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- very old BZD, rarely used
- main use in alcohol withdrawal
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.
- - upon discontinuation:
- 1) REM rebound: increase in nightmares and fear
- 2) Rebound insomnia: prolonged sleep onset latency
- 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)
- DIs: CNS depressants, grapefruit juice, CYP3A4 inducers/inhibitors, CYP2C19 inducers/inhibitors
Zopiclone, Zolpidem, Zaleplon
- - 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.
- Overdose: suicide attempts, drug automatism (due to anterograde amnesia). Drowsiness/confusion -> ataxia/hyporeflexia -> hypotension, arrhythmias, pulmonary edema -> shock, coma, death.
- Tx overdose: respiratory/hemodynamic support, activated charcoal.
- Tolerance and physical dependence...abuse and euphorogenic effects. Withdrawal - insomnia, nightmares,sweating, irritablity, tremor, anorexia, weight loss, delirium, seizures, death.
- DI: barbs are hepatic enzyme inducers...increase CNS depression with other CNS depressants (ESP alcohol).
- MoA: metab'd to trichloroethanol in liver, exact MoA not clear. Act like barbiturates.
- Use: rare, for paradoxical reactions to BZDs and in peds
- Sleep: similar to barbs
- SE: irritate mucosa membranes, cause GI upset **MUST EAT BEFORE TAKING, dizziness, ataxia, nightmares, confusion, vertigo, "hangover effect", paradoxical effect, minimal effect on respiration and blood pressure.
- Tox: accumulate. Acute overdose similar to barbs, death due to cardiac arrhythmias.
- Chronic overdose GI irritation/perforation, skin rash, hypotension, renal and cardiac toxicity.
- Tx overdose: resp and hemodynamic support, activated charcoal, beta blocker.
- Tolerance: develop after 2weeks. Abuse potential high, similar to alcohol.
- Delirium tremens: severe withdrawal if abrupt d/c after prolonged use (autonomic instability, confusion, nightmares, agitation, visual disturbances, significant mortality rate)
- MoA: antichol, antiadrenergic, antihistaminergic...sedation.
- But risk of other side effects (dry mouth, cardiac) also significant.
- Cause drowsiness, reduce latency to sleep onset.
- MoA: useful anxiolytic, not cause sedation. Not ass'd with dependence or withdrawal.
- MoA: unclear. partial agonist at 5-HT1A receptors in raphe nuclei, amygdala, hippocampus.(mood and anxiety)
- Activation of post-synaptic 5-HT1A R -> hyperpolarizaton and inhibition.
- Also affinity to DA2 receptors.
- Onset: 2 weeks...not for acute anxiety attacks.
- SE: light-headedness, dizziness, nervousness, H/A, insomnia, restlessness, GI...more common at beginning.
- If switching from BZD to buspirone, need to taper BZD + have wash-out period to differentiate btwn BZD withdrawal and buspirone failure.
- DI: serotonergic drugs (serotonin syndrome), MAOIs (hypertensive crisis), CYP3A4 interactions (inducers rifampin, inhibitors grapefruit juice, macs, azoles, CCBs)