Barbiturates, General
Anesthetics, and Antiepileptic
Drugs
Laureen Trail
Spring 2003
1
History
Humans have always sought ways to induce sleep, relieve
stress and anxiety
Natural CNS depressants
Alcohol
Morphine (opium alkaloid)
Manufactured CNS depressants
Phenobarbital (1912) – 1st barbiturate
1912-50 many tested/marketed
Dominated 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 functioning
Five areas affected in dementia
SENSORY – clouded; disorientation to
time/place
MEMORY – forgetfulness, loss of ST
INTELLECT – depressed reasoning
JUDGMENT – altered insight
AFFECT – 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 hrs
Redistribution in body
Fast-acting >> lipid (fat) soluble – results
in seconds
Long-acting>> water soluble – slower to
penetrate CNS (20-30 minutes)
Metabolized in liver; eliminated through
kidneys
Urinalysis 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
Respiratory
Low dose – none
High dose – suppression >> death
Few effects at low dosage
Cardiovascular, gastrointestinal
Liver - drug stimulates enzymes that
metabolize it >>> tolerance
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Psychological Effects
Depressed behavior
Cognitive/Motor inhibition akin to alcohol
inebriation >> impaired driving
Low dose – reduced anxiety OR emotional
withdrawal, aggression or violence
Set/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 SedativeHypnotic Drugs
Most obsolete, not used or prescribed
Methaqualone (Quaaludes) –1970’s, 80’s
“Love Drug” ?? NOT!
Opposite effect like alcohol – set and
setting gave it the reputation
Meprobamate (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
33
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
–Generation Anxiolytics
Laureen Trail
University of Idaho
Spring 2003
35
History
Benzodiazepines (BDZ) introduced in 1960’s
40 years - drug of choice
Still widely used – 1 in 5 prescriptions
Many properties – anxiolytic, sedative,
anticonvulsant, amnestic, relaxant
Anxiolytic synonymous with BDZ
Newer antidepressants rapidly replacing
36
Effects
Safer than barbiturates
– much less respiratory depression
- lg. doses rarely fatal (except w/alcohol)
CNS toxicity in chronic use/high doses
- headaches irritability, confusion, impaired
memory, depression
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Mechanism of Action
BDZs - agonists of GABA-BDZ-Chloride
receptor complex, facilitate GABA binding
Action >> aids influx of Cl- ions >>
hyperpolarization of postsynaptic neuron >>
excitability depressed
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Sites of Action
MRIs, PETs research - fear and anxiety
responses in amygdala, orbitofrontal cortex,
insula
Decreased GABAergic function >>
elevated anxiety states
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Pharmacokinetics
15 BDZ derivatives used in U.S.
-differ in pharmacokinetics parameters
a. Metabolism rates to active intermediates
b. Plasma ½ life of parent + active
metabolite = long- or short-acting
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Familiar BDZs
Long-acting (6)
Valium & Librium (50-100 hrs.)
Intermediate-acting (4)
Ativan & ProSom (10-50 Hrs.**)
Short-acting (5)
Halcion & Xanax (1.5-35 hrs.)
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Absorption >>> Excretion
BDZs taken orally well absorbed
Peak plasma concentration >> I hour
Most psychoactive drugs metabolized to
inactive, water-soluble product
Exceptions for some BDZs
Some long-acting ones transformed to longacting metabolites
- nordiazepam 60 hrs.
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Problem Population
CAUTION with elderly patients!
Metabolize BDZs much more slowly
-up to I month to eliminate single dose
BDZs can easily cause dementia
-too often overlooked in elderly
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Pharmacological Effects
BZDs facilitate GABA-induced neuron
inhibition at GABAA receptors in many CNS
areas
Complete agonists dependably aid GABA
binding
Partial agonists bind to subgroups of GABAA
receptors
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Specific Sites and Actions
Cerebral cortex and hippocampus
- Mental confusion and amnesia
Amygdala, orbitofrontal cortex & insula
- Alleviation of anxiety, agitation and fear
Spinal cord, cerebellum & brain stem
- Muscle relaxation (also anxiolytic)
Cerebellum and hippocampus
- Antiepileptic action
Ventral tegmentum and nucleus accumbens
- Rewarding behavioral effects (depend/abuse)
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Uses and Effects of BDZs
Severe anxiety relief – PRIMARY
- usually psychological relief leads to
physiological relief
Sedative – hypnotic effect for insomnia
- fast-acting = no daytime sedation
- long-acting = some daytime sedation
Muscle relaxant - direct physiological relief or
indirect with psychological relief
49
Uses and Effects, cont.
Amnestic effect - before or during surgery
Panic Attacks and Phobias (controversial)
Somewhat effective – Serotonin-type
antidepressant better
++ anxiety relief, minimal side effects, patient
compatibility
--- impaired psychomotor and alertness,
potential for dependence/abuse
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Uses and Effects, cont.
Anticonvulsant - secondary medication
- Effective at raising seizure threshold
Treatment of Alcoholism
- alcohol “substitute” in treating withdrawal
- helps reduce relapse rate
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Side Effects and Toxicity
Usually dose-related effects of intended
actions – sedation, drowsiness, ataxia,
lethargy, mental confusion, amnesia,
onset/extension of dementia
High doses – mental/motor dysfunction>>
hypnosis
HALCION – controversial paradoxical
effects – agitation, aggression, disinhibition,
hallucinations
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Side Effects/Toxicity, cont.
Alone – even high doses no respiratory
suppression
Successful suicides rare
BDZ + alcohol = highly toxic >>> fatal
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Complex Side Effects
Sleep pattern disturbances –
Daytime sedation or night time rebound
insomnia – related to long or short action
Impaired motor abilities - especially driving
Irrational self-assessment about effects
Cognitive deficits – learning, academic,
psychomotor interference
DISCONTINUATION >>> normal function
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Tolerance-Dependence-Withdrawal
Extended periods of use >>> dependence
Withdrawal symptoms – rebound and
intensified – anxiety, insomnia, restlessness,
agitation, irritability
Rare – hallucinations, psychosis,
seizures
Abuse patterns typical of polydrug users
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BDZs and Pregnancy
BDZs and metabolites freely cross placenta
- small but possible risk of fetal damage
Near delivery, high-dose mothers risk BDZdependence/withdrawal in infants –
“floppy infant syndrome”
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Unique Antagonist
Flumazenil (Romazicon) – high-affinity binding
to GABAA complex – but shows no activity!
Blocks access of active BDZs to produce
reverse effect
Used as antidote for BDZ overdose - short ½
life an advantage
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Second-Generation Anxiolytics
Not benzodiazepines, but similar agonist activity at
GABA receptors
Zolpidem (1993) – sedative and sleep pattern
normalizer; short ½ life; mild to moderate side
effects – stronger in elderly
(strong nausea discourages suicide attempts)
Zaleplon & Zopiclone (1999)
Primarily hypnotics w/o rebound insomnia
Agonist qualities similar to Zolpidem
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Partial Agonists
Desired anxiolytic effects without usual side effects, rebound
anxiety, or physical dependence - 5 studied in Europe
Alpidem – anxiolytic, little sedation, no alcohol reaction
Etizolam – potent anxiolytic, low side effects
Imidazenil – anxiolytic, minimal cognitive disruption and side
effects
Abecarnil – rapid anxiolytic effects, low physical dependence
Bretazenil – anxiolytic and antipsychotic, minimal side effects
and dependence
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Serotoninergic Drugs as Anxiolytics
Role of serotonin neurotransmission in anxiety
– behavioral disinhibition
Recent interest focused on presynaptic
transporters and postsynaptic 5-HT1A and
5-HT3 receptors – “fear” area of the brain,
rich in 5-HT1A receptors, studied in mice
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Serotonin Agonists
Serotonin 5-HT1A agonists known collectively
as “second-generation anxiolytics”
Buspirone (BuSpar) marketed in 1986 –
unique anxiety relief
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Buspirone Properties
1.Anxiolytic w/o sedation, drowsiness, hypnosis;
minimal amnesia, mental or psychomotor
impairment
2. Doesn’t enhance CNS depressant effects of
alcohol, sedatives, BDZ
3. No cross-tolerance, cross-dependence with BDZs;
no addiction/abuse potential
4. Additional antidepressant effect potential for
depressive disorders w/anxiety (weak agonist)
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Busipone, cont.
5. Slow onset/subtle effects works for patients
who can tolerate delayed gratification
6. May augment beneficial effects of
psychotropics
7. May reduce some negative effects of
developmental disorders in children
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Serotonin Reuptake Inhibitors
Rapidly becoming meds of choice for variety
of anxiety disorders –
Slow onset but effects compare favorable
w/BDZs without dependence
Serotonin receptor antagonists also under
studied for anxiety
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