Transquilizer and sedatives-

hypnotic

Dr. Jarir At Thobari, MSc, PhD, FISPE

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

Transquilizer and sedatives-hypnotic

• Introduction
– Terms
• Tranquilizer or anxiolytic:
• drugs used therapeutically to treat agitation or
anxiety
• Sedative-Hypnotic:
• drugs used to sedate and aid in sleep

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

Transquilizer and sedatives-hypnotic

• Barbiturates: barbital, phenobarbital,

secobarbital, etc

• Benzodiazepines: diazepam (Valium),

clordiazepoxide (Librium), alprazolam (Xanax),
clonazepam (Klonopin), lorazepam (Ativan), etc…

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

Transquilizer and sedatives-hypnotic
• Others: meprobamate , methaqualone ,
abecarnal, alpidem
• All have same ultimate effect, medical use
depends on pk properties
• sedative-hypnotics: fast action, short effect
• tranquilizers: slow action and long effect

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

 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

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

 Barbiturates (history)

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 1962

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

 Barbiturates (history)
Generic Name Street Name
Amobarbital Downers, blue heavens, blue
velvet, blue devils
Pentobarbital Nembies, yellow jackets, abbots,
Mexican yellows
Phenobarbital Purple hearts, goof balls
Secobarbital Reds, red birds, red devils, lilly, F-
40s, pinks, pink ladies, seggy
Tuinal Rainbows, reds and blues, tooies,
(Combination of Amobarbital and
Secobarbital) double trouble, gorilla pills, F-66s

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

 Benzodiazepine (history)
In the 1930s, Leo Sternback synthesized a class of drugs known as
heptoxdiazines (benzo-heptox-diazine).
1950s, Hoffman - LaRoche in the US -- new tranquilizer/sedative
1957, he tested Ro 5-0690, chlordiazepoxide; it was behaviorally
active.
It was eventually marketed as Librium.
Diazepam was marketed as Valium.
Alprazolam marketed as Xanax
Many more were developed; replaced the barbiturates

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

 Benzodiazepine (history)

• 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.

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

 Benzodiazepine (history)
• 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

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

 Other drugs (history)
• Methaqualone (Quaalude) and meprobamate Quaaludes
(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.
Miltown
• Z drugs: now replacing the BDZs.
• Can be targeted to specific symptoms,
insomnia and anxiety.
Zopiclone

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

 Tranquilizers & Sedative-Hypnotics
• Route of Administration and Absorption
Barbiturates and Benzodiazepines are weak acids, readily
absorbed after injection and oral administration routes
 Wide range in lipid solubility
 Barbiturates pKa = 4.1 – 8.4
 BZD pKa = 1.5 – 10
 Different Forms:
 Short-acting, intermediate-acting, long-acting
 Diazepam: fast acting; peak concentration 30-60
minutes

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

 Tranquilizers & Sedative-Hypnotics

• Route of Administration and Absorption

 Z drugs: Absorbed orally and reach peak in about
an hour
 Pka ~6.6
 Absorption from the digestive system may be
greatly increased by the drinking of alcohol; risk of
overdose increases when drugs are combined.

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

 Tranquilizers & Sedative-Hypnotics

• Distribution and Excretion

– Distribution and Duration of Action determined by Lipid
Solubility
– More lipid soluble = fast onset & short duration of action, BUT…
– sequestered by body fat
– and as brain levels fall, released slowly from fat cells back into
blood
– Two-Phase Excretion Curve – 2 Half-Lives
– Rapid drop in blood level as drug is redistributed; 2-10 hr half-
life
– Released from body fat; 27-48 hr half-life

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

 Two-Phase Excretion Curve – 2 Half-Lives

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

Tranquilizers & Sedative-Hypnotics

• Metabolism of Benzodiazepine
– Mainly Liver CYP450 (also Glucoronidation)
• Active Metabolites & Half-Lives
– Alprazolam (Xanax) CYP3A4
» Hydroxylated in liver to α-hydroxyalprazolam
» Active metabolite; lesser degree than parent drug
• What effects would you expect if you inhibited CYP3A4?
– Alcohol Consumption & BDZ Metabolism
• Half-life of chlordiazepoxide increased by 60%
– clearance is already slow (5-30 hr)

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

Tranquilizers & Sedative-Hypnotics
• Neurophysiology
– Barbiturates and Benzodiazepines
• Positive GABAA Modulators
• Affects GABAA only; not GABAB Receptors
• Receptor Sites on GABA-Chloride Ionophore Complex
• GABA Neurotransmitter Made More Effective
• No direct alteration of levels of GABA and no binding to
GABA receptor site
• In high enough dosage, barbiturates can open GABAA Cl- channel on their own
• Affinity of drug to site will determine level of modulation

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

 Barbiturate and Benzodiazepine

1) GABA is responsible for overall level

of inhibitory tone in the brain.
2) GABA binds to receptor site and
chloride ions entering the cell
stabilize the membrane and make it
more difficult for excitatory
transmitters to fire the cell.
3) Barbiturates and BDZs have their
own receptor sites on the complex.

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

 Barbiturate and Benzodiazepine

1) At low doses, both BDZ and

barbiturates enhance the effect
of GABA by increasing GABA
affinity for receptor
2) At high doses, barbiturates can
open the ion channel; upper limit
of facilitating effect of BDZ but
not Barbiturate

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

 Tranquilizers & Sedative-Hypnotics
How do Z Drugs Work at GABAA receptor?

Z-drugs like Ambien

targets GABAa
1 5
Receptors with Alpha-1
subunit

Different types of alpha,

beta, gamma subunits
means we can have a
large variety of GABAa
receptor types.
2 4

3
Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM
Tranquilizers & Sedative-Hypnotics
How do Z Drugs Work at GABAA receptor?

• The GABAA is made of 5 subunits

• alpha (α), beta (β) and gamma (δ)
• There are many subtypes of alpha, beta and gamma.
• Making possible a large variety of possible GABAA
receptor types.
• Different brain mechanisms mediate a variety of
behaviors via different types of GABAA receptors
• Receptor types are differentially sensitive (affinity) to
different molecules.

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

Tranquilizers & Sedative-Hypnotics
How do Z Drugs Work at GABAA receptor?

• Therefore - design a drug to target GABAA

receptors in specific parts of the brain
• Drug will have different affinities for receptors with
different subunits responsible for specific actions,
such as sedation

• Z-drugs: Zolpidem (Ambien) high affinity for

receptors with the α -1 subunit; sedatives without
anti-anxiety effects.
• Drugs that can block anxiety without making a person sleepy are being developed.

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

Effects on the nucleus accumbens (NAcc)

1. Net effect of other drugs of abuse (i.e., cocaine, amphetamine)

is to increase DA release in NAcc
2. If positive GABAA modulators decrease dopamine release in
the NAcc, how can these drugs be reinforcing?
3. DA has an inhibitory effect on cells of the NAcc; when DA is
released, the cells of the NAcc are inhibited and so is there
output.
4. Activation of GABA cells in the NAcc may have the same
inhibitory effect on cells of the NAcc.
5. Thus, positive GABAA modulators are reinforcing

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

 Effects on the Body

1. Respiratory depression caused by barbiturates which is lethal at

high doses.
• BDZs have few effects on respiration, heart rate or blood pressure.
2. BDZs increase appetite & relax muscles - useful in treating muscle
spasms, back pain (CNS effect), etc.
3. Seizures
• Barbiturates are useful as anticonvulsants in the long term
• BDZs (particularly clonazepam) can treat petit mal seizures and
infantile spasms

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

 Effects on Sleep

1. BDZs and Z drugs are useful in treating insomnia.

• Decrease the time to go to sleep
• Decreased wakefulness and increased sleeping time depending on speed
of absorption and half-life.
2. BDZs decrease REM sleep, but this effect shows tolerance with continued
use.
• REM rebound with drug discontinuance
• increased REM causes rebound insomnia, increased wakefulness,
increased, bizarre dreaming, restlessness
• Stopped instantly with resumption of drug.
3. Rebound less with Z drugs and flunitrazepam after short term use.

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

• Effects on Behavior and Performance of
Humans
– Subjective Effects of BDZ In General

– Subjects report euphoria and liking along with

sedation and fatigue

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

Subjective Effects of Benzodiazepine
1. Diazepam: Increase POMS scores of sedation and
confusion and decreased arousal and vigor scores
2. Reports of Increase liking and take again scores: people
with a history of sedative alcohol, or opiate use (people
on methadone maintenance).
3. Flunitrazepam most likely to generate increased liking
scores in normal volunteers
4. Effectiveness: in relieving anxiety in 60 to 70% of cases;
current and prior exposure to stress is a factor

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

 Effects on Performance
1. BDZs & Anterograde Amnesia
– memory for events that happen while people are under the
influence of the drug
2. Explicit Memory vs. Implicit Memory
– people can use information, but not recall it to working memory
3. Sedation
– Decrease working memory, attention and psychomotor
performance
4. Residual Effects
– impairment can last after the drug is gone. Sleeping pills can
interfere with performance (driving) the next day after use.

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

Effects on Behavior and Performance of
non-Humans
1. Unconditioned Behavior
• Taming effect –reduces defensive aggression. No
change in unprovoked aggression
2. Conditioned Behavior
• Avoidance behavior blocked at doses 1/4 to 1/6
of doses that block escape.
• Increase punishment-suppressed behavior.

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

Discriminative Stimulus Properties

1. BDZs easily discriminated – potentiated by alcohol

2. Generalize to barbiturates and other BDZs, but not to
ketamine and antipsychotics.
3. Animals can be trained to discriminate BDZs from
barbiturates and alcohol
4. Not blocked by stimulants.
5. Blocked by GABA receptor blockers
6. Z drugs – only partial generalization to BDZs and none
to alcohol

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

 Tolerance
1. Acute tolerance:
• Some effects of BDZs and barbiturates may show acute tolerance.

2. 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 acting

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

 Cross Tolerance
1. Overall Effect of Drug
• -Barbiturate tolerance crosses to alcohol and BDZs
• -BDZ tolerant subjects are tolerant to alcohol
• only partially tolerant to barbiturates.
2. Effect of Drowsiness
– Alcohol and barbiturate abusers show less
drowsiness to therapeutic doses of BDZs.
3. Ataxic effects of alcohol, barbiturates and BDZs
show tolerance after one administration in mice

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

Tranquilizers & Sedative-Hypnotics

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?

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

• Withdrawal in General
– Sedative-Hypnotic Type
• Tremors, delirium, cramps, and convulsions
– Low-Dose Withdrawal
• Anxiety, panic, irregular heartbeat, increased blood
pressure, impairment of memory, feelings of
unreality, muscle spasm, and a sensitivity to light
and sounds

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

Benzodiazepine withdrawal in Humans

• High doses of BDZs would cause

withdrawal symptoms similar to
barbiturates and alcohol
• Agitation, depression, abdominal
pain, DTs, insomnia and seizure
• Most people believed that there was
no withdrawal from therapeutic
doses.

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

Tranquilizers & Sedative-Hypnotics

• Smith and Wesson (1983) suggested that there

are two types of withdrawal from BDZs;
– Sedative-Hypnotic type
– Low dose withdrawal

• Sedative-Hypnotic Type: tremors, delirium,

cramps, convulsions.
• Higher than therapeutic doses for more than one
month

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

Tranquilizers & Sedative-Hypnotics

• 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.

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

Tranquilizers & Sedative-Hypnotics

Withdrawal

Two types of withdrawal

symptoms that may be
seen after use of the
benzodiazepines

People who take high doses for longer than 6

months may report both types of withdrawal.

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

Tranquilizers & Sedative-Hypnotics

• Self-Administration in Humans
– Laboratory Studies
• Choice Experiments
– Johanson and Uhlenhurth (1980): no preference for
diazepam vs. placebo in normal sample.
– High doses avoided BDZ, chose placebo
– Highly anxious subjects also did not prefer diazepam
• Self-Administration
– Griffiths and colleagues (1979): pentobarbitol acted as
positive reinforcer in male volunteers with history of
sedative use

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

 Patterns of abuse of benzodiazepine

• Iatrogenic Use (physician caused):

• 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.

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

 Patterns of abuse of benzodiazepine

• Many people in BDZ abuse clinics have a legitimate

medical need, but take 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.

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

 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.

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

 Overdose
• 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.

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

 Treatment
• 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.

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM

Department of Pharmacology & Pharmacotherapy, Fac. Medicine UGM