiazepines is also mediated by the ?1-GABAA receptors. The ability to learn and form new memories is also impaired.
4. Anticonvulsant: Several benzodiazepines have anticonvulsant activity. This effect is partially, although not completely, mediated by ?1-GABAA receptors.
5. Muscle relaxant: At high doses, the benzodiazepines relax the spasticity of skeletal muscle, probably by increasing presynaptic inhibition in the spinal cord, where the ?2-GABAA receptors are largely located. Therapeutic uses
1. Anxiety disorders: Benzodiazepines are effective for the treatment of the anxiety symptoms secondary to, panic disorder generalized anxiety disorder (GAD), social anxiety disorder, performance anxiety, posttraumatic stress disorder, obsessive–compulsive disorder, and extreme anxiety associated with phobias, such as fear of flying.
2. Sleep disorders: A few of the benzodiazepines are useful as hypnotic agents. These agents decrease the latency to sleep onset and increase stage II of non–rapid eye movement (REM) sleep. Commonly prescribed benzodiazepines for sleep disorders include intermediate-acting Temazepam and short-acting Triazolam .
3. Amnesia: The shorter-acting agents are often employed as premedication for anxiety-provoking and unpleasant procedures, such as endoscopy, dental procedures, and angioplasty. They cause a form of conscious sedation, allowing the person to be receptive to instructions during these procedures. Midazolam is a benzodiazepine used to facilitate amnesia while causing sedation prior to anesthesia.
4. Seizures: Clonazepam is occasionally used as an adjunctive therapy for certain types of seizures, whereas Lorazepam and Diazepam are the drugs of choice in terminating status epilepticus
5. Muscular disorders: Diazepam is useful in the treatment of skeletal muscle spasms, such as occur in muscle strain, and in treating spasticity from degenerative disorders, such as multiple sclerosis and cerebral palsy.
Adverse effects
Drowsiness and confusion are the most common side effects of the benzodiazepines. Cognitive impairment (decreased long-term recall and retention of new knowledge) can occur with use of benzodiazepines.
Dependence: Psychological and physical dependence on benzodiazepines can develop if high doses of the drugs are given for a prolonged period. Abrupt discontinuation of the benzodiazepines results in withdrawal symptoms, including confusion, anxiety, agitation, restlessness, insomnia, tension, and (rarely) seizures. Benzodiazepines with a short elimination half-life, such as Triazolam, induce more abrupt and severe withdrawal reactions than those seen with drugs that are slowly eliminated such as Flurazepam