Sedatives, hypnotics, and anxiolytics Flashcards
How is GABA synthesized
- Synthesized from glutamate (glutamic acid) via glutamic acid decarboxylase in presynaptic neurons
- Transported by vesicular inhibitory amino acid transporters (VIATTs) into synaptic vesicles
GABA action in synapse terminated by:
- presynaptic GABA transporter / GABA reuptake pump
- Enzyme GABA transaminase (GABA-T) metabolizes to inactive substance
What are the predominant GABA receptors
GABA-A and GABA-C
- Ligand-gated ion channels that form inhibitory chloride channel
- GABA-A is target of benzodiazepines, sedative hypnotics, barbiturates, and alcohol - Involved with tonic or phasic inhibitory neurotransmission
GABA-B:
•G-protein-linked receptors
- Coupled to calcium and/or potassium channels
- May be involved in pain, memory, mood, other CNS functions
Structure of GABA-A receptors
Formed from 5 subunits
Each subunit has 4 transmembrane regions
Chloride channel in the center
- Presence of different subunits determines function
- Benzodiazepine-insensitive GABA-A receptors
- Benzodiazepine-sensitive GABA-A receptors
Info about Benzodiazepine-insensitive GABA-A Receptors
•Include α4, α6, γ1, δ subunits
•Bind to naturally occurring neurosteroids, alcohol, some general anesthetics
•Located extrasynaptically
•Not involved in anxiolytic actions of benzodiazepines
Info about Benzodiazepine-sensitive GABA-A Receptors
Two β units + γ2 or γ3 + two α units (α1, α2, or α3)
•α1 subunit – important in regulating sleep (sedative-hypnotic agents)
•α2 and/or α3 – important in regulating anxiety (benzodiazepines)
- Located postsynaptically
- Each receptor binds 2 molecules of GABA
- Binding of GABA increases frequency of opening of chloride channels à inhibitory transmission
•Each receptor binds two GABA molecules and can bind one benzodiazepine molecule
•GABA binds at different location on receptor than modulator (benzodiazepine)
Benzodiazepine Mechanism of Action
GABA - key points
Benzos absorption and distribution
•Absorption and distribution and dependent on lipophilicity
•All benzodiazepines are lipid soluble:
- Benzodiazepines and their active metabolites are bound to plasma proteins
- All cross placental barrier
- All detectable in breast milk
Characteristics of High lipid soluble benzos
•Rapidly absorbed from GI tract -> distributed rapidly to brain by passive diffusion along a concentration gradient
•RAPID ONSET OF ACTION
•Concentration increases in brain and decreases in bloodstream -> reversal of concentration gradient -> medication leaves the brain rapidly
•FAST CESSATION OF DRUG EFFECT
Benzos metabolism
•Parent drug undergoes CYP-mediated oxidation (CYP3A4 and CYP2C19) to active intermediate metabolite –> undergoes conjugation –> urinary excretion
What impacts benzo metabolism
Duration of action is dependent on nature of hepatic metabolism and by the half-life of active intermediate metabolites rather than the half-life of the parent drug
Oxidative pathway is slowed in hepatic impairment and with advancing age
•Benzodiazepine and metabolites may accumulate and cause adverse reactions in patients with hepatic impairment and the elderly
Conjugation is less effected by global hepatic function
•In patients with hepatic impairment, want to use benzodiazepines that only undergo conjugation
Benzos side effects
•Drowsiness, dizziness, ataxia, impaired psychomotor function, amnesia, mild cognitive impairment, “paradoxical effects” (aggression, disinhibition, anxiety)
- Respiratory depression
- Hypotension
- Falls, hip fractures
Benzos special populations
- Use with caution in hepatic and renal impairment
- Use with caution in elderly
- Clinically significant impairment of respiration in persons with COPD and sleep apnea
- Use with caution in patients with history of substance abuse due to high abuse potential
- Use with caution in patients with cognitive disorders
- Use during pregnancy is not advised
- Use in third-trimester can precipitate withdrawal syndrome in newborn
Benzos drug interactions
- Alcohol and other CNS depressants (barbiturates, narcotics) will increase CNS depression
- Drugs that inhibit CYP enzymes or alter activity of conjugation
Benzos examples
Advantages of long half life vs short half life
- Advantages of long-half-life drugs over short-half-life drugs include less frequent dosing, less variation in plasma concentration, and less severe withdrawal phenomena
- Disadvantages include drug accumulation, increased risk of daytime psychomotor impairment, and increased daytime sedation
- Rebound insomnia and anterograde amnesia are more problematic with short-half-life drugs than with long-half-life drugs
Benzos tolerance and dependence
•Short term use (1-2 weeks) in moderate doses does not cause significant tolerance, dependence or withdrawal
Benzos withdrawal
Anxiety, irritability, insomnia, hyperacusis, nausea, difficulty concentrating, diaphoresis, restlessness, tremor, depersonalization, hallucinations (particularly visual hallucinations), paranoia, delirium, seizures, autonomic instability
- Clinically indistinguishable from alcohol withdrawal
- Onset may be delayed by 1-2 weeks with long half-life drugs (such as diazepam)
Alprazolam causes immediate and severe withdrawal syndrome
Flutazemil MOA and use
•Antagonist at benzodiazepine allosteric site of GABA-A receptor
•IV administration
•Used to reverse benzodiazepine overdose
•Use with caution as can induce seizures or withdrawal in benzodiazepine dependent patients
Buspirone (Buspar) MOA, indications, etc
Propranolol info
Insomnia categories
Most useful ways to treat insomnia
•Behavioral therapies are most useful
- Cognitive behavioral therapy for Insomnia (CBT-I)
- Sleep hygiene
- Sleep restriction therapy
- Relaxation therapy and biofeedback
