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Chapter 7 Tranquilizers and SedativeHypnotics


Many more were developed and they quickly replaced the barbiturates which had a ... Smith and Wesson (1983) suggested that there are two types of withdrawal from ... – PowerPoint PPT presentation

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Title: Chapter 7 Tranquilizers and SedativeHypnotics

Chapter 7Tranquilizers and Sedative-Hypnotics
Robert DeNiro in Meet the Parents with pentothal
(truth serum)
Tranquilizers (anxiolytics) Treat agitation and
anxiety Sedative-Hypnotics (sleeping pills)
Sedation and sleep
Barbiturates barbital, phenobarbital,
secobarbital, etc Benzodiazepines diazepam
(Valium), clordiazepoxide (Librium), etc Others
meprobamate (Miltown) methaqualone (Quaalude),
abecarnal, alpidem All have same effect, but
medical use depends on pharmacokinetic properties
sedative-hypnotics fast action, short effect,
tranquilizers slow action and long
effect. Z-Drugs zopiclone (esopicone is an
optical isomer marketed as Lunesta), zolpidem,
zaleplon able to target specific symptoms GHB
- discussed with club drugs in Chapter 16
Baeyer, discoverer of barbiturates
Barbiturates History
Original sedatives (before development of
barbiturates) - brandy, chloral hydrate,
bromides, opium - only marginally effective,
unwanted side-effects Barbiturates (1860s) -
1000s of different barbiturates developed - 50
marketed - treat 77 disorders (from arthritis to
bed-wetting!) By 1990s, barbiturates replaced by
benzodiazepines - exceptions phenobarbital
seizures butalbital - headaches
Barbiturates were widely diverted from medical
use and used on the street in the 60s where they
were called downers and sold under a variety of
different names. Illicit use has declined as
medical use has declined. They had a low
therapeutic index and were often used for suicide.
Marilyn Monroe died of barbiturate overdose in
  • 1960s barbiturates sold illicitly on the street
    as downers (diverted from medical use)

History - Benzodiazepines
In the 30s, Leo Sternback was experimenting with
dies and he synthesized a class of drugs known as
heptoxdiazines. Later in the 50s, he was working
for Hoffman - LaRoche in the US looking for a
possible new tranquilizer/sedative. He made many
variations on the molecule. In 1957, he tested Ro
5-0690, chlordizepoxide, and it was behaviorally
active. It was eventually marketed as Librium.
Later diazepam was marketed as Valium. Many more
were developed and they quickly replaced the
barbiturates which had a very low therapeutic
index and were involved in many overdose deaths
and suicides.
Leo Sternback
Sternback is credited with the invention of
chlordiazepoxide (Librium), diazepam (Valium),
flurazepam (Dalmane), nitrazepam (Mogadon),
clonazepam (Klonopin), and trimethaphan
(Arfonad). Flunitrazepam (Rohypnol), most widely
abused BDZ. Sold as roofies, roaches, Mexican
Valium. Possible date rape drug.
Methaqualone (Quaalude) and meprobamate (Miltown)
were used in the 60s as non barbiturate
tranquilizers. They were widely sold on the
street. Methaqualone no longer in use, but
meprobamate is still being used. Z drugs now
replacing the BDZs. Can be targeted to specific
symptoms, insomnia and anxiety.
Rohypnol (flunitrazepam) Mexican Valium, roofies,
Not licensed for medical use in US and Canada,
but used in Europe and South America Widely
smuggled into U.S. Used as a club drug. Used at
raves Known as a date rape drug
Pharmacokinetics absorption Barbiturates acids,
pKa8.0 range in lipid solubility Benzodiazepines
acids, pKa5.0 range of lipid solubility peak
blood levels 30-60 min for valium and the
sedative hypnotics to several hours for
oxazepam individual variability in blood levels
and absorption absorption speeded by alcohol Z
drugs Absorbed orally and reach peak in about an
Distribution and Elimination Lipid solubility
increases the speed of action, but also means
short duration of action because if
redistribution (sequesterization) to body
fat. There is often a two stage excretion curve
with 2 half-lives. Sometimes BDZs have active
metabolites which extend effect.
BDZ metabolism can be slowed by alcohol.
Neurophysiology All drugs are positive GABAA
modulators They increase the ability of GABA to
open the chloride (Cl-) ion channel
Chloride ions entering the cell stabilize the
membrane and make it more difficult for
excitatory transmitters to fire the cell. GABA is
responsible for overall level of inhibitory tone
in the brain. Barbiturates and BDZs have their
own receptor sites on the complex. At low doses,
both BDZ and barbiturates enhance the effect of
GABA, but at high doses, barbiturates can open
the ion channel
The GABAA receptor-chloride ionophore complex is
made of 5 subunits, alpha (a), beta (ß) and gamma
(d) There are 6 subtypes of alpha, and three each
of beta and gamma. This means that there is a
large variety of possible GABAA receptor types.
Different brain mechanisms have different types
of GABAA receptors and the receptor types are
differentially sensitive to different molecules.
Therefore it is possible to design a drug that
will target GABAA receptors in specific parts
of the brain. The Z-drugs can do this. Zolpidem
is effective at receptors with the a -1 subunit.
Therefore they can act as sedatives without any
antianxiety effects. Drugs that can block anxiety
without making a person sleepy are being
Endogenous benzodiazepines? If we have BDZ
receptors it is possible we have an endogenous
substance that works there to protect from
stress. It could be an inverse agonist. This is a
drug that has the opposite effect on the
receptor, i.e., rather that enhancing GABA, it
blocks GABA and has a completely opposite effect
on sleep, anxiety and protection from seizures.
Such drugs are anxiogenic and cause seizures,
eg, the amethystic RO15-4513 is an inverse
agonist at the BDZ receptor. In inverse agonist
is not an antagonist which simply blocks the
Effects on the nucleus accumbens Positive GABAA
modulators decrease dopamine release in the n.
accumbens. DA has an inhibitory effect on the
cells in n. accumbens, so do positive GABAA
Respiratory depression caused by barbiturates
which is lethal at high doses. BDZs have few
effects on respiration, heart rate or blood
pressure. BDZs increase appetite relax muscles
- Useful in treating muscle spasms, back pain,
etc. Barbiturates are useful as anticonvulsants
in the long term, BDZs (particularly clonazepam)
can treat petit mal seizures and infantile spasms
BDZs and Z drugs are useful in treating insomnia.
They generally decrease the time to go to sleep,
decrease wakefulness and increase sleeping time
depending on speed of absorption and
half-life. BDZs decrease REM sleep, but this
effect shows tolerance with continued use. REM
rebound seen when drug is discontinued
increased REM causes rebound insomnia, increased
wakefulness, increased and bizarre dreaming,
restlessness which may take weeks to go away.
Stopped instantly with resumption of
drug. Rebound less with Z drugs and flunitrazepam
after short term use.
Subjective effects of Benzodiazepines Increase
POMS scores of sedation and confusion and
decreased arousal and vigor scores Increase
liking and take again scores in people with a
history of sedative alcohol, or opiate use
(people on methadone maintenance). Flunitrazepam
most likely to generate increased liking scores
in normal volunteers Effective in relieving
anxiety in 60 to 70 of cases.
Effects on memory BDZs cause anterograde amnesia,
memory for events that happen while people are
under the influence of the drug. Happens at low
therapeutic doses. Affects explicit memory rather
than implicit memory, i.e., people can use
information, but not recall it to working memory.
Retrieval cues can help (similar to alcoholic
greyout, dissociation?) Sedation at higher doses
interfere with decrease in working memory,
attention and psychomotor performance .
Residual effects Impairment can last after the
drug is gone. Sleeping pills can interfere with
performance (driving) the next day after
use. Enhanced by alcohol Not seen with some Z
Driving Impaired driving in a simulated driving
test. Effect amplified by alcohol Greatest in
first time users Some tolerance, but slow to
develop (3 weeks) Residual effect on driving seen
with some drugs may be a result of active
metabolites. Epidemiological studies do not show
BDZs to be a contributing factor in road
accidents after the effects of alcohol have been
Behavior of nonhumans
Unconditioned Behavior Taming effect reduces
defensive aggression. No change in unprovoked
aggression Conditioned Behavior Avoidance
behavior blocked at doses ¼ to 1/6 of doses that
block escape. Increase punishment-suppressed
Stimulus Properties
BDZs easily discriminated potentiated by
alcohol Generalize to barbiturates and other
BDZs, but not to ketamine and antipsychotics.
Animals can be trained to discriminate BDZs from
barbiturates and alcohol Not blocked by
stimulants. Blocked by GABA receptor blockers Z
drugs only partial generalization to BDZs and
none to alcohol.
Acute tolerance Some effects of BDZs and
barbiturates may show acute tolerance. Chronic
tolerance Effect of BDZs on GABA modulation
shows tolerance Demonstrated for avoidance
blocking in nonhumans. Slow development of
tolerance to anticonvulsant effect and drowsiness
in humans Tolerance to hypnotic effect in of
zolpidem and BDZs - about 4 weeks Short acting
hypnotics develop tolerance faster than fast
Cross Tolerance
Alcohol and barbiturate abusers show less
drowsiness to therapeutic doses of BDZs. Ataxic
effects of alcohol, barbiturates and BDZs show
tolerance after one administration in mice.
Barbiturate tolerance crosses to alcohol and
BDZs, but BDZ tolerant subjects are tolerant to
alcohol but only partially tolerant to
barbiturates. Mechanisms of tolerance are
similar, but not identical.
In laboratory animals there is withdrawal from
barbiturates and BDZs. Cross dependence
withdrawal from one can be blocked by the
other. Barbiturates have been known to cause
withdrawal in humans since the 1930s, but what of
therapeutic doses of benzodiazepines?
Benzodiazepine withdrawal in Humans
It was known that high doses of BDZs would cause
withdrawal symptoms similar to barbiturates and
alcohol, e.g. Agitation, depression, abdominal
pain, DTs, insomnia and seizures, but most people
believed that there was no withdrawal from
therapeutic doses. In 1981, Halstrom and Later
showed that this was wrong. They found that there
were withdrawal symptoms even in low dose
patients. These symptoms, however were different
from alcohol-barbiturate withdrawal, sleep
disturbances, anxiety, intolerance of bright
lights and noises, weight loss, unsteadiness,
numbness and tingling feelings. Peaked at 5 days
and were gone in 2 weeks.
Smith and Wesson (1983) suggested that there are
two types of withdrawal from BDZs A)
Sedative-Hypnotic type, and B) Low dose
withdrawal Sedative-Hypnotic Type tremors,
delirium, cramps, convulsions. Higher than
therapeutic doses for more than one month.
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Low dose withdrawal
Therapeutic doses longer than three
months. Emerge slowly 15-44 of users Anxiety,
panic, irregular heart beat, increased blood
pressure, impairment of memory and concentration,
feelings of unreality, muscle spasms, sensitivity
to light and sounds. Last 2 weeks to a year Occur
in cycles (10 days?) Should not be confused with
symptom reemergence.
People who take high doses for longer than 6
months may report both types of withdrawal.
Self-administration in Humans
Choice studies show no preference for diazepam in
normal sample. High doses avoided Highly anxious
subjects also did not prefer diazepam Moderate
alcohol users and former sedative-hypnotic
abusers do prefer diazepam. Diazepam preferred if
followed by a relaxation task.
Patterns of abuse of benzodiazepines
Iatrogenic (physician caused) use People escalate
prescription use taking larger doses for than
longer than necessary. Sometimes escalates to
street use. Physical dependence Doctor shopping.
Early requests for refills, etc Some surveys show
that most users of benzodiazepines do have a
medical condition, e.g. anxiety. Much anxiety
goes untreated. Many people in BDZ abuse clinics
have a legitimate medical need, but tale too
large a dose. Many use BDZs in conjunction with
other drugs like alcohol, cocaine and
opiates. Flunitrazepam preferred by methadone
users, but no special property of flunitrazepam
has been identified.
Street use
BDZs often used on the street by opiate users.
Diazepam has been shown to enhance the effects
of opiates. Use is increasing by High school
students in the US.
Monitoring the Future study
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Self-administration in Non-humans
Rats and monkeys will self-administer
barbiturates. Short acting barbiturates better
reinforcers. BDZs are effective reinforcers, but
not as effective as barbiturates. Prior exposure
to BDZs enhances reinforcing ability. Human
preference for flunitrazepam has not been
demonstrated in non-humans
Harmful Effects
Human birth defects have not been
confirmed Behavioral teratology in rats Prenatal
administration causes absence of startle response
and immobility. Alters response to
stressors. Newborn infants show withdrawal if
mother used BDZs BDZs during labor can have
effects on newborn Depressed respiration and
feeding Floppy baby syndrome Low Apgar scores.
Floppy Baby syndrome
Barbiturates, meprobamate and methaqualone have
low TIs. Cause death by depressing the
respiratory centre. Widely used for
suicide. Benzodiazepines are much safer. Very few
deaths have been caused by BDZs alone. Short
acting BDZs are more dangerous Overdose causes
Drowsiness No coma or respiratory
depression Symptoms disappear within 48
hrs. Treated with flinazemil BDZ receptor
antagonist BDZ overdoses are fatal when combined
with alcohol or other depressant.
Long term high dose withdrawal should be
medically supervised because of possible
convulsions Usually accomplished by gradual dose
reduction in conjunction with counseling,
self-help groups and family and social
support. Reemergence of symptoms need to be
handled Most severe symptoms when last few mg are
withdrawn. Iatrogenic overuse treatment usually
successful (88). Invloves counseling,
education, 12-steps program, and sympathetic
physician supervision. Street users BDZ use is
usually secondary to another drug. Primary
addiction needs to be treated.