• any drug causing calming effect
  • most are CNS depressants
• classes
  • benzodiazapines
  • barbituates
  • alcohol
  • various antipsychotics
  • antidepressants
  • antihistamines
• ideal sedative has minimal effect on motor function or mental status

• sleep inducing or promoting drug
  • some hypnotics are not sedative
  • but sedatives can produce sleep at high enough doses

• drugs to reduce anxiety
  • most sedatives are calming and could acutely reduce anxiety
  • many forms of anxiety and some are treated with non-sedative drugs

• anxiolytic/sedative effects at lower doses
• as does increase, can produce sleep, ansesthesia, coma, and death (in that order with increases)
• with older drugs, there isa linear dose resposne relationship
  • alcohol
  • barbiturates
  • chloral hydrate
• benzodiazepines require proportionally much higher doses to produce anesthesia or coma
  • SAFER

• SSRI's
• alprazolam (can have rebound anxiety when discontinued and risk of dependence)
• TCA's
• MAOI's

At lower doses than with depression.

• SSRI's
• alprazolam (can cause rebound anxiety if discontinued and risk of dependence)
• imipramine
• MAOI's

• SSRI's
• MAOI"s
• buproprion
• clonazepam
• behavioral therapy
• beta blockers (suppress tremors, shaking)

• SSRI's
• MAOI's
• bupropion
• behavioral therapy

• SSRI's
• MAOI's
• TCA's

• SSRI's
• clomipramine (TCA) (require long tx period for efficacy)

• benzodiazepines
• buspirone
• venlafaxine

• persistent and/or repeated episodes of unreasonable worry lasting for months

• muscle tension
• restlessness
• fatigue
• insomina
• impaired conc.
• irritability

Hard to distinguish between worry and pathological anxiety, so lot of over prescription

• patient assertion
• observation of restless, tachycardia, agitation, excessive sweating, GI disorders, weeping
• disruption of normal productive activities

• Hamilton clinical rating skills
• Galvonic skin response (novel stimulus increases GSR and repitition cause habituation while anxiety leads to slower habituation
• animal models to mimic anxiety

• ex: haloperidol, chlorpromazine
• indication- acute sedation of agitated and/or manic patients

No good for GAD

• indications- useful in other forms of anxiety, not really GAD
  • show some anxiolytic activity esp. with anxious depression

• examples- first generation sedating, OTC sleep aids
• many antidepressants and antipsychotics have antihistamine activity

1. bind to GABA_A receptor
2. enhance duration of GABA mediated chlorine flux
3. leads to hyperpolarization and neuronal inhibation
   • suppress glutamate transmission via AMPA receptors
   • direct membrane effects to inhibit neurons

At high conc., it can directly open GABA_A channel.

• low TI (dangerous in overdose)
  • hypnosis, anesthesia, amnesia, coma, resp. dep. as dose increases
  • high incidence of dependence and addiction
• steep dose response curve
• barbituates induce CYP enzymes, causing significant drug interactions

• rarely today as sedative hypnotic (secobarbitol)
• anesthesia induction (thiopental)
• seizure disorders (phenobarbitol)

Other barbituates rarely used

Alprazolam

Clonazepam

DIazepam

Lorazepam

1. bind to specific site of GABA_A receptor (allosteric activators)
   1. subtypes alpha 1, 2, 3, 5
      • alpha 4's found in cerebellum, so no cerebellar affects (ex: motor dysfunc. of barbituates)
   2. need gamma subunit
2. facilitates GABA mediated chloride influx
3. leads to hyperpolarizations and neuronal inhibition

Unlike barbituates, no direct activity, only enhance existing activity. Also, there is only one site/receptor and binding site for BZ's not found on all GABA_A receptors.

• two alphas
  • alpha 1 subunit- mediate sedation, amnesia, ataxia
  • alpha 2,3 subunits- mediate anxiolysis, muscle relaxation
  • alpha 5 subunit- memory impairment
• three other subunits (mult. subtypes)

1. bind to BZ receptor
2. inhibit GABA mediated channel opening

Induce anxiety, seizures. Can inhibit BZ's.

• antagonist to BZ site
• competitively binds to BZ receptor but does not change GABA effects

No effects when given alone, but will competitively inhibit effects of both full agonsts.

Will not block barbituates (remember, this drug acts at BZ R)

• CNS
  • sedation- calming effects without impairment of psychomotor and cognitive functions (at high doses, cause cognitive impairement)
    • disinh.- impairment judgment, euphoria, loss of self control
  • hypnosis
  • amnesia
  • anesthesia (at higher doses) (typically as adjuncts IV)
  • anticonvulsant
• skeletal muscles: relaxation at high doses
  • inh. polysynaptic reflexes
  • depress transmission at neuromuscular junction
• respiration: inhibition (caution: pulm. disease, and death with OD)
• CV- some inhibition (likely CNS effect) (caution: HF, cardiac disease, hypovolemia)

• occurs with all sedative hypnotics
• some cross tolerance that occurs with other sedative hypnotics
• thought to involve change in receptors

BZ less than alcohol or barbituates, but still significant

• occur with all sedatives (greatest with barbituates)
• symptoms
  • anxiety
  • insomnia
  • irritability
  • CNS excitability
  • seizures
• hard to distinguish withdrawl from re emergent symptoms- rebound anxiety or insomnia
• severity depends on many factors, but greater with higher doses and shorter acting drugs

• can occur with all sedative hypnotics
  • barbiturates schedule II; BZ's usually schedule III or IV (distinguish btw more likely, les likely drugs)
  • flunitrazepam not legal in US

• anxiety
  • GAD (efficacious, but long term use complicated by tolerance, dependence)
  • situational anxiety
  • panic disorders
  • agoraphobia
• sleep disorders (all efficacious, but only some used)
• epilepsy- all potentially efficacious (common: clonazepam, diazepam)
• anesthesia
  • IV use esp. for induction
  • provide amnestic component of balanced anesthesia
• managing withdrawal from alcohol dep.
• muscle relaxation in specific neurological disorders

• much safer (high TI) than older stuff and you got an available antagonist (flumazenil)
• flatter dose response curve
  • provide significant anxiolytic effects with minimal impairments
• no PK drug interactions (no sign. effects on CYP)
• relatively long duration (QD dosing for most)

• BZ overdose
• hasten recovery after use in surgery

Not as good with resp. depression. Does NOT work against alcohol or barbituates

• agitation
• confusion
• dizziness
• nausae

Precipitate severe withdrawl in patients with physiol. dependence

• dependence liability
• tolerance can develop
• can cause anterograde amnesia
• can cause weight gain, nausae, headache, light headed
• potentiate CNS depression from alcohol (true of all sedatives
• impair psychomotor skills (falls esp. in old folks)

• some rapidly absorbed (diazepam, triazolam, alprazolam)
• rate of entry in CNS controled by lipophilicity
  • fast entry useful for anesthesia
  • associated with higher abuse liability (alprazolam)
• most long acting
  • QD dosing (but you get daytime drowsiness)
  • exception: triazolam, lorazepam, oxazepam

• many converted to active metabolites
• mainly via CYP3A4
• many active metabolites have long half life
• conjugated to glucoronides for urinary excretion

• partial agonist in CNS 5-HT_1a receptors
  • others to lesser extent: alpha 1, alpha 2, D2
• no sedative hypnotic, antiseizure, euphoric effects

• some efficacy as anti depressant
• best for GAD (not good for acute anxiety: efficacy requires more than one week)

• rapidly absorbed
• first pass metabolism with several active metabolites
  • half life 2-3 hrs, but DOA much longer

• advantages
  • no tolerance
  • dependence or abuse liability
  • no psychomotor impairment
  • no drug interactions w/sedatives and alcohol
• disadvantages
  • slow to act
  • poor efficacy in panic disorders
  • not all patients respond well (difficult to predict)

• nonspecific chest pain
• tachycardia
• palpitations
• dizziness
• nervousness
• tinnitis
• GI problems

CI: MAOI's

• difficulty falling asleep (increased latency: greater than 1/2 hr)
• short duration (less than 6 hrs)
• frequent awakenings

• transient- ID stressors (usually less than 3 days)
• short term- stressors, grief, illness (3 days- 3 weeks)
• long term- no ID stressors (more than 3 weeks)
  • need medical work up
  • probably not good candidates for hypnotic drugs

• stimulants or other psychoactive drugs
• hormonal status (esp. decreased E2 in menopause)
• circadium disturbances
• stress, anxiety, grieving
• poor sleep  hygiene
• medical conditions (pain, hyperT, brain injury)

1. awake (low voltage, random and fast)
2. drowsy (alpha waves)
3. stage 1 (theta waves)
4. stage 2 (sleep spindles)
5. delta sleep (delta waves) slow
6. REM (random and fast with sawtooth waves)
7. go back to theta waves and back to REM and so on
8. eventually, back to awake

• with age, total sleep time may or may not decrease
• latency to fall asleep and number of awakenings do increase

• proportion of REM sleep decreased with hypnotic drugs (BZ's do this less than others, but still do)
• when withdrawn, have REM rebound

• antihistamines
• melatonin receptor agents
• older sedative hypnotics
• BZ's
• BZ receptor agonists (BRA's)

• mech of action- synthetic at MT1 and MT2 melatonin receptors (no activity at GABA)
• indication
  • FDA for long term use in insomnia (no effect on sleep patterns)
  • best for delayed onset sleep, circadian rhythm problems
• adverse effects
  • dizziness
  • hyperPRL
  • decreased testosterone

Remember, melatonin and L tryptophan efficacy has yet to be demonstrated

• we want to have quick enough onset to help with sleep latency, long enough to last through the night, but avoid problems the next day (sedation, anterograde amnesia)

• short DOA drugs (triazolam)- minimize next day effects, but potential of rebound insomnia
• intermediate DOA drugs (alprazolam)- balance of daytime sedation and rebound insomnia
• long DOA drugs (diazepam)- significant propensity for daytime sedation

• up to 3 wks continuous use
• if longer, tolerance likely

describe the chemical nature of BRA's as compared to BZ's as well as mechanism of action

• chemically distinct from BZ's, but bind to same BZ binding site
• bind to GABA_A receptors, and the ones only with alpha 1 subunit
• like BZ's, effects can be reversed by flumazenil

• favorable kinetic profile
  • Zolpidam available as sustained release prep
  • Zalpion has short DOA (for patients who wake too early
  • zalepion, eszoplicone have little day after psychomotor effects (ataxia), amnesia
• less REM suppression (lil effect on sleep stages
• less tolerance (eszoplicone unique in that it is not restricted to short term use)

• clearance decreased in elderly
• reduced doses in:
  • elderly
  • hepatidc dysfunction
  • patients taking cimetidine
• resp. dep. in high doses (made worse with other CNS depressants)
• with zolipidem:
  • retrograde amnesia
  • sleep walking and other activities that are not remembered