1. No category

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
2
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”
6
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
27
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
28
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
34
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
37
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
40
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
41
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.)
42
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.
43
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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
45
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
53
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
55
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”
56
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
57
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
58
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
60
Serotonin Agonists
Serotonin 5-HT1A agonists known collectively
as “second-generation anxiolytics”
Buspirone (BuSpar) marketed in 1986 –
unique anxiety relief
61
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)
62
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
63
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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