commonly used, often prescribed to stop episodes of epilepsy, muscle relaxant, alcohol withdrawal, pre-op
sleep, anxiety, alcohol withdrawal
pre-op and for anxiety
rarely used: accumulates with use causing "hangover effect"
high rate of misuse and tolerance
withdrawal and rebound effects common
anxiety, panic attacks, social phobias
anxiety and panic attacks
severe withdrawal can occur
commonly used for sleep
benzodiazepines (for hypnosis/anti-anxiety)
- act allosterically to GABA-A receptors, enhance GABA-mediated presyn and postsyn inhibition by increasing Cl- ion influx --> hyperpolarization
- increase frequency of GABA-mediated Cl- channel openings...lowers [GABA] required toopen Cl- channels
- increase amplitude of IPSP, lengthen decay phase proportionally (slope not change)
- need GABA to function.
Sleep - Acute Effects:
- dec. sleep onset latency (to stage 2), inc. NREM stage 3 & 4 in first half of period, delayed onset of first REM period and dec. total REM sleep time, more stage 2 and less stag 3/4 in 2nd half of period, reduced phasic muscular twitches during REM, fewer awakenings.
Sleep - Chronic Effects:
- tolerance to REM effects (and some tolerance to NREM effects)...REM deficit remains een after tolerance develops.
Anxiolytic MoA: linked to activation of BZD receptors...
- hx substance abuse, sleep apnea, CNS depression (synergistic with alcohol), poor cognitive state, renal dysfunction (chlordiazepoxide need dose decrease), hepatic dysfunction (diazepam need dose decrease), elderly, MG
- avoid in pregnancy: oral cleft 1st tri, floppy infant syndrome/neonatal withdrawal 3rd tri
- avoid in lactation: excreted in breast milk
SE: drowsiness, dizziness, CNS depresson, ataxia, psychomotor impairment, disorientation and confusion, anterograde amnesia, dependence and tolerance (withdrawal: insomnia, N/V, twitching, paresthesias, irritability and anxiety, tinnitus, delirium, seizures...can be life-threatening; rebound effects e.g. anxiety or insomnia), aggression and excitement (paradoxical), depression, cardiovascular side effects (hypotension).
Signs of overdose: drowsiness, lethargy, impaired coordination and confusion, ataxia, ypotonia & hyporeflexia, hypotension, resp depression, seizures, coma, cardiac arrest.
Tx of overdose: supportive, charcoal, flumazenil (BZD antagonist, CI if BZD chronic or taking TCA)
PK: well-absorbed, highly PPB but no interactions, CYP enzyme metabolized, oxidation impared in hepatic dysfunction and elderly (avoid chlordiazepoxide, diazepam, flurazepam), others metab'd by conjugation (pref'd in elderly...LOT)
- bind to GABA-A receptors close to BZD site, enhance GABA-mediated inhibition by increasng Cl- ion influx, resulting in hyperpolarization.
- increase frequency of GABA-mediated Cl- channel openings
- increase amplitude of GABA-mediated IPSPs and lengthen decay phase proportionally.
- more selective for GABA-A receptors with alpha-1 subunit, most important for sedation.
Effect on sleep: decrease sleep latency, minimal changes in sleep architecture otherwise...but high doses may suppress REM sleep.
SE: bitter taste, CNS(somnolence, dizziness, confusion, anterograde amnesia, behavioural changes, nightmares, depression, coordination problems, "sleep-driving"), elderly at higher risk of SE, lower dose for hepatic/renal dysfunction, caution with CYP3A4 inhibitors and inducers, tolerance and dependence.
Overdose similar to BZD, withdrawal similar to BZD (has rebound insomnia: anxiety, agitation, delirium, seizures)
DI: increase CNS depression with other CNS depressants, CYP3A4.
barbiturates (for hypnosis/anti-anxiety...but no longer used as sedatives b/c of SE and toxicity)
- increase duration of GABA-mediated Cl- channel open times presynaptically and postsynaptically.
- increase amplitude of IPSP, lengthen decay phase 4-5x normal (slope decreased) because Cl- channels kept open for longer
- at high doses, do not need GABA to function...can activate Cl- channels directly --> basis of toxicity and lethality (massive inhibition ad CNS depression, shut down vasomotor centre...heart stops beating, coma, death.)
- can also reduce glutamate-induced depol by blocking AMPA receptors.
- narrow TI and low degree of selectivity.
Effect on sleep: dose-dependent. dec. sleep onset latency, dec. awakenings, inc. total sleep time, decrease slow wave sleep (stage 3 and 4 NREM), decrease REM duration. Tolerance of effects on sleep can develop within a few days...
CI: pts with porphyria (barbs increase levels of porphyrins), severe resp depression, pulm insufficiency.
Caution in pts with impaired hepatic, hx of drug abuse, elderly.
SE: generalized CNS Depression, decreased respiratory drive (higher doses depress neurogenic, hypoxic, chemoreceptor drive), low doses dec. BP and HR, high doses inhibit cardiovascular reflexes, chronic use induces CYP enzymes to increase metabolism of several drugs and substances, residual CNS depression, paradoxical excitement.