complete and detail study of the topic of sedative and hypnotics under the guidance of faculty member. the ppt is made for the benefit of all the peoples

1. Sedative-hypnotics
Anti-anxiety drugs
Ravish Yadav

2. SEDATIVE-HYPNOTIC DRUGS
SEDATION
 Reduction of anxiety
 Calming effect
ANXIOLYTIC
 Drug that reduces anxiety
 Sedative
HYPNOSIS
 Induction of sleep

3. Various antianxiety agents (minor tranquilizers, psychosedatives) have been
used throughout the ages to alleviate feelings of stress, anxiety, discomfort,
etc
Currently, benzodiazepines are among the most widely prescribed
antianxiety drugs because of their higher therapeutic index (severe CNS
depressant doses/antianxiety doses) than older agents
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

4. 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: History
Baeyer, discoverer
of barbiturates

5. 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.
HISTORY - BARBITURATES
Marilyn Monroe
died of barbiturate
overdose in 1962

6. 1960s – barbiturates sold illicitly on the street
as “downers” (diverted from medical use)
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, double trouble, gorilla
pills, F-66s

7. 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.
Quaaludes
Miltown
Zopiclone

8. SLEEP
Normally stages 0 to 4 and REM occur in succession over a period of 80-100
min. then stages 1-4 REM are repeated cyclically.

11. Dose-response curves for two hypothetical sedative-hypnotics

12. 12

13. 13

14. Functional Diversity of the GABAA Receptor Subunits
Studies (largely in knockout animals—with specific subunit
deletions or animals with variant alleles of specific subunits) indicate
(strongly suggest) functional specificity of different GABAA
subunits:
● α1 subunit-containing GABAA receptors: sedation
● α2 subunit-: anxiolysis.
● α3 subunit-: processing of sensory motor information related to a
schizophrenia endophenotype.
● α4 subunit-: sedative, hypnotic and anesthetic effects of some
agents in the thalamus.
● α5 subunit- (extrasynaptic): associative temporal and spatial
memory by inhibitory modulation of activities in the hippocampus.
● β3 subunit-: sedation, hypnosis and anesthesia by, e.g.,
pentobarbital, propofol and etomidate, but not by the neurosteroidal
anesthetic alphaxalone). 14

15. Pharmacokinetics
absorption
Barbiturates
acids, pKa=8.0
range in lipid solubility
Benzodiazepines
acids, pKa=5.0
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 hour

16. 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.

17. 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

18. The GABAA receptor-chloride ionophore
complex is made of 5 subunits, alpha (α),
beta (β) and gamma (δ)
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 α -1
subunit. Therefore they can act as sedatives without any antianxiety effects.
Drugs that can block anxiety without making a person sleepy are being
developed.

21. 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 receptor.

22. 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 modulators.
The nucleus accumbens definitely plays a central role in the reward circuit. Its operation
is based chiefly on two essential neurotransmitters: dopamine, which promotes desire,
and serotonin, whose effects include satiety and inhibition.

23. Benzodiazepines
Mechanism of Action
• Binds to the benzodiazepine receptors on GABA neuron
• GABA is the major inhibitory neurotransmitter in the CNS
• Benzodiazepines relieve anxiety through enhancement of the
inhibitory activity of GABA
• No antipsychotic, No analgesic, Not affect ANS
23

24. Benzodiazepines-Indications
• Generalized Anxiety Disorder
• Panic Disorder (alprazolam)
• Insomnia
• Schizophrenia
• Muscular spasms (duiazepam)
• Depression
• Seizure Disorders, epilepsy
(clonazepam , diazepam)
• Delirium
• Alcohol Withdrawal
• Conscious Sedation insomnia
(flurazepam long acting,
temazepam intermediate,
triazolam short)
24

25. Biotransformation of benzodiazepines

26. Drug Peak Blood Level
(hours)
Elimination Half-
Life
1
(hours)
Comments
Alprazolam 1-2 12-15 Rapid oral absorption
Chlordiazepoxid
e
2-4 15-40 Active metabolites; erratic
bioavailability from IM injection
Clorazepate 1-2 (nordiazepam) 50-100 Prodrug; hydrolyzed to active form in
stomach
Diazepam 1-2 20-80 Active metabolites; erratic
bioavailability from IM injection
Eszopiclone 1 6 Minor active metabolites
Flurazepam 1-2 40-100 Active metabolites with long half-lives
Lorazepam 1-6 10-20 No active metabolites
Oxazepam 2-4 10-20 No active metabolites
Temazepam 2-3 10-40 Slow oral absorption
Triazolam 1 2-3 Rapid onset; short duration of action
Zaleplon <1 1-2 Metabolized via aldehyde
dehydrogenase
Zolpidem 1-3 1.5-3.5 No active metabolites
1
Includes half-lives of major metabolites.
Pharmacokinetic properties of some benzodiazepines and newer hypnotics in humans

27. Benzodiazepines
Pharmacokinetic Differences
Benzodiazepine Peak Plasma
Level (Hour)
Speed of onset Elimination
Half Life (Hour)
Alprazolam 1-2 Intermediate 7-27
Chlordiazepoxide 1-4 Intermediate 5-30
Clonazepam 1-2 Intermediate 18-50
Diazepam 0.5-2 Very Fast 20-80
Lorazepam 2-4 Intermediate 10-20
Oxazepam 2-4 Slow 5-20
27
Facts and Comparison

28. Benzodiazepines
Parenteral Administration
Used for acute anxiety/agitation, seizures, sedation
IM lorazepam & midazolam provides rapid, reliable and
complete absorption
Avoid IM administration of diazepam and
chlordiazepoxide due to variability in rate and extent of
absorption
IV lorazepam
 onset of action 1-5 minutes
IM lorazepam
 onset of action 15-30 minutes
 inject undiluted, deep into muscle mass
28

29. Benzodiazepines
Parenteral Administration
• Parenteral administration may produce apnea, hypotension,
bradycardia, or cardiac arrest (particularly in severely ill, geriatric,
unstable cardiovascular system, limited pulmonary reserve, or if
drug administered to rapidly IV)
• Avoid co-administration of lorazepam IM with olanzapine IM due
to reports of death related to combination
• Lipophylic, rapidly absorbed after oral administration
• Fate: hepatic microsomal, excreted in urine as glucoronides or
oxidized metabolites
• Cross placenta, secreted in milk
29

30. Benzodiazepines-DDI
• Clozapine: severe hypotension, respiratory or cardiac arrest, loss of
consciousness
• Cigarette smoking may decrease the sedative effects of usual
benzodiazepine doses
• Alcohol increases sedation
• Anti-fungals may increase plasma concentration of benzodiazepines
30

31. Benzodiazepines
Adverse Reactions
• CNS depression: drowsiness, sedation, psychomotor impairment,
ataxia
• Disorientation, confusion, irritability
• Impairment in memory and recall
• Respiratory depression
• Precaution: liver disease, glaucoma, alcohol, CNS depressant
31

32. Combination CNS depressants

33. Benzodiazepines
• Tolerance
• Decrease in response to the medication effects
• Dependence
• Physical Dependence: when medication is stopped, withdrawal or
discontinuation symptoms occur
• Addiction: complex behavioral syndrome that includes an
obsession with obtaining and using the drug, excessive, prolonged
and harmful use despite adverse consequences, denial,
rationalization, minimization and justification
33

34. Benzodiazepine Withdrawal
 Symptoms: insomnia, anxiety, autonomic instability (increased heart
rate and BP, tremor, diaphoresis(excessive sweating)) insomnia,
muscle cramps, confusion, seizures, irritability, ataxia
 Time frame for emergence of symptoms corresponds to half-life of the
benzodiazepine
 Example: alprazolam has high risk of withdrawal- due to short half-life
 To Avoid Benzodiazepine Withdrawal …. Convert to longer acting
agent to taper slowly
34

36. Benzodiazepine Overdose
• May be intentional or secondary to accumulation of doses
• Symptoms: drowsiness, impaired coordination, slurred speech,
diminished reflexes, confusion, respiratory depression, hypotension
36

37. Benzodiazepine Overdose
• Treatment Options
• Supportive and symptomatic care
• Gastric lavage
• Activated Charcoal
• IV hydration and maintain
adequate airway
• IV Flumazenil (Romazicon®):
Benzodiazepine antagonist
37

38. Flumazenil (Romazicon®)
• Benzodiazepine antagonist that competitively binds to
benzodiazepine receptors
• 0.2 mg IV over 30 seconds, then 0.5 mg at 1 minute interval, up to 3
mg
• Rapid response: 1-2 min, up to 10 min
• Duration: 1-5 hours
38

39. Flumazenil is a benzodiazepine Antagonist =
Blocker
Flumazenil binds to GABA receptor displacing benzodizepine

40. Flumazenil (Romazicon®)
• Use with caution if patient ingest TCA and benzodiazepine
due to risk of seizures
• Monitor patients respiratory rate and cardiac status
• SE: Agitation, confusion, sweating, nausea/vomiting, blurred
vision, seizure
• Re-sedation can occur due to short half-life, may repeat dose
at 20 minutes intervals with maximum of 1 mg/dose and
3mg/hr
40

41. Zolpidem (Ambien®)
• Produces sedative properties by binding selectively to a1-subunit.
• Same site that also binds benzodiazepines.
• Evidence – pharmacological effects blocked by flumazenil.
• Structurally unrelated to benzodiazepines.
• Used clinically for treatment of insomnia.
• Minimal muscle relaxing and anticonvulsant effects.
• Less potential for dependence and withdrawal.
• Pharmacokinetics:
• Elimination half-life = 1.5-3.5 hrs.
• Largely metabolized in the liver.

43. Non benzodiazepines Anxiolytic: Buspirone
(Buspar)
•Different action to bzd.
•Not a CNS depressant.
•Partial agonist (stimulant) of dopaminergic &
serotoninergic receptors.
•No sedation, anti-convulsant or muscle relaxant
properties - just anxiolytic.
•Delayed action (1-2 weeks)
•Effect reduced if benzodiazepine used in last 3/12

44. Comparison of benzodiazepine &
buspirone
Benzodiazepine
Rapid onset
Can cause sedation
May impair performance
Additive effects with alcohol
May cause dependence &
withdrawal
Pharmacokinetic change with
age
Associated with falls in elderly
(Keltner & Folks, 2001)
Buspirone
Delayed onset
Does not cause sedation
Does not impair performance
No additive effect with alcohol
Non addictive
No pharmacokinetic change
with age
Does not cause falls in elderly
Expensive

45. 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 flumazenil – BDZ receptor antagonist
BDZ overdoses are fatal when combined with alcohol or other
depressant.

46. 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

47. 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.

48. Effects on memory
BDZs cause anterograde amnesia (is a loss of the ability to create new memories after the
event that caused the amnesia, leading to a partial or complete inability to recall the recent past, while long-term
memories from before the event remain intact.), memory for events that happen while
people are under the influence of the drug. Happens at low
therapeutic doses.
Affects explicit memory (Explicit memory is the conscious, intentional recollection of previous
experiences and information.) 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 drugs.

49. Tolerance
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 acting.

50. 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.

51. USES:
1. As hypnotic:
Chronic insomnia (>3 weeks); short-term insomnia (3-21 days); transient insomnia
(1-3 days)
2. Other uses
(a) As anxiolytic and for day-time sedation .
(b) As anticonvulsant, especially emergency control of status epilepticus, febrile
convulsions,tetanus, etc.
(c) As centrally acting muscle relaxant.
(d) For preanaesthetic medication, i.v. anaesthesia and conscious sedation .
(e) Before ECT, electrical cardioversion of arrhythmias, cardiac catheterization,
endoscopies, in obstetrics and many minor proceduresdiazepam i.v. has gained
popularity because of its calming-amnesic-analgesic and muscle
relaxant properties and relative safety.
(f) Alcohol withdrawal in dependent subjects.
(g) Along with analgesics, NSAIDs, spasmolytics, antiulcer and many other drugs.