Sedatives and Hypnotics Flashcards
What do sedatives do?
Relieve anxiety, cause relaxation, mild CNS depressants
What do hypnotics do?
Cause drowsiness and sleep
What drug class do barbiturates fall under?
Schedule IV (USA)
What are some characteristics of sedatives and hypnotics?
Orexin antagonists, melatonin agonists, anti-histamines
What drugs treat anxiety?
Benzos = ‘aze’-pams
What type of drugs treats seizure disorder?
Anti-convulsants
Longer-acting
Phenobarbital
What type of drugs causes anesthesia?
Short-acting drugs
Thiopental, midazolam, trazolam
What is the difference between sedatives and hypnotics?
Sedatives are for calming
Hypnotics are for sleeping
How are sedatives classified?
Lipophilic class = faster onset due to rapid distribution
Longer-acting = anticonvulsants, muscle relaxants, anxiolytics
Shorter-acting = pre-anesthetic sedatives or to treat insomnia
What does the presence of a triazole ring do?
Higher potency
Decreased duration of action
Binds GABA better
What are the routes of administration of sedatives?
Oral, rectal, injection
How are benzos and barbiturates distributed?
Benzos are less lipid soluble than barbituates, absorbed more slowly, slower onset of action
Both are highly bound to plasma proteins
Cross the placenta
What metabolized sedatives?
Liver CYP450
What do some sedatives do during metabolism?
Some produce active metabolites that prolong the duration of action
What is the half-life of midazolam?
2 hours
What is the half-life of diazepam?
100 hours
How many half-lives are required for elimination?
4-5
What types of people have decreased sedative metabolism?
Infants, pregnant women, those with liver disease, the elderly
What is floppy infant syndrome?
Reduced muscle tone in infants that causes an inability to nurse that can last for months
What is the mechanism of GABAa receptor binding of sedatives?
GABA binds between alpha and beta subunits
Benzos bind between alpha and gamma subunits in those receptors that contain these subunits
What is the mechanism of benzo binding?
Bind to a site on the GABAa receptor which increases the frequency of chloride channel openings
Where are GABA receptors with benzo binding sites located?
Limbic system, reticular activating system, cortex
Do GABA receptors that control respiration have benzo sites?
Not many
What is the mechanism of barbiturate binding?
More general effect on GABA receptors
When they bind, the enhance the affinity of the receptor for GABA, which increases the duration of time that they chloride channel is open which leads to neuronal inhibition
Can do this even when GABA isn’t present
Benzos are allosteric _?
Modulators
Barbiturates are allosteric _?
Activators
What are the acute effects of sedatives?
Reduce muscle tone, impair coordination, and increase sedation and sleep
-total sleep time increased, but deep sleep reduced
Reduce anxiety, learning, memory, and can cause bizarre and uninhibited behaviours
What are the common side effects of sedatives?
Drowsiness, lethargy, dizziness, confusion, reduced libido, diminished concentration, incoordination, and impairment of driving skills
Prevent consolidation of short-term memories, especially alpha subunit-containing receptors
Combined with alcohol to facilitate assault
What are the effects of sedatives on a fetus?
Rapid entry, increased half-life due to under-developed liver
Potential increased risk of cleft palate, floppy infant syndrome, withdrawal
No risk of major malformations
What are the drugs interactions of sedatives?
Synergistic with other depressants such as alcohol and opioids
Interact with other drugs metabolized by CYP450 system
How is sedative overdose treated?
With flumazenil
Relatively rare for benzos by themselves
Barbiturates have a low therapeutic index
What rate does tolerance to sedatives happen at?
Different rates
Tolerance for sedative effects = days to weeks
Tolerance for anxiolytic effects = 3-4 months
Does not develop for respiratory depression
Users can require 40x the original dose
What mechanisms for tolerance develop to barbees?
Cellular and metabolic mechanisms
What are benzos well-known for?
Producing tolerance
What are the chronic effects of sedative tolerance?
Associated with daytime fatigue, accidents, depression, violence, and increased overall mortality
Is withdrawal worse for short-acting or long-acting sedatives?
Short-acting
Should be medically supervised due to hyperexcitability
What are the symptoms of sedative withdrawal?
Insomnia, anxiety, tremor, headache, confusion, difficulty concentrating
What is sedative dependence like?
Physical and psychological dependence
Are benzos or barbiturates more addictive?
Barbiturates are more addictive
What is the abuse potential in sedatives like?
Lower than drugs like cocaine and opioids
What does disinhibition of VTA DA-ergic neurons increase?
Increases DA release in the NAc
What is GHB?
Date rape
GABAb receptor agonist = Gi/o linked, inhibits Ca channels, activates GIRK
Precursor of GABA, Glu, and Gly
Dose dependent effects
What do low doses of GHB do?
Stimulatory effect
What do high doses of GHB do?
Binds to GABA receptors and can cause sedation
