Anxiolytics and hypnotics drugs and their derivatives

anxiolytic drugs

1. SEDATIVE/HYPNOTICS
ANXIOLYTICS
Novia Elisa, M.Si, Apt

2. Sedated
Optimal
Performance
Nervous
Breakdown
P
e
r
f
o
r
m
a
n
c
e
Anxiety
GOAL

3. Manifestations of anxiety:
Verbal complaints. The patient says he/she is
anxious, nervous, edgy.
Somatic and autonomic effects. The patient is
restless and agitated, has tachycardia, increased
sweating, weeping and often gastrointestinal
disorders.
Social effects. Interference with normal productive
activities.

4. Pathological Anxiety
Generalized anxiety disorder (GAD): People suffering
from GAD have general symptoms of motor
tension, autonomic hyperactivity, etc. for at least
one month.
Phobic anxiety:
Simple phobias, fear of animals, etc.
Social phobias.
Panic disorders: Characterized by acute attacks of
fear as compared to the chronic presentation of
GAD.
Obsessive-compulsive behaviors: These patients
show repetitive ideas (obsessions) and behaviors
(compulsions).

5. Anxiolytics
Strategy for treatment
Reduce anxiety without causing sedation.

6. Anxiolytics
1)Benzodiazepines (BZDs).
2)Barbiturates (BARBs).
3)5-HT
1A receptor agonists.
4)5-HT
2A, 5-HT
2C & 5-HT
3 receptor
antagonists.
If ANS symptoms are prominent:
•ß-Adrenoreceptor antagonists.

2-AR agonists (clonidine).

7. Anxiolytics
Other Drugs with anxiolytic activity.
TCAs (Fluvoxamine). Used for Obsessive
compulsive Disorder.
MAOIs. Used in panic attacks.
Antihistaminic agents. Present in over the
counter medications.
Antipsychotics (Ziprasidone).

8. Sedative/Hypnotics
•A hypnotic should produce, as much as
possible, a state of sleep that resembles
normal sleep.

9. Properties of Sedative/Hypnotics in Sleep
1) The latency of sleep onset is decreased (time to
fall asleep).
2) The duration of stage 2 NREM sleep is
increased.
3) The duration of REM sleep is decreased.
4) The duration of slow-wave sleep (when
somnambulism and nightmares occur) is
decreased.
Tolerance occurs after 1-2 weeks.

10. Sedative/Hypnotics
1)Benzodiazepines (BZDs):
Alprazolam, diazepam, oxazepam, triazolam
2)Barbiturates:
Pentobarbital, phenobarbital
3)Alcohols:
Ethanol, chloral hydrate, paraldehyde,
trichloroethanol,
4)Imidazopyridine Derivatives:
Zolpidem
5)Pyrazolopyrimidine
Zaleplon

11. Sedative/Hypnotics
6) Propanediol carbamates:
Meprobamate
7) Piperidinediones
Glutethimide
8)Azaspirodecanedione
Buspirone
9) -Blockers**
Propranolol
10) 2-AR partial agonist**
Clonidine

12. Sedative/Hypnotics
Others:
11) Antyipsychotics **
Ziprasidone
12)Antidepressants **
TCAs, SSRIs
13)Antihistaminic drugs **
Dephenhydramine
**All others differ in their effects and therapeutic uses. Just as
adjunction

13. Sedative/Hypnotics
All of the anxiolytics/sedative/hypnotics should be
used only for symptomatic relief.
*************
All the drugs used alter the normal sleep cycle and
should be administered only for days or weeks, never
for months.
************
USE FOR
SHORT-TERM TREATMENT
ONLY!!

14. Sedative/Hypnotics
Relationship between
Older vs Newer Drugs
BarbituratesBenzodiazepines
GlutethimideZolpidem
Meprobamate Zaleplon

15. SEDATIVE/HYPNOTICS
ANXYOLITICS
BENZODIAZEPINES BARBITURATES
GABAergic SYSTEM

16. Sedative/Hypnotics
The benzodiazepines are the most
important sedative hypnotics.
Developed to avoid undesirable
effects of barbiturates (abuse
liability).

17. Benzodiazepines
Diazepam
• Chlordiazepoxide
Triazolam
Lorazepam
Alprazolam
Clorazepate => nordiazepam
Halazepam
Clonazepam
Oxazepam
Prazepam

18. Barbiturates
Phenobarbital
Pentobarbital
Amobarbital
Mephobarbital
Secobarbital
Aprobarbital

19. Respiratory
Depression
Coma/
Anesthesia
Ataxia
Sedation
Anxiolytic
Anticonvulsant
DOSE
R
E
S
P
O
N
S
E
BARBS
BDZs
ETOH

20. Respiratory
Depression
Coma/
Anesthesia
Ataxia
Sedation
Anxiolytic
Anticonvulsant
DOSE
R
E
S
P
O
N
S
E
BARBS
BDZs

21. GABAergic SYNAPSE
GABA
glutamate
glucose
Cl
-
GAD

22. GABA-A Receptor
Oligomeric
(glycoprot
ein.
Major player in
Inhibitory Synapses.
It is a Cl
-
Channel.
Binding of GABA
causes the channel
to open and Cl
-
to
flow into the cell with
the resultant
membrane
hyperpolarization.
GABA AGONISTS
BDZs



BARBs



23. Mechanisms of Action
1) Enhance GABAergic Transmission
 frequency of openings of GABAergic channels.
Benzodiazepines
 opening time of GABAergic channels. Barbiturates
 receptor affinity for GABA. BDZs and BARBS
2) Stimulation of 5-HT
1A receptors.
3) Inhibit 5-HT
2A, 5-HT
2C, and 5-HT
3 receptors.

24. Benzodiazepines
PHARMACOLOGY
BDZs potentiate GABAergic inhibition at all levels
of the neuraxis.
BDZs cause more frequent openings of the GABA-
Cl
-
channel via membrane hyperpolarization, and
increased receptor affinity for GABA.
BDZs act on BZ
1 (
1 and 
2 subunit-containing) and
BZ
2 (
5 subunit-containing) receptors.
May cause euphoria, impaired judgement, loss of
cell control and anterograde amnesic effects.

25. Pharmacokinetics of Benzodiazepines
Although BDZs are highly protein bound (60-95%),
few clinically significant interactions.*
High lipid solubility  high rate of entry into CNS 
rapid onset.
*The only exception is chloral hydrate and
warfarin

26. C
N
S
E
f
f
e
c
t
s
(
R
a
t
e
o
f
O
n
s
e
t
)
Lipid solubility

27. Pharmacokinetics of Benzodiazepines
Hepatic metabolism. Almost all BDZs undergo microsomal
oxidation (N-dealkylation and aliphatic hydroxylation) and
conjugation (to glucoronides).
Rapid tissue redistribution  long acting  long half lives
and elimination half lives (from 10 to > 100 hrs).
All BDZs cross the placenta  detectable in breast milk
 may exert depressant effects on the CNS of the
lactating infant.

28. Pharmacokinetics of Benzodiazepines
Many have active metabolites with half-lives greater than
the parent drug.
Prototype drug is diazepam (Valium), which has active
metabolites (desmethyl-diazepam and oxazepam) and is
long acting (t½ = 20-80 hr).
Differing times of onset and elimination half-lives (long
half-life => daytime sedation).

29. Biotransformation of Benzodiazepines

30. Biotransformation of Benzodiazepines
Keep in mind that with formation of active metabolites, the
kinetics of the parent drug may not reflect the time course of
the pharmacological effect.
Estazolam, oxazepam, and lorazepam, which are directly
metabolized to glucoronides have the least residual
(drowsiness) effects.
All of these drugs and their metabolites are excreted in
urine.

31. Properties of Benzodiazepines
BDZs have a wide margin of safety if used for
short periods. Prolonged use may cause
dependence.
BDZs have little effect on respiratory or
cardiovascular function compared to BARBS and
other sedative-hypnotics.

32. Side Effects of Benzodiazepines
Related primarily to the CNS depression and
include: drowsiness, excess sedation, impaired
coordination, nausea, vomiting, confusion and
memory loss. Tolerance develops to most of these
effects.
Dependence with these drugs may develop.
Serious withdrawal syndrome can include
convulsions and death.

33. Toxicity/Overdose with
Benzodiazepines
Drug overdose is treated with flumazenil (a BDZ
receptor antagonist, short half-life), but respiratory
function should be adequately supported and
carefully monitored.
Flumazenil is not effective against BARBs
overdose.

34. Drug-Drug Interactions with BDZs
BDZ's have additive effects with other CNS
depressants (narcotics), alcohol => have a greatly
reduced margin of safety.
BDZs reduce the effect of antiepileptic drugs.
Combination of anxiolytic drugs should be avoided.
Concurrent use with ODC antihistaminic and
anticholinergic drugs as well as the consumption of
alcohol should be avoided.
SSRI’s and oral contraceptives decrease metabolism of
BDZs.

35. Pharmacokinetics of Barbiturates
Rapid absorption following oral
administration.
Rapid onset of central effects.
Extensively metabolized in liver (except
phenobarbital), however, there are no
active metabolites.
Phenobarbital is excreted unchanged. Its
excretion can be increased by
alkalinization of the urine.

36. Pharmacokinetics of Barbiturates
In the elderly and in those with limited
hepatic function, dosages should be
reduced.
Phenobarbital and meprobamate cause
autometabolism by induction of liver
enzymes.

37. Properties of Barbiturates
Mechanism of Action.
•They increase the duration of GABA-gated
channel openings.
•At high concentrations may be GABA-mimetic.
Less selective than BDZs, they also:
•Depress actions of excitatory neurotransmitters.
•Exert nonsynaptic membrane effects.

38. Toxicity/Overdose
Strong physiological dependence may
develop upon long-term use.
Depression of the medullary respiratory
centers is the usual cause of death of
sedative/hypnotic overdose. Also loss of
brainstem vasomotor control and myocardial
depression.

39. Toxicity/Overdose
Withdrawal is characterized by increase
anxiety, insomnia, CNS excitability and
convulsions.
Drugs with long-half lives have mildest
withdrawal
No medication against overdose with BARBs.
Contraindicated in patients with porphyria.

40. Miscellaneous Drugs
Buspirone
Chloral hydrate
Hydroxyzine
Meprobamate (Similar to BARBS)
Zolpidem (BZ
1 selective)
Zaleplon (BZ
1 selective)

41. BUSPIRONE
Most selective anxiolytic currently available.
The anxiolytic effect of this drug takes several weeks
to develop => used for GAD.
Buspirone does not have sedative effects and does
not potentiate CNS depressants.
No rebound anxiety or signs of withdrawal when
discontinued.

42. BUSPIRONE
Side effects:
•Tachycardia, palpitations, nervousness,
GI distress and paresthesias may occur.

43. BUSPIRONE
Mechanism of Action:
•Acts as a partial agonist at the 5-HT
1A
receptor presynaptically inhibiting
serotonin release.

44. Pharmacokinetics of BUSPIRONE
Not effective in panic disorders.
Rapidly absorbed orally.
Undergoes extensive hepatic metabolism
(hydroxylation and dealkylation) to form
several active metabolites (e.g. 1-(2-pyrimidyl-
piperazine, 1-PP)
Well tolerated by elderly, but may have slow
clearance.
Analogs: Ipsapirone, gepirone, tandospirone.

45. Zolpidem
Structurally unrelated but as effective as BDZs.
Minimal muscle relaxing and anticonvulsant
effect.
Rapidly metabolized by liver enzymes into
inactive metabolites.
Dosage should be reduced in patients with
hepatic dysfunction, the elderly and patients
taking cimetidine.

46. Properties of Zolpidem
Mechanism of Action:
•Binds selectively to BZ
1 receptors.
•Facilitates GABA-mediated neuronal
inhibition.
•Actions are antagonized by flumazenil

47. Properties of Other drugs.
Chloral hydrate
Is used in institutionalized patients. It displaces
warfarin (anti-coagulant) from plasma proteins.
Extensive biotransformation.

48. Properties of Other Drugs
2-Adrenoreceptor Agonists (eg. Clonidine)
•Antihypertensive.
•Has been used for the treatment of panic attacks.
•Has been useful in suppressing anxiety during the
management of withdrawal from nicotine and
opioid analgesics.
•Withdrawal from clonidine, after protracted use,
may lead to a life-threatening hypertensive crisis.

49. Properties of Other Drugs
-Adrenoreceptor Antagonists
(eg. Propranolol)
•Use to treat some forms of anxiety, particularly
when physical (autonomic) symptoms (sweating,
tremor, tachycardia) are severe.
•Adverse effects of propranolol may include:
lethargy, vivid dreams, hallucinations.

50. OTHER USES
1. Generalized Anxiety Disorder
Diazepam, lorazepam, alprazolam,
buspirone
2. Phobic Anxiety
a. Simple phobia. BDZs
b. Social phobia. BDZs
3. Panic Disorders
TCAs and MAOIs, alprazolam
4. Obsessive-Compulsive Behavior
Clomipramine (TCA), SSRI’s
5. Posttraumatic Stress Disorder (?)
Antidepressants, buspirone

51. ANXYOLITICS
Alprazolam
Chlordiazepoxide
Buspirone
Diazepam
Lorazepam
Oxazepam
Triazolam
Phenobarbital
Halazepam
Prazepam
HYPNOTICS
Chloral hydrate
Estazolam
Flurazepam
Pentobarbital
Lorazepam
Quazepam
Triazolam
Secobarbital
Temazepam
Zolpidem

52. Assignment
Find the the scientific article about the
novel drug for
anxiolytic/sedative/hypnotic!
Due date: next week (Sept, 13 2016) 
before 3
rd
lecture