Lect 2 Sedative-Hypnotic and Anxiolytic Drugs

1. DRUGS USED IN DISORDERS OF THE
CENTRAL NERVOUS SYSTEM AND
TREATMENT OF PAIN
Lecture 2:
Sedative-Hypnotic and Anxiolytic Drugs
Marc Imhotep Cray, M.D.

2. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 2
Learning Objectives:
2
1. The structural aspects of the GABAA receptor and the
receptor components (i.e. binding sites) mediating the effects
of drugs that modulate GABAA receptor activity.
2. The differences between benzodiazepines with respect to
Phase I only versus Phase I & II pharmacokinetics.
3. The similarities and differences among the benzodiazepines
with respect to: a) time of onset, b) potency, c) metabolism
and d) elimination half-lives.
4. The similarities and differences between the
benzodiazepines and the barbiturates in producing sedative-
hypnotic effects.

3. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 2
Learning Objectives: cont.
3
5. The factors to consider in choosing the most appropriate
drug for specific clinical situations and/or individuals.
6. The characteristics of benzodiazepines and other sedative-
hypnotics that contribute to different degrees of abuse
liability and withdrawal symptoms.
7. The target sites or putative mechanisms of non-
benzodiazepine drugs that can be used to treat sleep
disorders.

4. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 2Classification Schema:
Sedative-Hypnotic and Anxiolytic Drugs
4
BENZODIAZEPINES
Alprazolam XANAX
Chlordiazepoxide LIBRIUM
Clonazepam KLONOPIN
Clorazepate TRANXENE
Diazepam VALIUM
Estazolam
Flurazepam DALMANE
Lorazepam ATIVAN
Midazolam VERSED
Oxazepam
Quazepam DORAL
Temazepam RESTORIL
Triazolam HALCION
BENZODIAZEPINE
ANTAGONIST
Flumazenil ROMAZICON
OTHER ANXIOLYTIC DRUGS
Antidepressants (Various)
Buspirone BUSPAR
BARBITURATES
Amobarbital AMYTAL
Pentobarbital NEMBUTAL
Phenobarbital LUMINAL
Secobarbital SECONAL
Thiopental PENTOTHAL
OTHER HYPNOTIC AGENTS
Antihistamines (Various)
Doxepin SILENOR
Eszopiclone LUNESTA
Ramelteon ROZEREM
Zaleplon SONATA
Zolpidem AMBIEN

5. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 2
Sedative-Hypnotic and Antianxiety Drugs
5
Hypnotics are medications that induce sleep, and
antianxiety drugs are medications that reduce anxiety
 Many of these drugs have both hypnotic and antianxiety
activity
The common MOA (mechanism of action) is to enhance
the inhibitory effects of GABA in the CNS
 This hyperpolarizes neurons by increasing the entry
of chloride ions

6. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 2
Side Effects
6
Side Effects common to these drugs include:
1. Decreased REM sleep with a rebound increase in REM
sleep upon withdrawal
2. Drowsiness
3. Hangover
4. Tolerance with prolonged administration due to
 Increased metabolism from activation of mixed
function oxidases (MFOs)
 Reduced effects on the CNS

7. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 2
Side Effects cont.
7
5. Respiratory depression
 These drugs reduce the sensitivity of the medullary respiratory
centers to CO2
 Respiratory depression is increased when these drugs are combined
with any other sedating drug (alcohol, opiates)
 This is the cause of death from an overdose
 Tolerance does not develop to the depressant action on respiration
 Respiratory depression is very marked with barbiturates and very
weak with benzodiazepines
6. Abuse potential
 Physical dependence occurs with all these drugs and results in an
abstinence syndrome upon withdrawal

8. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 2
Clinical Uses
8
Clinical Uses of sedative–hypnotic and antianxiety drugs
include:
1. Treatment of anxiety
2. Treatment of insomnia
3. Muscle relaxation
4. Treatment of seizures
5 Replacement therapy during withdrawal from sedative–
hypnotics (e.g., ethanol)
6. IV anesthesia or sedation before surgical procedures

9. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 2
Anxiety
9
 Anxiety is an unpleasant state of tension, apprehension, or
uneasiness
 Episodes of mild anxiety are common life experiences and do
not warrant treatment
 Disorders involving anxiety are among the most common
mental disorders
 Physical symptoms of severe anxiety are similar to those of
fear (tachycardia, sweating, trembling, and palpitations) and
involve sympathetic activation

10. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 2
Clinical Anxiety
10
 Clinical anxiety, whether chronic or in the
form of a panic attack, often impedes
normal functioning and adversely affects
the quality of life
 Clinical anxiety is approximately twice as
common (possibly more often reported)
in women than in men
 The age at onset is usually between 20
and 30 years

11. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 2
Clinical Anxiety (2)
11
 Common adult anxiety disorders include:
 generalized anxiety disorder
 social phobia
 obsessive-compulsive disorder (OCD)
 panic disorder
 posttraumatic stress syndrome

12. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 2
12

13. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 2
Clinical Anxiety (3)
13
 Severe, chronic, debilitating anxiety may be treated with
antianxiety drugs (also called anxiolytics) and/or some form
of psychotherapy
 Drugs for treating anxiety disorders, or anxiolytics, include
benzodiazepines, non-benzodiazepines GABAergics, SSRI and
buspirone
 Because many antianxiety drugs also cause some sedation,
they may be used clinically as both anxiolytic and hypnotic
(sleep inducing) agents (to treat insomnia)

14. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 2
Anxiolytics
14
Two main categories of anxiolytics are benzodiazepines
and miscellaneous (e.g., buspirone, zolpidem, zaleplon)
 Subclassification of benzodiazepines is based on speed of
onset or duration of action, metabolism, and adverse
effects

15. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 2
Non-benzodiazepines Anxiolytics
15
 Zolpidem and zaleplon resemble BZD in pharmacology
(MOA) but differ chemically
 Buspirone (an azapirone) acts on 5-HT1A receptors
 Not an effective hypnotic agent
All 3 of these drugs have fewer adverse effects and less
abuse potential

16. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 2
Benzodiazepines (BDZs)
16
Alprazolam
Chlordiazepoxide
Clonazepam
Clorazepate
Diazepam
Estazolam
Flurazepam
Lorazepam
Midazolam
Oxazepam
Quazepam
Temazepam
Triazolam
Benzodiazepine Antagonist
Flumazenil
Miscellaneous Agents
Buspirone
Zaleplon
Zolpidem

17. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 2
Benzodiazepines (2)
17
Benzodiazepines preparations differ primarily in their duration of
action
1. Antianxiety preparations usually have long durations of action ranging
from 12 hours to several days. They include:
 Chlordiazepoxide (Librium), also used for alcohol withdrawal
 Diazepam (Valium), also used for skeletal muscle spasms and seizures
 Alprazolam (Xanax), used to treat panic disorders
2. Hypnotic preparations (sleeping pills) have shorter durations of action
than the antianxiety drugs
 Flurazepam (Dalmane) has a short half-life, however, its active metabolites give it a
long clinical effect (up to 100 hours) and result in daytime drowsiness
 Temazepam (Restoril) has a t1/2 of 10 hours with no active metabolites
 Triazolam (Halcion) has a short t1/2 of 2.5 hours, which can result in early morning
awakening

18. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 2
Benzodiazepines (3)
18
 BDZs bind to benzodiazepine site on GABAA receptors, which leads to
an enhancement of GABA inhibition
 Effects include:
1. Calming of behavior
2. Reduction of anxiety
3. Induction of sleep
4. Anticonvulsant actions
5. Muscle relaxation
 There are no autonomic effects (Why?)
 Side effects include:
 Drowsiness and confusion
 Dependence, especially with quick onset agents (e.g., alprazolam,
diazepam), thus long-term use should be avoided
 A prolonged withdrawal syndrome

19. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 2
BZD (4)
19
 Contraindications:
 Benzodiazepines should not be given to people with
bronchopulmonary disease, and
 they have additive or synergistic effects with other
central depressants such as alcohol, barbiturates and
antihistamines

20. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 2
Benzodiazepines(4)
20
BZDs have many advantages over barbiturates, including:
 They are less likely to be abused, although abuse still
occurs
 Suicide potential is lower due to the high therapeutic
index (TI)
 Less reduction of REM sleep occurs
 Induction of MFOs is less pronounced
 Flumazenil, a benzodiazepine antagonist, will reverse
the sedation effects of the benzodiazepines

21. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 2
BZD GABAA Receptor
21
 Benzodiazepines cross the blood-
brain barrier and bind to specific
receptors on the GABAA complex;
these receptors occur in many brain
regions
The BZDs do not bind to the same
sites as does GABA but potentiate
GABA action

22. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 2
Distribution of Benzodiazepine
Receptors in the Brain
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23. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 2
23
Schematic diagram of BDZ–
GABA–Cl ion channel complex.
GABA = γ-aminobutyric acid.
LippincottIllustratedReviews-Pharmacology6Ed.2014

24. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 2
Metabolism of Benzodiazepines
24
 Diazepam, chlordiazepoxide, prazepam,
and the prodrug clorazepate undergo
hepatic metabolism to the intermediate
Oxazepam
 Alprazolam, flurazepam, lorazepam, and
triazolam directly undergo conjugation
before excretion

25. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 2
Barbiturates
25
Amobarbital AMYTAL
Pentobarbital NEMBUTAL
Phenobarbital LUMINAL
Secobarbital SECONAL
Thiopental PENTOTHAL

26. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 2
Barbiturates (2)
26
Barbiturates are derived from barbituric acid, a combination of urea and
malonic acid
They are frequently provided as Na salts (e.g., Na pentobarbital) because
the salt is more water soluble; however, it is very alkaline
 The barbiturates are classified by duration of action:
 Ultrashort-acting barbiturates (e.g., thiopental [Pentothal]) have very high lipid
solubilities due to sulfur in the structure. They are used as IV anesthetics.
 Short- and intermediate-acting barbiturates (e.g., pentobarbital [Nembutal]) have lower
lipid solubilities and longer durations of action than are appropriate for sleeping pills
 Long-acting barbiturates (e.g., phenobarbital [Luminal]) have the lowest lipid solubilities
and the longest durations of action
Clinical Use: They can be used as sedatives, anticonvulsants, or
antianxiety drugs
Note: Barbiturates are largely obsolete as sedative-
hypnotics due to there adverse effects profile,
include dependence, ataxia, and drowsiness.

27. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 2
Barbiturates (3)
27
PPB and Metabolism:
Binding to plasma proteins is highest for the highly lipid-soluble
barbiturates
Metabolism by side chain oxidation accounts for the clearance of all
barbiturates from the body
 Only phenobarbital has some clearance (30%) by the kidney, and
this can be increased by increasing the urinary pH (urinary
alkalization)
 Barbiturates greatly induce the cytochrome P450 enzymes in
the liver, which decreases the activities of other drugs that are
metabolized by these enzymes

28. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 2
Barbiturates (4)
28
Adverse Effects:
There are multiple adverse effects:
 Drowsiness and impaired concentration
 Hangovers
 Dependence and severe withdrawal that can be lethal
 Overdoses due to the narrow therapeutic index (e.g., patients who
overdose on barbiturates develop respiratory depression, which is
managed symptomatically by assisting respiration and stabilizing
blood pressure)
 Due to an increase in porphyrin synthesis, acute intermittent
porphyria is an absolute contraindication for the use of
barbiturates

29. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 2
Zolpidem
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Zolpidem (Ambien), eszopiclone (Lunesta), and zaleplon (Sonata)
are hypnotics with little effect on the stages of sleep
 Although they are not benzodiazepines, they bind to a
subgroup of benzodiazepine receptors (BZ1)
 They are antagonized by flumazenil
 They have little anxiolytic, anticonvulsant, or muscle relaxant
activity

30. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 2
Eszopiclone
30
 An oral non-benzodiazepine hypnotic that also acts on the BZ1 receptor
 Effective for insomnia for up to 6 months
 Rapidly absorbed (time to peak, 1 hour), extensively metabolized by
oxidation and demethylation via the CYP450 system, and mainly
 Excreted in urine
 Elimination half-life is approximately 6 hours
 Adverse events with eszopiclone include anxiety, dry mouth, headache,
peripheral edema, somnolence, and unpleasant taste

31. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 2
Ramelteon
31
 Ramelteon is a selective agonist at the MT1 and MT2 subtypes of
melatonin receptors
 Melatonin is a hormone secreted by the pineal gland that helps to
maintain the circadian rhythm underlying the normal sleep–wake
cycle
 Stimulation of MT1 and MT2 receptors by ramelteon is thought to
induce and promote sleep
 Indication-treatment of insomnia characterized by difficulty falling
asleep (increased sleep latency)
 It has minimal potential for abuse, and no evidence of dependence or
withdrawal effects has been observed
 Can be administered long term
 Common adverse effects include dizziness, fatigue, may also increase
prolactin levels

32. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 2
Buspirone
32
Buspirone (BuSpar) is an antianxiety drug that
1. Is not a benzodiazepine
2. Is a partial agonist at 5HT1A receptors
3. Does not have abuse potential
4. Has few CNS side effects (e.g., drowsiness is minimal)
5. Mildly increases respiratory drive

33. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 2
Antihistamines and Ethanol
33
 Antihistamines and Ethanol also have sedating properties:
1. Hydroxyzine (Atarax, Vistaril) is an antihistamine with
antianxiety activity, low abuse potential, and marked sedative
and anticholinergic effects.
Other antihistamines (e.g., diphenhydramine) are found in many
over-the-counter sleep preparations
2. Ethanol has both antianxiety and sedating effects
However, it is not a therapeutically useful drug due to the high
potential for abuse and dependence

34. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 2
THE END
34

35. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 2
35
Lectures/discussions to follow:
3. Antiepileptic Agents
4. Antidepressants
5. Antipsychotic Agents
6. Drugs Affecting Bipolar Disorder
7. Drugs Affecting Movement Disorders and
Other Neurodegenerative Disorders
8. CNS Skeletal Muscle Relaxants
9. Analgesics
10. Anesthetics
Further study (SDL):
MedPharm Digital Guidebook: Unit 3-Drugs Used for CNS Disorders
Companion eNotes: CNS- Central Nervous System Pharmacology
Textbook Reading: Trevor AJ & Walter LW Ch. 22 Sedative-Hypnotic Drugs
In: Katzung BG, ed. Basic & Clinical Pharmacology. 12th ed. Pgs. 373-88
Online resource center: Medical Pharmacology Cloud Folder