10/11 Sedative Hypnotic Agents - Pilch Flashcards
sedatives
hyponotics
sedative (anxiolytic) agents reduce anxiety and exert a calming effect
hypnotic drugs produce drowsiness and encourage onset/maintenance of sleep state
- hypnotic effects require more pronounced CNS depression than sedation
- hypnotic effect can be achieved with some anxiolytic drugs by increasing dose
goals of therapy for GAD (gen anx disorder)
short term
long term
short term
- reduce severity and duration of anx sx
- improve overall fx
long term
- remission with minimal or no anx sx
- no fx impairment
- incr quality of life
treatment of GAD
components
factors to consider
- plan
- initiating treatment
usually comprises psychotherapy and drug therapy
plan depends on:
- severity/chronicity of sx
- med history
- comorbid med/psych conditions
initiation of tx? consider:
- anticipated adverse effects
- hx of prior response in pt or family member
- pt preference
anxiolytic medication indicated for patients experiencing sx severe enough to produce fxnl disability
short term pharmacotherapy for acute anxiety states
category
examples (7)
similarities/diffs
benzodiazepines (BZs) are most effective and commonly prescribed drugs for rapid relief of acute anxiety sx (incl panic attacks)
- alprazolam (Xanax)
- chlordiazepoxide (Librium)
- clonazapam (Klonopin)
- clorazepate (tranxene)
- diazepam (Valium)
- lorazepam (Ativan)
- oxazepam (Serax)
similarities: all effective as anxiolytics
differences: PK!
- need to consider PK and clinical situation to choose most effective agent
benzodiazepines
PK
absorption: v good at crossing bbb! …but also crosses barriers you might not want
lipophilicity is major determinant of rate at which a BZ enters the CNS
- cross placental barrier → can contribute to depression of neonatal vital fx if administered pre-delivery
- detectable in breastmilk → may exert depressant effects in nursing infant
elimination
clearance generally reduced in elderly
midazolam
peaks at .4-.8 hr
half life 1-7 hr
use?
why not GAD?
useful for procedural sedation!
- quick onset, will wear off soon after procedure
BUT
not so good for GAD because wears off too quick!
why do some drugs have longer half-lives?
what is the effect of multiple doses?
BZs for which parent drug AND metabolites are active tend to have long half-life
- more likely to have cumulative effects (ex. drowsiness) with multiple doses
benzodiazepines
pharmacodynamics
site of action
mechanism of action
BZ are GABA-ergic (potentiates action of GABA at GABAa receptor) → enhance inhibition!
GABAa receptor : Cl ion channel
- heteropentameric glycoprotein assembled from 5 subunits
- major isoform in brain is (alpha1)2(beta2)2(gamma2)
- activated by GABA (gamma-aminobutyric acid)
- GABA binds at 2 sites between alpha and beta subunits → channel opening → hyperpol → inhibition
BZ mechanism of action: bind to single site between alpha and gamma subunits → increase freqency of GABA-gated channel openings
- same site targeted by flumazenil (BZ antagonist), zolpidem/zaleplon/eszopiclone (hypnotics)
- NOT targeted by barbiturates!
overall effect:
- potentiate Cl ion channel effects of GABA
- potentiate GABAergic inhibition at all levels of neuraxis
BZ advantages / disadvantages
advantages
- rapid onset of action
- relatively high therapeutic index AND availability of flumazenil (for OD, if required)
- low risk of drug interactions based on liver enzyme induction
- minimal effects on CV and autonomic fx
disadvantages
- risk of dependence/addiction
- depression of CNS fx
- amnesic effects
BZ dosing considerations
general principle: want minimum dose possible for the shortest period of time
- want a dose that does not impair mentation or motor functions
specifics
- rx should be written for short periods (2-4wk) bc little justification for longer term tx
- elderly? → approx half doses are safer, usually effective
- combination with other anti-anx agents, antihistamines, anticholinergics, ethanol should be avoided
BZ toxic effects
- anxiolytic doses → drowsiness, impaired judgment, diminished motor skills (can impact driving, job perf, personal relationships)
- overuse is a common cause of confusional state in elderly
- high dose → toxicity presenting as lethargy or state of exhaustion or gross sx of ethanol intox (behavioral inhibition)
- can cause significant dose-related anterograde amnesia and significantly impair ability to learn new info
BZ
tolerance, psychologic dependence, physiologic dependende
all potential results of prolonged use of BZ
- after extended use, abrupt cessation → withdrawal sx (states of incr anx, insomnia, CNS excitability)
- BZ with longer half-life is eliminated more slowly → cause less severe withdrawal signs
- to avoid withdrawal sx…taper doses slowly over weeks!
BZ toxicity:
ODs
dedative-hypnotics are durgs most frequently involved in deliberate OD!
severe toxicity: respiratory depression complicated by aspiration of gastric contents (more likely if ethanol present)
good news → even after v high dose ingenstion, outcome is rarely fatal if discovered early and conservative tx regimen started
- ensure patent airway (ventilate if necessary), maintain plasma volume, renal output, cardiac fx
- rapid reversal agent: flumazenil
flumazenil
synthetic BZ derivative used to
- reverse CNS depressant effects of BZ OD
- hasten recovery after BZ use in medical procedures
mechanism: competitive inhibitor of BZ on GABAa receptors
- antagonizes actions of BZ and zolpidem, zaleplon, eszopiclone, but not barbiturates → i.e. ANY GABA-ERGIC DRUGS!
IV flumazenil acts rapidly, but with short half-life (0.7-1.3hr)
- rapid action: so fast it can precipitate withdrawal
- short half-life: all BZs have longer duration of action than flumazenil → sedation commonly recurs → repeated admin is required
long term pharmacotx for GAD
classes
examples
how do they work?
considered first-line drugs in chronic management of GAD, esp in presence of depressive sx
selective serotonin reuptake inhibitors (SSRIs)
- escitalopram (Lexapro)
- paroxetine (Paxil)
- sertraline (Zoloft)
- fluoxetine (Prozac)
serotonin-norepinephrine reuptake inhibitors (SNRIs)
- duloxetine (Cymbalta)
- venlafaxine (Effexor)
anti-anx response of antideps requires 2-4wk or longer!
how do they work?
potentially reduce somatic anxiety symptoms by activating stress-adapting neuronal pathways
- not reducing activation (like BZ)
- instead, activating pathways for coping!
buspirone (BuSpar)
has selective anxiolytic effects without causing marked sedative, hypnotic, euphoric effects
- NOT GABA-ergic → low risk of dependence, low tolerance, can be taken chronically
- takes 2 weeks or longer → NOT suitable for acute anx states
mechanism: believed to be through…
- partial agonist activity at 5-HT1a receptors
- affinity for brain dopamine D2 receptors
considered second-line agent bc of inconsistent reports of long-term efficacy and lack of efficacy for other potential concurrent depressive disorders
buspirone toxicity
better toxicological profile than BZs or antidepressants!
adverse rxns: nausea, abd pain, drowsiness, dizziness
- typically transient
drug interactions → interacts with CPY3A4 :(
- inducers and inhibitors of CYP3A4
- MAO inhibitors → can result in elevated bp
hypnotics
categories
examples
drugs used for tx of insomnia
GABAergic drugs
1. benzodiazepines
- triazolam (Halcion)
- temazepam (Restoril)
- estazolam (ProSom)
- flurazepam (Dalmane)
- quazepam (Doral)
2. non-BZ hypnotics
- zaleplon (Sonata)
- zolpidem (Ambien)
- eszopiclone (Lunesta)
*. new non-GABAergic hypnotics
- ramleteon (Rozerem)
- suvorexant (Belsomra)
hypnotics goal of tx
- correct underlying sleep complaint
- consolidate sleep
- improve daytime fx
- avoid adverse effects
same principle holds: wants lowest possible dose for shortest possible time to be effective
GABAergic drugs used as hypnotic agends
most commonly used drugs for insomnia
1. benzodiazepines
- hypnotic doses are higher than anxiolytic doses → effects
- incr total sleep time
- decr sleep latency (time to fal asleep) and awakenings
- prolonged use at hypnotic dose? dependency!
- cessation → withdrawal! and associated rebound insomnia :(
2. non-BZ hypnotics (zolpidem, zaleplon, eszopiclone)
- bind to same GABAa site as BZs (more selective → only hit alpha1 subunits)
-
effects
- decrease time to persistent sleep
-
zolpidem/eszopiclone → incr total sleep time
- zaleplon does not incr total sleep time
-
risk of dependency!!! not recommended for long-term use
- abrupt cessation → withdrawal sx (less severe than BZ) and rebound insomnia (zolpidem and zaleplon at high doses)
-
favorable clinical features: rapid onset of activity, short half-lives, modest day-after psychomotor depression, few amnesic effects
- unlike some BZs, no anticonvulsant and muscle-relax activities
hypnotic agents : benzodiazepines
effects
dependency risk
1. benzodiazepines
- hypnotic doses are higher than anxiolytic doses → effects
- incr total sleep time
- decr sleep latency (time to fal asleep) and awakenings
- prolonged use at hypnotic dose? dependency!
- cessation → withdrawal! and associated rebound insomnia :(
hypnotics: non-BZ GABAergics
mech of action
effects
dependency risk
favorable ft
diff from BZ
2. non-BZ hypnotics (zolpidem, zaleplon, eszopiclone)
- bind to same GABAa site as BZs (more selective → only hit alpha1 subunits)
-
effects
- decrease time to persistent sleep
-
zolpidem/eszopiclone → incr total sleep time
- zaleplon does not incr total sleep time
-
risk of dependency!!! not recommended for long-term use
- abrupt cessation → withdrawal sx (less severe than BZ) and rebound insomnia (zolpidem and zaleplon at high doses)
-
favorable clinical features: rapid onset of activity, short half-lives, modest day-after psychomotor depression, few amnesic effects
- short half-life means you recover from them quicker
major diffs from BZ:
- shorter half lives
- unlike some BZs, no anticonvulsant and muscle-relax activities
non-GABAergic hypnotics
ramelteon (Rozerem)
mech
effects
adv effects
new nonGABAergic hypnotic
mechanism:
- agonist at MT1 and MT2 receptors in brain
- MT receptors thought to be involved in maintaining circadian rhythm underlying sleep-wake cycle
- has NO GABAergic effects in CNS
effects:
- decr sleep latency
- increases sleep periods
- NO rebound insomnia, NO risk of dependence
- effective for treatment of sleep apnea too
common adv effects: dizziness, headache, somnolence
caveat: not as effective as the z-drugs
non-GABAergic hypnotics
suvorexant (Belsomra)
mech
effects
adv effects
new nonGABAergic hypnotic
mechanism:
- antagonist at orexin receptors in brain
- orexin is an nt in the wakefulness pathway → central promoter of wakefulness
- has NO GABAergic effects in CNS
effects:
- decr sleep latency
- increases sleep periods
- associated with risk of abuse or dependence (controlled sub)
common adv effects: day-after somnolence, headache, dizziness
- can cause “sleep-driving” behavior, amnesic effects
