Medical Pharmacology Topics   

Anxiolytics and Sedatives

A sedative is a calming agent, i.e. it decreases activity. A hypnotic agent facilitates sleep. An anxiolytic decreases anxiety. These effects can be accomplished by a variety of drug types: CNS depressants, non-benzodizepine anxiolytics, antidepressants and beta blockers.

The CNS depressants include benzodiazepines, barbiturates, propanedials and antihistamines. At least the barbiturates and benzodiazepines act by enhancing GABA binding to the GABA-A receptor.

Benzodiazepines

Benzodiazepines act through specific receptors closely linked to GABA-A receptors. The benzodiazepine receptor enhances the inhibitory function of GABA. There are at least two major subtypes of benzodiazepine receptors, and most currently available drugs are non-selective agonists at both receptors.

All the benzodiazepines have a benzene and a diazepine ring in their structure. As a drug class, they all have similar CNS effects, and the major differences between agents are pharmacokinetic.

According to their elimination rates, non-selective benzodiazepines are classified as rapid, intermediate or slow. Rapid benzodiazepines like midazolam and triazolam have a half-life < 6 hrs. Intermediate agents like alprazolam, lorazepam and temazepam have a half-life between 6 and 20 hrs. Slow agents like clonazepam, diazepam and chlordiazepoxide have a half-life > 20 hrs.

The non-selective benzodiazepines are used as sedative-hypnotics, anxiolytics, anticonvulsants, muscle relaxants, antipanics, amnesics (antergrade), and preanesthetics. Temazepam and triazolam (intermediate and rapid pharmacokinetics, respectively) are generally used as hypnotics. Diazepam, lorazepam and alprazolam (slow and intermediate pharmacokinetics) are indicated as anxiolytics. Diazepam is also used as a muscle relaxant. Clonazepam and diazepam (both slow pharmacokinetics) are used as anticonvulsants. Short acting agents like midazolam are used IV as preanesthetics or anesthetic for outpatient procedures, due both to the short action and the lack of active metabolites (there is a lesser chance of respiratory suppression than barbiturates usualy used as preanesthetics). Lorazepam is used in the treatment of catatonia.

The partially selective GABA benzodiazepine receptor agonists like zolpidem and zalaplon, bind to the omega-1 receptor on the a-subunit of the GABA receptor. These agents have a short (zolpidem t1/2 < 4 hrs) or ultra-short (zaleplon t1/2 ~ 1 hr) duration of action. They are effective sleep aids because of her short duration of action and lower probability of dependence.

Adverse effects of benzodiazepines include sedation, motor incoordination, interaction with other CNS sedatives (alcohol, barbiturates), dependence and abuse. Any person taking benzodiazepines daily for 6-8 weeks my develop dependence. Although there are no documented risks of long term use, it should be avoided whenever possible.

The best way to treat benzodiazepine dependence is by a very gradual tapering of the dose. Acute withdrawal is characterized by rebound anxiety, muscle twitching, tremors, GI disturbances, perceptual distorsion, hallucinations, delutions, delirium and seizures.

Other agents

Buspirone repesents a new class of anxiolytic, a partial agonist of the 5-HT1A receptor. Although effective in reducing symptoms, it takes 2-4 weeks to see results. Adverse effects include agitation, nausea and dizziness.

Some selective seratonin reuptake inhibitors (SSRI) and other antidepressants are used in the treatment of anxiety. Venlafaxine and paroxentine are used to treat generalized anxiety disorder. Paroxentine and sertraline are used to treat panic disorder, social anxiety disorder and post-traumatic stress disorder. All the SSRI can be used to treat obsessive compulsive disorder. Chlomipramine, a tricyclic antidepressant, is used to treat obsesive-compulsive disorder.

The barbiturates are sedatives most commonly used as anesthetic inducers, amoung them thiopental and methohexital. These agents induce rapid anesthesia but may induce respiratory depression at higher doses.

Propofol is a newer sedative used to induce anesthesia with a smoother post-infussion recovery than barbiturates. It has a very rapid onset, with an initial phase half-life under 10 min (?). Propofol may still cause respiratory depression at higher doses.

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