CNS DEPRESSANTS

SEDATIVE-HYPNOTIC DRUGS
ANXIETY 2

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 Unlike other mental disorders, anxiety can be
both:
 a normal emotion
 and a psychiatric illness.

 It is a universal human emotion, and a certain

amount is useful to the individual, acting as a
stimulant and increasing efficiency.
 but when it becomes excessive and
disproportionate to the situation, an anxiety
state develops; it becomes a pathological
(disabling) and needs treatment.
ANXIETY DISORDERS 3
It usually involves both:

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 Mental features
 worry,fear, difficulty in concentration, sleep
problems.
 Physical symptoms
 Tachycardia; muscle aches, nausea,
shortness of breath, trembling, pacing
ANXIETY 4
CLASSIFICATION

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#Primary
 Generalized anxiety disorder (GAD): apprehensive
and tense for no particular reason.
 Panic disorder: unexpected attacks of anxiety.
 Phobic disorders: fears certain situation
“agoraphobia”
 Obsessive compulsive disorder: repetitive, anxiety
driven behavior or obsessive thoughts and doubts
(check things more than once)
 Post-traumatic stress disorder (rape or warfare)
#Secondary due to medical causes or substances
SEDATIVE-HYPNOTIC 5
DRUGS

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The sedative-hypnotics belong to a chemically
heterogeneous class of drug.

The most important are:

 Benzodiazepines (BZs), Diazepam,
 Non benzodiazepines:

buspirone, zolpidem, and Zaleplon

 Barbiturates: phenobarbital,
 Miscellaneous: carbamates, alcohol
SEDATIVE-HYPNOTIC
SEDATIVE-HYPNOTIC 6
DRUGS
DRUGS

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SEDATIVE-HYPNOTICS

Benzodiazepines Barbiturates Miscellaneous agents

Short Ultrashort
acting acting
Intermediate Short Buspirone
acting acting Chloral hydrate
Long Long Zaleplon
acting acting Zolpidem
Ramelteon
Tasimelteon
THE EFFECTS OF CNS 7
DEPRESSANTS

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 Sedatives cause mild depression and
relaxation
 Anxiolytic—drugs that relieve anxiety
Site of action is on the limbic system which regulates thought and mental
function.

 Hypnotics induce drowsiness and

encourage sleep
 Amnesiac effects can cause the loss of memory

Site of action is on the midbrain and ascending RAS which maintain wakefulness.
THE EFFECTS OF CNS 8
DEPRESSANTS (continued)

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 The same drug can cause different effects based on dose.
 Low dose (sedatives—relieve anxiety and
promote relaxation)
 Higher doses (hypnotics—can cause
drowsiness and promote sleep)
 Even higher doses (anesthetics—can cause
anesthesia and are used for patient
management during surgery)
 SEDATIVE HYPNOTIC 9
MECHANISMS OF ACTION

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 MostS-H drugs facilitate the actions of
GABA, a major inhibitory transmitter in
the CNS,
 GABA receptor activation leads to
A
increased Cl- ion influx;
 GABA receptor activation causes
B
increased efflux of K+.
 Both mechanisms result in membrane
hyperpolarization.
 GABAA RECEPTOR 1
The pentapeptide structure of the GABAA 0
receptor has binding sites for BZs and for other

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.drugs, including Barbiturates and ethanol
 BENZODIZEPINES 1
1

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 Sedative (Anxiolytics) :
Alprazolam Chlordiazepoxide oxazepam
Diazepam lorazepam

 Hypnotics :
Triazolam Diazepam Alprazolam
Lorazepam Estazolam Temazepam
Flurazepam Nitrazepam Quazepam

 Preanesthetics :
Diazepam - Midazolam
DURATION OF 1
ACTION OF BZS 2

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 Short acting (3-8 hrs)
Oxazepam, triazolam
 Intermediate (10-20 hrs)
temazepam, lorazepam, alprazolam,
estazolam.
 Long acting (1-3 days):
chlordiazepoxide, diazepam,
flurazepam, Quazepam,
chlorazepate
BENZODIAZEPINE
1
MECHANISMS OF ACTION3
Affect neurons that have receptors for the neurotransmitter

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GABA
BZs potentiate GABA → increase frequency of Cl- ion channel
opening→ causes hyperpolarization→ raise firing threshold→
and thus inhibits the formation of action potentials 
inhibitory effect on different sites of the brain especially
motor cortex, and limbic system.

GABA—inhibitory transmitter in brain regions

 Limbic system (alter mood)
 RAS (cause drowsiness)
 Motor cortex (relax muscles)
1
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4
 PHARMACOKINETICS 1
5

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 Most of them are well absorbed orally.
 Bzs are lipid soluble and widely distributed
 Redistribution from CNS to skeletal muscles,
adipose tissue.
 Cross placental barrier during pregnancy and
are excreted in milk (Fetal & neonatal
depression).
 Highly bound to plasma protein.
 PHARMACOKINETICS 1
6

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 All Bzs are metabolized in the liver

Phase I: ( liver microsomal system)

Phase II: glucouronide conjugation and excreted
in the urine.
ACTIONS AND THERAPEUTIC
1
DOSES: 7

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1.Reduction of anxiety at low dose:
Affect alpha 2 subunit of GABA Receptor

2.Sedative and hypnotic actions at higher

dose:
Affect alpha 1 subunit of GABA Receptor.
ACTIONS AND THERAPEUTIC
1
DOSES: 8
3.Anterograde amnesia:

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Temporary impairment of memory.The
ability to learn and form new memories is
also impaired
Affect alpha 2 GABA Receptor
short acting BZs used in premedication for endoscopic,
bronchoscopic, angioplasty.
In anesthesia :
Preanesthetic medication
4.Anticonvulsant: Treatment of epilepsy.
Affect alpha 1 GABA Receptor.
ACTIONS AND THERAPEUTIC
1
DOSES: 9

5.Muscle relaxant at higher doses;

diazepam is useful in the Rx of skeletal
muscle spasm. Affect Alpha 2 GABA
Receptors in the spinal cord.
TOLERANCE
TOLERANCE 2
0
 Tolerance: reduction in drug effect

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requiring an increase in dosage to
maintain the same response.
 Chronicuse leads to tolerance (cross
with other S-H drugs), possibly via
downregulation of BZ receptors.
 The antianxiety effects of the BZ are
less subject to tolerance than sedative
and hypnotic effects.
DEPENDENCE 2
1

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 Physiological dependence: removal of
the drug evokes unpleasant symptoms,
usually the opposite of the drugs effects
 Psychological dependence: the drug
taker feels compelled to use the drug &
suffers anxiety when separated from drug.
WITHDRAWAL SYMPTOMS2
2
Abrupt discontinuation, particularly if high

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doses used for prolong period.
1. Confusion,
2. anxiety,
3. agitation,
4. restlessness,
5. insomnia
6. tension
ADVERSE EFFECTS OF BZS2
3
 Drowsiness and confusion

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 Ataxia at high doses-precludes
activities like driving
 Cognitive impairment:
↓long term recall,
↓ retention of knowledge
Should be used cautiously in
patients with liver disease.
FLUMAZENIL 2
4
BZS ANTAGONIST

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Flumazenil: I.V only, reverses
the effect of the BZs
(competitive antagonist),
onset is rapid, and duration
is short.
MISCELLANEOUS; NON
BENZODIAZEPINES 2
Zolpidem : 5

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 act on BZ1 (a subtype of BZ receptor family),
 are more selective hypnotics
 are not effective in chronic anxiety, seizure
disorders, or muscle relaxing.
 Possibly less tolerance occur with prolong use
 and lower abuse liability and dependence
than BZs.
 they show no withdrawal effects, Minimal
rebound insomnia
BUSPIRONE
2
6
totally different anxiolytic from BZs, no

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effects on GABA systems, possible partial
agonist at 5-HT1A receptors some affinity
for D2 & 5-HT2A.

Indication:
 Indicated for generalized anxiety disorders
but takes 1 to 2 weeks to exert anxiolytic
effects.
BUSPIRONE
2
7
Buspirone lucks anticonvulsant and Muscle

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relaxant property of BZs and cause
minimal sedation.
 No additive CNS depression with other
drugs.
Adverse effects:
nausea
Light headedness
headache,
dizziness,
nervousness
 BARBITURATES 2
8
 Formerly used as sedative hypnotic

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replaced by BZs, because barbiturates
induce:
1. tolerance,

2. dependence
3. and very severe withdrawal symptom.
4. Flumazenil does not block the effects
of barbiturates.
 BARBITURATES MECHANISM OF 2
ACTION 9
 interact with GABA receptors, the binding site is

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distinct from that of the BZs.
 potentiate GABA action on Cl- entry into the
neuron by increase the duration of Cl- ion channel
opening.
 In addition, barbiturates can block excitatory
glutamate receptor (sub anesthetic dose).
• at high doses (anesthetics conc. of pentobarbital,
also
 open Cl- ion channels directly
 and block high frequency Na+ channels.
 Duration of Action 3
0
of Barbiturates

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 Long acting (1-2 days) Anticonvulsant
Phenobarbital

 Short (3-8hrs) Sedative & Hypnotic

Pentobarbital, secobarbital and amobarbital

 Ultrashort (20 min) I.V induction of

anesthesia
Thiopental
ACTIONS 3
1
CNS DEPRESSION

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 Low doses----sedation
 High doses-----hypnosis
followed by anesthesia,and
finally coma and death
 Do not raise the pain threshold
and have no analgesic
properties.
 Chronic use leads to tolerance.
RESPIRATORY 3
2
DEPRESSION

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Suppress the hypoxic and
chemoreceptor response
to carbondioxide.
Overdose leads to
respiratory depression and
death.
ADVERSE EFFECTS OF 3
BARBITURATES 3

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 Dose-dependent CNS depression
 Impaired concentration.
 Mental and physical sluggishness.
 Hypnotic doses produce HANGOVER.
 Respiratory depression.

 no specific antidote in overdose.

 Additive CNS depression with other drugs.
 PHARMACOKINETICS 3
4

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 Redistribute in the body from the brain to
skeletal muscles- adipose tissues.
 metabolized in the liver to inactive
metabolites
 Excreted in the urine
 Cross the placenta ( pregnancy).
Thank you 3
5

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