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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