Sedative-hypnotics

Question 1

Benzodiazepines

Answer 1

• like 13 of them, check book
• MOA
• bind to specific GABA_A receptor subunits at CNS synapses facilitating GABA-mediated Cl ion channel opening frequency
• enhance membrane hyperpolarization
• Effects
• dose-dependent depressant effects on CNS including sedation and relief of anxiety, amnesia, hypnosis, anesthesia, coma, respiratory depression
• Clinical
• acute anxiety states, panic attacks, GAD, insomnia, relaxation of skeletal muscle, anesthesia adjunctive, seizure disorders
• Kinetics, tox, int.
• t_1/2 2-40h, oral activity, hepatic metabolism - some active metabolites
• tox: extensions of CNS depressant effects, dependence liability
• int: additive CNS depression with ethanol and many other drugs

Question 2

Flumazenil

Answer 2

• Benzodiazepine antagonist
• MOA
• antagonist at benzodiazepine-binding sites on GABA_A receptor
• Effects
• blocks actions of benzo and zolpidem
• Clinical
• benzo overdose
• Kinetics, tox, int.
• IV, short t_1/2
• tox: agitation, confusion
• possible withdrawal symptoms in benzo dependence

Question 3

Barbiturates

Answer 3

• 6 of them, check book
• MOA
• bind to specific GABA_A receptor subunits at CNS neuronal synapses facilitating GABA-mediated Cl ion channel opening duration
• enhance membrane hyperpolarization
• Effects
• dose-dependent depressant effects on CNS including sedation and relief of anxiety
• amnesia, hypnosis, anesthesia, coma, respiratory depression
• steeper dose-response relationship than benzo! (less safe)
• Clinical
• anesthesia (thiopental)
• insomnia (secobarbital)
• seizure disorders (phenobarbital)
• Kinetics, tox, int.
• t_1/2 4-60h, oral activity, hepatic metabolism
• tox: extensions of CNS depressant effects
• dependence liability>benzo!
• int: additive CNS depression with ethanol and many other drugs, induction of hepatic drug-metabolizing enzymes

Question 4

Newer hypnotics

Answer 4

• Eszopiclone, zaleplon, zolpidem
• MOA
• bind selectively to a subgroup of GABA_A receptors, acting like benzo to enhance membrane hyperpolarization
• Effects
• rapid onset of hypnosis with few amnestic effects or day-after psychomotor depression or somnolence
• Clinical
• sleep disorders, especially those involving induction of sleep
• Kinetics, tox, int.
• oral activity, short t_1/2, CYP substrates
• tox: extensions of CNS depressant effects
• dependence liability
• int: additive CNS depression with ethanol and many other drugs

Question 5

Ramelteon

Answer 5

• Melatonin receptor agonist
• MOA
• activates MT₁ and MT₂ receptors in suprachiasmatic nuclei in CNS
• Effects
• rapid onset of sleep with minimal rebound insomnia or withdrawal symptoms
• Clinical
• sleep disorders, especially those affecting sleep induction
• not a controlled substance!
• Kinetics, tox, int.
• oral activity, forms active metabolite via CYP1A2
• tox: dizziness, fatigue, endocrine changes
• interactions: fluvoxamine inhibits metabolism

Question 6

Buspirone

Answer 6

• 5-HT receptor agonist
• MOA
• uncertain, partial agonist at 5-HT receptors but affinity for D₂ receptors also possible
• Effects
• slow onset (1-2 weeks) of anxiolytic effects, minimal psychomotor impairment - no additive CNS depression with sedative-hypnotic drugs
• Clinical
• generalized anxiety
• Kinetics, tox, int.
• oral activity, forms active metabolite, short t_1/2
• tox: tachycardia, paresthesias, GI distress
• int: CYP3A4 inducers and inhibitors