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Barbiturates, General Anesthetics, and Antiepileptic
DrugsLaureen Trail
Spring 2003
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History
Humans have always sought ways to induce sleep, relieve stress and anxiety
Natural CNS depressantsAlcoholMorphine (opium alkaloid)
Manufactured CNS depressantsPhenobarbital (1912) – 1st barbiturate
1912-50 many tested/marketedDominated market until 1960
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Action Sites and Mechanisms
Early understanding -
“Depressed” neuronal pathways in brain stem/cerebral cortex
Severe depression = DEATH
Present day –
Reduced metabolic and brain electrical activity
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Neurotransmitters & Receptor Sites
Glutamate (excitatory)
Reduce excitatory activity
GABA (inhibitory)
Augment inhibitory activity
Barbiturates/benzodiazepines bind here
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GABA Site
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GABAA Site Action
Binding to GABAA receptors
Facilitates GABAA-induced neurotransmission
Channel opens, influx of Cl- ions, hyperpolarization
Reason for sedative-hypnotic & anesthetic effects of barbiturates, benzodiazepines, anesthetics, other “depressants”
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Barbiturate Problem
Barbiturates can open Cl- channel
without GABA
Possibility of extreme toxicity in overdose!
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Uses of Barbiturates
Only 10% of depressant prescriptions
Lethal in overdose
Narrow therapeutic-to-toxic range
High potential for tolerance, dependence, abuse
Dangerous interaction with other drugs
Still used as anticonvulsant, intravenous anesthetics, death inducing, “brain protection” (head injury), psychiatric sedation
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Sedation-Induced Brain Dysfunction
“Blackout” is antegrade amnesia
All sedatives can produce Alzheimer-like amnesia
Dementias produce characteristic patterns
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Mental Status Exam
Used to evaluate mental functioningFive areas affected in dementia
SENSORY – clouded; disorientation to time/place
MEMORY – forgetfulness, loss of STINTELLECT – depressed reasoningJUDGMENT – altered insightAFFECT – wide mood swings
Severe in elderly – STOP MEDS!
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Specific CNS Depressants
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Barbiturates
Primary prescription for anxiety, insomnia from 1912-1960
Associated with suicides, accidental overdose, dependence/abuse, dangerous drug interactions
Still prototype for drug comparison
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Pharmacokinetics
Wide range of half-life – 3 min to 120 hrsRedistribution in body
Fast-acting >> lipid (fat) soluble – results in secondsLong-acting>> water soluble – slower to penetrate CNS (20-30 minutes)
Metabolized in liver; eliminated through kidneysUrinalysis detects 30 hours to weeks
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Pharmacological Effects
With lowered anxiety, also sedation
Not analgesic – no sleep/sedation with moderate pain
Suppressed dreaming during REM
Cognitive inhibition
Changes in thinking, judgment, motor skills, behavior – over hours or days
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Affects on Other Systems
RespiratoryLow dose – noneHigh dose – suppression >> death
Few effects at low dosageCardiovascular, gastrointestinalLiver - drug stimulates enzymes that metabolize it >>> tolerance
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Psychological Effects
Depressed behaviorCognitive/Motor inhibition akin to alcohol
inebriation >> impaired drivingLow dose – reduced anxiety OR emotional
withdrawal, aggression or violenceSet/setting determines positive or
negative response High doses – general behavioral depression,
sleep
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Adverse Reactions
Side effects
Drowsiness; intellectual/motor impairment
Effects like alcohol – don’t need to be “drunk”
OVERDOSE – no antidote, only life support
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Tolerance
Two ways to induce tolerance
1) Liver enzymes metabolize drug
2) Neurons in brain adapt to drug
Primarily sedative effects
Narrow safety margin for brain stem depression
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Physiological Dependence
Wide range of effects
Low dose – sleep difficulties
High dose – hallucinations, restlessness, disorientation, life-threatening convulsions
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Psychological Dependence
Pleasurable effects –
Reduced anxiety
Sedation
Euphoria
Lead to compulsive use and abuse
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Effects in Pregnancy
Mixed results in testing anticonvulsants
Some show harm to fetus, others none
Best to avoid during pregnancy, but…
Need to prevent seizures that could harm fetus
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Misc. Nonbarbiturate Sedative-Hypnotic Drugs
Most obsolete, not used or prescribedMethaqualone (Quaaludes) –1970’s, 80’s
“Love Drug” ?? NOT!Opposite effect like alcohol – set and
setting gave it the reputationMeprobamate (Equanil, Miltown) – 1950’s
1st non-barbiturate “tranquilizer” Less respiratory suppression
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Misc. Drugs, cont.
Chloral Hydrate (Noctec) – since 1880’s
Metabolized like alcohol
Tolerance like barbiturates
Bedtime sedative for elderly
“Mickey Finn” (w/alcohol) – 1st date rape drug
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Misc. Drugs, cont.
Paraldehyde – precedes barbiturates
By-product of ethyl alcohol metabolism
Used to treat DT’s
Dependence – toxicity for stomach, liver, kidneys
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General Anesthetics
Potent CNS depressants
General anesthesia = most severe state of intentional drug-induced CNS depression
= opioid narcotic + volatile anesthetic
(no pain +unconsciousness)
Depression of all CNS functions
- sedation, sleep, depressed reflexes, amnesia, unconsciousness
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Route of Administration
Inhalation – gases or volatile liquids
Nitrous oxide – dentistry
Abuse with canned whipped cream sniffing
= hypoxia (Oxygen deprivation)
= brain damage
Injection – Thiopental (Pentothal) barbiturate
Propofol and others resemble GABA N.T.
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GHB
Gamma-hydroxybutyrate
Naturally occurring 4-carbon molecule
in mammal brains
Structure like, synthesized from GABA
Anesthetic in other countries
Use in sleep disorders, alcohol and opioid
dependence
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GHB Abuse
Euphoriant – makes you feel good!
Common “date rape” drug
Doesn’t enhance body building or sex!
Effects – disinhibition, excitement, drunkenness, amnesia
Dangerous overdose – stupor, delirium, unconsciousness, coma
NO ANTIDOTE – only life support
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Antiepileptic Drugs
Epilepsy = CNS disorders of brief, chronic , reoccurring seizures (brain electronic disturbance) assoc. with brain lesions
How drugs suppress seizures –
Limit neuron firing at sodium channels, block depolarization
Reduce GABA metabolism, aid GABA release from presynaptic neurons
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Research Findings
Multiple effects of drug – sedation, anxiolytic, antiepiletic, antimanic>>>>>
Help several disorders – bipolar, explosive psych. disorders, mania
Reinforces previous knowledge –
Stabilizes neurons by aiding inhibition or limiting excitation
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Traditional Antiepileptics
Barbiturates (Phenobarbital) – still used occasionally, but hard on children (hyperactivity & learning problems)
Hydantoins (Dilantin) - common use as anticonvulsant
Benzodiazepines (Clonazepan) – anticonvulsant, hard on children (personality changes and learning problems)
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Modern Antiepileptics
Resemble GABA & act on GABA receptors
Inhibit glutamate action – “brain protection” from hypoxia & ischemia
NEWEST CLASS – Epalons - steroid derivatives
No hormonal action, but traditional effects
Bind to steroid-sensitive GABAA receptors
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Antiepileptics and Pregnancy
Stillbirth and infant mortality rate higher
Antiseizure meds in early months increase birth defects
Balance danger of seizures with possible birth defects – discontinue meds or move to single drug at lowest effective dose
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Benzodiazepines and Second Benzodiazepines and Second –Generation Anxiolytics–Generation Anxiolytics
Laureen TrailLaureen Trail
University of IdahoUniversity of Idaho
Spring 2003Spring 2003
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HistoryHistory
Benzodiazepines (BDZ) introduced in 1960’sBenzodiazepines (BDZ) introduced in 1960’s
40 years - drug of choice40 years - drug of choice
Still widely used – 1 in 5 prescriptionsStill widely used – 1 in 5 prescriptions
Many properties – anxiolytic, sedative, Many properties – anxiolytic, sedative, anticonvulsant, amnestic, relaxantanticonvulsant, amnestic, relaxant
Anxiolytic Anxiolytic synonymous with synonymous with BDZBDZ
Newer antidepressants rapidly replacing Newer antidepressants rapidly replacing
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EffectsEffects
Safer than barbituratesSafer than barbiturates
– – much less respiratory depressionmuch less respiratory depression
- lg. doses rarely fatal (except w/alcohol)- lg. doses rarely fatal (except w/alcohol)
CNS toxicity in chronic use/high dosesCNS toxicity in chronic use/high doses
- headaches irritability, confusion, impaired - headaches irritability, confusion, impaired memory, depressionmemory, depression
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Mechanism of ActionMechanism of Action
BDZs - agonists of GABA-BDZ-Chloride BDZs - agonists of GABA-BDZ-Chloride receptor complex, facilitate GABA bindingreceptor complex, facilitate GABA binding
Action >> aids influx of ClAction >> aids influx of Cl- - ions >> ions >> hyperpolarization of postsynaptic neuron >> hyperpolarization of postsynaptic neuron >> excitability depressedexcitability depressed
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Sites of ActionSites of Action
MRIs, PETs research - fear and anxiety MRIs, PETs research - fear and anxiety responses in amygdala, orbitofrontal cortex, responses in amygdala, orbitofrontal cortex, insulainsula
Decreased GABAergic function >>Decreased GABAergic function >>
elevated anxiety states elevated anxiety states
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PharmacokineticsPharmacokinetics
15 BDZ derivatives used in U.S.15 BDZ derivatives used in U.S.
-differ in pharmacokinetics parameters-differ in pharmacokinetics parameters
a. Metabolism rates to active intermediatesa. Metabolism rates to active intermediates
b. Plasma ½ life of parent + active b. Plasma ½ life of parent + active metabolite = long- or short-actingmetabolite = long- or short-acting
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Familiar BDZsFamiliar BDZs
Long-acting (6)Long-acting (6)
Valium & Librium (50-100 hrs.)Valium & Librium (50-100 hrs.)
Intermediate-acting (4)Intermediate-acting (4)
Ativan & ProSom (10-50 Hrs.**)Ativan & ProSom (10-50 Hrs.**)
Short-acting (5)Short-acting (5)
Halcion & Xanax (1.5-35 hrs.)Halcion & Xanax (1.5-35 hrs.)
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Absorption >>> ExcretionAbsorption >>> Excretion
BDZs taken orally well absorbedBDZs taken orally well absorbed
Peak plasma concentration >> I hourPeak plasma concentration >> I hour
Most psychoactive drugs metabolized to Most psychoactive drugs metabolized to inactive, water-soluble productinactive, water-soluble product
Exceptions for some BDZsExceptions for some BDZs
Some long-acting ones transformed to long-Some long-acting ones transformed to long-acting metabolites acting metabolites
- nordiazepam 60 hrs.- nordiazepam 60 hrs.
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Problem PopulationProblem Population
CAUTION with elderly patients!CAUTION with elderly patients!
Metabolize BDZs much more slowlyMetabolize BDZs much more slowly
-up to I month to eliminate single dose-up to I month to eliminate single dose
BDZs can easily cause dementiaBDZs can easily cause dementia
-too often overlooked in elderly-too often overlooked in elderly
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Pharmacological EffectsPharmacological Effects
BZDs facilitate GABA-induced neuron BZDs facilitate GABA-induced neuron inhibition at GABAinhibition at GABAA A receptors in many CNS receptors in many CNS
areasareas
Complete agonistsComplete agonists dependably aid GABA dependably aid GABA bindingbinding
Partial agonistsPartial agonists bind to subgroups of GABA bind to subgroups of GABAAA
receptorsreceptors
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Specific Sites and ActionsSpecific Sites and Actions
Cerebral cortex and hippocampusCerebral cortex and hippocampus - Mental confusion and amnesia- Mental confusion and amnesia
Amygdala, orbitofrontal cortex & insulaAmygdala, orbitofrontal cortex & insula - Alleviation of anxiety, agitation and fear- Alleviation of anxiety, agitation and fear
Spinal cord, cerebellum & brain stemSpinal cord, cerebellum & brain stem - Muscle relaxation (also anxiolytic)- Muscle relaxation (also anxiolytic)Cerebellum and hippocampusCerebellum and hippocampus
- Antiepileptic action- Antiepileptic actionVentral tegmentum and nucleus accumbensVentral tegmentum and nucleus accumbens
- Rewarding behavioral effects (depend/abuse)- Rewarding behavioral effects (depend/abuse)
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Uses and Effects of BDZsUses and Effects of BDZs
Severe anxiety reliefSevere anxiety relief – PRIMARY – PRIMARY
- usually psychological relief leads to - usually psychological relief leads to physiological reliefphysiological relief
SedativeSedative – hypnotic effect for insomnia – hypnotic effect for insomnia
- fast-acting = no daytime sedation- fast-acting = no daytime sedation
- long-acting = some daytime sedation- long-acting = some daytime sedation
Muscle relaxantMuscle relaxant - direct physiological relief or - direct physiological relief or indirect with psychological reliefindirect with psychological relief
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Uses and Effects, cont.Uses and Effects, cont.
Amnestic effectAmnestic effect - before or during surgery - before or during surgery
Panic Attacks and PhobiasPanic Attacks and Phobias (controversial) (controversial)
Somewhat effective – Serotonin-type Somewhat effective – Serotonin-type antidepressant betterantidepressant better
++ anxiety relief, minimal side effects, patient ++ anxiety relief, minimal side effects, patient compatibilitycompatibility
--- impaired psychomotor and alertness, --- impaired psychomotor and alertness, potential for dependence/abusepotential for dependence/abuse
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Uses and Effects, cont.Uses and Effects, cont.
AnticonvulsantAnticonvulsant - secondary medication - secondary medication
- Effective at raising seizure threshold- Effective at raising seizure threshold
Treatment of AlcoholismTreatment of Alcoholism
- alcohol “substitute” in treating withdrawal- alcohol “substitute” in treating withdrawal
- helps reduce relapse rate- helps reduce relapse rate
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Side Effects and ToxicitySide Effects and Toxicity
Usually dose-related effects of intended Usually dose-related effects of intended actions – sedation, drowsiness, ataxia, actions – sedation, drowsiness, ataxia, lethargy, mental confusion, amnesia, lethargy, mental confusion, amnesia, onset/extension of dementiaonset/extension of dementia
High doses – mental/motor dysfunction>>High doses – mental/motor dysfunction>>hypnosishypnosis
HALCION – controversial paradoxical HALCION – controversial paradoxical effects – agitation, aggression, disinhibition, effects – agitation, aggression, disinhibition, hallucinationshallucinations
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Side Effects/Toxicity, cont.Side Effects/Toxicity, cont.
Alone – even high doses no respiratory Alone – even high doses no respiratory suppressionsuppression
Successful suicides rareSuccessful suicides rare
BDZ + alcohol = highly toxic >>> fatalBDZ + alcohol = highly toxic >>> fatal
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Complex Side EffectsComplex Side Effects
Sleep pattern disturbances – Sleep pattern disturbances –
Daytime sedation or night time rebound Daytime sedation or night time rebound insomnia – related to long or short actioninsomnia – related to long or short action
Impaired motor abilities - especially drivingImpaired motor abilities - especially driving
Irrational self-assessment about effectsIrrational self-assessment about effects
Cognitive deficits – learning, academic, Cognitive deficits – learning, academic, psychomotor interferencepsychomotor interference
DISCONTINUATION >>> normal functionDISCONTINUATION >>> normal function
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Tolerance-Dependence-WithdrawalTolerance-Dependence-Withdrawal
Extended periods of use >>> dependenceExtended periods of use >>> dependence
Withdrawal symptoms – rebound and Withdrawal symptoms – rebound and intensified – anxiety, insomnia, restlessness, intensified – anxiety, insomnia, restlessness, agitation, irritabilityagitation, irritability
Rare – hallucinations, psychosis, Rare – hallucinations, psychosis, seizuresseizures
Abuse patterns typical of polydrug usersAbuse patterns typical of polydrug users
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BDZs and PregnancyBDZs and Pregnancy
BDZs and metabolites freely cross placentaBDZs and metabolites freely cross placenta
- small but possible risk of fetal damage- small but possible risk of fetal damage
Near delivery, high-dose mothers risk BDZ-Near delivery, high-dose mothers risk BDZ-dependence/withdrawal in infants –dependence/withdrawal in infants –
““floppy infant syndrome”floppy infant syndrome”
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Unique AntagonistUnique Antagonist
Flumazenil (Romazicon) – high-affinity binding Flumazenil (Romazicon) – high-affinity binding to GABAto GABAA A complex – but shows no activity!complex – but shows no activity!
Blocks access of active BDZs to produce Blocks access of active BDZs to produce reverse effectreverse effect
Used as antidote for BDZ overdose - short ½ Used as antidote for BDZ overdose - short ½ life an advantagelife an advantage
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Second-Generation AnxiolyticsSecond-Generation Anxiolytics
Not benzodiazepines, but similar agonist activity at Not benzodiazepines, but similar agonist activity at GABA receptorsGABA receptors
Zolpidem (1993) – sedative and sleep pattern Zolpidem (1993) – sedative and sleep pattern normalizer; short ½ life; mild to moderate side normalizer; short ½ life; mild to moderate side effects – stronger in elderlyeffects – stronger in elderly
(strong nausea discourages suicide attempts)(strong nausea discourages suicide attempts)
Zaleplon & Zopiclone (1999)Zaleplon & Zopiclone (1999)
Primarily hypnotics w/o rebound insomniaPrimarily hypnotics w/o rebound insomnia
Agonist qualities similar to ZolpidemAgonist qualities similar to Zolpidem
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Partial Agonists Partial Agonists
Desired Desired anxiolyticanxiolytic effects without usual side effects, rebound effects without usual side effects, rebound anxiety, or physical dependence - 5 studied in Europeanxiety, or physical dependence - 5 studied in Europe
Alpidem Alpidem – anxiolytic, little sedation, no alcohol reaction– anxiolytic, little sedation, no alcohol reactionEtizolamEtizolam – potent anxiolytic, low side effects – potent anxiolytic, low side effectsImidazenilImidazenil – anxiolytic, minimal cognitive disruption and side – anxiolytic, minimal cognitive disruption and side
effectseffectsAbecarnilAbecarnil – rapid anxiolytic effects, low physical dependence – rapid anxiolytic effects, low physical dependenceBretazenilBretazenil – anxiolytic and antipsychotic, minimal side effects – anxiolytic and antipsychotic, minimal side effects
and dependenceand dependence
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Serotoninergic Drugs as Anxiolytics Serotoninergic Drugs as Anxiolytics
Role of serotonin neurotransmission in anxiety Role of serotonin neurotransmission in anxiety – behavioral disinhibition– behavioral disinhibition
Recent interest focused on presynaptic Recent interest focused on presynaptic transporters and postsynaptic 5-HTtransporters and postsynaptic 5-HT1A1A and and
5-HT5-HT33 receptors – “fear” area of the brain, receptors – “fear” area of the brain,
rich in 5-HTrich in 5-HT1A1A receptors, studied in mice receptors, studied in mice
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Serotonin AgonistsSerotonin Agonists
Serotonin 5-HTSerotonin 5-HT1A1A agonists known collectively agonists known collectively
as “second-generation anxiolytics”as “second-generation anxiolytics”
Buspirone (BuSpar) marketed in 1986 – Buspirone (BuSpar) marketed in 1986 – unique anxiety reliefunique anxiety relief
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Buspirone PropertiesBuspirone Properties
1.Anxiolytic w/o sedation, drowsiness, hypnosis; 1.Anxiolytic w/o sedation, drowsiness, hypnosis; minimal amnesia, mental or psychomotor minimal amnesia, mental or psychomotor impairmentimpairment
2. Doesn’t enhance CNS depressant effects of 2. Doesn’t enhance CNS depressant effects of alcohol, sedatives, BDZalcohol, sedatives, BDZ
3. No cross-tolerance, cross-dependence with BDZs; 3. No cross-tolerance, cross-dependence with BDZs; no addiction/abuse potentialno addiction/abuse potential
4. Additional antidepressant effect potential for 4. Additional antidepressant effect potential for depressive disorders w/anxiety (weak agonist)depressive disorders w/anxiety (weak agonist)
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Busipone, cont.Busipone, cont.
5. Slow onset/subtle effects works for patients 5. Slow onset/subtle effects works for patients who can tolerate delayed gratificationwho can tolerate delayed gratification
6. May augment beneficial effects of 6. May augment beneficial effects of psychotropicspsychotropics
7. May reduce some negative effects of 7. May reduce some negative effects of developmental disorders in childrendevelopmental disorders in children
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Serotonin Reuptake InhibitorsSerotonin Reuptake Inhibitors
Rapidly becoming meds of choice for variety Rapidly becoming meds of choice for variety of anxiety disorders – of anxiety disorders –
Slow onset but effects compare favorable Slow onset but effects compare favorable w/BDZs without dependencew/BDZs without dependence
Serotonin receptor Serotonin receptor antagonistsantagonists also under also under studied for anxietystudied for anxiety