HYPNOTICS AND SEDATIVES

• Hypnotics


  Drugs that produce drowsiness and facilitate the onset and maintenance of a state of sleep that resembles natural sleep
• Sedatives


  Drugs that decrease activity, moderate excitement, and calm the recipient
• Hypnotics and sedatives


  • Depress the central nervous system in a dose-dependent fashion, progressively producing sedation, sleep, unconsciousness, surgical anesthesia, coma, and ultimately, fatal depression of respiration and cardiovascular regulation
• Sedative drug


  Decreases activity, moderates excitement, and calms the recipient
• Hypnotic drug


  Produces drowsiness and facilitates the onset and maintenance of a state of sleep that resembles natural sleep
• Nonbenzodiazepine sedative-hypnotic drugs


  Depress the central nervous system in a dose-dependent fashion, progressively producing calming or drowsiness (sedation), sleep (pharmacological hypnosis), unconsciousness, coma, surgical anesthesia, and fatal depression of respiration and cardiovascular regulation
• Surgical anesthesia


  • A state in which painful stimuli elicit no behavioral or autonomic response
• Death


  • Resulting from sufficient depression of medullary neurons to disrupt coordination of cardiovascular function and respiration
• Sedation


  A side effect of many drugs that are not general central nervous system depressants (e.g., antihistamines and neuroleptics)
• Benzodiazepine sedative-hypnotics


  • Cannot induce surgical anesthesia or fatal intoxication in the absence of other drugs with central nervous system-depressant actions
• Benzodiazepines


  Promote the binding of the major inhibitory neurotransmitter γ-aminobutyric acid (GABA) to the GABAA subtype of GABA receptors, thereby enhancing the GABA-induced ionic currents through these channels
• Benzodiazepine-like properties


  • Reflect selective actions on one or more subtypes of GABA receptors
• Zolpidem, zaleplon, indiplon


  Exert sedative-hypnotic effects by interacting with a subset of benzodiazepine binding sites
• Benzodiazepines


  • Exert qualitatively similar clinical effects, but have important quantitative differences in their pharmacodynamic spectra and pharmacokinetic properties
• GABAA receptors


  Ionotropic receptors composed of five subunits that co-assemble to form an integral chloride channel, responsible for most inhibitory neurotransmission in the central nervous system
• GABAB receptors


  Metabotropic, G protein-coupled receptors
• Benzodiazepines


  Act at GABAA but not GABAB receptors by binding directly to a specific site that is distinct from that of GABA binding
• Benzodiazepines


  Modulate the effects of GABA, but do not activate GABAA receptors directly like barbiturates
• Benzodiazepine binding site


  Agonists increase, antagonists block, and inverse agonists decrease the amount of chloride current generated by GABAA-receptor activation
• Flumazenil


  An antagonist at the benzodiazepine binding site, used clinically to reverse the effects of high doses of benzodiazepines
• Therapeutic uses of benzodiazepines

  Depend on their half-life - short half-life is desirable for hypnotics, long half-life is better for antianxiety agents
• Barbiturates


  Used extensively as sedative-hypnotic drugs, but have largely been replaced by the much safer benzodiazepines
• Barbiturates


  • Act throughout the central nervous system, preferentially suppressing polysynaptic responses, diminishing facilitation, and enhancing inhibition
• Barbiturates


  Exert several distinct effects on excitatory and inhibitory synaptic transmission, including potentiating GABA-induced increases in chloride conductance and depressing voltage-activated Ca2+ currents
• Barbiturates


  • Can produce all degrees of depression of the central nervous system, ranging from mild sedation to general anesthesia
• Effects of barbiturates on sleep

  Increase total sleep time and alter the stages of sleep in a dose-dependent manner, decreasing sleep latency, number of awakenings, and durations of REM and slow wave sleep