Sedative-Hypnotic drugs

Question 1

Sedative = ?; hypnotic = ?;

uses of sedative-hypnotic drugs

Answer 1

Sedative = calming = anxiolytic effect;
Hypnotic = induce sleep (can achieve usually with sedatives simply by increasing the dose);
1. induce sleep
2. Acute treatment of anxiety disorders
3. Muscle relaxation
4. Anticonvulsant
5. Pre-anesthetic
6. Recreation
I Am MAPR!!

Question 2

Most sedative-hypnotic drugs bind

Answer 2

to some site on GABA A receptor complex and POTENTIATE GABA-mediated inhibition

Question 3

Description of GABA A transmembrane ionotropic receptor complex:

Answer 3

1. Cl channel core
2. Pentameric structure
3. Multiple sub-units
4. Receptor heterogeneity
5. DIFFERING AFFINITIES and differing spectrum of pharm activity
6. GABA will bind to alpha or beta sub-units

Question 4

Benzos, barbs, ethanol can

Answer 4

allosterically enhance GABA binding to GABA A receptor

Question 5

Benzodiazepines can bind to what particular GABA A receptor sub-types?

Answer 5

BDZ1 (omega 1) and BDZ2 (omega2)

Question 6

If BDZ1 and 2 are activated with a benzo like diazepam, what do you get?

Answer 6

1. Sedation to HYPNOSIS
2. Muscle relaxation
3. Anticonvulsant activity
4. Anterograde amnesia
   HAAM

Question 7

What is the difference between benzos and barbs (and alcohol, general anesthetics) for degree of CNS depression?

Answer 7

1. Benzos (ceiling effect) with augmentation of action of GABA to get sedation, hypnosis, and anesthesia (BUT NOT COMA OR DEATH)
2. Barbs, ethanol, general anesthetics can give FULL CNS DEPRESSION by augmenting action of GABA but in HIGH DOSES can directly open the Cl channel

Question 8

Diazepam (Valium)

Answer 8

Class: Benzodiazepine
Mech: GABAa agonist; binds between a1 and y2 subunits; half-life of 43 hours (active metabolites up to 100 hours)
Thera: Short-term depression treatment; maintenance of bipolar; severe bipolar; anticonvulsant; muscle relaxant
Other SE’s: Daytime sedation and drowsiness, anterograde amnesia, synergistic depression of CNS with other drugs, pyschologic and physiologic dependence (chronic use)
Misc: “Ceiling effect” due to augmenting action of GABA

Question 9

Chlordiazepoxide (Librium)

Answer 9

Class: Benzodiazepine
Mech: GABAa agonist; binds between a1 and y2 subunits; half-life of 10 hours (active metabolites up to 100 hours)
Thera: Short-term depression treatment; maintenance of bipolar; severe bipolar
Other SE’s: Daytime sedation and drowsiness, anterograde amnesia, synergistic depression of CNS with other drugs, pyschologic and physiologic dependence (chronic use)
Misc: “Ceiling effect” due to augmenting action of GABA

Question 10

Lorazepam (Ativan): differences from first two benzos

Answer 10

Mech: GABAa agonist; binds between a1 and y2 subunits; half-life of 14 hours
Thera: Short-term depression treatment; maintenance of bipolar; severe bipolar; sedation; anticonvulsant; prevent withdrawal symptoms in alcoholics (less of a HANGOVER)
Misc: “Ceiling effect” due to augmenting action of GABA; directly conjugated into inactive metabolite

Question 11

Flurazepam (Dalmane)

Answer 11

Mech: GABAa agonist; binds between a1 and y2 subunits; half-life of 74 hours (active metabolites up to 100 hours)
Thera: Short-term depression treatment; maintenance of bipolar; severe bipolar
Misc: “Ceiling effect” due to augmenting action of GABA

Question 12

Alprazolam (Xanax)

Answer 12

Mech: GABAa agonist; binds between a1 and y2 subunits; half-life of 12 hours
Thera: Short-term depression treatment; maintenance of bipolar; severe bipolar; sedation
Misc: “Ceiling effect” due to augmenting action of GABA

Question 13

Midazolam (Versed)

Answer 13

Mech: GABAa agonist; binds between a1 and y2 subunits; half-life of 1.9 hours
Thera: Anesthesia (calming effects, production of anterograde amnesia)
Misc: “Ceiling effect” due to augmenting action of GABA

Question 14

Triazolam (Halcion)

Answer 14

Mech: GABAa agonist; binds between a1 and y2 subunits; half-life of 2.9 hours
Thera: Short-term depression treatment; maintenance of bipolar; severe bipolar; induce sleep
Misc: “Ceiling effect” due to augmenting action of GABA

Question 15

Zolpidem (Ambien)

Answer 15

Class: Non-benzodiazepine receptor agonist
Mech: BDZ-1 selective agonist; short half-life of 2 hours
Thera: Sedation and hypnosis without muscle relaxation or anticonvulsant activity
Important SE’s: Sleep-walking, sleep-driving; next morning impairment

Question 16

Flumazenil (Romazicon)

Answer 16

Class: Benzodiazepine antagonist
Mech: Competitive non-selective antagonist
Thera: Benzodiazapine overdose
Important SE’s: Withdrawal (may be life-threatening); seizures in mixed overdoses
Misc: Non uniform in reversal of respiratory depression

Question 17

Thiopental (Pentothal)

Answer 17

Class: Barbiturate
Mech: GABAa agonist (binds a or b subunit); highly lipid soluble, fast-on, fast-off
Thera: Induce anesthesia
Other SE’s: Daytime sedation and drowsiness, dose-dependent depression of CNS, pyschologic and physiologic dependence (chronic use)
Misc: Abrupt withdrawal life-threatening; redistribute from brain to muscle and fat, metabolized by liver; dosed based on lean body mass; significant P450 enzyme induction

Question 18

Phenobarbitol

Answer 18

Class: Barbiturate
Mech: GABAa agonist (binds a or b subunit); less lipid soluble with slower onset, slow elimination
Thera: Antiepileptic, anticonvulsant
Other SE’s: Daytime sedation and drowsiness, dose-dependent depression of CNS, pyschologic and physiologic dependence (chronic use)
Misc: Abrupt withdrawal life-threatening

Question 19

Buspirone (Buspar)

Answer 19

Mech: No GABAa interaction; may be partial agonist at 5HT1A
Thera: Anxiolytic without marked sedation

Question 20

How could one treat acute anxiety, GAD, panic disorder, OCD, PTSD?

Answer 20

acute anxiety with BENZOS;

GAD with SSRIs (for long term) and/or benzos;

Panic disorder: SSRIs or benzos;

OCD: SSRI’s

PTSD: various antidepressants;

RULE OF THUMB: benzos for SHORT-TERM, antidepressants (SSRI’s) for LONG-TERM